Study Findings

Have you ever wondered how your participation impacts others? Below is a list of publications that have been made possible thanks to volunteers like you.
Search findings by study, institution, or publication
Optimizing Psychosocial Treatment of Interstitial Cystitis/Bladder Pain Syndrome
Vanderbilt University Medical Center
  • A randomized-controlled pilot trial of telemedicine-delivered cognitive-behavioral therapy tailored for interstitial cystitis/bladder pain syndrome.
    Pain (2024)
    McKernan LC, McGonigle T, Vandekar SN, Crofford LJ, Williams DA, Clauw DJ, Bruehl S, Corbett BA, Dmochowski RR, Walsh EG, Kelly AG, Sutherland SL, Connors EL, Ryden A, Reynolds WS. A randomized-controlled pilot trial of telemedicine-delivered cognitive-behavioral therapy tailored for interstitial cystitis/bladder pain syndrome. Pain. 2024 Feb 27; :.
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder, the Polaris Trial
The Ohio State University
  • Effects of Adjunctive Brexpiprazole on Individual Depressive Symptoms and Functioning in Patients With Major Depressive Disorder and Anxious Distress: Post Hoc Analysis of Three Placebo-Controlled Studies.
    Journal of clinical psychopharmacology (2024)
    McIntyre RS, Bubolic S, Zhang Z, MacKenzie EM, Therrien F, Miguelez M, Boucher M. Effects of Adjunctive Brexpiprazole on Individual Depressive Symptoms and Functioning in Patients With Major Depressive Disorder and Anxious Distress: Post Hoc Analysis of Three Placebo-Controlled Studies. J Clin Psychopharmacol. 2024 Mar-Apr 01; 44(2):133-140.
    Abstract: Anxiety symptoms in major depressive disorder (MDD) are frequent, and they decrease response to antidepressant treatment (ADT), and affect patient functioning. This post hoc analysis examined the efficacy of adjunctive brexpiprazole on individual depressive symptoms and functioning in patients with MDD with anxious distress.
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  • Changes in Metabolic Parameters and Body Weight in Patients With Prediabetes Treated With Adjunctive Brexpiprazole for Major Depressive Disorder: Pooled Analysis of Short- and Long-Term Clinical Studies.
    The Journal of clinical psychiatry (2023)
    Newcomer JW, Meehan SR, Chen D, Brubaker M, Weiss C. Changes in Metabolic Parameters and Body Weight in Patients With Prediabetes Treated With Adjunctive Brexpiprazole for Major Depressive Disorder: Pooled Analysis of Short- and Long-Term Clinical Studies. J Clin Psychiatry. 2023 Aug 28; 84(5):.
    Abstract: Certain atypical antipsychotics, while efficacious as adjunctive treatments in major depressive disorder (MDD), are associated with metabolic adverse effects and weight gain. This analysis determined the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with MDD and prediabetes (ie, at risk of developing diabetes) based on pooled data from 3 short-term studies and 1 long-term study. The short-term studies were 6-week, randomized, double-blind, placebo-controlled studies of adjunctive oral brexpiprazole 1-3 mg/d in outpatients with MDD ( criteria) and inadequate response to antidepressant treatment, conducted between June 2011 and May 2016. The long-term study was a 26- to 52-week, open-label extension study conducted between October 2011 and May 2017. was defined based on fasting serum glucose and glycated hemoglobin (HbA1c) levels. Shifts in diabetes status and shifts/changes in fasting metabolic parameters and body weight were determined. Most patients receiving adjunctive brexpiprazole maintained their baseline diabetes status in the short term (568/751; 75.6%) and long term (1,919/2,746; 69.9%). The incidence of categorical shifts in fasting metabolic parameters generally did not differ between treatment groups or between prediabetes and non-diabetes subgroups. Mean changes from baseline in metabolic parameters were small in the short term (all < 5 mg/dL) and long term (all < 6 mg/dL, except < 20 mg/dL for triglycerides). Moderate weight gain was observed in the short term (1.5 kg) and long term (3.4-4.1 kg). Adjunctive brexpiprazole had a limited impact on the metabolic profile of patients with MDD, regardless of diabetes status (prediabetes/non-diabetes). Data used in this post hoc analysis came from studies with ClinicalTrials.gov identifiers NCT01360645, NCT01360632, NCT02196506, and NCT01360866.
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  • Effects of adjunctive brexpiprazole on patient life engagement in major depressive disorder: Post hoc analysis of Inventory of Depressive Symptomatology Self-Report data.
    Journal of psychiatric research (2023)
    McIntyre RS, Therrien F, Ismail Z, Meehan SR, Miguelez M, Larsen KG, Chen D, MacKenzie EM, Thase ME. Effects of adjunctive brexpiprazole on patient life engagement in major depressive disorder: Post hoc analysis of Inventory of Depressive Symptomatology Self-Report data. J Psychiatr Res. 2023 Jun; 162:71-78.
    Abstract: Patient-reported outcomes can capture domains that are meaningful to patients, such as life engagement in major depressive disorder (MDD), which reflects life fulfillment, well-being, and participation in valued and meaningful activities. This analysis investigated the effects of brexpiprazole adjunct to antidepressant treatment (ADT) on patient life engagement over the short and long term, using the 10-item Inventory of Depressive Symptomatology Self-Report (IDS-SR) Life Engagement subscale.
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  • Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies.
    The Journal of clinical psychiatry (2019)
    Newcomer JW, Eriksson H, Zhang P, Meehan SR, Weiss C. Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies. J Clin Psychiatry. 2019 Oct 1; 80(6):.
    Abstract: To analyze the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with major depressive disorder (MDD) based on pooled data from 4 short-term studies and 1 long-term extension study.
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  • Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale.
    The international journal of neuropsychopharmacology (2019)
    Hobart M, Zhang P, Weiss C, Meehan SR, Eriksson H. Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale. Int J Neuropsychopharmacol. 2019 Mar 1; 22(3):173-179.
    Abstract: Patients with major depressive disorder and inadequate response to antidepressant treatments may experience a prolonged loss of functioning. This post hoc analysis aimed to determine the effect of adjunctive brexpiprazole on functioning in such patients.
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  • Brexpiprazole as adjunctive treatment of major depressive disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials.
    Journal of affective disorders (2016)
    McIntyre RS, Weiller E, Zhang P, Weiss C. Brexpiprazole as adjunctive treatment of major depressive disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials. J Affect Disord. 2016 Sep 1; 201:116-23.
    Abstract: Anxiety symptoms are prevalent in major depressive disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). The efficacy and safety of brexpiprazole - a serotonin-dopamine activity modulator - as adjunctive treatment in patients with MDD was recently evaluated in two phase 3 studies. We here present a post-hoc analysis of the efficacy of adjunctive brexpiprazole in patients with MDD and symptoms of anxious distress, defined using proxies for DSM-5 criteria.
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  • Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study.
    The Journal of clinical psychiatry (2015)
    Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, Nyilas M, Carson WH, Sanchez R, Eriksson H. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015 Sep; 76(9):1232-40.
    Abstract: To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with inadequate response to ADTs.
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Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects with Type 2 Diabetes Mellitus and Diabetic Nephropathy
University of Chicago Medical Center
  • Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.
    American heart journal (2024)
    Januzzi JL Jr, Liu Y, Sattar N, Yavin Y, Pollock CA, Butler J, Jardine M, Heerspink HJL, Masson S, Breyer M, Hansen MK. Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial. Am Heart J. 2024 Feb 22; 271:38-47.
    Abstract: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established.
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  • Primary and Secondary Cardiovascular and Kidney Prevention With Canagliflozin: Insights From the CANVAS Program and CREDENCE Trial.
    Journal of the American Heart Association (2024)
    Sharma A, Razaghizad A, Joury A, Levin A, Bajaj HS, Mancini GBJ, Wong NC, Slee A, Ang FG, Rapattoni W, Neuen BL, Arnott C, Perkovic V, Mahaffey KW. Primary and Secondary Cardiovascular and Kidney Prevention With Canagliflozin: Insights From the CANVAS Program and CREDENCE Trial. J Am Heart Assoc. 2024 Feb 6; 13(3):e031586.
    Abstract: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention).
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  • Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points.
    Clinical journal of the American Society of Nephrology : CJASN (2024)
    Mohebi R, Liu Y, Hansen MK, Yavin Y, Sattar N, Pollock CA, Butler J, Jardine M, Masson S, Heerspink HJL, Januzzi JL Jr. Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points. Clin J Am Soc Nephrol. 2024 Apr 1; 19(4):429-437.
    Abstract: Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor-A (VEGF-A) and may play a role in diabetic kidney disease (DKD). We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations.
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  • Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.
    Journal of the American Society of Nephrology : JASN (2023)
    Fletcher RA, Jongs N, Chertow GM, McMurray JJV, Arnott C, Jardine MJ, Mahaffey KW, Perkovic V, Rockenschaub P, Rossing P, Correa-Rotter R, Toto RD, Vaduganathan M, Wheeler DC, Heerspink HJL, Neuen BL. Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials. J Am Soc Nephrol. 2023 Dec 1; 34(12):1965-1975.
    Abstract: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD.
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  • Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression.
    Journal of the American Society of Nephrology : JASN (2023)
    Heerspink HJL, Jongs N, Schloemer P, Little DJ, Brinker M, Tasto C, Karpefors M, Wheeler DC, Bakris G, Perkovic V, Nkulikiyinka R, Rossert J, Gasparyan SB. Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression. J Am Soc Nephrol. 2023 Dec 1; 34(12):2025-2038.
    Abstract: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point.
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  • The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.
    Diabetes, obesity & metabolism (2023)
    Yu J, Sweeting AN, Gianacas C, Houston L, Lee V, Fletcher RA, Perkovic V, Li Q, Neuen BL, Berwanger O, Heerspink HJL, de Zeeuw D, Arnott C. The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial. Diabetes Obes Metab. 2023 Dec; 25(12):3724-3735.
    Abstract: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial.
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  • Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial.
    Circulation (2023)
    Januzzi JL, Mohebi R, Liu Y, Sattar N, Heerspink HJL, Tefera E, Vaduganathan M, Butler J, Yavin Y, Li J, Pollock CA, Perkovic V, Neal B, Hansen MK. Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial. Circulation. 2023 Aug 22; 148(8):651-660.
    Abstract: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear.
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  • Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial.
    Cardiovascular diabetology (2023)
    Mohebi R, Liu Y, Hansen MK, Yavin Y, Sattar N, Pollock CA, Butler J, Jardine M, Masson S, Heerspink HJL, Januzzi JL Jr. Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial. Cardiovasc Diabetol. 2023 Jul 12; 22(1):176.
    Abstract: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes.
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  • Canagliflozin, Blood Pressure Variability, and Risk of Cardiovascular, Kidney, and Mortality Outcomes: Pooled Individual Participant Data From the CANVAS and CREDENCE Trials.
    Journal of the American Heart Association (2023)
    Fletcher RA, Arnott C, Rockenschaub P, Schutte AE, Carpenter L, Vaduganathan M, Agarwal R, Bakris G, Chang TI, Heerspink HJL, Jardine MJ, Mahaffey KW, Neal B, Pollock C, Jun M, Rodgers A, Perkovic V, Neuen BL. Canagliflozin, Blood Pressure Variability, and Risk of Cardiovascular, Kidney, and Mortality Outcomes: Pooled Individual Participant Data From the CANVAS and CREDENCE Trials. J Am Heart Assoc. 2023 Jul 4; 12(13):e028516.
    Abstract: Background Sodium glucose cotransporter-2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Methods and Results Using individual participant data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, we assessed the effect of canagliflozin on SBP variability in people with type 2 diabetes across 4 study visits over 1.5 years as measured by standard deviation, coefficient of variation, and variability independent of the mean. We used multivariable Cox regression models to estimate associations of SBP variability with cardiovascular, kidney, and mortality outcomes. In 11 551 trial participants, canagliflozin modestly lowered the standard deviation of SBP variability (-0.25 mm Hg [95% CI, -0.44 to -0.06]), but there was no effect on coefficient of variation (0.02% [95% CI, -0.12 to 0.16]) or variability independent of the mean (0.08 U [95% CI, -0.11 to 0.26]) when adjusting for correlation with mean SBP. Each 1 standard deviation increase in standard deviation of SBP variability was independently associated with higher risk of hospitalization for heart failure (hazard ratio [HR], 1.19 [95% CI, 1.02-1.38]) and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25]), with consistent results observed for coefficient of variation and variability independent of the mean. Increases in SBP variability were not associated with kidney outcomes. Conclusions In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit-to-visit SBP variability is independently associated with risks of hospitalization for heart failure and all-cause mortality. Canagliflozin has little to no effect on SBP variability, independent of its established SBP-lowering effect. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.
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  • Extremes of both weight gain and weight loss are associated with increased incidence of heart failure and cardiovascular death: evidence from the CANVAS Program and CREDENCE.
    Cardiovascular diabetology (2023)
    Ferrannini G, Pollock C, Natali A, Yavin Y, Mahaffey KW, Ferrannini E. Extremes of both weight gain and weight loss are associated with increased incidence of heart failure and cardiovascular death: evidence from the CANVAS Program and CREDENCE. Cardiovasc Diabetol. 2023 Apr 29; 22(1):100.
    Abstract: Obesity is an independent risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). However, it is not known to what extent weight fluctuations might be associated with adverse outcomes. We aimed at assessing the associations between extreme weight changes and cardiovascular outcomes in two large randomised controlled trials of canagliflozin in patients with T2D and high cardiovascular (CV) risk.
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  • Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR: A Post Hoc Analysis of the CREDENCE Trial.
    Clinical journal of the American Society of Nephrology : CJASN (2023)
    van der Hoek S, Jongs N, Oshima M, Neuen BL, Stevens J, Perkovic V, Levin A, Mahaffey KW, Pollock C, Greene T, Wheeler DC, Jardine MJ, Heerspink HJL. Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR: A Post Hoc Analysis of the CREDENCE Trial. Clin J Am Soc Nephrol. 2023 Jun 1; 18(6):748-758.
    Abstract: In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and CKD. In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according to patient subgroups by baseline glycated hemoglobin A1c (HbA1c).
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  • Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial.
    American journal of kidney diseases : the official journal of the National Kidney Foundation (2023)
    Yi TW, Smyth B, Di Tanna GL, Arnott C, Cardoza K, Kang A, Pollock C, Agarwal R, Bakris G, Charytan DM, de Zeeuw D, Heerspink HJL, Neal B, Wheeler DC, Cannon CP, Zhang H, Zinman B, Perkovic V, Levin A, Mahaffey KW, Jardine M, CREDENCE Trial Investigators. Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial. Am J Kidney Dis. 2023 Jul; 82(1):84-96.e1.
    Abstract: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.
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  • Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria.
    Journal of the American College of Cardiology (2022)
    Sarraju A, Bakris G, Cannon CP, Cherney D, Damaraju CV, Figtree GA, Gogate J, Greene T, Heerspink HJL, Januzzi JL Jr, Neal B, Jardine MJ, Blais J, Kosiborod M, Levin A, Lingvay I, Weir MR, Perkovic V, Mahaffey KW. Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria. J Am Coll Cardiol. 2022 Nov 1; 80(18):1721-1731.
    Abstract: People with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial.
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  • Canagliflozin, mental health adverse events and diabetes: Exploratory analysis of the CREDENCE trial and CANVAS Program.
    Diabetes, obesity & metabolism (2022)
    Nunes JC, Yu J, Arnott C, Jardine MJ, Perkovic V, Mahaffey KW. Canagliflozin, mental health adverse events and diabetes: Exploratory analysis of the CREDENCE trial and CANVAS Program. Diabetes Obes Metab. 2022 Dec; 24(12):2459-2464.
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  • Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial.
    Journal of the American Heart Association (2022)
    Li JW, Arnott C, Heerspink HJL, MBiostat QL, Cannon CP, Wheeler DC, Charytan DM, Barraclough J, Figtree GA, Agarwal R, Bakris G, de Zeeuw D, Greene T, Levin A, Pollock C, Zhang H, Zinman B, Mahaffey KW, Perkovic V, Neal B, Jardine MJ. Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial. J Am Heart Assoc. 2022 Aug 5; :e025045.
    Abstract: Background The sodium-glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m, over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63-0.86]; <0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59-0.86]; <0.001). The absolute risk difference per 1000 patients treated over 2.5 years was -44 (95% CI, -67 to -21) first cardiovascular events and -73 (95% CI, -114 to -33) total events. Conclusions Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events. Registration Information URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02065791.
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  • Potential Effects of Elimination of the Black Race Coefficient in eGFR Calculations in the CREDENCE Trial.
    Clinical journal of the American Society of Nephrology : CJASN (2022)
    Charytan DM, Yu J, Jardine MJ, Cannon CP, Agarwal R, Bakris G, Greene T, Levin A, Pollock C, Powe NR, Arnott C, Mahaffey KW, CREDENCE study investigators.. Potential Effects of Elimination of the Black Race Coefficient in eGFR Calculations in the CREDENCE Trial. Clin J Am Soc Nephrol. 2022 Mar; 17(3):361-373.
    Abstract: The effect of including race in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation on screening, recruitment, and outcomes of clinical trials is unclear.
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  • Canagliflozin and Kidney-Related Adverse Events in Type 2 Diabetes and CKD: Findings From the Randomized CREDENCE Trial.
    American journal of kidney diseases : the official journal of the National Kidney Foundation (2022)
    Heerspink HJL, Oshima M, Zhang H, Li J, Agarwal R, Capuano G, Charytan DM, Craig J, de Zeeuw D, Di Tanna GL, Levin A, Neal B, Perkovic V, Wheeler DC, Yavin Y, Jardine MJ. Canagliflozin and Kidney-Related Adverse Events in Type 2 Diabetes and CKD: Findings From the Randomized CREDENCE Trial. Am J Kidney Dis. 2022 Feb; 79(2):244-256.e1.
    Abstract: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs).
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  • Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis.
    Stroke (2021)
    Zhou Z, Jardine MJ, Li Q, Neuen BL, Cannon CP, de Zeeuw D, Edwards R, Levin A, Mahaffey KW, Perkovic V, Neal B, Lindley RI, CREDENCE Trial Investigators*.. Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis. Stroke. 2021 May; 52(5):1545-1556.
    Abstract: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.
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  • Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial.
    Cardiovascular research (2022)
    Yu J, Li J, Leaver PJ, Arnott C, Huffman MD, Udell JA, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Rosenthal N, Neal B, Figtree GA. Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial. Cardiovasc Res. 2022 Mar 16; 118(4):1103-1114.
    Abstract: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post hoc analysis of CANVAS Programme and CREDENCE trial.
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  • Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis.
    Clinical journal of the American Society of Nephrology : CJASN (2021)
    Jardine M, Zhou Z, Lambers Heerspink HJ, Hockham C, Li Q, Agarwal R, Bakris GL, Cannon CP, Charytan DM, Greene T, Levin A, Li JW, Neuen BL, Neal B, Oh R, Oshima M, Pollock C, Wheeler DC, de Zeeuw D, Zhang H, Zinman B, Mahaffey KW, Perkovic V. Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis. Clin J Am Soc Nephrol. 2021 Mar 8; 16(3):384-395.
    Abstract: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.
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  • Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial.
    Circulation (2021)
    Ye N, Jardine MJ, Oshima M, Hockham C, Heerspink HJL, Agarwal R, Bakris G, Schutte AE, Arnott C, Chang TI, Górriz JL, Cannon CP, Charytan DM, de Zeeuw D, Levin A, Mahaffey KW, Neal B, Pollock C, Wheeler DC, Luca Di Tanna G, Cheng H, Perkovic V, Neuen BL. Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial. Circulation. 2021 May 4; 143(18):1735-1749.
    Abstract: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown.
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  • Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial.
    American heart journal (2021)
    Sarraju A, Li J, Cannon CP, Chang TI, Agarwal R, Bakris G, Charytan DM, de Zeeuw D, Greene T, Heerspink HJL, Levin A, Neal B, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Perkovic V, Jardine M, Mahaffey KW. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial. Am Heart J. 2021 Mar; 233:141-148.
    Abstract: We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.
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  • Linear Projection of Estimated Glomerular Filtration Rate Decline with Canagliflozin and Implications for Dialysis Utilization and Cost in Diabetic Nephropathy.
    Diabetes therapy : research, treatment and education of diabetes and related disorders (2021)
    Durkin M, Blais J. Linear Projection of Estimated Glomerular Filtration Rate Decline with Canagliflozin and Implications for Dialysis Utilization and Cost in Diabetic Nephropathy. Diabetes Ther. 2021 Feb; 12(2):499-508.
    Abstract: Diabetes is a common cause of end-stage kidney disease leading to dialysis or kidney transplantation. Estimated glomerular filtration rate (eGFR) measures kidney function, and differences in the rate (slope) of eGFR decline can be used to assess treatment effects on kidney function over time. In the CREDENCE trial, the sodium glucose co-transporter 2 inhibitor canagliflozin slowed the rate of eGFR decline by 60% compared to placebo in patients with diabetes and chronic kidney disease. This analysis utilized eGFR slopes from CREDENCE to estimate the difference in time to dialysis by treatment arm and estimated the economic value of that delay.
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  • Cost-Effectiveness of Canagliflozin Added to Standard of Care for Treating Diabetic Kidney Disease (DKD) in Patients with Type 2 Diabetes Mellitus (T2DM) in England: Estimates Using the CREDEM-DKD Model.
    Diabetes therapy : research, treatment and education of diabetes and related disorders (2021)
    Willis M, Nilsson A, Kellerborg K, Ball P, Roe R, Traina S, Beale R, Newell I. Cost-Effectiveness of Canagliflozin Added to Standard of Care for Treating Diabetic Kidney Disease (DKD) in Patients with Type 2 Diabetes Mellitus (T2DM) in England: Estimates Using the CREDEM-DKD Model. Diabetes Ther. 2021 Jan; 12(1):313-328.
    Abstract: On the basis of reductions in diabetic kidney disease (DKD) progression and major adverse cardiovascular events observed in the landmark CREDENCE trial, canagliflozin 100 mg received an extension to its EU marketing authorisation in July 2020 to include the treatment of DKD in people with type 2 diabetes mellitus (T2DM) making it the first pharmacological therapy to receive regulatory authorisation for treatment of DKD since the RENAAL and IDNT trials in nearly 20 years. Efficient allocation of limited healthcare resources requires evaluation not only of clinical safety and efficacy but also economic consequences. The study aim was to estimate the cost-effectiveness of canagliflozin when added to current standard of care (SoC) versus SoC alone from the perspective of the NHS in England.
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  • Development and Internal Validation of a Discrete Event Simulation Model of Diabetic Kidney Disease Using CREDENCE Trial Data.
    Diabetes therapy : research, treatment and education of diabetes and related disorders (2020)
    Willis M, Asseburg C, Slee A, Nilsson A, Neslusan C. Development and Internal Validation of a Discrete Event Simulation Model of Diabetic Kidney Disease Using CREDENCE Trial Data. Diabetes Ther. 2020 Nov; 11(11):2657-2676.
    Abstract: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study showed that compared with placebo, canagliflozin 100 mg significantly reduced the risk of major cardiovascular events and adverse renal outcomes in patients with diabetic kidney disease (DKD). We developed a simulation model that can be used to estimate the long-term health and economic consequences of DKD treatment interventions for patients matching the CREDENCE study population.
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  • Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.
    Journal of the American Society of Nephrology : JASN (2020)
    Jardine MJ, Zhou Z, Mahaffey KW, Oshima M, Agarwal R, Bakris G, Bajaj HS, Bull S, Cannon CP, Charytan DM, de Zeeuw D, Di Tanna GL, Greene T, Heerspink HJL, Levin A, Neal B, Pollock C, Qiu R, Sun T, Wheeler DC, Zhang H, Zinman B, Rosenthal N, Perkovic V, C. Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial. J Am Soc Nephrol. 2020 May; 31(5):1128-1139.
    Abstract: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).
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  • Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c
    Circulation (2020)
    Cannon CP, Perkovic V, Agarwal R, Baldassarre J, Bakris G, Charytan DM, de Zeeuw D, Edwards R, Greene T, Heerspink HJL, Jardine MJ, Levin A, Li JW, Neal B, Pollock C, Wheeler DC, Zhang H, Zinman B, Mahaffey KW. Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease According to Baseline HbA1c, Including Those With HbA1c Circulation. 2020 Feb 4; 141(5):407-410.
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  • Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups.
    Circulation (2019)
    Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkov. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27; 140(9):739-750.
    Abstract: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention).
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  • Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.
    The New England journal of medicine (2019)
    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaff. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13; 380(24):2295-2306.
    Abstract: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
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  • The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics.
    American journal of nephrology (2017)
    Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, Bull S, Cannon CP, Charytan DM, de Zeeuw D, Edwards R, Greene T, Heerspink HJL, Levin A, Pollock C, Wheeler DC, Xie J, Zhang H, Zinman B, Desai M, Perkovic V, CREDENCE study investigators.. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017 Dec 13; 46(6):462-472.
    Abstract: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease.
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Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth
Stanford University
  • Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.
    Journal of child and adolescent psychopharmacology (2024)
    Honeycutt DC, Blom TJ, Ramsey LB, Strawn JR, Bruns KM, Welge JA, Patino LR, Singh MK, DelBello MP. Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study. J Child Adolesc Psychopharmacol. 2024 Feb; 34(1):42-51.
    Abstract: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes ( or ), the serotonin transporter (), and the serotonin receptor 2A subtype (). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC;  = 0.025), trough concentrations (C;  = 0.013), and elimination half-lives (t;  < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia ( = 0.015) scores. and genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores ( = 0.017). Escitalopram maximum concentration, AUC, CYP2C19 phenotype, and genotype were not associated with adverse events. CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and or genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. ClinicalTrials.gov identifier: NCT02553161.
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Evaluating the EVO treatment optimized for resource constraints: Elements Vital to treat Obesity
Northwestern University
  • Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity.
    The Cochrane database of systematic reviews (2024)
    Metzendorf MI, Wieland LS, Richter B. Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity. Cochrane Database Syst Rev. 2024 Feb 20; 2(2):CD013591.
    Abstract: Obesity is considered to be a risk factor for various diseases, and its incidence has tripled worldwide since 1975. In addition to potentially being at risk for adverse health outcomes, people with overweight or obesity are often stigmatised. Behaviour change interventions are increasingly delivered as mobile health (m-health) interventions, using smartphone apps and wearables. They are believed to support healthy behaviours at the individual level in a low-threshold manner.
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SMART 2.0: Social Mobile Approaches to Reducing weighT in Young Adults
University of California San Diego
  • Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity.
    The Cochrane database of systematic reviews (2024)
    Metzendorf MI, Wieland LS, Richter B. Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity. Cochrane Database Syst Rev. 2024 Feb 20; 2(2):CD013591.
    Abstract: Obesity is considered to be a risk factor for various diseases, and its incidence has tripled worldwide since 1975. In addition to potentially being at risk for adverse health outcomes, people with overweight or obesity are often stigmatised. Behaviour change interventions are increasingly delivered as mobile health (m-health) interventions, using smartphone apps and wearables. They are believed to support healthy behaviours at the individual level in a low-threshold manner.
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  • Social Mobile Approaches to Reducing Weight (SMART) 2.0: protocol of a randomized controlled trial among young adults in university settings.
    Trials (2022)
    Mansour-Assi SJ, Golaszewski NM, Costello VL, Wing D, Persinger H, Coleman A, Lytle L, Larsen BA, Jain S, Weibel N, Rock CL, Patrick K, Hekler E, Godino JG. Social Mobile Approaches to Reducing Weight (SMART) 2.0: protocol of a randomized controlled trial among young adults in university settings. Trials. 2022 Jan 3; 23(1):7.
    Abstract: Excess weight gain in young adulthood is associated with future weight gain and increased risk of chronic disease. Although multimodal, technology-based weight-loss interventions have the potential to promote weight loss among young adults, many interventions have limited personalization, and few have been deployed and evaluated for longer than a year. We aim to assess the effects of a highly personalized, 2-year intervention that uses popular mobile and social technologies to promote weight loss among young adults.
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TREAT (Time Restricted EATing) to improve cardiometabolic health
Columbia University
  • Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity.
    The Cochrane database of systematic reviews (2024)
    Metzendorf MI, Wieland LS, Richter B. Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity. Cochrane Database Syst Rev. 2024 Feb 20; 2(2):CD013591.
    Abstract: Obesity is considered to be a risk factor for various diseases, and its incidence has tripled worldwide since 1975. In addition to potentially being at risk for adverse health outcomes, people with overweight or obesity are often stigmatised. Behaviour change interventions are increasingly delivered as mobile health (m-health) interventions, using smartphone apps and wearables. They are believed to support healthy behaviours at the individual level in a low-threshold manner.
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  • Time-restricted eating to improve cardiometabolic health: The New York time-restricted eating randomized clinical trial - Protocol overview.
    Contemporary clinical trials (2022)
    Santos-Báez LS, Garbarini A, Shaw D, Cheng B, Popp CJ, Manoogian ENC, Panda S, Laferrère B. Time-restricted eating to improve cardiometabolic health: The New York time-restricted eating randomized clinical trial - Protocol overview. Contemp Clin Trials. 2022 Aug 4; :106872.
    Abstract: Re-aligning eating patterns with biological rhythm can reduce the burden of metabolic syndrome in older adults with overweight or obesity. Time-restricted eating (TRE) has been shown to result in weight loss and improved cardiometabolic health while being less challenging than counting calories. The New York Time-Restricted EATing study (NY-TREAT) is a two-arm, randomized clinical trial (RCT) that aims to examine the efficacy and sustainability of TRE (eating window ≤10 h/day) vs. a habitual prolonged eating window (HABIT, ≥14 h/day) in metabolically unhealthy midlife adults (50-75 years) with overweight or obesity and prediabetes or type 2 diabetes (T2D). Our primary hypothesis is that the TRE will result in greater weight loss compared to HABIT at 3 months. The efficacy of the TRE intervention on body weight, fat mass, energy expenditure, and glucose is tested at 3 months, and the sustainability of its effect is measured at 12 months, with ambulatory assessments of sleep and physical activity (ActiGraph), eating pattern (smartphone application), and interstitial glucose (continuous glucose monitoring). The RCT also includes state-of-the-art measurements of body fat (quantitative magnetic resonance), total energy expenditure (doubly-labelled water), insulin secretion, insulin resistance, and glucose tolerance. Adherence to self-monitoring and reduced eating window are monitored remotely in real-time. This RCT will provide further insight into the effects of TRE on cardiometabolic health in individuals with high metabolic risk. Sixty-two participants will be enrolled, and with estimated 30% attrition, 42 participants will return at 12 months. This protocol describes the design, interventions, methods, and expected outcomes. Clinical trial registration:NCT04465721 IRB: AAAS7791.
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Insulin Detemir in Obesity Management (IDIOM)
Vanderbilt University Medical Center
  • Poorly controlled glycemia and worse beta cell function associate with higher resting and total energy expenditure in adults with obesity and type 2 diabetes: A doubly labeled water study.
    Clinical nutrition (Edinburgh, Scotland) (2024)
    Lillegard K, Del Castillo JA, Silver HJ. Poorly controlled glycemia and worse beta cell function associate with higher resting and total energy expenditure in adults with obesity and type 2 diabetes: A doubly labeled water study. Clin Nutr. 2024 Mar; 43(3):729-738.
    Abstract: Some studies comparing persons with and without type 2 diabetes (T2DM) show no difference in resting energy expenditure (REE). However, the degree of glycemic control may be a crucial factor in determining energy requirements. Few studies have employed the doubly labeled water (DLW) method in persons with T2DM to objectively measure daily energy expenditure.
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RIC Financial Incentive Study
Vanderbilt University Medical Center
  • Development, implementation, and dissemination of operational innovations across the trial innovation network.
    Journal of clinical and translational science (2023)
    Palm ME, Edwards TL, Wieber C, Kay MT, Marion E, Boone L, Nanni A, Jones M, Pham E, Hildreth M, Lane K, McBee N, Benjamin DK Jr, Bernard GR, Dean JM, Dwyer JP, Ford DE, Hanley DF, Harris PA, Wilkins CH, Selker HP. Development, implementation, and dissemination of operational innovations across the trial innovation network. J Clin Transl Sci. 2023; 7(1):e251.
    Abstract: Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations. We provide an overview of the roadblocks that led to opportunities for operational innovation, our work to develop, define, and map innovations across the network, and how we implemented and disseminated mature innovations.
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  • ResearchMatch on FHIR: Development and evaluation of a recruitment registry and electronic health record system interface for volunteer profile completion.
    Journal of clinical and translational science (2023)
    Cheng AC, Dunkel L, Byrne LM, Tischbein M, Burts D, Hamilton J, Phillips K, Embry B, Tan J, Olson E, Harris PA. ResearchMatch on FHIR: Development and evaluation of a recruitment registry and electronic health record system interface for volunteer profile completion. J Clin Transl Sci. 2023; 7(1):e222.
    Abstract: Obtaining complete and accurate information in recruitment registries is essential for matching potential participants to research studies for which they qualify. Since electronic health record (EHR) systems are required to make patient data available to external systems, an interface between EHRs and recruitment registries may improve accuracy and completeness of volunteers' profiles. We tested this hypothesis on ResearchMatch (RM), a disease- and institution-neutral recruitment registry with 1357 studies across 255 institutions.
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  • Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.
    JAMA network open (2023)
    Harris PA, Dunsmore SE, Atkinson JC, Benjamin DK Jr, Bernard GR, Dean JM, Dwyer JP, Ford DF, Selker HP, Waddy SP, Wiley KL, Wilkins CH, Cook SK, Burr JS, Edwards TL, Huvane J, Kennedy N, Lane K, Majkowski R, Nelson S, Palm ME, Stroud M, Thompson DD, Busac. Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials. JAMA Netw Open. 2023 Oct 2; 6(10):e2336470.
    Abstract: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support.
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  • Effects of financial incentives on volunteering for clinical trials: A randomized vignette experiment.
    Contemporary clinical trials (2021)
    Bickman L, Domenico HJ, Byrne DW, Jerome RN, Edwards TL, Stroud M, Lebo L, Mcguffin K, Wilkins CH, Harris PA. Effects of financial incentives on volunteering for clinical trials: A randomized vignette experiment. Contemp Clin Trials. 2021 Nov; 110:106584.
    Abstract: Financial incentives may aid recruitment to clinical trials, but evidence regarding risk/burden-driven variability in participant preferences for incentives is limited. We developed and tested a framework to support real-world decisions on recruitment budget.
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Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease—Aim 1
Vanderbilt University Medical Center
  • A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis.
    Journal of cachexia, sarcopenia and muscle (2024)
    Ertuglu LA, Deger SM, Alsouqi A, Hung A, Gamboa J, Mambungu C, Sha F, Siew E, Abumrad NN, Ikizler TA. A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis. J Cachexia Sarcopenia Muscle. 2024 Feb; 15(1):401-411.
    Abstract: Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting. We conducted a pilot, randomized, placebo-controlled trial of recombinant human interleukin-1 receptor antagonist (IL-1ra) and pioglitazone to explore the safety, feasibility and efficacy for insulin-mediated protein metabolism in patients undergoing MHD.
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  • Insulin resistance is a significant determinant of sarcopenia in advanced kidney disease.
    American journal of physiology. Endocrinology and metabolism (2018)
    Deger SM, Hewlett JR, Gamboa J, Ellis CD, Hung AM, Siew ED, Mamnungu C, Sha F, Bian A, Stewart TG, Abumrad NN, Ikizler TA. Insulin resistance is a significant determinant of sarcopenia in advanced kidney disease. Am J Physiol Endocrinol Metab. 2018 Dec 1; 315(6):E1108-E1120.
    Abstract: Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass·min for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: -83.7 and 64.7) μg·100 ml·min for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.
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  • Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients.
    JCI insight (2017)
    Deger SM, Hung AM, Gamboa JL, Siew ED, Ellis CD, Booker C, Sha F, Li H, Bian A, Stewart TG, Zent R, Mitch WE, Abumrad NN, Ikizler TA. Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients. JCI Insight. 2017 Nov 16; 2(22):.
    Abstract: Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients.
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  • Leucine disposal rate for assessment of amino acid metabolism in maintenance hemodialysis patients.
    BMC nutrition (2016)
    Denny GB, Deger SM, Chen G, Bian A, Sha F, Booker C, Kesler JT, David S, Ellis CD, Ikizler TA. Leucine disposal rate for assessment of amino acid metabolism in maintenance hemodialysis patients. BMC Nutr. 2016; 2:.
    Abstract: Protein energy wasting (PEW) is common in patients undergoing maintenance hemodialysis (MHD) and closely associated with poor outcomes. Insulin resistance and associated alterations in amino acid metabolism are potential pathways leading to PEW. We hypothesized that the measurement of leucine disposal during a hyperinsulinemic- euglycemic-euaminoacidemic clamp (HEAC) procedure would accurately measure the sensitivity to insulin for its actions on concomitant carbohydrate and protein metabolism in MHD patients.
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Enhancing Social Competence in Adults with Autism Spectrum Disorder: A Pilot RCT
Vanderbilt University Medical Center
  • Investigating Social Competence in a Pilot Randomized Clinical Trial of a Theatre-Based Intervention Enhanced for Adults with Autism Spectrum Disorder.
    Journal of autism and developmental disorders (2023)
    Corbett BA, Key AP, Klemencic ME, Muscatello RA, Jones D, Pilkington J, Burroughs C, Vandekar S. Investigating Social Competence in a Pilot Randomized Clinical Trial of a Theatre-Based Intervention Enhanced for Adults with Autism Spectrum Disorder. J Autism Dev Disord. 2023 Dec 18; :.
    Abstract: Autism spectrum disorder (ASD) is characterized by challenges in social competence that persist in adulthood, yet few treatment options exist. A pilot randomized clinical trial (RCT) of a peer-mediated, theatre-based intervention with established efficacy in youth with ASD was examined in autistic adults. The final sample consisted of forty-seven 18-to-40-year-old participants randomized to the experimental (EXP N = 23) or waitlist control (WLC N = 24) condition. A multimodal, social interdependent model was employed to examine social competence changes in brain (incidental face memory (IFM) using event-related potentials), cognition (Wechsler Memory Scale-III), behavior (Contextual Assessment of Social Skills) and function (Social Responsiveness Scale (SRS); Adaptive Behavior Assessment Scale (ABAS) Social Composite). Using analysis of covariance in which pretest was controlled in the model, posttest between-group differences were observed on IFM (p = 0.016, η = 0.139, d = 0.79) and several social and adaptive functional (SRS, ABAS) outcomes in social communication and interaction (SCI) (p = 0.019, η = 0.121, d = -00.45), communication (p = 0.044 η = 0.09, d = -00.31), and motivation (p = 0.001, η = 0.229, d = -0.79) domains. At two-month follow-up, gains in social motivation remained (p = 0.041, η = 0.100, d = -0.77). The results offer preliminary support for a unique theatre-based social skills intervention for autistic adults who have few treatment options to enhance social competence. The trial was pre-registered with ClinicalTrials.gov (Identifier: NCT04349644).
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Positive Affect as a Source of Resilience for Adults in Chronic Pain
Weill Cornell Medical College
  • Feasibility, Acceptability, and Preliminary Efficacy of a Positive Affect Skills Intervention for Adults With Fibromyalgia.
    Innovation in aging (2023)
    Ong AD, Wilcox KT, Moskowitz JT, Wethington E, Addington EL, Sanni MO, Kim P, Reid MC. Feasibility, Acceptability, and Preliminary Efficacy of a Positive Affect Skills Intervention for Adults With Fibromyalgia. Innov Aging. 2023; 7(10):igad070.
    Abstract: To examine the feasibility, acceptability, and preliminary efficacy of a positive affect skills intervention for middle-aged and older adults with fibromyalgia syndrome (FMS).
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  • Lessons in Affect Regulation to Keep Stress and Pain UndeR control (LARKSPUR): Design of a randomized controlled trial to increase positive affect in middle-aged and older adults with fibromyalgia.
    Contemporary clinical trials (2022)
    Ong AD, Moskowitz JT, Wethington E, Addington EL, Sanni M, Goktas S, Sluys E, Swong S, Kim P, Reid MC. Lessons in Affect Regulation to Keep Stress and Pain UndeR control (LARKSPUR): Design of a randomized controlled trial to increase positive affect in middle-aged and older adults with fibromyalgia. Contemp Clin Trials. 2022 Aug 11; :106880.
    Abstract: Fibromyalgia syndrome (FMS) is a leading cause of functional limitations and disability for which there is no cure. Positive psychological interventions for improving health have received increasing attention, but evidence of the feasibility, acceptability, and impact of such interventions in adult populations with FMS is limited.
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Improving emotional well-being and quality of life in older adults experiencing dementia-related fear
Northwestern University
  • Reducing fear and avoidance of memory loss improves mood and social engagement in community-based older adults: a randomized trial.
    BMC geriatrics (2023)
    Farina FR, Regan J, Marquez M, An H, O'Loughlin P, Pavithra P, Taddeo M, Knight RC, Bennett M, Lenaert B, Griffith JW. Reducing fear and avoidance of memory loss improves mood and social engagement in community-based older adults: a randomized trial. BMC Geriatr. 2023 Nov 29; 23(1):786.
    Abstract: Alzheimer's disease and related dementias (ADRD) are among the most feared age-related conditions. The aim of this study was to evaluate a brief psychological intervention to promote adaptive coping in older adults experiencing heightened fear of ADRD and investigate positive downstream effects on health-related secondary outcomes, including frequency of reported memory failures, psychosocial functioning, and quality of life.
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  • A Randomized Controlled Trial Investigating the Feasibility of a Low-Intensity Psychological Intervention for Fear of Memory Loss and Quality of Life in Older Adults: Protocol for the Reducing Fear and Avoidance of Memory Loss (REFRAME) Study.
    JMIR research protocols (2021)
    O'Loughlin P, Pavithra P, Regan J, Bennett M, Knight R, Lenaert B, Marquez M, Taddeo M, Griffith J, Shapiro R, Farina F. A Randomized Controlled Trial Investigating the Feasibility of a Low-Intensity Psychological Intervention for Fear of Memory Loss and Quality of Life in Older Adults: Protocol for the Reducing Fear and Avoidance of Memory Loss (REFRAME) Study. JMIR Res Protoc. 2021 Jul 30; 10(7):e30514.
    Abstract: Dementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults.
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ASPirin in Reducing Events in the Elderly
University of Iowa
  • Long-term blood pressure variability and frailty risk in older adults.
    Journal of hypertension (2023)
    Fravel MA, Ernst ME, Woods RL, Beilin L, Zhou Z, Orchard SG, Chowdhury E, Reid CM, Saifuddin Ekram A, Espinoza SE, Nelson MR, Stocks N, Polkinghorne KR, Wolfe R, Ryan J. Long-term blood pressure variability and frailty risk in older adults. J Hypertens. 2023 Nov 21; :.
    Abstract: In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain.
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  • Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.
    Journal of the American Heart Association (2023)
    Yu C, Bakshi A, Watts GF, Renton AE, Fulton-Howard B, Goate AM, Natarajan P, Chasman DI, Robman L, Woods RL, Guymer R, Wolfe R, Thao LTP, McNeil JJ, Tonkin AM, Nicholls SJ, Lacaze P. Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene. J Am Heart Assoc. 2023 Nov 6; :e031459.
    Abstract: Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (<5×10) and rs56156922 (<10), in the (cholesteryl ester transfer protein) gene. The gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified variants reduce gene expression across various tissues. Previously reported associations between genetic inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
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  • Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants.
    Journal of the American Heart Association (2023)
    Salih A, Ardissino M, Wagen AZ, Bard A, Szabo L, Ryten M, Petersen SE, Altmann A, Raisi-Estabragh Z. Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants. J Am Heart Assoc. 2023 Nov 7; 12(21):e030661.
    Abstract: BACKGROUND Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity-adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. METHODS AND RESULTS The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome-wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance-derived measures of left ventricular structure and function. We discovered 12 genome-wide significant variants, with 2 independent sentinel variants (rs6428792, =4.20×10 and rs11992444, =1.30×10) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T-box transcription factor 15 (), tryptophanyl tRNA synthetase 2, mitochondrial () and early B-cell factor-2 () through functional annotation. Bayesian colocalization additionally suggested a role of RP4-712E4.1. Genetically predicted differences in adiposity-adjusted PAT were causally associated with adverse left ventricular remodeling. CONCLUSIONS This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.
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  • Associations between low sex hormone concentrations and depression in older women: An observational study.
    Maturitas (2023)
    Islam RM, Bell RJ, Berk M, Handelsman DJ, McNeil JJ, Wolfe R, Woods RL, Davis SR. Associations between low sex hormone concentrations and depression in older women: An observational study. Maturitas. 2023 Aug 4; 176:107822.
    Abstract: We investigated whether low sex hormone concentrations are associated with depression in older women.
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  • Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial.
    Annals of internal medicine (2023)
    McQuilten ZK, Thao LTP, Pasricha SR, Artz AS, Bailey M, Chan AT, Cohen HJ, Lockery JE, Murray AM, Nelson MR, Schneider HG, Wolfe R, Woods RL, Wood EM, McNeil JJ. Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial. Ann Intern Med. 2023 Jul; 176(7):913-921.
    Abstract: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia.
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  • Potentially inappropriate medication use is associated with increased risk of incident disability in healthy older adults.
    Journal of the American Geriatrics Society (2023)
    Lockery JE, Collyer TA, Woods RL, Orchard SG, Murray A, Nelson MR, Stocks NP, Wolfe R, Moran C, Ernst ME, ASPREE Investigator Group. Potentially inappropriate medication use is associated with increased risk of incident disability in healthy older adults. J Am Geriatr Soc. 2023 Aug; 71(8):2495-2505.
    Abstract: Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications (PIMs). However, most PIMs research has focused on older people in aged or inpatient care, creating an evidence gap for community-dwelling older adults. To address this gap, we investigated the impact of PIMs use in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial cohort.
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  • Associations of body size with all-cause and cause-specific mortality in healthy older adults.
    Scientific reports (2023)
    Carr PR, Webb KL, Neumann JT, Thao LTP, Beilin LJ, Ernst ME, Fitzgibbon B, Gasevic D, Nelson MR, Newman AB, Orchard SG, Owen A, Reid CM, Stocks NP, Tonkin AM, Woods RL, McNeil JJ. Associations of body size with all-cause and cause-specific mortality in healthy older adults. Sci Rep. 2023 Mar 7; 13(1):3799.
    Abstract: In the general population, body mass index (BMI) and waist circumference are recognized risk factors for several chronic diseases and all-cause mortality. However, whether these associations are the same for older adults is less clear. The association of baseline BMI and waist circumference with all-cause and cause-specific mortality was investigated in 18,209 Australian and US participants (mean age: 75.1 ± 4.5 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) study, followed up for a median of 6.9 years (IQR: 5.7, 8.0). There were substantially different relationships observed in men and women. In men, the lowest risk of all-cause and cardiovascular mortality was observed with a BMI in the range 25.0-29.9 kg/m [HR: 0.85; 95% CI, 0.73-1.00] while the highest risk was in those who were underweight [HR: 1.82; 95% CI 1.30-2.55], leading to a clear U-shaped relationship. In women, all-cause mortality was highest in those with the lowest BMI leading to a J-shaped relationship (HR: 1.64; 95% CI 1.26-2.14). Waist circumference showed a weaker relationship with all-cause mortality in both men and women. There was little evidence of a relationship between either index of body size and subsequent cancer mortality in men or women, while non-cardiovascular non-cancer mortality was higher in underweight participants. For older men, being overweight was found to be associated with a lower risk of all-cause mortality, while among both men and women, a BMI in the underweight category was associated with a higher risk. Waist circumference alone had little association with all-cause or cause-specific mortality risk.Trial registration ASPREE https://ClinicalTrials.gov number NCT01038583.
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  • Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes.
    JNCI cancer spectrum (2023)
    Orchard SG, Lockery JE, Broder JC, Ernst ME, Espinoza S, Gibbs P, Wolfe R, Polekhina G, Zoungas S, Loomans-Kropp HA, Woods RL, ASPREE Investigator Group. Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes. JNCI Cancer Spectr. 2023 Mar 1; 7(2):.
    Abstract: Metformin and aspirin are commonly co-prescribed to people with diabetes. Metformin may prevent cancer, but in older people (over 70 years), aspirin has been found to increase cancer mortality. This study examined whether metformin reduces cancer mortality and incidence in older people with diabetes; it used randomization to 100 mg aspirin or placebo in the ASPirin in Reducing Events in the Elderly (ASPREE) trial to quantify aspirin's impact on metformin users.
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  • Sex hormones, SHBG and cognitive performance among older Australian women: an observational study.
    Climacteric : the journal of the International Menopause Society (2023)
    Sultana F, Davis SR, Murray AM, Woods RL, McNeil JJ, Islam RM. Sex hormones, SHBG and cognitive performance among older Australian women: an observational study. Climacteric. 2023 Apr; 26(2):121-128.
    Abstract: This study aims to explore the associations between sex hormones and cognitive performance in older women.
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  • The Association between Metabolic Syndrome, Frailty and Disability-Free Survival in Healthy Community-dwelling Older Adults.
    The journal of nutrition, health & aging (2023)
    Saifuddin Ekram ARM, Espinoza SE, Ernst ME, Ryan J, Beilin L, Stocks NP, Ward SA, McNeil JJ, Shah RC, Woods RL. The Association between Metabolic Syndrome, Frailty and Disability-Free Survival in Healthy Community-dwelling Older Adults. J Nutr Health Aging. 2023; 27(1):1-9.
    Abstract: To examine the association between metabolic syndrome (MetS) and frailty, and determine whether co-existent MetS and frailty affect disability-free survival (DFS), assessed through a composite of death, dementia or physical disability.
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  • The Association between Frailty and Dementia-Free and Physical Disability-Free Survival in Community-Dwelling Older Adults.
    Gerontology (2023)
    Ekram ARMS, Ryan J, Espinoza SE, Newman AB, Murray AM, Orchard SG, Fitzgerald SM, McNeil JJ, Ernst ME, Woods RL. The Association between Frailty and Dementia-Free and Physical Disability-Free Survival in Community-Dwelling Older Adults. Gerontology. 2023; 69(5):549-560.
    Abstract: Frailty is a common geriatric syndrome that adversely impacts health outcomes. This study examined correlates of physical frailty in healthy community-dwelling older adults and studied the effect of frailty on disability-free survival (DFS), defined as survival free of independence-limiting physical disability or dementia.
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  • Does Aspirin Prevent Incident Heart Failure in Healthy Older Adults? Examining the Evidence From the ASPREE Trial.
    Circulation. Heart failure (2022)
    Zhou Z, Nelson M, Ernst ME, Reid C, McNeil J, Tonkin A, ASPREE Investigator Group. Does Aspirin Prevent Incident Heart Failure in Healthy Older Adults? Examining the Evidence From the ASPREE Trial. Circ Heart Fail. 2022 Jun; 15(6):e009511.
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  • Association between hypertension and cutaneous melanoma, and the effect of aspirin: extended follow-up of a large randomised controlled trial.
    Cancer epidemiology (2022)
    Yan MK, Orchard SG, Adler NR, Wolfe R, McLean C, Rodríguez LM, Woods RL, Gibbs P, Chan AT, Haydon A, Mar VJ. Association between hypertension and cutaneous melanoma, and the effect of aspirin: extended follow-up of a large randomised controlled trial. Cancer Epidemiol. 2022 Aug; 79:102173.
    Abstract: The association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals.
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  • Effect of Aspirin on CKD Progression in Older Adults: Secondary Analysis From the ASPREE Randomized Clinical Trial.
    American journal of kidney diseases : the official journal of the National Kidney Foundation (2022)
    Polkinghorne KR, Wetmore JB, Thao LTP, Wolfe R, Woods RL, Ernst ME, Nelson MR, Reid CM, Shah RC, McNeil JJ, Murray AM. Effect of Aspirin on CKD Progression in Older Adults: Secondary Analysis From the ASPREE Randomized Clinical Trial. Am J Kidney Dis. 2022 Dec; 80(6):810-813.
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  • Prediction of disability-free survival in healthy older people.
    GeroScience (2022)
    Neumann JT, Thao LTP, Murray AM, Callander E, Carr PR, Nelson MR, Wolfe R, Woods RL, Reid CM, Shah RC, Newman AB, Williamson JD, Tonkin AM, McNeil JJ, ASPREE investigators. Prediction of disability-free survival in healthy older people. Geroscience. 2022 Jun; 44(3):1641-1655.
    Abstract: Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6-77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people.Trial registration Clinicaltrials.gov (NCT01038583).
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  • Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.
    The lancet. Healthy longevity (2022)
    Islam RM, Bell RJ, Handelsman DJ, McNeil JJ, Nelson MR, Reid CM, Tonkin AM, Wolfe RS, Woods RL, Davis SR. Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial. Lancet Healthy Longev. 2022 Feb; 3(2):e109-e118.
    Abstract: Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive-aged women early in the eighth decade. We aimed to establish the association between the concentration of testosterone in the blood and risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women.
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  • Prognostic Value of a Polygenic Risk Score for Coronary Heart Disease in Individuals Aged 70 Years and Older.
    Circulation. Genomic and precision medicine (2022)
    Neumann JT, Riaz M, Bakshi A, Polekhina G, Thao LTP, Nelson MR, Woods RL, Abraham G, Inouye M, Reid CM, Tonkin AM, McNeil J, Lacaze P. Prognostic Value of a Polygenic Risk Score for Coronary Heart Disease in Individuals Aged 70 Years and Older. Circ Genom Precis Med. 2022 Feb; 15(1):e003429.
    Abstract: The use of a polygenic risk score (PRS) to improve risk prediction of coronary heart disease (CHD) events has been demonstrated to have clinical utility in the general adult population. However, the prognostic value of a PRS for CHD has not been examined specifically in older populations of individuals aged ≥70 years, who comprise a distinct high-risk subgroup. The objective of this study was to evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of older individuals without a history of cardiovascular events.
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  • Effect of methotrexate on melanoma risk in older adults: Secondary analysis of a randomised controlled trial.
    The Australasian journal of dermatology (2022)
    Yan MK, Wolfe R, Orchard SG, Ernst ME, Mar VJ. Effect of methotrexate on melanoma risk in older adults: Secondary analysis of a randomised controlled trial. Australas J Dermatol. 2022 Feb; 63(1):114-115.
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  • Long-Term Blood Pressure Variability and Kidney Function in Participants of the ASPREE Trial.
    American journal of hypertension (2022)
    Ernst ME, Fravel MA, Webb KL, Wetmore JB, Wolfe R, Chowdhury E, Reid CM, Woods RL, Beilin L, Margolis KL, Murray AM, Polkinghorne KR. Long-Term Blood Pressure Variability and Kidney Function in Participants of the ASPREE Trial. Am J Hypertens. 2022 Feb 1; 35(2):173-181.
    Abstract: Whether long-term blood pressure variability (BPV) predicts kidney function decline in generally healthy older adults is unknown. We investigated this association in ASPirin in Reducing Events in the Elderly (ASPREE) trial participants.
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  • Protective lipid-lowering variants in healthy older individuals without coronary heart disease.
    Open heart (2021)
    Lacaze P, Riaz M, Sebra R, Hooper AJ, Pang J, Tiller J, Polekhina G, Tonkin A, Reid C, Zoungas S, Murray AM, Nicholls S, Watts G, Schadt E, McNeil JJ. Protective lipid-lowering variants in healthy older individuals without coronary heart disease. Open Heart. 2021 Jul; 8(2):.
    Abstract: Genetic variants that disrupt the function of the (proprotein convertase subtilisin kexin type 9) and (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD.
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  • Long-Term Blood Pressure Variability and Risk of Cognitive Decline and Dementia Among Older Adults.
    Journal of the American Heart Association (2021)
    Ernst ME, Ryan J, Chowdhury EK, Margolis KL, Beilin LJ, Reid CM, Nelson MR, Woods RL, Shah RC, Orchard SG, Wolfe R, Storey E, Tonkin AM, Brodtmann A, McNeil JJ, Murray AM. Long-Term Blood Pressure Variability and Risk of Cognitive Decline and Dementia Among Older Adults. J Am Heart Assoc. 2021 Jul 6; 10(13):e019613.
    Abstract: Background Blood pressure variability (BPV) in midlife increases risk of late-life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long-term, visit-to-visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow-up visits. Time-to-event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction =0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19-2.39) but not women (HR, 1.01; 95% CI, 0.72-1.42). For cognitive decline, similar increased risks were observed for men and women (interaction =0.15; men: HR, 1.36; 95% CI, 1.16-1.59; women: HR, 1.14; 95% CI, 0.98-1.32). Conclusions High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583; isrctn.com. Identifier: ISRCTN83772183.
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  • Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population.
    Stroke (2021)
    Neumann JT, Riaz M, Bakshi A, Polekhina G, Thao LTP, Nelson MR, Woods RL, Abraham G, Inouye M, Reid CM, Tonkin AM, Williamson JD, Donnan GA, Brodtmann A, Cloud GC, McNeil JJ, Lacaze P. Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population. Stroke. 2021 Aug; 52(9):2882-2891.
    Abstract: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur.
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  • A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.
    Journal of general internal medicine (2021)
    Lockery JE, Broder JC, Ryan J, Stewart AC, Woods RL, Chong TT, Cloud GC, Murray A, Rigby JD, Shah R, Storey E, Ward SA, Wolfe R, Reid CM, Collyer TA, Ernst ME, ASPREE Investigator Group, ASPREE Investigator Group listed on www.aspree.org. A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults. J Gen Intern Med. 2021 Jun; 36(6):1629-1637.
    Abstract: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.
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  • Longitudinal changes over three years in sex steroid hormone levels in women aged 70 years and over.
    Clinical endocrinology (2021)
    Islam RM, Bell RJ, Handelsman DJ, Robinson PJ, Wolfe R, Davis SR, ASPREE Investigator Group. Longitudinal changes over three years in sex steroid hormone levels in women aged 70 years and over. Clin Endocrinol (Oxf). 2021 Mar; 94(3):443-448.
    Abstract: Sex steroid levels in women vary with increasing age from the age of 70 years (70+). Whether this reflects change within individuals with age or a survival advantage is not known. This study aimed to determine the stability of circulating sex steroids and SHBG over time in individual women aged 70+.
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The role of endogenous opioids in mindfulness-based chronic pain relief.
University of California San Diego
  • The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial.
    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2023)
    Khatib L, Dean JG, Oliva V, Riegner G, Gonzalez NE, Birenbaum J, Cruanes GF, Miller J, Patterson M, Kim HC, Chakravarthy K, Zeidan F. The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial. Neuropsychopharmacology. 2023 Nov 20; :.
    Abstract: Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.Trial Registration: ClinicalTrials.gov identifier: NCT04034004.
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Children's Growth and Behavior Study
The National Institutes of Health
  • Independent and Interactive Associations of Subjective and Objective Socioeconomic Status With Body Composition and Parent-Reported Hyperphagia Among Children.
    Childhood obesity (Print) (2023)
    Smith MR, Bittner JMP, Loch LK, Haynes HE, Bloomer BF, Te-Vazquez J, Bowling AI, Brady SM, Tanofsky-Kraff M, Chen KY, Yanovski JA, Cheon BK. Independent and Interactive Associations of Subjective and Objective Socioeconomic Status With Body Composition and Parent-Reported Hyperphagia Among Children. Child Obes. 2023 Nov 9; :.
    Abstract: Subjective socioeconomic status (SSES) and objective socioeconomic status (OSES) have been independently associated with body composition and eating behavior in children. While low OSES may constrain access to healthier foods, low SSES has been associated with increased preference for and motivation to consume higher energy foods and portions independent of OSES. Despite these distinct ways that OSES and SSES may affect children's eating behavior and adiposity, their joint contributions remain unclear. We investigated the independent and interactive associations of SSES and OSES with children's BMI, fat mass index (FMI), and caregiver-reported hyperphagia. Data were derived from the Children's Growth and Behavior Study, an ongoing observational study. Multiple linear regressions used child's SSES and OSES of the family as independent factors and modeled the statistical interaction of SSES and OSES with BMI ( = 128), FMI ( = 122), and hyperphagia and its subscales ( = 76) as dependent variables. SSES was independently and negatively associated with hyperphagia severity and OSES was independently and negatively associated with both FMI and hyperphagia severity. There was a statistical interaction effect of SSES and OSES on hyperphagia severity-lower SSES was associated with greater hyperphagia severity only at lower levels of OSES. These findings demonstrate a relationship between low OSES and child adiposity and that the relationship between child SSES and hyperphagia severity may be most relevant for children from households with lower family OSES. Future research on socioeconomic disparities in children's body composition and eating behaviors should examine the interaction of SSES and OSES. NCT02390765.
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  • Associations between weight-based teasing and disordered eating behaviors among youth.
    Eating behaviors (2021)
    Rubin AG, Schvey NA, Shank LM, Altman DR, Swanson TN, Ramirez E, Moore NA, Jaramillo M, Ramirez S, Davis EK, Broadney MM, LeMay-Russell S, Byrne ME, Parker MK, Brady SM, Kelly NR, Tanofsky-Kraff M, Yanovski JA. Associations between weight-based teasing and disordered eating behaviors among youth. Eat Behav. 2021 Apr; 41:101504.
    Abstract: Weight-based teasing (WBT) is commonly reported among youth and is associated with disinhibited and disordered eating. Specifically, youth who experience WBT may engage in disordered eating behaviors to cope with the resultant negative affect. Therefore, we examined associations between WBT and disordered eating behaviors among youth and assessed whether negative affect mediated these relationships. Two hundred one non-treatment seeking youth (8-17y) completed questionnaires assessing WBT, disinhibited eating, depression, and anxiety. Disordered eating and loss-of-control (LOC) eating were assessed via semi-structured interview. Analyses of covariance were conducted to examine relationships between WBT and eating-related variables, and bootstrapping mediation models were used to evaluate negative affect (a composite of depressive and anxiety symptoms) as a mediator of these associations. All models were adjusted for sex, race, age, and adiposity. Among 201 participants (13.1 ± 2.8y; 54.2% female; 30.3% Black; 32.8% with overweight/obesity), WBT was associated with emotional eating, eating in the absence of hunger, and disordered eating attitudes and behaviors (ps ≤ 0.02). These associations were all mediated by negative affect. WBT was also associated with a threefold greater likelihood of reporting a recent LOC eating episode (p = .049). Among boys and girls across weight strata, WBT was associated with multiple aspects of disordered eating and these relationships were mediated by negative affect. Longitudinal studies are needed to clarify the directionality of these associations and to identify subgroups of youth that may be particularly vulnerable to WBT and its sequelae.
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  • Weight-based teasing in youth: Associations with metabolic and inflammatory markers.
    Pediatric obesity (2021)
    Schvey NA, Shank LM, Tanofsky-Kraff M, Ramirez S, Altman DR, Swanson T, Rubin AG, Kelly NR, LeMay-Russell S, Byrne ME, Parker MN, Broadney MM, Brady SM, Yanovski SZ, Yanovski JA. Weight-based teasing in youth: Associations with metabolic and inflammatory markers. Pediatr Obes. 2021 Mar; 16(3):e12729.
    Abstract: Research among adults suggests that weight stigma is associated with worsened cardiometabolic health. However, these relationships have not been examined among youth.
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A Randomized, Multicountry, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Atrasentan on Renal Outcomes in Subjects With Type 2 Diabetes and Nephropathy SONAR: Study Of Diabetic Nephropathy With Atrasentan
University of Chicago Medical Center
  • Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression.
    Journal of the American Society of Nephrology : JASN (2023)
    Heerspink HJL, Jongs N, Schloemer P, Little DJ, Brinker M, Tasto C, Karpefors M, Wheeler DC, Bakris G, Perkovic V, Nkulikiyinka R, Rossert J, Gasparyan SB. Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression. J Am Soc Nephrol. 2023 Dec 1; 34(12):2025-2038.
    Abstract: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point.
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  • Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease.
    Cardiovascular diabetology (2023)
    Smeijer JD, Kohan DE, Rossing P, Correa-Rotter R, Liew A, Tang SCW, de Zeeuw D, Gansevoort RT, Ju W, Lambers Heerspink HJ. Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease. Cardiovasc Diabetol. 2023 Sep 16; 22(1):251.
    Abstract: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD.
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  • Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease.
    Kidney international (2023)
    Chan KW, Smeijer JD, Schechter M, Jongs N, Vart P, Kohan DE, Gansevoort RT, Liew A, Tang SCW, Wanner C, de Zeeuw D, Heerspink HJL. Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease. Kidney Int. 2023 Dec; 104(6):1219-1226.
    Abstract: Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.
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  • Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure.
    JACC. Heart failure (2022)
    Smeijer JD, Koomen J, Kohan DE, McMurray JJV, Bakris GL, Correa-Rotter R, Hou FF, Januzzi JL, Kitzman DW, Kolansky DM, Makino H, Perkovic V, Tobe S, Parving HH, de Zeeuw D, Heerspink HJL. Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure. JACC Heart Fail. 2022 Jul; 10(7):498-507.
    Abstract: The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.
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  • The Effect of Atrasentan on Kidney and Heart Failure Outcomes by Baseline Albuminuria and Kidney Function: A Post Hoc Analysis of the SONAR Randomized Trial.
    Clinical journal of the American Society of Nephrology : CJASN (2021)
    Waijer SW, Gansevoort RT, Bakris GL, Correa-Rotter R, Hou FF, Kohan DE, Kitzman DW, Makino H, McMurray JJV, Perkovic V, Tobe S, Parving HH, de Zeeuw D, Heerspink HJL. The Effect of Atrasentan on Kidney and Heart Failure Outcomes by Baseline Albuminuria and Kidney Function: A Post Hoc Analysis of the SONAR Randomized Trial. Clin J Am Soc Nephrol. 2021 Dec 1; :.
    Abstract: Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial.
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  • Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.
    Clinical pharmacology and therapeutics (2021)
    Koomen JV, Stevens J, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan DE, Makino H, McMurray JJV, Parving HH, Perkovic V, Tobe SW, de Zeeuw D, Heerspink HJL. Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease. Clin Pharmacol Ther. 2021 Jun; 109(6):1631-1638.
    Abstract: Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
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  • Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.
    Lancet (London, England) (2019)
    Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D, SONAR Committees and Investigators.. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019 May 11; 393(10184):1937-1947.
    Abstract: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.
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National Institute of Health (NIH) - 03496883 (FASTEST), rFVIIa for Acute hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial (Pro00041014)
OhioHealth Corporation
  • Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage.
    The Cochrane database of systematic reviews (2023)
    Eilertsen H, Menon CS, Law ZK, Chen C, Bath PM, Steiner T, Desborough MJ, Sandset EC, Sprigg N, Al-Shahi Salman R. Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Oct 23; 10(10):CD005951.
    Abstract: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018.
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  • Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial.
    International journal of stroke : official journal of the International Stroke Society (2022)
    Naidech AM, Grotta J, Elm J, Janis S, Dowlatshahi D, Toyoda K, Steiner T, Mayer SA, Khanolkar P, Denlinger J, Audebert HJ, Molina C, Khatri P, Sprigg N, Vagal A, Broderick JP. Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial. Int J Stroke. 2022 Aug; 17(7):806-809.
    Abstract: Intracerebral hemorrhage is the deadliest form of stroke. Hematoma expansion, growth of the hematoma between the baseline computed tomography scan and a follow-up computed tomography scan at 24 ± 6 h, predicts long-term disability or death. Recombinant factor VIIa (rFVIIa) has reduced hematoma expansion in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on hematoma expansion and potential benefit when administered within 2 h of symptom onset.
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National Institute of Health (NIH) - 03496883 (FASTEST), rFVIIa for Acute hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial (Pro00041014)
Massachusetts General Hospital
  • Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage.
    The Cochrane database of systematic reviews (2023)
    Eilertsen H, Menon CS, Law ZK, Chen C, Bath PM, Steiner T, Desborough MJ, Sandset EC, Sprigg N, Al-Shahi Salman R. Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Oct 23; 10(10):CD005951.
    Abstract: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018.
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  • Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial.
    International journal of stroke : official journal of the International Stroke Society (2022)
    Naidech AM, Grotta J, Elm J, Janis S, Dowlatshahi D, Toyoda K, Steiner T, Mayer SA, Khanolkar P, Denlinger J, Audebert HJ, Molina C, Khatri P, Sprigg N, Vagal A, Broderick JP. Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial. Int J Stroke. 2022 Aug; 17(7):806-809.
    Abstract: Intracerebral hemorrhage is the deadliest form of stroke. Hematoma expansion, growth of the hematoma between the baseline computed tomography scan and a follow-up computed tomography scan at 24 ± 6 h, predicts long-term disability or death. Recombinant factor VIIa (rFVIIa) has reduced hematoma expansion in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on hematoma expansion and potential benefit when administered within 2 h of symptom onset.
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Promoting Transportation Safety in Adolescence
University of Pennsylvania
  • Promoting transportation safety in adolescence: the drivingly randomized controlled trial.
    BMC public health (2023)
    Hafetz J, McDonald CC, Long DL, Ford CA, Mdluli T, Weiss A, Felkins J, Wilson N, MacDonald B. Promoting transportation safety in adolescence: the drivingly randomized controlled trial. BMC Public Health. 2023 Oct 17; 23(1):2020.
    Abstract: The impact of young drivers' motor vehicle crashes (MVC) is substantial, with young drivers constituting only 14% of the US population, but contributing to 30% of all fatal and nonfatal injuries due to MVCs and 35% ($25 billion) of the all medical and lost productivity costs. The current best-practice policy approach, Graduated Driver Licensing (GDL) programs, are effective primarily by delaying licensure and restricting crash opportunity. There is a critical need for interventions that target families to complement GDL. Consequently, we will determine if a comprehensive parent-teen intervention, the Drivingly Program, reduces teens' risk for a police-reported MVC in the first 12 months of licensure. Drivingly is based on strong preliminary data and targets multiple risk and protective factors by delivering intervention content to teens, and their parents, at the learner and early independent licensing phases.
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Imaging Lymphatic Function for a Differential Diagnosis of Lipedema and Obesity
Vanderbilt University Medical Center
  • National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States.
    Vascular medicine (London, England) (2023)
    Aday AW, Donahue PM, Garza M, Crain VN, Patel NJ, Beasley JA, Herbst KL, Beckman JA, Taylor SL, Pridmore M, Chen SC, Donahue MJ, Crescenzi R. National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States. Vasc Med. 2023 Oct 16; :1358863X231202769.
    Abstract: National survey data exploring the patient experience with lipedema are lacking.
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  • Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions.
    Lymphatic research and biology (2021)
    Donahue PMC, Crescenzi R, Petersen KJ, Garza M, Patel N, Lee C, Chen SC, Donahue MJ. Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions. Lymphat Res Biol. 2021 Nov 8; :.
    Abstract: Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema. Participants with Stage 1-2 lipedema and early Stage 0-1 lymphedema ( = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0-10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's for pain VAS = -2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's for skin sodium = -1.2 and SAT sodium = -0.9). This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.
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  • Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema.
    Breast cancer research and treatment (2022)
    Crescenzi R, Donahue PMC, Garza M, Lee CA, Patel NJ, Gonzalez V, Jones RS, Donahue MJ. Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema. Breast Cancer Res Treat. 2022 Jan; 191(1):115-124.
    Abstract: Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL.
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A Phase 2, Randomized, Double-blind, Placebo-controlled Study of VX-765 in Subjects With Treatment-resistant Partial Epilepsy
Johns Hopkins University
  • Immunomodulatory interventions for focal epilepsy.
    The Cochrane database of systematic reviews (2023)
    Panebianco M, Walker L, Marson AG. Immunomodulatory interventions for focal epilepsy. Cochrane Database Syst Rev. 2023 Oct 16; 10(10):CD009945.
    Abstract: This is an updated version of an original Cochrane Review published in 2013 (Walker 2013). Epilepsy is a common neurological disorder affecting 0.5% to 1% of the population. Pharmacological treatment remains the first choice to control epilepsy. However, up to 30% of people do not respond to drug treatment, and therefore do not achieve seizure remission. Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy.
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The Endocrine, Metabolic and Microbiome Influence on the Post-COVID Syndrome
University of Texas Medical Branch
  • Low growth hormone secretion associated with post-acute sequelae SARS-CoV-2 infection (PASC) neurologic symptoms: A case-control pilot study.
    Molecular and cellular endocrinology (2024)
    Wright TJ, Pyles RB, Sheffield-Moore M, Deer RR, Randolph KM, McGovern KA, Danesi CP, Gilkison CR, Ward WW, Vargas JA, Armstrong PA, Lindsay SE, Zaidan MF, Seashore J, Wexler TL, Masel BE, Urban RJ. Low growth hormone secretion associated with post-acute sequelae SARS-CoV-2 infection (PASC) neurologic symptoms: A case-control pilot study. Mol Cell Endocrinol. 2024 Jan 1; 579:112071.
    Abstract: To determine if patients that develop lingering neurologic symptoms of fatigue and "brain fog" after initial recovery from coronavirus disease 2019 (COVID-19) have persistent low growth hormone (GH) secretion as seen in other conditions with similar symptom etiology.
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An Open-label (Part One) and a Randomized, Double-blind, Placebo-Controlled (Part Two) Study of the Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Pediatric Patients With Autism
The Ohio State University
  • Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD).
    The Cochrane database of systematic reviews (2023)
    Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2023 Oct 9; 10:CD011769.
    Abstract: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs).
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  • Memantine for autism spectrum disorder.
    The Cochrane database of systematic reviews (2022)
    Brignell A, Marraffa C, Williams K, May T. Memantine for autism spectrum disorder. Cochrane Database Syst Rev. 2022 Aug 25; 8(8):CD013845.
    Abstract: Autism spectrum disorder (ASD; also known as autism) is a developmental disability that begins in childhood and is typically seen in around 1% to 2% of children. It is characterised by social communication difficulties and repetitive and restricted behaviours and routines that can have a negative impact on a child's quality of life, achievement at school, and social interactions with others. It has been hypothesised that memantine, which is traditionally used to treat dementia, may be effective in reducing the core symptoms of autism as well as some co-occurring symptoms such as hyperactivity and language difficulties. If memantine is being used to treat the core symptoms of autism, it is important to review the evidence of its effectiveness.
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Atomoxetine, Placebo, and Parent Training in Autism
The Ohio State University
  • Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD).
    The Cochrane database of systematic reviews (2023)
    Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2023 Oct 9; 10:CD011769.
    Abstract: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs).
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  • A 1.5-Year Follow-Up of Parent Training and Atomoxetine for Attention-Deficit/Hyperactivity Disorder Symptoms and Noncompliant/Disruptive Behavior in Autism.
    Journal of child and adolescent psychopharmacology (2018)
    Arnold LE, Ober N, Aman MG, Handen B, Smith T, Pan X, Hyman SL, Hollway J, Lecavalier L, Page K, Rice R Jr. A 1.5-Year Follow-Up of Parent Training and Atomoxetine for Attention-Deficit/Hyperactivity Disorder Symptoms and Noncompliant/Disruptive Behavior in Autism. J Child Adolesc Psychopharmacol. 2018 Jun; 28(5):322-330.
    Abstract: To examine status of children with autism spectrum disorder (ASD) 10 months after a 34-week clinical trial of atomoxetine (ATX) and parent training (PT).
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  • Parent Stress in a Randomized Clinical Trial of Atomoxetine and Parent Training for Children with Autism Spectrum Disorder.
    Journal of autism and developmental disorders (2018)
    Lecavalier L, Pan X, Smith T, Handen BL, Arnold LE, Silverman L, Tumuluru RV, Hollway J, Aman MG. Parent Stress in a Randomized Clinical Trial of Atomoxetine and Parent Training for Children with Autism Spectrum Disorder. J Autism Dev Disord. 2018 Apr; 48(4):980-987.
    Abstract: We previously reported a 2 × 2 randomized clinical trial of atomoxetine (ATX) and parent training (PT) for attention deficit hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 children with autism spectrum disorder, ages 5-14 years. Children were randomized to one of four conditions: ATX alone, placebo alone, ATX + PT, or PT + placebo. Both ATX and PT improved some indices of ADHD and behavioral compliance. In this report, we describe parent stress over time and across conditions. All four treatments improved parent self-rated stress from baseline to week 10. However, there were no statistically significant differences between treatment groups. Significantly more improvement in parent stress scores was observed for clinical responders than non-responders. ClinicalTrials.gov Title: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) ClinicalTrials.gov Identifier: NCT00844753.
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  • Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study.
    Journal of the American Academy of Child and Adolescent Psychiatry (2016)
    Smith T, Aman MG, Arnold LE, Silverman LB, Lecavalier L, Hollway J, Tumuluru R, Hyman SL, Buchan-Page KA, Hellings J, Rice RR Jr, Brown NV, Pan X, Handen BL. Atomoxetine and Parent Training for Children With Autism and Attention-Deficit/Hyperactivity Disorder: A 24-Week Extension Study. J Am Acad Child Adolesc Psychiatry. 2016 Oct; 55(10):868-876.e2.
    Abstract: The authors previously reported on a 2-by-2 randomized clinical trial of individual and combined treatment with atomoxetine (ATX) and parent training (PT) for attention-deficit/hyperactivity disorder (ADHD) symptoms and behavioral noncompliance in 128 5- to 14-year-old children with autism spectrum disorder. In the present report, they describe a 24-week extension of treatment responders and nonresponders.
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  • Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.
    Journal of the American Academy of Child and Adolescent Psychiatry (2015)
    Handen BL, Aman MG, Arnold LE, Hyman SL, Tumuluru RV, Lecavalier L, Corbett-Dick P, Pan X, Hollway JA, Buchan-Page KA, Silverman LB, Brown NV, Rice RR Jr, Hellings J, Mruzek DW, McAuliffe-Bellin S, Hurt EA, Ryan MM, Levato L, Smith T. Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2015 Nov; 54(11):905-15.
    Abstract: Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance.
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Diagnostics, Imaging And Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project
Boston University
  • Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project.
    Alzheimer's research & therapy (2023)
    Stern RA, Trujillo-Rodriguez D, Tripodis Y, Pulukuri SV, Alosco ML, Adler CH, Balcer LJ, Bernick C, Baucom Z, Marek KL, McClean MD, Johnson KA, McKee AC, Stein TD, Mez J, Palmisano JN, Cummings JL, Shenton ME, Reiman EM, DIAGNOSE CTE Research Project Inve. Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project. Alzheimers Res Ther. 2023 Oct 5; 15(1):166.
    Abstract: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.
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  • Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project.
    Alzheimer's research & therapy (2021)
    Alosco ML, Mariani ML, Adler CH, Balcer LJ, Bernick C, Au R, Banks SJ, Barr WB, Bouix S, Cantu RC, Coleman MJ, Dodick DW, Farrer LA, Geda YE, Katz DI, Koerte IK, Kowall NW, Lin AP, Marcus DS, Marek KL, McClean MD, McKee AC, Mez J, Palmisano JN, Peskind ER. Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project. Alzheimers Res Ther. 2021 Aug 12; 13(1):136.
    Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project.
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Determinants of alpha-aminoadipic acid (2-AAA) and relationship to diabetes: Study 1
Vanderbilt University Medical Center
  • Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals.
    Frontiers in endocrinology (2023)
    Desine S, Gabriel CL, Smith HM, Antonetti OR, Wang C, Calcutt MW, Doran AC, Silver HJ, Nair S, Terry JG, Carr JJ, Linton MF, Brown JD, Koethe JR, Ferguson JF. Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals. Front Endocrinol (Lausanne). 2023; 14:1122391.
    Abstract: Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease.
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Developing and Testing the Opioid Rapid Response System
Indiana University
  • Developing the Opioid Rapid Response System™ for Lay Citizen Response to the Opioid Overdose Crisis: a Randomized Controlled Trial.
    Prevention science : the official journal of the Society for Prevention Research (2023)
    Hecht ML, Jayawardene W, Henderson C, Pezalla A, Flood-Grady E, Krieger JL, Frederick A, Parker M, Ables E. Developing the Opioid Rapid Response System™ for Lay Citizen Response to the Opioid Overdose Crisis: a Randomized Controlled Trial. Prev Sci. 2023 Oct; 24(7):1386-1397.
    Abstract: Emergency responders face challenges in arriving timely to administer naloxone in opioid overdoses. Therefore, interest in having lay citizens administer naloxone nasal spray has emerged. These citizens, however, must be recruited and trained, and be in proximity to the overdose. This study aimed to develop the Opioid Rapid Response System (ORRS) to meet this need by developing a system to recruit and train citizen responders and evaluate outcomes in a randomized clinical trial. ORRS recruitment messages and training platform were developed iteratively and then outcomes for each were evaluated in a randomized, unblinded two-arm waitlist-controlled trial. ORRS was field tested in 5 Indiana counties, recruiting adult citizen responders (age 18 or older) who did not self-identity as a certified first responder. Participants were recruited using either personal or communal messages and then randomly assigned to online naloxone training and waitlisted-control conditions. Pre- and post-surveys were administered online to measure the exposure to recruitment messages and training effects on knowledge of opioid overdose, confidence responding, concerns about responding, and intent to respond. Of the 220 randomized participants (114 training, 106 waitlisted-control), 140 were analyzed (59 training, 81 waitlisted-control). Recruited participants more frequently identified with communal appeal than with the personal appeal (chi-square = 53.5; p < 0.0001). Between-group differences for intervention effects were significant for knowledge of overdose signs (Cohen's d = 1.17), knowledge of overdose management (d = 1.72), self-efficacy (d = 1.39), and concerns (d = 1.31), but not for intent (d = 0.17), which suffered from a ceiling effect. ORRS provides stronger support for efficacy than that reported for other training interventions and the digital modality eases rapid dissemination.Trial Registration: NCT04589676.
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  • Development of opioid rapid response system: Protocol for a randomized controlled trial.
    Contemporary clinical trials (2022)
    Jayawardene W, Pezalla A, Henderson C, Hecht M. Development of opioid rapid response system: Protocol for a randomized controlled trial. Contemp Clin Trials. 2022 Apr; 115:106727.
    Abstract: Opioid overdoses require a rapid response, but emergency responders are limited in how quickly they can arrive at the scene for administering naloxone. If laypersons are trained to administer naloxone and are notified of overdoses, more lives can be saved.
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HATIM
Vanderbilt University Medical Center
  • Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.
    Frontiers in immunology (2023)
    Bailin SS, Kropski JA, Gangula RD, Hannah L, Simmons JD, Mashayekhi M, Ye F, Fan R, Mallal S, Warren CM, Kalams SA, Gabriel CL, Wanjalla CN, Koethe JR. Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV. Front Immunol. 2023; 14:1152003.
    Abstract: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population.
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  • Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV.
    Hepatology communications (2021)
    Gabriel CL, Ye F, Fan R, Nair S, Terry JG, Carr JJ, Silver H, Baker P, Hannah L, Wanjalla C, Mashayekhi M, Bailin S, Lima M, Woodward B, Izzy M, Ferguson JF, Koethe JR. Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV. Hepatol Commun. 2021 Jul; 5(7):1224-1237.
    Abstract: Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus-negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long-term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m, and CD4 count of 492 cells/mm. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl-CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low-density lipoprotein. Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene-expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways.
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Inflammatory Characterization of Known or Possible Cardiovascular Diseases
The National Institutes of Health
  • Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects.
    Cell reports. Medicine (2023)
    Han K, Singh K, Meadows AM, Sharma R, Hassanzadeh S, Wu J, Goss-Holmes H, Huffstutler RD, Teague HL, Mehta NN, Griffin JL, Tian R, Traba J, Sack MN. Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects. Cell Rep Med. 2023 Sep 19; 4(9):101157.
    Abstract: To evaluate whether nicotinamide adenine dinucleotide-positive (NAD) boosting modulates adaptive immunity, primary CD4 T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4 T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD boosting in CD4 T cell-linked inflammation.
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WalkIT: Neighborhood Walkability and Moderation of Adaptive Walking Interventions
Arizona State University
  • The moderating impact of neighborhood walkability on mHealth interventions to increase moderate to vigorous physical activity for insufficiently active adults in a randomized trial.
    The international journal of behavioral nutrition and physical activity (2023)
    McEntee ML, Hurley JC, Phillips CB, Hooker SP, Todd M, Frank LD, Adams MA. The moderating impact of neighborhood walkability on mHealth interventions to increase moderate to vigorous physical activity for insufficiently active adults in a randomized trial. Int J Behav Nutr Phys Act. 2023 Aug 15; 20(1):97.
    Abstract: Ecological models suggest that interventions targeting specific behaviors are most effective when supported by the environment. This study prospectively examined the interactions between neighborhood walkability and an mHealth intervention in a large-scale, adequately powered trial to increase moderate-to-vigorous physical activity (MVPA).
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  • Adaptive Goals and Reinforcement Timing to Increase Physical Activity in Adults: A Factorial Randomized Trial.
    American journal of preventive medicine (2022)
    Adams MA, Todd M, Angadi SS, Hurley JC, Stecher C, Berardi V, Phillips CB, McEntee ML, Hovell MF, Hooker SP. Adaptive Goals and Reinforcement Timing to Increase Physical Activity in Adults: A Factorial Randomized Trial. Am J Prev Med. 2022 Feb; 62(2):e57-e68.
    Abstract: Potent lifestyle interventions to increase moderate-to-vigorous physical activity are urgently needed for population-level chronic disease prevention. This trial tested the independent and joint effects of a mobile health system automating adaptive goal setting and immediate financial reinforcement for increasing daily walking among insufficiently active adults.
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  • Effects of Goal Type and Reinforcement Type on Self-Reported Domain-Specific Walking Among Inactive Adults: 2×2 Factorial Randomized Controlled Trial.
    JMIR formative research (2020)
    McEntee ML, Cantley A, Foreman E, Berardi V, Phillips CB, Hurley JC, Hovell MF, Hooker S, Adams MA. Effects of Goal Type and Reinforcement Type on Self-Reported Domain-Specific Walking Among Inactive Adults: 2×2 Factorial Randomized Controlled Trial. JMIR Form Res. 2020 Dec 4; 4(12):e19863.
    Abstract: WalkIT Arizona was a 2×2 factorial trial examining the effects of goal type (adaptive versus static) and reinforcement type (immediate versus delayed) to increase moderate to vigorous physical activity (MVPA) among insufficiently active adults. The 12-month intervention combined mobile health (mHealth) technology with behavioral strategies to test scalable population-health approaches to increasing MVPA. Self-reported physical activity provided domain-specific information to help contextualize the intervention effects.
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Phase 1 Study of the Safety and Immunogenicity of Pfs230D1M-EPA/Alhydrogel® and Pfs25M-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum Malaria, in Adults in the US and Mali
The National Institutes of Health
  • Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial.
    The Lancet. Infectious diseases (2023)
    Sagara I, Healy SA, Assadou MH, Kone M, Swihart BJ, Kwan JL, Fintzi J, Sissoko K, Kamate B, Samake Y, Guindo MA, Doucoure M, Niaré K, Dolo A, Diarra B, Rausch KM, Narum DL, Jones DS, MacDonald NJ, Zhu D, Gorres JP, Imeru A, Mohan R, Thera I, Zaidi I, Sal. Malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults; a phase 1, randomised, controlled trial. Lancet Infect Dis. 2023 Nov; 23(11):1266-1279.
    Abstract: Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians.
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  • Immunological characterization of a VIR protein family member (VIR-14) in Plasmodium vivax-infected subjects from different epidemiological regions in Africa and South America.
    PLoS neglected tropical diseases (2023)
    Fantin RF, Coelho CH, Berhe AD, Magalhães LMD, Pereira DB, Salinas ND, Tolia NH, Amaratunga C, Suon S, Sagara I, Narum DL, Fujiwara RT, Abejon C, Campos-Neto A, Duffy PE, Bueno LL. Immunological characterization of a VIR protein family member (VIR-14) in Plasmodium vivax-infected subjects from different epidemiological regions in Africa and South America. PLoS Negl Trop Dis. 2023 Apr 7; 17(4):e0011229.
    Abstract: Plasmodium vivax is a major challenge for malaria control due to its wide geographic distribution, high frequency of submicroscopic infections, and ability to induce relapses due to the latent forms present in the liver (hypnozoites). Deepening our knowledge of parasite biology and its molecular components is key to develop new tools for malaria control and elimination. This study aims to investigate and characterize a P. vivax protein (PvVir14) for its role in parasite biology and its interactions with the immune system. We collected sera or plasma from P.vivax-infected subjects in Brazil (n = 121) and Cambodia (n = 55), and from P. falciparum-infected subjects in Mali (n = 28), to assess antibody recognition of PvVir14. Circulating antibodies against PvVir14 appeared in 61% and 34.5% of subjects from Brazil and Cambodia, respectively, versus none (0%) of the P. falciparum-infected subjects from Mali who have no exposure to P. vivax. IgG1 and IgG3 most frequently contributed to anti-PvVir14 responses. PvVir14 antibody levels correlated with those against other well-characterized sporozoite/liver (PvCSP) and blood stage (PvDBP-RII) antigens, which were recognized by 7.6% and 42% of Brazilians, respectively. Concerning the cellular immune profiling of Brazilian subjects, PvVir14 seroreactive individuals displayed significantly higher levels of circulating atypical (CD21- CD27-) B cells, raising the possibility that atypical B cells may be contribute to the PvVir14 antibody response. When analyzed at a single-cell level, the B cell receptor gene hIGHV3-23 was only seen in subjects with active P.vivax infection where it comprised 20% of V gene usage. Among T cells, CD4+ and CD8+ levels differed (lower and higher, respectively) between subjects with versus without antibodies to PvVir14, while NKT cell levels were higher in those without antibodies. Specific B cell subsets, anti-PvVir14 circulating antibodies, and NKT cell levels declined after treatment of P. vivax. This study provides the immunological characterization of PvVir14, a unique P. vivax protein, and possible association with acute host's immune responses, providing new information of specific host-parasite interaction. Trial registration: TrialClinicalTrials.gov Identifier: NCT00663546 & ClinicalTrials.gov NCT02334462.
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  • Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice.
    The Journal of clinical investigation (2021)
    Healy SA, Anderson C, Swihart BJ, Mwakingwe A, Gabriel EE, Decederfelt H, Hobbs CV, Rausch KM, Zhu D, Muratova O, Herrera R, Scaria PV, MacDonald NJ, Lambert LE, Zaidi I, Coelho CH, Renn JP, Wu Y, Narum DL, Duffy PE. Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice. J Clin Invest. 2021 Apr 1; 131(7):.
    Abstract: BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
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  • "Spatial heterogeneity of environmental risk in randomized prevention trials: consequences and modeling".
    BMC medical research methodology (2019)
    Guindo A, Sagara I, Ouedraogo B, Sallah K, Assadou MH, Healy S, Duffy P, Doumbo OK, Dicko A, Giorgi R, Gaudart J. "Spatial heterogeneity of environmental risk in randomized prevention trials: consequences and modeling". BMC Med Res Methodol. 2019 Jul 15; 19(1):149.
    Abstract: In the context of environmentally influenced communicable diseases, proximity to environmental sources results in spatial heterogeneity of risk, which is sometimes difficult to measure in the field. Most prevention trials use randomization to achieve comparability between groups, thus failing to account for heterogeneity. This study aimed to determine under what conditions spatial heterogeneity biases the results of randomized prevention trials, and to compare different approaches to modeling this heterogeneity.
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Feasibility of the First Known Adaptive Intervention Delivering Innovative Exercise Program Optimized for People with SCI
The University of Alabama at Birmingham
  • Increasing Physical Activity in Persons With Spinal Cord Injury With an eHealth-Based Adaptive Exercise Intervention: Protocol for a Sequential Multiple Assignment Randomized Trial.
    JMIR research protocols (2023)
    Wilroy J, Kim Y, Lai B, Young HJ, Giannone J, Powell D, Thirumalai M, Mehta T, Rimmer J. Increasing Physical Activity in Persons With Spinal Cord Injury With an eHealth-Based Adaptive Exercise Intervention: Protocol for a Sequential Multiple Assignment Randomized Trial. JMIR Res Protoc. 2023 Jul 27; 12:e47665.
    Abstract: Participating in an adequate amount of physical activity to acquire health benefits is challenging for people with spinal cord injury (SCI) due to personal and logistic barriers. Barriers in the built and social environments may include lack of transportation, lack of accessible facilities or programs, and lack of training among fitness personnel. Low self-efficacy, lack of self-regulation skills, and improper outcome expectations are examples of personal barriers. Current approaches to investigating physical activity programs in people with SCI have been limited to traditional "one-size-fits-all" design, which has yielded low adherence rates, high dropout rates, and participants not maintaining physical activity levels at follow-up.
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Metformin to Prevent Inactivity-Induced Loss of Muscle Health During Aging
University of Utah
  • Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.
    Aging cell (2023)
    Petrocelli JJ, McKenzie AI, de Hart NMMP, Reidy PT, Mahmassani ZS, Keeble AR, Kaput KL, Wahl MP, Rondina MT, Marcus RL, Welt CK, Holland WL, Funai K, Fry CS, Drummond MJ. Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment. Aging Cell. 2023 Nov; 22(11):e13936.
    Abstract: Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.
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  • Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail.
    Aging (2023)
    Petrocelli JJ, de Hart NMMP, Lang MJ, Yee EM, Ferrara PJ, Fix DK, Chaix A, Funai K, Drummond MJ. Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail. Aging (Albany NY). 2023 Mar 20; 15(6):1808-1832.
    Abstract: Aging coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence-associated secretory phenotype, but the relationship of senescent cells to muscle atrophy is unclear. Previously, we found that a metformin + leucine (MET+LEU) treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the study's purpose was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during atrophy. Additionally, aged mouse single myofibers and older human donor primary myoblasts were individually isolated to determine the translational potential of MET+LEU on muscle cells. MET+LEU (25 + 125 μM) treatment increased myotube differentiation and prevented myotube atrophy. Low concentration (0.1 + 0.5 μM) MET+LEU had unique effects to prevent muscle atrophy and increase transcripts related to protein synthesis and decrease transcripts related to protein breakdown. Myotube atrophy resulted in dysregulated proteostasis that was reversed with MET+LEU and individually with proteasome inhibition (MG-132). Inflammatory and cellular senescence transcriptional pathways and respective transcripts were increased following myotube atrophy yet reversed with MET+LEU treatment. Dasatinib + quercetin (D+Q) senolytic prevented myotube atrophy similar to MET+LEU. Finally, MET+LEU prevented loss in myotube size in alternate models of muscle atrophy as well as in aged myofibers while, in human primary myotubes, MET+LEU prevented reductions in myonuclei fusion. These data support that MET+LEU has skeletal muscle cell-autonomous properties to prevent atrophy by reversing senescence and improving proteostasis.
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  • Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial.
    Experimental gerontology (2022)
    McKenzie AI, Mahmassani ZS, Petrocelli JJ, de Hart NMMP, Fix DK, Ferrara PJ, LaStayo PC, Marcus RL, Rondina MT, Summers SA, Johnson JM, Trinity JD, Funai K, Drummond MJ. Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial. Exp Gerontol. 2022 Jun 15; 163:111804.
    Abstract: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults.
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Imaging genetics of spasmodic dysphonia
Mount Sinai School of Medicine
  • Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.
    Movement disorders : official journal of the Movement Disorder Society (2023)
    O'Flynn LC, Frucht SJ, Simonyan K. Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study. Mov Disord. 2023 Oct; 38(10):1936-1944.
    Abstract: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities.
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  • A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity.
    Scientific reports (2018)
    Simonyan K, Frucht SJ, Blitzer A, Sichani AH, Rumbach AF. A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity. Sci Rep. 2018 Oct 31; 8(1):16111.
    Abstract: Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.
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  • Alcohol responsiveness in laryngeal dystonia: a survey study.
    Journal of neurology (2015)
    Kirke DN, Frucht SJ, Simonyan K. Alcohol responsiveness in laryngeal dystonia: a survey study. J Neurol. 2015 Jun; 262(6):1548-56.
    Abstract: Laryngeal dystonia (LD) is a task-specific focal dystonia of unknown pathophysiology affecting speech production. We examined the demographics of anecdotally reported alcohol use and its effects on LD symptoms using an online survey based on Research Electronic Data Capture (REDCap™) and National Spasmodic Dysphonia Association's patient registry. From 641 participants, 531 were selected for data analysis, and 110 were excluded because of unconfirmed diagnosis. A total of 406 patients (76.5 %) had LD and 125 (23.5 %) had LD and voice tremor (LD/VT). The consumption of alcohol was reported by 374 LD (92.1 %) and 109 LD/VT (87.2 %) patients. Improvement of voice symptoms after alcohol ingestion was noted by 227 LD (55.9 % of all patients) and 73 LD/VT (58.4 %), which paralleled the improvement observed by patient's family and/or friends in 214 LD (57.2 %) and 69 LD/VT (63.3 %) patients. The benefits lasted 1-3 h in both groups with the maximum effect after 2 drinks in LD patients (p = 0.002), whereas LD/VT symptoms improved independent of the consumed amount (p = 0.48). Our data suggest that isolated dystonic symptoms, such as in LD, are responsive to alcohol intake and this responsiveness is not attributed to the presence of VT, which is known to have significant benefits from alcohol ingestion. Alcohol may modulate the pathophysiological mechanisms underlying abnormal neurotransmission of γ-aminobutyric acid (GABA) in dystonia and as such provide new avenues for novel therapeutic options in these patients.
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Connectivity Affecting the Antidepressant REsponse (The CAARE study)
Vanderbilt University Medical Center
  • Cognitive, Disability, and Treatment Outcome Implications of Symptom-Based Phenotyping in Late-Life Depression.
    The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (2023)
    Sudol K, Conway C, Szymkowicz SM, Elson D, Kang H, Taylor WD. Cognitive, Disability, and Treatment Outcome Implications of Symptom-Based Phenotyping in Late-Life Depression. Am J Geriatr Psychiatry. 2023 Nov; 31(11):919-931.
    Abstract: Late-life depression is associated with substantial heterogeneity in clinical presentation, disability, and response to antidepressant treatment. We examined whether self-report of severity of common symptoms, including anhedonia, apathy, rumination, worry, insomnia, and fatigue were associated with differences in presentation and response to treatment. We also examined whether these symptoms improved during treatment with escitalopram.
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  • Influences of resting-state intrinsic functional brain connectivity on the antidepressant treatment response in late-life depression.
    Psychological medicine (2023)
    Ahmed R, Boyd BD, Elson D, Albert K, Begnoche P, Kang H, Landman BA, Szymkowicz SM, Andrews P, Vega J, Taylor WD. Influences of resting-state intrinsic functional brain connectivity on the antidepressant treatment response in late-life depression. Psychol Med. 2023 Oct; 53(13):6261-6270.
    Abstract: Late-life depression (LLD) is characterized by differences in resting state functional connectivity within and between intrinsic functional networks. This study examined whether clinical improvement to antidepressant medications is associated with pre-randomization functional connectivity in intrinsic brain networks.
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  • Cognitive phenotypes in late-life depression.
    International psychogeriatrics (2022)
    Szymkowicz SM, Ryan C, Elson DM, Kang H, Taylor WD. Cognitive phenotypes in late-life depression. Int Psychogeriatr. 2022 Jun 29; :1-13.
    Abstract: To identify cognitive phenotypes in late-life depression (LLD) and describe relationships with sociodemographic and clinical characteristics.
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  • Preliminary Evidence That Cortical Amyloid Burden Predicts Poor Response to Antidepressant Medication Treatment in Cognitively Intact Individuals With Late-Life Depression.
    The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (2021)
    Taylor WD, Boyd BD, Elson D, Andrews P, Albert K, Vega J, Newhouse PA, Woodward ND, Kang H, Shokouhi S. Preliminary Evidence That Cortical Amyloid Burden Predicts Poor Response to Antidepressant Medication Treatment in Cognitively Intact Individuals With Late-Life Depression. Am J Geriatr Psychiatry. 2021 May; 29(5):448-457.
    Abstract: Amyloid accumulation, the pathological hallmark of Alzheimer's disease, may predispose some older adults to depression and cognitive decline. Deposition of amyloid also occurs prior to the development of cognitive decline. It is unclear whether amyloid influences antidepressant outcomes in cognitively intact depressed elders.
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  • Accelerated brain aging predicts impaired cognitive performance and greater disability in geriatric but not midlife adult depression.
    Translational psychiatry (2020)
    Christman S, Bermudez C, Hao L, Landman BA, Boyd B, Albert K, Woodward N, Shokouhi S, Vega J, Andrews P, Taylor WD. Accelerated brain aging predicts impaired cognitive performance and greater disability in geriatric but not midlife adult depression. Transl Psychiatry. 2020 Sep 18; 10(1):317.
    Abstract: Depression is associated with markers of accelerated aging, but it is unclear how this relationship changes across the lifespan. We examined whether a brain-based measure of accelerated aging differed between depressed and never-depressed subjects across the adult lifespan and whether it was related to cognitive performance and disability. We applied a machine-learning approach that estimated brain age from structural MRI data in two depressed cohorts, respectively 170 midlife adults and 154 older adults enrolled in studies with common entry criteria. Both cohorts completed broad cognitive batteries and the older subgroup completed a disability assessment. The machine-learning model estimated brain age from MRI data, which was compared to chronological age to determine the brain-age gap (BAG; estimated age-chronological age). BAG did not differ between midlife depressed and nondepressed adults. Older depressed adults exhibited significantly higher BAG than nondepressed elders (Wald χ = 8.84, p = 0.0029), indicating a higher estimated brain age than chronological age. BAG was not associated with midlife cognitive performance. In the older cohort, higher BAG was associated with poorer episodic memory performance (Wald χ = 4.10, p = 0.0430) and, in the older depressed group alone, slower processing speed (Wald χ = 4.43, p = 0.0354). We also observed a statistical interaction where greater depressive symptom severity in context of higher BAG was associated with poorer executive function (Wald χ = 5.89, p = 0.0152) and working memory performance (Wald χ = 4.47, p = 0.0346). Increased BAG was associated with greater disability (Wald χ = 6.00, p = 0.0143). Unlike midlife depression, geriatric depression exhibits accelerated brain aging, which in turn is associated with cognitive and functional deficits.
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  • Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression.
    Biological psychiatry. Cognitive neuroscience and neuroimaging (2019)
    Gandelman JA, Albert K, Boyd BD, Park JW, Riddle M, Woodward ND, Kang H, Landman BA, Taylor WD. Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Feb; 4(2):160-170.
    Abstract: Late-life depression (LLD) has been associated with alterations in intrinsic functional networks, best characterized in the default mode network (DMN), cognitive control network (CCN), and salience network. However, these findings often derive from small samples, and it is not well understood how network findings relate to clinical and cognitive symptomatology.
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  • Medial temporal lobe volumes in late-life depression: effects of age and vascular risk factors.
    Brain imaging and behavior (2020)
    Taylor WD, Deng Y, Boyd BD, Donahue MJ, Albert K, McHugo M, Gandelman JA, Landman BA. Medial temporal lobe volumes in late-life depression: effects of age and vascular risk factors. Brain Imaging Behav. 2020 Feb; 14(1):19-29.
    Abstract: Substantial work associates late-life depression with hippocampal pathology. However, there is less information about differences in hippocampal subfields and other connected temporal lobe regions and how these regions may be influenced by vascular factors. Individuals aged 60 years or older with and without a DSM-IV diagnosis of Major Depressive Disorder completed clinical assessments and 3 T cranial MRI using a protocol allowing for automated measurement of medial temporal lobe subfield volumes. A subset also completed pseudo-continuous arterial spin labeling, allowing for the measurement of hippocampal cerebral blood flow. In 59 depressed and 21 never-depressed elders (mean age = 66.4 years, SD = 5.8y, range 60-86y), the depressed group did not exhibit statistically significant volumetric differences for the total hippocampus or hippocampal subfields but did exhibit significantly smaller volumes of the perirhinal cortex, specifically in the BA36 region. Additionally, age had a greater effect in the depressed group on volumes of the cornu ammonis, entorhinal cortex, and BA36 region. Finally, both clinical and radiological markers of vascular risk were associated with smaller BA36 volumes, while reduced hippocampal blood flow was associated with smaller hippocampal and cornu ammonis volumes. In conclusion, while we did not observe group differences in hippocampal regions, we observed group differences and an effect of vascular pathology on the BA36 region, part of the perirhinal cortex. This is a critical region exhibiting atrophy in prodromal Alzheimer's disease. Moreover, the observed greater effect of age in the depressed groups is concordant with past longitudinal studies reporting greater hippocampal atrophy in late-life depression.
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Group Exercise Training for Functional Improvement after Treatment
Oregon Health & Science University
  • Reply to Y.-T. Hu et al.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2023)
    Winters-Stone KM, Roeland EJ, Li F, Eckstrom E, Horak F, Dieckmann NF, Stoyles SA, Luoh SW. Reply to Y.-T. Hu et al. J Clin Oncol. 2023 Jun 28; :JCO2301034.
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  • GET FIT: A Randomized Clinical Trial of Tai Ji Quan Versus Strength Training for Fall Prevention After Chemotherapy in Older, Postmenopausal Women Cancer Survivors.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2023)
    Winters-Stone KM, Horak F, Dieckmann NF, Luoh SW, Eckstrom E, Stoyles SA, Roeland EJ, Li F. GET FIT: A Randomized Clinical Trial of Tai Ji Quan Versus Strength Training for Fall Prevention After Chemotherapy in Older, Postmenopausal Women Cancer Survivors. J Clin Oncol. 2023 Mar 8; :JCO2201519.
    Abstract: To compare the efficacy of tai ji quan versus strength training to prevent falls after chemotherapy in older, postmenopaual women.
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  • Association of fall rate and functional status by APOE genotype in cancer survivors after exercise intervention.
    Oncotarget (2022)
    McGinnis GJ, Holden S, Yu B, Ransom C, Guidarelli C, De B, Diao K, Boyce D, Thomas CR Jr, Winters-Stone K, Raber J. Association of fall rate and functional status by APOE genotype in cancer survivors after exercise intervention. Oncotarget. 2022 Nov 17; 13:1259-1270.
    Abstract: Cancer treatment survivors often report impaired functioning and increased falls. Not all survivors experience the same symptom burden, suggesting individual susceptibilities. genotype is a potential genetic risk factor for cancer treatment related side effects. Lifestyle factors such as physical activity can mitigate the effect of genotype on measures of clinical interest in individuals without a history of cancer. We tested the hypothesis that genotype influences cancer treatment related side effects and symptoms as well as response to exercise intervention.
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  • Comparison of tai chi vs. strength training for fall prevention among female cancer survivors: study protocol for the GET FIT trial.
    BMC cancer (2012)
    Winters-Stone KM, Li F, Horak F, Luoh SW, Bennett JA, Nail L, Dieckmann N. Comparison of tai chi vs. strength training for fall prevention among female cancer survivors: study protocol for the GET FIT trial. BMC Cancer. 2012 Dec 5; 12:577.
    Abstract: Women with cancer are significantly more likely to fall than women without cancer placing them at higher risk of fall-related fractures, other injuries and disability. Currently, no evidence-based fall prevention strategies exist that specifically target female cancer survivors. The purpose of the GET FIT (Group Exercise Training for Functional Improvement after Treatment) trial is to compare the efficacy of two distinct types of exercise, tai chi versus strength training, to prevent falls in women who have completed treatment for cancer. The specific aims of this study are to: 1) Determine and compare the efficacy of both tai chi training and strength training to reduce falls in older female cancer survivors, 2) Determine the mechanism(s) by which tai chi and strength training each reduces falls and, 3) Determine whether or not the benefits of each intervention last after structured training stops.
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Long_Acting Beta Agonist Step Down Study-- LASST
The Ohio State University
  • Comprehension by Caregivers and Adolescents of Clinical Trial Information Delivered via Multimedia Video Versus Conventional Practice: Nonrandomized Controlled Trial.
    JMIR pediatrics and parenting (2023)
    Blake KV, Antal H, Bunnell HT, He J, Henderson R, Holbrook JT, McCahan SM, Pennington C, Rogers L, Shade D, Sugar EA, Taylor A, Wise RA, Wysocki T. Comprehension by Caregivers and Adolescents of Clinical Trial Information Delivered via Multimedia Video Versus Conventional Practice: Nonrandomized Controlled Trial. JMIR Pediatr Parent. 2023 Jun 22; 6:e44252.
    Abstract: Research participants often misunderstand the required elements of informed consent information, whether provided in written or oral format. Informed consent instruments with embedded evidence-based learning theory principles administered in multimedia electronic formats may improve comprehension and retention.
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  • Risk Factors for Asthma Exacerbation and Treatment Failure in Adults and Adolescents with Well-controlled Asthma during Continuation and Step-Down Therapy.
    Annals of the American Thoracic Society (2018)
    DiMango E, Rogers L, Reibman J, Gerald LB, Brown M, Sugar EA, Henderson R, Holbrook JT. Risk Factors for Asthma Exacerbation and Treatment Failure in Adults and Adolescents with Well-controlled Asthma during Continuation and Step-Down Therapy. Ann Am Thorac Soc. 2018 Aug; 15(8):955-961.
    Abstract: Although national and international guidelines recommend reduction of asthma controller therapy or "step-down" therapy in patients with well-controlled asthma, it is expected that some individuals may experience worsening of asthma symptoms or asthma exacerbations during step-down. Characteristics associated with subsequent exacerbations during step-down therapy have not been well defined. The effect of environmental tobacco smoke exposure on risk of treatment failure during asthma step-down therapy has not been reported.
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The electronic Medical Records and GEnomics (eMERGE) Network Genomic Risk Assessment
Cincinnati Children's Hospital Medical Center
  • Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores.
    Genetics in medicine : official journal of the American College of Medical Genetics (2023)
    Connolly JJ, Berner ES, Smith M, Levy S, Terek S, Harr M, Karavite D, Suckiel S, Holm IA, Dufendach K, Nelson C, Khan A, Chisholm RL, Allworth A, Wei WQ, Bland HT, Clayton EW, Soper ER, Linder JE, Limdi NA, Miller A, Nigbur S, Bangash H, Hamed M, Sherafat. Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores. Genet Med. 2023 Sep; 25(9):100906.
    Abstract: Polygenic risk scores (PRS) have potential to improve health care by identifying individuals that have elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and health care systems. The electronic Medical Records and Genomics (eMERGE) network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for 1 or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes. All 10 eMERGE clinical sites conducted focus groups, interviews, and/or surveys to understand educational needs among key stakeholders-participants, providers, and/or study staff. Together, these studies highlighted the need for tools that address the perceived benefit/value of PRS, types of education/support needed, accessibility, and PRS-related knowledge and understanding. Based on findings from these preliminary studies, the network harmonized training initiatives and formal/informal educational resources. This paper summarizes eMERGE's collective approach to assessing educational needs and developing educational approaches for primary stakeholders. It discusses challenges encountered and solutions provided.
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  • Returning integrated genomic risk and clinical recommendations: The eMERGE study.
    Genetics in medicine : official journal of the American College of Medical Genetics (2023)
    Linder JE, Allworth A, Bland HT, Caraballo PJ, Chisholm RL, Clayton EW, Crosslin DR, Dikilitas O, DiVietro A, Esplin ED, Forman S, Freimuth RR, Gordon AS, Green R, Harden MV, Holm IA, Jarvik GP, Karlson EW, Labrecque S, Lennon NJ, Limdi NA, Mittendorf KF,. Returning integrated genomic risk and clinical recommendations: The eMERGE study. Genet Med. 2023 Apr; 25(4):100006.
    Abstract: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.
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The electronic Medical Records and GEnomics (eMERGE) Network Genomic Risk Assessment
Vanderbilt University Medical Center
  • Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores.
    Genetics in medicine : official journal of the American College of Medical Genetics (2023)
    Connolly JJ, Berner ES, Smith M, Levy S, Terek S, Harr M, Karavite D, Suckiel S, Holm IA, Dufendach K, Nelson C, Khan A, Chisholm RL, Allworth A, Wei WQ, Bland HT, Clayton EW, Soper ER, Linder JE, Limdi NA, Miller A, Nigbur S, Bangash H, Hamed M, Sherafat. Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores. Genet Med. 2023 Sep; 25(9):100906.
    Abstract: Polygenic risk scores (PRS) have potential to improve health care by identifying individuals that have elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and health care systems. The electronic Medical Records and Genomics (eMERGE) network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for 1 or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes. All 10 eMERGE clinical sites conducted focus groups, interviews, and/or surveys to understand educational needs among key stakeholders-participants, providers, and/or study staff. Together, these studies highlighted the need for tools that address the perceived benefit/value of PRS, types of education/support needed, accessibility, and PRS-related knowledge and understanding. Based on findings from these preliminary studies, the network harmonized training initiatives and formal/informal educational resources. This paper summarizes eMERGE's collective approach to assessing educational needs and developing educational approaches for primary stakeholders. It discusses challenges encountered and solutions provided.
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  • Returning integrated genomic risk and clinical recommendations: The eMERGE study.
    Genetics in medicine : official journal of the American College of Medical Genetics (2023)
    Linder JE, Allworth A, Bland HT, Caraballo PJ, Chisholm RL, Clayton EW, Crosslin DR, Dikilitas O, DiVietro A, Esplin ED, Forman S, Freimuth RR, Gordon AS, Green R, Harden MV, Holm IA, Jarvik GP, Karlson EW, Labrecque S, Lennon NJ, Limdi NA, Mittendorf KF,. Returning integrated genomic risk and clinical recommendations: The eMERGE study. Genet Med. 2023 Apr; 25(4):100006.
    Abstract: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.
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Investigating Social Competence in Youth with Autism: A Multisite RCT
Vanderbilt University Medical Center
  • Peers, play, and performance to build social salience in autistic youth: A multisite randomized clinical trial.
    Journal of consulting and clinical psychology (2023)
    Corbett BA, White S, Lerner M, Preacher KJ, Klemencic ME, Simmons GL, Pilkington J, Gable P, Gioia A, Key AP. Peers, play, and performance to build social salience in autistic youth: A multisite randomized clinical trial. J Consult Clin Psychol. 2023 Jul; 91(7):411-425.
    Abstract: Individuals with autism spectrum disorder (ASD) have significant impairment in social competence and reduced social salience. SENSE Theatre, a peer-mediated, theater-based intervention has demonstrated posttreatment gains in face memory and social communication. The multisite randomized clinical trial compared the Experimental (EXP; SENSE Theatre) to an Active Control Condition (ACC; Tackling Teenage Training, TTT) at pretest, posttest, and follow-up. It was hypothesized that the EXP group would demonstrate greater incidental face memory (IFM) and better social behavior (interaction with novel peers) and social functioning (social engagement in daily life) than the ACC group, and posttest IFM would mediate the treatment effect on follow-up social behavior and functioning.
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Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Volunteers
The National Institutes of Health
  • Aneuploidy effects on human gene expression across three cell types.
    Proceedings of the National Academy of Sciences of the United States of America (2023)
    Liu S, Akula N, Reardon PK, Russ J, Torres E, Clasen LS, Blumenthal J, Lalonde F, McMahon FJ, Szele F, Disteche CM, Cader MZ, Raznahan A. Aneuploidy effects on human gene expression across three cell types. Proc Natl Acad Sci U S A. 2023 May 23; 120(21):e2218478120.
    Abstract: Aneuploidy syndromes impact multiple organ systems but understanding of tissue-specific aneuploidy effects remains limited-especially for the comparison between peripheral tissues and relatively inaccessible tissues like brain. Here, we address this gap in knowledge by studying the transcriptomic effects of chromosome X, Y, and 21 aneuploidies in lymphoblastoid cell lines, fibroblasts and iPSC-derived neuronal cells (LCLs, FCL, and iNs, respectively). We root our analyses in sex chromosome aneuploidies, which offer a uniquely wide karyotype range for dosage effect analysis. We first harness a large LCL RNA-seq dataset from 197 individuals with one of 6 sex chromosome dosages (SCDs: XX, XXX, XY, XXY, XYY, and XXYY) to i) validate theoretical models of SCD sensitivity and ii) define an expanded set of 41 genes that show obligate dosage sensitivity to SCD and are all in (i.e., reside on the X or Y chromosome). We then use multiple complementary analyses to show that effects of SCD in LCLs are preserved in both FCLs (n = 32) and iNs (n = 24), whereas effects (i.e., those on autosomal gene expression) are mostly not preserved. Analysis of additional datasets confirms that the greater cross-cell type reproducibility of vs. effects is also seen in trisomy 21 cell lines. These findings i) expand our understanding of X, Y, and 21 chromosome dosage effects on human gene expression and ii) suggest that LCLs may provide a good model system for understanding effects of aneuploidy in harder-to-access cell types.
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  • Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome.
    Journal of neurodevelopmental disorders (2023)
    Raznahan A, Rau S, Schaffer L, Liu S, Fish AM, Mankiw C, Xenophontos A, Clasen LS, Joseph L, Thurm A, Blumenthal JD, Bassett DS, Torres EN. Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome. J Neurodev Disord. 2023 Feb 20; 15(1):8.
    Abstract: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome.
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  • A Cross-Species Neuroimaging Study of Sex Chromosome Dosage Effects on Human and Mouse Brain Anatomy.
    The Journal of neuroscience : the official journal of the Society for Neuroscience (2023)
    Guma E, Beauchamp A, Liu S, Levitis E, Clasen LS, Torres E, Blumenthal J, Lalonde F, Qiu LR, Hrncir H, MacKenzie-Graham A, Yang X, Arnold AP, Lerch JP, Raznahan A. A Cross-Species Neuroimaging Study of Sex Chromosome Dosage Effects on Human and Mouse Brain Anatomy. J Neurosci. 2023 Feb 22; 43(8):1321-1333.
    Abstract: All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellar, parietal, and orbitofrontal cortex), thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT. Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.
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  • Youth with Down syndrome display widespread increased functional connectivity during rest.
    Scientific reports (2022)
    Csumitta KD, Gotts SJ, Clasen LS, Martin A, Raitano Lee N. Youth with Down syndrome display widespread increased functional connectivity during rest. Sci Rep. 2022 Jun 14; 12(1):9836.
    Abstract: Studies of resting-state functional connectivity in young people with Down syndrome (DS) have yielded conflicting results. Some studies have found increased connectivity while others have found a mix of increased and decreased connectivity. No studies have examined whole-brain connectivity at the voxel level in youth with DS during an eyes-open resting-state design. Additionally, no studies have examined the relationship between connectivity and network selectivity in youth with DS. Thus, the current study sought to fill this gap in the literature. Nineteen youth with DS (M = 16.5; range 7-23; 13 F) and 33 typically developing (TD) youth (M = 17.5; range 6-24; 18 F), matched on age and sex, completed a 5.25-min eyes-open resting-state fMRI scan. Whole-brain functional connectivity (average Pearson correlation of each voxel with every other voxel) was calculated for each individual and compared between groups. Network selectivity was then calculated and correlated with functional connectivity for the DS group. Results revealed that whole-brain functional connectivity was significantly higher in youth with DS compared to TD controls in widespread regions throughout the brain. Additionally, participants with DS had significantly reduced network selectivity compared to TD peers, and selectivity was significantly related to connectivity in all participants. Exploratory behavioral analyses revealed that regions showing increased connectivity in DS predicted Verbal IQ, suggesting differences in connectivity may be related to verbal abilities. These results indicate that network organization is disrupted in youth with DS such that disparate networks are overly connected and less selective, suggesting a potential target for clinical interventions.
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  • Variegation of autism related traits across seven neurogenetic disorders.
    Translational psychiatry (2022)
    Lee NR, Niu X, Zhang F, Clasen LS, Kozel BA, Smith ACM, Wallace GL, Raznahan A. Variegation of autism related traits across seven neurogenetic disorders. Transl Psychiatry. 2022 Apr 7; 12(1):149.
    Abstract: Gene dosage disorders (GDDs) constitute a major class of genetic risks for psychopathology, but there is considerable debate regarding the extent to which different GDDs induce different psychopathology profiles. The current research speaks to this debate by compiling and analyzing dimensional measures of several autism-related traits (ARTs) across seven diverse GDDs. The sample included 350 individuals with one of 7 GDDs, as well as reference idiopathic autism spectrum disorder (ASD; n = 74) and typically developing control (TD; n = 171) groups. The GDDs were: Down, Williams-Beuren, and Smith-Magenis (DS, WS, SMS) syndromes, and varying sex chromosome aneuploidies ("plusX", "plusXX", "plusY", "plusXY"). The Social Responsiveness Scale (SRS-2) was used to measure ARTs at different levels of granularity-item, subscale, and total. General linear models were used to examine ART profiles in GDDs, and machine learning was used to predict genotype from SRS-2 subscales and items. These analyses were completed with and without covariation for cognitive impairment. Twelve of all possible 21 pairwise GDD group contrasts showed significantly different ART profiles (7/21 when co-varying for IQ, all Bonferroni-corrected). Prominent GDD-ART associations in post hoc analyses included relatively preserved social motivation in WS and relatively low levels of repetitive behaviors in plusX. Machine learning revealed that GDD group could be predicted with plausible accuracy (~60-80%) even after controlling for IQ. GDD effects on ARTs are influenced by GDD subtype and ART dimension. This observation has consequences for mechanistic, clinical, and translational aspects of psychiatric neurogenetics.
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  • Sex-specific associations between subcortical morphometry in childhood and adult alcohol consumption: A 17-year follow-up study.
    NeuroImage. Clinical (2021)
    Mankiw C, Whitman ET, Torres E, Lalonde F, Clasen LS, Blumenthal JD, Chakravarty MM, Raznahan A. Sex-specific associations between subcortical morphometry in childhood and adult alcohol consumption: A 17-year follow-up study. Neuroimage Clin. 2021; 31:102771.
    Abstract: Men and women tend to differ in the age of first alcohol consumption, transition into disordered drinking, and the prevalence of alcohol use disorder. Here, we use a unique longitudinal dataset to test for potentially predispositonal sex-biases in brain organization prior to initial alcohol exposure. Our study combines measures of subcortical morphometry gathered in alcohol naive individuals during childhood (mean age: 9.43 years, SD = 2.06) with self-report measures of alcohol use in the same individuals an average of 17 years later (N = 81, 46 males, 35 females). We observe that pediatric amygdala and hippocampus volume both show sex-biased relationships with adult drinking. Specifically, females show a stronger association between subcortical volumetric reductions in childhood and peak drinking in adulthood as compared to males. Detailed analysis of subcortical shape localizes these effects to the rostro-medial hippocampus and basolateral amygdala subnuclei. In contrast, we did not observe sex-specific associations between striatal anatomy and peak alcohol consumption. These results are consistent with a model in which organization of the amygdala and hippocampus in childhood is more relevant for subsequent patterns of peak alcohol use in females as compared to males. Differential neuroanatomical precursors of alcohol use in males and females could provide a potential developmental basis for well recognized sex-differences in alcohol use behaviors.. Thus, our findings not only indicate that brain correlates of human alcohol consumption are manifest long before alcohol initiation, but that some of these correlates are not equivalent between males and females.
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  • Sex Chromosome Dosage Effects on White Matter Structure in the Human Brain.
    Cerebral cortex (New York, N.Y. : 1991) (2021)
    Warling A, Yavi M, Clasen LS, Blumenthal JD, Lalonde FM, Raznahan A, Liu S. Sex Chromosome Dosage Effects on White Matter Structure in the Human Brain. Cereb Cortex. 2021 Oct 22; 31(12):5339-5353.
    Abstract: Sex chromosome aneuploidies, a group of neurogenetic conditions characterized by aberrant sex chromosome dosage (SCD), are associated with increased risks for psychopathology as well as alterations in gray matter structure. However, we still lack a comprehensive understanding of potential SCD-associated changes in white matter structure, or knowledge of how these changes might relate to known alterations in gray matter anatomy. Thus, here, we use voxel-based morphometry on structural neuroimaging data to provide the first comprehensive maps of regional white matter volume (WMV) changes across individuals with varying SCD (n = 306). We show that mounting X- and Y-chromosome dosage are both associated with widespread WMV decreases, including in cortical, subcortical, and cerebellar tracts, as well as WMV increases in the genu of the corpus callosum and posterior thalamic radiation. We also correlate X- and Y-chromosome-linked WMV changes in certain regions to measures of internalizing and externalizing psychopathology. Finally, we demonstrate that SCD-driven WMV changes show a coordinated coupling with SCD-driven gray matter volume changes. These findings represent the most complete maps of X- and Y-chromosome effects on human white matter to date, and show how such changes connect to psychopathological symptoms and gray matter anatomy.
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  • Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY).
    Cerebral cortex (New York, N.Y. : 1991) (2021)
    Whitman ET, Liu S, Torres E, Warling A, Wilson K, Nadig A, McDermott C, Clasen LS, Blumenthal JD, Lalonde FM, Gotts SJ, Martin A, Raznahan A. Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY). Cereb Cortex. 2021 Jul 29; 31(9):4180-4190.
    Abstract: Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.
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  • Morphological integration of the human brain across adolescence and adulthood.
    Proceedings of the National Academy of Sciences of the United States of America (2021)
    Nadig A, Seidlitz J, McDermott CL, Liu S, Bethlehem R, Moore TM, Mallard TT, Clasen LS, Blumenthal JD, Lalonde F, Gur RC, Gur RE, Bullmore ET, Satterthwaite TD, Raznahan A. Morphological integration of the human brain across adolescence and adulthood. Proc Natl Acad Sci U S A. 2021 Apr 6; 118(14):.
    Abstract: Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.
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  • Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome.
    Journal of neurodevelopmental disorders (2021)
    Wilson KE, Fish AM, Mankiw C, Xenophontos A, Warling A, Whitman E, Clasen L, Torres E, Blumenthal J, Raznahan A. Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome. J Neurodev Disord. 2021 Mar 22; 13(1):12.
    Abstract: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology.
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  • X-chromosome regulation and sex differences in brain anatomy.
    Neuroscience and biobehavioral reviews (2021)
    Raznahan A, Disteche CM. X-chromosome regulation and sex differences in brain anatomy. Neurosci Biobehav Rev. 2021 Jan; 120:28-47.
    Abstract: Humans show reproducible sex-differences in cognition and psychopathology that may be contributed to by influences of gonadal sex-steroids and/or sex-chromosomes on regional brain development. Gonadal sex-steroids are well known to play a major role in sexual differentiation of the vertebrate brain, but far less is known regarding the role of sex-chromosomes. Our review focuses on this latter issue by bridging together two literatures that have to date been largely disconnected. We first consider "bottom-up" genetic and molecular studies focused on sex-chromosome gene content and regulation. This literature nominates specific sex-chromosome genes that could drive developmental sex-differences by virtue of their sex-biased expression and their functions within the brain. We then consider the complementary "top down" view, from magnetic resonance imaging studies that map sex- and sex chromosome effects on regional brain anatomy, and link these maps to regional gene-expression within the brain. By connecting these top-down and bottom-up approaches, we emphasize the potential role of X-linked genes in driving sex-biased brain development and outline key goals for future work in this field.
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  • The Heritability of Cortical Folding: Evidence from the Human Connectome Project.
    Cerebral cortex (New York, N.Y. : 1991) (2021)
    Schmitt JE, Raznahan A, Liu S, Neale MC. The Heritability of Cortical Folding: Evidence from the Human Connectome Project. Cereb Cortex. 2021 Jan 1; 31(1):702-715.
    Abstract: The mechanisms underlying cortical folding are incompletely understood. Prior studies have suggested that individual differences in sulcal depth are genetically mediated, with deeper and ontologically older sulci more heritable than others. In this study, we examine FreeSurfer-derived estimates of average convexity and mean curvature as proxy measures of cortical folding patterns using a large (N = 1096) genetically informative young adult subsample of the Human Connectome Project. Both measures were significantly heritable near major sulci and primary fissures, where approximately half of individual differences could be attributed to genetic factors. Genetic influences near higher order gyri and sulci were substantially lower and largely nonsignificant. Spatial permutation analysis found that heritability patterns were significantly anticorrelated to maps of evolutionary and neurodevelopmental expansion. We also found strong phenotypic correlations between average convexity, curvature, and several common surface metrics (cortical thickness, surface area, and cortical myelination). However, quantitative genetic models suggest that correlations between these metrics are largely driven by nongenetic factors. These findings not only further our understanding of the neurobiology of gyrification, but have pragmatic implications for the interpretation of heritability maps based on automated surface-based measurements.
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  • Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans.
    Proceedings of the National Academy of Sciences of the United States of America (2020)
    Liu S, Seidlitz J, Blumenthal JD, Clasen LS, Raznahan A. Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans. Proc Natl Acad Sci U S A. 2020 Aug 4; 117(31):18788-18798.
    Abstract: Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice-a major model organism for studying neurobiological sex differences-have established: 1) highly consistent sex biases in regional gray matter volume (GMV) involving the cortex and classical subcortical foci, 2) a preponderance of regional GMV sex differences in brain circuits for social and reproductive behavior, and 3) a spatial coupling between regional GMV sex biases and brain expression of sex chromosome genes in adulthood. Here, we directly test translatability of rodent findings to humans. First, using two independent structural-neuroimaging datasets ( > 2,000), we find that the spatial map of sex-biased GMV in humans is highly reproducible ( > 0.8 within and across cohorts). Relative GMV is female biased in prefrontal and superior parietal cortices, and male biased in ventral occipitotemporal, and distributed subcortical regions. Second, through systematic comparison with functional neuroimaging meta-analyses, we establish a statistically significant concentration of human GMV sex differences within brain regions that subserve face processing. Finally, by imaging-transcriptomic analyses, we show that GMV sex differences in human adulthood are specifically and significantly coupled to regional expression of sex-chromosome (vs. autosomal) genes and enriched for distinct cell-type signatures. These findings establish conserved aspects of sex-biased brain development in humans and mice, and shed light on the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.
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  • Editorial: Do Different Neurogenetic Disorders Impart Different Profiles of Psychiatric Risk?
    Journal of the American Academy of Child and Adolescent Psychiatry (2020)
    Raznahan A. Editorial: Do Different Neurogenetic Disorders Impart Different Profiles of Psychiatric Risk? J Am Acad Child Adolesc Psychiatry. 2020 Sep; 59(9):1022-1024.
    Abstract: The best-studied examples of genetically defined developmental disorders, such as Down syndrome (trisomy 21) and velocardiofacial syndrome (del22q11), have been known since before the genomic era and were initially recognized as distinct syndromes based on their own unique constellation of dysmorphic and multisystem features. For example, Down syndrome is characterized by the co-occurrence of several dysmorphic features, including a flattened facial profile, slanted palpebral fissures, protruding tongue, and transverse palmar crease, with accompanying hypotonia, cardiac issues, and developmental delay. None of these features in isolation is specific to Down syndrome, and all features are not present in all cases, but the co-occurrence of multiple features from this set is a specific and sensitive marker for the presence of trisomy 21. To what extent might similar principles apply to the patterning of cognitive and behavioral features across different neurogenetic syndromes?
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  • A local group differences test for subject-level multivariate density neuroimaging outcomes.
    Biostatistics (Oxford, England) (2021)
    Dworkin JD, Linn KA, Solomon AJ, Satterthwaite TD, Raznahan A, Bakshi R, Shinohara RT. A local group differences test for subject-level multivariate density neuroimaging outcomes. Biostatistics. 2021 Jul 17; 22(3):646-661.
    Abstract: A great deal of neuroimaging research focuses on voxel-wise analysis or segmentation of damaged tissue, yet many diseases are characterized by diffuse or non-regional neuropathology. In simple cases, these processes can be quantified using summary statistics of voxel intensities. However, the manifestation of a disease process in imaging data is often unknown, or appears as a complex and nonlinear relationship between the voxel intensities on various modalities. When the relevant pattern is unknown, summary statistics are often unable to capture differences between disease groups, and their use may encourage post hoc searches for the optimal summary measure. In this study, we introduce the multi-modal density testing (MMDT) framework for the naive discovery of group differences in voxel intensity profiles. MMDT operationalizes multi-modal magnetic resonance imaging (MRI) data as multivariate subject-level densities of voxel intensities and utilizes kernel density estimation to develop a local two-sample test for individual points within the density space. Through simulations, we show that this method controls type I error and recovers relevant differences when applied to a specified point. Additionally, we demonstrate the ability to maintain power while controlling the family-wise error rate and false discovery rate when applying the test over a grid of points within the density space. Finally, we apply this method to a study of subjects with either multiple sclerosis (MS) or conditions that tend to mimic MS on MRI, and find significant differences between the two groups in their voxel intensity profiles within the thalamus.
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  • Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance.
    Cerebral cortex (New York, N.Y. : 1991) (2020)
    Xenophontos A, Seidlitz J, Liu S, Clasen LS, Blumenthal JD, Giedd JN, Alexander-Bloch A, Raznahan A. Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance. Cereb Cortex. 2020 Apr 14; 30(4):2215-2228.
    Abstract: Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.
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  • Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder.
    Molecular psychiatry (2020)
    Bedford SA, Park MTM, Devenyi GA, Tullo S, Germann J, Patel R, Anagnostou E, Baron-Cohen S, Bullmore ET, Chura LR, Craig MC, Ecker C, Floris DL, Holt RJ, Lenroot R, Lerch JP, Lombardo MV, Murphy DGM, Raznahan A, Ruigrok ANV, Smith E, Spencer MD, Suckling. Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder. Mol Psychiatry. 2020 Mar; 25(3):614-628.
    Abstract: Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.
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  • The Dynamic Associations Between Cortical Thickness and General Intelligence are Genetically Mediated.
    Cerebral cortex (New York, N.Y. : 1991) (2019)
    Schmitt JE, Raznahan A, Clasen LS, Wallace GL, Pritikin JN, Lee NR, Giedd JN, Neale MC. The Dynamic Associations Between Cortical Thickness and General Intelligence are Genetically Mediated. Cereb Cortex. 2019 Dec 17; 29(11):4743-4752.
    Abstract: The neural substrates of intelligence represent a fundamental but largely uncharted topic in human developmental neuroscience. Prior neuroimaging studies have identified modest but highly dynamic associations between intelligence and cortical thickness (CT) in childhood and adolescence. In a separate thread of research, quantitative genetic studies have repeatedly demonstrated that most measures of intelligence are highly heritable, as are many brain regions associated with intelligence. In the current study, we integrate these 2 streams of prior work by examining the genetic contributions to CT-intelligence relationships using a genetically informative longitudinal sample of 813 typically developing youth, imaged with high-resolution MRI and assessed with Wechsler Intelligence Scales (IQ). In addition to replicating the phenotypic association between multimodal association cortex and language centers with IQ, we find that CT-IQ covariance is nearly entirely genetically mediated. Moreover, shared genetic factors drive the rapidly evolving landscape of CT-IQ relationships in the developing brain.
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  • Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures.
    eNeuro (2018)
    Nadig A, Reardon PK, Seidlitz J, McDermott CL, Blumenthal JD, Clasen LS, Lalonde F, Lerch JP, Chakravarty MM, Raznahan A. Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures. eNeuro. 2018 Sep-Oct; 5(5):.
    Abstract: Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes ( = 132) and typically developing controls ( = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population ( = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.
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  • Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology.
    The Journal of neuroscience : the official journal of the Society for Neuroscience (2019)
    McDermott CL, Seidlitz J, Nadig A, Liu S, Clasen LS, Blumenthal JD, Reardon PK, Lalonde F, Greenstein D, Patel R, Chakravarty MM, Lerch JP, Raznahan A. Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology. J Neurosci. 2019 Feb 20; 39(8):1365-1373.
    Abstract: Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with human structural brain development is not yet well characterized. Here, we analyzed 1243 longitudinally acquired structural MRI scans from 623 youth (299 female/324 male) to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were stable between ages 5 and 25. Surface-based shape analysis revealed that higher SES is associated with areal expansion of lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and ventrolateral thalamic, and medial amygdalo-hippocampal subregions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Although SES is clearly a complex construct that likely relates to development through diverse, nondeterministic processes, our findings elucidate potential neuroanatomical mediators of the association between SES and cognitive outcomes. Childhood socioeconomic status (SES) has been associated with developmental disparities in mental health, cognitive ability, and academic achievement, but efforts to understand underlying SES-brain relationships are ongoing. Here, we leverage a unique developmental neuroimaging dataset to longitudinally map the associations between SES and regional brain anatomy at high spatiotemporal resolution. We find widespread associations between SES and global cortical and subcortical volumes and surface area and localize these correlations to a distributed set of cortical, thalamic, and amygdalo-hippocampal subregions. Anatomical variation within a subset of these regions partially mediates the positive relationship between SES and IQ. Our findings help to localize cortical and subcortical systems that represent candidate biological substrates for the known relationships between SES and cognition.
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  • Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome.
    Journal of neurodevelopmental disorders (2018)
    Joseph L, Farmer C, Chlebowski C, Henry L, Fish A, Mankiw C, Xenophontos A, Clasen L, Sauls B, Seidlitz J, Blumenthal J, Torres E, Thurm A, Raznahan A. Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome. J Neurodev Disord. 2018 Oct 22; 10(1):30.
    Abstract: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data.
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  • Pediatric Brain Development in Down Syndrome: A Field in Its Infancy.
    Journal of the International Neuropsychological Society : JINS (2018)
    Hamner T, Udhnani MD, Osipowicz KZ, Lee NR. Pediatric Brain Development in Down Syndrome: A Field in Its Infancy. J Int Neuropsychol Soc. 2018 Oct; 24(9):966-976.
    Abstract: As surprisingly little is known about the developing brain studied in vivo in youth with Down syndrome (DS), the current review summarizes the small DS pediatric structural neuroimaging literature and begins to contextualize existing research within a developmental framework.
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  • A case-control study of brain structure and behavioral characteristics in 47,XXX syndrome.
    Genes, brain, and behavior (2014)
    Lenroot RK, Blumenthal JD, Wallace GL, Clasen LS, Lee NR, Giedd JN. A case-control study of brain structure and behavioral characteristics in 47,XXX syndrome. Genes Brain Behav. 2014 Nov; 13(8):841-9.
    Abstract: Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age- and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample.
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Digital game for heart failure
University of Texas Austin
  • Sensor-Controlled Digital Game for Heart Failure Self-management: Protocol for a Randomized Controlled Trial.
    JMIR research protocols (2023)
    Radhakrishnan K, Julien C, O'Hair M, Tunis R, Lee G, Rangel A, Custer J, Baranowski T, Rathouz PJ, Kim MT. Sensor-Controlled Digital Game for Heart Failure Self-management: Protocol for a Randomized Controlled Trial. JMIR Res Protoc. 2023 May 10; 12:e45801.
    Abstract: Heart failure (HF) is the leading cause of hospitalization among older adults in the United States. There are substantial racial and geographic disparities in HF outcomes, with patients living in southern US states having a mortality rate 69% higher than the national average. Self-management behaviors, particularly daily weight monitoring and physical activity, are extremely important in improving HF outcomes; however, patients typically have particularly low adherence to these behaviors. With the rise of digital technologies to improve health outcomes and motivate health behaviors, sensor-controlled digital games (SCDGs) have become a promising approach. SCDGs, which leverage sensor-connected technologies, offer the benefits of being portable and scalable and allowing for continuous observation and motivation of health behaviors in their real-world contexts. They are also becoming increasingly popular among older adults and offer an immersive and accessible way to measure self-management behaviors and improve adherence. No SCDGs have been designed for older adults or evaluated to test their outcomes.
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Tissue Sodium in Pre-hypertensive Patients
Vanderbilt University Medical Center
  • High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals.
    Nutrition, metabolism, and cardiovascular diseases : NMCD (2023)
    Ertuglu LA, Sahinoz M, Alsouqi A, Deger SM, Guide A, Stewart TG, Pike M, Robinson-Cohen C, Akwo E, Pridmore M, Crescenzi R, Madhur MS, Harrison DG, Luft FC, Titze J, Ikizler TA. High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals. Nutr Metab Cardiovasc Dis. 2023 Apr 10; :.
    Abstract: High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association.
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  • Tissue Sodium in Patients With Early Stage Hypertension: A Randomized Controlled Trial.
    Journal of the American Heart Association (2022)
    Alsouqi A, Deger SM, Sahinoz M, Mambungu C, Clagett AR, Bian A, Guide A, Stewart TG, Pike M, Robinson-Cohen C, Crescenzi R, Madhur MS, Harrison DG, Ikizler TA. Tissue Sodium in Patients With Early Stage Hypertension: A Randomized Controlled Trial. J Am Heart Assoc. 2022 Apr 19; 11(8):e022723.
    Abstract: Background Sodium (Na) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na. In this study, we evaluated tissue Na in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na diet. Methods and Results In a double-blinded, placebo-controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (<2 g of sodium), chlorthalidone, spironolactone, or placebo for 8 weeks. Muscle and skin Na using sodium magnetic resonance imaging and pulse wave velocity were assessed at the beginning and end of the study. Ninety-eight patients were enrolled to undergo baseline measurements and 54 completed randomization. Median baseline muscle and skin Na in 98 patients were 16.4 mmol/L (14.9, 18.9) and 13.1 mmol/L (11.1, 16.1), respectively. After 8 weeks, muscle Na increased in the diet and chlorthalidone arms compared with placebo. Skin sodium was decreased only in the diet arm compared with placebo. These associations remained significant after adjustment for age, sex, body mass index, systolic blood pressure, and urinary sodium. No changes were observed in pulse wave velocity among the different groups when compared with placebo. Conclusions Diuretic therapy for 8 weeks did not decrease muscle or skin sodium or improve pulse wave velocity in patients with elevated blood pressure or stage I hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02236520.
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  • Sex differences in sodium deposition in human muscle and skin.
    Magnetic resonance imaging (2017)
    Wang P, Deger MS, Kang H, Ikizler TA, Titze J, Gore JC. Sex differences in sodium deposition in human muscle and skin. Magn Reson Imaging. 2017 Feb; 36:93-97.
    Abstract: The aim of this work was to investigate possible sex differences in the patterns of sodium deposition between muscle and skin using sodium MRI. A total of 38 subjects were examined for comparisons: 20 males, aged 25-79years with a median age of 51; 18 females, aged 38-66years, median age 53. All subjects underwent sodium MRI scans of the calf muscles together with cross sections through four calibration standards containing known sodium contents (10mM, 20mM, 30mM, and 40mM). Tissue sodium concentrations (TSC) in muscle and skin were then calculated by comparing signal intensities between tissues and reference standards using a linear analysis. A Wilcoxon rank sum test was applied to the ΔTSC (=TSC-TSC) series of males and females to examine if they were significantly different. Finally, a multiple linear regression was utilized to account for the effects from two potential confounders, age and body mass index (BMI). We found that sodium content appears to be higher in skin than in muscle for men, however women tend to have higher muscle sodium than skin sodium. This sex-relevant sodium deposition is statistically significant (P=3.10×10) by the Wilcoxon rank sum test, and this difference in distribution seems to be more reliable with increasing age. In the multiple linear regression, gender still has a statistically significant effect (P<1.0×10) on the difference between sodium deposition in muscle and skin, while taking the effects of age and BMI into account.
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Development for a Novel Transdiagnostic Intervention for Anhedonia
Duke University
  • Parsing within & between-person dynamics of therapy homework completion and clinical symptoms in two cognitive behavioral treatments for adults with anhedonia.
    Behaviour research and therapy (2023)
    Cernasov PM, Kinard JL, Walsh E, Kelley L, Phillips R, Pisoni A, Arnold M, Lowery SC, Ammirato M, Nagy GA, Oliver JA, Haworth K, Daughters SB, Dichter GS, Smoski M. Parsing within & between-person dynamics of therapy homework completion and clinical symptoms in two cognitive behavioral treatments for adults with anhedonia. Behav Res Ther. 2023 Jul; 166:104322.
    Abstract: Homework is a key theoretical component of cognitive-behavioral therapies, however, the effects of homework on clinical outcomes have largely been evaluated between-persons rather than within-persons.
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  • Longitudinal associations between perceived stress and anhedonia during psychotherapy.
    Journal of affective disorders (2023)
    Phillips R, Walsh E, Jensen T, Nagy G, Kinard J, Cernasov P, Smoski M, Dichter G. Longitudinal associations between perceived stress and anhedonia during psychotherapy. J Affect Disord. 2023 Jun 1; 330:206-213.
    Abstract: Chronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia.
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Smoking Cessation and the natural history of HIV-associated emphysema.
The Ohio State University
  • Nicotine receptor partial agonists for smoking cessation.
    The Cochrane database of systematic reviews (2023)
    Livingstone-Banks J, Fanshawe TR, Thomas KH, Theodoulou A, Hajizadeh A, Hartman L, Lindson N. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2023 May 5; 5(5):CD006103.
    Abstract: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007.
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Advarra: AHEAD 3-45 Study: A Placebo-Controlled, Double-Blind, Parallel-Treatment Arm, 216 Week Study to Evaluate Efficacy and Safety of Treatment With BAN2401 in Subjects With Preclinical Alzheimers Disease and Elevated Amyloid (A45 Trial) and in Subjects With Early Preclinical Alzheimers Disease and Intermediate Amyloid (A3 Trial)
Vanderbilt University Medical Center
  • Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment.
    Alzheimer's research & therapy (2023)
    Kirn DR, Grill JD, Aisen P, Ernstrom K, Gale S, Heidebrink J, Jicha G, Jimenez-Maggiora G, Johnson L, Peskind E, McCann K, Shaffer E, Sultzer D, Wang S, Sperling R, Raman R. Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment. Alzheimers Res Ther. 2023 May 2; 15(1):88.
    Abstract: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening.
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Vitamin D and type 2 diabetes
Northwestern University
  • Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study.
    Journal of diabetes and its complications (2023)
    Corbin KD, Pittas AG, Desouza C, Grdinovac KK, Herzig KH, Kashyap SR, Kim SH, Nelson J, Rasouli N, Vickery EM, Knowler WC, Pratley RE. Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study. J Diabetes Complications. 2023 Jun; 37(6):108475.
    Abstract: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD.
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  • Effect of intra-trial mean 25(OH)D level on diabetes risk, by race and weight: an ancillary analysis in the D2d randomized study cohort.
    The American journal of clinical nutrition (2023)
    Chatterjee R, Davenport CA, Vickery EM, Johnson KC, Kashyap SR, LeBlanc ES, Nelson J, Dagogo-Jack S, Pittas AG, Hughes BD, D2d Research Group, Steering Committee, Past Steering Committee members, Advisor. Effect of intra-trial mean 25(OH)D level on diabetes risk, by race and weight: an ancillary analysis in the D2d randomized study cohort. Am J Clin Nutr. 2023 Mar 29; :.
    Abstract: Higher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight.
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  • The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study.
    Journal of diabetes and its complications (2022)
    Desouza C, Chatterjee R, Vickery EM, Nelson J, Johnson KC, Kashyap SR, Lewis MR, Margolis K, Pratley R, Rasouli N, Sheehan PR, Pittas AG, D2d Research Group. Electronic address: d2d@tuftsmedicalcenter.org.. The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study. J Diabetes Complications. 2022 Jun 12; :108230.
    Abstract: Low blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes.
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  • Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes.
    European journal of clinical nutrition (2022)
    Johnson KC, Pittas AG, Margolis KL, Peters AL, Phillips LS, Vickery EM, Nelson J, Sheehan PR, Reboussin D, Malozowski S, Chatterjee R, D2d research group.. Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes. Eur J Clin Nutr. 2022 Feb 9; :.
    Abstract: Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D in the vitamin D and type 2 diabetes (D2d) study.
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  • Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study.
    The Journal of clinical endocrinology and metabolism (2021)
    Chatterjee R, Fuss P, Vickery EM, LeBlanc ES, Sheehan PR, Lewis MR, Dolor RJ, Johnson KC, Kashyap SR, Nelson J, Pittas AG, D2d Research Group.. Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study. J Clin Endocrinol Metab. 2021 Aug 18; 106(9):2767-2778.
    Abstract: Observational studies suggest that low vitamin D status may be a risk factor for cancer.
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  • Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes.
    The Journal of clinical endocrinology and metabolism (2020)
    Hsia DS, Rasouli N, Pittas AG, Lary CW, Peters A, Lewis MR, Kashyap SR, Johnson KC, LeBlanc ES, Phillips LS, Hempe JM, Desouza CV, D2d Research Group.. Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes. J Clin Endocrinol Metab. 2020 Mar 1; 105(3):.
    Abstract: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis.
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  • Vitamin D Supplementation and Prevention of Type 2 Diabetes.
    The New England journal of medicine (2019)
    Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, Brodsky I, Ceglia L, Chadha C, Chatterjee R, Desouza C, Dolor R, Foreyt J, Fuss P, Ghazi A, Hsia DS, Johnson KC, Kashyap SR, Kim S, LeBlanc ES, Lewis MR, Liao E, Neff LM, Nelson J, O'Ne. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019 Aug 8; 381(6):520-530.
    Abstract: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.
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  • Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience.
    Clinical trials (London, England) (2019)
    Aroda VR, Sheehan PR, Vickery EM, Staten MA, LeBlanc ES, Phillips LS, Brodsky IG, Chadha C, Chatterjee R, Ouellette MG, Desouza C, Pittas AG, D2d Research Group.. Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience. Clin Trials. 2019 Jun; 16(3):306-315.
    Abstract: To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record-supported and conventional recruitment methods.
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  • Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts.
    Diabetes care (2018)
    LeBlanc ES, Pratley RE, Dawson-Hughes B, Staten MA, Sheehan PR, Lewis MR, Peters A, Kim SH, Chatterjee R, Aroda VR, Chadha C, Neff LM, Brodsky IG, Rosen C, Desouza CV, Foreyt JP, Hsia DS, Johnson KC, Raskin P, Kashyap SR, O'Neil P, Phillips LS, Rasouli N,. Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts. Diabetes Care. 2018 Aug; 41(8):1590-1599.
    Abstract: To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes.
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  • Management of Hemoglobin Variants Detected Incidentally in HbA1c Testing: A Common Problem Currently Lacking a Standard Approach.
    Diabetes care (2017)
    Lewis MR, Macauley RC, Sheehan PR, Staten MA, Phillips LS, Rasouli N, Pittas AG, D2d Research Group.. Management of Hemoglobin Variants Detected Incidentally in HbA1c Testing: A Common Problem Currently Lacking a Standard Approach. Diabetes Care. 2017 Feb; 40(2):e8-e9.
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  • Rationale and design of the Vitamin D and Type 2 Diabetes (D2d) study: a diabetes prevention trial.
    Diabetes care (2014)
    Pittas AG, Dawson-Hughes B, Sheehan PR, Rosen CJ, Ware JH, Knowler WC, Staten MA, D2d Research Group. Rationale and design of the Vitamin D and Type 2 Diabetes (D2d) study: a diabetes prevention trial. Diabetes Care. 2014 Dec; 37(12):3227-34.
    Abstract: Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes.
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Positive affect skills for depression: Optimizing internet and mobile delivery (MARIGOLD)
Northwestern University
  • Positive Psychological Intervention Effects on Depression: Positive Emotion Does Not Mediate Intervention Impact in a Sample with Elevated Depressive Symptoms.
    Affective science (2023)
    Moskowitz JT, Jackson K, Freedman ME, Grote VE, Kwok I, Schuette SA, Cheung EO, Addington EL. Positive Psychological Intervention Effects on Depression: Positive Emotion Does Not Mediate Intervention Impact in a Sample with Elevated Depressive Symptoms. Affect Sci. 2023 Mar; 4(1):163-173.
    Abstract: Positive psychological interventions (PPIs), programs that specifically target positive emotions, cognitions, and behaviors, have been shown to reduce depression and improve other aspects of psychological well-being. However, potential pathways linking PPIs to better outcomes have been under-explored. In this paper, we report the results of a randomized trial of a self-guided online delivered PPI called MARIGOLD (Mobile Affect Regulation Intervention with the Goal of Lowering Depression). Participants with elevated depression were randomized to receive MARIGOLD ( = 539) or an emotion reporting control condition ( = 63). In addition to testing direct effects of the intervention on depressive symptoms, we explored whether positive or negative emotion-operationalized as past day, past week, reactivity, or flexibility-mediated the intervention impact on depression. Results demonstrated that participants in the MARIGOLD condition had reduced depressive symptoms compared to controls and, although the effect did not reach statistical significance, reductions in past day negative emotion appeared to mediate this effect. Contrary to hypotheses, the intervention did not increase positive emotion compared to the control condition. Discussion focuses on the need for future studies to continue investigating the mechanisms of action for PPIs with emphasis on theoretically-based measurement and operationalization of emotion and other potential mediators to maximize the ultimate impact of PPIs on psychological well-being. Clinical Trials registration #NCT02861755.
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  • Facilitator Contact, Discussion Boards, and Virtual Badges as Adherence Enhancements to a Web-Based, Self-guided, Positive Psychological Intervention for Depression: Randomized Controlled Trial.
    Journal of medical Internet research (2021)
    Moskowitz JT, Addington EL, Shiu E, Bassett SM, Schuette S, Kwok I, Freedman ME, Leykin Y, Saslow LR, Cohn MA, Cheung EO. Facilitator Contact, Discussion Boards, and Virtual Badges as Adherence Enhancements to a Web-Based, Self-guided, Positive Psychological Intervention for Depression: Randomized Controlled Trial. J Med Internet Res. 2021 Sep 22; 23(9):e25922.
    Abstract: Adherence to self-guided interventions tends to be very low, especially in people with depression. Prior studies have demonstrated that enhancements may increase adherence, but little is known about the efficacy of various enhancements in comparison to, or in combination with, one another.
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  • A Self-Paced, Web-Based, Positive Emotion Skills Intervention for Reducing Symptoms of Depression: Protocol for Development and Pilot Testing of MARIGOLD.
    JMIR research protocols (2018)
    Cheung EO, Addington EL, Bassett SM, Schuette SA, Shiu EW, Cohn MA, Leykin Y, Saslow LR, Moskowitz JT. A Self-Paced, Web-Based, Positive Emotion Skills Intervention for Reducing Symptoms of Depression: Protocol for Development and Pilot Testing of MARIGOLD. JMIR Res Protoc. 2018 Jun 5; 7(6):e10494.
    Abstract: Living with elevated symptoms of depression can have debilitating consequences for an individual's psychosocial and physical functioning, quality of life, and health care utilization. A growing body of evidence demonstrates that skills for increasing positive emotion can be helpful to individuals with depression. Although Web-based interventions to reduce negative emotion in individuals with depression are available, these interventions frequently suffer from poor retention and adherence and do not capitalize on the potential benefits of increasing positive emotion.
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Cognitive, emotional, and linguistic contributions to childhood stuttering
Vanderbilt University Medical Center
  • Behavioral and cognitive-affective features of stuttering in preschool-age children: Regression and exploratory cluster analyses.
    Journal of fluency disorders (2023)
    Millager RA, Dietrich MS, Jones RM. Behavioral and cognitive-affective features of stuttering in preschool-age children: Regression and exploratory cluster analyses. J Fluency Disord. 2023 Jun; 76:105972.
    Abstract: The purpose of this study was to investigate associations among behavioral and cognitive-affective features of stuttering in preschool-age children who stutter, and the extent to which participants may or may not cluster together based on multiple indices of stuttering.
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  • Differences in the relation between temperament and vocabulary based on children's stuttering trajectories.
    Journal of communication disorders (2019)
    Singer CM, Walden TA, Jones RM. Differences in the relation between temperament and vocabulary based on children's stuttering trajectories. J Commun Disord. 2019 Mar - Apr; 78:57-68.
    Abstract: The purpose of this study was to assess the relation between temperament and vocabulary development for children who stutter and persist, children who stutter and recover and children who do not stutter.
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  • Cortical associates of emotional reactivity and regulation in childhood stuttering.
    Journal of fluency disorders (2018)
    Zengin-Bolatkale H, Conture EG, Key AP, Walden TA, Jones RM. Cortical associates of emotional reactivity and regulation in childhood stuttering. J Fluency Disord. 2018 Jun; 56:81-99.
    Abstract: This study sought to determine the cortical associates of emotional reactivity and emotion regulation (as indexed by the amplitude of evoked response potentials [ERP]) in young children who do and do not stutter during passive viewing of pleasant, unpleasant and neutral pictures.
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A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and Safety of a Combined Oral Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone
The Ohio State University
  • Combined Oral Contraceptive Adherence and Pregnancy Rates.
    Obstetrics and gynecology (2023)
    Creinin MD, Jensen JT, Chen MJ, Black A, Costescu D, Foidart JM. Combined Oral Contraceptive Adherence and Pregnancy Rates. Obstet Gynecol. 2023 May 1; 141(5):989-994.
    Abstract: To assess the relationship of adherence and pregnancy in participants using an estetrol and drospirenone combined oral contraceptive.
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Diabetes Self-Management
Duke University
  • Learning in a Virtual Environment to Improve Type 2 Diabetes Outcomes: Randomized Controlled Trial.
    JMIR formative research (2023)
    Johnson CM, D'Eramo Melkus G, Reagan L, Pan W, Amarasekara S, Pereira K, Hassell N, Nowlin S, Vorderstrasse A. Learning in a Virtual Environment to Improve Type 2 Diabetes Outcomes: Randomized Controlled Trial. JMIR Form Res. 2023 Apr 20; 7:e40359.
    Abstract: Given the importance of self-management in type 2 diabetes mellitus (T2DM), a major aspect of health is providing diabetes self-management education and support. Known barriers include access, availability, and the lack of follow through on referral to education programs. Virtual education and support have increased in use over the last few years.
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  • Creating a sustainable collaborative consumer health application for chronic disease self-management.
    Journal of biomedical informatics (2017)
    Johnson CM, McIlwain S, Gray O, Willson B, Vorderstrasse A. Creating a sustainable collaborative consumer health application for chronic disease self-management. J Biomed Inform. 2017 Jul; 71:198-206.
    Abstract: As the prevalence of chronic diseases increase, there is a need for consumer-centric health informatics applications that assist individuals with disease self-management skills. However, due to the cost of development of these applications, there is also a need to build a disease agnostic architecture so that they could be reused for any chronic disease. This paper describes the architecture of a collaborative virtual environment (VE) platform, LIVE©, that was developed to teach self-management skills and provide social support to those individuals with type 2 diabetes. However, a backend database allows for the application to be easily reused for any chronic disease. We tested its usability in the context of a larger randomized controlled trial of its efficacy. The usability was scored as 'good' by half of the participants in the evaluation. Common errors in the testing and solutions to address initial usability issues are discussed. Overall, LIVE© represents a usable and generalizable platform that will be adapted to other chronic diseases and health needs in future research and applications.
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  • Diabetes Learning in Virtual Environments: Testing the Efficacy of Self-Management Training and Support in Virtual Environments (Randomized Controlled Trial Protocol).
    Nursing research (2015)
    Vorderstrasse AA, Melkus GD, Pan W, Lewinski AA, Johnson CM. Diabetes Learning in Virtual Environments: Testing the Efficacy of Self-Management Training and Support in Virtual Environments (Randomized Controlled Trial Protocol). Nurs Res. 2015 Nov-Dec; 64(6):485-93.
    Abstract: Ongoing self-management improves outcomes for those with Type 2 diabetes (T2D); however, there are many barriers to patients receiving assistance in this from the healthcare system and peers. Findings from our pilot study showed that a virtual diabetes community on the Internet with real-time interaction among peers with T2D-and with healthcare professionals-is feasible and has the potential to influence clinical and psychosocial outcomes.
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The IMPACT Study: Inflammatory Responses, Mood, and Physical Fitness after Cancer Treatment
The Ohio State University
  • Conflicts hurt: social stress predicts elevated pain and sadness after mild inflammatory increases.
    Pain (2023)
    Madison AA, Renna M, Andridge R, Peng J, Shrout MR, Sheridan J, Lustberg M, Ramaswamy B, Wesolowski R, Williams NO, Noonan AM, Reinbolt RE, Stover DG, Cherian MA, Malarkey WB, Kiecolt-Glaser JK. Conflicts hurt: social stress predicts elevated pain and sadness after mild inflammatory increases. Pain. 2023 Sep 1; 164(9):1985-1994.
    Abstract: Individuals respond differently to inflammation. Pain, sadness, and fatigue are common correlates of inflammation among breast cancer survivors. Stress may predict response intensity. This study tested whether breast cancer survivors with greater exposure to acute or chronic social or nonsocial stress had larger increases in pain, sadness, and fatigue during an acute inflammatory response. In total, 156 postmenopausal breast cancer survivors (ages 36-78 years, stage I-IIIA, 1-9 years posttreatment) were randomized to either a typhoid vaccine/saline placebo or the placebo/vaccine sequence, which they received at 2 separate visits at least 1 month apart. Survivors had their blood drawn every 90 minutes for the next 8 hours postinjection to assess levels of interleukin-6 and interleukin-1 receptor antagonist (IL-1Ra). Shortly after each blood draw, they rated their current levels of pain, sadness, and fatigue. Women also completed the Test of Negative Social Exchange to assess chronic social stress and the Trier Inventory of Chronic Stressors screen to index chronic general stress. At each visit, a trained experimenter administered the Daily Inventory of Stressful Events to assess social and nonsocial stress exposure within the past 24 hours. After statistical adjustment for relevant demographic and behavioral covariates, the most consistent results were that survivors who reported more chronic social stress reported more pain and sadness in response to IL-1Ra increases. Frequent and ongoing social stress may sensitize the nervous system to the effects of inflammation, with potential implications for chronic pain and depression risk among breast cancer survivors.
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Breast Risk Assessment - Focus Groups
Vanderbilt University Medical Center
  • Black Women's Perspectives on Breast Cancer Risk Assessment.
    Journal of the American College of Radiology : JACR (2023)
    Spalluto LB, Bonnet K, Sonubi C, Reid SA, Lewis JA, Ernst LL, Davis KM, Wahab R, Agrawal P, D'Agostino C, Gregory K, Berardi E, Hartsfield C, Sanderson M, Selove R, Schlundt D, Audet CM. Black Women's Perspectives on Breast Cancer Risk Assessment. J Am Coll Radiol. 2023 Mar; 20(3):314-323.
    Abstract: The aim of this study was to gather the perspectives of Black women on breast cancer risk assessment through a series of one-on-one interviews.
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Optimizing Outcomes of Treatment Resistant Depression in Older Adults
New York State Psychiatric Institute and Research Foundation for Mental Hygiene
  • Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.
    The New England journal of medicine (2023)
    Lenze EJ, Mulsant BH, Roose SP, Lavretsky H, Reynolds CF 3rd, Blumberger DM, Brown PJ, Cristancho P, Flint AJ, Gebara MA, Gettinger TR, Lenard E, Miller JP, Nicol GE, Oughli HA, Pham VT, Rollman BL, Yang L, Karp JF. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression. N Engl J Med. 2023 Mar 23; 388(12):1067-1079.
    Abstract: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied.
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HVTN 106; A Phase 1 Randomized, Double-Blinded, Placebo Controlled Clinical Trial to Evaluate the Safety and Immunogenicity of 3 Different HIV-1 DNA Priming Regimens (Nat-B env, CON-S env, and Mosaic env) with MVA CMDR Boosts in Healthy, HIV-1-Uninfected Adults
The University of Alabama at Birmingham
  • Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults.
    The Journal of clinical investigation (2023)
    Cohen KW, Fiore-Gartland A, Walsh SR, Yusim K, Frahm N, Elizaga ML, Maenza J, Scott H, Mayer KH, Goepfert PA, Edupuganti S, Pantaleo G, Hutter J, Morris DE, De Rosa SC, Geraghty DE, Robb ML, Michael NL, Fischer W, Giorgi EE, Malhi H, Pensiero MN, Ferrari. Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults. J Clin Invest. 2023 Feb 15; 133(4):.
    Abstract: BACKGROUNDMosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODSThis double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara-vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTSEnv-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2-4.2) for mosaic recipients, 1.6 (95% CI, 0.82-2.6) for CON-S recipients, and 1.1 (95% CI, 0.62-1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSIONPriming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02296541.FUNDINGUS NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.
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  • Preexisting memory CD4+ T cells contribute to the primary response in an HIV-1 vaccine trial.
    The Journal of clinical investigation (2021)
    Campion SL, Brenna E, Thomson E, Fischer W, Ladell K, McLaren JE, Price DA, Frahm N, McElrath JM, Cohen KW, Maenza JR, Walsh SR, Baden LR, Haynes BF, Korber B, Borrow P, McMichael AJ. Preexisting memory CD4+ T cells contribute to the primary response in an HIV-1 vaccine trial. J Clin Invest. 2021 Dec 1; 131(23):.
    Abstract: Naive and memory CD4+ T cells reactive with human immunodeficiency virus type 1 (HIV-1) are detectable in unexposed, unimmunized individuals. The contribution of preexisting CD4+ T cells to a primary immune response was investigated in 20 HIV-1-seronegative volunteers vaccinated with an HIV-1 envelope (Env) plasmid DNA prime and recombinant modified vaccinia virus Ankara (MVA) boost in the HVTN 106 vaccine trial (clinicaltrials.gov NCT02296541). Prevaccination naive or memory CD4+ T cell responses directed against peptide epitopes in Env were identified in 14 individuals. After priming with DNA, 40% (8/20) of the elicited responses matched epitopes detected in the corresponding preimmunization memory repertoires, and clonotypes were shared before and after vaccination in 2 representative volunteers. In contrast, there were no shared epitope specificities between the preimmunization memory compartment and responses detected after boosting with recombinant MVA expressing a heterologous Env. Preexisting memory CD4+ T cells therefore shape the early immune response to vaccination with a previously unencountered HIV-1 antigen.
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Customized Cortical Stimulation Therapy in the Rehabilitation of Stroke Patients
Emory University
  • Stroke Lesion Volume and Injury to Motor Cortex Output Determines Extent of Contralesional Motor Cortex Reorganization.
    Neurorehabilitation and neural repair (2023)
    Buetefisch CM, Haut MW, Revill KP, Shaeffer S, Edwards L, Barany DA, Belagaje SR, Nahab F, Shenvi N, Easley K. Stroke Lesion Volume and Injury to Motor Cortex Output Determines Extent of Contralesional Motor Cortex Reorganization. Neurorehabil Neural Repair. 2023 Feb-Mar; 37(2-3):119-130.
    Abstract: After stroke, increases in contralesional primary motor cortex (M1) activity and excitability have been reported. In pre-clinical studies, M1 reorganization is related to the extent of ipsilesional M1 (M1) injury, but this has yet to be tested clinically.
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A phase 1b clinical trial to evaluate the safety and immunogenicity of different combinations of DNA-HIV-PT123 and AIDSVAX® B/E in healthy, HIV uninfected adult participants (HVTN 105)
Vanderbilt University Medical Center
  • Mixed Origins: HIV gp120-Specific Memory Develops from Pre-Existing Memory and Naive B Cells Following Vaccination in Humans.
    AIDS research and human retroviruses (2023)
    Basu M, Fucile C, Piepenbrink MS, Bunce CA, Man LX, Liesveld J, Rosenberg AF, Keefer MC, Kobie JJ. Mixed Origins: HIV gp120-Specific Memory Develops from Pre-Existing Memory and Naive B Cells Following Vaccination in Humans. AIDS Res Hum Retroviruses. 2023 Mar 22; :.
    Abstract: The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naive B cell receptor, fail to bind Env, suggesting that the initial responding B cell population not only exclusively comprises a naive population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing, focused on immunoglobulin G (IgG), IgA, and IgM, VH-lineage tracking, we identified four of these mAb lineages in pre-immune peripheral blood. We also looked through the ∼7 month postvaccination bone marrow, and interestingly, several of these lineages that were found in prevaccination blood were still persistent in the postvaccination bone marrow, including the CD138+ long-lived plasma cell compartment. The majority of the pre-immune lineage members included IgM, however, IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naive and cross-reactive memory B cells. ClinicalTrials.gov NCT02207920.
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  • Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials.
    PLoS pathogens (2021)
    Fischinger S, Cizmeci D, Deng D, Grant SP, Frahm N, McElrath J, Fuchs J, Bart PA, Pantaleo G, Keefer M, O Hahn W, Rouphael N, Churchyard G, Moodie Z, Donastorg Y, Streeck H, Alter G. Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials. PLoS Pathog. 2021 Nov; 17(11):e1010016.
    Abstract: Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies. Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).
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  • Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans.
    Cell reports. Medicine (2020)
    Basu M, Piepenbrink MS, Francois C, Roche F, Zheng B, Spencer DA, Hessell AJ, Fucile CF, Rosenberg AF, Bunce CA, Liesveld J, Keefer MC, Kobie JJ. Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans. Cell Rep Med. 2020 May 19; 1(2):.
    Abstract: Induction of persistent HIV-1 Envelope (Env) specific antibody (Ab) is a primary goal of HIV vaccine strategies; however, it is unclear whether HIV Env immunization in humans induces bone marrow plasma cells, the presumed source of long-lived systemic Ab. To define the features of Env-specific plasma cells after vaccination, samples were obtained from HVTN 105, a phase I trial testing the same gp120 protein immunogen, AIDSVAX B/E, used in RV144, along with a DNA immunogen in various prime and boost strategies. Boosting regimens that included AIDSVAX B/E induced robust peripheral blood plasmablast responses. The Env-specific immunoglobulin repertoire of the plasmablasts is dominated by VH1 gene usage and targeting of the V3 region. Numerous plasmablast-derived immunoglobulin lineages persisted in the bone marrow >8 months after immunization, including in the CD138 long-lived plasma cell compartment. These findings identify a cellular linkage for the development of sustained Env-specific Abs following vaccination in humans.
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  • DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.
    The Journal of clinical investigation (2019)
    Rouphael NG, Morgan C, Li SS, Jensen R, Sanchez B, Karuna S, Swann E, Sobieszczyk ME, Frank I, Wilson GJ, Tieu HV, Maenza J, Norwood A, Kobie J, Sinangil F, Pantaleo G, Ding S, McElrath MJ, De Rosa SC, Montefiori DC, Ferrari G, Tomaras GD, Keefer MC, HVTN. DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial. J Clin Invest. 2019 Nov 1; 129(11):4769-4785.
    Abstract: BACKGROUNDRV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).METHODSOne hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4) and received intramuscular injections at 0, 1, 3, and 6 months (M): T1 received protein at M0 and M1 and DNA at M3 and M6; T2 received DNA at M0 and M1 and protein at M3 and M6; T3 received DNA at M0, M1, M3, and M6 with protein coadministered at M3 and M6; and T4 received protein and DNA coadministered at each vaccination visit.RESULTSAll regimens were well tolerated. Antibodies binding to gp120 and V1V2 scaffold were observed in 95%-100% of participants in T3 and T4, two weeks after final vaccination at high magnitude. While IgG3 responses were highest in T3, a lower IgA/IgG ratio was observed in T4. Binding antibodies persisted at 12 months in 35%-100% of participants. Antibody-dependent cell-mediated cytotoxicity and tier 1 neutralizing-antibody responses had higher response rates for T3 and T4, respectively. CD4+ T cell responses were detectable in all treatment groups (32%-64%) without appreciable CD8+ T cell responses.CONCLUSIONThe DNA/protein combination regimens induced high-magnitude and long-lasting HIV V1V2-binding antibody responses, and early coadministration of the 2 vaccines led to a more rapid induction of these potentially protective responses.TRIAL REGISTRATIONClinicalTrials.gov NCT02207920.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069511, UM1 AI069470, UM1 AI069534, P30 AI450008, UM1 AI069439, UM1 AI069481, and UM1 AI069496; the National Center for Advancing Translational Sciences, NIH (grant UL1TR001873); and the Bill & Melinda Gates Foundation (grant OPP52845).
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Stanford Center for Back Pain
Stanford University
  • Self-reported physical function is strongly related to pain behavior and pain interference and weakly related to physical capacity in people with chronic low back pain.
    Musculoskeletal science & practice (2023)
    Karayannis NV, Smuck M, Law C, Mackey SC, Gross JJ, Darnall BD, Hush J. Self-reported physical function is strongly related to pain behavior and pain interference and weakly related to physical capacity in people with chronic low back pain. Musculoskelet Sci Pract. 2023 Feb; 63:102721.
    Abstract: Inclusion of self-reported and capacity-based measures may help to further elucidate the interactive link between how people think and move.
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  • Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials.
    JMIR research protocols (2022)
    Mackey S, Gilam G, Darnall B, Goldin P, Kong JT, Law C, Heirich M, Karayannis N, Kao MC, Tian L, Manber R, Gross J. Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials. JMIR Res Protoc. 2022 Sep 27; 11(9):e37823.
    Abstract: Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated.
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  • Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial.
    Trials (2018)
    Kong JT, MacIsaac B, Cogan R, Ng A, Law CSW, Helms J, Schnyer R, Karayannis NV, Kao MC, Tian L, Darnall BD, Gross JJ, Mackey S, Manber R. Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial. Trials. 2018 Dec 13; 19(1):685.
    Abstract: Chronic low back pain (CLBP) is the most common chronic pain condition and is often resistant to conventional treatments. Acupuncture is a popular alternative for treating CLBP but its mechanisms of action remain poorly understood. Evidence suggests that pain regulatory mechanisms (particularly the ascending and secondarily the descending pain modulatory pathways) and psychological mechanisms (e.g., expectations, pain catastrophizing and self-efficacy) may be involved in the pathogenesis of CLBP and its response to treatments. We will examine these mechanisms in the treatment of CLBP by electroacupuncture (EA).
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Phase I Study of the Safety of a Replication-Defective Herpes Simplex Virus-2 Vaccine, HSV529, in Adults Aged 18 to 40 Years With or Without HSV Infection
The National Institutes of Health
  • Sex and prior exposure jointly shape innate immune responses to a live herpesvirus vaccine.
    eLife (2023)
    Cheung F, Apps R, Dropulic L, Kotliarov Y, Chen J, Jordan T, Langweiler M, Candia J, Biancotto A, Han KL, Rachmaninoff N, Pietz H, Wang K, Tsang JS, Cohen JI. Sex and prior exposure jointly shape innate immune responses to a live herpesvirus vaccine. Elife. 2023 Jan 17; 12:.
    Abstract: Both sex and prior exposure to pathogens are known to influence responses to immune challenges, but their combined effects are not well established in humans, particularly in early innate responses critical for shaping subsequent outcomes.
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  • A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection.
    The Journal of infectious diseases (2019)
    Dropulic LK, Oestreich MC, Pietz HL, Laing KJ, Hunsberger S, Lumbard K, Garabedian D, Turk SP, Chen A, Hornung RL, Seshadri C, Smith MT, Hosken NA, Phogat S, Chang LJ, Koelle DM, Wang K, Cohen JI. A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection. J Infect Dis. 2019 Aug 9; 220(6):990-1000.
    Abstract: Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide.
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Efficacy of Bimodal Visual-Olfactory Training in Patients with COVID-19 resultant Hyposmia or Anosmia Using Patient-Preferred Scents (VOLT Trial – Visual-OLfactory Training)
Washington University in St. Louis
  • Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial.
    JAMA otolaryngology-- head & neck surgery (2023)
    Khan AM, Piccirillo J, Kallogjeri D, Piccirillo JF. Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2023 Feb 1; 149(2):141-149.
    Abstract: The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential.
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Positive Emotional Processing: Exploring Novel Treatment Targets in Social Phobia - New Data
University of California San Diego
  • Randomized controlled trial of computerized approach/avoidance training in social anxiety disorder: Neural and symptom outcomes.
    Journal of affective disorders (2022)
    Bomyea J, Sweet A, Davey DK, Boland M, Paulus MP, Stein MB, Taylor CT. Randomized controlled trial of computerized approach/avoidance training in social anxiety disorder: Neural and symptom outcomes. J Affect Disord. 2022 Dec 19; :.
    Abstract: Social anxiety is associated with diminished automatic approach toward positive social cues that may limit the ability to connect with others. This diminished approach bias may be a modifiable treatment target. We evaluated the effects of an approach avoidance training procedure on positive emotions, social relationship outcomes, clinical symptoms, and neural indices of social approach and reward processing. Forty-five individuals with social anxiety disorder were randomized (parallel 1:1 randomization) to complete computerized Approach Positive training (n = 21) or Balanced training(n = 24). Sessions included a standardized social interaction task. Participants were blind to training group. Participants completed clinical outcome measures and functional magnetic resonance imaging at baseline and post intervention with an MRI-compatible AAT and the social incentive delay task (SID). Both groups displayed significant improvements of similar magnitude on the primary outcome of social connectedness (between group post-treatment d = -0.21) but not positive affect, d = -0.09 from before to after treatment, persisting through follow-up. Groups demonstrated significant improvements on additional outcomes including anxiety, depression, and anhedonia symptoms. Participants in Approach Positive AAT demonstrated increased activation in the thalamus and medial prefrontal cortex during social versus neutral- approach relative to Balanced AAT during the fMRI AAT. Participants in Balanced AAT showed increased activation in regions within an a priori-defined striatum region of interest mask during anticipation of social reward (vs. baseline) in the SID relative to Approach Positive AAT. At a neural processing level AAT may influence the valuation and motivations associated with positive social cues regulated by the mPFC and thalamus. NCT02136212, NIMH R00MH090243.
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A Phase 1b Study to Evaluate the Safety and Immunogenicity of MEDI7510 in Older Adults
Vanderbilt University Medical Center
  • A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine.
    Science translational medicine (2022)
    Chang LA, Phung E, Crank MC, Morabito KM, Villafana T, Dubovsky F, Falloon J, Esser MT, Lin BC, Chen GL, Graham BS, Ruckwardt TJ. A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine. Sci Transl Med. 2022 Dec 21; 14(676):eade0424.
    Abstract: There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [prefusion (pre-F)] and MEDI7510 [postfusion (post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neutralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1-vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells.
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  • Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses.
    Clinical and vaccine immunology : CVI (2017)
    Falloon J, Talbot HK, Curtis C, Ervin J, Krieger D, Dubovsky F, Takas T, Yu J, Yu L, Lambert SL, Villafana T, Esser MT. Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses. Clin Vaccine Immunol. 2017 Sep; 24(9):.
    Abstract: This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this randomized, double-blind study, 261 subjects aged ≥60 years received inactivated influenza vaccine (IIV), a vaccine containing 120 μg sF with escalating doses of GLA (1, 2.5, or 5 μg) in SE, or a vaccine containing 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were also randomized to receive IIV or placebo. Immunity to RSV was assessed by detection of microneutralizing, anti-F immunoglobulin G, and palivizumab-competitive antibodies and F-specific gamma interferon enzyme-linked immunosorbent spot assay T-cell responses. Higher adjuvant doses increased injection site discomfort, but at the highest dose, the reactogenicity was similar to that of IIV. Significant humoral and cellular immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulation resulted in the highest responses in all subjects and in older subjects. These results confirm previous observations of vaccine tolerability, safety, and immunogenicity and were used to select the 120 μg sF plus 5.0 μg GLA formulation for phase 2 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT02289820.).
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SmokefreeSGM, A Text-based Smoking Cessation Feasibility Trial for Sexual and Gender Minority Groups
University of Texas Health Science Center at Houston
  • A Text-Based Smoking Cessation Intervention for Sexual and Gender Minority Groups: Protocol for a Feasibility Trial.
    JMIR research protocols (2022)
    Tami-Maury I, Klaff R, Hussin A, Smith NG, Chang S, McNeill L, Reitzel LR, Shete S, Abroms LC. A Text-Based Smoking Cessation Intervention for Sexual and Gender Minority Groups: Protocol for a Feasibility Trial. JMIR Res Protoc. 2022 Dec 9; 11(12):e42553.
    Abstract: Smoking among sexual and gender minority (SGM) groups, which include lesbian, gay, bisexual, transgender, and queer individuals, has been reported to be highly prevalent. This is attributed to several factors, including minority-specific stress and targeted tobacco marketing. Therefore, this population is at an increased risk for tobacco-related diseases. SMS text messaging programs have been found to be effective for smoking cessation and appeal to traditionally hard-to-reach populations over other interventions. It has also been suggested that targeted and tailored interventions could be more effective among SGM smokers because they can be designed to assure a safe, validating health care environment that enhances receptivity to cessation.
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Assessment of the Efficacy of Digital CBT for Anxiety in Adults who Have Experienced An Acute Cardiovascular Event
Boston University
  • Initial assessment of the feasibility and efficacy of a scalable digital CBT for generalized anxiety and associated health behaviors in a cardiovascular disease population.
    Contemporary clinical trials (2023)
    Parsons EM, Hiserodt M, Otto MW. Initial assessment of the feasibility and efficacy of a scalable digital CBT for generalized anxiety and associated health behaviors in a cardiovascular disease population. Contemp Clin Trials. 2023 Jan; 124:107018.
    Abstract: Generalized anxiety disorder (GAD) is a significant yet modifiable risk factor for worse cardiovascular disease (CVD) outcomes. The treatment of GAD in an accessible manner represents an unmet need in CVD, given that patients with CVD experience numerous barriers to in-person treatment engagement. This paper presents the rationale and design for an investigation of a strategy to enhance care for patients with CVD by introducing a scalable, affordable, and system-friendly digital intervention that targets a prominent modifiable risk factor (generalized anxiety and associated worry) for negative health behaviors in CVD. In the context of a randomized clinical trial design, we describe an experimental medicine approach for evaluating the degree to which a digital cognitive behavior therapy (dCBT), relative to a waitlist control group, engages anxiety and worry outcomes in a sample of 90 adults who have experienced an acute CVD event and who have comorbid GAD symptoms. We also investigate the degree to which dCBT leads to greater changes in GAD symptoms compared to the control condition and whether reductions in these symptoms are associated with corresponding reductions in cardiac anxiety and cardiac health behaviors (including smoking, physical activity, heart-healthy diet, and medication adherence). We propose that by targeting GAD symptoms in CVD in a way that does not tax ongoing medical care provision, we have the potential to improve the uptake of effective care and address both GAD and associated health behaviors.
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Effect of Critical Distance and Reverberation on Listening Effort for Adults with Normal Hearing
Vanderbilt University Medical Center
  • Effects of Critical Distance and Reverberation on Listening Effort in Adults.
    Journal of speech, language, and hearing research : JSLHR (2022)
    Huang H, Ricketts TA, Hornsby BWY, Picou EM. Effects of Critical Distance and Reverberation on Listening Effort in Adults. J Speech Lang Hear Res. 2022 Dec 12; 65(12):4837-4851.
    Abstract: Mixed historical data on how listening effort is affected by reverberation and listener-to-speaker distance challenge existing models of listening effort. This study investigated the effects of reverberation and listener-to-speaker distance on behavioral and subjective measures of listening effort: (a) when listening at a fixed signal-to-noise ratio (SNR) and (b) at SNRs that were manipulated so that word recognition would be comparable across different reverberation times and listening distances. It was expected that increased reverberation would increase listening effort but only when listening outside critical distance.
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Utilizing Augmented Reality as an Adjunct for Smoking Cessation; Development and Initial Validation
Moffitt Cancer Center
  • Augmented reality as a novel approach for addiction treatment: development of a smoking cessation app.
    Annals of medicine (2022)
    Yang MJ, Brandon KO, Sutton SK, Kleinjan M, Sawyer LE, Brandon TH, Vinci C. Augmented reality as a novel approach for addiction treatment: development of a smoking cessation app. Ann Med. 2022 Dec; 54(1):3096-3106.
    Abstract: Augmented reality (AR) is a rapidly developing technology that has substantial potential as a novel approach for addiction treatment, including tobacco use. AR can facilitate the delivery of cue exposure therapy (CET) such that individuals can experience the treatment in their natural environments as viewed via a smartphone screen, addressing the limited generalizbility of extinction learning. Previously, our team developed a basic AR app for smoking cessation and demonstrated the necessary mechanisms for CET. Specifically, we showed that the AR smoking cues, compared to neutral cues, elicited substantial cue reactivity (i.e. increased urge) and that repeated exposure to the AR smoking cues reduced urge (i.e. extinction) in a laboratory setting. Here we report the next step in the systematic development of the AR app, in which we assessed the usability and acceptability of the app among daily smokers in their natural environments.
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  • Augmented reality for extinction of cue-provoked urges to smoke: Proof of concept.
    Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors (2022)
    Yang MJ, Brandon KO, Sutton SK, Kleinjan M, Hernandez LM, Sawyer LE, Brandon TH, Vinci C. Augmented reality for extinction of cue-provoked urges to smoke: Proof of concept. Psychol Addict Behav. 2022 Jul 14; :.
    Abstract: Cue-exposure therapy (CET) aims to extinguish conditioned cue reactivity (CR) to aid in smoking cessation. A key disadvantage of extant CET is its limited ability to generalize extinction to the real world. Our team developed a set of augmented reality smoking-related and neutral cues that can appear in real-time in smokers' natural environments as viewed through a smartphone screen. Prior to deployment as a clinical tool, the present study tested the ability of AR smoking cues to extinguish CR in a controlled laboratory study with an AR smartphone application developed for this project. We hypothesized that daily smokers who completed a single session of cue exposure with AR smoking cues (extinction condition) would demonstrate lower cue-provoked urge to smoke at posttest compared to those who viewed AR neutral cues (control condition).
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Preventing Alzheimer's Disease with Cognitive Training The PACT Trial
Duke University
  • The Preventing Alzheimer's with Cognitive Training (PACT) randomized clinical trial.
    Contemporary clinical trials (2022)
    Nicholson JS, Hudak EM, Phillips CB, Chanti-Ketterl M, O'Brien JL, Ross LA, Lister JJ, Burke JR, Potter G, Plassman BL, Woods AJ, Krischer J, Edwards JD. The Preventing Alzheimer's with Cognitive Training (PACT) randomized clinical trial. Contemp Clin Trials. 2022 Oct 28; 123:106978.
    Abstract: To address the rising prevalence of Alzheimer's disease and related dementias, effective interventions that can be widely disseminated are warranted. The Preventing Alzheimer's with Cognitive Training study (PACT) investigates a commercially available computerized cognitive training program targeting improved Useful Field of View Training (UFOVT) performance. The primary goal is to test the effectiveness of UFOVT to reduce incidence of clinically defined mild cognitive impairment (MCI) or dementia with a secondary objective to examine if effects are moderated by plasma β-amyloid level or apolipoprotein E e4 (APOE e4) allele status.
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Examining Stress and Arousal Across Pubertal Development in ASD
Vanderbilt University Medical Center
  • Examination of pubertal timing and tempo in females and males with autism spectrum disorder compared to typically developing youth.
    Autism research : official journal of the International Society for Autism Research (2022)
    Corbett BA, Muscatello RA, Kim A, Vandekar S, Duffus S, Sparks S, Tanguturi Y. Examination of pubertal timing and tempo in females and males with autism spectrum disorder compared to typically developing youth. Autism Res. 2022 Aug 1; :.
    Abstract: Autism spectrum disorder (ASD) is characterized by impaired social communication and poor adaptation to change; thus, pubertal development may be precarious. Pubertal timing and tempo were measured in 244 youth (7.9% Black, 83.3% White, and 8.7% multiracial) with ASD (N = 140) and typical development (N = 104). Pubertal development was measured using Tanner staging of Genital (G, males), Breast (B, females), and pubic hair (PH) in both sexes at Year 1 (10-13 years), Year 2 (11-14 years), and Year 3 (12-15 years). Nonlinear mixed effects models analyzed interindividual differences in timing and tempo. For both sexes, ASD and higher body mass index were associated with earlier pubertal timing. Males generally exhibited faster tempo than females. Linear regression models did not show associations between pubertal timing and internalizing symptoms at time three. Findings showing advanced pubertal maturation in ASD youth suggest greater risk of psychological, social, and physiological challenges. LAY SUMMARY: Youth with ASD have difficulty in social communication and adaption to change, thus puberty may be a challenging transition. The study examined onset (timing) and progression (tempo) of puberty over three years, using physical exam, in 244 adolescents with and without ASD, enrolled at ages 10-13. ASD youth started puberty earlier, while males generally progressed at a faster pace. Further examination of puberty in ASD should identify impact on social, behavioral, and mental health outcomes.
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  • Camouflaging in Autism: Examining Sex-Based and Compensatory Models in Social Cognition and Communication.
    Autism research : official journal of the International Society for Autism Research (2021)
    Corbett BA, Schwartzman JM, Libsack EJ, Muscatello RA, Lerner MD, Simmons GL, White SW. Camouflaging in Autism: Examining Sex-Based and Compensatory Models in Social Cognition and Communication. Autism Res. 2021 Jan; 14(1):127-142.
    Abstract: Camouflaging refers to behavioral adaptations that individuals with autism spectrum disorder (ASD), especially females, use to mask symptoms during social situations. Compensation is a component of camouflaging in which an individual's observed behavior is considerably better than actual ability. The study explored diagnostic, sex-based, and compensatory differences using the Contextual Assessment of Social Skills (CASS). The sample included 161 youth 10:0-to-16:11 years (115 males, 46 females). T-tests were performed based on sex (female, male) or High (good ADOS + poor Theory of Mind (TOM)) compared to Low (poor ADOS + poor TOM) Compensation groups. Comparisons were examined for Social Affect (SA), Restricted Repetitive Behavior, (RRB), IQ, social behavior (Positive Affect, Overall Involvement) and communication (Vocal Expression, Gestures). Females exhibited fewer RRB t(158) = 3.05, P = 0.003, d = 0.54. For the CASS, females evidenced more Vocal Expressiveness t(157) = -2.03, P = 0.05, d = 0.35, which corroborates sex-based differences in the literature. Compensation group differences indicated the High compared to Low group showed stronger Social and Communication behaviors on the CASS for Vocal Expression t(72) = 2.56, P = 0.01, d = 0.62, and overall rapport t(72) = 2.36, P = 0.02, d = 0.56. Several differences were observed when the groups were stratified based on level of compensation, with the High compensation participants showing stronger social engagement and communication behaviors. Findings may inform efforts to understand camouflaging, compensation, and clinical practices for male and female adolescents with ASD. A more nuanced consideration of camouflaging alongside compensation models reveals subtle differences in cognition, behavior, and affect that may reflect underlying profiles of challenge and strength in youth with ASD. LAY SUMMARY: Camouflaging refers to ways individuals with autism spectrum disorder (ASD), especially females, mask symptoms. Compensation occurs when a person's observed behavior appears more typical than what would be expected based on underlying ability and symptoms. The study explored camouflaging and compensation differences in 161 youth with ASD. Findings suggest sex-based differences with females showing better vocal expression. However, several compensation differences were observed with the High compensators showing stronger social communication and rapport. A more nuanced consideration of camouflaging using compensation models reveal subtle differences in underlying challenge and strength.
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  • Pubertal Timing During Early Adolescence: Advanced Pubertal Onset in Females with Autism Spectrum Disorder.
    Autism research : official journal of the International Society for Autism Research (2020)
    Corbett BA, Vandekar S, Muscatello RA, Tanguturi Y. Pubertal Timing During Early Adolescence: Advanced Pubertal Onset in Females with Autism Spectrum Disorder. Autism Res. 2020 Dec; 13(12):2202-2215.
    Abstract: Autism spectrum disorder (ASD) is characterized by impaired social communication and poor adaptation to change; thus, the onset of puberty may be a pivotal transition. This cross-sectional study measured pubertal timing to examine hypothesized differences for sex (female vs. male) and group (ASD vs. typical development [TD]). Participants included 239 children (137 ASD, 102 TD) between 10 and 13 years. The ASD group included 35 females and 102 males; the TDs included 44 females and 58 males. Pubertal onset measured by genital or pubic stage was investigated with linear regression using main effects of sex and age-by-sex interactions in TD and ASD groups and main effects of diagnosis and diagnosis-by-age interactions in males and females, controlling for body mass index, socioeconomic status, and race. In TD, examination of main effects for genital (penis/breast) stage showed no difference for male and female children (t = 1.33, P = 0.187, rdf = 92); however, there were significant differences in ASD (t = 2.70, P = 0.008, rdf = 121). For diagnosis modeled separately by sex, there was significantly earlier pubertal development in females with ASD (t = 1.97, P = 0.053, rdf = 70, but not males (t = 1.329, P = 0.186, rdf = 143). In addition, analysis of menses revealed females with ASD had significantly earlier onset than TD (t = -2.56, P = 0.018, rdf = 21). Examination of pubic stage revealed expected sex differences for TD (t = 2,674, P = 0.009, rdf = 91) and ASD (t = 3.482, P = 0.001, rdf = 121). Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for enhanced understanding of pubertal development in ASD, as differences may have significant psychological, social, physiological, and developmental consequences. LAY SUMMARY: Children with autism spectrum disorder (ASD) have difficulty with social communication and respond poorly to change, which may include the onset and course of puberty. The study measured the timing of puberty in 239 children (137 ASD and 102 typical development [TD]) between 10 and 13 years based on pubertal stage of genital (breast/penis) and pubic hair development. Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for an enhanced understanding of pubertal development in ASD.
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Four Conversations RCT
Duke University
  • Interventions for interpersonal communication about end of life care between health practitioners and affected people.
    The Cochrane database of systematic reviews (2022)
    Ryan RE, Connolly M, Bradford NK, Henderson S, Herbert A, Schonfeld L, Young J, Bothroyd JI, Henderson A. Interventions for interpersonal communication about end of life care between health practitioners and affected people. Cochrane Database Syst Rev. 2022 Jul 8; 7:CD013116.
    Abstract: Communication about end of life (EoL) and EoL care is critically important for providing quality care as people approach death. Such communication is often complex and involves many people (patients, family members, carers, health professionals). How best to communicate with people in the period approaching death is not known, but is an important question for quality of care at EoL worldwide. This review fills a gap in the evidence on interpersonal communication (between people and health professionals) in the last year of life, focusing on interventions to improve interpersonal communication and patient, family member and carer outcomes.
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  • Four Conversations: A Randomized Controlled Trial of an Online, Personalized Coping and Decision Aid for Metastatic Breast Cancer Patients.
    Journal of palliative medicine (2020)
    Smith SK, Westbrook K, MacDermott K, Amarasekara S, LeBlanc M, Pan W. Four Conversations: A Randomized Controlled Trial of an Online, Personalized Coping and Decision Aid for Metastatic Breast Cancer Patients. J Palliat Med. 2020 Mar; 23(3):353-358.
    Abstract: Anticipating and making health care decisions about appropriate or preferred treatment around end-of-life care are intellectually challenging and emotionally distressing for metastatic breast cancer (MBC) patients, new interventions are needed. This study examined the effect of , an online and personalized coping and decision aid curriculum, on the completion of advance care directives and shared decision making among patients and their loved ones, clinicians, and spirit. Participants were randomized 1:1 to or wait-listed usual care conditions. Adult breast cancer survivors with metastatic disease were recruited nationally. Electronic surveys collected self-reported demographic, clinical, and outcome data at baseline and four weeks postintervention. Participants ( = 252) were mean age 53.6 ± 11.0 years; 100% female; 88% Caucasian; 67% married; and 33% employed. Over half (54%) of treatment arm participants without an advance directive completed one by study end, most (62%) felt that helped them quite a bit or a great deal in making a better decision, and 90% would recommend to others. Difference in the change in decisional conflict scores for treatment and control conditions was not significant ( = 0.07). These results suggest that facilitated the completion of advance care directives. Given that reductions in decisional conflict scores between the treatment and control arms were not significant, we cannot conclude that program use was associated with improved decisional conflict among MBC survivors. Online programs can be a feasible and effective alternative to in-person support.
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Sensory Symptoms in Patients with Tourette Syndrome or Obsessive Compulsive Disorder
Vanderbilt University Medical Center
  • Altered Interoceptive Sensibility in Adults With Chronic Tic Disorder.
    Frontiers in psychiatry (2022)
    Narapareddy A, Eckland MR, Riordan HR, Cascio CJ, Isaacs DA. Altered Interoceptive Sensibility in Adults With Chronic Tic Disorder. Front Psychiatry. 2022; 13:914897.
    Abstract: Interoception refers to the sensing, interpretation, integration, and regulation of signals about the body's internal physiological state. Interoceptive sensibility is the subjective evaluation of interoceptive experience, as assessed by self-report measures, and is abnormal in numerous neuropsychiatric disorders. Research examining interoceptive sensibility in individuals with chronic tic disorders (CTDs), however, has yielded conflicting results, likely due to methodologic differences between studies and small sample sizes.
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  • Sensory Hypersensitivity Severity and Association with Obsessive-Compulsive Symptoms in Adults with Tic Disorder.
    Neuropsychiatric disease and treatment (2020)
    Isaacs D, Key AP, Cascio CJ, Conley AC, Walker HC, Wallace MT, Claassen DO. Sensory Hypersensitivity Severity and Association with Obsessive-Compulsive Symptoms in Adults with Tic Disorder. Neuropsychiatr Dis Treat. 2020; 16:2591-2601.
    Abstract: Sensory hypersensitivity, defined as heightened awareness of and reactivity to external stimuli, is a bothersome symptom that affects up to 80% of adults with Tourette syndrome (TS). Such widespread prevalence suggests sensory hypersensitivity is a core feature of the disorder, but its severity and association with other clinical features of TS remain largely unexplored. Complicating matters, sensory hypersensitivity has been observed in two neurodevelopmental disorders commonly comorbid with TS: obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD).
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Using the multiphase optimization strategy (MOST) to optimize an intervention to increase COVID-19 testing for Black and Latino/Hispanic frontline essential workers
New York University
  • Using the multiphase optimization strategy (MOST) framework to optimize an intervention to increase COVID-19 testing for Black and Latino/Hispanic frontline essential workers: A study protocol.
    BMC public health (2022)
    Gwadz M, Cleland CM, Lizardo M, Hawkins RL, Bangser G, Parameswaran L, Stanhope V, Robinson JA, Karim S, Hollaway T, Ramirez PG, Filippone PL, Ritchie AS, Banfield A, Silverman E. Using the multiphase optimization strategy (MOST) framework to optimize an intervention to increase COVID-19 testing for Black and Latino/Hispanic frontline essential workers: A study protocol. BMC Public Health. 2022 Jun 21; 22(1):1235.
    Abstract: Among those at highest risk for COVID-19 exposure is the large population of frontline essential workers in occupations such food service, retail, personal care, and in-home health services, among whom Black and Latino/Hispanic persons are over-represented. For those not vaccinated and at risk for exposure to COVID-19, including frontline essential workers, regular (approximately weekly) COVID-19 testing is recommended. However, Black and Latino/Hispanic frontline essential workers in these occupations experience serious impediments to COVID-19 testing at individual/attitudinal- (e.g., lack of knowledge of guidelines), social- (e.g., social norms), and structural-levels of influence (e.g., poor access), and rates of testing for COVID-19 are insufficient.
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Evaluation of Medical Cannabis and Prescription Opioid Taper Support for Reduction of Pain and Opioid Dose in Patients with Chronic Non-Cancer Pain
Massachusetts General Hospital
  • Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol.
    BMJ open (2022)
    Jashinski J, Grossman E, Quaye A, Cather C, Potter K, Schoenfeld DA, Evins AE, Gilman JM. Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol. BMJ Open. 2022 Jun 9; 12(6):e064457.
    Abstract: Chronic, non-cancer pain impacts approximately 50 million adults in the USA (20%), approximately 25% of whom receive chronic prescription opioids for pain despite limited empirical efficacy data and strong dose-related risk for opioid use disorder and opioid overdose. Also despite lack of efficacy data, there are many reports of people using cannabis products to manage chronic pain and replace or reduce chronic opioids. Here we describe the protocol for a randomised trial of the effect of cannabis, when added to a behavioural pain management and prescription opioid taper support programme, on opioid utilisation, pain intensity and pain interference.
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Mechanisms of Mindfulness-based Interventions
Vanderbilt University Medical Center
  • Mindfulness-Based Cognitive Therapy: A Preliminary Examination of the (Event-Related) Potential for Modifying Threat-Related Attentional Bias in Anxiety.
    Mindfulness (2022)
    Gupta RS, Kujawa A, Fresco DM, Kang H, Vago DR. Mindfulness-Based Cognitive Therapy: A Preliminary Examination of the (Event-Related) Potential for Modifying Threat-Related Attentional Bias in Anxiety. Mindfulness (N Y). 2022; 13(7):1719-1732.
    Abstract: Mindfulness-based cognitive therapy (MBCT) can reduce anxiety and depression symptoms in adults with anxiety disorders, and changes in threat-related attentional bias may be a key mechanism driving the intervention's effects on anxiety symptoms. Event-related potentials (ERPs) can illuminate the physiological mechanism through which MBCT targets threat bias and reduces symptoms of anxiety. This preliminary study examined whether P1 ERP threat-related attentional bias markers in anxious adults change from pre- to post-MBCT delivered in-person or virtually (via Zoom) and investigated the relationship between P1 threat-related attentional bias markers and treatment response.
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  • A Preliminary Investigation of ERP Components of Attentional Bias in Anxious Adults using Temporospatial Principal Component Analysis.
    Journal of psychophysiology (2021)
    Gupta RS, Kujawa A, Vago DR. A Preliminary Investigation of ERP Components of Attentional Bias in Anxious Adults using Temporospatial Principal Component Analysis. J Psychophysiol. 2021 Oct; 35(4):223-236.
    Abstract: Threat-related attention bias is thought to contribute to the development and maintenance of anxiety disorders. Dot-probe studies using event-related potentials (ERPs) have indicated that several early ERP components are modulated by threatening and emotional stimuli in anxious populations, suggesting enhanced allocation of attention to threat and emotion at earlier stages of processing. However, ERP components selected for examination and analysis in these studies vary widely and remain inconsistent. The present study used temporospatial principal component analysis (PCA) to systematically identify ERP components elicited to face pair cues and probes in a dot-probe task in anxious adults. Cue-locked components sensitive to emotion included an early occipital C1 component enhanced for happy versus angry face pair cues and an early parieto-occipital P1 component enhanced for happy versus angry face pair cues. Probe-locked components sensitive to congruency included a parieto-occipital P2 component enhanced for incongruent probes (probes replacing neutral faces) versus congruent probes (probes replacing emotional faces). Split-half correlations indicated that the mean value around the PCA-derived peaks were reliably measured in the ERP waveforms. These results highlight promising neurophysiological markers for attentional bias research that can be extended to designs comparing anxious and healthy comparison groups. Results from a secondary exploratory PCA analysis investigating the effects of emotional face position and analyses on behavioral reaction time data are also presented.
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  • The neural chronometry of threat-related attentional bias: Event-related potential (ERP) evidence for early and late stages of selective attentional processing.
    International journal of psychophysiology : official journal of the International Organization of Psychophysiology (2019)
    Gupta RS, Kujawa A, Vago DR. The neural chronometry of threat-related attentional bias: Event-related potential (ERP) evidence for early and late stages of selective attentional processing. Int J Psychophysiol. 2019 Dec; 146:20-42.
    Abstract: Rapid and accurate detection of threat is adaptive. Yet, threat-related attentional biases, including hypervigilance, avoidance, and attentional disengagement delays, may contribute to the etiology and maintenance of anxiety disorders. Behavioral measures of attentional bias generally indicate that threat demands more attentional resources; however, indices exploring differential allocation of attention using reaction time fail to clarify the time course by which attention is deployed under threatening circumstances in healthy and anxious populations. In this review, we conduct an interpretive synthesis of 28 attentional bias studies focusing on event-related potentials (ERPs) as a primary outcome to inform an ERP model of the neural chronometry of attentional bias in healthy and anxious populations. The model posits that both healthy and anxious populations display modulations of early ERP components, including the P1, N170, P2, and N2pc, in response to threatening and emotional stimuli, suggesting that both typical and abnormal patterns of attentional bias are characterized by enhanced allocation of attention to threat and emotion at earlier stages of processing. Compared to anxious populations, healthy populations more clearly demonstrate modulations of later components, such as the P3, indexing conscious and evaluative processing of threat and emotion and disengagement difficulties at later stages of processing. Findings from the interpretive synthesis, existing bias models, and extant neural literature on attentional systems are then integrated to inform a conceptual model of the processes and substrates underlying threat appraisal and resource allocation in healthy and anxious populations. To conclude, we discuss therapeutic interventions for attentional bias and future directions.
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Online Collaborative Intervention to Prevent Postpartum Depression
University of Illinois at Chicago
  • Randomized controlled trial of Sunnyside: Individual versus group-based online interventions to prevent postpartum depression.
    Journal of affective disorders (2022)
    Duffecy J, Grekin R, Long JD, Mills JA, O'Hara M. Randomized controlled trial of Sunnyside: Individual versus group-based online interventions to prevent postpartum depression. J Affect Disord. 2022 Aug 15; 311:538-547.
    Abstract: Postpartum depression (PPD) is a serious mental health problem that has a prevalence rate of nearly 20% in the first three months after delivery. The purpose of this study was to evaluate the benefit of Sunnyside, an internet-based cognitive-behavioral intervention, delivered in a group format compared to the same intervention delivered individually for the prevention of PPD.
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  • A Group-Based Online Intervention to Prevent Postpartum Depression (Sunnyside): Feasibility Randomized Controlled Trial.
    JMIR mental health (2019)
    Duffecy J, Grekin R, Hinkel H, Gallivan N, Nelson G, O'Hara MW. A Group-Based Online Intervention to Prevent Postpartum Depression (Sunnyside): Feasibility Randomized Controlled Trial. JMIR Ment Health. 2019 May 28; 6(5):e10778.
    Abstract: Postpartum depression (PPD) has a 20% 3-month prevalence rate. The consequences of PPD are significant for the mother, infant, and the family. There is a need for preventive interventions for PPD, which are effective and accessible; however, many barriers exist for women who attempt to access perinatal depression prevention programs. Internet interventions for the treatment and prevention of depression are widely accepted as efficacious and may overcome some of the issues pertaining to access to treatment barriers perinatal women face. However, internet interventions offered without any human support tend to have low adherence but positive outcomes for those who do complete treatment. Internet support groups often have high levels of adherence but minimal data supporting efficacy as a treatment for depression. Taken together, these findings suggest that combining the treatment components of individual interventions with the support provided by an internet support group might create an intervention with the scalability and cost-effectiveness of an individual intervention and the better outcomes typically found in supported interventions.
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Phase 4 Randomized double-blind, active and placebo-controlled multicenter study evaluating the neuropsychiatric safety and efficacy of 12 weeks varenicline tartrate 1 mg bid and bupropion hydrochloride 150 mg bid for smoking cessation in subjects with and without a history of psychiatric disorders
University of Minnesota
  • Medication-assisted quit rates in participants with smoking-related diseases in EAGLES: Post hoc analyses of a double-blind, randomized, placebo-controlled clinical trial.
    Tobacco induced diseases (2022)
    Tønnesen P, Lawrence D, Tonstad S. Medication-assisted quit rates in participants with smoking-related diseases in EAGLES: Post hoc analyses of a double-blind, randomized, placebo-controlled clinical trial. Tob Induc Dis. 2022; 20:46.
    Abstract: Greater understanding is required of how smokers with smoking-related diseases respond to smoking cessation medications. This analysis of EAGLES data compared continuous abstinence rates (CARs) in smokers with/without smoking-related diseases and assessed participant demographic and baseline characteristics that may serve as predictors of continuous abstinence (CA).
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  • The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial.
    Depression and anxiety (2022)
    Cinciripini PM, Kypriotakis G, Green C, Lawrence D, Anthenelli RM, Minnix J, Blalock JA, Beneventi D, Morris C, Karam-Hage M. The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial. Depress Anxiety. 2022 May; 39(5):429-440.
    Abstract: Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications.
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  • In Reply: Changing the Culture of Tobacco Dependence Treatment Among Not Only Patients, But Also Prescribers.
    Mayo Clinic proceedings (2021)
    Ebbert JO, Jimenez-Ruiz C, Dutro MP, Fisher M, Li J, Hays JT. In Reply: Changing the Culture of Tobacco Dependence Treatment Among Not Only Patients, But Also Prescribers. Mayo Clin Proc. 2021 Sep; 96(9):2495.
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  • Frequently Reported Adverse Events With Smoking Cessation Medications: Post Hoc Analysis of a Randomized Trial.
    Mayo Clinic proceedings (2021)
    Ebbert J, Jimenez-Ruiz C, Dutro MP, Fisher M, Li J, Hays JT. Frequently Reported Adverse Events With Smoking Cessation Medications: Post Hoc Analysis of a Randomized Trial. Mayo Clin Proc. 2021 Jul; 96(7):1801-1811.
    Abstract: To compare the incidence, severity, and clinical course of frequently reported adverse events (AEs) after treatment with smoking cessation pharmacotherapies.
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  • Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors.
    Addiction (Abingdon, England) (2021)
    Beard E, Jackson SE, Anthenelli RM, Benowitz NL, Aubin LS, McRae T, Lawrence D, Russ C, Krishen A, Evins AE, West R. Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors. Addiction. 2021 Oct; 116(10):2816-2824.
    Abstract: Analysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.
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  • Psychiatric Comorbidity and Multimorbidity in the EAGLES Trial: Descriptive Correlates and Associations With Neuropsychiatric Adverse Events, Treatment Adherence, and Smoking Cessation.
    Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco (2021)
    Correa JB, Lawrence D, McKenna BS, Gaznick N, Saccone PA, Dubrava S, Doran N, Anthenelli RM. Psychiatric Comorbidity and Multimorbidity in the EAGLES Trial: Descriptive Correlates and Associations With Neuropsychiatric Adverse Events, Treatment Adherence, and Smoking Cessation. Nicotine Tob Res. 2021 Aug 29; 23(10):1646-1655.
    Abstract: Psychiatric and substance use disorders represent barriers to smoking cessation. We sought to identify correlates of psychiatric comorbidity (CM; 2 diagnoses) and multimorbidity (MM; 3+ diagnoses) among smokers attempting to quit and to evaluate whether these conditions predicted neuropsychiatric adverse events (NPSAEs), treatment adherence, or cessation efficacy (CE).
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  • Assessment of Racial Differences in Pharmacotherapy Efficacy for Smoking Cessation: Secondary Analysis of the EAGLES Randomized Clinical Trial.
    JAMA network open (2021)
    Nollen NL, Ahluwalia JS, Sanderson Cox L, Okuyemi K, Lawrence D, Samuels L, Benowitz NL. Assessment of Racial Differences in Pharmacotherapy Efficacy for Smoking Cessation: Secondary Analysis of the EAGLES Randomized Clinical Trial. JAMA Netw Open. 2021 Jan 4; 4(1):e2032053.
    Abstract: Understanding Black vs White differences in pharmacotherapy efficacy and the underlying reasons is critically important to reducing tobacco-related health disparities.
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  • Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES.
    Psychiatric services (Washington, D.C.) (2021)
    Evins AE, West R, Benowitz NL, Russ C, Lawrence D, McRae T, Maravic MC, Heffner JL, Anthenelli RM. Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES. Psychiatr Serv. 2021 Jan 1; 72(1):7-15.
    Abstract: This study aimed to evaluate the efficacy and safety of varenicline, bupropion, and nicotine replacement therapy (NRT) among smokers with schizophrenia spectrum disorders in post hoc analyses of Evaluating Adverse Events in a Global Smoking Cessation Study data.
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  • Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: Subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial.
    Depression and anxiety (2020)
    Ayers CR, Heffner JL, Russ C, Lawrence D, McRae T, Evins AE, Anthenelli RM. Efficacy and safety of pharmacotherapies for smoking cessation in anxiety disorders: Subgroup analysis of the randomized, active- and placebo-controlled EAGLES trial. Depress Anxiety. 2020 Mar; 37(3):247-260.
    Abstract: Smoking rates are high in adults with anxiety disorders (ADs), yet little is known about the safety and efficacy of smoking-cessation pharmacotherapies in this group.
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  • Safety and efficacy of first-line smoking cessation pharmacotherapies in bipolar disorders: Subgroup analysis of a randomized clinical trial.
    Journal of affective disorders (2019)
    Heffner JL, Evins AE, Russ C, Lawrence D, Ayers CR, McRae T, Aubin LS, Krishen A, West R, Anthenelli RM. Safety and efficacy of first-line smoking cessation pharmacotherapies in bipolar disorders: Subgroup analysis of a randomized clinical trial. J Affect Disord. 2019 Sep 1; 256:267-277.
    Abstract: Post hoc analyses of EAGLES data to examine safety and efficacy of first-line smoking cessation pharmacotherapies in smokers with bipolar disorders (BD).
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  • Predictors of Neuropsychiatric Adverse Events with Smoking Cessation Medications in the Randomized Controlled EAGLES Trial.
    Journal of general internal medicine (2019)
    Anthenelli RM, Gaffney M, Benowitz NL, West R, McRae T, Russ C, Lawrence D, St Aubin L, Krishen A, Evins AE. Predictors of Neuropsychiatric Adverse Events with Smoking Cessation Medications in the Randomized Controlled EAGLES Trial. J Gen Intern Med. 2019 Jun; 34(6):862-870.
    Abstract: Pre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown.
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  • Factors associated with the efficacy of smoking cessation treatments and predictors of smoking abstinence in EAGLES.
    Addiction (Abingdon, England) (2018)
    West R, Evins AE, Benowitz NL, Russ C, McRae T, Lawrence D, St Aubin L, Krishen A, Maravic MC, Anthenelli RM. Factors associated with the efficacy of smoking cessation treatments and predictors of smoking abstinence in EAGLES. Addiction. 2018 Aug; 113(8):1507-1516.
    Abstract: To assess (1) how far the efficacies of front-line smoking cessation pharmacotherapies vary as a function of smoker characteristics and (2) associations between these characteristics and success of smoking cessation attempts.
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  • Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.
    Lancet (London, England) (2016)
    Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016 Jun 18; 387(10037):2507-20.
    Abstract: Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders.
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A randomized placebo-controlled, double blind phase 2 clinical trial of memantine for the treatment of cognitive impairment in systemic lupus erythematosus
Vanderbilt University Medical Center
  • Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus.
    JCI insight (2022)
    Patrick DM, de la Visitación N, Krishnan J, Chen W, Ormseth MJ, Stein CM, Davies SS, Amarnath V, Crofford LJ, Williams JM, Zhao S, Smart CD, Dikalov S, Dikalova A, Xiao L, Van Beusecum JP, Ao M, Fogo AB, Kirabo A, Harrison DG. Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus. JCI Insight. 2022 Jul 8; 7(13):.
    Abstract: We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
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  • Altered Mitochondrial Homeostasis during Systemic Lupus Erythematosus Impairs Neutrophil Extracellular Trap Formation Rendering Neutrophils Ineffective at Combating Staphylococcus aureus.
    Journal of immunology (Baltimore, Md. : 1950) (2022)
    Monteith AJ, Miller JM, Williams JM, Voss K, Rathmell JC, Crofford LJ, Skaar EP. Altered Mitochondrial Homeostasis during Systemic Lupus Erythematosus Impairs Neutrophil Extracellular Trap Formation Rendering Neutrophils Ineffective at Combating Staphylococcus aureus. J Immunol. 2022 Jan 15; 208(2):454-463.
    Abstract: Inflammation involves a delicate balance between pathogen clearance and limiting host tissue damage, and perturbations in this equilibrium promote disease. Patients suffering from autoimmune diseases, such as systemic lupus erythematosus (SLE), have higher levels of serum S100A9 protein and increased risk for infection. S100A9 is highly abundant within neutrophils and modulates antimicrobial activity in response to bacterial pathogens. We reasoned that increased serum S100A9 in SLE patients reflects accumulation of S100A9 protein in neutrophils and may indicate altered neutrophil function. In this study, we demonstrate elevated S100A9 protein within neutrophils from SLE patients, and MRL/ mice associates with lower mitochondrial superoxide, decreased suicidal neutrophil extracellular trap formation, and increased susceptibility to infection. Furthermore, increasing mitochondrial superoxide production restored the antibacterial activity of MRL/ neutrophils in response to These results demonstrate that accumulation of intracellular S100A9 associates with impaired mitochondrial homeostasis, thereby rendering SLE neutrophils inherently less bactericidal.
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A Longitudinal Study of COVID-19 Sequelae and Immunity
The National Institutes of Health
  • A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings.
    Annals of internal medicine (2022)
    Sneller MC, Liang CJ, Marques AR, Chung JY, Shanbhag SM, Fontana JR, Raza H, Okeke O, Dewar RL, Higgins BP, Tolstenko K, Kwan RW, Gittens KR, Seamon CA, McCormack G, Shaw JS, Okpali GM, Law M, Trihemasava K, Kennedy BD, Shi V, Justement JS, Buckner CM, Bl. A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings. Ann Intern Med. 2022 Jul; 175(7):969-979.
    Abstract: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC).
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Natural history and biomarkers of C9ORF72 ALS and FTD
The National Institutes of Health
  • Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD.
    Nature communications (2022)
    Krishnan G, Raitcheva D, Bartlett D, Prudencio M, McKenna-Yasek DM, Douthwright C, Oskarsson BE, Ladha S, King OD, Barmada SJ, Miller TM, Bowser R, Watts JK, Petrucelli L, Brown RH, Kankel MW, Gao FB. Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD. Nat Commun. 2022 May 19; 13(1):2799.
    Abstract: GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at disease onset, disease duration, or rate of decline of ALS Functional Rating Scale, and the average levels of these DPR proteins were similar in symptomatic and pre-symptomatic patients with C9ORF72 mutations. However, in a patient with C9ORF72-ALS who was treated with antisense oligonucleotide (ASO) targeting the aberrant C9ORF72 transcript, CSF poly(GA) and poly(GR) levels decreased approximately 50% within 6 weeks, indicating they may serve as sensitive fluid-based biomarkers in studies directed against the production of GGGGCC repeat RNAs or DPR proteins.
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Treatment of Obesity Targeting Appetite and Cue Reactivity
University of California San Diego
  • Effect of a Novel Intervention Targeting Appetitive Traits on Body Mass Index Among Adults With Overweight or Obesity: A Randomized Clinical Trial.
    JAMA network open (2022)
    Boutelle KN, Eichen DM, Peterson CB, Strong DR, Kang-Sim DE, Rock CL, Marcus BH. Effect of a Novel Intervention Targeting Appetitive Traits on Body Mass Index Among Adults With Overweight or Obesity: A Randomized Clinical Trial. JAMA Netw Open. 2022 May 2; 5(5):e2212354.
    Abstract: Behavioral weight loss (BWL) programs result in weight loss for some, but most individuals regain the weight. The behavioral susceptibility theory proposes that genetically determined appetitive traits, such as food responsiveness (FR) and satiety responsiveness (SR), interact with the environment and lead to overeating and weight gain; the regulation of cues (ROC) intervention was developed specifically to target FR and SR.
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FAST: Fibromyalgia Activity Study with TENS
Vanderbilt University Medical Center
  • Test-Retest Reliability and Responsiveness of PROMIS Sleep Short Forms Within an RCT in Women With Fibromyalgia.
    Frontiers in pain research (Lausanne, Switzerland) (2021)
    Chimenti RL, Rakel BA, Dailey DL, Vance CGT, Zimmerman MB, Geasland KM, Williams JM, Crofford LJ, Sluka KA. Test-Retest Reliability and Responsiveness of PROMIS Sleep Short Forms Within an RCT in Women With Fibromyalgia. Front Pain Res (Lausanne). 2021; 2:682072.
    Abstract: Nonrestorative sleep is commonly reported by individuals with fibromyalgia, but there is limited information on the reliability and responsiveness of self-reported sleep measures in this population. (1) Examine the reliability and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) sleep measures in women with fibromyalgia, and (2) Determine the responsiveness of the PROMIS sleep measures to a daily transcutaneous electrical nerve stimulation (TENS) intervention in women with fibromyalgia over 4 weeks compared with other measures of restorative sleep. In a double-blinded, dual-site clinical trial, 301 women with fibromyalgia were randomly assigned to utilize either Active-TENS, Placebo-TENS, or No-TENS at home. Measures were collected at baseline and after 4 weeks of treatment. To assess self-reported sleep, the participants completed three PROMIS short forms: Sleep Disturbance, Sleep-Related Impairment, Fatigue, and the Pittsburgh Sleep Quality Index (PSQI). To assess device-measured sleep, actigraphy was used to quantify total sleep time, wake after sleep onset, and sleep efficiency. Linear mixed models were used to examine the effects of treatment, time, and treatment*time interactions. The PROMIS short forms had moderate test-retest reliability (ICC 0.62 to 0.71) and high internal consistency (Cronbach's alpha 0.89 to 0.92). The PROMIS sleep measures [mean change over 4 weeks, 95% confidence interval (CI)], Sleep Disturbance: -1.9 (-3.6 to -0.3), Sleep-Related Impairment: -3 (-4.6 to -1.4), and Fatigue: -2.4 (-3.9 to -0.9) were responsive to improvement in restorative sleep and specific to the Active-TENS group but not in the Placebo-TENS [Sleep Disturbance: -1.3 (-3 to 0.3), Sleep-Related Impairment: -1.2 (-2.8 to 0.4), Fatigue: -1.1 (-2.7 to 0.9)] or No-TENS [Sleep Disturbance: -0.1 (-1.6 to 1.5), Sleep-Related Impairment: -0.2 (-1.7 to 1.4), Fatigue: -.3 (-1.8 to 1.2)] groups. The PSQI was responsive but not specific with improvement detected in both the Active-TENS: -0.9 (-1.7 to -0.1) and Placebo-TENS: -0.9 (-1.7 to 0) groups but not in the No-TENS group: -0.3 (-1.1 to 0.5). Actigraphy was not sensitive to any changes in restorative sleep with Active-TENS [Sleep Efficiency: -1 (-2.8 to 0.9), Total Sleep Time: 3.3 (-19.8 to 26.4)]. The PROMIS sleep measures are reliable, valid, and responsive to improvement in restorative sleep in women with fibromyalgia. www.ClinicalTrials.gov, identifier: NCT01888640.
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  • Reduction in movement-evoked pain and fatigue during initial 30-minute transcutaneous electrical nerve stimulation treatment predicts transcutaneous electrical nerve stimulation responders in women with fibromyalgia.
    Pain (2021)
    Vance CGT, Zimmerman MB, Dailey DL, Rakel BA, Geasland KM, Chimenti RL, Williams JM, Golchha M, Crofford LJ, Sluka KA. Reduction in movement-evoked pain and fatigue during initial 30-minute transcutaneous electrical nerve stimulation treatment predicts transcutaneous electrical nerve stimulation responders in women with fibromyalgia. Pain. 2021 May 1; 162(5):1545-1555.
    Abstract: We previously showed that 1 month of transcutaneous electrical nerve stimulation (TENS) reduces movement-evoked pain and fatigue in women with fibromyalgia (FM). Using data from this study (Fibromyalgia Activity Study with TENS [FAST]), we performed a responder analysis to identify predictors of clinical improvement in pain and fatigue with TENS, validated these models using receiver operator characteristic, and determined number needed to treat and number needed to harm. Participants were randomly assigned to active-TENS (2-125 Hz; highest-tolerable intensity), placebo-TENS, or no-TENS for 1 month. At the end of the randomized phase, placebo-TENS and no-TENS groups received active-TENS for 1 month. The predictor model was developed using data from the randomized phase for the active-TENS group (n = 103) and validated using data from placebo-TENS and no-TENS groups after active-TENS for 1 month (n = 155). Participant characteristics, initial response to TENS for pain and fatigue, sleep, psychological factors, and function were screened for association with changes in pain or fatigue using a logistic regression model. Predictors of clinical improvement in pain were initial response to pain and widespread pain index (area under the curve was 0.80; 95% confidence interval: 0.73-0.87). Predictors of clinical improvement in fatigue were marital status, sleep impairment, and initial response to TENS (area under the curve was 0.67; 95% confidence interval: 0.58-0.75). Number needed to treat for pain and fatigue ranged between 3.3 and 5.3. Number needed to harm ranged from 20 to 100 for minor TENS-related adverse events. The response to an initial 30-minute TENS treatment predicts who responds to longer-term TENS use in women with FM, making this a clinically useful procedure. Number needed to treat and number needed to harm suggest that TENS is effective and safe for managing pain and fatigue in FM.
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  • IL-5 mediates monocyte phenotype and pain outcomes in fibromyalgia.
    Pain (2021)
    Merriwether EN, Agalave NM, Dailey DL, Rakel BA, Kolker SJ, Lenert ME, Spagnola WH, Lu Y, Geasland KM, Allen LH, Burton MD, Sluka KA. IL-5 mediates monocyte phenotype and pain outcomes in fibromyalgia. Pain. 2021 May 1; 162(5):1468-1482.
    Abstract: Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM is not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. Lipopolysaccharide-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. In addition, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Furthermore, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14++/CD16+) and a greater percentage of nonclassical monocytes (CD14+/CD16++) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206+). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.
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  • Transcutaneous Electrical Nerve Stimulation Reduces Movement-Evoked Pain and Fatigue: A Randomized, Controlled Trial.
    Arthritis & rheumatology (Hoboken, N.J.) (2020)
    Dailey DL, Vance CGT, Rakel BA, Zimmerman MB, Embree J, Merriwether EN, Geasland KM, Chimenti R, Williams JM, Golchha M, Crofford LJ, Sluka KA. Transcutaneous Electrical Nerve Stimulation Reduces Movement-Evoked Pain and Fatigue: A Randomized, Controlled Trial. Arthritis Rheumatol. 2020 May; 72(5):824-836.
    Abstract: Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM.
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  • Development of a method to maximize the transcutaneous electrical nerve stimulation intensity in women with fibromyalgia.
    Journal of pain research (2018)
    Vance CG, Chimenti RL, Dailey DL, Hadlandsmyth K, Zimmerman MB, Geasland KM, Williams JM, Merriwether EN, Alemo Munters L, Rakel BA, Crofford LJ, Sluka KA. Development of a method to maximize the transcutaneous electrical nerve stimulation intensity in women with fibromyalgia. J Pain Res. 2018; 11:2269-2278.
    Abstract: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological intervention clinically used for pain relief. The importance of utilizing the adequate stimulation intensity is well documented; however, clinical methods to achieve the highest possible intensity are not established.
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  • Physical activity is related to function and fatigue but not pain in women with fibromyalgia: baseline analyses from the Fibromyalgia Activity Study with TENS (FAST).
    Arthritis research & therapy (2018)
    Merriwether EN, Frey-Law LA, Rakel BA, Zimmerman MB, Dailey DL, Vance CGT, Golchha M, Geasland KM, Chimenti R, Crofford LJ, Sluka KA. Physical activity is related to function and fatigue but not pain in women with fibromyalgia: baseline analyses from the Fibromyalgia Activity Study with TENS (FAST). Arthritis Res Ther. 2018 Aug 29; 20(1):199.
    Abstract: Although exercise is an effective treatment for fibromyalgia, the relationships between lifestyle physical activity and multiple symptomology domains of fibromyalgia are not clear. Thus, the purpose of this study was to comprehensively examine the relationships between lifestyle physical activity with multiple outcome domains in women with fibromyalgia, including pain, fatigue, function, pain-related psychological constructs, and quality of life.
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  • Somatic symptom presentations in women with fibromyalgia are differentially associated with elevated depression and anxiety.
    Journal of health psychology (2020)
    Hadlandsmyth K, Dailey DL, Rakel BA, Zimmerman MB, Vance CG, Merriwether EN, Chimenti RL, Geasland KM, Crofford LJ, Sluka KA. Somatic symptom presentations in women with fibromyalgia are differentially associated with elevated depression and anxiety. J Health Psychol. 2020 May; 25(6):819-829.
    Abstract: This study examined whether depression and anxiety differentially relate to fatigue, sleep disturbance, pain catastrophizing, fear of movement, and pain severity in women with fibromyalgia. Baseline data from the Fibromyalgia Activity Study with Transcutaneous Electrical Nerve Stimulation were analyzed. Of 191 participants, 50 percent reported high anxiety and/or depression (17% high anxiety, 9% high depression, and 24% both). Fatigue and sleep impairment were associated with high depression ( < 0.05). Pain severity, pain catastrophizing, and fear of movement were associated with high anxiety and high depression ( < 0.05). Possible implications for underlying mechanisms and the need for targeted treatments are discussed.
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  • Reliability and Construct Validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Instruments in Women with Fibromyalgia.
    Pain medicine (Malden, Mass.) (2017)
    Merriwether EN, Rakel BA, Zimmerman MB, Dailey DL, Vance CGT, Darghosian L, Golchha M, Geasland KM, Chimenti R, Crofford LJ, Sluka KA. Reliability and Construct Validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Instruments in Women with Fibromyalgia. Pain Med. 2017 Aug 1; 18(8):1485-1495.
    Abstract: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed to standardize measurement of clinically relevant patient-reported outcomes. This study evaluated the reliability and construct validity of select PROMIS static short-form (SF) instruments in women with fibromyalgia.
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  • Perceived function and physical performance are associated with pain and fatigue in women with fibromyalgia.
    Arthritis research & therapy (2016)
    Dailey DL, Frey Law LA, Vance CG, Rakel BA, Merriwether EN, Darghosian L, Golchha M, Geasland KM, Spitz R, Crofford LJ, Sluka KA. Perceived function and physical performance are associated with pain and fatigue in women with fibromyalgia. Arthritis Res Ther. 2016 Mar 16; 18:68.
    Abstract: Fibromyalgia is a condition characterized by chronic widespread muscle pain and fatigue and associated with significant impairment in perceived function and reduced physical performance. The purpose of this study was to determine the degree to which pain and fatigue are associated with perceived function and physical performance in women with fibromyalgia.
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  • Psychological aspects of chronic musculoskeletal pain.
    Best practice & research. Clinical rheumatology (2015)
    Crofford LJ. Psychological aspects of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2015 Feb; 29(1):147-55.
    Abstract: Chronic musculoskeletal pain, by its very nature, is associated with negative emotions and psychological distress. There are individual differences in personality, coping skills, behavioral adaptation, and social support that dramatically alter the psychological outcomes of patients with chronic pain. Patients who have an aspect of central pain amplification associated with mechanical or inflammatory pain and patients with fibromyalgia (FM) are likely to exhibit higher levels of psychological distress and illness behaviors. This manuscript discusses several different constructs for the association between chronic pain, central pain amplification, and psychological distress. The first key question addresses mechanisms shared in common between chronic pain and mood disorders, including the individual factors that influence psychological comorbidity, and the second addresses how pain affects mood and vice versa. Finally, the utility of cognitive behavioral approaches in the management of chronic pain symptoms is discussed.
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  • Effect of transcutaneous electrical nerve stimulation on pain, function, and quality of life in fibromyalgia: a double-blind randomized clinical trial.
    Physical therapy (2015)
    Noehren B, Dailey DL, Rakel BA, Vance CG, Zimmerman MB, Crofford LJ, Sluka KA. Effect of transcutaneous electrical nerve stimulation on pain, function, and quality of life in fibromyalgia: a double-blind randomized clinical trial. Phys Ther. 2015 Jan; 95(1):129-40.
    Abstract: Fibromyalgia is a common chronic pain condition that has a significant impact on quality of life and often leads to disability. To date, there have been few well-controlled trials assessing the utility of nonpharmacological treatment modalities such as transcutaneous electrical nerve stimulation (TENS) in the management of pain and improvement in function in individuals with fibromyalgia.
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Psychiatric Genotype/Phenotype Repository
Vanderbilt University Medical Center
  • Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study.
    Schizophrenia research (2022)
    McHugo M, Rogers BP, Avery SN, Armstrong K, Blackford JU, Vandekar SN, Roeske MJ, Woodward ND, Heckers S. Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study. Schizophr Res. 2022 Mar; 241:260-266.
    Abstract: Neuroimaging studies have revealed hippocampal hyperactivity in schizophrenia. In the early stage of the illness, hyperactivity is present in the anterior hippocampus and is thought to spread to other regions as the illness progresses. However, there is limited evidence for changes in basal hippocampal function following the onset of psychosis. Resting state functional MRI signal amplitude may be a proxy measure for increased metabolism and disrupted oscillatory activity, both consequences of an excitation/inhibition imbalance underlying hippocampal hyperactivity. Here, we used fractional amplitude of low frequency fluctuations (fALFF) to test the hypothesis of progressive hippocampal hyperactivity in a two-year longitudinal case-control study. We found higher fALFF in the anterior and posterior hippocampus of individuals in the early stage of non-affective psychosis at study entry. Contrary to our hypothesis of progressive hippocampal dysfunction, we found evidence for normalization of fALFF over time in psychosis. Our findings support a model in which hippocampal fALFF is a marker of psychosis vulnerability or acute illness state rather than an enduring feature of the illness.
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  • Anterior hippocampal dysfunction in early psychosis: a 2-year follow-up study.
    Psychological medicine (2021)
    McHugo M, Avery S, Armstrong K, Rogers BP, Vandekar SN, Woodward ND, Blackford JU, Heckers S. Anterior hippocampal dysfunction in early psychosis: a 2-year follow-up study. Psychol Med. 2021 Apr 20; :1-10.
    Abstract: Cross-sectional studies indicate that hippocampal function is abnormal across stages of psychosis. Neural theories of psychosis pathophysiology suggest that dysfunction worsens with illness stage. Here, we test the hypothesis that hippocampal function is impaired in the early stage of psychosis and declines further over the next 2 years.
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  • Incomplete hippocampal inversion in schizophrenia: prevalence, severity, and impact on hippocampal structure.
    Molecular psychiatry (2021)
    Roeske MJ, McHugo M, Vandekar S, Blackford JU, Woodward ND, Heckers S. Incomplete hippocampal inversion in schizophrenia: prevalence, severity, and impact on hippocampal structure. Mol Psychiatry. 2021 Sep; 26(9):5407-5416.
    Abstract: Incomplete hippocampal inversion (IHI) is an anatomical variant of the human brain resulting from an arrest in brain development, especially prevalent in the left hemisphere. We hypothesized that IHI is more common in schizophrenia and contributes to the well-known hippocampal structural differences. We studied 199 schizophrenia patients and 161 healthy control participants with 3 T MRI to establish IHI prevalence and the relationship of IHI with hippocampal volume and asymmetry. IHI was more prevalent (left hemisphere: 15% of healthy control participants, 27% of schizophrenia patients; right hemisphere: 4% of healthy control participants, 10% of schizophrenia patients) and more severe in schizophrenia patients compared to healthy control participants. Severe IHI cases were associated with a higher rate of automated segmentation failure. IHI contributed to smaller hippocampal volume and increased R > L volume asymmetry in schizophrenia. The increased prevalence and severity of IHI supports the neurodevelopmental model of schizophrenia. The impact of this developmental variant deserves further exploration in studies of the hippocampus in schizophrenia.
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  • Stable habituation deficits in the early stage of psychosis: a 2-year follow-up study.
    Translational psychiatry (2021)
    Avery SN, McHugo M, Armstrong K, Blackford JU, Woodward ND, Heckers S. Stable habituation deficits in the early stage of psychosis: a 2-year follow-up study. Transl Psychiatry. 2021 Jan 5; 11(1):20.
    Abstract: Neural habituation, the decrease in brain response to repeated stimuli, is a fundamental, highly conserved mechanism that acts as an essential filter for our complex sensory environment. Convergent evidence indicates neural habituation is disrupted in both early and chronic stages of schizophrenia, with deficits co-occurring in brain regions that show inhibitory dysfunction. As inhibitory deficits have been proposed to contribute to the onset and progression of illness, habituation may be an important treatment target. However, a crucial first step is clarifying whether habituation deficits progress with illness. In the present study, we measured neural habituation in 138 participants (70 early psychosis patients (<2 years of illness), 68 healthy controls), with 108 participants assessed longitudinally at both baseline and 2-year follow-up. At follow-up, all early psychosis patients met criteria for a schizophrenia spectrum disorder (i.e., schizophreniform disorder, schizophrenia, schizoaffective disorder). Habituation slopes (i.e., rate of fMRI signal change) to repeated images were computed for the anterior hippocampus, occipital cortex, and the fusiform face area. Habituation slopes were entered into a linear mixed model to test for effects of group and time by region. We found that early psychosis patients showed habituation deficits relative to healthy control participants across brain regions, and that these deficits were maintained, but did not worsen, over two years. These results suggest a stable period of habituation deficits in the early stage of schizophrenia.
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  • Relational memory in the early stage of psychotic bipolar disorder.
    Psychiatry research (2020)
    McKinney RA, Avery SN, Armstrong K, Blackford JU, Woodward ND, Heckers S. Relational memory in the early stage of psychotic bipolar disorder. Psychiatry Res. 2020 Dec; 294:113508.
    Abstract: Relational memory is impaired in psychotic disorders. In non-affective psychotic disorders, relational memory deficits are present in the early stage of illness and become more pronounced in the chronic stage. Previous studies have demonstrated cognitive deficits in early-stage psychotic bipolar disorder, but it is unclear whether relational memory is impaired. We examined relational memory using a face-scene binding task in early-stage psychotic bipolar disorder patients (n = 33) and compared their performance with healthy control (n = 40) and early-stage non-affective psychosis participants (n = 40). During training, participants learned to associate faces with background scenes. During testing, participants viewed a scene overlaid by three faces and were asked to recall the matching face. Relational memory was assessed indirectly using eye movements and explicitly using forced-choice recognition. Preferential viewing of the matching face, as captured by overall proportion of viewing and viewing across time, was significantly lower in psychotic bipolar disorder than in the healthy control group. However, preferential viewing of the matching face in psychotic bipolar disorder was significantly better than in non-affective psychosis. These findings provide novel evidence that relational memory in patients with early-stage psychotic bipolar disorder is intermediate between healthy control and early-stage non-affective psychosis subjects.
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  • BNST-insula structural connectivity in humans.
    NeuroImage (2020)
    Flook EA, Feola B, Avery SN, Winder DG, Woodward ND, Heckers S, Blackford JU. BNST-insula structural connectivity in humans. Neuroimage. 2020 Apr 15; 210:116555.
    Abstract: The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.
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  • Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis.
    The American journal of psychiatry (2019)
    McHugo M, Talati P, Armstrong K, Vandekar SN, Blackford JU, Woodward ND, Heckers S. Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis. Am J Psychiatry. 2019 Dec 1; 176(12):1030-1038.
    Abstract: In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing.
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  • Disrupted Habituation in the Early Stage of Psychosis.
    Biological psychiatry. Cognitive neuroscience and neuroimaging (2019)
    Avery SN, McHugo M, Armstrong K, Blackford JU, Woodward ND, Heckers S. Disrupted Habituation in the Early Stage of Psychosis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Nov; 4(11):1004-1012.
    Abstract: Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis.
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  • Brain function during stages of working memory in schizophrenia and psychotic bipolar disorder.
    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2019)
    Huang AS, Rogers BP, Anticevic A, Blackford JU, Heckers S, Woodward ND. Brain function during stages of working memory in schizophrenia and psychotic bipolar disorder. Neuropsychopharmacology. 2019 Nov; 44(12):2136-2142.
    Abstract: Working memory (WM) is impaired in psychotic disorders and linked to functional outcome. Most neurobiological models emphasize prefrontal cortex (PFC) dysfunction in the etiology of WM impairment. However, WM is composed of multiple processes, including encoding and maintenance, and the delineation of the neurobiology of these sub-processes has not been well characterized in schizophrenia and psychotic bipolar disorder. Functional MRI was obtained during an event-related spatial delayed match-to-sample task from 58 healthy individuals, 72 individuals with schizophrenia and 41 people with bipolar I disorder with psychotic features in order to: 1) characterize neural responses during encoding, maintenance and retrieval stages of WM using complementary region-of-interest and whole brain approaches; 2) determine whether schizophrenia and psychotic bipolar disorder exhibit similar abnormalities in WM-related brain function; and 3) elucidate the associations between WM-related brain function, task performance, and neuropsychological functioning. Both schizophrenia and psychotic bipolar disorder groups showed encoding- and maintenance-related impairments in the posterior parietal cortex (PPC) and frontal eye fields (FEF). BOLD response in the PPC and FEF, during encoding and maintenance respectively, was associated with task performance independent of group. Additionally, encoding-related activation in the PPC correlated with general neuropsychological functioning independent of group. Only encoding-related activation in the right ventral striatum differed between schizophrenia and psychotic bipolar disorder; individuals with schizophrenia showed significantly lower activation than both psychotic bipolar disorder and healthy groups. Our results are consistent with emerging evidence implicating PPC dysfunction in WM impairment and suggest interventions targeting neural activation in PPC may improve WM and neuropsychological functioning across psychotic disorders.
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  • Regionally specific volume deficits along the hippocampal long axis in early and chronic psychosis.
    NeuroImage. Clinical (2018)
    McHugo M, Talati P, Woodward ND, Armstrong K, Blackford JU, Heckers S. Regionally specific volume deficits along the hippocampal long axis in early and chronic psychosis. Neuroimage Clin. 2018; 20:1106-1114.
    Abstract: Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions.
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  • Impact of substance use disorder on gray matter volume in schizophrenia.
    Psychiatry research. Neuroimaging (2018)
    Quinn M, McHugo M, Armstrong K, Woodward N, Blackford J, Heckers S. Impact of substance use disorder on gray matter volume in schizophrenia. Psychiatry Res Neuroimaging. 2018 Oct 30; 280:9-14.
    Abstract: Substance use may confound the study of brain structure in schizophrenia. We used voxel-based morphometry (VBM) to examine whether differences in regional gray matter volumes exist between schizophrenia patients with (n = 92) and without (n = 66) clinically significant cannabis and/or alcohol use histories compared to 88 healthy control subjects. Relative to controls, patients with schizophrenia had reduced gray matter volume in the bilateral precentral gyrus, right medial frontal cortex, right visual cortex, right occipital pole, right thalamus, bilateral amygdala, and bilateral cerebellum regardless of substance use history. Within these regions, we found no volume differences between patients with schizophrenia and a history of cannabis and/or alcohol compared to patients with schizophrenia without a clinically significant substance use history. Our data support the idea that a clinically meaningful history of alcohol or cannabis use does not significantly compound the gray matter deficits associated with schizophrenia.
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  • Impaired associative inference in the early stage of psychosis.
    Schizophrenia research (2018)
    Armstrong K, Avery S, Blackford JU, Woodward N, Heckers S. Impaired associative inference in the early stage of psychosis. Schizophr Res. 2018 Dec; 202:86-90.
    Abstract: Relational memory is impaired in chronic schizophrenia. It is unclear if similar deficits are already present in the early stage of psychosis. We used the Associative Inference Paradigm to test relational memory ability in the early stage of a non-affective psychotic disorder. Eighty-two early stage psychosis patients and 67 healthy control subjects were trained on 3 sets of 30 paired associates: H-F1 (house paired with face), H-F2 (same house paired with new face), F3-F4 (two new faces). Subjects who reached 80% recall accuracy of the paired associates during training were then tested for their ability to recall the previously seen pairs and solve a novel, inferential pairing F1-F2 (faces linked through association to same house). Sixty early psychosis patients (73%) and 67 healthy control subjects (100%) successfully reached the accuracy threshold (80%) during training and were included in the analysis of relational memory. The early stage psychosis patients showed less of an associative inference effect than the healthy controls (pair type by group interaction: F (1,125) = 5.04, p < 0.05). However, the majority of early psychosis patients (52%) displayed intact inferential memory, compared to our prior study which revealed just 16% of chronic schizophrenia patients had intact inferential memory. Patients in the early stage of psychosis show a relational memory deficit, although less pronounced than in chronic schizophrenia. Longitudinal studies are needed to examine the progression of relational memory deficits in schizophrenia and its associations with clinical, functional, and biological measures.
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  • Hippocampal Network Modularity Is Associated With Relational Memory Dysfunction in Schizophrenia.
    Biological psychiatry. Cognitive neuroscience and neuroimaging (2018)
    Avery SN, Rogers BP, Heckers S. Hippocampal Network Modularity Is Associated With Relational Memory Dysfunction in Schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 May; 3(5):423-432.
    Abstract: Functional dysconnectivity has been proposed as a major pathophysiological mechanism for cognitive dysfunction in schizophrenia. The hippocampus is a focal point of dysconnectivity in schizophrenia, with decreased hippocampal functional connectivity contributing to the marked memory deficits observed in patients. Normal memory function relies on the interaction of complex corticohippocampal networks. However, only recent technological advances have enabled the large-scale exploration of functional networks with accuracy and precision.
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  • Multi-Scale Hippocampal Parcellation Improves Atlas-Based Segmentation Accuracy.
    Proceedings of SPIE--the International Society for Optical Engineering (2017)
    Plassard AJ, McHugo M, Heckers S, Landman BA. Multi-Scale Hippocampal Parcellation Improves Atlas-Based Segmentation Accuracy. Proc SPIE Int Soc Opt Eng. 2017 Feb 11; 10133:.
    Abstract: Known for its distinct role in memory, the hippocampus is one of the most studied regions of the brain. Recent advances in magnetic resonance imaging have allowed for high-contrast, reproducible imaging of the hippocampus. Typically, a trained rater takes 45 minutes to manually trace the hippocampus and delineate the anterior from the posterior segment at millimeter resolution. As a result, there has been a significant desire for automated and robust segmentation of the hippocampus. In this work we use a population of 195 atlases based on T1-weighted MR images with the left and right hippocampus delineated into the head and body. We initialize the multi-atlas segmentation to a region directly around each lateralized hippocampus to both speed up and improve the accuracy of registration. This initialization allows for incorporation of nearly 200 atlases, an accomplishment which would typically involve hundreds of hours of computation per target image. The proposed segmentation results in a Dice similiarity coefficient over 0.9 for the full hippocampus. This result outperforms a multi-atlas segmentation using the BrainCOLOR atlases (Dice 0.85) and FreeSurfer (Dice 0.75). Furthermore, the head and body delineation resulted in a Dice coefficient over 0.87 for both structures. The head and body volume measurements also show high reproducibility on the Kirby 21 reproducibility population (R greater than 0.95, p < 0.05 for all structures). This work signifies the first result in an ongoing work to develop a robust tool for measurement of the hippocampus and other temporal lobe structures.
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  • Reducing the Diagnostic Heterogeneity of Schizoaffective Disorder.
    Frontiers in psychiatry (2017)
    Seldin K, Armstrong K, Schiff ML, Heckers S. Reducing the Diagnostic Heterogeneity of Schizoaffective Disorder. Front Psychiatry. 2017; 8:18.
    Abstract: Clinical outcome studies of schizoaffective disorder patients have yielded conflicting results. One reason is the heterogeneity of samples drawn from the schizoaffective disorder population. Here, we studied schizoaffective disorder patients who showed marked functional impairment and continuous signs of illness for at least 6 months (i.e., DSM criteria B and C for schizophrenia).
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  • Manual segmentation of the human bed nucleus of the stria terminalis using 3T MRI.
    NeuroImage (2017)
    Theiss JD, Ridgewell C, McHugo M, Heckers S, Blackford JU. Manual segmentation of the human bed nucleus of the stria terminalis using 3T MRI. Neuroimage. 2017 Feb 1; 146:288-292.
    Abstract: The bed nucleus of the stria terminalis (BNST)-a small gray matter region located in the basal forebrain-has been implicated in both anxiety and addiction based on compelling evidence from rodent and non-human primate studies. However, the BNST's small size and proximity to other gray matter regions has hindered non-invasive study in human subjects using standard neuroimaging methods. While initial studies have benefitted from a BNST mask created from a single human subject using a 7T scanner, individual variability is likely-especially in patient populations-thus a manual segmentation protocol is needed. Here we report on the development of a reliable manual segmentation protocol performed on 3T MRI images using a scanning sequence that provides high gray matter/white matter/cerebrospinal fluid contrast. Inter- and intra-rater reliabilities, measured in 10 healthy individuals, demonstrate that the protocol can be reliably implemented (intra-rater Dice similarity coefficient≥0.85, inter-rater≥0.77). This BNST tracing protocol provides the necessary foundation for future 3T MRI studies of the BNST in healthy controls and patient populations.
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  • Personality traits predicting quality of life and overall functioning in schizophrenia.
    Schizophrenia research (2017)
    Ridgewell C, Blackford JU, McHugo M, Heckers S. Personality traits predicting quality of life and overall functioning in schizophrenia. Schizophr Res. 2017 Apr; 182:19-23.
    Abstract: Clinical symptoms and sociodemographic variables predict level of functioning and quality of life in patients with schizophrenia. However, few studies have examined the effect of personality traits on quality of life and overall functioning in schizophrenia. Personality traits are premorbid to illness and may predict the way patients experience schizophrenia. The aim of this study was to examine the individual and additive effects of two core personality traits-neuroticism and extraversion-on quality of life and functioning.
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Social Media and Young Women Intervention Phase
University of Connecticut/UConn Health
  • Proof-of-Concept Feasibility Trial of a Dissonance-Based Sun Safety Intervention for Young Adult Tanners.
    Annals of behavioral medicine : a publication of the Society of Behavioral Medicine (2022)
    Pagoto SL, Waring ME, Groshon LC, Rosen AO, Schroeder MW, Goetz JM. Proof-of-Concept Feasibility Trial of a Dissonance-Based Sun Safety Intervention for Young Adult Tanners. Ann Behav Med. 2022 Feb 18; :.
    Abstract: Melanoma is the second most common cancer in young adults. Social media may be a means to conduct interventions to increase sun safety in young adults.
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Cannabinoid Control of Fear Extinction Neural Circuits
University of Illinois at Chicago
  • Early pharmacological interventions for universal prevention of post-traumatic stress disorder (PTSD).
    The Cochrane database of systematic reviews (2022)
    Bertolini F, Robertson L, Bisson JI, Meader N, Churchill R, Ostuzzi G, Stein DJ, Williams T, Barbui C. Early pharmacological interventions for universal prevention of post-traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2022 Feb 10; 2:CD013443.
    Abstract: Post-traumatic stress disorder (PTSD) is a severe and debilitating condition. Several pharmacological interventions have been proposed with the aim to prevent or mitigate it. These interventions should balance efficacy and tolerability, given that not all individuals exposed to a traumatic event will develop PTSD. There are different possible approaches to preventing PTSD; universal prevention is aimed at individuals at risk of developing PTSD on the basis of having been exposed to a traumatic event, irrespective of whether they are showing signs of psychological difficulties.
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Home Sleep and Metabolism
University of Chicago Medical Center
  • Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults With Overweight in Real-life Settings: A Randomized Clinical Trial.
    JAMA internal medicine (2022)
    Tasali E, Wroblewski K, Kahn E, Kilkus J, Schoeller DA. Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults With Overweight in Real-life Settings: A Randomized Clinical Trial. JAMA Intern Med. 2022 Apr 1; 182(4):365-374.
    Abstract: Short sleep duration has been recognized as a risk factor for obesity. Whether extending sleep duration may mitigate this risk remains unknown.
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Phase II-b Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus Crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis
University of California San Diego
  • Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli.
    The Journal of clinical investigation (2022)
    Armstrong E, Hemmerling A, Miller S, Burke KE, Newmann SJ, Morris SR, Reno H, Huibner S, Kulikova M, Liu R, Crawford ED, Castañeda GR, Nagelkerke N, Coburn B, Cohen CR, Kaul R. Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli. J Clin Invest. 2022 Mar 15; 132(6):.
    Abstract: BackgroundBacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODSTo evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTSTopical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, and soluble immune markers of epithelial barrier disruption. Although the vaginal microbiota shifted to dominance by L. iners or L. jensenii, this proportional shift was primarily driven by a 2 to 4 log10-fold reduction in BV-associated bacteria absolute abundance. BV treatment induced no change in the absolute abundance of L. crispatus or L. iners and only minor (<1 log10-fold) increases in L. gasseri and L. jensenii that were not independently associated with reduced inflammation in multivariable models.CONCLUSIONThe genital immune benefits that are associated with Lactobacillus dominance after BV treatment were not directly attributable to an absolute increase in lactobacilli, but rather to the loss of BV-associated bacteria.Trial REGISTRATIONParticipants were recruited as part of a randomized controlled trial (ClinicalTrials.gov NCT02766023) from 2016 to 2019.FUNDINGCanadian Institutes of Health Research (PJT-156123) and the National Institute of Allergy and Infectious Diseases (HHSN2722013000141 and HHSN27200007).
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  • Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis.
    The New England journal of medicine (2020)
    Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, Green L, Miller S, Powell J, Parks T, Hemmerling A. Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis. N Engl J Med. 2020 May 14; 382(20):1906-1915.
    Abstract: Bacterial vaginosis affects 15 to 50% of women of reproductive age, and recurrence is common after treatment with an antibiotic agent. The high incidence of recurrence suggests the need for new treatments to prevent recurrent bacterial vaginosis.
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Phase II-b Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis
University of California San Francisco
  • Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli.
    The Journal of clinical investigation (2022)
    Armstrong E, Hemmerling A, Miller S, Burke KE, Newmann SJ, Morris SR, Reno H, Huibner S, Kulikova M, Liu R, Crawford ED, Castañeda GR, Nagelkerke N, Coburn B, Cohen CR, Kaul R. Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli. J Clin Invest. 2022 Mar 15; 132(6):.
    Abstract: BackgroundBacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODSTo evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTSTopical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, and soluble immune markers of epithelial barrier disruption. Although the vaginal microbiota shifted to dominance by L. iners or L. jensenii, this proportional shift was primarily driven by a 2 to 4 log10-fold reduction in BV-associated bacteria absolute abundance. BV treatment induced no change in the absolute abundance of L. crispatus or L. iners and only minor (<1 log10-fold) increases in L. gasseri and L. jensenii that were not independently associated with reduced inflammation in multivariable models.CONCLUSIONThe genital immune benefits that are associated with Lactobacillus dominance after BV treatment were not directly attributable to an absolute increase in lactobacilli, but rather to the loss of BV-associated bacteria.Trial REGISTRATIONParticipants were recruited as part of a randomized controlled trial (ClinicalTrials.gov NCT02766023) from 2016 to 2019.FUNDINGCanadian Institutes of Health Research (PJT-156123) and the National Institute of Allergy and Infectious Diseases (HHSN2722013000141 and HHSN27200007).
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  • Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis.
    The New England journal of medicine (2020)
    Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, Green L, Miller S, Powell J, Parks T, Hemmerling A. Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis. N Engl J Med. 2020 May 14; 382(20):1906-1915.
    Abstract: Bacterial vaginosis affects 15 to 50% of women of reproductive age, and recurrence is common after treatment with an antibiotic agent. The high incidence of recurrence suggests the need for new treatments to prevent recurrent bacterial vaginosis.
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An Observational Cohort Study of Adipose Tissue and Immune Activation in Treated HIV Infection
Vanderbilt University Medical Center
  • Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV.
    Frontiers in immunology (2021)
    Fuseini H, Smith R, Nochowicz CH, Simmons JD, Hannah L, Wanjalla CN, Gabriel CL, Mashayekhi M, Bailin SS, Castilho JL, Hasty AH, Koethe JR, Kalams SA. Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV. Front Immunol. 2021; 12:796898.
    Abstract: While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4 T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m, is positively correlated with greater CD4 T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4 T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4 T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4 T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4 T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4 T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4 T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4 T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4 T reconstitution in PLWH initiating ART.
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  • Elevated Eosinophils as a Feature of Inflammation Associated With Hypertension in Virally Suppressed People Living With HIV.
    Journal of the American Heart Association (2020)
    Masenga SK, Elijovich F, Hamooya BM, Nzala S, Kwenda G, Heimburger DC, Mutale W, Munsaka SM, Zhao S, Koethe JR, Kirabo A. Elevated Eosinophils as a Feature of Inflammation Associated With Hypertension in Virally Suppressed People Living With HIV. J Am Heart Assoc. 2020 Feb 18; 9(4):e011450.
    Abstract: Background People living with HIV (PLWH) are at increased risk of cardiovascular disease, including hypertension, which persists despite effective plasma viral suppression on antiretroviral therapy. HIV infection is characterized by long-term alterations in immune function, but the contribution of immune factors to hypertension in PLWH is not fully understood. Prior studies have found that both innate and adaptive immune cell activation contributes to hypertension. Methods and Results We hypothesized that chronic inflammation may contribute to hypertension in PLWH. To test this hypothesis, we enrolled a cohort of 70 PLWH (44% hypertensive) on a long-term single antiretroviral therapy regimen for broad phenotyping of inflammation biomarkers. We found that hypertensive PLWH had higher levels of inflammatory cytokines, including tumor necrosis factor-α receptor 1, interleukin-6, interleukin-17, interleukin-5, intercellular adhesion molecule 1 and macrophage inflammatory protein-1α. After adjustment for age, sex, and fat mass index, the circulating eosinophils remained significantly associated with hypertension. On the basis of these results, we assessed the relationship of eosinophils and hypertension in 2 cohorts of 50 and 81 039 similar HIV-negative people; although eosinophil count was associated with prevalent hypertension, this relationship was abrogated by body mass index. Conclusions These findings may represent a unique linkage between immune status and cardiovascular physiological characteristics in HIV infection, which should be evaluated further.
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  • Brief Report: Circulating Markers of Immunologic Activity Reflect Adiposity in Persons With HIV on Antiretroviral Therapy.
    Journal of acquired immune deficiency syndromes (1999) (2018)
    Koethe JR, Jenkins CA, Furch BD, Lake JE, Barnett L, Hager CC, Smith R, Hulgan T, Shepherd BE, Kalams SA. Brief Report: Circulating Markers of Immunologic Activity Reflect Adiposity in Persons With HIV on Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2018 Sep 1; 79(1):135-140.
    Abstract: Obesity alters adipose tissue immunology, and these changes may be reflected in circulating soluble inflammatory biomarker and T-cell subset profiles measured in HIV research studies.
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  • Lower Concentrations of Circulating Medium and Long-Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV.
    AIDS research and human retroviruses (2018)
    Bailin SS, Jenkins CA, Petucci C, Culver JA, Shepherd BE, Fessel JP, Hulgan T, Koethe JR. Lower Concentrations of Circulating Medium and Long-Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV. AIDS Res Hum Retroviruses. 2018 Jun; 34(6):536-543.
    Abstract: In human immunodeficiency virus (HIV)-negative individuals, a plasma metabolite profile, characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines, is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 nondiabetic, HIV-positive individuals (50% with body mass index ≥30 kg/m) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (<50 copies/mL) for at least 2 years and a CD4 count over 350 cells/μL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids (FFA) using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4 count was 701 cells/μL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p = .01), but not BCAA or C5 acylcarnitines. However, insulin resistance was associated with lower plasma levels of C18, C16, C12, and C2 acylcarnitines (p ≤ .03 for all), and lower C18 and C16 acylcarnitine:FFA ratios (p = .002, and p = .03, respectively). In HIV-positive persons, lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, are a more prominent feature of insulin resistance than changes in BCAA, suggesting impaired fatty acid uptake and/or mitochondrial oxidation is a central aspect of glucose intolerance in this population.
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  • Association of T Cell and Macrophage Activation with Arterial Vascular Health in HIV.
    AIDS research and human retroviruses (2017)
    Grome HN, Barnett L, Hagar CC, Harrison DG, Kalams SA, Koethe JR. Association of T Cell and Macrophage Activation with Arterial Vascular Health in HIV. AIDS Res Hum Retroviruses. 2017 Feb; 33(2):181-186.
    Abstract: HIV-infected individuals are at increased risk of cardiovascular disease (CVD), but the arterial vascular functions affected by persistent innate and cellular immune activation are not well described. We assessed the relationship between immunologic and vascular parameters in 70 HIV-infected adults on efavirenz, tenofovir, and emtricitabine with more than 2 years of virologic suppression and no history of CVD. We measured brachial artery flow-mediated dilation (FMD) using ultrasound and circulating intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) by multiple immunoassay. We also measured circulating naive (CD45ROCCR7CD27), activated (CD38 and CD38DR), exhausted (PD1), senescent (CD57), and memory (CD45RO) CD4 and CD8 T cell subsets by flow cytometry, and macrophage activation markers by ELISA and multiple immunoassay. Regression models were adjusted for age, sex, smoking, duration of antiretroviral therapy (ART), and body mass index. Median age was 45 years (IQR 39, 50), median CD4 count 701 cells/μl (IQR 540, 954), and 43% were female. Lower brachial FMD was associated with a higher percentage of activated CD8 T cells (p < .01), but not associated with macrophage activation. In contrast, higher ICAM-1 and VCAM-1 were associated with sCD163 (p < = .01 for both), macrophage inflammatory protein-1α (p < = .02 for both), and sCD14 (p = .01 for ICAM-1 only). These findings are consistent with the hypothesis that circulating CD8 T cell activation may impair arterial smooth muscle relaxation, while macrophage activation has a role in the expression of endothelial cell proteins involved in immune cell translocation. Both innate and cellular immune activation appear to promote arterial vascular disease in HIV-infected persons on ART using differing mechanisms.
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  • Superior Glucose Tolerance and Metabolomic Profiles, Independent of Adiposity, in HIV-Infected Women Compared With Men on Antiretroviral Therapy.
    Medicine (2016)
    Koethe JR, Jenkins CA, Petucci C, Culver J, Shepherd BE, Sterling TR. Superior Glucose Tolerance and Metabolomic Profiles, Independent of Adiposity, in HIV-Infected Women Compared With Men on Antiretroviral Therapy. Medicine (Baltimore). 2016 May; 95(19):e3634.
    Abstract: In epidemiologic studies, human immunodeficiency virus (HIV)-infected men on antiretroviral therapy (ART) are at higher risk of incident diabetes mellitus compared with women with similar treatment histories. We used metabolomics to determine whether a sex difference in plasma amino acids, acylcarnitines, and organic acids predictive of diabetes and impaired energy metabolism is present in HIV-infected persons on long-term ART.We enrolled 70 HIV-infected adults (43% women) on efavirenz, tenofovir, and emtricitabine (Atripla) with HIV-1 RNA <50 copies/mL for over 2 years. Half of the HIV-infected subjects were obese, and these were matched with 30 obese HIV-negative controls. All subjects had no history of diabetes, statin use, or heavy alcohol use. Fasting insulin sensitivity was measured using homeostatic model assessment 2 (HOMA2), and adipose tissue was measured using dual-energy x-ray absorptiometry (DEXA). Liquid chromatography/mass spectrometry was used to quantitate fasting plasma branched chain and aromatic amino acids predictive of incident diabetes, and C3 and C5 acylcarnitinines and organic acids indicative of impaired energy metabolism.HIV-infected women had more baseline risk factors for insulin resistance: women were older (46 vs 44 years) and had a longer ART duration (8.4 vs 5.1 years, P < 0.05 for both) compared with men but had similar CD4+ count (median 701 cells/μL), smoking and hepatic C prevalence, and body mass index (BMI) (median 30.3 kg/m). However, women had higher insulin sensitivity compared with men (P < 0.01), and lower plasma levels of isoleucine, leucine, valine, phenylalanine, and tyrosine (P < 0.01 for all), and lower C3 and C5 acylcarnitines (P < 0.01 for all), in multivariable regression models after adjusting for DEXA fat mass index, age, race, CD4+ count, smoking, and ART duration. In the obese HIV-infected subjects and HIV-negative controls, the relationship of sex and plasma metabolite levels did not significantly differ according to HIV-status.HIV-infected women on non-nucleoside reverse transcriptase inhibitor-based ART had superior glucose tolerance and lower plasma metabolites associated with the development of diabetes compared with men with similar metabolic disease risk profiles. The relationship between sex and plasma metabolite levels did not significantly differ according to HIV-status among obese subjects, suggesting the observed sex-differences may not be specific to HIV infection.
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  • The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy.
    AIDS (London, England) (2016)
    Koethe JR, Grome H, Jenkins CA, Kalams SA, Sterling TR. The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy. AIDS. 2016 Jan 2; 30(1):83-91.
    Abstract: This study assessed the effect of obesity on metabolic and cardiovascular disease risk factors in HIV-infected adults on antiretroviral therapy with sustained virologic suppression.
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The dynamics of HIV, aging, and T lymphocyte senescence
Vanderbilt University Medical Center
  • Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV.
    Frontiers in immunology (2021)
    Fuseini H, Smith R, Nochowicz CH, Simmons JD, Hannah L, Wanjalla CN, Gabriel CL, Mashayekhi M, Bailin SS, Castilho JL, Hasty AH, Koethe JR, Kalams SA. Leptin Promotes Greater Ki67 Expression in CD4+ T Cells From Obese Compared to Lean Persons Living With HIV. Front Immunol. 2021; 12:796898.
    Abstract: While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4 T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m, is positively correlated with greater CD4 T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4 T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4 T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4 T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4 T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4 T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4 T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4 T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4 T reconstitution in PLWH initiating ART.
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MTN 036, Version 1.0: A Phase 1, Randomized Pharmacokinetics and Safety Study of Extended Duration Dapivirine Vaginal Rings
University of California San Francisco
  • Users' Preferred Characteristics of Vaginal Rings for HIV Prevention: A Qualitative Analysis of Two Phase I Trials.
    AIDS research and human retroviruses (2022)
    Hawley I, Song M, Scheckter R, McClure T, Piper J, Chen BA, Hoesley C, Liu AY, van der Straten A. Users' Preferred Characteristics of Vaginal Rings for HIV Prevention: A Qualitative Analysis of Two Phase I Trials. AIDS Res Hum Retroviruses. 2022 Apr; 38(4):313-326.
    Abstract: Vaginal rings address a critical need for an independently initiated, long-acting HIV prevention method, but their design must be acceptable to promote uptake and adherence. Human-centered design (HCD) may help address design preference questions. In two Phase I studies of vaginal rings for HIV prevention conducted in the United States, we used qualitative interviews to assess participants' perceptions and opinions of the physical characteristics of the ring they used and of a ring's physical characteristics after comparing four ring designs presented via a visual tool. Users were found to prefer ring designs that appear easy to use, are physically comfortable, that function well, and are aesthetically pleasing. The parameters for these features varied widely. Product developers and marketers should consider marketing messages in which the target users feel this product is made to meet their needs and desires. Product developers are encouraged to design using HCD early in ring development (Clinical Trial Registration number: NCT03234400 and NCT03670355).
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  • Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States.
    Journal of the International AIDS Society (2021)
    Liu AY, Dominguez Islas C, Gundacker H, Neradilek B, Hoesley C, van der Straten A, Hendrix CW, Beamer M, Jacobson CE, McClure T, Harrell T, Bunge K, Devlin B, Nuttall J, Spence P, Steytler J, Piper JM, Marzinke MA, MTN-036/IPM 047 Protocol Team for the Mi. Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States. J Int AIDS Soc. 2021 Jun; 24(6):e25747.
    Abstract: Vaginal rings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring.
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Collection of biological samples of Convalescent patients from COVID-19
Vanderbilt University Medical Center
  • Standardized two-step testing of antibody activity in COVID-19 convalescent plasma.
    iScience (2022)
    Gilchuk P, Thomsen I, Yoder S, Brady E, Chappell JD, Stevens LJ, Denison MR, Sutton RE, Chen RE, VanBlargan LA, Suryadevara N, Zost SJ, Schmitz J, Pulley JM, Diamond MS, Rhoads JP, Bernard GR, Self WH, Rice TW, Wheeler AP, Crowe JE Jr, Carnahan RH. Standardized two-step testing of antibody activity in COVID-19 convalescent plasma. iScience. 2022 Jan 21; 25(1):103602.
    Abstract: The COVID-19 pandemic revealed an urgent need for rapid profiling of neutralizing antibody responses and development of antibody therapeutics. The current Food and Drug Administration-approved serological tests do not measure antibody-mediated viral neutralization, and there is a need for standardized quantitative neutralization assays. We report a high-throughput two-step profiling approach for identifying neutralizing convalescent plasma. Screening and downselection for serum antibody binding to the receptor-binding domain are followed by quantitative neutralization testing using a chimeric vesicular stomatitis virus expressing spike protein of SARS-CoV-2 in a real-time cell analysis assay. This approach enables a predictive screening process for identifying plasma units that neutralize SARS-CoV-2. To calibrate antibody neutralizing activity in serum from convalescent plasma donors, we introduce a neutralizing antibody standard reagent composed of two human antibodies that neutralize SARS-CoV strains, including SARS-CoV-2 variants of concern. Our results provide a framework for establishing a standardized assessment of antibody-based interventions against COVID-19.
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  • A high-throughput liquid bead array assay confirms strong correlation between SARS-CoV-2 antibody level and COVID-19 severity.
    iScience (2021)
    Bennett M, Yoder S, Brady E, Pulley JM, Rhoads JP, Stewart TG, Bernard GR, Creech CB, Wheeler AP, Thomsen I. A high-throughput liquid bead array assay confirms strong correlation between SARS-CoV-2 antibody level and COVID-19 severity. iScience. 2021 Feb 19; 24(2):102052.
    Abstract: A detailed understanding of the adaptive host response to SARS-CoV-2 infection in humans is urgently needed. We developed a sensitive, high-throughput, and efficient assay using liquid bead array technology. We observed advantages over traditional ELISA for the detection and quantification of binding IgG against the receptor binding domain (RBD) of SARS-CoV-2. To determine whether COVID-19 symptom severity correlates with SARS-CoV-2 IgG, we measured anti-RBD IgG levels from 67 subjects recovered from PCR-confirmed COVID-19. We found that COVID-19 symptom severity strongly correlated with RBD IgG level (p < 0.001). These findings have substantial implications for public policy surrounding assessments of antibody responses and possible immunity, as not all cases of COVID-19 can be assumed to generate a protective antibody response, and mild disease in particular is capable of generating very low-level anti-RBD IgG levels. These findings also have important implications for the selection of donors for convalescent plasma to be used therapeutically.
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Technology to Enhance Treatment for Early Conduct Problems in Low Income Families
University of North Carolina at Chapel Hill
  • A randomized controlled trial of technology-enhanced behavioral parent training: sustained parent skill use and child outcomes at follow-up.
    Journal of child psychology and psychiatry, and allied disciplines (2021)
    Parent J, Anton MT, Loiselle R, Highlander A, Breslend N, Forehand R, Hare M, Youngstrom JK, Jones DJ. A randomized controlled trial of technology-enhanced behavioral parent training: sustained parent skill use and child outcomes at follow-up. J Child Psychol Psychiatry. 2021 Dec 9; :.
    Abstract: Early-onset (3-8 years old) disruptive behavior disorders (DBDs) have been linked to a range of psychosocial sequelae in adolescence and beyond, including delinquency, depression, and substance use. Given that low-income families are overrepresented in statistics on early-onset DBDs, prevention and early-intervention targeting this population is a public health imperative. The efficacy of Behavioral Parent Training (BPT) programs such as Helping the Noncompliant Child (HNC) has been called robust; however, given the additional societal and structural barriers faced by low-income families, family engagement and retention barriers can cause effects to wane with time. This study extends preliminary work by examining the potential for a Technology-Enhanced HNC (TE-HNC) program to improve and sustain parent skill proficiency and child outcomes among low-income families.
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  • The relationships between religiosity and youth internalizing symptoms in African American parent-adolescent dyads.
    Cultural diversity & ethnic minority psychology (2018)
    Faro AL, McKee LG, Garcia RL, Jones DJ. The relationships between religiosity and youth internalizing symptoms in African American parent-adolescent dyads. Cultur Divers Ethnic Minor Psychol. 2018 Jan; 24(1):139-149.
    Abstract: African American (AA) adolescents face a greater risk of internalizing symptoms, including symptoms of both depression and anxiety, compared with other racial groups; yet, relatively less is known about the variables that contribute to internalizing symptoms. With the aim of advancing this work, this study examined factors that may buffer against such symptoms (maternal warmth, religiosity), as well as those that may confer additional risk (maternal psychopathology).
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  • Socioeconomic status, parenting, and externalizing problems in African American single-mother homes: A person-oriented approach.
    Journal of family psychology : JFP : journal of the Division of Family Psychology of the American Psychological Association (Division 43) (2015)
    Anton MT, Jones DJ, Youngstrom EA. Socioeconomic status, parenting, and externalizing problems in African American single-mother homes: A person-oriented approach. J Fam Psychol. 2015 Jun; 29(3):405-415.
    Abstract: African American youth, particularly those from single-mother homes, are overrepresented in statistics on externalizing problems. The family is a central context in which to understand externalizing problems; however, reliance on variable-oriented approaches to the study of parenting, which originate from work with intact, middle-income, European American families, may obscure important information regarding variability in parenting styles among African American single mothers, and in turn, variability in youth outcomes as well. The current study demonstrated that within African American single-mother families: (a) a person-, rather than variable-, oriented approach to measuring parenting style may further elucidate variability; (b) socioeconomic status may provide 1 context within which to understanding variability in parenting style; and (c) 1 marker of socioeconomic status, income, and parenting style may each explain variability in youth externalizing problems; however, the interaction between income and parenting style was not significant. Findings have potential implications for better understanding the specific contexts in which externalizing problems may be most likely to occur within this at-risk and underserved group.
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The TrialNet Natural History Study of the Development of Type 1 Diabetes
University of Minnesota
  • Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes.
    The Journal of clinical endocrinology and metabolism (2022)
    Triolo TM, Pyle L, Broncucia H, Armstrong T, Yu L, Gottlieb PA, Steck AK. Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes. J Clin Endocrinol Metab. 2022 Mar 24; 107(4):e1510-e1517.
    Abstract: Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes.
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  • β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis.
    JCI insight (2018)
    Evans-Molina C, Sims EK, DiMeglio LA, Ismail HM, Steck AK, Palmer JP, Krischer JP, Geyer S, Xu P, Sosenko JM, Type 1 Diabetes TrialNet Study Group.. β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis. JCI Insight. 2018 Aug 9; 3(15):.
    Abstract: The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined.
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  • The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults.
    The Journal of clinical endocrinology and metabolism (2017)
    Ferrara CT, Geyer SM, Evans-Molina C, Libman IM, Becker DJ, Wentworth JM, Moran A, Gitelman SE, Redondo MJ, Type 1 Diabetes TrialNet Study Group.. The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults. J Clin Endocrinol Metab. 2017 Dec 1; 102(12):4596-4603.
    Abstract: Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown.
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  • Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives.
    The Journal of clinical endocrinology and metabolism (2017)
    Bosi E, Boulware DC, Becker DJ, Buckner JH, Geyer S, Gottlieb PA, Henderson C, Kinderman A, Sosenko JM, Steck AK, Bingley PJ, Type 1 Diabetes TrialNet Study Group.. Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives. J Clin Endocrinol Metab. 2017 Aug 1; 102(8):2881-2886.
    Abstract: Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease.
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  • β cell death and dysfunction during type 1 diabetes development in at-risk individuals.
    The Journal of clinical investigation (2015)
    Herold KC, Usmani-Brown S, Ghazi T, Lebastchi J, Beam CA, Bellin MD, Ledizet M, Sosenko JM, Krischer JP, Palmer JP, Type 1 Diabetes TrialNet Study Group. β cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest. 2015 Mar 2; 125(3):1163-73.
    Abstract: Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data.
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Self-management for people with epilepsy and a history of negative health events (SMART): Targeting rural and underserved people with epilepsy
University of Iowa
  • A randomized controlled trial of self-management for people with epilepsy and a history of negative health events (SMART) targeting rural and underserved people with epilepsy: a methodologic report.
    Trials (2021)
    Ghearing GR, Briggs F, Cassidy K, Privitera M, Blixen C, Sajatovic M. A randomized controlled trial of self-management for people with epilepsy and a history of negative health events (SMART) targeting rural and underserved people with epilepsy: a methodologic report. Trials. 2021 Nov 20; 22(1):821.
    Abstract: Many people living with epilepsy (PLWE) reside in rural communities, and epilepsy self-management may help address some of the gaps in epilepsy care for these communities. A prior randomized control trial of a remotely delivered, Web-based group format 12-week self-management program (SMART) conducted in Northeast Ohio, a primarily urban and suburban community, demonstrated improved outcomes in negative health events such as depression symptoms and quality of life. However, there is a paucity of research addressing the needs of PLWE in rural settings.
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Role of Sympathethic Activity and Splanchnic Capacitance in Obesity Hypertension: Specific Aims 1 and 2
Vanderbilt University Medical Center
  • Effect of nitroglycerin on splanchnic and pulmonary blood volume.
    Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (2021)
    Okamoto LE, Dupont WD, Biaggioni I, Kronenberg MW. Effect of nitroglycerin on splanchnic and pulmonary blood volume. J Nucl Cardiol. 2021 Nov 2; :.
    Abstract: Sublingual nitroglycerin (SL NTG) is useful for treating acute decompensated heart failure, possibly by increasing splanchnic capacitance and reducing left ventricular (LV) preload. We evaluated a radionuclide method to study these effects, initially in subjects without heart failure.
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Message-based psychotherapy and digital treatment sequences for depression
University of Washington
  • Protocol for a sequential, multiple assignment, randomised trial to test the effectiveness of message-based psychotherapy for depression compared with telepsychotherapy.
    BMJ open (2021)
    Arean P, Hull D, Pullmann MD, Heagerty PJ. Protocol for a sequential, multiple assignment, randomised trial to test the effectiveness of message-based psychotherapy for depression compared with telepsychotherapy. BMJ Open. 2021 Nov 2; 11(11):e046958.
    Abstract: Digital mental health tools have become popular alternatives to traditional psychotherapy. One emerging form of digital mental health is message-based care, the use of text messages or asynchronous voice or video messaging to provide psychotherapy. There has been no research into whether this is an effective method of psychotherapy as a stand-alone treatment or in combination with traditional psychotherapy.
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Saturated Fat and Protein Effects on Atherogenic Dyslipidemia
Children\'s Hospital and Research Center at Oakland
  • Fecal Microbiome Composition Does Not Predict Diet-Induced TMAO Production in Healthy Adults.
    Journal of the American Heart Association (2021)
    Ferrell M, Bazeley P, Wang Z, Levison BS, Li XS, Jia X, Krauss RM, Knight R, Lusis AJ, Garcia-Garcia JC, Hazen SL, Tang WHW. Fecal Microbiome Composition Does Not Predict Diet-Induced TMAO Production in Healthy Adults. J Am Heart Assoc. 2021 Nov 2; 10(21):e021934.
    Abstract: Background Trimethylamine--oxide (TMAO) is a small molecule derived from the metabolism of dietary nutrients by gut microbes and contributes to cardiovascular disease. Plasma TMAO increases following consumption of red meat. This metabolic change is thought to be partly because of the expansion of gut microbes able to use nutrients abundant in red meat. Methods and Results We used data from a randomized crossover study to estimate the degree to which TMAO can be estimated from fecal microbial composition. Healthy participants received a series of 3 diets that differed in protein source (red meat, white meat, and non-meat), and fecal, plasma, and urine samples were collected following 4 weeks of exposure to each diet. TMAO was quantitated in plasma and urine, while shotgun metagenomic sequencing was performed on fecal DNA. While the cai gene cluster was weakly correlated with plasma TMAO (rho=0.17, =0.0007), elastic net models of TMAO were not improved by abundances of bacterial genes known to contribute to TMAO synthesis. A global analysis of all taxonomic groups, genes, and gene families found no meaningful predictors of TMAO. We postulated that abundances of known genes related to TMAO production do not predict bacterial metabolism, and we measured choline- and carnitine-trimethylamine lyase activity during fecal culture. Trimethylamine lyase genes were only weakly correlated with the activity of the enzymes they encode. Conclusions Fecal microbiome composition does not predict systemic TMAO because, in this case, gene copy number does not predict bacterial metabolic activity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01427855.
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  • Effects of red meat, white meat, and nonmeat protein sources on atherogenic lipoprotein measures in the context of low compared with high saturated fat intake: a randomized controlled trial.
    The American journal of clinical nutrition (2019)
    Bergeron N, Chiu S, Williams PT, M King S, Krauss RM. Effects of red meat, white meat, and nonmeat protein sources on atherogenic lipoprotein measures in the context of low compared with high saturated fat intake: a randomized controlled trial. Am J Clin Nutr. 2019 Jul 1; 110(1):24-33.
    Abstract: Dietary recommendations to limit red meat are based on observational studies linking intake to cardiovascular disease (CVD) risk together with the potential of its saturated fatty acid (SFA) content to raise low-density lipoprotein (LDL) cholesterol. However, the relation of white meat to CVD risk, and the effects of dietary protein source on lipoprotein particle subfractions, have not been extensively evaluated.
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An Adaptive Intervention to Improve Health, Safety and Empowerment Outcomes Among Immigrant Women with Intimate Partner Violence Experiences
Johns Hopkins University
  • A technology-based intervention to improve safety, mental health and empowerment outcomes for immigrant women with intimate partner violence experiences: it's weWomen plus sequential multiple assignment randomized trial (SMART) protocol.
    BMC public health (2021)
    Sabri B, Glass N, Murray S, Perrin N, Case JR, Campbell JC. A technology-based intervention to improve safety, mental health and empowerment outcomes for immigrant women with intimate partner violence experiences: it's weWomen plus sequential multiple assignment randomized trial (SMART) protocol. BMC Public Health. 2021 Oct 28; 21(1):1956.
    Abstract: Intimate partner violence (IPV) disproportionately affects immigrant women, an understudied and underserved population in need for evidence-based rigorously evaluated culturally competent interventions that can effectively address their health and safety needs.
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Understanding the Lived Experience of Couples Across the Trajectory of Dementia Short Title: Couples and Dementia
New York University
  • Longitudinal study: understanding the lived experience of couples across the trajectory of dementia.
    BMC geriatrics (2021)
    Mittelman MS, O'Connor MK, Donley T, Epstein-Smith C, Nguyen A, Nicholson R, Salant R, Shirk SD, Stevenson E. Longitudinal study: understanding the lived experience of couples across the trajectory of dementia. BMC Geriatr. 2021 Oct 15; 21(1):558.
    Abstract: The longitudinal study, "Couples Lived Experiences," focuses on whether and how relationship characteristics of older couples change with the cognitive decline of one member of the couple, and how these changes affect each individual's emotional and physical health outcomes. Until now, most psychosocial research in dementia has focused either on the person with dementia (PWD) or the caregiver separately. The previous literature examining relationship characteristics and their role in outcomes for the caregiver and PWD is scant and suffers from methodological issues that limit the understanding of which relationship characteristics most influence outcomes for caregivers and care-receivers and what other factors may mitigate or exacerbate their effects.
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The Neurobiology of Approach Avoidance Training in Depression
University of California San Diego
  • Neural Changes in Reward Processing Following Approach Avoidance Training for Depression.
    Social cognitive and affective neuroscience (2021)
    Bomyea J, Choi SH, Sweet A, Stein M, Paulus M, Taylor C. Neural Changes in Reward Processing Following Approach Avoidance Training for Depression. Soc Cogn Affect Neurosci. 2021 Oct 13; :.
    Abstract: Altered approach motivation is hypothesized to be critical for the maintenance of depression. Computer-administered approach-avoidance training programs to increase approach action tendencies toward positive stimuli produce beneficial outcomes. However, there have been few studies examining neural changes following approach-avoidance training. Participants with Major Depressive Disorder were randomized to an Approach Avoidance Training (AAT) manipulation intended to increase approach tendencies for positive social cues (n=13) or a control procedure (n=15). We examined changes in neural activation (primary outcome) and connectivity patterns using Group Iterative Multiple Model Estimation during a social reward anticipation task (exploratory). A laboratory-based social affiliation task was also administered following the manipulation to measure affect during anticipation of real-world social activity. Individuals in the AAT group demonstrated increased activation in reward processing regions during social reward anticipation relative to the control group from pre to post-training. Following training, connectivity patterns across reward regions were observed in the full sample and connectivity between the medial PFC and caudate was associated with anticipatory positive affect before the social interaction; preliminary evidence of differential connectivity patterns between the two groups also emerged. Results support models whereby modifying approach-oriented behavioral tendencies with computerized training leads to alterations in reward circuitry. (NCT02330744).
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Stereotactic Radiosurgery for Essential Tremor and Parkinsonian Tremor
Vanderbilt University Medical Center
  • Noninvasive Thalamotomy for Refractory Tremor by Frameless Radiosurgery.
    International journal of radiation oncology, biology, physics (2022)
    Khattab MH, Cmelak AJ, Sherry AD, Luo G, Wang L, Yu H, Hedera P, Phibbs FT, Lindsell CJ, Neimat J, Kirschner AN. Noninvasive Thalamotomy for Refractory Tremor by Frameless Radiosurgery. Int J Radiat Oncol Biol Phys. 2022 Jan 1; 112(1):121-130.
    Abstract: We sought to determine whether a more widely accessible, noninvasive, frameless approach to radiosurgical thalamotomy would improve objective measures of refractory essential or parkinsonian tremor without added toxicity compared with reports of frame-based radiosurgery.
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The Decision to Speed in the United States – A Mixed Methods Approach
University of Minnesota
  • To speed or not to speed: Thematic analysis of American driving narratives.
    Journal of safety research (2021)
    Peterson CM, Gaugler JE. To speed or not to speed: Thematic analysis of American driving narratives. J Safety Res. 2021 Sep; 78:129-137.
    Abstract: Speeding is a major cause of unintentional roadway death in the United States. Existing data show that U.S. drivers tend to speed less as they age, but reasons for this change remain largely unknown. Limited research has examined why U.S. drivers decide to speed or why U.S. drivers decide not to speed, and none to date has determined why speeding behaviors change over the life course. Research into these issues can provide insight that may be harnessed for more effective anti-speeding interventions that catalyze decisions not to speed.
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Evaluation of a Multimedia Sleep Education Package in Children with ASD
Vanderbilt University Medical Center
  • A REDCap-based model for online interventional research: Parent sleep education in autism.
    Journal of clinical and translational science (2021)
    Malow BA, Galion A, Lu F, Kennedy N, Lawrence CE, Tassone A, O'Neal L, Wilson TM, Parker RA, Harris PA, Neumeyer AM. A REDCap-based model for online interventional research: Parent sleep education in autism. J Clin Transl Sci. 2021; 5(1):e138.
    Abstract: The use of online platforms for pediatric healthcare research is timely, given the current pandemic. These platforms facilitate trial efficiency integration including electronic consent, randomization, collection of patient/family survey data, delivery of an intervention, and basic data analysis.
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Quantitative Evaluation of Visual and Auditory Dysfunction and Multi-Sensory Integration in Complex TBI Patients
Vanderbilt University Medical Center
  • Joint analysis of structural connectivity and cortical surface features: correlates with mild traumatic brain injury.
    Proceedings of SPIE--the International Society for Optical Engineering (2021)
    Kerley CI, Cai LY, Yu C, Crawford LM, Elenberger JM, Singh ES, Schilling KG, Aboud KS, Landman BA, Rex TS. Joint analysis of structural connectivity and cortical surface features: correlates with mild traumatic brain injury. Proc SPIE Int Soc Opt Eng. 2021; 11596:.
    Abstract: Mild traumatic brain injury (mTBI) is a complex syndrome that affects up to 600 per 100,000 individuals, with a particular concentration among military personnel. About half of all mTBI patients experience a diverse array of chronic symptoms which persist long after the acute injury. Hence, there is an urgent need for better understanding of the white matter and gray matter pathologies associated with mTBI to map which specific brain systems are impacted and identify courses of intervention. Previous works have linked mTBI to disruptions in white matter pathways and cortical surface abnormalities. Herein, we examine these hypothesized links in an exploratory study of joint structural connectivity and cortical surface changes associated with mTBI and its chronic symptoms. Briefly, we consider a cohort of 12 mTBI and 26 control subjects. A set of 588 cortical surface metrics and 4,753 structural connectivity metrics were extracted from cortical surface regions and diffusion weighted magnetic resonance imaging in each subject. Principal component analysis (PCA) was used to reduce the dimensionality of each metric set. We then applied independent component analysis (ICA) both to each PCA space individually and together in a joint ICA approach. We identified a stable independent component across the connectivity-only and joint ICAs which presented significant group differences in subject loadings (p<0.05, corrected). Additionally, we found that two mTBI symptoms, slowed thinking and forgetfulness, were significantly correlated (p<0.05, corrected) with mTBI subject loadings in a surface-only ICA. These surface-only loadings captured an increase in bilateral cortical thickness.
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  • MRI correlates of chronic symptoms in mild traumatic brain injury.
    Proceedings of SPIE--the International Society for Optical Engineering (2020)
    Kerley CI, Schilling KG, Blaber J, Miller B, Newton A, Anderson AW, Landman BA, Rex TS. MRI correlates of chronic symptoms in mild traumatic brain injury. Proc SPIE Int Soc Opt Eng. 2020; 11313:.
    Abstract: Some veterans with a history of mild traumatic brain injury (mTBI) have reported experiencing auditory and visual dysfunction that persist beyond the acute phase of the incident. The etiology behind these symptoms is difficult to characterize, since mTBI is defined by negative imaging findings on current clinical imaging. There are several competing hypotheses that could explain functional deficits; one example is shear injury, which may manifest in diffusion-weighted magnetic resonance (MR) imaging (DWI). Herein, we explore this alternative hypothesis in a pilot study of multi-parametric MR imaging. Briefly, we consider a cohort of 8 mTBI patients relative to 22 control subjects using structural T1-weighted imaging (T1w) and connectivity with DWI. 1,344 metrics were extracted per subject from whole brain regions and connectivity patterns in sensory networks. For each set of imaging-derived metrics, the control subject metrics were embedded in a low-dimensional manifold with principal component analysis, after which mTBI subject metrics were projected into the same space. These manifolds were employed to train support vector machines (SVM) to classify subjects as controls or mTBI. Two of the SVMs trained achieved near-perfect accuracy averaged across four-fold cross-validation. Additionally, we present correlations between manifold dimensions and 22 self-reported mTBI symptoms and find that five principal components from the manifolds (one component from the T1w manifold and four components from the DWI manifold) are significantly correlated with symptoms (p<0.05, uncorrected). The novelty of this work is that the DWI and T1w imaging metrics seem to contain information critical for distinguishing between mTBI and control subjects. This work presents an analysis of the pilot phase of data collection of the Quantitative Evaluation of Visual and Auditory Dysfunction and Multi-Sensory Integration in Complex TBI Patients study and defines specific hypotheses to be tested in the full sample.
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  • Distortion correction of diffusion weighted MRI without reverse phase-encoding scans or field-maps.
    PloS one (2020)
    Schilling KG, Blaber J, Hansen C, Cai L, Rogers B, Anderson AW, Smith S, Kanakaraj P, Rex T, Resnick SM, Shafer AT, Cutting LE, Woodward N, Zald D, Landman BA. Distortion correction of diffusion weighted MRI without reverse phase-encoding scans or field-maps. PLoS One. 2020; 15(7):e0236418.
    Abstract: Diffusion magnetic resonance images may suffer from geometric distortions due to susceptibility induced off resonance fields, which cause geometric mismatch with anatomical images and ultimately affect subsequent quantification of microstructural or connectivity indices. State-of-the art diffusion distortion correction methods typically require data acquired with reverse phase encoding directions, resulting in varying magnitudes and orientations of distortion, which allow estimation of an undistorted volume. Alternatively, additional field maps acquisitions can be used along with sequence information to determine warping fields. However, not all imaging protocols include these additional scans and cannot take advantage of state-of-the art distortion correction. To avoid additional acquisitions, structural MRI (undistorted scans) can be used as registration targets for intensity driven correction. In this study, we aim to (1) enable susceptibility distortion correction with historical and/or limited diffusion datasets that do not include specific sequences for distortion correction and (2) avoid the computationally intensive registration procedure typically required for distortion correction using structural scans. To achieve these aims, we use deep learning (3D U-nets) to synthesize an undistorted b0 image that matches geometry of structural T1w images and intensity contrasts from diffusion images. Importantly, the training dataset is heterogenous, consisting of varying acquisitions of both structural and diffusion. We apply our approach to a withheld test set and show that distortions are successfully corrected after processing. We quantitatively evaluate the proposed distortion correction and intensity-based registration against state-of-the-art distortion correction (FSL topup). The results illustrate that the proposed pipeline results in b0 images that are geometrically similar to non-distorted structural images, and more closely match state-of-the-art correction with additional acquisitions. In addition, we show generalizability of the proposed approach to datasets that were not in the original training / validation / testing datasets. These datasets included varying populations, contrasts, resolutions, and magnitudes and orientations of distortion and show efficacious distortion correction. The method is available as a Singularity container, source code, and an executable trained model to facilitate evaluation.
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Grounded theory methods to explore emerging adult-aged women's sexual and reproductive health promotion and risk reduction
The Ohio State University
  • Practical strategies for qualitative inquiry in a virtual world.
    Journal of advanced nursing (2021)
    Schlegel EC, Tate JA, Pickler RH, Smith LH. Practical strategies for qualitative inquiry in a virtual world. J Adv Nurs. 2021 Oct; 77(10):4035-4044.
    Abstract: The aim of this article is to provide practical strategies for maintaining methodological rigour in executing a virtual qualitative study. Strategies are based on evidence from existing research about virtual qualitative methods and on the strategies used by the authors to convert a planned in-person qualitative, grounded theory study to an entirely virtual grounded theory study during the COVID-19 pandemic. The study began in-person in September 2019 and was converted to virtual in March 2020. Virtual data collection was completed in September 2020.
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Enhancing Fear Extinction Via Angiotensin Type 1 Receptor Inhibition: A Randomized Controlled Trial in Posttraumatic Stress Disorder
University of California San Diego
  • Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder.
    Biological psychiatry (2021)
    Stein MB, Jain S, Simon NM, West JC, Marvar PJ, Bui E, He F, Benedek DM, Cassano P, Griffith JL, Howlett J, Malgaroli M, Melaragno A, Seligowski AV, Shu IW, Song S, Szuhany K, Taylor CT, Ressler KJ, LOSe-PTSD Investigators.. Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder. Biol Psychiatry. 2021 Oct 1; 90(7):473-481.
    Abstract: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD.
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Alzheimer's Disease Neuroimaging Initiative 3
Vanderbilt University Medical Center
  • Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition.
    Journal of neurology, neurosurgery, and psychiatry (2021)
    Rauchmann BS, Schneider-Axmann T, Perneczky R, Alzheimer's Disease Neuroimaging Initiative (ADNI).. Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition. J Neurol Neurosurg Psychiatry. 2021 Dec; 92(12):1289-1295.
    Abstract: To explore if changes over time of plasma phosphorylated tau (p-tau)181 and neurofilament light chain (NfL) predict future tau and amyloid β (Aβ) PET load and cognitive performance, we studied a subsample of the Alzheimer's disease (AD) neuroimaging cohort with longitudinal blood peptide assessments.
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  • Early detection of amyloid load using 18F-florbetaben PET.
    Alzheimer's research & therapy (2021)
    Bullich S, Roé-Vellvé N, Marquié M, Landau SM, Barthel H, Villemagne VL, Sanabria Á, Tartari JP, Sotolongo-Grau O, Doré V, Koglin N, Müller A, Perrotin A, Jovalekic A, De Santi S, Tárraga L, Stephens AW, Rowe CC, Sabri O, Seibyl JP, Boada M. Early detection of amyloid load using 18F-florbetaben PET. Alzheimers Res Ther. 2021 Mar 27; 13(1):67.
    Abstract: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition.
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Acupressure for Fatigue in Ovarian Cancer Survivors
University of Michigan Ann Arbor
  • Acupressure for Cancer-fatigue in Ovarian Cancer Survivor (AcuOva) Study: A community-based clinical trial study protocol examining the impact of self-acupressure on persistent cancer-related fatigue in ovarian cancer survivors.
    Contemporary clinical trials (2021)
    Zick SM, Kruger G, Harte S, Sen A, Harris RE, Pearce CL. Acupressure for Cancer-fatigue in Ovarian Cancer Survivor (AcuOva) Study: A community-based clinical trial study protocol examining the impact of self-acupressure on persistent cancer-related fatigue in ovarian cancer survivors. Contemp Clin Trials. 2021 Aug; 107:106477.
    Abstract: Background Persistent cancer-related fatigue is one of the most common and burdensome symptoms experienced by ovarian cancer survivors. Despite the high burden of fatigue in ovarian cancer survivors, there are few available treatments. Previous research has shown self-acupressure to be a safe method for improving persistent fatigue, sleep, and quality of life among fatigued breast cancer survivors, yet there are no studies examining self-acupressure for fatigue in ovarian cancer survivors. Methods A three group parallel, randomized controlled trial will be conducted to evaluate the efficacy of self-acupressure taught and delivered via a patient-designed, custom-built mobile app ("MeTime") and accompanying hand-held device ("AcuWand") to help guide correct pressure application. A sample of 165 ovarian cancer survivors, who have completed primary cancer treatment will be recruited from tumor registries in Michigan and Los Angeles. Participants will be mailed a tablet preloaded with the app and a device, and all visits will be conducted remotely. Participants will be randomized to 6-weeks of daily self-acupressure via the app and device, or a sham app and device, or no care group. Self-report measures will be completed at baseline, 6-weeks (post-intervention), 3-, and 6-months. Primary outcome is the Brief Fatigue Inventory; secondary outcomes are sleep, quality of life, and symptoms commonly associated with persistent fatigue. Discussion An app based self-acupressure treatment may be an easily-accessible and inexpensive treatment to reduce fatigue in ovarian cancer survivors. The results of the study will provide information on the possible benefits of app-based self-acupressure for fatigue in ovarian cancer survivors. Trial registration: This study is registered at ClinicalTrials.gov Identifier: NCT03763838, date registered on December 4, 2018.
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A phase 1 double-blind, randomized, controlled clinical trial in healthy, HIV-1-uninfected adult participants to compare the safety, tolerability and immunogenicity of CH505TF gp 120 produced from stably transfected cells to CH505TF gp 120 produced from transiently transfected cells
Vanderbilt University Medical Center
  • Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates.
    Vaccine (2021)
    Wolfe LS, Smedley JG 3rd, Bubna N, Hussain A, Harper R, Mostafa S. Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates. Vaccine. 2021 Jun 29; 39(29):3852-3861.
    Abstract: Preclinical development of vaccine candidates is an important link between the discovery and manufacture of vaccines for use in human clinical trials. Here, an exploratory clinical study utilizing multiple gp120 envelope proteins as vaccine antigens was pursued, which required a harmonized platform development approach for timely and efficient manufacture of the combined HIV vaccine product. Development of cell lines, processes, and analytical methods was initiated with a transmitted founder envelope protein (CH505TF), then applied to produce three subsequent gp120 Env (envelope) variants. Cell lines were developed using the commercially available Freedom CHO DG44 kit (Life Technologies). The fed-batch cell culture production process was based on a commercially-available medium with harmonized process parameters across the variants. A platform purification process was developed utilizing a mixed mode chromatography capture step, with ceramic hydroxyapatite and ion exchange polishing steps. A suite of analytical methods was developed to establish and monitor the Quality Target Profile (QTP), release and long-term stability testing of the vaccine products. The platform development strategy was successfully implemented to produce four gp120 envelope protein variants. In some cases, minor changes to the platform were required to optimize for a particular variant; however, baseline conditions for the processes (cell line type, media & feed system, chromatography resins, and analytical approaches) remained constant, leading to successful transfer and manufacture of all four proteins in a cGMP facility. This body of work demonstrates successful pursuit of a platform development approach to manufacture important vaccine candidates and can be used as a model for other vaccine glycoproteins, such as HIV gp140 trimers or other viral glycoproteins with global health implications. Clinical trial identifier. NCT03220724, NCT03856996.
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HVTN 123: A phase 1 double-blind, randomized, controlled clinical trial in healthy, HIV-1– uninfected adult participants to compare the safety, tolerability and immunogenicity of CH505TF gp120 produced from stably transfected cells to CH505TF gp120 produced from transiently transfected cells
Emory University
  • Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates.
    Vaccine (2021)
    Wolfe LS, Smedley JG 3rd, Bubna N, Hussain A, Harper R, Mostafa S. Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates. Vaccine. 2021 Jun 29; 39(29):3852-3861.
    Abstract: Preclinical development of vaccine candidates is an important link between the discovery and manufacture of vaccines for use in human clinical trials. Here, an exploratory clinical study utilizing multiple gp120 envelope proteins as vaccine antigens was pursued, which required a harmonized platform development approach for timely and efficient manufacture of the combined HIV vaccine product. Development of cell lines, processes, and analytical methods was initiated with a transmitted founder envelope protein (CH505TF), then applied to produce three subsequent gp120 Env (envelope) variants. Cell lines were developed using the commercially available Freedom CHO DG44 kit (Life Technologies). The fed-batch cell culture production process was based on a commercially-available medium with harmonized process parameters across the variants. A platform purification process was developed utilizing a mixed mode chromatography capture step, with ceramic hydroxyapatite and ion exchange polishing steps. A suite of analytical methods was developed to establish and monitor the Quality Target Profile (QTP), release and long-term stability testing of the vaccine products. The platform development strategy was successfully implemented to produce four gp120 envelope protein variants. In some cases, minor changes to the platform were required to optimize for a particular variant; however, baseline conditions for the processes (cell line type, media & feed system, chromatography resins, and analytical approaches) remained constant, leading to successful transfer and manufacture of all four proteins in a cGMP facility. This body of work demonstrates successful pursuit of a platform development approach to manufacture important vaccine candidates and can be used as a model for other vaccine glycoproteins, such as HIV gp140 trimers or other viral glycoproteins with global health implications. Clinical trial identifier. NCT03220724, NCT03856996.
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Tesamorelin Effects on Liver fat and Histology in HIV
The National Institutes of Health
  • Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.
    Scientific reports (2021)
    Fourman LT, Stanley TL, Billingsley JM, Sui SJH, Feldpausch MN, Boutin A, Zheng I, McClure CM, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Chung RT, Grinspoon SK. Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach. Sci Rep. 2021 May 18; 11(1):10485.
    Abstract: NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.
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  • Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2021)
    Stanley TL, Fourman LT, Wong LP, Sadreyev R, Billingsley JM, Feldpausch MN, Zheng I, Pan CS, Boutin A, Lee H, Corey KE, Torriani M, Kleiner DE, Chung RT, Hadigan CM, Grinspoon SK. Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease. Clin Infect Dis. 2021 Aug 16; 73(4):621-630.
    Abstract: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).
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  • Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.
    The Journal of clinical endocrinology and metabolism (2021)
    Stanley TL, Fourman LT, Zheng I, McClure CM, Feldpausch MN, Torriani M, Corey KE, Chung RT, Lee H, Kleiner DE, Hadigan CM, Grinspoon SK. Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab. 2021 Jan 23; 106(2):e520-e533.
    Abstract: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).
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  • Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.
    The lancet. HIV (2019)
    Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, Aepfelbacher J, Buckless C, Tsao A, Kellogg A, Branch K, Lee H, Liu CY, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV. 2019 Dec; 6(12):e821-e830.
    Abstract: Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD.
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Speech Performance in Dysarthria
Vanderbilt University Medical Center
  • Articulatory Correlates of Stress Pattern Disturbances in Talkers With Dysarthria.
    Journal of speech, language, and hearing research : JSLHR (2021)
    Kim D, Kuruvilla-Dugdale M, de Riesthal M, Jones R, Bagnato F, Mefferd A. Articulatory Correlates of Stress Pattern Disturbances in Talkers With Dysarthria. J Speech Lang Hear Res. 2021 Jun 18; 64(6S):2287-2300.
    Abstract: Purpose Reduced stress commonly occurs in talkers with Parkinson's disease (PD), whereas excessive and equal stress is frequently associated with dysarthria of talkers with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). This study sought to identify articulatory impairment patterns that underlie these two impaired stress patterns. We further aimed to determine if talkers with the same stress pattern disturbance but different diseases (ALS and MS) exhibit disease-specific articulatory deficits. Method Fifty-seven talkers participated in the study-33 talkers with dysarthria and 24 controls. Talkers with dysarthria were grouped based on their medical diagnosis: PD ( = 15), ALS ( = 10), MS ( = 8). Participants repeated target words embedded in a carrier phrase. Kinematic data were recorded using electromagnetic articulography. Duration, displacement, peak speed, stiffness, time-to-peak speed, and parameter c were extracted for the initial lower lip opening stroke of each target word, which was either stressed or unstressed. Results Stress effects were significant for all kinematic measures across groups except for stiffness and time-to-peak speed, which were nonsignificant in ALS. For comparisons with controls, more kinematic measures significantly differed in the ALS group than in the PD and MS groups. Additionally, ALS and MS showed mostly similar articulatory impairment patterns. Conclusions In general, significant stress effects were observed in talkers with dysarthria. However, stress-specific between-group differences in articulatory performance, particularly displacement, may explain the perceptual impression of disturbed stress patterns. Furthermore, similar findings for ALS and MS suggest that articulatory deficits underlying similar stress pattern disturbances are not disease-specific.
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  • Detection of Articulatory Deficits in Parkinson's Disease: Can Systematic Manipulations of Phonetic Complexity Help?
    Journal of speech, language, and hearing research : JSLHR (2020)
    Kuruvilla-Dugdale M, Salazar M, Zhang A, Mefferd AS. Detection of Articulatory Deficits in Parkinson's Disease: Can Systematic Manipulations of Phonetic Complexity Help? J Speech Lang Hear Res. 2020 Jul 20; 63(7):2084-2098.
    Abstract: Purpose This study sought to determine the feasibility of using phonetic complexity manipulations as a way to systematically assess articulatory deficits in talkers with progressive dysarthria due to Parkinson's disease (PD). Method Articulatory kinematics were recorded using three-dimensional electromagnetic articulography from 15 talkers with PD (58-84 years old) and 15 healthy controls (55-80 years old) while they produced target words embedded in a carrier phrase. Majority of the talkers with PD exhibited a relatively mild dysarthria. For stimuli selection, phonetic complexity was calculated for a variety of words using the framework proposed by Kent (1992), and six words representative of low, medium, and high phonetic complexity were selected as targets. Jaw, posterior tongue, and anterior tongue kinematic measures that were used to test for phonetic complexity effects included movement speed, cumulative path distance, movement range, movement duration, and spatiotemporal variability. Results Significantly smaller movements and slower movement speeds were evident in talkers with PD, predominantly for words with high phonetic complexity. The effect sizes of between-groups differences were larger for several jaw kinematic measures than those of the tongue. Discussion and Conclusion Findings suggest that systematic manipulations of phonetic complexity can support the detection of articulatory deficits in talkers with PD. Phonetic complexity should therefore be leveraged for the assessment of articulatory performance in talkers with progressive dysarthria. Future work will be directed toward linking speech kinematic and auditory-perceptual measures to determine the clinical significance of the current findings.
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  • A first investigation of tongue, lip, and jaw movements in persons with dysarthria due to multiple sclerosis.
    Multiple sclerosis and related disorders (2019)
    Mefferd AS, Lai A, Bagnato F. A first investigation of tongue, lip, and jaw movements in persons with dysarthria due to multiple sclerosis. Mult Scler Relat Disord. 2019 Jan; 27:188-194.
    Abstract: Multiple sclerosis can affect the speech motor system and result in dysarthria.
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  • Tongue- and Jaw-Specific Contributions to Acoustic Vowel Contrast Changes in the Diphthong /ai/ in Response to Slow, Loud, and Clear Speech.
    Journal of speech, language, and hearing research : JSLHR (2017)
    Mefferd AS. Tongue- and Jaw-Specific Contributions to Acoustic Vowel Contrast Changes in the Diphthong /ai/ in Response to Slow, Loud, and Clear Speech. J Speech Lang Hear Res. 2017 Nov 9; 60(11):3144-3158.
    Abstract: This study sought to determine decoupled tongue and jaw displacement changes and their specific contributions to acoustic vowel contrast changes during slow, loud, and clear speech.
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  • Spatiotemporal movement variability in ALS: Speaking rate effects on tongue, lower lip, and jaw motor control.
    Journal of communication disorders (2017)
    Kuruvilla-Dugdale M, Mefferd A. Spatiotemporal movement variability in ALS: Speaking rate effects on tongue, lower lip, and jaw motor control. J Commun Disord. 2017 May; 67:22-34.
    Abstract: Although it is frequently presumed that bulbar muscle degeneration in Amyotrophic Lateral Sclerosis (ALS) is associated with progressive loss of speech motor control, empirical evidence is limited. Furthermore, because speaking rate slows with disease progression and rate manipulations are used to improve intelligibility in ALS, this study sought to (i) determine between and within-group differences in articulatory motor control as a result of speaking rate changes and (ii) identify the strength of association between articulatory motor control and speech impairment severity.
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Eating Disorders Genetic Initiative (EDGI)
University of North Carolina at Chapel Hill
  • The Eating Disorders Genetics Initiative (EDGI): study protocol.
    BMC psychiatry (2021)
    Bulik CM, Thornton LM, Parker R, Kennedy H, Baker JH, MacDermod C, Guintivano J, Cleland L, Miller AL, Harper L, Larsen JT, Yilmaz Z, Grove J, Sullivan PF, Petersen LV, Jordan J, Kennedy MA, Martin NG. The Eating Disorders Genetics Initiative (EDGI): study protocol. BMC Psychiatry. 2021 May 4; 21(1):234.
    Abstract: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder.
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Single Dose, Dose-Ranging and 28-Day Repeat-Dose Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Dimethandrolone Undecanoate (DMAU) in Healthy Men
Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center
  • Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β-MNTDC in healthy men.
    Andrology (2021)
    Yuen F, Thirumalai A, Fernando FA, Swerdloff RS, Liu PY, Pak Y, Hull L, Bross R, Blithe DL, Long JE, Page ST, Wang C. Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11β-MNTDC in healthy men. Andrology. 2021 Sep; 9(5):1526-1539.
    Abstract: Dimethandrolone (DMA) and 11β-methyl-19-nortestosterone (11β-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men.
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  • Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days.
    The Journal of clinical endocrinology and metabolism (2021)
    Thirumalai A, Yuen F, Amory JK, Hoofnagle AN, Swerdloff RS, Liu PY, Long JE, Blithe DL, Wang C, Page ST. Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days. J Clin Endocrinol Metab. 2021 Jan 1; 106(1):e171-e181.
    Abstract: Dimethandrolone undecanoate (DMAU) is being developed as a male contraceptive. Daily oral administration of DMAU, a potent androgen that is not aromatized, markedly suppresses serum testosterone (T) and estradiol (E2) in healthy men. E2 deficiency can increase bone resorption in men.
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  • Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill.
    The Journal of clinical endocrinology and metabolism (2019)
    Thirumalai A, Ceponis J, Amory JK, Swerdloff R, Surampudi V, Liu PY, Bremner WJ, Harvey E, Blithe DL, Lee MS, Hull L, Wang C, Page ST. Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill. J Clin Endocrinol Metab. 2019 Feb 1; 104(2):423-432.
    Abstract: Dimethandrolone (DMA) has androgenic and progestational activity. Single oral doses of DMA undecanoate (DMAU) were well tolerated and reversibly suppressed serum LH and testosterone (T) in men.
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  • Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.
    Andrology (2017)
    Ayoub R, Page ST, Swerdloff RS, Liu PY, Amory JK, Leung A, Hull L, Blithe D, Christy A, Chao JH, Bremner WJ, Wang C. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology. 2017 Mar; 5(2):278-285.
    Abstract: Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be advantageous for the application of DMAU as a male contraceptive.
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Novel Behavioral Intervention to Target Social Reward Sensitivity and Attachment.
University of California San Diego
  • Changes in neural reward processing following Amplification of Positivity treatment for depression and anxiety: Preliminary findings from a randomized waitlist controlled trial.
    Behaviour research and therapy (2021)
    Kryza-Lacombe M, Pearson N, Lyubomirsky S, Stein MB, Wiggins JL, Taylor CT. Changes in neural reward processing following Amplification of Positivity treatment for depression and anxiety: Preliminary findings from a randomized waitlist controlled trial. Behav Res Ther. 2021 Jul; 142:103860.
    Abstract: Positive valence system (PVS) deficits are increasingly recognized as important treatment targets for depression and anxiety. Emerging behavioral treatments designed to upregulate the PVS show initial promise; however, neural mechanisms underlying these approaches remain unknown. This study investigated neural reward-processing-related changes following Amplification of Positivity (AMP)-a treatment designed to enhance positive thinking, emotions and behaviors through positive activity interventions (Clinicaltrials.gov: NCT02330627). Individuals with depression and/or anxiety (N = 29) were randomized to 10 sessions of AMP (n = 16) or waitlist (WL; n = 13). Participants completed a monetary incentive delay task during fMRI at baseline and post-assessment. Hypothesis-driven region of interest (ventral striatum, insula, anterior cingulate) and exploratory whole-brain activation and connectivity analyses evaluated pre-to-post changes for AMP vs. WL when anticipating potential monetary gain or loss. No between-group brain activation changes emerged in regions of interest or whole-brain analyses. Increased neural connectivity from pre-to-post-treatment was observed in AMP vs. WL, including ventral striatum, anterior insula, and anterior cingulate connectivity with prefrontal, limbic, occipital and parietal regions-predominantly during loss anticipation. This preliminary study is the first to examine neural mechanisms of positive activity interventions in depression and anxiety and suggests that AMP may strengthen brain connectivity in reward processing, attention, and emotion regulation networks.
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  • Enhancing Social Connectedness in Anxiety and Depression Through Amplification of Positivity: Preliminary Treatment Outcomes and Process of Change.
    Cognitive therapy and research (2020)
    Taylor CT, Pearlstein SL, Kakaria S, Lyubomirsky S, Stein MB. Enhancing Social Connectedness in Anxiety and Depression Through Amplification of Positivity: Preliminary Treatment Outcomes and Process of Change. Cognit Ther Res. 2020 Aug; 44(4):788-800.
    Abstract: Anxiety and depressive disorders are often characterized by perceived social disconnection, yet evidence-based treatments produce only modest improvements in this domain. The well-established link between positive affect (PA) and social connectedness suggests that directly targeting PA in treatment may be valuable.
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  • Upregulating the positive affect system in anxiety and depression: Outcomes of a positive activity intervention.
    Depression and anxiety (2017)
    Taylor CT, Lyubomirsky S, Stein MB. Upregulating the positive affect system in anxiety and depression: Outcomes of a positive activity intervention. Depress Anxiety. 2017 Mar; 34(3):267-280.
    Abstract: Research suggests that the positive affect system may be an important yet underexplored treatment target in anxiety and depression. Existing interventions primarily target the negative affect system, yielding modest effects on measures of positive emotions and associated outcomes (e.g., psychological well-being). The objective of the present pilot study was to evaluate the efficacy of a new transdiagnostic positive activity intervention (PAI) for anxiety and depression.
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Cognitive Training and Practice Effects
University of Utah
  • Computerized Cognitive Training in Amnestic Mild Cognitive Impairment: A Randomized Clinical Trial.
    Journal of geriatric psychiatry and neurology (2022)
    Duff K, Ying J, Suhrie KR, Dalley BCA, Atkinson TJ, Porter SM, Dixon AM, Hammers DB, Wolinsky FD. Computerized Cognitive Training in Amnestic Mild Cognitive Impairment: A Randomized Clinical Trial. J Geriatr Psychiatry Neurol. 2022 May; 35(3):400-409.
    Abstract: Computerized cognitive training has been successful in healthy older adults, but its efficacy has been mixed in patients with amnestic Mild Cognitive Impairment (MCI).
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Energy Expenditure Responses to a Range of Environmental Temperatures around the Thermal Neutral Zone
The National Institutes of Health
  • Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids.
    Radiology (2021)
    Ouwerkerk R, Hamimi A, Matta J, Abd-Elmoniem KZ, Eary JF, Abdul Sater Z, Chen KY, Cypess AM, Gharib AM. Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids. Radiology. 2021 May; 299(2):396-406.
    Abstract: Background Activation of brown adipose tissue (BAT) in rodents increases lipolysis in white adipose tissue (WAT) and improves glucose tolerance. Adult humans can have metabolically active BAT. Implications for diabetes and obesity in humans require a better characterization of BAT in humans. Purpose To study fat depots with localized proton MR spectroscopy relaxometry and to identify differences between WAT and fluorine 18 fluorodeoxyglucose (FDG) PET/CT proven cold-activated BAT in humans. Materials and Methods Participants were consecutively enrolled in this prospective study (ClinicalTrials.gov identifiers: NCT01568671 and NCT01399385) from August 2016 to May 2019. Supraclavicular potential BAT regions were localized with MRI. Proton densities, T1, and T2 were measured with localized MR spectroscopy in potential BAT and in subcutaneous WAT. FDG PET/CT after cold stimulation was used to retrospectively identify active supraclavicular BAT or supraclavicular quiescent adipose tissue (QAT) regions. MR spectroscopy results from BAT and WAT were compared with grouped and paired tests. Results Of 21 healthy participants (mean age, 36 years ± 16 [standard deviation]; 13 men) FDG PET/CT showed active BAT in 24 MR spectroscopy-targeted regions in 16 participants (eight men). Four men had QAT. The T2 for methylene protons was shorter in BAT (mean, 69 msec ± 6, 24 regions) than in WAT (mean, 83 msec ± 3, 18 regions, < .01) and QAT (mean, 78 msec ± 2, five regions, < .01). A T2 cut-off value of 76 msec enabled the differentiation of BAT from WAT or QAT with a sensitivity of 85% and a specificity of 95%. Densities of protons adjacent and between double bonds were 33% and 24% lower, respectively, in BAT compared with those in WAT ( = .01 and = .03, respectively), indicating a lower content of unsaturated and polyunsaturated fatty acids, respectively, in BAT compared with WAT. Conclusion Proton MR spectroscopy showed shorter T2 and lower unsaturated fatty acids in brown adipose tissue (BAT) than that in white adipose tissue in healthy humans. It was feasible to identify BAT with MR spectroscopy without the use of PET/CT or cold stimulation. © RSNA, 2021 See also the editorial by Barker in this issue.
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  • Quantification of the Capacity for Cold-Induced Thermogenesis in Young Men With and Without Obesity.
    The Journal of clinical endocrinology and metabolism (2019)
    Brychta RJ, Huang S, Wang J, Leitner BP, Hattenbach JD, Bell SL, Fletcher LA, Perron Wood R, Idelson CR, Duckworth CJ, McGehee S, Courville AB, Bernstein SB, Reitman ML, Cypess AM, Chen KY. Quantification of the Capacity for Cold-Induced Thermogenesis in Young Men With and Without Obesity. J Clin Endocrinol Metab. 2019 Oct 1; 104(10):4865-4878.
    Abstract: Cold exposure increases energy expenditure (EE) and could have a role in combating obesity. To understand this potential, we determined the capacity for cold-induced thermogenesis (CIT), the EE increase above the basal metabolic rate at the individualized coldest tolerable temperature before overt shivering.
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VTEU 01.10 Comparison of the Safety and Immunogenicity of Lyophilized IMVAMUNE (1x108 TCID50) versus Liquid Formulation IMVAMUNE (1x108 TCID50) administered by the Subcutaneous Route and a Lower Dose Liquid Formulation IMVAMUNE (2x107 TCID50) Administered by the Intradermal Route in Healthy Vaccinia-naive Individuals (DMID 09-0002)
Vanderbilt University Medical Center
  • Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses.
    The Journal of infectious diseases (2021)
    Frey SE, Stapleton JT, Ballas ZK, Rasmussen WL, Kaufman TM, Blevins TP, Jensen TL, Davies DH, Tary-Lehmann M, Chaplin P, Hill H, Goll JB, DMID 09-0002 MVA Vaccine Study Group. Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses. J Infect Dis. 2021 Oct 28; 224(8):1372-1382.
    Abstract: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine.
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Anticholinergic vs. Botox Comparison Study: The ABC Trial Efficacy and impact of Botulinum Toxin A versus Anticholinergic Therapy for the Treatment of Bothersome Urge Urinary Incontinence (Perioperative Pelvic Floor Rehab: A Randomized Trial)
The University of Alabama at Birmingham
  • Comparison of 100 U With 200 U of Intradetrusor OnabotulinumToxinA for Nonneurogenic Urgency Incontinence.
    Female pelvic medicine & reconstructive surgery (2021)
    Hendrickson WK, Amundsen CL, Rahn DD, Meyer I, Bradley MS, Smith AL, Myers DL, Jelovsek JE, Lukacz ES. Comparison of 100 U With 200 U of Intradetrusor OnabotulinumToxinA for Nonneurogenic Urgency Incontinence. Female Pelvic Med Reconstr Surg. 2021 Mar 1; 27(3):140-146.
    Abstract: The objective of this study was to compare efficacy and adverse events between 100 U and 200 U of onabotulinumtoxinA for 6 months in women with nonneurogenic urgency incontinence.
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  • Cost-Effectiveness Analysis of Anticholinergics Versus Botox for Urgency Urinary Incontinence: Results From the Anticholinergic Versus Botox Comparison Randomized Trial.
    Female pelvic medicine & reconstructive surgery (2016)
    Visco AG, Zyczynski H, Brubaker L, Nygaard I, Xu X, Lukacz ES, Paraiso MF, Greer J, Rahn DD, Meikle SF, Honeycutt AA. Cost-Effectiveness Analysis of Anticholinergics Versus Botox for Urgency Urinary Incontinence: Results From the Anticholinergic Versus Botox Comparison Randomized Trial. Female Pelvic Med Reconstr Surg. 2016 Sep-Oct; 22(5):311-6.
    Abstract: This study aimed to compare the cost-effectiveness of Botox and anticholinergic (AC) medications for the management of urgency urinary incontinence (UUI).
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  • Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial.
    Female pelvic medicine & reconstructive surgery (2016)
    Visco AG, Brubaker L, Jelovsek JE, Wilson TS, Norton P, Zyczynski HM, Spino C, Sirls L, Nguyen JN, Rahn DD, Meikle SF, Nolen TL, Pelvic Floor Disorders Network. Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial. Female Pelvic Med Reconstr Surg. 2016 Jan-Feb; 22(1):24-8.
    Abstract: Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence.
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  • Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence.
    The New England journal of medicine (2012)
    Visco AG, Brubaker L, Richter HE, Nygaard I, Paraiso MF, Menefee SA, Schaffer J, Lowder J, Khandwala S, Sirls L, Spino C, Nolen TL, Wallace D, Meikle SF, Pelvic Floor Disorders Network. Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. N Engl J Med. 2012 Nov 8; 367(19):1803-13.
    Abstract: Anticholinergic medications and onabotulinumtoxinA are used to treat urgency urinary incontinence, but data directly comparing the two types of therapy are needed.
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  • Anticholinergic versus botulinum toxin A comparison trial for the treatment of bothersome urge urinary incontinence: ABC trial.
    Contemporary clinical trials (2012)
    Visco AG, Brubaker L, Richter HE, Nygaard I, Paraiso MF, Menefee SA, Schaffer J, Wei J, Chai T, Janz N, Spino C, Meikle S, Pelvic Floor Disorders Network. Anticholinergic versus botulinum toxin A comparison trial for the treatment of bothersome urge urinary incontinence: ABC trial. Contemp Clin Trials. 2012 Jan; 33(1):184-96.
    Abstract: This trial compares the change in urgency urinary incontinence episodes over 6 months, tolerability and cost effectiveness between women receiving daily anticholinergic therapy plus a single intra-detrusor injection of saline versus a single intra-detrusor injection of 100 U of botulinum toxin A plus daily oral placebo tablets. We present the rationale and design of a randomized-controlled trial, Anticholinergic versus Botulinum Toxin, Comparison Trial for the Treatment of Bothersome Urge Urinary Incontinence: ABC trial, conducted by the NICHD-funded Pelvic Floor Disorders Network. We discuss the innovative nature of this trial and the challenges related to choice of patient population, maintaining masking, cost effectiveness, ethical considerations, measuring adherence, and placebo development and testing. Enrollment began in April, 2010. 242 participants will be randomized and primary outcome data analysis is anticipated to begin in mid 2012. Several challenges in the trial design are discussed. Randomization to placebo intra-detrusor injections may limit recruitment, potentially impacting generalizability. Other challenges included the heavy marketing of drugs for overactive bladder which could impact recruitment of drug-naïve women. In addition, anticholinergic medications often cause dry mouth, making masking difficult. Finally, adverse reporting of transient urinary retention is challenging as there is no standardized definition; yet this is the most common adverse event following intra-detrusor botulinum toxin injection. The ABC trial will help women with urgency urinary incontinence balance efficacy, side effects and cost of anticholinergic medication versus botulinum toxin intra-detrusor injection. The results have the potential to fundamentally change the therapeutic approach to this condition.
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Using Innovative Communication Technology to Improve the Health of Young African American Women
Boston University
  • Using Health Information Technology to Engage African American Women on Nutrition and Supplement Use During the Preconception Period.
    Frontiers in endocrinology (2020)
    Gardiner P, Bickmore T, Yinusa-Nyahkoon L, Reichert M, Julce C, Sidduri N, Martin-Howard J, Woodhams E, Aryan J, Zhang Z, Fernandez J, Loafman M, Srinivasan J, Cabral H, Jack BW. Using Health Information Technology to Engage African American Women on Nutrition and Supplement Use During the Preconception Period. Front Endocrinol (Lausanne). 2020; 11:571705.
    Abstract: Healthy nutrition and appropriate supplementation during preconception have important implications for the health of the mother and newborn. The best way to deliver preconception care to address health risks related to nutrition is unknown.
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  • Improving the health of young African American women in the preconception period using health information technology: a randomised controlled trial.
    The Lancet. Digital health (2020)
    Jack BW, Bickmore T, Yinusa-Nyahkoon L, Reichert M, Julce C, Sidduri N, Martin-Howard J, Zhang Z, Woodhams E, Fernandez J, Loafman M, Cabral HJ. Improving the health of young African American women in the preconception period using health information technology: a randomised controlled trial. Lancet Digit Health. 2020 Sep; 2(9):e475-e485.
    Abstract: Preconception care focuses on improving women's health before pregnancy as a means to improve their health and future pregnancy outcomes. How to effectively deliver such care is unknown. The aim of this research was to assess the impact of an embodied conversational agent system on preconception risks among African American and Black women.
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Galectin-3 Inhibition With Modified Citrus Pectin in Hypertension
Massachusetts General Hospital
  • Galectin-3 Inhibition With Modified Citrus Pectin in Hypertension.
    JACC. Basic to translational science (2021)
    Lau ES, Liu E, Paniagua SM, Sarma AA, Zampierollo G, López B, Díez J, Wang TJ, Ho JE. Galectin-3 Inhibition With Modified Citrus Pectin in Hypertension. JACC Basic Transl Sci. 2021 Jan; 6(1):12-21.
    Abstract: We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation.
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Phase 1 Study of the Safety and Immunogencity of Ad4-H5-VTN in Seronegative Volunteers
The National Institutes of Health
  • A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity.
    The Journal of clinical investigation (2021)
    Matsuda K, Migueles SA, Huang J, Bolkhovitinov L, Stuccio S, Griesman T, Pullano AA, Kang BH, Ishida E, Zimmerman M, Kashyap N, Martins KM, Stadlbauer D, Pederson J, Patamawenu A, Wright N, Shofner T, Evans S, Liang CJ, Candia J, Biancotto A, Fantoni G, P. A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity. J Clin Invest. 2021 Mar 1; 131(5):.
    Abstract: BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).
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A Reduced Carbohydrate Diet Intervention for PCOS
The University of Alabama at Birmingham
  • Changes in Ghrelin and Glucagon following a Low Glycemic Load Diet in Women with PCOS.
    The Journal of clinical endocrinology and metabolism (2021)
    Hoover SE, Gower BA, Cedillo YE, Chandler-Laney PC, Deemer SE, Goss AM. Changes in Ghrelin and Glucagon following a Low Glycemic Load Diet in Women with PCOS. J Clin Endocrinol Metab. 2021 Apr 23; 106(5):e2151-e2161.
    Abstract: Altered satiety hormones in women with polycystic ovarian syndrome (PCOS) may contribute to obesity. Diets with a low glycemic load (GL) may influence appetite-regulating hormones including glucagon and ghrelin.
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  • A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes.
    The Journal of nutrition (2015)
    Gower BA, Goss AM. A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes. J Nutr. 2015 Jan; 145(1):177S-83S.
    Abstract: Obesity, particularly visceral and ectopic adiposity, increases the risk of type 2 diabetes.
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Nashville Early Diagnosis Lung Cancer Trial
Vanderbilt University Medical Center
  • Establishing a Cohort and a Biorepository to Identify Biomarkers for Early Detection of Lung Cancer: The Nashville Lung Cancer Screening Trial Cohort.
    Annals of the American Thoracic Society (2021)
    Lakhani DA, Chen SC, Antic S, Muterspaugh A, Cook C, Liu N, Shujat H, Jouan S, Winston B, Fields K, Wenstrup J, Block SL, Hinton A, Miller A, Atmajoana S, Helton JT, Patel K, Balar AB, Brewer K, Nag S, Singh R, Disher A, Huerta L, Fremont R, Rickman O, Ch. Establishing a Cohort and a Biorepository to Identify Biomarkers for Early Detection of Lung Cancer: The Nashville Lung Cancer Screening Trial Cohort. Ann Am Thorac Soc. 2021 Jul; 18(7):1227-1234.
    Abstract: A prospective longitudinal cohort of individuals at high risk of developing lung cancer was established to build a biorepository of carefully annotated biological specimens and low-dose computed tomography (LDCT) chest images for derivation and validation of candidate biomarkers for early detection of lung cancer. The goal of this study is to characterize individuals with high risk for lung cancer, accumulating valuable biospecimens and LDCT chest scans longitudinally over 5 years. Participants 55-80 years of age with a 5-year estimated risk of developing lung cancer >1.5% were recruited and enrolled from clinics at the Vanderbilt University Medical Center, Veteran Affairs Medical Center, and Meharry Medical Center. Individual demographic characteristics were assessed via questionnaire at baseline. Participants underwent an LDCT scan, spirometry, sputum cytology, and research bronchoscopy at the time of enrollment. Participants will be followed yearly for 5 years. Positive LDCT scans are followed-up according to standard of care. The clinical, imaging, and biospecimen data are collected prospectively and stored in a biorepository. Participants are offered smoking cessation counseling at each study visit. A total of 480 participants were enrolled at study baseline and consented to sharing their data and biospecimens for research. Participants are followed with yearly clinic visits to collect imaging data and biospecimens. To date, a total of 19 cancers (13 adenocarcinomas, four squamous cell carcinomas, one large cell neuroendocrine, and one small-cell lung cancer) have been identified. We established a unique prospective cohort of individuals at high risk for lung cancer, enrolled at three institutions, for whom full clinical data, well-annotated LDCT scans, and biospecimens are being collected longitudinally. This repository will allow for the derivation and independent validation of clinical, imaging, and molecular biomarkers of risk for diagnosis of lung cancer.Clinical trial registered with ClinicalTrials.gov (NCT01475500).
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  • Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial.
    Chest (2018)
    Silvestri GA, Tanner NT, Kearney P, Vachani A, Massion PP, Porter A, Springmeyer SC, Fang KC, Midthun D, Mazzone PJ, PANOPTIC Trial Team.. Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. Chest. 2018 Sep; 154(3):491-500.
    Abstract: Lung nodules are a diagnostic challenge, with an estimated yearly incidence of 1.6 million in the United States. This study evaluated the accuracy of an integrated proteomic classifier in identifying benign nodules in patients with a pretest probability of cancer (pCA) ≤ 50%.
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  • Radiological Image Traits Predictive of Cancer Status in Pulmonary Nodules.
    Clinical cancer research : an official journal of the American Association for Cancer Research (2017)
    Liu Y, Balagurunathan Y, Atwater T, Antic S, Li Q, Walker RC, Smith GT, Massion PP, Schabath MB, Gillies RJ. Radiological Image Traits Predictive of Cancer Status in Pulmonary Nodules. Clin Cancer Res. 2017 Mar 15; 23(6):1442-1449.
    Abstract: We propose a systematic methodology to quantify incidentally identified pulmonary nodules based on observed radiological traits (semantics) quantified on a point scale and a machine-learning method using these data to predict cancer status. We investigated 172 patients who had low-dose CT images, with 102 and 70 patients grouped into training and validation cohorts, respectively. On the images, 24 radiological traits were systematically scored and a linear classifier was built to relate the traits to malignant status. The model was formed both with and without size descriptors to remove bias due to nodule size. The multivariate pairs formed on the training set were tested on an independent validation data set to evaluate their performance. The best 4-feature set that included a size measurement (set 1), was short axis, contour, concavity, and texture, which had an area under the receiver operator characteristic curve (AUROC) of 0.88 (accuracy = 81%, sensitivity = 76.2%, specificity = 91.7%). If size measures were excluded, the four best features (set 2) were location, fissure attachment, lobulation, and spiculation, which had an AUROC of 0.83 (accuracy = 73.2%, sensitivity = 73.8%, specificity = 81.7%) in predicting malignancy in primary nodules. The validation test AUROC was 0.8 (accuracy = 74.3%, sensitivity = 66.7%, specificity = 75.6%) and 0.74 (accuracy = 71.4%, sensitivity = 61.9%, specificity = 75.5%) for sets 1 and 2, respectively. Radiological image traits are useful in predicting malignancy in lung nodules. These semantic traits can be used in combination with size-based measures to enhance prediction accuracy and reduce false-positives. .
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  • Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease.
    Virchows Archiv : an international journal of pathology (2015)
    Du RH, Richmond BW, Blackwell TS Jr, Cates JM, Massion PP, Ware LB, Lee JW, Kononov AV, Lawson WE, Blackwell TS, Polosukhin VV. Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease. Virchows Arch. 2015 Dec; 467(6):657-665.
    Abstract: Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported. However, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) fluid has not been consistently observed. To explain this discrepancy, we analyzed BAL fluid and lung tissue from patients with COPD and control subjects. Immunohistochemical analysis of large and small airways of COPD patients showed that MUC5AC is the predominant mucin expressed by airway epithelial cells, whereas MUC5B is expressed in submucosal glands of large airways. Dual immunostaining with anti-IgA and anti-MUC5B antibodies showed reduction of IgA on the airway surface as well as accumulation of IgA within MUC5B-positive luminal mucus plugs, suggesting that luminal SIgA originates from submucosal glands in COPD patients. We found that the concentration of SIgA in BAL is inversely correlated with forced expiratory volume in 1 s (FEV) in COPD, but that the ratio of SIgA/MUC5B is a better predictor of FEV, particularly in patients with moderate COPD. Together, these findings suggest that SIgA production by submucosal glands, which are expanded in COPD, is insufficient to compensate for reduced SIgA transcytosis by airway epithelial cells. Localized SIgA deficiency on the surface of small airways is associated with COPD progression and represents a potential new therapeutic target in COPD.
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  • Reproducibility of Volumetric Computed Tomography of Stable Small Pulmonary Nodules with Implications on Estimated Growth Rate and Optimal Scan Interval.
    PloS one (2015)
    Smith GT, Rahman AR, Li M, Moore B, Gietema H, Veronesi G, Massion PP, Walker RC. Reproducibility of Volumetric Computed Tomography of Stable Small Pulmonary Nodules with Implications on Estimated Growth Rate and Optimal Scan Interval. PLoS One. 2015; 10(9):e0138144.
    Abstract: To use clinically measured reproducibility of volumetric CT (vCT) of lung nodules to estimate error in nodule growth rate in order to determine optimal scan interval for patient follow-up.
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Reduced Opioid Analgesic Requirements Via Improved Endogenous Opioid Function
Vanderbilt University Medical Center
  • Does aerobic exercise training alter responses to opioid analgesics in individuals with chronic low back pain? A randomized controlled trial.
    Pain (2021)
    Bruehl S, Burns JW, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Wu YH, Stone A. Does aerobic exercise training alter responses to opioid analgesics in individuals with chronic low back pain? A randomized controlled trial. Pain. 2021 Aug 1; 162(8):2204-2213.
    Abstract: We tested whether aerobic exercise training altered morphine analgesic responses or reduced morphine dosages necessary for adequate analgesia. Patients with chronic back pain were randomized to an 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 45). Before and after the intervention, participants underwent 3 laboratory sessions (double-blinded, crossover) to assess effects of saline placebo, i.v. morphine (0.09 mg/kg), and i.v. naloxone (12 mg) on low back pain and evoked heat pain responses. Differences in evoked and back pain measures between the placebo and morphine conditions indexed morphine analgesia, with pre-post intervention changes the primary outcome. Endogenous opioid analgesia was indexed by differences in evoked and low back pain measures between the naloxone and placebo conditions. A Sex X Intervention interaction on the analgesic effects of morphine on visual analogue scale back pain intensity was observed (P = 0.046), with a similar trend for evoked pain threshold (P = 0.093). Male exercisers showed reduced morphine analgesia pre-post intervention, whereas male controls showed increased analgesia (with no differences in females). Of clinical significance were findings that relative to the control group, aerobic exercise produced analgesia more similar to that observed after receiving ≈7 mg morphine preintervention (P < 0.045). Greater pre-post intervention increases in endogenous opioid function (from any source) were significantly associated with larger pre-post intervention decreases in morphine analgesia (P < 0.046). The overall pattern of findings suggests that regular aerobic exercise has limited direct effects on morphine responsiveness, reducing morphine analgesia in males only.
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  • Are endogenous opioid mechanisms involved in the effects of aerobic exercise training on chronic low back pain? A randomized controlled trial.
    Pain (2020)
    Bruehl S, Burns JW, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Wu YH, Qu'd D, Stone A. Are endogenous opioid mechanisms involved in the effects of aerobic exercise training on chronic low back pain? A randomized controlled trial. Pain. 2020 Dec; 161(12):2887-2897.
    Abstract: Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or intravenous naloxone (opioid antagonist) in a double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. Endogenous opioid analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (Ps < 0.04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (P = 0.03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; P = 0.04). Enhanced EO analgesia (MPQ-Total) was associated with a significantly greater improvement in average chronic pain intensity (P = 0.009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.
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  • Self-reported cumulative medical opioid exposure and subjective responses on first use of opioids predict analgesic and subjective responses to placebo-controlled opioid administration.
    Regional anesthesia and pain medicine (2019)
    Bruehl S, Stone AL, Palmer C, Edwards DA, Buvanendran A, Gupta R, Chont M, Kennedy M, Burns JW. Self-reported cumulative medical opioid exposure and subjective responses on first use of opioids predict analgesic and subjective responses to placebo-controlled opioid administration. Reg Anesth Pain Med. 2019 Jan; 44(1):92-99.
    Abstract: To expand the evidence base needed to enable personalized pain medicine, we evaluated whether self-reported cumulative exposure to medical opioids and subjective responses on first opioid use predicted responses to placebo-controlled opioid administration.
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Patient-Centered Treatment for Interstitial Cystitis/Bladder Pain Syndrome
Vanderbilt University Medical Center
  • Qualitative Analysis of Treatment Needs in Interstitial Cystitis/Bladder Pain Syndrome: Implications for Intervention.
    Canadian journal of pain = Revue canadienne de la douleur (2020)
    McKernan LC, Bonnet KR, Finn MTM, Williams DA, Bruehl S, Reynolds WS, Clauw D, Dmochowski RR, Schlundt DG, Crofford LJ. Qualitative Analysis of Treatment Needs in Interstitial Cystitis/Bladder Pain Syndrome: Implications for Intervention. Can J Pain. 2020; 4(1):181-198.
    Abstract: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition carrying substantial psychosocial burden. Psychological treatment for IC/BPS is little studied, and there are barriers to its use in clinical management. Whether psychological treatments benefit patients with IC/BPS is unclear and we do not know if such treatments would meet patient needs.
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Disability services in the coronavirus pandemic.
Northwestern University
  • The Impact of the Novel Coronavirus Disease 2019 on Therapy Service Delivery for Children with Disabilities.
    The Journal of pediatrics (2021)
    Murphy A, Pinkerton LM, Bruckner E, Risser HJ. The Impact of the Novel Coronavirus Disease 2019 on Therapy Service Delivery for Children with Disabilities. J Pediatr. 2021 Apr; 231:168-177.e1.
    Abstract: To assess the impact of the novel coronavirus disease 2019 (COVID-19) pandemic on the delivery of, and parent satisfaction with, therapy services for children with disabilities in early intervention, school, and outpatient settings.
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Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause
University of North Carolina at Chapel Hill
  • Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.
    Journal of clinical lipidology (2021)
    Vaisar T, Gordon JL, Wimberger J, Heinecke JW, Hinderliter AL, Rubinow DR, Girdler SS, Rubinow KB. Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors. J Clin Lipidol. 2021 Jan-Feb; 15(1):151-161.e0.
    Abstract: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown.
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  • IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women.
    The Journal of clinical endocrinology and metabolism (2020)
    Zannas AS, Gordon JL, Hinderliter AL, Girdler SS, Rubinow DR. IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women. J Clin Endocrinol Metab. 2020 Oct 1; 105(10):.
    Abstract: Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the United States. Cardiometabolic risk further increases with psychosocial stress exposure and during menopausal transition in women. Because disease risk and stress burden are associated with aberrant immune signaling, we hypothesized that responses of interleukin-6 (IL-6) to psychosocial stress may predict longitudinal cardiometabolic outcomes in perimenopausal women.
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  • The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.
    The Journal of clinical endocrinology and metabolism (2020)
    Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease. J Clin Endocrinol Metab. 2020 May 1; 105(5):.
    Abstract: The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease.
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  • Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial.
    JAMA psychiatry (2018)
    Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1; 75(2):149-157.
    Abstract: The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms.
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Comparing Imitation Across Tasks
George Washington University
  • Optimizing imitation: Examining cognitive factors leading to imitation, overimitation, and goal emulation in preschoolers.
    Journal of experimental child psychology (2021)
    Speidel R, Zimmermann L, Green L, Brito NH, Subiaul F, Barr R. Optimizing imitation: Examining cognitive factors leading to imitation, overimitation, and goal emulation in preschoolers. J Exp Child Psychol. 2021 Mar; 203:105036.
    Abstract: Humans imitate patently irrelevant actions known as overimitation, and rather than decreasing with age, overimitation increases with age. Whereas most overimitation research has focused on social factors associated with overimitation, comparatively little is known about the cognitive- and task-specific features that influence overimitation. Specifically, developmental contrasts between imitation and overimitation are confounded by the addition of irrelevant actions to causally necessary actions, increasing sequence length, cognitive load, and processing costs-variables known to be age dependent. We constructed a novel puzzle box task such that a four-step imitation, four-step overimitation, and two-step efficient sequence could be demonstrated using the same apparatus on video. In Experiments 1 and 2, 2.5- to 5-year-olds randomly assigned to imitation and overimitation groups performed significantly more target actions than baseline control groups. Rates of imitation and overimitation increased as a function of age, with older preschoolers outperforming younger preschoolers in both conditions. In Experiment 3, preschoolers were shown a video of an efficient two-step demonstration prior to testing. After they responded, they were shown a four-step overimitation video and were tested on the same puzzle box. Children imitated the efficient demonstration, but after watching the overimitation video, they also overimitated the irrelevant actions. Once again, older children overimitated more than younger children. Together, results show that preschoolers are faithful, flexible, and persistent overimitators. The fidelity and flexibility of overimitation are constrained not only by social factors but also by basic cognitive processes that vary across age groups. As these constraints diminish, overimitation and flexible (optimal) imitation increases.
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  • Applying computational modeling to assess age-, sex-, and strategy-related differences in Spin the Pots, a working memory task for 2- to 4-year-olds.
    Developmental psychobiology (2021)
    Zimmermann L, Frank HE, Subiaul F, Barr R. Applying computational modeling to assess age-, sex-, and strategy-related differences in Spin the Pots, a working memory task for 2- to 4-year-olds. Dev Psychobiol. 2021 Jan; 63(1):42-53.
    Abstract: Working memory (WM) develops rapidly during early childhood. In the present study, visual WM (VSM) was measured using the well-established Spin the Pots task (Hughes & Ensor, 2005), a complex non-verbal eight-location object occlusion task. A self-ordered hiding procedure was adopted to allow for an examination of children's strategy use during a VWM task. Participants (N = 640) between the ages of 2 and 4 years were tested under semi-naturalistic conditions, in the home or in a museum. Computational modeling was used to estimate an expected value for the total trials to complete Spin the Pots via a random search and child performance was compared to expected values. Based on this approach, we determined that children who found six stickers retrieved them in significantly fewer trials than the expected value, excluding chance performance and implicating VWM. Results also showed age-related and sex-related changes in VWM. Between 2 and 4 years of age, 4-year-olds performed significantly better than younger children and girls out-performed the boys. Spontaneous use of a color matching hiding strategy was associated with a higher success rate on the task. Implications of these findings for early development of VWM are discussed.
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  • Specialization in the vicarious learning of novel arbitrary sequences in humans but not orangutans.
    Philosophical transactions of the Royal Society of London. Series B, Biological sciences (2020)
    Renner E, Patterson EM, Subiaul F. Specialization in the vicarious learning of novel arbitrary sequences in humans but not orangutans. Philos Trans R Soc Lond B Biol Sci. 2020 Aug 17; 375(1805):20190442.
    Abstract: Sequence learning underlies many uniquely human behaviours, from complex tool use to language and ritual. To understand whether this fundamental cognitive feature is uniquely derived in humans requires a comparative approach. We propose that the vicarious (but not individual) learning of novel arbitrary sequences represents a human cognitive specialization. To test this hypothesis, we compared the abilities of human children aged 3-5 years and orangutans to learn different types of arbitrary sequences (item-based and spatial-based). Sequences could be learned individually (by trial and error) or vicariously from a human (social) demonstrator or a computer (ghost control). We found that both children and orangutans recalled both types of sequence following trial-and-error learning; older children also learned both types of sequence following social and ghost demonstrations. Orangutans' success individually learning arbitrary sequences shows that their failure to do so in some vicarious learning conditions is not owing to general representational problems. These results provide new insights into some of the most persistent discontinuities observed between humans and other great apes in terms of complex tool use, language and ritual, all of which involve the cultural learning of novel arbitrary sequences. This article is part of the theme issue 'Ritual renaissance: new insights into the most human of behaviours'.
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  • Only domain-specific imitation practice makes imitation perfect.
    Journal of experimental child psychology (2019)
    Subiaul F, Patterson EM, Zimmermann L, Barr R. Only domain-specific imitation practice makes imitation perfect. J Exp Child Psychol. 2019 Jan; 177:248-264.
    Abstract: Does imitation involve specialized mechanisms or general-unspecialized-learning processes? To address this question, preschoolers (3- and 4-year-olds) were assigned to one of four "practice" groups. Before and after the practice phases, each group was tested on a novel Spatial Imitation sequence. During the practice phase, children in the Spatial Imitation group practiced jointly attending, vicariously encoding, and copying the novel spatial sequences. In the Item Imitation group, children practiced jointly attending, vicariously encoding, and copying novel item sequences. In the Trial-and-Error group, children practiced encoding and recalling a series of novel spatial sequences entirely through individual (operant) learning. In the Free Play (no practice) control group, children played a touchscreen drawing game that controlled for practice time on the touchscreen and mirrored some of the same actions and responses used in the experimental conditions. Results of the difference between pre- and post-practice effects on novel spatial imitation sequences showed that only the Spatial Imitation practice group significantly improved relative to the Free Play group. Individual Spatial Trial-and-Error practice did not significantly improve spatial imitation. The effect of Item Imitation practice was intermediate. These results are inconsistent with the hypothesis that general processes alone--or primarily--support imitation learning and is more consistent with a mosaic model that posits an additive-interaction-effect on imitation performance where a more general social cognitive mechanism (i.e., natural pedagogy) gathers the relevant information from the demonstration and another more specialized mechanism (i.e., imitation specific) transforms that information into a matching response.
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  • Children with autism spectrum disorder have an exceptional explanatory drive.
    Autism : the international journal of research and practice (2016)
    Rutherford MD, Subiaul F. Children with autism spectrum disorder have an exceptional explanatory drive. Autism. 2016 Aug; 20(6):744-53.
    Abstract: An "explanatory drive" motivates children to explain ambiguity. Individuals with autism spectrum disorders are interested in how systems work, but it is unknown whether they have an explanatory drive. We presented children with and without autism spectrum disorder unsolvable problems in a physical and in a social context and evaluated problem-solving and explanation-seeking responses. In the physical context (but not the social context), the children with autism spectrum disorder showed a stronger explanatory drive than controls. Importantly, the number of explanatory behaviors made by children with autism spectrum disorder in the social context was independent of social and communicative impairments. Children with autism spectrum disorder did not show an exceptional explanatory drive in the social domain. These results suggest that children with autism spectrum disorder have an explanatory drive and that the explanatory drive may be domain specific.
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  • The cognitive structure of goal emulation during the preschool years.
    The British journal of developmental psychology (2016)
    Subiaul F, Patterson EM, Barr R. The cognitive structure of goal emulation during the preschool years. Br J Dev Psychol. 2016 Mar; 34(1):132-49.
    Abstract: Humans excel at mirroring both others' actions (imitation) as well as others' goals and intentions (emulation). As most research has focused on imitation, here we focus on how social and asocial learning predict the development of goal emulation. We tested 215 preschool children on two social conditions (imitation, emulation) and two asocial conditions (trial-and-error and recall) using two touch screen tasks. The tasks involved responding to either three different pictures in a specific picture order (Cognitive: apple→boy→cat) or three identical pictures in a specific spatial order (Motor-Spatial: up→down→right). Generalized linear models demonstrated that during the preschool years, Motor-Spatial emulation is associated with social and asocial learning, while cognitive emulation is associated only with social learning, including motor-spatial emulation and multiple forms of imitation. This result contrasts with those from a previous study using this same data set showing that motor-spatial and cognitive imitation were neither associated with one another nor, generally, predicted by other forms of social or asocial learning. Together, these results suggests that while developmental changes in imitation are associated with multiple - specialized - mechanisms, developmental changes in emulation are associated with age-related changes and a more unitary, domain-general mechanism that receives input from several different cognitive and learning processes, including some that may not necessarily be specialized for social learning.
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  • Sequential recall of meaningful and arbitrary sequences by orangutans and human children: Does content matter?
    Animal cognition (2016)
    Renner E, Price EE, Subiaul F. Sequential recall of meaningful and arbitrary sequences by orangutans and human children: Does content matter? Anim Cogn. 2016 Jan; 19(1):39-52.
    Abstract: Do visual cues such as size, color, and number facilitate sequential recall in orangutans and human children? In Experiment 1, children and adult orangutans solved two types of sequences, arbitrary (unrelated pictures) and meaningful (pictures varied along a spectrum according to the size, color, or number of items shown), in a touchscreen paradigm. It was found that visual cues did not increase the percentage of correct responses for either children or orangutans. In order to demonstrate that the failure to spontaneously seriate along these dimensions was not due to a general inability to perceive the dimensions nor to an inability to seriate items, in Experiment 2, orangutans were trained on one type of sequence and tested on novel sequences organized according to the same rule (i.e., pictures varied on the number spectrum only). The orangutans performed significantly better on novel meaningful sequences in this task than on novel arbitrary sequences. These results indicate that, while orangutans and human children share the ability to learn how to order items according to their size, color, or number, both orangutans and humans lack a cognitive propensity to spontaneously (i.e., without prior training or enculturation) order multiple items by size, color, or number.
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  • Becoming a high-fidelity - super - imitator: what are the contributions of social and individual learning?
    Developmental science (2015)
    Subiaul F, Patterson EM, Schilder B, Renner E, Barr R. Becoming a high-fidelity - super - imitator: what are the contributions of social and individual learning? Dev Sci. 2015 Nov; 18(6):1025-35.
    Abstract: In contrast to other primates, human children's imitation performance goes from low to high fidelity soon after infancy. Are such changes associated with the development of other forms of learning? We addressed this question by testing 215 children (26-59 months) on two social conditions (imitation, emulation) - involving a demonstration - and two asocial conditions (trial-and-error, recall) - involving individual learning - using two touchscreen tasks. The tasks required responding to either three different pictures in a specific picture order (Cognitive: Airplane→Ball→Cow) or three identical pictures in a specific spatial order (Motor-Spatial: Up→Down→Right). There were age-related improvements across all conditions and imitation, emulation and recall performance were significantly better than trial-and-error learning. Generalized linear models demonstrated that motor-spatial imitation fidelity was associated with age and motor-spatial emulation performance, but cognitive imitation fidelity was only associated with age. While this study provides evidence for multiple imitation mechanisms, the development of one of those mechanisms - motor-spatial imitation - may be bootstrapped by the development of another social learning skill - motor-spatial emulation. Together, these findings provide important clues about the development of imitation, which is arguably a distinctive feature of the human species.
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  • Working memory constraints on imitation and emulation.
    Journal of experimental child psychology (2014)
    Subiaul F, Schilder B. Working memory constraints on imitation and emulation. J Exp Child Psychol. 2014 Dec; 128:190-200.
    Abstract: Does working memory (WM) constrain the amount and type of information children copy from a model? To answer this question, preschool-age children (N=165) were trained and then tested on a touch-screen task that involved touching simultaneously presented pictures. Prior to responding, children saw a model generate two target responses: Order (touching all of the pictures on the screen in a target sequence three consecutive times) and Multi-Tap (consistently touching one of the pictures two times). Children's accuracy copying Order and Multi-Tap was assessed on two types of sequences: low WM load (2 pictures) and high WM load (3 pictures). Results showed that more children copied both Order and Multi-Tap on 2-picture sequences than on 3-picture sequences. Children who copied only one of the two target responses tended to copy only Order on 2-picture sequences but only Multi-Tap on 3-picture sequences. Instructions to either copy or ignore the Multi-Tap response did not affect this overall pattern of results. In sum, results are consistent with the hypothesis that WM constrains not just the amount but also the type of information children copy from models, potentially modulating whether children imitate or emulate in a given task.
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  • Multiple imitation mechanisms in children.
    Developmental psychology (2012)
    Subiaul F, Anderson S, Brandt J, Elkins J. Multiple imitation mechanisms in children. Dev Psychol. 2012 Jul; 48(4):1165-79.
    Abstract: Four studies using a computerized paradigm investigated whether children's imitation performance is content-specific and to what extent dependent on other cognitive processes such as trial-and-error learning, recall, and observational learning. Experiment 1 showed that 3-year-olds could successfully imitate what we call novel cognitive rules (e.g., first → second → third), which involved responding to 3 different pictures whose spatial configuration varied randomly from trial to trial. However, these same children failed to imitate what we call novel motor-spatial rules (e.g., up → down → right), which involved responding to 3 identical pictures that remained in a fixed spatial configuration from trial to trial. Experiment 2 showed that this dissociation was not due to a general difficulty in encoding motor-spatial content, as children successfully recalled, following a 30-s delay, a new motor-spatial sequence that had been learned by trial and error. Experiment 3 replicated these results and further demonstrated that 3-year-olds can infer a novel motor-spatial sequence following observation of a partially correct and partially incorrect response-a dissociation between imitation and observational learning (or emulation learning). Finally, Experiment 4 presented 3-year-olds with "familiar" motor-spatial sequences that involved making a linear response (e.g., left → middle → right) as well as "novel" motor-spatial sequences (e.g., right → up → down) used in Experiments 1-3 that were nonlinear and always involved a change in direction. Children had no difficulty imitating familiar motor-spatial sequences but again failed to imitate novel motor-spatial sequences. These results suggest that there may be multiple, dissociable imitation learning mechanisms that are content-specific. More importantly, the development of these imitation systems appears to be independent of the operations of other cognitive systems, including trial and error learning, recall, and observational learning.
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  • The ghosts in the computer: the role of agency and animacy attributions in "ghost controls".
    PloS one (2011)
    Subiaul F, Vonk J, Rutherford MD. The ghosts in the computer: the role of agency and animacy attributions in "ghost controls". PLoS One. 2011; 6(11):e26429.
    Abstract: Three studies evaluated the role of 4-year-old children's agency- and animacy-attributions when learning from a computerized ghost control (GC). In GCs, participants observe events occurring without an apparent agent, as if executed by a "ghost" or unobserved causal forces. Using a touch-screen, children in Experiment 1 responded to three pictures in a specific order under three learning conditions: (i) trial-and-error (Baseline), (ii) imitation and (iii) Ghost Control. Before testing in the GC, children were read one of three scripts that determined agency attributions. Post-test assessments confirmed that all children attributed agency to the computer and learned in all GCs. In Experiment 2, children were not trained on the computer prior to testing, and no scripts were used. Three different GCs, varying in number of agency cues, were used. Children failed to learn in these GCs, yet attributed agency and animacy to the computer. Experiment 3 evaluated whether children could learn from a human model in the absence of training under conditions where the information presented by the model and the computer was either consistent or inconsistent. Children evidenced learning in both of these conditions. Overall, learning in social conditions (Exp. 3) was significantly better than learning in GCs (Exp. 2). These results, together with other published research, suggest that children privilege social over non-social sources of information and are generally more adept at learning novel tasks from a human than from a computer or GC.
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A single-arm, open-label, multicenter phase 3 study of the contraceptive efficacy, safety and tolerability of the AG200-15 transdermal contraceptive delivery system (TCDS)
The Ohio State University
  • Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.
    Contraception (2021)
    Nelson AL, Kaunitz AM, Kroll R, Simon JA, Poindexter AN, Castaño PM, Ackerman RT, Flood L, Chiodo JA 3rd, Garner EI, SECURE Investigators.. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results. Contraception. 2021 Mar; 103(3):137-143.
    Abstract: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLA) containing levonorgestrel (LNG) and ethinyl estradiol (EE).
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Peripheral and Brain Manganese, and Other Metals, in Patients with Restless Legs Syndrome versus Controls
Vanderbilt University Medical Center
  • A potential role for zinc in restless legs syndrome.
    Sleep (2021)
    Chen P, Bornhorst J, Patton S, Bagai K, Nitin R, Miah M, Hare DJ, Kysenius K, Crouch PJ, Xiong L, Rouleau GA, Schwerdtle T, Connor J, Aschner M, Bowman AB, Walters AS. A potential role for zinc in restless legs syndrome. Sleep. 2021 Apr 9; 44(4):.
    Abstract: Evaluate serum and brain noniron metals in the pathology and genetics of restless legs syndrome (RLS).
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Continuous Glucose Monitoring in T2D Basal Insulin Users: The Mobile Study"
Vanderbilt University Medical Center
  • Glycaemic profiles of diverse patients with type 2 diabetes using basal insulin: MOBILE study baseline data.
    Diabetes, obesity & metabolism (2021)
    Peters A, Cohen N, Calhoun P, Ruedy KJ, Beck RW, Martens TW, Bao S, Njeru NM, Beck SE, Price DA. Glycaemic profiles of diverse patients with type 2 diabetes using basal insulin: MOBILE study baseline data. Diabetes Obes Metab. 2021 Feb; 23(2):631-636.
    Abstract: Basal insulin is often prescribed to patients with suboptimally controlled type 2 diabetes (T2D); however, its therapeutic efficacy is inadequate in many. During the MOBILE study's baseline phase, we evaluated 173 participants' continuous glucose monitoring (CGM) data (mean ± SD age 57 ± 9 years; 50% female; HbA1c 9.1% [range 7.1%-11.6%]; 40% using sulphonylureas; 19% using NPH; reported self-monitored blood glucose [SMBG] frequency median 1.0 checks/day) who were using basal, but not prandial insulin. Blinded CGM data were recorded for 10 days prior to randomization. The mean glucose value was 208 ± 47 mg/dL and it was lowest in the early morning. Mean time in the 70-180 mg/dL range was 9.6 ± 6.1 hours/day (40% ± 25%). Hyperglycaemia was extensive with medians of 14.7 (61%) and 5.0 (20.9%) hours/day with glucose greater than 180 and 250 mg/dL, respectively. Hypoglycaemia was infrequent (median [IQR] 0 [0, 4.3] minutes/day [0.0% {0.0%, 0.3%}] with glucose less than 70 mg/dL). Blinded CGM highlights the limitations of infrequent SMBG in basal insulin users with T2D and allows characterization of hyperglycaemia and hypoglycaemia in basal insulin users with suboptimal control. The MOBILE study randomized phase will define the benefits of using real-time CGM compared with SMBG in this population.
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A Pivotal, Multicenter, Non-Comparative Trial on the Contraceptive Efficacy, Safety, Tolerability and Pharmacokinetics of LF111 (Drospirenone 4.0 mg) During 13 Cycles
Columbia University
  • Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime.
    BMC women's health (2020)
    Palacios S, Colli E, Regidor PA. Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime. BMC Womens Health. 2020 Oct 2; 20(1):218.
    Abstract: A new estrogen-free contraceptive has been approved by both the FDA and more than 15 European authorities. It is composed of drospirenone (DRSP) at a dosage of 4 mg in a regimen 24/4. The molecule is known to have anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. The purpose of these clinical trials with a new estrogen-free contraceptive was to introduce a contraceptive method with high efficacy and showing a profile with low cardiovascular risks.
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Contribution of Substance P to Blood Pressure Regulation in the Setting of Dipeptidyl Peptidase IV and Angiotensin Converting Enzyme (ACE) Inhibition
Vanderbilt University Medical Center
  • Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal.
    Diabetes, obesity & metabolism (2021)
    Mashayekhi M, Wilson JR, Jafarian-Kerman S, Nian H, Yu C, Shuey MM, Luther JM, Brown NJ. Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal. Diabetes Obes Metab. 2021 Jan; 23(1):281-286.
    Abstract: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous glucagon-like peptide-1 (GLP-1). We hypothesized that genetic variation in the gene encoding the GLP-1 receptor (GLP1R) could affect the metabolic response to DPP-4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G-to-A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7-day treatment with placebo and the DPP-4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP-1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP-1 signalling merits study in large populations.
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  • Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin.
    Journal of the Endocrine Society (2017)
    Wilson JR, Shuey MM, Brown NJ, Devin JK. Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin. J Endocr Soc. 2017 Sep 1; 1(9):1168-1178.
    Abstract: Patients with diabetes often have comorbidities such as hypertension. It is not known how individual characteristics influence response to dipeptidyl peptidase-4 (DPP4) inhibitors.
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HEALTHY OILS FOR WOMEN: REDUCING VISCERAL ADIPOSE TISSUE IN WOMEN WITH METABOLIC SYNDROME (HOW STUDY),
The Ohio State University
  • Linoleic Acid-Rich Oil Supplementation Increases Total and High-Molecular-Weight Adiponectin and Alters Plasma Oxylipins in Postmenopausal Women with Metabolic Syndrome.
    Current developments in nutrition (2020)
    Cole RM, Puchala S, Ke JY, Abdel-Rasoul M, Harlow K, O'Donnell B, Bradley D, Andridge R, Borkowski K, Newman JW, Belury MA. Linoleic Acid-Rich Oil Supplementation Increases Total and High-Molecular-Weight Adiponectin and Alters Plasma Oxylipins in Postmenopausal Women with Metabolic Syndrome. Curr Dev Nutr. 2020 Sep; 4(9):nzaa136.
    Abstract: The onset of menopause increases the risk of metabolic syndrome (MetS). Adiponectin is an adipokine associated with insulin sensitivity that is lower in people with MetS. Supplementing diets with linoleic acid (LA)-rich oil increased adiponectin concentrations and improved glucose control in women with type 2 diabetes. The effect of LA on adipokines, especially total and the bioactive form of adiponectin, high-molecular-weight (HMW) adiponectin, in women with MetS is unknown.
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Pilot study of the effects of colchicine in non-diabetic adults with metabolic syndrome
The National Institutes of Health
  • Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity.
    Journal of clinical lipidology (2020)
    Levine JA, Han JM, Wolska A, Wilson SR, Patel TP, Remaley AT, Periwal V, Yanovski JA, Demidowich AP. Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity. J Clin Lipidol. 2020 Sep - Oct; 14(5):667-674.
    Abstract: Obesity-associated inflammation promotes metabolic dysfunction. However, it is unclear how different inflammatory biomarkers predict dysregulation in specific tissues/organs, particularly adipose tissue.
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  • Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial.
    Journal of clinical lipidology (2019)
    Demidowich AP, Wolska A, Wilson SR, Levine JA, Sorokin AV, Brady SM, Remaley AT, Yanovski JA. Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial. J Clin Lipidol. 2019 Nov - Dec; 13(6):1016-1022.e2.
    Abstract: Colchicine has received renewed interest for its potential beneficial effects in secondary prevention of cardiovascular disease. This was presumed to be primarily because of its anti-inflammatory effects; however, limited data exist regarding colchicine's impact on other cardiovascular risk factors.
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  • Associations of the melanocortin 3 receptor C17A + G241A haplotype with body composition and inflammation in African-American adults.
    Annals of human genetics (2019)
    Demidowich AP, Parikh VJ, Dedhia N, Branham RE, Madi SA, Marwitz SE, Roberson RB, Uhlman AJ, Levi NJ, Mi SJ, Jun JY, Broadney MM, Brady SM, Yanovski JA. Associations of the melanocortin 3 receptor C17A + G241A haplotype with body composition and inflammation in African-American adults. Ann Hum Genet. 2019 Sep; 83(5):355-360.
    Abstract: The MC3R haplotype C17A + G241A, which encodes a partially inactivated receptor, has high prevalence in individuals of predominately African ancestry. In pediatric cohorts, homozygosity for this common variant has been associated with obesity, reduced lean mass, and greater fasting insulin. However, metabolic and body composition measures have not been well studied in adults with this haplotype.
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"Postural OrthostaticTachycardia Syndrome and Gastrointestinal Symptoms: Contribution of Gastrointestinal Peptides"
Vanderbilt University Medical Center
  • Splanchnic Venous Compression Enhances the Effects of ß-Blockade in the Treatment of Postural Tachycardia Syndrome.
    Journal of the American Heart Association (2020)
    Smith EC, Diedrich A, Raj SR, Gamboa A, Shibao CA, Black BK, Peltier A, Paranjape SY, Biaggioni I, Okamoto LE. Splanchnic Venous Compression Enhances the Effects of ß-Blockade in the Treatment of Postural Tachycardia Syndrome. J Am Heart Assoc. 2020 Jul 21; 9(14):e016196.
    Abstract: Background Splanchnic venous pooling induced by upright posture triggers a compensatory increase in heart rate (HR), a response that is exaggerated in patients with postural tachycardia syndrome. To assess whether abdominal compression attenuates orthostatic tachycardia and improves symptoms, 18 postural tachycardia syndrome patients (32±2 years) were randomized to receive either abdominal compression (40 mm Hg applied with an inflatable binder ≈2 minutes before standing) or propranolol (20 mg) in a placebo-controlled, crossover study. Methods and Results Systolic blood pressure, HR, and symptoms were assessed while seated and standing, before and 2 hours postdrug. As expected, propranolol decreased standing HR compared with placebo (81±2 versus 98±4 beats per minute; <0.001) and was associated with lower standing systolic blood pressure (93±2 versus 100±2 mm Hg for placebo; =0.002). Compression had no effect on standing HR (96±4 beats per minute) but increased standing systolic blood pressure compared with placebo and propranolol (106±2 mm Hg; <0.01). Neither propranolol nor compression improved symptoms compared with placebo. In 16 patients we compared the combination of abdominal compression and propranolol with propranolol alone. The combination had no additional effect on standing HR (81±2 beats per minute for both interventions) but prevented the decrease in standing systolic blood pressure produced by propranolol (98±2 versus 93±2 mm Hg for propranolol; =0.029), and significantly improved total symptom burden (-6±2 versus -1±2 for propranolol; =0.041). Conclusions Splanchnic venous compression alone did not improve HR or symptoms but prevented the blood pressure decrease produced by propranolol. The combination was more effective in improving symptoms than either alone. Splanchnic venous compression can be a useful adjuvant therapy to propranolol in postural tachycardia syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00262470.
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  • Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review.
    Clinical autonomic research : official journal of the Clinical Autonomic Research Society (2018)
    Mehr SE, Barbul A, Shibao CA. Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review. Clin Auton Res. 2018 Aug; 28(4):411-421.
    Abstract: Gastrointestinal symptoms are among the most common complaints in patients with postural tachycardia syndrome (POTS). In some cases, they dominate the clinical presentation and cause substantial disabilities, including significant weight loss and malnutrition, that require the use of invasive treatment to support caloric intake. Multiple cross-sectional studies have reported a high prevalence of gastrointestinal symptoms in POTS patients with connective tissue diseases, such as Ehlers-Danlos, hypermobile type, and in patients with evidence of autonomic neuropathy. Previous studies that evaluated gastric motility in these patients reported a wide range of abnormalities, particularly delayed gastric emptying. The pathophysiology of gastrointestinal symptoms in POTS is likely multifactorial and probably depends on the co-morbid conditions. In patients with POTS and Ehlers-Danlos syndromes, structural and functional abnormalities in the gastrointestinal connective tissue may play a significant role, whereas in neuropathic POTS, the gastrointestinal tract motility and gut hormonal secretion may be directly impaired due to localized autonomic denervation. In patients with normal gastrointestinal motility but persistent gastrointestinal symptoms, gastrointestinal functional disorders should be considered. We performed a systematic review of the literature related to POTS and gastrointestinal symptoms have proposed possible mechanisms and discussed diagnosis and treatment approaches for delayed gastric emptying, the most common gastrointestinal abnormality reported in patients with POTS.
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The impact of life events and emotional expression on the subjective experience of chronic pain
Vanderbilt University Medical Center
  • Exploring the links among borderline personality disorder symptoms, trauma, and pain in patients with chronic pain disorders.
    Journal of psychosomatic research (2020)
    Johnson BN, Lumley MA, Cheavens JS, McKernan LC. Exploring the links among borderline personality disorder symptoms, trauma, and pain in patients with chronic pain disorders. J Psychosom Res. 2020 Aug; 135:110164.
    Abstract: Chronic pain and borderline personality disorder (BPD) are commonly comorbid and jointly associated with increased symptoms of both disorders and clinical and functional impairment. Little is known, however, about specific links between these disorders. In a cross-sectional study of patients with chronic pain, we compared participants high or low on BPD symptoms on patterns of pain experience and types of child and adult traumas.
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  • Posttraumatic stress disorder in interstitial cystitis/bladder pain syndrome: Relationship to patient phenotype and clinical practice implications.
    Neurourology and urodynamics (2019)
    McKernan LC, Johnson BN, Reynolds WS, Williams DA, Cheavens JS, Dmochowski RR, Crofford LJ. Posttraumatic stress disorder in interstitial cystitis/bladder pain syndrome: Relationship to patient phenotype and clinical practice implications. Neurourol Urodyn. 2019 Jan; 38(1):353-362.
    Abstract: The relationship between exposure to abuse and interstitial cystitis/bladder pain syndrome (IC/BPS) is well-documented. However, studies have yet to examine posttraumatic stress disorder (PTSD), which develops following exposure to trauma and worsens health outcomes in chronic pain. We aimed to assess the prevalence and impact of PTSD in patients with IC/BPS, including their relation to genitourinary symptom presentation and widespread pain phenotype.
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Introducing Early Geriatric Palliative Care to Patients and Family Caregivers
Vanderbilt University Medical Center
  • Receptivity of Hospitalized Older Adults and Family Caregivers to Prognostic Information about Aging, Injury, and Frailty: A Qualitative Study.
    International journal of nursing studies (2020)
    Maxwell CA, Mixon AS, Conner E, Phillippi JC. Receptivity of Hospitalized Older Adults and Family Caregivers to Prognostic Information about Aging, Injury, and Frailty: A Qualitative Study. Int J Nurs Stud. 2020 Sep; 109:103602.
    Abstract: Frailty is the leading prognosticator for poor outcomes and palliative care among older adults. Delivery of negative prognostic information entails potentially difficult conversations about decline and death.
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Magnesium Supplementation for the Prevention of Supraventricular Arrhythmias
University of Minnesota
  • Effect of Magnesium Supplementation on Circulating Biomarkers of Cardiovascular Disease.
    Nutrients (2020)
    Alonso A, Chen LY, Rudser KD, Norby FL, Rooney MR, Lutsey PL. Effect of Magnesium Supplementation on Circulating Biomarkers of Cardiovascular Disease. Nutrients. 2020 Jun 6; 12(6):.
    Abstract: (1) Background: Magnesium supplementation may be effective for the prevention of cardiometabolic diseases, but the mechanisms are unclear. Proteomic approaches can assist in identifying the underlying mechanisms. (2) Methods: We collected repeated blood samples from 52 individuals enrolled in a double-blind trial which randomized participants 1:1 to oral magnesium supplementation (400 mg magnesium/day in the form of magnesium oxide) or a matching placebo for 10 weeks. Plasma levels of 91 proteins were measured at baseline with follow-up samples using the Olink Cardiovascular Disease III proximity extension assay panel and were modeled as arbitrary units in a log scale. We evaluated the effect of oral magnesium supplementation for changes in protein levels and the baseline association between serum magnesium and protein levels. The Holm procedure was used to adjust for multiple comparisons. (3) Results: Participants were 73% women, 94% white, and had a mean age of 62. Changes in proteins did not significantly differ between the two intervention groups after correction for multiple comparisons. The most statistically significant effects were on myoglobin [difference -0.319 log units, 95% confidence interval (CI) (-0.550, -0.088), 0.008], tartrate-resistant acid phosphatase type 5 (-0.187, (-0.328, -0.045), 0.011), tumor necrosis factor ligand superfamily member 13B (-0.181, (-0.332, -0.031), 0.019), ST2 protein (-0.198, (-0.363, -0.032), 0.020), and interleukin-1 receptor type 1 (-0.144, (-0.273, -0.015), 0.029). Similarly, none of the associations of baseline serum magnesium with protein levels were significant after correction for multiple comparisons. (4) Conclusions: Although we did not identify statistically significant effects of oral magnesium supplementation in this relatively small study, this study demonstrates the value of proteomic approaches for the investigation of mechanisms underlying the beneficial effects of magnesium supplementation. Clinical Trials Registration: ClinicalTrials.gov NCT02837328.
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Comprehensive Evaluation of the Impact of a Short-Term Analytical Treatment Interruption and Re-Initiation of Antiretroviral Therapy on Immunologic and Virologic Parameters in HIV-Infected Individuals
The National Institutes of Health
  • Kinetics of Plasma HIV Rebound in the Era of Modern Antiretroviral Therapy.
    The Journal of infectious diseases (2020)
    Sneller MC, Huiting ED, Clarridge KE, Seamon C, Blazkova J, Justement JS, Shi V, Whitehead EJ, Schneck RF, Proschan M, Moir S, Fauci AS, Chun TW. Kinetics of Plasma HIV Rebound in the Era of Modern Antiretroviral Therapy. J Infect Dis. 2020 Oct 13; 222(10):1655-1659.
    Abstract: Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.
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Evaluation of a novel PET radioligand to image cyclooxygenase-1 (COX-1)
The National Institutes of Health
  • First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain.
    European journal of nuclear medicine and molecular imaging (2020)
    Kim MJ, Lee JH, Juarez Anaya F, Hong J, Miller W, Telu S, Singh P, Cortes MY, Henry K, Tye GL, Frankland MP, Montero Santamaria JA, Liow JS, Zoghbi SS, Fujita M, Pike VW, Innis RB. First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain. Eur J Nucl Med Mol Imaging. 2020 Dec; 47(13):3143-3151.
    Abstract: This study assessed whether the newly developed PET radioligand [C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain.
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A Prospective, Double Blind, Randomized, Controlled Study to Evaluate the Safety and Efficacy of the Deep Transcranial Magnetic Stimulation (DTMS) for the treatment of Obsessive Compulsive Disorder
Mount Sinai School of Medicine
  • Do comorbid OCD-MDD patients need two separate dTMS protocols?
    Brain stimulation (2020)
    Harmelech T, Tendler A, Roth Y, Zangen A. Do comorbid OCD-MDD patients need two separate dTMS protocols? Brain Stimul. 2020 Jul - Aug; 13(4):1000-1001.
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  • Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.
    The American journal of psychiatry (2019)
    Crowell AL, Riva-Posse P, Holtzheimer PE, Garlow SJ, Kelley ME, Gross RE, Denison L, Quinn S, Mayberg HS. Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression. Am J Psychiatry. 2019 Nov 1; 176(11):949-956.
    Abstract: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression.
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  • Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.
    The American journal of psychiatry (2019)
    Carmi L, Tendler A, Bystritsky A, Hollander E, Blumberger DM, Daskalakis J, Ward H, Lapidus K, Goodman W, Casuto L, Feifel D, Barnea-Ygael N, Roth Y, Zangen A, Zohar J. Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry. 2019 Nov 1; 176(11):931-938.
    Abstract: Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study.
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The Effect of Obesity on Immune Responses to Pneumovax 23
University of Florida
  • Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy.
    JCI insight (2020)
    Sebastian M, Hsiao CJ, Futch HS, Eisinger RS, Dumeny L, Patel S, Gobena M, Katikaneni DS, Cohen J, Carpenter AM, Spiryda L, Heldermon CD, Jin L, Brantly ML. Obesity and STING1 genotype associate with 23-valent pneumococcal vaccination efficacy. JCI Insight. 2020 May 7; 5(9):.
    Abstract: BACKGROUNDObesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy.METHODSNonobese (BMI 22-25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4-6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples.RESULTSForty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693).CONCLUSIONSThese observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype.TRIAL REGISTRATIONClinicalTrials.gov NCT02471014.FUNDINGThis research was supported by the NIH and the University of Florida MD-PhD Training Program.
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Cardiovascular Health and Resilience among Blacks: The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity Study
Emory University
  • Cardiovascular Risk and Resilience Among Black Adults: Rationale and Design of the MECA Study.
    Journal of the American Heart Association (2020)
    Islam SJ, Kim JH, Topel M, Liu C, Ko YA, Mujahid MS, Sims M, Mubasher M, Ejaz K, Morgan-Billingslea J, Jones K, Waller EK, Jones D, Uppal K, Dunbar SB, Pemu P, Vaccarino V, Searles CD, Baltrus P, Lewis TT, Quyyumi AA, Taylor H. Cardiovascular Risk and Resilience Among Black Adults: Rationale and Design of the MECA Study. J Am Heart Assoc. 2020 May 5; 9(9):e015247.
    Abstract: Background Cardiovascular disease incidence, prevalence, morbidity, and mortality have declined in the past several decades; however, disparities persist among subsets of the population. Notably, blacks have not experienced the same improvements on the whole as whites. Furthermore, frequent reports of relatively poorer health statistics among the black population have led to a broad assumption that black race reliably predicts relatively poorer health outcomes. However, substantial intraethnic and intraracial heterogeneity exists; moreover, individuals with similar risk factors and environmental exposures are often known to experience vastly different cardiovascular health outcomes. Thus, some individuals have good outcomes even in the presence of cardiovascular risk factors, a concept known as resilience. Methods and Results The MECA (Morehouse-Emory Center for Health Equity) Study was designed to investigate the multilevel exposures that contribute to "resilience" in the face of risk for poor cardiovascular health among blacks in the greater Atlanta, GA, metropolitan area. We used census tract data to determine "at-risk" and "resilient" neighborhoods with high or low prevalence of cardiovascular morbidity and mortality, based on cardiovascular death, hospitalization, and emergency department visits for blacks. More than 1400 individuals from these census tracts assented to demographic, health, and psychosocial questionnaires administered through telephone surveys. Afterwards, ≈500 individuals were recruited to enroll in a clinical study, where risk biomarkers, such as oxidative stress, and inflammatory markers, endothelial progenitor cells, metabolomic and microRNA profiles, and subclinical vascular dysfunction were measured. In addition, comprehensive behavioral questionnaires were collected and ideal cardiovascular health metrics were assessed using the American Heart Association's Life Simple 7 measure. Last, 150 individuals with low Life Simple 7 were recruited and randomized to a behavioral mobile health (eHealth) plus health coach or eHealth only intervention and followed up for improvement. Conclusions The MECA Study is investigating socioenvironmental and individual behavioral measures that promote resilience to cardiovascular disease in blacks by assessing biological, functional, and molecular mechanisms. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03308812.
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Patient Experience Recommender System for Persuasive Communication Tailoring
University of Massachusetts Worcester
  • Comparison of a Collective Intelligence Tailored Messaging System on Smoking Cessation Between African American and White People Who Smoke: Quasi-Experimental Design.
    JMIR mHealth and uHealth (2020)
    Faro JM, Nagawa CS, Allison JA, Lemon SC, Mazor KM, Houston TK, Sadasivam RS. Comparison of a Collective Intelligence Tailored Messaging System on Smoking Cessation Between African American and White People Who Smoke: Quasi-Experimental Design. JMIR Mhealth Uhealth. 2020 Apr 27; 8(4):e18064.
    Abstract: The Patient Experience Recommender System for Persuasive Communication Tailoring (PERSPeCT) is a machine learning recommender system with a database of messages to motivate smoking cessation. PERSPeCT uses the collective intelligence of users (ie, preferences and feedback) and demographic and smoking profiles to select motivating messages. PERSPeCT may be more beneficial for tailoring content to minority groups influenced by complex, personally relevant factors.
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  • Impact of a Collective Intelligence Tailored Messaging System on Smoking Cessation: The Perspect Randomized Experiment.
    Journal of medical Internet research (2016)
    Sadasivam RS, Borglund EM, Adams R, Marlin BM, Houston TK. Impact of a Collective Intelligence Tailored Messaging System on Smoking Cessation: The Perspect Randomized Experiment. J Med Internet Res. 2016 Nov 8; 18(11):e285.
    Abstract: Outside health care, content tailoring is driven algorithmically using machine learning compared to the rule-based approach used in current implementations of computer-tailored health communication (CTHC) systems. A special class of machine learning systems ("recommender systems") are used to select messages by combining the collective intelligence of their users (ie, the observed and inferred preferences of users as they interact with the system) and their user profiles. However, this approach has not been adequately tested for CTHC.
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Community-based evaluation of APOL1 Genetic Testing in African Americans
Vanderbilt University Medical Center
  • At the Research-Clinical Interface: Returning Individual Genetic Results to Research Participants.
    Clinical journal of the American Society of Nephrology : CJASN (2020)
    West KM, Blacksher E, Cavanaugh KL, Fullerton SM, Umeukeje EM, Young BA, Burke W. At the Research-Clinical Interface: Returning Individual Genetic Results to Research Participants. Clin J Am Soc Nephrol. 2020 Aug 7; 15(8):1181-1189.
    Abstract: Whether individual results of genetic research studies ought to be disclosed to study participants has been debated in recent decades. Previously, the prevailing expert view discouraged the return of individual research results to participants because of the potential lack of analytic validity, questionable clinical validity and medical actionability, and questions about whether it is the role of research to provide participants with their data. With additional knowledge of participant perspectives and shifting views about the benefits of research and respect for participants, current expert consensus is moving toward support of returning such results. Significant ethical controversies remain, and there are many practical questions left to address, including appropriate procedures for returning results and the potential burden to clinicians when patients seek guidance about the clinical implications of research results. In this review, we describe current views regarding the return of genetic research results, including controversies and practical challenges, and consider the application of these issues to research on apolipoprotein L1 (), a gene recently associated with health disparities in kidney disease. Although this case is unique, it illustrates the complexities involved in returning results and highlights remaining questions.
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"A Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Circadin® To Alleviate Sleep Disturbances in Children with Neurodevelopment Disabilities NEU CH 7911" (Neurim Pharmaceuticals, Ltd.)
Vanderbilt University Medical Center
  • Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder.
    Journal of the American Academy of Child and Adolescent Psychiatry (2021)
    Malow BA, Findling RL, Schroder CM, Maras A, Breddy J, Nir T, Zisapel N, Gringras P. Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2021 Feb; 60(2):252-261.e3.
    Abstract: A recent 3-month double-blind, placebo-controlled study demonstrated efficacy and safety of pediatric prolonged-release melatonin (PedPRM) for insomnia in children with autism spectrum disorder. This study examined the long-term effects of PedPRM treatment on sleep, growth, body mass index, and pubertal development.
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  • Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver's Quality of Life.
    Journal of autism and developmental disorders (2019)
    Schroder CM, Malow BA, Maras A, Melmed RD, Findling RL, Breddy J, Nir T, Shahmoon S, Zisapel N, Gringras P. Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver's Quality of Life. J Autism Dev Disord. 2019 Aug; 49(8):3218-3230.
    Abstract: A randomized, 13-weeks, placebo-controlled double-blind study in 125 subjects aged 2-17.5 years with Autism Spectrum Disorder or Smith-Magenis syndrome and insomnia demonstrated efficacy and safety of easily-swallowed prolonged-release melatonin mini-tablets (PedPRM; 2-5 mg) in improving sleep duration and onset. Treatment effects on child behavior and caregiver's quality of life were evaluated. PedPRM treatment resulted in significant improvement in externalizing but not internalizing behavior (Strengths and Difficulties questionnaire; SDQ) compared to placebo (p = 0.021) with clinically-relevant improvements in 53.7% of PedPRM-treated versus 27.6% of placebo-treated subjects (p = 0.008). Caregivers' quality of life also improved with PedPRM versus placebo (p = 0.010) and correlated with the change in total SDQ (p = 0.0005). PedPRM alleviates insomnia-related difficulties, particularly externalizing behavior in the children, subsequently improving caregivers' quality of life.
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The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment with B3-Adrenergic Receptor Agonists
The National Institutes of Health
  • Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.
    The Journal of clinical investigation (2020)
    O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Sater ZA, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Ber. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest. 2020 May 1; 130(5):2209-2219.
    Abstract: BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
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A CBT Intervention to Reduce Fear of Hypoglycemia
University of Illinois at Chicago
  • A cognitive behavioral therapy intervention to reduce fear of hypoglycemia in young adults with type 1 diabetes (FREE): study protocol for a randomized controlled trial.
    Trials (2019)
    Martyn-Nemeth P, Duffecy J, Quinn L, Park C, Mihailescu D, Penckofer S. A cognitive behavioral therapy intervention to reduce fear of hypoglycemia in young adults with type 1 diabetes (FREE): study protocol for a randomized controlled trial. Trials. 2019 Dec 30; 20(1):796.
    Abstract: In persons with type 1 diabetes (T1D), hypoglycemia is the major limiting factor in achieving optimal glycemic control. All persons with T1D are at risk for hypoglycemia (blood glucose level < 70 mg/dl), which is life-threatening and accompanied by serious physical and psychological symptoms, resulting in profound fear of hypoglycemia (FOH) and reduced quality of life. Young adults with T1D are at risk for FOH and have worse glycemic control and self-management behavior than other age groups with T1D. FOH also results in increased glycemic variability (GV). A major gap exists in how to manage FOH. Our overall objective is to reduce FOH and improve diabetes self-management, glycemic control, and GV in young adults with T1D to reduce or delay diabetes complications and improve quality of life. We aim to (1) determine the feasibility and acceptability of an eight-week cognitive behavioral therapy (CBT)-based Fear Reduction Efficacy Evaluation (FREE) intervention in young adults with T1D who experience FOH; and (2) determine the impact of the FREE intervention, compared to an attention control group, on the outcomes FOH, self-management, glycemic control (A1C), and glycemic variability (continuous glucose monitoring recordings).
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Mindfulness-based Cognitive Therapy and Cognitive Behavioral Therapy for Chronic Pain in Multiple Sclerosis
University of Washington
  • Mindfulness-based cognitive therapy and cognitive behavioral therapy for chronic pain in multiple sclerosis: a randomized controlled trial protocol.
    Trials (2019)
    Ehde DM, Alschuler KN, Day MA, Ciol MA, Kaylor ML, Altman JK, Jensen MP. Mindfulness-based cognitive therapy and cognitive behavioral therapy for chronic pain in multiple sclerosis: a randomized controlled trial protocol. Trials. 2019 Dec 27; 20(1):774.
    Abstract: Chronic pain is one of the most prevalent and disabling symptoms associated with multiple sclerosis (MS). Individuals with MS are interested in nonpharmacologic pain management approaches. Cognitive-behavioral therapy (CBT) is efficacious in improving MS-related pain outcomes. Mindfulness-based cognitive therapy (MBCT) is a promising, alternative approach. Little is known about moderators of these treatments' outcomes, however. This article describes the study protocol for the first randomized controlled trial comparing MBCT, CBT, and usual care and examining treatment effect moderators in individuals with chronic pain and MS.
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On-Line Migraine Education
University of Iowa
  • One-Day Acceptance and Commitment Therapy Compared to Support for Depressed Migraine Patients: a Randomized Clinical Trial.
    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2020)
    Dindo LN, Recober A, Calarge CA, Zimmerman BM, Weinrib A, Marchman JN, Turvey C. One-Day Acceptance and Commitment Therapy Compared to Support for Depressed Migraine Patients: a Randomized Clinical Trial. Neurotherapeutics. 2020 Apr; 17(2):743-753.
    Abstract: In patients with migraine, depression is associated with poorer medical prognosis, decreased quality of life, and increased risk of suicidality and disability; yet, behavioral interventions have rarely been investigated. The current study compared the efficacy of two 1-day (5- to 6-h) interventions for co-occurring migraine and depression: (1) acceptance and commitment therapy plus migraine education (ACT-ED), and (2) support plus migraine education (S-ED). One hundred and thirty-six patients with comorbid depression and migraine were randomized to a treatment. One hundred and three (76%) completed the ACT-ED (N = 56) or S-ED (N = 47) workshop. Primary outcomes were depression diagnosis and symptoms. Secondary outcomes were anxiety symptoms, headache-related disability and general functioning, and quality of life. Assessments were completed at baseline and 3 and 6 months following the workshop. At the 6-month follow-up, on categorical outcomes, a significantly greater number of people in the ACT-ED condition no longer met criteria for a major depressive episode and exhibited a > 50% drop in symptoms on the Hamilton Rating Scale of Depression. Similarly, though, weaker results were found when examining depressive symptoms dimensionally. On secondary outcomes, people in the ACT-ED condition exhibited significantly greater improvements in anxiety, headache-related disability, and quality of social relationships, compared to S-ED, No differences between groups were observed in general functioning. A 1-day (5- to 6-h) ACT workshop can deliver substantial and lasting benefits to depressed migraineurs, over and above those provided by group support and education. This approach is an attractive alternative to weekly psychotherapy. Clinicaltrials.gov # NCT02108678.
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Communication App to Manage Symptoms and Improve Adjuvant Endocrine Therapy Adherence
University of Tennessee Health Science Center
  • THRIVE study protocol: a randomized controlled trial evaluating a web-based app and tailored messages to improve adherence to adjuvant endocrine therapy among women with breast cancer.
    BMC health services research (2019)
    Paladino AJ, Anderson JN, Krukowski RA, Waters T, Kocak M, Graff C, Blue R, Jones TN, Buzaglo J, Vidal G, Schwartzberg L, Graetz I. THRIVE study protocol: a randomized controlled trial evaluating a web-based app and tailored messages to improve adherence to adjuvant endocrine therapy among women with breast cancer. BMC Health Serv Res. 2019 Dec 19; 19(1):977.
    Abstract: Long-term use of adjuvant endocrine therapy (AET) among women with early-stage, hormone receptor-positive breast cancer significantly reduces the risk of hospitalizations, cancer recurrence, and mortality. AET is associated with adverse symptoms that often result in poor adherence. A web-enabled app offers a novel way to communicate and manage symptoms for women on AET. In a region with significant racial disparities in breast cancer outcomes, our study tests the impact of a web-enabled app that collects and transmits patient-reported symptoms to healthcare teams to facilitate timely and responsive symptom management on medication adherence.
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Strength of specific memory representation and absent reference comprehension in 12-months-old babies
Vanderbilt University Medical Center
  • Twelve-Month-Old Infants Respond to Speech About Absent Inaccessible Objects.
    Child development (2020)
    Osina MA, Needham AW, Saylor MM. Twelve-Month-Old Infants Respond to Speech About Absent Inaccessible Objects. Child Dev. 2020 Jul; 91(4):1353-1363.
    Abstract: This article investigated the interplay of 12-month-old infants' perception of affordances for locomotion and their ability to respond to the mention of hidden objects. In Experiment I, a toy was hidden in an ottoman that was placed on a cabinet out of infants' reach. Infants were more likely to look at, point to or approach the ottoman when there were stairs leading to it than when there were none. The stairs did not help infants respond by highlighting the target corner of the room (Experiment II) or by boosting their engagement with the study events (Experiment III). This suggests that infants' perception of the accessibility of the hiding location influences their ability to respond to speech about absent things.
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The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome
Vanderbilt University Medical Center
  • Sitagliptin Decreases Visceral Fat and Blood Glucose in Women With Polycystic Ovarian Syndrome.
    The Journal of clinical endocrinology and metabolism (2020)
    Devin JK, Nian H, Celedonio JE, Wright P, Brown NJ. Sitagliptin Decreases Visceral Fat and Blood Glucose in Women With Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2020 Jan 1; 105(1):.
    Abstract: Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion.
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A Randomized, Placebo-Controlled Trial of Duloxetine Added to Nonsteroidal Anti-inflammatory Drugs in Patients with Knee Pain due to Osteoarthritis who have had Suboptimal Response to Nonsteroidal Anti-inflammatory Drug Treatment
University of Cincinnati
  • The Clinical Relevance of Pain Severity Changes: Is There Any Difference Between Asian and Caucasian Patients With Osteoarthritis Pain?
    Pain practice : the official journal of World Institute of Pain (2020)
    Yue L, Wang J, Enomoto H, Fujikoshi S, Alev L, Cheng YY, Skljarevski V. The Clinical Relevance of Pain Severity Changes: Is There Any Difference Between Asian and Caucasian Patients With Osteoarthritis Pain? Pain Pract. 2020 Feb; 20(2):129-137.
    Abstract: The objective of the present analysis was to determine whether changes in Brief Pain Inventory (BPI) average pain scores by patient global impression of improvement (PGI-I) category and the cut-off for clinically important difference (CID) were different between Asian and Caucasian patients with chronic pain due to osteoarthritis. This analysis used data from 3 (Caucasian) and 2 (Asian) randomized, placebo-controlled, 10- to 14-week duloxetine studies for the treatment of patients ≥40 years of age with osteoarthritis pain. The receiver operating characteristic (ROC) analysis was used to characterize the association between changes in BPI average pain scores and PGI-I levels at study endpoint. The CID was characterized by PGI-I, and the cut-off point for CID in BPI average pain scores was determined by the intersection of a 45-degree tangent line with each ROC curve. Data from 668 Asian and 868 Caucasian patients were available for analysis. Baseline BPI average pain ratings including worst and least pain were comparable between Asians and Caucasians. Ratings for percentage change from baseline to endpoint for BPI average pain scores in Asian patients and Caucasian patients were similar across the 7 PGI-I categories, regardless of age, gender, study, and treatment. The ROC analysis results of cut-off points in BPI average pain scores demonstrated the raw change cut-off was -3.0, and percentage change cut-off was -40% for both Asian and Caucasian patients. Overall, the present analysis concludes changes in BPI average pain scores by PGI-I category and the cut-off for CID were similar for Asian and Caucasian patients with chronic pain due to osteoarthritis.
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  • Responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) scale in a trial of duloxetine for treatment of osteoarthritis knee pain.
    Osteoarthritis and cartilage (2013)
    Risser RC, Hochberg MC, Gaynor PJ, D'Souza DN, Frakes EP. Responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) scale in a trial of duloxetine for treatment of osteoarthritis knee pain. Osteoarthritis Cartilage. 2013 May; 21(5):691-4.
    Abstract: To assess the change in the Intermittent and Constant Osteoarthritis Pain (ICOAP)-scale scores in patients taking duloxetine or placebo and to characterize the responsiveness of the ICOAP by comparing the effect size associated with its scales to effect sizes seen with other pain scales used in this study.
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  • Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial.
    Current medical research and opinion (2011)
    Frakes EP, Risser RC, Ball TD, Hochberg MC, Wohlreich MM. Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin. 2011 Dec; 27(12):2361-72.
    Abstract: To determine the efficacy, tolerability, and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis (OA) of the knee with pain of moderate or greater severity.
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CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia
Duke University
  • Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry.
    Atherosclerosis (2019)
    Duell PB, Gidding SS, Andersen RL, Knickelbine T, Anderson L, Gianos E, Shrader P, Kindt I, O'Brien EC, McCann D, Hemphill LC, Ahmed CD, Martin SS, Larry JA, Ahmad ZS, Kullo IJ, Underberg JA, Guyton J, Thompson P, Wilemon K, Roe MT, Rader DJ, Cuchel M, Li. Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry. Atherosclerosis. 2019 Oct; 289:85-93.
    Abstract: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH).
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Cardiometabolic Risk and Obesity in Adolescents With Down Syndrome
Children's National Hospital
  • Cardiometabolic Risk and Body Composition in Youth With Down Syndrome.
    Pediatrics (2019)
    Magge SN, Zemel BS, Pipan ME, Gidding SS, Kelly A. Cardiometabolic Risk and Body Composition in Youth With Down Syndrome. Pediatrics. 2019 Aug; 144(2):.
    Abstract: Whether BMI captures adiposity and cardiometabolic risk in Down syndrome (DS), a condition associated with obesity, short stature, and altered body proportions, is not known. We compared cardiometabolic risk measures in youth with DS and typically developing matched controls.
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  • Cross-Sectional Study of Arterial Stiffness in Adolescents with Down Syndrome.
    The Journal of pediatrics (2019)
    Kelly A, Magge SN, Walega R, Cochrane C, Pipan ME, Zemel BS, Cohen MS, Gidding SS, Townsend R. Cross-Sectional Study of Arterial Stiffness in Adolescents with Down Syndrome. J Pediatr. 2019 Sep; 212:79-86.e1.
    Abstract: To test whether youth with Down syndrome have aortic stiffness indices, as measured by pulse wave velocity (PWV), that differ from youth without Down syndrome and to compare reference-based age-adjusted (age-PWV-Z) and height-adjusted (Ht-PWV-Z) in youth with and without Down syndrome.
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  • Relationships of Body Composition to Cardiac Structure and Function in Adolescents With Down Syndrome are Different than in Adolescents Without Down Syndrome.
    Pediatric cardiology (2019)
    Kelly A, Gidding SS, Walega R, Cochrane C, Clauss S, Townsend RR, Xanthopoulos M, Pipan ME, Zemel BS, Magge SN, Cohen MS. Relationships of Body Composition to Cardiac Structure and Function in Adolescents With Down Syndrome are Different than in Adolescents Without Down Syndrome. Pediatr Cardiol. 2019 Feb; 40(2):421-430.
    Abstract: Median survival in Down syndrome (DS) is 60 years, but cardiovascular disease risk and its markers such as left ventricular mass (LVM) have received limited attention. In youth, LVM is typically scaled to height as a surrogate for lean body mass (LBM), the strongest predictor of LVM, but whether this algorithm applies to DS, a condition which features short stature, is unknown. To examine the relationships of LVM and function with height, LBM, and moderate-to-vigorous physical activity(MVPA) in DS, DS youth aged 10-20 years, and age-, sex-, BMI-, race-matched nonDS controls underwent echocardiography for LVM, ejection fraction (EF), and left ventricular diastolic function (measured as E/E'); dual-energy X-ray absorptiometry (DXA)-measured LBM; accelerometry for MVPA. (DS vs. nonDS median [min-max]): DS had lower height (cm) (144.5 [116.7-170.3] vs. 163.3 [134.8-186.7]; p < 0.0001); LBM (kg) (33.48 [14.5-62.3] vs 41.8 [18.07-72.46], p < 0.0001); and LVM (g) (68.3 [32.1-135] vs 94.0 [43.9-164.6], p < 0.0001); similar EF (%) (65 [54-77] vs 64 [53-77], p = 0.59); and higher E/E' (8.41 [5.54-21.4] vs 5.81 [3.44-9.56], p < 0.0001). In height-adjusted models, LVM was lower in DS (β = - 7.7, p = 0.02). With adjustment for LBM, LVM was even lower in DS (β = - 15.1, p < 0.0001), a finding not explained by MVPA. E/E' remained higher in DS after adjustment for age, height, HR, SBP, and BMI (β = 2.6, p < 0.0001). DS was associated with stiffer left ventricles and lower LVM, the latter magnified with LBM adjustment. Scaling to height, the traditional approach for assessing LVM in youth, may underestimate LVM differences in DS. Whether lower LVM and diastolic function are intrinsic to DS, pathologic, or protective remains unknown.Clinical Trial Registration: NCT01821300.
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  • Caregiver-Reported Quality of Life in Youth with Down Syndrome.
    The Journal of pediatrics (2017)
    Xanthopoulos MS, Walega R, Xiao R, Prasad D, Pipan MM, Zemel BS, Berkowitz RI, Magge SN, Kelly A. Caregiver-Reported Quality of Life in Youth with Down Syndrome. J Pediatr. 2017 Oct; 189:98-104.e1.
    Abstract: To describe caregiver-reported quality of life (QOL) in youth with Down syndrome (DS) and to examine the role of obesity on QOL.
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Vanderbilt Memory & Aging Project
Vanderbilt University Medical Center
  • Frailty Is Related to Subjective Cognitive Decline in Older Women without Dementia.
    Journal of the American Geriatrics Society (2019)
    Gifford KA, Bell SP, Liu D, Neal JE, Turchan M, Shah AS, Jefferson AL. Frailty Is Related to Subjective Cognitive Decline in Older Women without Dementia. J Am Geriatr Soc. 2019 Sep; 67(9):1803-1811.
    Abstract: Physical frailty (or loss of physiologic reserve) is associated with cognitive impairment and dementia. Subjective cognitive decline (SCD) may represent early pathologic changes of dementia. The association between these disease markers is unclear.
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  • Perivascular spaces contribute to cognition beyond other small vessel disease markers.
    Neurology (2019)
    Passiak BS, Liu D, Kresge HA, Cambronero FE, Pechman KR, Osborn KE, Gifford KA, Hohman TJ, Schrag MS, Davis LT, Jefferson AL. Perivascular spaces contribute to cognition beyond other small vessel disease markers. Neurology. 2019 Mar 19; 92(12):e1309-e1321.
    Abstract: To cross-sectionally relate multiple small vessel disease (SVD) neuroimaging markers to cognition among older adults.
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  • Neurofilament relates to white matter microstructure in older adults.
    Neurobiology of aging (2018)
    Moore EE, Hohman TJ, Badami FS, Pechman KR, Osborn KE, Acosta LMY, Bell SP, Babicz MA, Gifford KA, Anderson AW, Goldstein LE, Blennow K, Zetterberg H, Jefferson AL. Neurofilament relates to white matter microstructure in older adults. Neurobiol Aging. 2018 Oct; 70:233-241.
    Abstract: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (n = 77), early mild cognitive impairment (n = 15), and MCI (n = 55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values < 0.05). An NFL × diagnosis interaction (excluding early mild cognitive impairment) on WM microstructure (p-values < 0.05) was detected, with associations strongest among MCI. Multiple NFL × CSF biomarker interactions were detected. Associations between NFL and worse WM metrics were strongest among amyloid-β-negative, tau-positive, and suspected nonamyloid pathology participants. Findings suggest increased NFL, a biomarker of axonal injury, is correlated with compromised WM microstructure. Results highlight the role of elevated NFL in predicting WM damage in cognitively impaired older adults who are amyloid-negative, tau-positive, or meet suspected nonamyloid pathology criteria.
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  • Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.
    Circulation (2018)
    Jefferson AL, Cambronero FE, Liu D, Moore EE, Neal JE, Terry JG, Nair S, Pechman KR, Rane S, Davis LT, Gifford KA, Hohman TJ, Bell SP, Wang TJ, Beckman JA, Carr JJ. Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults. Circulation. 2018 Oct 30; 138(18):1951-1962.
    Abstract: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults.
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  • Increased Left Ventricular Mass Index Is Associated With Compromised White Matter Microstructure Among Older Adults.
    Journal of the American Heart Association (2018)
    Moore EE, Liu D, Pechman KR, Terry JG, Nair S, Cambronero FE, Bell SP, Gifford KA, Anderson AW, Hohman TJ, Carr JJ, Jefferson AL. Increased Left Ventricular Mass Index Is Associated With Compromised White Matter Microstructure Among Older Adults. J Am Heart Assoc. 2018 Jun 26; 7(13):.
    Abstract: Left ventricular (LV) hypertrophy is associated with cerebrovascular disease and cognitive decline. Increased LV mass index is a subclinical imaging marker that precedes overt LV hypertrophy. This study relates LV mass index to white matter microstructure and cognition among older adults with normal cognition and mild cognitive impairment.
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  • Cerebrospinal fluid β-amyloid42 and neurofilament light relate to white matter hyperintensities.
    Neurobiology of aging (2018)
    Osborn KE, Liu D, Samuels LR, Moore EE, Cambronero FE, Acosta LMY, Bell SP, Babicz MA, Gordon EA, Pechman KR, Davis LT, Gifford KA, Hohman TJ, Blennow K, Zetterberg H, Jefferson AL. Cerebrospinal fluid β-amyloid42 and neurofilament light relate to white matter hyperintensities. Neurobiol Aging. 2018 Aug; 68:18-25.
    Abstract: White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of β-amyloid deposition (Aβ), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 ± 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-ε4 carrier status. Aβ (β = -0.001, p = 0.007) and NFL (β = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Aβ accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury.
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  • APOE genotype modifies the association between central arterial stiffening and cognition in older adults.
    Neurobiology of aging (2018)
    Cambronero FE, Liu D, Neal JE, Moore EE, Gifford KA, Terry JG, Nair S, Pechman KR, Osborn KE, Hohman TJ, Bell SP, Sweatt JD, Wang TJ, Beckman JA, Carr JJ, Jefferson AL. APOE genotype modifies the association between central arterial stiffening and cognition in older adults. Neurobiol Aging. 2018 Jul; 67:120-127.
    Abstract: Arterial stiffening is associated with cognitive impairment and prodromal Alzheimer's disease. This study tested the interaction between arterial stiffening and an Alzheimer's disease genetic risk factor (apolipoprotein E [APOE] genotype) on cognition among older adults. Vanderbilt Memory & Aging Project participants with normal cognition (n = 162, 72 ± 7 years, 29% APOE-ε4 carrier) and mild cognitive impairment (n = 121, 73 ± 8 years, 42% APOE-ε4 carrier) completed neuropsychological assessment and cardiac MRI to assess aortic stiffening using pulse wave velocity (PWV, m/s). Linear regression models stratified by cognitive diagnosis related aortic PWV × APOE-ε4 status to neuropsychological performances, adjusting for demographic and vascular risk factors. PWV × APOE-ε4 related to poorer performance on measures of lexical retrieval (β = -0.29, p = 0.01), executive function (β = -0.44, p = 0.02), and episodic memory (β = -3.07, p = 0.02). Among participants with higher aortic PWV, APOE-ε4 modified the association between central arterial stiffening and cognition, such that carriers had worse performances than noncarriers. Findings add to a growing body of evidence for APOE-vascular interactions on cognition in older adults and warrant further research into less heart-healthy cohorts where the association between PWV and cognition among older adults might be stronger.
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  • Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults.
    Journal of the American Heart Association (2018)
    Kresge HA, Khan OA, Wagener MA, Liu D, Terry JG, Nair S, Cambronero FE, Gifford KA, Osborn KE, Hohman TJ, Pechman KR, Bell SP, Wang TJ, Carr JJ, Jefferson AL. Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults. J Am Heart Assoc. 2018 Feb 13; 7(4):.
    Abstract: Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults.
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  • Lower cardiac index levels relate to lower cerebral blood flow in older adults.
    Neurology (2017)
    Jefferson AL, Liu D, Gupta DK, Pechman KR, Watchmaker JM, Gordon EA, Rane S, Bell SP, Mendes LA, Davis LT, Gifford KA, Hohman TJ, Wang TJ, Donahue MJ. Lower cardiac index levels relate to lower cerebral blood flow in older adults. Neurology. 2017 Dec 5; 89(23):2327-2334.
    Abstract: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults.
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  • Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients.
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2018)
    Watchmaker JM, Juttukonda MR, Davis LT, Scott AO, Faraco CC, Gindville MC, Jordan LC, Cogswell PM, Jefferson AL, Kirshner HS, Donahue MJ. Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients. J Cereb Blood Flow Metab. 2018 Sep; 38(9):1618-1630.
    Abstract: Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.
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  • The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview.
    Journal of Alzheimer's disease : JAD (2016)
    Jefferson AL, Gifford KA, Acosta LM, Bell SP, Donahue MJ, Davis LT, Gottlieb J, Gupta DK, Hohman TJ, Lane EM, Libon DJ, Mendes LA, Niswender K, Pechman KR, Rane S, Ruberg FL, Su YR, Zetterberg H, Liu D. The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. J Alzheimers Dis. 2016 Mar 8; 52(2):539-59.
    Abstract: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.
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Uremic Modulation of Macrophage Lipid Homeostasis and Inflammatory Functions
Vanderbilt University Medical Center
  • Lipoprotein modulation of proteinuric renal injury.
    Laboratory investigation; a journal of technical methods and pathology (2019)
    Tsuchida Y, Zhong J, Otsuka T, Dikalova A, Pastan I, Anantharamaiah GM, Linton MF, Yancey PG, Ikizler TA, Fogo AB, Yang H, Kon V. Lipoprotein modulation of proteinuric renal injury. Lab Invest. 2019 Jul; 99(8):1107-1116.
    Abstract: High-density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain to renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, and apoAI mimetic (L-4F), and the in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis, and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25) mice, which express human CD25 on podocytes. Podocyte injury was induced by using immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25:apoE mice, was generated by mating apoE-deficient (apoE) mice with NEP25 mice. Animals received L-4F or control vehicle. Renal function, podocyte injury, and atherosclerosis were assessed. PAN reduced podocyte viability, migration, and increased ROS production, all significantly lessened by apoAI, HDL, and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/signal transducers and activators of transcription 3. In NEP25 mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25:apoE mice had more atherosclerosis than non-proteinuric apoE mice, and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL, and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be a novel candidate to lessen podocyte damage and its complications.
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  • Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism.
    BMC nephrology (2018)
    Kaseda R, Tsuchida Y, Yang HC, Yancey PG, Zhong J, Tao H, Bian A, Fogo AB, Linton MRF, Fazio S, Ikizler TA, Kon V. Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. BMC Nephrol. 2018 Jan 27; 19(1):17.
    Abstract: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism.
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  • Importance of high-density lipoprotein quality: evidence from chronic kidney disease.
    Current opinion in nephrology and hypertension (2013)
    Kon V, Ikizler TA, Fazio S. Importance of high-density lipoprotein quality: evidence from chronic kidney disease. Curr Opin Nephrol Hypertens. 2013 May; 22(3):259-65.
    Abstract: This review will examine advances in our understanding of the association between high-density lipoprotein (HDL) function and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD).
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  • Dysfunctional high-density lipoprotein in patients on chronic hemodialysis.
    Journal of the American College of Cardiology (2012)
    Yamamoto S, Yancey PG, Ikizler TA, Jerome WG, Kaseda R, Cox B, Bian A, Shintani A, Fogo AB, Linton MF, Fazio S, Kon V. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J Am Coll Cardiol. 2012 Dec 11; 60(23):2372-9.
    Abstract: This study examined the functionality of high-density lipoprotein (HDL) in individuals with end-stage renal disease on dialysis (ESRD-HD).
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Dopaminergic Modulation of Subjective Valuation
Vanderbilt University Medical Center
  • Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age.
    Human brain mapping (2019)
    Seaman KL, Smith CT, Juarez EJ, Dang LC, Castrellon JJ, Burgess LL, San Juan MD, Kundzicz PM, Cowan RL, Zald DH, Samanez-Larkin GR. Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age. Hum Brain Mapp. 2019 Jul; 40(10):3125-3138.
    Abstract: Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age-related change in function across cortical and subcortical sub-regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross-sectional adult age differences in estimates of D2-like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [ F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6-16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3-5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0-2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging.
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  • Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.
    The Journal of neuroscience : the official journal of the Society for Neuroscience (2019)
    Castrellon JJ, Seaman KL, Crawford JL, Young JS, Smith CT, Dang LC, Hsu M, Cowan RL, Zald DH, Samanez-Larkin GR. Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults. J Neurosci. 2019 Jan 9; 39(2):321-332.
    Abstract: Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: = 144 males and females across 3 samples) and one meta-analytic (Study 2: = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa. Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior.
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  • Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET.
    Psychopharmacology (2019)
    Smith CT, Dang LC, Burgess LL, Perkins SF, San Juan MD, Smith DK, Cowan RL, Le NT, Kessler RM, Samanez-Larkin GR, Zald DH. Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET. Psychopharmacology (Berl). 2019 Feb; 236(2):581-590.
    Abstract: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed.
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  • Individual differences in dopamine D2 receptor availability correlate with reward valuation.
    Cognitive, affective & behavioral neuroscience (2018)
    Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH. Individual differences in dopamine D2 receptor availability correlate with reward valuation. Cogn Affect Behav Neurosci. 2018 Aug; 18(4):739-747.
    Abstract: Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.
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  • Subjective value representations during effort, probability and time discounting across adulthood.
    Social cognitive and affective neuroscience (2018)
    Seaman KL, Brooks N, Karrer TM, Castrellon JJ, Perkins SF, Dang LC, Hsu M, Zald DH, Samanez-Larkin GR. Subjective value representations during effort, probability and time discounting across adulthood. Soc Cogn Affect Neurosci. 2018 May 1; 13(5):449-459.
    Abstract: Every day, humans make countless decisions that require the integration of information about potential benefits (i.e. rewards) with other decision features (i.e. effort required, probability of an outcome or time delays). Here, we examine the overlap and dissociation of behavioral preferences and neural representations of subjective value in the context of three different decision features (physical effort, probability and time delays) in a healthy adult life span sample. While undergoing functional neuroimaging, participants (N = 75) made incentive compatible choices between a smaller monetary reward with lower physical effort, higher probability, or a shorter time delay versus a larger monetary reward with higher physical effort, lower probability, or a longer time delay. Behavioral preferences were estimated from observed choices, and subjective values were computed using individual hyperbolic discount functions. We found that discount rates were uncorrelated across tasks. Despite this apparent behavioral dissociation between preferences, we found overlapping subjective value-related activity in the medial prefrontal cortex across all three tasks. We found no consistent evidence for age differences in either preferences or the neural representations of subjective value across adulthood. These results suggest that while the tolerance of decision features is behaviorally dissociable, subjective value signals share a common representation across adulthood.
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  • FTO affects food cravings and interacts with age to influence age-related decline in food cravings.
    Physiology & behavior (2018)
    Dang LC, Samanez-Larkin GR, Smith CT, Castrellon JJ, Perkins SF, Cowan RL, Claassen DO, Zald DH. FTO affects food cravings and interacts with age to influence age-related decline in food cravings. Physiol Behav. 2018 Aug 1; 192:188-193.
    Abstract: The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability.
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  • Partial-volume correction increases estimated dopamine D2-like receptor binding potential and reduces adult age differences.
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (2019)
    Smith CT, Crawford JL, Dang LC, Seaman KL, San Juan MD, Vijay A, Katz DT, Matuskey D, Cowan RL, Morris ED, Zald DH, Samanez-Larkin GR. Partial-volume correction increases estimated dopamine D2-like receptor binding potential and reduces adult age differences. J Cereb Blood Flow Metab. 2019 May; 39(5):822-833.
    Abstract: The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BP) may be underestimated. Given structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2.5 mm). Results across both data sets revealed that PVC increased estimated BP and reduced, though did not eliminate, age effects on BP. As expected, the effects of PVC were smaller in higher compared to lower resolution data. Analyses using uncorrected data that controlled for grey matter volume in each region of interest approximated PVC corrected data for some but not all regions. Overall, the findings suggest that PVC increases estimated BP in general and reduces adult age differences especially when using lower resolution cameras. The findings suggest that the past 30 years of research on dopamine receptor availability, for which very few studies use PVC, may overestimate effects of aging on dopamine receptor availability.
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  • The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum.
    Translational psychiatry (2017)
    Smith CT, Dang LC, Buckholtz JW, Tetreault AM, Cowan RL, Kessler RM, Zald DH. The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry. 2017 Apr 11; 7(4):e1091.
    Abstract: Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BP), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BP (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BP of the high-affinity D2 receptor tracer F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BP bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BP in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.
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  • Reduced effects of age on dopamine D2 receptor levels in physically active adults.
    NeuroImage (2017)
    Dang LC, Castrellon JJ, Perkins SF, Le NT, Cowan RL, Zald DH, Samanez-Larkin GR. Reduced effects of age on dopamine D2 receptor levels in physically active adults. Neuroimage. 2017 Mar 1; 148:123-129.
    Abstract: Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.
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  • Adult age differences in decision making across domains: Increased discounting of social and health-related rewards.
    Psychology and aging (2016)
    Seaman KL, Gorlick MA, Vekaria KM, Hsu M, Zald DH, Samanez-Larkin GR. Adult age differences in decision making across domains: Increased discounting of social and health-related rewards. Psychol Aging. 2016 Nov; 31(7):737-746.
    Abstract: Although research on aging and decision making continues to grow, the majority of studies examine decisions made to maximize monetary earnings or points. It is not clear whether these results generalize to other types of rewards. To investigate this, we examined adult age differences in 92 healthy participants aged 22 to 83. Participants completed 9 hypothetical discounting tasks, which included 3 types of discounting factors (time, probability, effort) across 3 reward domains (monetary, social, health). Participants made choices between a smaller magnitude reward with a shorter time delay/higher probability/lower level of physical effort required and a larger magnitude reward with a longer time delay/lower probability/higher level of physical effort required. Older compared with younger individuals were more likely to choose options that involved shorter time delays or higher probabilities of experiencing an interaction with a close social partner or receiving health benefits from a hypothetical drug. These findings suggest that older adults may be more motivated than young adults to obtain social and health rewards immediately and with certainty. (PsycINFO Database Record
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Short title: CRC Narratives - Internet Full title: Evaluating Strategies to Present Colon Cancer Screening Information on the Internet
Washington University in St. Louis
  • Improving Adherence to Colorectal Cancer Screening: A Randomized Intervention to Compare Screener vs. Survivor Narratives.
    Journal of health communication (2019)
    McQueen A, Caburnay C, Kreuter M, Sefko J. Improving Adherence to Colorectal Cancer Screening: A Randomized Intervention to Compare Screener vs. Survivor Narratives. J Health Commun. 2019; 24(2):141-155.
    Abstract: Interventions are needed to increase colorectal cancer screening (CRCS) uptake. Narratives may have advantages over didactic information. We tested different narratives for increasing CRCS intentions and behaviors, and examined their mechanisms of influence. We randomized 477 unscreened adults 50-75 years old to one of three groups: CRCS information only (1) or CRCS information plus a photo and text narrative of a CRC survivor (2) or CRC screener who did not have cancer (3). Photos were tailored on participants' sex, age group, and race/ethnicity. Participants completed online surveys before and after intervention exposure, and 1-, 6-, and 12-months follow-up. Thirty percent of participants completed CRCS. Narrative conditions (vs. information only) were negatively associated with intention, but also positively influenced intentions through greater emotional engagement. Survivor (vs. screener) narratives were positively associated with CRCS, and had mixed effects on intention - positively through emotional engagement and negatively through self-referencing engagement to self-efficacy. Survivor narratives elicited more negative affect, which had positive and negative influences on intention. Continued research using path models to understand the mechanisms of narrative effects will inform theory development and message design. Additional measurement evaluation is needed to adequately capture and then compare the effects of different components of narrative engagement.
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Identifying children with diabetes type 1 at high risk for cardiovascular disease.
Georgetown University
  • Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case-control study.
    Cardiovascular diabetology (2019)
    Gourgari E, Ma J, Playford MP, Mehta NN, Goldman R, Remaley AT, Gordon SM. Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case-control study. Cardiovasc Diabetol. 2019 Mar 28; 18(1):43.
    Abstract: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.
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  • Low cholesterol efflux capacity and abnormal lipoprotein particles in youth with type 1 diabetes: a case control study.
    Cardiovascular diabetology (2018)
    Gourgari E, Playford MP, Campia U, Dey AK, Cogen F, Gubb-Weiser S, Mete M, Desale S, Sampson M, Taylor A, Rother KI, Remaley AT, Mehta NN. Low cholesterol efflux capacity and abnormal lipoprotein particles in youth with type 1 diabetes: a case control study. Cardiovasc Diabetol. 2018 Dec 19; 17(1):158.
    Abstract: Patients with type 1 diabetes (T1DM) have increased mortality from cardiovascular disease (CVD). Risk factors for CVD include an elevation of LDL (LDLp) and small HDL (sHDLp) particles, and a decrease in reverse cholesterol transport i.e. HDL-cholesterol efflux capacity (CEC). Our objective was to compare lipoprotein particles and CEC between T1DM and healthy controls (HC) and to explore the associations between NMR lipid particles and cholesterol efflux.
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Affect and Reward in Autism Spectrum Disorder and Depression
Vanderbilt University Medical Center
  • Social and nonsocial reward moderate the relation between autism symptoms and loneliness in adults with ASD, depression, and controls.
    Autism research : official journal of the International Society for Autism Research (2019)
    Han GT, Tomarken AJ, Gotham KO. Social and nonsocial reward moderate the relation between autism symptoms and loneliness in adults with ASD, depression, and controls. Autism Res. 2019 Jun; 12(6):884-896.
    Abstract: Individuals with autism spectrum disorder (ASD) report high levels of co-occurring mood disorders. Previous work suggests that people with ASD also experience aberrant responses to social reward compared to typically developing (TD) peers. In the TD population, aberrant reward processing has been linked to anhedonia (i.e., loss of pleasure), which is a hallmark feature of depression. This study examined the interplay between self-reported pleasure from social and nonsocial rewards, autism symptom severity, loneliness, and depressive symptoms across adults with autism spectrum disorder (ASD; N = 49), TD currently depressed adults (TD-dep; N = 30), and TD never depressed controls (TD-con; N = 28). The ASD cohort reported levels of social and nonsocial anhedonia that were greater than TD-con but not significantly different from TD-dep. Across cohorts, both social and nonsocial hedonic capacity moderated the relationship between autism symptoms and loneliness: individuals with low capacity for pleasure experienced elevated loneliness regardless of autism symptom severity, while those with intact capacity for pleasure (i.e., less anhedonia) experienced greater loneliness as a function of increased autism symptoms. Loneliness was the strongest predictor of depressive symptoms across clinical cohorts. Our findings suggest a putative pathway from trait-like anhedonia in ASD to depression via elevated loneliness and indicate that variability in hedonic capacity within the autism spectrum may differentially confer risk for depression in adults with ASD. Results underscore potential mental health benefits of social skills interventions and community inclusion programs for adults with ASD. Autism Res 2019, 12: 884-896. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The relationship between autism symptoms and loneliness depended on one's ability to experience both social and nonsocial pleasure. Adults who experienced less pleasure reported high levels of loneliness that did not depend autism severity, while adults with high capacity for pleasure were especially lonely if they also had many autism symptoms. Loneliness was the strongest predictor of depressive symptoms, compared to capacity for social and nonsocial pleasure and autism symptoms.
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  • Pupil response to social-emotional material is associated with rumination and depressive symptoms in adults with autism spectrum disorder.
    PloS one (2018)
    Gotham KO, Siegle GJ, Han GT, Tomarken AJ, Crist RN, Simon DM, Bodfish JW. Pupil response to social-emotional material is associated with rumination and depressive symptoms in adults with autism spectrum disorder. PLoS One. 2018; 13(8):e0200340.
    Abstract: Autism spectrum disorder (ASD) is marked by repetitive thinking and high rates of depression. Understanding the extent to which repetitive negative thinking in ASD reflects autistic stereotypy versus general depressive thinking patterns (e.g., rumination) could help guide treatment research to improve emotional health in ASD. We compared associations between rumination, depressive symptoms, and pupil response to social-emotional material in adults with ASD and typically developing (TD) adults with and without depression.
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  • Adults with Autism and Adults with Depression Show Similar Attentional Biases to Social-Affective Images.
    Journal of autism and developmental disorders (2020)
    Unruh KE, Bodfish JW, Gotham KO. Adults with Autism and Adults with Depression Show Similar Attentional Biases to Social-Affective Images. J Autism Dev Disord. 2020 Jul; 50(7):2336-2347.
    Abstract: Individuals with ASD have increased rates of depression compared to the general population. Repetitive cognition is a core feature of ASD; in typically developing adults, repetitive cognition has been associated with attentional biases to negative emotional material and increased prospective depression risk. We compared adults with ASD to typically developing adults with depression and never-depressed controls, using a paired preference paradigm sensitive to affective biases in the context of repetitive cognition. Both clinical cohorts oriented faster to negative social-emotional material and spent less time overall on positive material, compared to healthy controls. Exploratory analyses within ASD revealed specific influences of repetitive behavior on patterns of affective bias. Findings help pinpoint susceptibilities in ASD that may confer increased risk for depression.
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Community Review Board
Vanderbilt University Medical Center
  • Enhancing translational researchers' ability to collaborate with community stakeholders: Lessons from the Community Engagement Studio.
    Journal of clinical and translational science (2018)
    Joosten YA, Israel TL, Head A, Vaughn Y, Villalta Gil V, Mouton C, Wilkins CH. Enhancing translational researchers' ability to collaborate with community stakeholders: Lessons from the Community Engagement Studio. J Clin Transl Sci. 2018 Aug; 2(4):201-207.
    Abstract: Community engagement is considered essential to effectively translate research into practice and is increasingly recognized as a key to successful clinical trial recruitment. Challenges to engaging community stakeholders in research persist and new methods are needed to facilitate meaningful stakeholder involvement. The Community Engagement Studio (CE Studio), a consultative model, has been used at every stage of the research process. Best practices drawn from the model could inform other methods of engagement. Using a mixed-methods approach that included evaluation surveys, impact surveys and interviews, we assessed the CE Studio program. We analyzed data from 75 CE Studios; 65 researchers and 591 community members completed surveys and 10 researchers completed interviews. Surveys indicate that 100% of researchers would request a CE Studio in the future, and 99.3% of community members would participate in a CE Studio again. We identified 6 practices to enhance community engagement in clinical and translational research: early input, researcher coaching, researcher humility, balancing power, neutral facilitator, and preparation of community stakeholders. These best practices may enhance the quality of existing community engagement approaches and improve the effectiveness of translational researchers' efforts to engage community stakeholders in their work.
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Impression Management and Avoidance
University of Florida
  • Powerful audiences are linked to health information avoidance: Results from two surveys.
    Social science & medicine (1982) (2019)
    Lipsey NP, Shepperd JA. Powerful audiences are linked to health information avoidance: Results from two surveys. Soc Sci Med. 2019 Mar; 225:51-59.
    Abstract: We examined the extent to which community members avoid medical information that they may very much want, yet fear that others may use to harm them.
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Markers of Disease Progression in MECP2 Duplication Syndrome
Vanderbilt University Medical Center
  • Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.
    Clinical genetics (2019)
    Peters SU, Fu C, Suter B, Marsh E, Benke TA, Skinner SA, Lieberman DN, Standridge S, Jones M, Beisang A, Feyma T, Heydeman P, Ryther R, Kaufmann WE, Glaze DG, Neul JL, Percy AK. Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome. Clin Genet. 2019 May; 95(5):575-581.
    Abstract: Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.
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Cognitive and Behavioral Effects of Sleep Restriction in Adolescents With ADHD
Cincinnati Children's Hospital Medical Center
  • Shortened Sleep Duration Causes Sleepiness, Inattention, and Oppositionality in Adolescents With Attention-Deficit/Hyperactivity Disorder: Findings From a Crossover Sleep Restriction/Extension Study.
    Journal of the American Academy of Child and Adolescent Psychiatry (2019)
    Becker SP, Epstein JN, Tamm L, Tilford AA, Tischner CM, Isaacson PA, Simon JO, Beebe DW. Shortened Sleep Duration Causes Sleepiness, Inattention, and Oppositionality in Adolescents With Attention-Deficit/Hyperactivity Disorder: Findings From a Crossover Sleep Restriction/Extension Study. J Am Acad Child Adolesc Psychiatry. 2019 Apr; 58(4):433-442.
    Abstract: Although poor sleep is often reported in adolescents with attention-deficit/hyperactivity disorder (ADHD), prior studies have been correlational. This study investigated whether sleep duration is causally linked to sleepiness, inattention, and behavioral functioning in adolescents with ADHD.
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Cortical Associates of Speech-in-Noise Perception from Childhood to Adulthood
Vanderbilt University Medical Center
  • Effect of competing noise on cortical auditory evoked potentials elicited by speech sounds in 7- to 25-year-old listeners.
    Hearing research (2019)
    Gustafson SJ, Billings CJ, Hornsby BWY, Key AP. Effect of competing noise on cortical auditory evoked potentials elicited by speech sounds in 7- to 25-year-old listeners. Hear Res. 2019 Mar 1; 373:103-112.
    Abstract: Child listeners have particular difficulty with speech perception when competing speech noise is present; this challenge is often attributed to their immature top-down processing abilities. The purpose of this study was to determine if the effects of competing speech noise on speech-sound processing vary with age. Cortical auditory evoked potentials (CAEPs) were measured during an active speech-syllable discrimination task in 58 normal-hearing participants (age 7-25 years). Speech syllables were presented in quiet and embedded in competing speech noise (4-talker babble, +15 dB signal-to-noise ratio; SNR). While noise was expected to similarly reduce amplitude and delay latencies of N1 and P2 peaks in all listeners, it was hypothesized that effects of noise on the P3b peak would be inversely related to age due to the maturation of top-down processing abilities throughout childhood. Consistent with previous work, results showed that a +15 dB SNR reduces amplitudes and delays latencies of CAEPs for listeners of all ages, affecting speech-sound processing, delaying stimulus evaluation, and causing a reduction in behavioral speech-sound discrimination. Contrary to expectations, findings suggest that competing speech noise at a +15 dB SNR may have similar effects on various stages of speech-sound processing for listeners of all ages. Future research directions should examine how more difficult listening conditions (poorer SNRs) might affect results across ages.
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The Placenta Project
Vanderbilt University Medical Center
  • The PathLink Acquired Gestational Tissue Bank: Feasibility of Project PLACENTA.
    Journal of reproductive biotechnology & fertility (2018)
    Linder JE, Batey K, Johnston R, Cohen EM, Wang Y, Wang X, Zaleski NM, Rogers LM, McDonald WH, Reyzer ML, Judd A, Goldstein J, Correa H, Pulley J, Aronoff DM. The PathLink Acquired Gestational Tissue Bank: Feasibility of Project PLACENTA. J Reprod Biotechnol Fertil. 2018; 7:14-27.
    Abstract: The Vanderbilt Institute for Clinical and Translational Research piloted the development of Project PLACENTA (PathLink Acquired gEstatioNal Tissue bAnk). This project investigated the feasibility of a fresh gestational tissue biobank, which provides tissue linked to electronic medical records for investigators interested in maternal-fetal health.
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Effect of breaking up prolonged sitting on metabolic flexibility
University of Colorado Denver
  • Effect of frequent interruptions of sedentary time on nutrient metabolism in sedentary overweight male and female adults.
    Journal of applied physiology (Bethesda, Md. : 1985) (2019)
    De Jong NP, Rynders CA, Goldstrohm DA, Pan Z, Lange AH, Mendez C, Melanson EL, Bessesen DH, Bergouignan A. Effect of frequent interruptions of sedentary time on nutrient metabolism in sedentary overweight male and female adults. J Appl Physiol (1985). 2019 Apr 1; 126(4):984-992.
    Abstract: This study compared 24-h nutrient oxidation responses between a sedentary condition (SED) and a condition in which short 5-min bouts of moderate-intensity physical activity were performed hourly for nine consecutive hours over 4 days (MICRO). To determine whether any shifts in fuel use were due solely to increases in energy expenditure, we also studied a condition consisting of a single isoenergetic 45-min bout of moderate-intensity exercise (ONE). Twenty sedentary overweight or obese adults (10 men/10 women; 32.4 ± 6.3 yr; BMI, 30.6 ± 2.9 kg/m) completed all three conditions (MICRO, SED, and ONE) in a randomized order. Each condition consisted of a 3-day free-living run-in followed by a 24-h stay in a whole-room calorimeter to measure total energy expenditure (TEE) and substrate utilization. Dietary fat oxidation was also assessed during the chamber stay by administering a [1-C] oleic acid tracer at breakfast. Energy intake was matched across conditions. Both MICRO and ONE increased TEE relative to SED, resulting in a negative energy balance. HOMA-IR improved in both activity conditions. MICRO increased 24-h carbohydrate oxidation compared with both ONE and SED ( P < 0.01 for both). ONE was associated with higher 24-h total fat oxidation compared with SED, and higher 24-h dietary fat oxidation compared with both SED and MICRO. Differences in substrate oxidation remained significant after adjusting for energy balance. In overweight and obese men and women, breaking up sitting time increased reliance upon carbohydrate as fuel over 24 h, while a single energy-matched continuous bout of exercise preferentially relies upon fat over 24 h. NEW & NOTEWORTHY Insulin sensitivity, as assessed by HOMA-IR, was improved after 4 days of physical activity, independent of frequency and duration of activity bouts. Temporal patterns of activity across the day differentially affect substrate oxidation. Frequent interruptions of sedentary time with short bouts of walking primarily increase 24-h carbohydrate oxidation, whereas an energy-matched single continuous bout of moderate intensity walking primarily increased 24-h fat oxidation.
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The Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism
Vanderbilt University Medical Center
  • Human PAH is characterized by a pattern of lipid-related insulin resistance.
    JCI insight (2019)
    Hemnes AR, Luther JM, Rhodes CJ, Burgess JP, Carlson J, Fan R, Fessel JP, Fortune N, Gerszten RE, Halliday SJ, Hekmat R, Howard L, Newman JH, Niswender KD, Pugh ME, Robbins IM, Sheng Q, Shibao CA, Shyr Y, Sumner S, Talati M, Wharton J, Wilkins MR, Ye F, Y. Human PAH is characterized by a pattern of lipid-related insulin resistance. JCI Insight. 2019 Jan 10; 4(1):.
    Abstract: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH.
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  • Hyperglycemic clamp-derived disposition index is negatively associated with metabolic syndrome severity in obese subjects.
    Metabolism: clinical and experimental (2016)
    Shah SS, Ramirez CE, Powers AC, Yu C, Shibao CA, Luther JM. Hyperglycemic clamp-derived disposition index is negatively associated with metabolic syndrome severity in obese subjects. Metabolism. 2016 Jun; 65(6):835-42.
    Abstract: Metabolic syndrome is associated with insulin resistance and increased future risk of type 2 diabetes. This study investigates the relationship between insulin secretion, insulin resistance and individual metabolic syndrome components in subjects without a prior diagnosis of diabetes.
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A PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF CARIPRAZINE AS ADJUNCTIVE THERAPY IN MAJOR DEPRESSIVE DISORDER
The Ohio State University
  • Cariprazine Augmentation to Antidepressant Therapy in Major Depressive Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Trial.
    Psychopharmacology bulletin (2018)
    Earley WR, Guo H, Németh G, Harsányi J, Thase ME. Cariprazine Augmentation to Antidepressant Therapy in Major Depressive Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Trial. Psychopharmacol Bull. 2018 Jun 20; 48(4):62-80.
    Abstract: Cariprazine is an atypical antipsychotic currently under investigation as an adjunctive to antidepressant treatment (ADT) for patients with major depressive disorder (MDD). Here results of an 18- to 19-week randomized double-blind placebo-controlled Phase 3 study evaluating the efficacy of adjunctive cariprazine (1.5-4.5 mg/day[d]) with ADT in participants with previous inadequate response to ADT are presented. ADT response was assessed in an 8-week open-label period; inadequate responders were randomized (N = 530) to open-label ADT plus placebo (n = 261) or cariprazine (n = 269) for the 8-week double-blind phase (NCT01715805). Primary and secondary endpoints were changes at week 8 (cariprazine versus placebo) in Montgomery-Åsberg Depression Rating Scale (MADRS) total score and in Sheehan Disability Scale (SDS) score, respectively, which were analyzed by mixed-effect models for repeated measures. Cariprazine did not significantly improve scores in either compared to placebo, but non-significantly reduced depressive symptoms (MADRS least-squares mean difference [LSMD]: -0.2, P = 0.7948 and SDS LSMD: -0.7, P = 0.2784). Of additional efficacy parameters, cariprazine significantly improved Clinical Global Impressions - Improvement (CGI-I) scores versus placebo (LSMD: -0.2; P = 0.0410). A greater proportion of participants achieved MADRS response with cariprazine vs placebo, but differences were not significant. Cariprazine was generally well-tolerated, and metabolic parameters and body weight changes were not meaningfully different than placebo. Common newly-emergent adverse events included akathisia and restlessness. The lack of significant improvement in depressive symptoms with adjunctive cariprazine and ADT for MDD in inadequate responders contrasts with previously published results, therefore additional studies are needed to understand role of adjunctive cariprazine in MDD.
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Differentiating Unipolar and Bipolar Depression in Young Adults Using fMRI
Cleveland Clinic
  • Sub-threshold bipolar disorder in medication-free young subjects with major depression: Clinical characteristics and antidepressant treatment response.
    Journal of psychiatric research (2019)
    Koirala P, Hu B, Altinay M, Li M, DiVita AL, Bryant KA, Karne HS, Fiedorowicz JG, Anand A. Sub-threshold bipolar disorder in medication-free young subjects with major depression: Clinical characteristics and antidepressant treatment response. J Psychiatr Res. 2019 Mar; 110:1-8.
    Abstract: This study, for the first time, compared illness and antidepressant response characteristics of young subjects with major depression (MDD) at low (LRMDD) or high-risk (HRMDD) for developing bipolar disorder with characteristics of young bipolar (BPD) subjects and healthy controls (HC).
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Impression Management and Avoidance
University of Florida
  • The role of powerful audiences in health information avoidance.
    Social science & medicine (1982) (2019)
    Lipsey NP, Shepperd JA. The role of powerful audiences in health information avoidance. Soc Sci Med. 2019 Jan; 220:430-439.
    Abstract: Although people may want to learn information, concerns about how audiences (persons or entities privy to one's behavior or information) might respond may motivate people to avoid information that audiences could use to threaten resources or harm them.
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Measurement of Six-Minute Walk Distance in Healthy Young Adults
Vanderbilt University Medical Center
  • Reduced free-living activity levels in pulmonary arterial hypertension patients.
    Pulmonary circulation (2019)
    Halliday SJ, Shi H, Brittain EL, Hemnes AR. Reduced free-living activity levels in pulmonary arterial hypertension patients. Pulm Circ. 2019 Jan-Mar; 9(1):2045894018814182.
    Abstract: We conducted a survey of pulmonary arterial hypertension (PAH) patients and healthy controls who use either a smartphone or wearable fitness device that tracks daily step count. We found that PAH patients have markedly reduced activity levels compared to controls, after controlling for confounders.
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Frontal Hypoperfusion Effects on Antidepressant Outcomes in Late-Life Depression
Vanderbilt University Medical Center
  • Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression.
    Biological psychiatry. Cognitive neuroscience and neuroimaging (2019)
    Gandelman JA, Albert K, Boyd BD, Park JW, Riddle M, Woodward ND, Kang H, Landman BA, Taylor WD. Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Feb; 4(2):160-170.
    Abstract: Late-life depression (LLD) has been associated with alterations in intrinsic functional networks, best characterized in the default mode network (DMN), cognitive control network (CCN), and salience network. However, these findings often derive from small samples, and it is not well understood how network findings relate to clinical and cognitive symptomatology.
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  • Medial temporal lobe volumes in late-life depression: effects of age and vascular risk factors.
    Brain imaging and behavior (2020)
    Taylor WD, Deng Y, Boyd BD, Donahue MJ, Albert K, McHugo M, Gandelman JA, Landman BA. Medial temporal lobe volumes in late-life depression: effects of age and vascular risk factors. Brain Imaging Behav. 2020 Feb; 14(1):19-29.
    Abstract: Substantial work associates late-life depression with hippocampal pathology. However, there is less information about differences in hippocampal subfields and other connected temporal lobe regions and how these regions may be influenced by vascular factors. Individuals aged 60 years or older with and without a DSM-IV diagnosis of Major Depressive Disorder completed clinical assessments and 3 T cranial MRI using a protocol allowing for automated measurement of medial temporal lobe subfield volumes. A subset also completed pseudo-continuous arterial spin labeling, allowing for the measurement of hippocampal cerebral blood flow. In 59 depressed and 21 never-depressed elders (mean age = 66.4 years, SD = 5.8y, range 60-86y), the depressed group did not exhibit statistically significant volumetric differences for the total hippocampus or hippocampal subfields but did exhibit significantly smaller volumes of the perirhinal cortex, specifically in the BA36 region. Additionally, age had a greater effect in the depressed group on volumes of the cornu ammonis, entorhinal cortex, and BA36 region. Finally, both clinical and radiological markers of vascular risk were associated with smaller BA36 volumes, while reduced hippocampal blood flow was associated with smaller hippocampal and cornu ammonis volumes. In conclusion, while we did not observe group differences in hippocampal regions, we observed group differences and an effect of vascular pathology on the BA36 region, part of the perirhinal cortex. This is a critical region exhibiting atrophy in prodromal Alzheimer's disease. Moreover, the observed greater effect of age in the depressed groups is concordant with past longitudinal studies reporting greater hippocampal atrophy in late-life depression.
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  • Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression.
    Journal of psychiatric research (2018)
    Abi Zeid Daou M, Boyd BD, Donahue MJ, Albert K, Taylor WD. Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression. J Psychiatr Res. 2018 Feb; 97:1-7.
    Abstract: Vascular pathology is common in late-life depression, contributing to changes in cerebral function. We examined whether late-life depression was associated with differences in cerebral blood flow (CBF) and whether such differences were related to vascular risk and cerebrovascular pathology, specifically white matter hyperintensity (WMH) volumes. Twenty-three depressed elders and 20 age- and sex-matched elders with no psychiatric history completed cranial 3T MRI. MRI procedures included a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition obtained while on room air and during a hypercapnia challenge allowing for calculation of cerebrovascular reactivity (CVR). Brain segmentation identified frontal, temporal, parietal and cingulate sub-regions in which CBF and CVR were calculated. The depressed group exhibited an anterior-posterior gradient in CBF, with lower CBF throughout the frontal lobe but higher CBF in the parietal lobe, temporal lobe, thalamus and hippocampus. A similar anterior to posterior gradient was observed in the cingulate cortex, with anterior regions exhibiting lower CBF and posterior regions exhibiting higher CBF. We did not observe any group differences in CVR measures. We did not observe significant relationships between CBF and CVR with vascular risk or WMH volumes, aside from an isolated finding associating higher WMH volumes with lower CBF in the rostral anterior cingulate cortex. Decreased anterior CBF in depressed elders might reflect decreased metabolic activity in these regions, while increased posterior CBF may represent either compensatory processes or different activity of posterior intrinsic functional networks. Future work should examine how these findings are related to compensatory changes with aging.
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  • Longitudinal Cognitive Outcomes of Clinical Phenotypes of Late-Life Depression.
    The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (2017)
    Riddle M, Potter GG, McQuoid DR, Steffens DC, Beyer JL, Taylor WD. Longitudinal Cognitive Outcomes of Clinical Phenotypes of Late-Life Depression. Am J Geriatr Psychiatry. 2017 Oct; 25(10):1123-1134.
    Abstract: Late-life depression is associated with cognitive deficits and increased risk for cognitive decline. The purpose of the study was to determine whether clinical characteristics could serve as phenotypes informative of subsequent cognitive decline. Age at depression onset and antidepressant remission at 3 months (acute response) and 12 months (chronic response) were examined.
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  • Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
    Journal of affective disorders (2017)
    Abi Zeid Daou M, Boyd BD, Donahue MJ, Albert K, Taylor WD. Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression. J Affect Disord. 2017 Jun; 215:103-110.
    Abstract: Vascular pathology is common in late-life depression (LLD) and may contribute to alterations in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). In turn, such hemodynamic deficits may adversely affect brain function and clinical course. The goal of this study was to examine whether altered cerebral hemodynamics in depressed elders predicted antidepressant response.
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Depressed Mood Improvement through Nicotine Dosing
Vanderbilt University Medical Center
  • Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression.
    Biological psychiatry. Cognitive neuroscience and neuroimaging (2019)
    Gandelman JA, Albert K, Boyd BD, Park JW, Riddle M, Woodward ND, Kang H, Landman BA, Taylor WD. Intrinsic Functional Network Connectivity Is Associated With Clinical Symptoms and Cognition in Late-Life Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Feb; 4(2):160-170.
    Abstract: Late-life depression (LLD) has been associated with alterations in intrinsic functional networks, best characterized in the default mode network (DMN), cognitive control network (CCN), and salience network. However, these findings often derive from small samples, and it is not well understood how network findings relate to clinical and cognitive symptomatology.
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  • Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Nonsmokers With Late-Life Depression.
    The Journal of clinical psychiatry (2018)
    Gandelman JA, Kang H, Antal A, Albert K, Boyd BD, Conley AC, Newhouse P, Taylor WD. Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Nonsmokers With Late-Life Depression. J Clin Psychiatry. 2018 Aug 28; 79(5):.
    Abstract: Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD.
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Validation of a lymphedema symptom intensity and distress scale for lower limb lymphedema (LSIDS-L)
Vanderbilt University Medical Center
  • Development and Validation of the Lymphedema Symptom Intensity and Distress Survey-Lower Limb.
    Lymphatic research and biology (2018)
    Ridner SH, Doersam JK, Stolldorf DP, Dietrich MS. Development and Validation of the Lymphedema Symptom Intensity and Distress Survey-Lower Limb. Lymphat Res Biol. 2018 Dec; 16(6):538-546.
    Abstract: Lymphedema is a chronic, incurable condition that occurs most commonly in lower limbs (legs and feet). Increased morbidity is seen with this form of lymphedema, but there are few studies and even fewer tools intended to assess symptom burden in patients impacted by this condition. A questionnaire, the Lymphedema Symptom Intensity and Distress Survey-Lower Limb (LSIDS-L), was developed to fill this gap. The measure is composed of several clusters of symptoms thought to characterize lower limb lymphedema. The initial work was conducted to propose and assess the face validity of the clusters. Subsequently, work was undertaken to empirically evaluate the presence of the symptom clusters, assess the reliability of the cluster scores, and evaluate the validity of the scores by studying associations with other valid measures.
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Neuromodulation of Decision Making in Young and Middle-Aged Adults"
Vanderbilt University Medical Center
  • Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET.
    Psychopharmacology (2019)
    Smith CT, Dang LC, Burgess LL, Perkins SF, San Juan MD, Smith DK, Cowan RL, Le NT, Kessler RM, Samanez-Larkin GR, Zald DH. Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET. Psychopharmacology (Berl). 2019 Feb; 236(2):581-590.
    Abstract: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed.
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  • Spontaneous Eye Blink Rate (EBR) Is Uncorrelated with Dopamine D2 Receptor Availability and Unmodulated by Dopamine Agonism in Healthy Adults.
    eNeuro (2017)
    Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Newhouse PA, Zald DH. Spontaneous Eye Blink Rate (EBR) Is Uncorrelated with Dopamine D2 Receptor Availability and Unmodulated by Dopamine Agonism in Healthy Adults. eNeuro. 2017 Sep-Oct; 4(5):.
    Abstract: Spontaneous eye blink rate (EBR) has been proposed as a noninvasive, inexpensive marker of dopamine functioning. Support for a relation between EBR and dopamine function comes from observations that EBR is altered in populations with dopamine dysfunction and EBR changes under a dopaminergic manipulation. However, the evidence across the literature is inconsistent and incomplete. A direct correlation between EBR and dopamine function has so far been observed only in nonhuman animals. Given significant interest in using EBR as a proxy for dopamine function, this study aimed to verify a direct association in healthy, human adults. Here we measured EBR in healthy human subjects whose dopamine D2 receptor (DRD2) availability was assessed with positron emission tomography (PET)-[18F]fallypride to examine the predictive power of EBR for DRD2 availability. Effects of the dopamine agonist bromocriptine on EBR also were examined to determine the responsiveness of EBR to dopaminergic stimulation and, in light of the hypothesized inverted-U profile of dopamine effects, the role of DRD2 availability in EBR responsivity to bromocriptine. Results from 20 subjects (age 33.6 ± 7.6 years, 9F) showed no relation between EBR and DRD2 availability. EBR also was not responsive to dopaminergic stimulation by bromocriptine, and individual differences in DRD2 availability did not modulate EBR responsivity to bromocriptine. Given that EBR is hypothesized to be particularly sensitive to DRD2 function, these findings suggest caution in using EBR as a proxy for dopamine function in healthy humans.
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  • The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum.
    Translational psychiatry (2017)
    Smith CT, Dang LC, Buckholtz JW, Tetreault AM, Cowan RL, Kessler RM, Zald DH. The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry. 2017 Apr 11; 7(4):e1091.
    Abstract: Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BP), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BP (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BP of the high-affinity D2 receptor tracer F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BP bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BP in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.
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CDRN Healthy Weight Cohort
Vanderbilt University Medical Center
  • Body mass index and health-related quality of life.
    Obesity science & practice (2018)
    Apple R, Samuels LR, Fonnesbeck C, Schlundt D, Mulvaney S, Hargreaves M, Crenshaw D, Wallston KA, Heerman WJ. Body mass index and health-related quality of life. Obes Sci Pract. 2018 Oct; 4(5):417-426.
    Abstract: There are conflicting data regarding the association between body mass index (BMI) and health-related quality of life (HRQoL), especially among certain population subgroups and for mental and physical health domains.
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  • Recruitment methods for survey research: Findings from the Mid-South Clinical Data Research Network.
    Contemporary clinical trials (2017)
    Heerman WJ, Jackson N, Roumie CL, Harris PA, Rosenbloom ST, Pulley J, Wilkins CH, Williams NA, Crenshaw D, Leak C, Scherdin J, Muñoz D, Bachmann J, Rothman RL, Kripalani S. Recruitment methods for survey research: Findings from the Mid-South Clinical Data Research Network. Contemp Clin Trials. 2017 Nov; 62:50-55.
    Abstract: The objective of this study was to report survey response rates and demographic characteristics of eight recruitment approaches to determine acceptability and effectiveness of large-scale patient recruitment among various populations.
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  • Clusters of Healthy and Unhealthy Eating Behaviors Are Associated With Body Mass Index Among Adults.
    Journal of nutrition education and behavior (2017)
    Heerman WJ, Jackson N, Hargreaves M, Mulvaney SA, Schlundt D, Wallston KA, Rothman RL. Clusters of Healthy and Unhealthy Eating Behaviors Are Associated With Body Mass Index Among Adults. J Nutr Educ Behav. 2017 May; 49(5):415-421.e1.
    Abstract: To identify eating styles from 6 eating behaviors and test their association with body mass index (BMI) among adults.
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Sleep, Cognition, and Emotion
Vanderbilt University Medical Center
  • Time of day effects on the relationship between daily sleep and anxiety: An ecological momentary assessment approach.
    Behaviour research and therapy (2018)
    Cox RC, Sterba SK, Cole DA, Upender RP, Olatunji BO. Time of day effects on the relationship between daily sleep and anxiety: An ecological momentary assessment approach. Behav Res Ther. 2018 Dec; 111:44-51.
    Abstract: Previous research has linked sleep disturbance to anxiety. However, evidence for this relation has been inconsistent, largely limited to retrospective reports that do not account for daily variability, and silent on when the association is most pronounced. Thus, the present study utilized ecological momentary assessment (EMA) to examine the effects of daily deviations in total sleep time (TST) and person-average TST on anxiety and whether these effects varied as a function of time of day in a sample of unselected adults (N = 138). Results indicate that the amount of TST on a given night, relative to personal average TST, negatively predicted anxiety, and this relation was significant in the morning and afternoon, but not evening. In contrast, person-average TST was unrelated to average anxiety. Relations between TST and anxiety did not differ across objective (e.g., actigraphy) and subjective (e.g., sleep diary) measures. Furthermore, the pattern of results remained the same when controlling for previous day's anxiety and were not bidirectional. These findings suggest that getting less sleep than is typical for the individual predicts subsequent anxiety, and this effect is particularly strong in the morning. Average sleep duration may be less important to the experience of anxiety than deviations from that average. These findings highlight the importance of EMA to examine how and when variability in sleep confers vulnerability for anxiety symptoms.
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ANGI: Anorexia Nervosa Genetics Initiative
University of North Carolina at Chapel Hill
  • The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.
    Contemporary clinical trials (2018)
    Thornton LM, Munn-Chernoff MA, Baker JH, Juréus A, Parker R, Henders AK, Larsen JT, Petersen L, Watson HJ, Yilmaz Z, Kirk KM, Gordon S, Leppä VM, Martin FC, Whiteman DC, Olsen CM, Werge TM, Pedersen NL, Kaye W, Bergen AW, Halmi KA, Strober M, Kaplan AS, W. The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods. Contemp Clin Trials. 2018 Nov; 74:61-69.
    Abstract: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.
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Bridging sensory function to core ASD symptoms
Vanderbilt University Medical Center
  • Audiovisual multisensory integration in individuals with autism spectrum disorder: A systematic review and meta-analysis.
    Neuroscience and biobehavioral reviews (2018)
    Feldman JI, Dunham K, Cassidy M, Wallace MT, Liu Y, Woynaroski TG. Audiovisual multisensory integration in individuals with autism spectrum disorder: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2018 Dec; 95:220-234.
    Abstract: An ever-growing literature has aimed to determine how individuals with autism spectrum disorder (ASD) differ from their typically developing (TD) peers on measures of multisensory integration (MSI) and to ascertain the degree to which differences in MSI are associated with the broad range of symptoms associated with ASD. Findings, however, have been highly variable across the studies carried out to date. The present work systematically reviews and quantitatively synthesizes the large literature on audiovisual MSI in individuals with ASD to evaluate the cumulative evidence for (a) group differences between individuals with ASD and TD peers, (b) correlations between MSI and autism symptoms in individuals with ASD and (c) study level factors that may moderate findings (i.e., explain differential effects) observed across studies. To identify eligible studies, a comprehensive search strategy was employed using the ProQuest search engine, PubMed database, forwards and backwards citation searches, direct author contact, and hand-searching of select conference proceedings. A significant between-group difference in MSI was evident in the literature, with individuals with ASD demonstrating worse audiovisual integration on average across studies compared to TD controls. This effect was moderated by mean participant age, such that between-group differences were more pronounced in younger samples. The mean correlation between MSI and autism and related symptomatology was also significant, indicating that increased audiovisual integration in individuals with ASD is associated with better language/communication abilities and/or reduced autism symptom severity in the extant literature. This effect was moderated by whether the stimuli were linguistic versus non-linguistic in nature, such that correlation magnitudes tended to be significantly greater when linguistic stimuli were utilized in the measure of MSI. Limitations and future directions for primary and meta-analytic research are discussed.
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  • Atypical audiovisual temporal function in autism and schizophrenia: similar phenotype, different cause.
    The European journal of neuroscience (2018)
    Noel JP, Stevenson RA, Wallace MT. Atypical audiovisual temporal function in autism and schizophrenia: similar phenotype, different cause. Eur J Neurosci. 2018 May; 47(10):1230-1241.
    Abstract: Binding across sensory modalities yields substantial perceptual benefits, including enhanced speech intelligibility. The coincidence of sensory inputs across time is a fundamental cue for this integration process. Recent work has suggested that individuals with diagnoses of schizophrenia (SZ) and autism spectrum disorder (ASD) will characterize auditory and visual events as synchronous over larger temporal disparities than their neurotypical counterparts. Namely, these clinical populations possess an enlarged temporal binding window (TBW). Although patients with SZ and ASD share aspects of their symptomatology, phenotypic similarities may result from distinct etiologies. To examine similarities and variances in audiovisual temporal function in these two populations, individuals diagnosed with ASD (n = 46; controls n = 40) and SZ (n = 16, controls = 16) completed an audiovisual simultaneity judgment task. In addition to standard psychometric analyses, synchrony judgments were assessed using Bayesian causal inference modeling. This approach permits distinguishing between distinct causes of an enlarged TBW: an a priori bias to bind sensory information and poor fidelity in the sensory representation. Findings indicate that both ASD and SZ populations show deficits in multisensory temporal acuity. Importantly, results suggest that while the wider TBWs in ASD most prominently results from atypical priors, the wider TBWs in SZ results from a trend toward changes in prior and weaknesses in the sensory representations. Results are discussed in light of current ASD and SZ theories and highlight that different perceptual training paradigms focused on improving multisensory integration may be most effective in these two clinical populations and emphasize that similar phenotypes may emanate from distinct mechanistic causes.
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  • Disrupted integration of exteroceptive and interoceptive signaling in autism spectrum disorder.
    Autism research : official journal of the International Society for Autism Research (2018)
    Noel JP, Lytle M, Cascio C, Wallace MT. Disrupted integration of exteroceptive and interoceptive signaling in autism spectrum disorder. Autism Res. 2018 Jan; 11(1):194-205.
    Abstract: In addition to deficits in social communication, individuals diagnosed with Autism Spectrum Disorder (ASD) frequently exhibit changes in sensory and multisensory function. Recent evidence has focused on changes in audiovisual temporal processing, and has sought to relate these sensory-based changes to weaknesses in social communication. These changes in audiovisual temporal function manifest as differences in the temporal epoch or "window" within which paired auditory and visual stimuli are integrated or bound, with those with ASD exhibiting expanded audiovisual temporal binding windows (TBWs). However, it is unknown whether this impairment is unique to audiovisual pairings, perhaps because of their relevance for speech processing, or whether it generalizes across pairings in different sensory modalities. In addition to the exteroceptive senses, there has been growing interest in ASD research in interoception (e.g., the monitoring of respiration, heartbeat, hunger, etc.), as these internally directed sensory processes appear to be altered as well in autism. In the current study, we sought to examine both exteroception and interoception in individuals with ASD and a group of typically developing (TD) matched controls, with an emphasis on temporal perception of audiovisual (exteroceptive) and cardiovisual (interoceptive to exteroceptive) cues. Results replicate prior findings showing expanded audiovisual TBWs in ASD in comparison to TD. In addition, strikingly, cardiovisual TBWs were fourfold larger in ASD than in TD, suggesting a putative complete lack of cardiovisual temporal acuity in ASD individuals. Results are discussed in light of recent evidence indicating a reduced tendency to rely on sensory priors in ASD. Autism Res 2018, 11: 194-205. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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  • Multisensory speech perception in autism spectrum disorder: From phoneme to whole-word perception.
    Autism research : official journal of the International Society for Autism Research (2017)
    Stevenson RA, Baum SH, Segers M, Ferber S, Barense MD, Wallace MT. Multisensory speech perception in autism spectrum disorder: From phoneme to whole-word perception. Autism Res. 2017 Jul; 10(7):1280-1290.
    Abstract: Speech perception in noisy environments is boosted when a listener can see the speaker's mouth and integrate the auditory and visual speech information. Autistic children have a diminished capacity to integrate sensory information across modalities, which contributes to core symptoms of autism, such as impairments in social communication. We investigated the abilities of autistic and typically-developing (TD) children to integrate auditory and visual speech stimuli in various signal-to-noise ratios (SNR). Measurements of both whole-word and phoneme recognition were recorded. At the level of whole-word recognition, autistic children exhibited reduced performance in both the auditory and audiovisual modalities. Importantly, autistic children showed reduced behavioral benefit from multisensory integration with whole-word recognition, specifically at low SNRs. At the level of phoneme recognition, autistic children exhibited reduced performance relative to their TD peers in auditory, visual, and audiovisual modalities. However, and in contrast to their performance at the level of whole-word recognition, both autistic and TD children showed benefits from multisensory integration for phoneme recognition. In accordance with the principle of inverse effectiveness, both groups exhibited greater benefit at low SNRs relative to high SNRs. Thus, while autistic children showed typical multisensory benefits during phoneme recognition, these benefits did not translate to typical multisensory benefit of whole-word recognition in noisy environments. We hypothesize that sensory impairments in autistic children raise the SNR threshold needed to extract meaningful information from a given sensory input, resulting in subsequent failure to exhibit behavioral benefits from additional sensory information at the level of whole-word recognition. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1280-1290. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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  • The associations between multisensory temporal processing and symptoms of schizophrenia.
    Schizophrenia research (2017)
    Stevenson RA, Park S, Cochran C, McIntosh LG, Noel JP, Barense MD, Ferber S, Wallace MT. The associations between multisensory temporal processing and symptoms of schizophrenia. Schizophr Res. 2017 Jan; 179:97-103.
    Abstract: Recent neurobiological accounts of schizophrenia have included an emphasis on changes in sensory processing. These sensory and perceptual deficits can have a cascading effect onto higher-level cognitive processes and clinical symptoms. One form of sensory dysfunction that has been consistently observed in schizophrenia is altered temporal processing. In this study, we investigated temporal processing within and across the auditory and visual modalities in individuals with schizophrenia (SCZ) and age-matched healthy controls. Individuals with SCZ showed auditory and visual temporal processing abnormalities, as well as multisensory temporal processing dysfunction that extended beyond that attributable to unisensory processing dysfunction. Most importantly, these multisensory temporal deficits were associated with the severity of hallucinations. This link between atypical multisensory temporal perception and clinical symptomatology suggests that clinical symptoms of schizophrenia may be at least partly a result of cascading effects from (multi)sensory disturbances. These results are discussed in terms of underlying neural bases and the possible implications for remediation.
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  • Interactions between space and effectiveness in human multisensory performance.
    Neuropsychologia (2016)
    Nidiffer AR, Stevenson RA, Krueger Fister J, Barnett ZP, Wallace MT. Interactions between space and effectiveness in human multisensory performance. Neuropsychologia. 2016 Jul 29; 88:83-91.
    Abstract: Several stimulus factors are important in multisensory integration, including the spatial and temporal relationships of the paired stimuli as well as their effectiveness. Changes in these factors have been shown to dramatically change the nature and magnitude of multisensory interactions. Typically, these factors are considered in isolation, although there is a growing appreciation for the fact that they are likely to be strongly interrelated. Here, we examined interactions between two of these factors - spatial location and effectiveness - in dictating performance in the localization of an audiovisual target. A psychophysical experiment was conducted in which participants reported the perceived location of visual flashes and auditory noise bursts presented alone and in combination. Stimuli were presented at four spatial locations relative to fixation (0°, 30°, 60°, 90°) and at two intensity levels (high, low). Multisensory combinations were always spatially coincident and of the matching intensity (high-high or low-low). In responding to visual stimuli alone, localization accuracy decreased and response times (RTs) increased as stimuli were presented at more eccentric locations. In responding to auditory stimuli, performance was poorest at the 30° and 60° locations. For both visual and auditory stimuli, accuracy was greater and RTs were faster for more intense stimuli. For responses to visual-auditory stimulus combinations, performance enhancements were found at locations in which the unisensory performance was lowest, results concordant with the concept of inverse effectiveness. RTs for these multisensory presentations frequently violated race-model predictions, implying integration of these inputs, and a significant location-by-intensity interaction was observed. Performance gains under multisensory conditions were larger as stimuli were positioned at more peripheral locations, and this increase was most pronounced for the low-intensity conditions. These results provide strong support that the effects of stimulus location and effectiveness on multisensory integration are interdependent, with both contributing to the overall effectiveness of the stimuli in driving the resultant multisensory response.
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  • Deficits in audiovisual speech perception in normal aging emerge at the level of whole-word recognition.
    Neurobiology of aging (2015)
    Stevenson RA, Nelms CE, Baum SH, Zurkovsky L, Barense MD, Newhouse PA, Wallace MT. Deficits in audiovisual speech perception in normal aging emerge at the level of whole-word recognition. Neurobiol Aging. 2015 Jan; 36(1):283-91.
    Abstract: Over the next 2 decades, a dramatic shift in the demographics of society will take place, with a rapid growth in the population of older adults. One of the most common complaints with healthy aging is a decreased ability to successfully perceive speech, particularly in noisy environments. In such noisy environments, the presence of visual speech cues (i.e., lip movements) provide striking benefits for speech perception and comprehension, but previous research suggests that older adults gain less from such audiovisual integration than their younger peers. To determine at what processing level these behavioral differences arise in healthy-aging populations, we administered a speech-in-noise task to younger and older adults. We compared the perceptual benefits of having speech information available in both the auditory and visual modalities and examined both phoneme and whole-word recognition across varying levels of signal-to-noise ratio. For whole-word recognition, older adults relative to younger adults showed greater multisensory gains at intermediate SNRs but reduced benefit at low SNRs. By contrast, at the phoneme level both younger and older adults showed approximately equivalent increases in multisensory gain as signal-to-noise ratio decreased. Collectively, the results provide important insights into both the similarities and differences in how older and younger adults integrate auditory and visual speech cues in noisy environments and help explain some of the conflicting findings in previous studies of multisensory speech perception in healthy aging. These novel findings suggest that audiovisual processing is intact at more elementary levels of speech perception in healthy-aging populations and that deficits begin to emerge only at the more complex word-recognition level of speech signals.
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  • The construct of the multisensory temporal binding window and its dysregulation in developmental disabilities.
    Neuropsychologia (2014)
    Wallace MT, Stevenson RA. The construct of the multisensory temporal binding window and its dysregulation in developmental disabilities. Neuropsychologia. 2014 Nov; 64:105-23.
    Abstract: Behavior, perception and cognition are strongly shaped by the synthesis of information across the different sensory modalities. Such multisensory integration often results in performance and perceptual benefits that reflect the additional information conferred by having cues from multiple senses providing redundant or complementary information. The spatial and temporal relationships of these cues provide powerful statistical information about how these cues should be integrated or "bound" in order to create a unified perceptual representation. Much recent work has examined the temporal factors that are integral in multisensory processing, with many focused on the construct of the multisensory temporal binding window - the epoch of time within which stimuli from different modalities is likely to be integrated and perceptually bound. Emerging evidence suggests that this temporal window is altered in a series of neurodevelopmental disorders, including autism, dyslexia and schizophrenia. In addition to their role in sensory processing, these deficits in multisensory temporal function may play an important role in the perceptual and cognitive weaknesses that characterize these clinical disorders. Within this context, focus on improving the acuity of multisensory temporal function may have important implications for the amelioration of the "higher-order" deficits that serve as the defining features of these disorders.
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  • Evidence for diminished multisensory integration in autism spectrum disorders.
    Journal of autism and developmental disorders (2014)
    Stevenson RA, Siemann JK, Woynaroski TG, Schneider BC, Eberly HE, Camarata SM, Wallace MT. Evidence for diminished multisensory integration in autism spectrum disorders. J Autism Dev Disord. 2014 Dec; 44(12):3161-7.
    Abstract: Individuals with autism spectrum disorders (ASD) exhibit alterations in sensory processing, including changes in the integration of information across the different sensory modalities. In the current study, we used the sound-induced flash illusion to assess multisensory integration in children with ASD and typically-developing (TD) controls. Thirty-one children with ASD and 31 age and IQ matched TD children (average age = 12 years) were presented with simple visual (i.e., flash) and auditory (i.e., beep) stimuli of varying number. In illusory conditions, a single flash was presented with 2-4 beeps. In TD children, these conditions generally result in the perception of multiple flashes, implying a perceptual fusion across vision and audition. In the present study, children with ASD were significantly less likely to perceive the illusion relative to TD controls, suggesting that multisensory integration and cross-modal binding may be weaker in some children with ASD. These results are discussed in the context of previous findings for multisensory integration in ASD and future directions for research.
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  • The impact of multisensory integration deficits on speech perception in children with autism spectrum disorders.
    Frontiers in psychology (2014)
    Stevenson RA, Segers M, Ferber S, Barense MD, Wallace MT. The impact of multisensory integration deficits on speech perception in children with autism spectrum disorders. Front Psychol. 2014; 5:379.
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  • The interaction between stimulus factors and cognitive factors during multisensory integration of audiovisual speech.
    Frontiers in psychology (2014)
    Stevenson RA, Wallace MT, Altieri N. The interaction between stimulus factors and cognitive factors during multisensory integration of audiovisual speech. Front Psychol. 2014; 5:352.
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  • Multisensory temporal integration in autism spectrum disorders.
    The Journal of neuroscience : the official journal of the Society for Neuroscience (2014)
    Stevenson RA, Siemann JK, Schneider BC, Eberly HE, Woynaroski TG, Camarata SM, Wallace MT. Multisensory temporal integration in autism spectrum disorders. J Neurosci. 2014 Jan 15; 34(3):691-7.
    Abstract: The new DSM-5 diagnostic criteria for autism spectrum disorders (ASDs) include sensory disturbances in addition to the well-established language, communication, and social deficits. One sensory disturbance seen in ASD is an impaired ability to integrate multisensory information into a unified percept. This may arise from an underlying impairment in which individuals with ASD have difficulty perceiving the temporal relationship between cross-modal inputs, an important cue for multisensory integration. Such impairments in multisensory processing may cascade into higher-level deficits, impairing day-to-day functioning on tasks, such as speech perception. To investigate multisensory temporal processing deficits in ASD and their links to speech processing, the current study mapped performance on a number of multisensory temporal tasks (with both simple and complex stimuli) onto the ability of individuals with ASD to perceptually bind audiovisual speech signals. High-functioning children with ASD were compared with a group of typically developing children. Performance on the multisensory temporal tasks varied with stimulus complexity for both groups; less precise temporal processing was observed with increasing stimulus complexity. Notably, individuals with ASD showed a speech-specific deficit in multisensory temporal processing. Most importantly, the strength of perceptual binding of audiovisual speech observed in individuals with ASD was strongly related to their low-level multisensory temporal processing abilities. Collectively, the results represent the first to illustrate links between multisensory temporal function and speech processing in ASD, strongly suggesting that deficits in low-level sensory processing may cascade into higher-order domains, such as language and communication.
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  • Brief report: Arrested development of audiovisual speech perception in autism spectrum disorders.
    Journal of autism and developmental disorders (2014)
    Stevenson RA, Siemann JK, Woynaroski TG, Schneider BC, Eberly HE, Camarata SM, Wallace MT. Brief report: Arrested development of audiovisual speech perception in autism spectrum disorders. J Autism Dev Disord. 2014 Jun; 44(6):1470-7.
    Abstract: Atypical communicative abilities are a core marker of Autism Spectrum Disorders (ASD). A number of studies have shown that, in addition to auditory comprehension differences, individuals with autism frequently show atypical responses to audiovisual speech, suggesting a multisensory contribution to these communicative differences from their typically developing peers. To shed light on possible differences in the maturation of audiovisual speech integration, we tested younger (ages 6-12) and older (ages 13-18) children with and without ASD on a task indexing such multisensory integration. To do this, we used the McGurk effect, in which the pairing of incongruent auditory and visual speech tokens typically results in the perception of a fused percept distinct from the auditory and visual signals, indicative of active integration of the two channels conveying speech information. Whereas little difference was seen in audiovisual speech processing (i.e., reports of McGurk fusion) between the younger ASD and TD groups, there was a significant difference at the older ages. While TD controls exhibited an increased rate of fusion (i.e., integration) with age, children with ASD failed to show this increase. These data suggest arrested development of audiovisual speech integration in ASD. The results are discussed in light of the extant literature and necessary next steps in research.
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2-Hydroxybenzylamine for Prevention of Alzheimer's Disease: Initial Evaluation in Humans
Vanderbilt University Medical Center
  • In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (2018)
    Fuller JC Jr, Pitchford LM, Morrison RD, Daniels JS, Flynn CR, Abumrad NN, Oates JA, Boutaud O, Rathmacher JA. In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate. Food Chem Toxicol. 2018 Nov; 121:541-548.
    Abstract: 2-hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive γ-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2-HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA.
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An All-Night Functional Magnetic Resonance Imaging Sleep Study With Auditory Stimuli
The National Institutes of Health
  • All-night functional magnetic resonance imaging sleep studies.
    Journal of neuroscience methods (2019)
    Moehlman TM, de Zwart JA, Chappel-Farley MG, Liu X, McClain IB, Chang C, Mandelkow H, Özbay PS, Johnson NL, Bieber RE, Fernandez KA, King KA, Zalewski CK, Brewer CC, van Gelderen P, Duyn JH, Picchioni D. All-night functional magnetic resonance imaging sleep studies. J Neurosci Methods. 2019 Mar 15; 316:83-98.
    Abstract: Previous functional magnetic resonance imaging (fMRI) sleep studies have been hampered by the difficulty of obtaining extended amounts of sleep in the sleep-adverse environment of the scanner and often have resorted to manipulations such as sleep depriving subjects before scanning. These manipulations limit the generalizability of the results.
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Magnetic Resonance Imaging at High Field for Clinical Application
Vanderbilt University Medical Center
  • Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis.
    Multiple sclerosis (Houndmills, Basingstoke, England) (2019)
    O'Grady KP, Dula AN, Lyttle BD, Thompson LM, Conrad BN, Box BA, McKeithan LJ, Pawate S, Bagnato F, Landman BA, Newhouse P, Smith SA. Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis. Mult Scler. 2019 Oct; 25(12):1580-1592.
    Abstract: Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T- and T-weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM.
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Long-Term Nicotine Treatment for Mild Cognitive Impairment
Vanderbilt University Medical Center
  • Therapeutic Applications of Nicotinic Stimulation: Successes, Failures, and Future Prospects.
    Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco (2019)
    Newhouse PA. Therapeutic Applications of Nicotinic Stimulation: Successes, Failures, and Future Prospects. Nicotine Tob Res. 2019 Feb 18; 21(3):345-348.
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Diet Induced Weight Loss Reduces Inflammation and Crown-like Structures and Corrects Immune Dysfunction in Subcutaneous Adipose Tissue In Class 2-3 Obese Women: A Pilot Study
The Rockefeller University
  • Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women.
    Journal of translational medicine (2018)
    Alemán JO, Bokulich NA, Swann JR, Walker JM, De Rosa JC, Battaglia T, Costabile A, Pechlivanis A, Liang Y, Breslow JL, Blaser MJ, Holt PR. Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women. J Transl Med. 2018 Sep 3; 16(1):244.
    Abstract: Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity.
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Neurocognitive effects of mild hypothyroidism
Oregon Health & Science University
  • Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4.
    The Journal of clinical endocrinology and metabolism (2018)
    Samuels MH, Kolobova I, Niederhausen M, Purnell JQ, Schuff KG. Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4. J Clin Endocrinol Metab. 2018 Nov 1; 103(11):4163-4175.
    Abstract: It is unclear whether variations in thyroid status within or near the reference range affect energy expenditure, body mass, or body composition.
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  • Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects.
    The Journal of clinical endocrinology and metabolism (2018)
    Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG. Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. J Clin Endocrinol Metab. 2018 May 1; 103(5):1997-2008.
    Abstract: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition.
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  • Thyroid Function Variation in the Normal Range, Energy Expenditure, and Body Composition in L-T4-Treated Subjects.
    The Journal of clinical endocrinology and metabolism (2017)
    Samuels MH, Kolobova I, Antosik M, Niederhausen M, Purnell JQ, Schuff KG. Thyroid Function Variation in the Normal Range, Energy Expenditure, and Body Composition in L-T4-Treated Subjects. J Clin Endocrinol Metab. 2017 Jul 1; 102(7):2533-2542.
    Abstract: It is not clear whether upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. Thyroid hormone plays a critical role in determining energy expenditure, body mass, and body composition, and therefore clinically relevant variations in these parameters may occur across the normal range of thyroid function.
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  • Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects.
    Thyroid : official journal of the American Thyroid Association (2016)
    Samuels MH, Kolobova I, Smeraglio A, Niederhausen M, Janowsky JS, Schuff KG. Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects. Thyroid. 2016 Sep; 26(9):1173-84.
    Abstract: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function.
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  • Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition.
    Thyroid : official journal of the American Thyroid Association (2016)
    Samuels MH, Kolobova I, Smeraglio A, Peters D, Purnell JQ, Schuff KG. Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition. Thyroid. 2016 Mar; 26(3):347-55.
    Abstract: Thyrotropin (TSH)-suppressive doses of levothyroxine (LT4) have adverse effects on bone and cardiac function, but it is unclear whether metabolic function is also affected. The objective of this study was to determine whether women receiving TSH-suppressive LT4 doses have alterations in energy expenditure or body composition.
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  • The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition.
    The Journal of clinical endocrinology and metabolism (2014)
    Samuels MH, Kolobova I, Smeraglio A, Peters D, Janowsky JS, Schuff KG. The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition. J Clin Endocrinol Metab. 2014 Mar; 99(3):843-51.
    Abstract: TSH-suppressive doses of levothyroxine (L-T4) have adverse effects on bone and cardiac function, but it is unclear whether central nervous system function is also affected.
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Risk and Resiliency for Youth with Autism during the Transition to Adulthood
Vanderbilt University Medical Center
  • Differences in anticipatory versus reactive stress to social evaluative threat in adults versus adolescents with autism.
    Autism research : official journal of the International Society for Autism Research (2018)
    Taylor JL, Muscatello RA, Corbett BA. Differences in anticipatory versus reactive stress to social evaluative threat in adults versus adolescents with autism. Autism Res. 2018 Sep; 11(9):1276-1285.
    Abstract: Social evaluative threat is a potent activator of the hypothalamic-pituitary-adrenocortical (HPA) axis in typically developing (TD) populations. Studies have shown that children and adolescents with autism spectrum disorder (ASD) show a blunted cortisol response to this type of stressor; yet, a previous study in adults with ASD reported a more prototypical stress response. The current study compared 24 adolescents and 17 adults with ASD to investigate a possible developmental lag in autism resulting in a more adaptive stress response to social evaluation with development. Participants were exposed to the trier social stress test (TSST), and salivary cortisol was collected before and after stress induction. Multilevel modeling revealed that relative to adolescents, young adults with ASD evidenced a significant increase in cortisol in response to anticipatory stress, and 23.5% were classified as anticipatory responders. Adolescents, however, had a significant change in slope in response to the TSST, with 37.5% classified as reactive responders. In both groups, the majority of participants did not have a robust stress response to the TSST as would be expected in TD participants. Findings suggest significant differences in the cortisol trajectory; adults with ASD were more likely to show an anticipatory response to being socially evaluated, which was maintained throughout the stressor, whereas the adolescents had a more reactive response pattern with no anticipatory response. Further research is needed to determine if such patterns are adaptive or deleterious, and to determine underlying factors that may contribute to distinct stress profiles and to the overall diminished stress responses. Autism Res 2018, 11: 1276-1285. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Many individuals have increased stress when being socially evaluated. The current study shows that adults with ASD have increased stress in anticipation of a task in which individuals are required to give a speech to unfamiliar raters, while adolescents with ASD tend to show a stress response only during the task itself. Further research is necessary to understand whether developmental influences on stress response in ASD have significant impacts on other areas of functioning often affected by stress.
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  • Postsecondary Expectations of High-School Students With Autism Spectrum Disorders.
    Focus on autism and other developmental disabilities (2016)
    Anderson KA, McDonald TA, Edsall D, Smith LE, Taylor JL. Postsecondary Expectations of High-School Students With Autism Spectrum Disorders. Focus Autism Other Dev Disabl. 2016; 31(1):16-26.
    Abstract: This study examined the perceptions of adulthood among 31 high school students with autism spectrum disorder (ASD). We had two research aims: (1) to report students' postsecondary expectations in terms of school, work, friendships and living arrangement and (2) to describe how our sample defined adulthood. To better compare our sample's criteria of adulthood to the criteria traditionally endorsed in secondary schools, we used a directed content analysis approach. Data were derived from a semi-structured interview that questioned students about friendships, activities and the transition to adulthood. The majority of students expected to attain traditional markers of adulthood after high school; however, for some the pathways to achieving these outcomes were narrowly defined and perceived as a rigid, linear process. Independence, maturity and personal responsibility were the most highly endorsed characteristics of adulthood, followed by chronological age and traditional markers. Implications for transition planning and adult services are discussed.
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  • Brief Report: Postsecondary Work and Educational Disruptions for Youth on the Autism Spectrum.
    Journal of autism and developmental disorders (2017)
    Taylor JL, DaWalt LS. Brief Report: Postsecondary Work and Educational Disruptions for Youth on the Autism Spectrum. J Autism Dev Disord. 2017 Dec; 47(12):4025-4031.
    Abstract: This study examined vocational/educational disruption in the 2-3 years after high school for 36 youth with autism spectrum disorder (ASD). Data were collected three times from parents: during youth's last year of high school and two times after high school exit. Data were coded into categories indicating any versus no disruptions in postsecondary vocation/education, and group differences in individual (behavior problems, IQ, adaptive behavior, autism severity, stress reactivity) and family (parent depression, anxiety, quality of life; family income and climate) factors were examined. One-half of youth had experienced a postsecondary vocational/educational disruption; parents of those with a disruption had more depressive and anxiety symptoms and lower quality of life while their son/daughter was still in high school.
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  • Cumulative life events, traumatic experiences, and psychiatric symptomatology in transition-aged youth with autism spectrum disorder.
    Journal of neurodevelopmental disorders (2016)
    Taylor JL, Gotham KO. Cumulative life events, traumatic experiences, and psychiatric symptomatology in transition-aged youth with autism spectrum disorder. J Neurodev Disord. 2016; 8:28.
    Abstract: Co-occurring mood and anxiety symptomatology is commonly observed among youth with autism spectrum disorders (ASD) during adolescence and adulthood. Yet, little is known about the factors that might predispose youth with ASD to mood and anxiety problems. In this study, we focus on the role of cumulative stressful life events and trauma in co-occurring psychopathology among youth with ASD who are preparing to exit high school. Specifically, we examined the distribution of cumulative life events and traumatic experiences and their relations with mood and anxiety symptomatology.
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  • Frequency and correlates of service access among youth with autism transitioning to adulthood.
    Journal of autism and developmental disorders (2015)
    Taylor JL, Henninger NA. Frequency and correlates of service access among youth with autism transitioning to adulthood. J Autism Dev Disord. 2015 Jan; 45(1):179-91.
    Abstract: This study examined service receipt and unmet service needs among youth with autism spectrum disorders (ASD) in their last year of high school, as well as the youth (intellectual disability, race/ethnicity, autism severity, comorbid psychiatric diagnoses, behavior problems, adaptive behavior) and family (income, parental health, parental depressive symptoms, parental anxiety) correlates of service access. Thirty-nine families of youth with ASD participated. Data were collected via parental interview/questionnaire and youth psychological evaluation. Results suggested that this sample was underserved relative to a nationally-representative cohort. Those with a comorbid psychiatric diagnosis and lower levels of adaptive behavior received more services. Greater unmet needs were reported for youth who were racial/ethnic minorities, who had more behavior problems, and whose parents had greater anxiety.
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Audio-Visual Integration in Patients with Hearing Devices
Vanderbilt University Medical Center
  • Audiovisual Temporal Processing in Postlingually Deafened Adults with Cochlear Implants.
    Scientific reports (2018)
    Butera IM, Stevenson RA, Mangus BD, Woynaroski TG, Gifford RH, Wallace MT. Audiovisual Temporal Processing in Postlingually Deafened Adults with Cochlear Implants. Sci Rep. 2018 Jul 27; 8(1):11345.
    Abstract: For many cochlear implant (CI) users, visual cues are vitally important for interpreting the impoverished auditory speech information that an implant conveys. Although the temporal relationship between auditory and visual stimuli is crucial for how this information is integrated, audiovisual temporal processing in CI users is poorly understood. In this study, we tested unisensory (auditory alone, visual alone) and multisensory (audiovisual) temporal processing in postlingually deafened CI users (n = 48) and normal-hearing controls (n = 54) using simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks. We varied the timing onsets between the auditory and visual components of either a syllable/viseme or a simple flash/beep pairing, and participants indicated either which stimulus appeared first (TOJ) or if the pair occurred simultaneously (SJ). Results indicate that temporal binding windows-the interval within which stimuli are likely to be perceptually 'bound'-are not significantly different between groups for either speech or non-speech stimuli. However, the point of subjective simultaneity for speech was less visually leading in CI users, who interestingly, also had improved visual-only TOJ thresholds. Further signal detection analysis suggests that this SJ shift may be due to greater visual bias within the CI group, perhaps reflecting heightened attentional allocation to visual cues.
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MRI-based Quantitative Brain Oxygen Metabolism in Adults and Children with Sickle Cell Anemia
Vanderbilt University Medical Center
  • Silent infarct is a risk factor for infarct recurrence in adults with sickle cell anemia.
    Neurology (2018)
    Jordan LC, Kassim AA, Donahue MJ, Juttukonda MR, Pruthi S, Davis LT, Rodeghier M, Lee CA, Patel NJ, DeBaun MR. Silent infarct is a risk factor for infarct recurrence in adults with sickle cell anemia. Neurology. 2018 Aug 21; 91(8):e781-e784.
    Abstract: Because of the high prevalence of silent cerebral infarcts (SCIs) in adults with sickle cell anemia (SCA) and lack of information to guide treatment strategies, we evaluated the risk of recurrent SCIs and overt stroke in adults with SCA with preexisting SCI.
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Association of lower urinary tract symptoms and toileting behavior in women
Vanderbilt University Medical Center
  • Toileting Behaviors of Women-What is Healthy?
    The Journal of urology (2019)
    Kowalik CG, Daily A, Delpe S, Kaufman MR, Fowke J, Dmochowski RR, Reynolds WS. Toileting Behaviors of Women-What is Healthy? J Urol. 2019 Jan; 201(1):129-134.
    Abstract: The objective of this study was to assess toileting behaviors in community dwelling women.
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Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
Vanderbilt University Medical Center
  • DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition.
    Hypertension (Dallas, Tex. : 1979) (2018)
    Hubers SA, Wilson JR, Yu C, Nian H, Grouzmann E, Eugster P, Shibao CA, Billings FT 4th, Jafarian Kerman S, Brown NJ. DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition. Hypertension. 2018 Sep; 72(3):712-719.
    Abstract: DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P≤0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
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  • Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin.
    Journal of the Endocrine Society (2017)
    Wilson JR, Shuey MM, Brown NJ, Devin JK. Hypertension and Type 2 Diabetes Are Associated With Decreased Inhibition of Dipeptidyl Peptidase-4 by Sitagliptin. J Endocr Soc. 2017 Sep 1; 1(9):1168-1178.
    Abstract: Patients with diabetes often have comorbidities such as hypertension. It is not known how individual characteristics influence response to dipeptidyl peptidase-4 (DPP4) inhibitors.
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Implicit Bias Role in Predicting AOD Treatment Success and Duration
University of Pennsylvania
  • Substance use, recovery, and linguistics: The impact of word choice on explicit and implicit bias.
    Drug and alcohol dependence (2018)
    Ashford RD, Brown AM, Curtis B. Substance use, recovery, and linguistics: The impact of word choice on expli