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BACKGROUND: Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG. METHODS: Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight − nadir)/(preoperative weight − nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0–240 min) after 3–6 years post-bariatric surgery. RESULTS: All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m(2). Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m(2), non-WR: 30.3 ± 3.5 kg/m(2), p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 μg*min/dL, p = 0.015)). Incretin response did not differ between the groups. CONCLUSIONS: GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

BACKGROUND: People living with HIV (PLWH) on antiretroviral therapy (ART) are at increased risk of atherosclerotic disease. Abnormal adipose distribution is common in PLWH and may contribute to atherosclerosis. Because coronary artery endothelial function (CEF) is impaired in early atherosclerosis, predicts future cardiovascular events, and is reduced in PLWH, we investigated associations between body fat distribution and CEF in PLWH. SETTING: Prospective cohort study. METHODS: PLWH on stable ART underwent MRI to quantify CEF, measured as change in coronary cross-sectional area (CSA) from rest to that during isometric handgrip exercise, an endothelial-dependent stressor. Abdominal visceral and subcutaneous fat area (axial L4 level) and liver fat fraction were quantified via MRI. Linear regression was used to determine associations between CEF and independent variables. RESULTS: Among 84 PLWH (52±11 years; 33% women), mean CSA change was 0.74±11.7’%, indicating impaired CEF. On univariable regression analysis, CEF was inversely related to waist circumference (R=−0.31, p =0.014), hip circumference (R=−0.27, p =0.037), and subcutaneous fat area (R=−0.25, p =0.031). We did not observe significant relationships between CEF and liver fat fraction, waist/hip ratio, or visceral fat area. On multivariable regression adjusted for age, sex, and race, CEF was associated with waist circumference, hip circumference, subcutaneous fat, and liver fat fraction. CONCLUSION: Waist and hip circumference, and subcutaneous fat area are associated with impaired CEF, an established metric of abnormal vascular health in PLWH on stable ART, and may contribute to the increased rate of heart disease in this population.

Background Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed ( Methods We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to Results Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%–37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to Conclusions Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.

Funding Information: Financial support. This work was supported by the National Institutes of Health (grant numbers R01AI145453 to J. R. C.-M. and T32AI007387 to S. R. S.). Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America. Background: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (

BACKGROUND AND AIMSDiastolic dysfunction of the left ventricle is a precursor to heart failure with preserved ejection fraction (HFpEF). Detection by electrocardiography (ECG) when asymptomatic (stage B heart failure) would be valuable. We hypothesised that an explainable advanced ECG (A-ECG) score derived from standard 12-lead ECG could accurately diagnose diastolic dysfunction.METHODSIncluded patients had undergone resting 12-lead ECG and echocardiography demonstrating normal systolic function, with at most mild valve disease, and either the presence (n=150) or absence (n=264) of grade II or III diastolic dysfunction. Stepwise multivariable logistic regression was used to generate an A-ECG score that was crossvalidated using bootstrapping.RESULTSA 6-measure A-ECG score was able to identify diastolic dysfunction with an area under the receiver operating characteristics curve [95% confidence interval] of 0.91 [0.88-0.94], sensitivity 83 [76-91]%, specificity 87 [77-92]%, positive predictive value 78 [69-85]%, negative predictive value 90 [86-94]%, positive likelihood ratio 6.38 [3.30-11.38] and inverse negative likelihood ratio 5.12 [3.21-10.22].CONCLUSIONSStandard 12-lead ECG can be used to accurately identify diastolic dysfunction by echocardiography via A-ECG. This may have clinical utility for early identification of patients who may benefit from further cardiac assessment and risk factor management to prevent progression to symptomatic heart failure.

Purpose: The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment.Experimental Design: Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma.Results: HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings.Conclusion: Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment. Mol Cancer Res; 10(9); 1147–57. ©2012 AACR.

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Background Cardiometabolic disease in transgender women (TW) is affected by gender-affirming hormonal therapies (GAHTs), HIV, and antiretroviral therapy (ART). We evaluated the 48-week safety/tolerability of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs continued ART in TW on GAHT. Methods TW on GAHT and suppressive ART were randomized 1:1 to switch to B/F/TAF (Arm A) or continue current ART (Arm B). Cardiometabolic biomarkers, sex hormones, bone mineral density (BMD) and lean/fat mass by DXA scan, and hepatic fat (controlled continuation parameter [CAP]) were measured. Wilcoxon rank-sum/signed-rank and χ2 tests compared continuous and categorical variables. Results TW (Arm A n = 12, Arm B n = 9) had a median age of 45 years. Ninety-five percent were non-White; 70% were on elvitegravir or dolutegravir, 57% TAF, 24% abacavir, and 19% TDF; 29% had hypertension, 5% diabetes, and 62% dyslipidemia. There were no adverse events. Arm A/B had 91%/89% undetectable HIV-1 RNA at week 48 (w48). Baseline (BL) osteopenia (Arm A/B 42%/25%) and osteoporosis (17%/13%) were common, without significant changes. BL lean/fat mass were similar. At w48, Arm A had stable lean mass but increased limb (3 lbs) and trunk (3 lbs) fat (within-arm P < .05); fat in Arm B remained stable. No changes occurred in lipid or glucose profiles. Arm B had a greater w48 decrease (−25 vs −3 dB/m; P = .03) in CAP. BL and w48 concentrations of all biomarkers were similar. Conclusions In this cohort of TW, switch to B/F/TAF was safe and metabolically neutral, though greater fat gain occurred on B/F/TAF. Further study is needed to better understand cardiometabolic disease burden in TW with HIV.

To determine the longitudinal relationships between abnormal glucose metabolism and physical function in persons with HIV (PWH) and without HIV.Prospective cohort study of men with or at risk for HIV in four United States cities between 2006 and 2018.Men with or at risk for HIV from the Multicenter AIDS Cohort Study (MACS) had semi-annual assessments of glycemic status, grip strength, and gait speed. We used linear mixed models with random intercept to assess associations between glycemic status and physical function. Glycemic status was categorized as normal, impaired fasting glucose (IFG), controlled diabetes mellitus [hemoglobin A1C (HbA1C)7.5%], or uncontrolled diabetes mellitus (HbA1C ≥ 7.5%).Of 2240 men, 52% were PWH. Diabetes mellitus was similar among PWH (7.7%) vs. persons without HIV (6.7%, P = 0.36) at baseline. PWH had slower gait speed (1.17 vs. 1.20 m/s, P 0.01) but similar grip strength (40.1 vs. 39.8 kg, P = 0.76) compared with persons without HIV at baseline. In multivariate models, gait speed decline was greater with controlled diabetes mellitus [-0.018 m/s (-0.032 to -0.005), P = 0.01] and grip strength decline was greater with controlled [-0.560 kg (-1.096 to -0.024), P = 0.04] and uncontrolled diabetes mellitus [-0.937 kg (-1.684 to -0.190), P = 0.01), regardless of HIV serostatus compared with normoglycemic individuals.Abnormal glucose metabolism was associated with declines in gait speed and grip strength regardless of HIV serostatus. These data suggest that improvement in glucose control should be investigated as an intervenable target to prevent progression of physical function limitations among PWH.