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PURPOSE: The aim of this study was to determine whether highly active antiretroviral therapy (HAART), rather than the direct effect of HIV infection, limits peripheral muscle oxygen extraction-utilization (a-vO(2)) in individuals infected with the human immunodeficiency virus (HIV). METHODS: Fifteen subjects (6 female and 9 male) with HIV taking HAART, 15 subjects infected with HIV not taking HAART, and 15 healthy gender and activity level matched non-HIV infected controls (N = 45) performed an maximal treadmill exercise test to exhaustion. Noninvasive cardiac output Qt was measured at each stage and at peak exercise using the indirect Fick method based on the exponential rise carbon dioxide rebreathing method. Intergroup comparisons were adjusted for interactions of peak oxygen consumption ([V02), body surface area, and [V02]t using ANCOVA. RESULTS: Peak a-vO(2) was significantly lower (P < 0.05) in subjects with HIV taking HAART (10.0 +/- 0.5 vol%) compared with subjects with HIV not taking HAART (11.7 +/- 0.5 vol%) and noninfected controls (12.7 +/- 0.5 vol%). In subjects with HIV taking HAART, peak heart rate (HR) (170.5 +/- 3.9 bpm) was lower than (P < 0.05) and stroke volume (Vs) (123.0 +/- 3.9 mL x beat-1) at peak exercise was higher (P < 0.05) than subjects with HIV not taking HAART (179.9 +/- 3.5 bpm) (106.6 +/- 3.9 mL x beat-1) and noninfected controls (185.4 +/- 3.8 bpm) (100.6 +/- 4.0 mL.beat-1) upon ANCOVA. There were no significant differences in peak [VO2]t between groups. CONCLUSION: Peak a-vO(2) was diminished in subjects infected with HIV taking HAART compared with HIV-infected subjects not taking HAART and noninfected controls matched for age, gender, and physical activity level. Findings of the current study implicated HAART as a primary contributor to decreased muscle oxygen extraction-utilization in individuals infected with HIV. [ABSTRACT FROM AUTHOR]

Fibroblast-ECM (dys)regulation is associated with a plethora of diseases. The ECM acts as a reservoir of inflammatory factors and cytokines that mediate molecular mechanisms within cardiac cell populations. The role of ECM-mitochondria crosstalk in the development and progression of cardiac disorders remains uncertain. We evaluated the influence of ECM produced by stromal cells from patients with the mitochondrial cardiomyopathy (Barth syndrome, BTHS) and unaffected healthy controls on cardiac fibroblast (CF) metabolic function. To do this, cell-derived matrices CDMs were generated from BTHS and healthy human pluripotent stem cell-derived CFs (hPSC-CF) and used as cell culture substrates. BTHS CDMs negatively impacted the mitochondrial function of healthy hPSC-CFs while healthy CDMs improved mitochondrial function in BTHS hPSC-CFs. Mass spectrometry comparisons identified 5 matrisome proteins differentially expressed in BTHS compared to healthy CDM. Our results highlight a key role for the ECM in disease through its impact on mitochondrial function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Matching disease and treatment mechanisms is a goal of the Precision Medicine Initiative. Pro- and anti-inflammatory cytokines (e.g., Tumor Necrosis Factor-alpha, Transforming Growth Factor-beta, and Interleukin-2, 10, and 12) have gained a significant amount of interest in their potential role in persistent pain for musculoskeletal (MSK) conditions. Manual therapy (MT) and exercise are two guideline-recommended approaches for treating MSK conditions. The objective of this narrative overview was to investigate of the effects of MT and exercise on pro- and anti-inflammatory cytokines and determine the factors that lead to variability in results., Methods: Two reviewers evaluated the direction and variabilities of MT and exercise literature. A red, yellow, and green light scoring system was used to define consistencies., Results: Consistencies in responses were seen with acute and chronic exercise and both pro- and anti-inflammatory cytokines. Chronic exercise is associated with a consistent shift towards a more anti-inflammatory cytokine profile (Transforming Growth Factor-beta, and Interleukin-2 and 13, whereas acute bouts of intense exercise can transiently increase pro-inflammatory cytokine levels. The influence of MT on cytokines was less commonly studied and yielded more variable results., Conclusion: Variability in findings is likely related to the subject and their baseline condition or disease, when measurement occurs, and the exercise intensity, duration, and an individual's overall health and fitness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cook, Keter, Cade, Winkelstein and Reed.)

Objectives: (1) Examine the feasibility of a community-based exercise intervention for persons with spinal cord injury and (2) compare the cardiorespiratory fitness, skeletal muscle strength, and psychosocial well-being of participants in the intervention group versus control group., Design: Community-based pilot randomized controlled trial. Setting : Accessible community-based health and wellness center. Participants : Thirty-two sedentary community-dwelling adults with any level of spinal cord injury. Interventions: Participants were randomized to a 36-session/12-week community-based exercise program (intervention; EG) or to a 36-session/12-week physical activity education group (control; CG). Outcome measures : Primary outcome measures included cardiorespiratory fitness measured by a VO 2 peak test, a composite score of four upper extremity musculoskeletal strength 1-repetition maximum exercises, and feasibility measured by EG participants' adherence and exercise intensity achieved during the program. EG participants' acceptance of the program was also evaluated using a self-reported satisfaction scale. Self-efficacy, motivation, pain, and goal performance and satisfaction were secondary outcome measures. Adherence and acceptability were also measured., Results: Fifteen participants ( n  = 15) completed the community-based exercise intervention and seventeen ( n  = 17) completed the education program. While no statistically significant differences were found, the EG experienced changes of moderate effect size in cardiorespiratory fitness, strength, motivation, and satisfaction with their goals. The EG attended, on average, two sessions per week. The community-based exercise intervention was highly accepted by and satisfying for participants to engage in., Conclusions: The EG had improvements in the two primary measures, cardiorespiratory fitness and musculoskeletal strength, following the intervention. The community-based exercise intervention was feasible and accepted by participants.

Objective: To evaluate the metabolic alterations associated with gestational diabetes mellitus (GDM) in women with overweight or obesity., Research Design and Methods: We compared fasting and postprandial plasma glucose and free fatty acid (FFA) concentrations, insulin sensitivity (IS; Matsuda index), and β-cell function (i.e., β-cell responsiveness to glucose) by using a frequently sampled oral glucose tolerance test (OGTT) at 15 and 35 weeks' gestation in women with overweight or obesity who had GDM (n = 29) or did not have GDM (No-GDM; n = 164) at 35 weeks., Results: At 15 weeks, IS and β-cell function were lower, and fasting, 1-h, and total area-under-the-curve plasma glucose concentrations during the OGTT were higher (all P < 0.05) in the GDM than in the No-GDM group. At 35 weeks compared with 15 weeks, IS decreased, β-cell function increased, and postprandial suppression of plasma FFA was blunted in both the GDM and No-GDM groups, but the decrease in IS and the increase in postprandial FFA concentration were greater and the increase in β-cell function was less (all P ≤ 0.05) in the GDM than in the No-GDM group. A receiver operating characteristic curve analysis showed that both fasting plasma glucose and 1-h OGTT glucose concentration at 15 weeks are predictors of GDM, but the predictive power was <30%., Conclusions: Women with overweight or obesity and GDM, compared with those without GDM, have worse IS and β-cell function early during pregnancy and a greater subsequent decline in IS and blunted increase in β-cell function. Increased fasting and 1-h OGTT plasma glucose concentration early during pregnancy are markers of increased GDM risk, albeit with weak predictive power., (© 2023 by the American Diabetes Association.)

Introduction: The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy., Background: Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction., Methods: Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9., Results: We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise., Conclusions: Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle. However, the impact of Tafazzin deficiency on hepatic glucose production and the pathways contributing to hepatic glucose production during exercise is unknown. Therefore, the purpose of this study was to quantify in vivo liver gluconeogenesis and glycogenolysis in Tafazzin knockdown mice at rest and during acute exercise., Methods: Male TAFAZZIN shRNA transgenic (TG) and wild-type (WT) mice completed exhaustive treadmill running protocols to test exercise tolerance. Mice underwent 2H- and 13C-stable isotope infusions at rest and during a 30-minute treadmill running bout to quantify hepatic glucose production and associated nutrient fluxes under sedentary conditions and during acute exercise. Circulating and tissue (skeletal muscle and liver) samples were obtained during and following exercise to assess static metabolite levels., Results: TG mice reached exhaustion sooner during exhaustive treadmill running protocols and exhibited higher plasma lactate concentrations after exhaustive exercise compared to WT mice. Arterial glucose levels were comparable between genotypes at rest, but higher in TG mice compared to WT mice during exercise. Consistent with the higher blood glucose, TG mice showed increased endogenous glucose production owing to elevated glycogenolysis compared to WT mice during exercise. Total gluconeogenesis, gluconeogenesis from glycerol, gluconeogenesis from phosphoenolpyruvate, pyruvate cycling, total cataplerosis, and anaplerotic fluxes were similar between TG and WT mice at rest and during exercise. However, lactate dehydrogenase flux and TCA cycle fluxes trended higher in TG mice during exercise. Liver glycogen content in TG was higher in TG vs. controls., Conclusion: Our data in the Tafazzin knockdown mouse suggest that elevated anaerobic metabolism during rest and exercise previously reported in humans with BTHS are supported by the finding of higher hepatic glycogenolysis., Competing Interests: The authors declared no conflict of interest., (Copyright: © 2023 Schweitzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: With the advent of antiretrovirals, people living with HIV are living near-normal lifespans. However, people living with HIV are at greater risk of experiencing cognitive impairment and reduced brain integrity despite well-controlled viremia. A robust literature supports exercise interventions as a method of improving cognition and structural brain integrity in older individuals without HIV. The effects of exercise on cardiometabolic, neurocognitive, and neural structures in middle-aged to older people living with HIV are less well known, with few prospective studies examining these measures., Objective: This prospective randomized clinical trial will examine the effects of a 6-month exercise training intervention compared to a 6-month stretching intervention (control) on cardiorespiratory fitness, physical function and strength, cognition, and neuroimaging measures of brain volumes and cerebral blood flow in people living with HIV., Methods: Sedentary middle-aged to older people living with HIV (ages≥40; n=150) with undetectable HIV viral load (<20 copies/mL) will be enrolled in the study. At the baseline and final visit, fasting plasma lipid, insulin, glucose, and brain neurotrophic factor concentrations; cardiorespiratory fitness; cognitive performance; brain volumes; and cerebral blood flow via a magnetic resonance imaging scan will be measured. Participants will be randomized in a 2:1 ratio to either the exercise or control stretching intervention. All participants will complete their assigned programs at a community fitness center 3 times a week for 6 months. A professional fitness trainer will provide personal training guidance at all sessions for individuals enrolled in both arms. Individuals randomized to the exercise intervention will perform endurance and strength training exercises, while those randomized to the control intervention will perform stretches to increase flexibility. A midpoint visit (at 3 months) will assess cognitive performance, and at the end point visit, subjects will undergo cardiorespiratory fitness and cognition testing, and a magnetic resonance imaging scan. Physical activity throughout the duration of the trial will be recorded using an actigraph., Results: Recruitment and data collection are complete as of December 2020. Data processing, cleaning, and organization are complete as of December 2021. Data analysis began in January 2022, with the publication of study results for primary aims 1 and 2 expected by early 2023., Conclusions: This study will investigate the effects of a 6-month aerobic and resistance exercise training intervention to improve cardiometabolic risk factors, cognitive performance, cerebral structure, and blood flow in sedentary people living with HIV. Results will inform clinicians and patients of the potential benefits of a structured aerobic exercise training program on the cognitive, functional, and cardiometabolic health status of older people living with HIV. Assessment of compliance will inform the development and implementation of future exercise programs for people living with HIV., Trial Registration: ClinicalTrials.gov NCT02663934; https://clinicaltrials.gov/ct2/show/NCT02663934., International Registered Report Identifier (irrid): DERR1-10.2196/41421., (©Sarah Cooley, Brittany M Nelson, Alexander Rosenow, Elizabeth Westerhaus, W Todd Cade, Dominic N Reeds, Florin Vaida, Kevin E Yarasheski, Robert H Paul, Beau M Ances. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.03.2023.)

The extracellular matrix (ECM) provides both physical and chemical cues that dictate cell function and contribute to muscle maintenance. Muscle cells require efficient mitochondria to satisfy their high energy demand, however, the role the ECM plays in moderating mitochondrial function is not clear. We hypothesized that the ECM produced by stromal cells with mitochondrial dysfunction (Barth syndrome, BTHS) provides cues that contribute to metabolic dysfunction independent of muscle cell health. To test this, we harnessed the ECM production capabilities of human pluripotent stem-cell-derived cardiac fibroblasts (hPSC-CFs) from healthy and BTHS patients to fabricate cell-derived matrices (CDMs) with controlled topography, though we found that matrix composition from healthy versus diseased cells influenced myotube formation independent of alignment cues. To further investigate the effects of matrix composition, we then examined the influence of healthy- and BTHS-derived CDMs on myotube formation and metabolic function. We found that BTHS CDMs induced lower fusion index, lower ATP production, lower mitochondrial membrane potential, and higher ROS generation than the healthy CDMs. These findings imply that BTHS-derived ECM alone contributes to myocyte dysfunction in otherwise healthy cells. Finally, to investigate potential mechanisms, we defined the composition of CDMs produced by hPSC-CFs from healthy and BTHS patients using mass spectrometry and identified 15 ECM and related proteins that were differentially expressed in the BTHS-CDM compared to healthy CDM. Our results highlight that ECM composition affects skeletal muscle formation and metabolic efficiency in otherwise healthy cells, and our methods to generate patient-specific CDMs are a useful tool to investigate the influence of the ECM on disease progression and to investigate variability among diseased patients. STATEMENT OF SIGNIFICANCE: Muscle function requires both efficient metabolism to generate force and structured extracellular matrix (ECM) to transmit force, and we sought to examine the interactions between metabolism and ECM when metabolic disease is present. We fabricated patient-specific cell derived matrices (CDMs) with controlled topographic features to replicate the composition of healthy and mitochondrial-diseased (Barth syndrome) ECM. We found that disease-derived ECM negatively affects metabolic function of otherwise healthy myoblasts, and we identified several proteins in disease-derived ECM that may be mediating this dysfunction. We anticipate that our patient-specific CDM system could be fabricated with other topographies and cell types to study cell functions and diseases of interest beyond mitochondrial dysfunction and, eventually, be applied toward personalized medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Lifestyle therapy (energy restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, β cell function, and multi-organ insulin sensitivity, which were associated with changes in muscle NAD + biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, which are likely mediated by specific alterations in skeletal muscle and adipose tissue biology., Competing Interests: Declaration of interests S.K. serves on scientific advisory boards for Altimmune and Merck and as a consultant for B2M Medical., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Obesity increases the risk for pregnancy complications and maternal hyperglycemia. The Institute of Medicine developed guidelines for gestational weight gain (GWG) targets for women with overweight/obesity, but it is unclear whether exceeding these targets has adverse effects on maternal glucose metabolism., Methods: Insulin sensitivity (assessed using the Matsuda Insulin Sensitivity Index), β-cell function (assessed as insulin secretion rate in relation to plasma glucose), and plasma insulin clearance rate were evaluated using a frequently sampled oral glucose tolerance test at 15 and 35 weeks of gestation in 184 socioeconomically disadvantaged African American women with overweight/obesity., Results: Insulin sensitivity decreased, whereas β-cell function and insulin clearance increased from 15 to 35 weeks of gestation in the entire group. Compared with women who achieved the recommended GWG, excessive GWG was associated with a greater decrease in insulin sensitivity between 15 and 35 weeks. β-cell function and plasma insulin clearance were not affected by excessive GWG., Conclusions: These data demonstrate that gaining more weight during pregnancy than recommended by the Institute of Medicine is associated with functional effects on glucose metabolism., (© 2022 The Obesity Society.)

Barth Syndrome (BTHS) is an X-linked mitochondrial cardioskeletal myopathy caused by defects in TAFAZZIN, a gene responsible for cardiolipin remodeling. Altered mitochondrial levels of cardiolipin lead to cardiomyopathy (CM), muscle weakness, exercise intolerance, and mortality. Cardiac risk factors predicting outcome are unknown. Therefore, we conducted a longitudinal observational study to determine risk factors for outcome in BTHS. Subjects with minimum two evaluations (or one followed by death or transplant) were included. Cardiac size, function, and QTc data were measured by echocardiography and electrocardiography at 7 time points from 2002 to 2018. Analysis included baseline, continuous, and categorical variables. Categorical risk factors included prolonged QTc, abnormal right ventricle fractional area change (RV FAC), left ventricle (LV) or RV non-compaction, and restrictive CM phenotype. The association between variables and cardiac death or transplant (CD/TX) was assessed. Median enrollment age was 7 years (range 0.5-22; n = 44). Transplant-free survival (TFS) was 74.4% at 15 years from first evaluation. The cohort demonstrated longitudinal declines in LV size and stroke volume z-scores (end-diastolic volume, p = 0.0002; stroke volume p < 0.0001), worsening RV FAC (p = 0.0405), and global longitudinal strain (GLS) (p = 0.0001) with stable ejection (EF) and shortening (FS) fraction. CD/TX subjects (n = 9) displayed worsening LV dilation (p = 0.0066), EF (p ≤ 0.0001), FS (p = 0.0028), and RV FAC (p = .0032) versus stability in TFS. Having ≥ 2 categorical risk factors predicted CD/TX (p = 0.0073). Over 15 years, 25% of BTHS subjects progressed to CD/TX. Those with progressive LV enlargement, dysfunction, and multiple cardiac risk factors warrant increased surveillance and intense therapy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL < 50 copies/ml) men (≥50 years old) living with HIV (MLWH) who were switched to integrase inhibitors (INSTI), and compared their body composition parameters and proinflammatory/endocrine profiles to age-matched MLWH on integrase inhibitor free (non-INSTI) regimens, taking into account neighborhood-level measures of socioeconomic status (SES). In addition, we used previously published HIV-seronegative men of the same age as controls., Methods: We used dual energy X-ray absorptiometry to quantify body composition parameters, and measured plasma proinflammatory/endocrine markers in 56 MLWH. We compared body composition to a publicly available dataset of 450 HIV-seronegative men of similar age. Within the MLWH group, body composition and plasma proinflammatory/endocrine markers were compared between individuals on INSTI and non-INSTI regimens, accounting for SES., Results: Men living with HIV tended to have a greater android/gynoid ratio compared to HIV-seronegative men ( p < 0.001). INSTI usage in MLWH was associated with lower adiposity measures when compared to non-INSTI, although these differences largely disappeared after controlling for SES. Proinflammatory/endocrine markers were similar for INSTI and non-INSTI MLWH., Conclusions: Among cART-experienced MLWH, those receiving INSTI-containing regimens had modestly lower adiposity compared to non-INSTI MLWH, although these differences were explained by SES. Future studies examining the relationship between INSTI use and body composition should consider the impact of SES.

Background: Hypertension remains the major risk factor for cardiovascular diseases (CVDs) worldwide with a prevalence and mortality in low- and middle-income countries (LMICs) among the highest. The early detection of hypertension risk factors is a crucial pillar for CVD prevention., Design and Method: This cross-sectional study included 4284 subjects, mean age 46 ± 16SD, 56.4% females and mean BMI 26.6 ± 3.7 SD. Data were collected through a screening campaign in rural area of Kirehe District, Eastern of Rwanda, with the objective to characterize and examine the prevalence of elevated blood pressure (BP) and other CVD risk factors. An adapted tool from the World Health Organization STEPwise Approach was used for data collection. Elevated BP was defined as ≥ 140/90 mm/Hg and elevated blood glucose as blood glucose ≥ 100 mg/dL after a 6-h fast., Results: Of the sampled population, 21.2% (n = 910) had an elevated BP at screening; BP was elevated among individuals not previously known to have HTN in 18.7% (n = 752). Among individuals with a prior diagnosis of HTN, 62.2% (n = 158 of 254) BP was uncontrolled. Age, weight, smoking, alcohol history and waist circumference were associated with BP in both univariate analyses and multivariate analysis., Conclusion: High rates of elevated BP identified through a health screening campaign in this Rwandan district were surprising given the rural characteristics of the district and relatively low population age. These data highlight the need to implement an adequate strategy for the prevention, diagnosis, and control of HTN that includes rural areas of Rwanda as part of a multicomponent strategy for CVD prevention., (© 2022. The Author(s).)

Background: Despite improved survival rates, neurocognitive impairment persists in persons living with HIV (PLWH). An active lifestyle is linked to improved cognition among PLWH, yet the neural substrates remain unclear. Diffusion tensor imaging and diffusion basis spectrum imaging measure HIV-related changes in brain white matter integrity. We used these measures of structural brain integrity to assess white matter changes, physical fitness, and cognition in a cross-sectional study of PLWH., Methods: Forty-four virologically well-controlled PLWH were recruited (average age of 56 years, a median recent CD4+ count of 682 cells/mm3). Diffusion tensor imaging -derived fractional anisotropy (FA) and diffusion basis spectrum imaging-derived axonal density were calculated. Cardiorespiratory fitness [maximal volume of oxygen consumption (VO2 max)] was measured by performing indirect calorimetry during exercise to volitional exhaustion. Cardiovascular risk was assessed by the Framingham risk score. Neuropsychological performance (NP) testing evaluated learning, memory, psychomotor/processing speed, and executive function. Partial correlations assessed the relationships among cardiorespiratory fitness, neuroimaging, NP, and HIV clinical metrics (CD4+ count and time since diagnosis)., Results: Higher VO2 max was associated with higher FA and higher axonal density in multiple white matter tracts, including the corticospinal tract and superior longitudinal fasciculus. Better NP in the motor/psychomotor domain was positively associated with FA and axonal density in diverse tracts including those associated with motor and visuospatial processing. However, higher VO2 max was not associated with NP or HIV clinical metrics., Conclusions: An active lifestyle promoting cardiorespiratory fitness may lead to better white matter integrity and decreased susceptibility to cognitive decline in virologically well-controlled PLWH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Tinius, RA, Blankenship, M, Maples, JM, Pitts, BC, Furgal, K, Norris, ES, Hoover, DL, Olenick, A, Lambert, J, and Cade, WT. Validity of the 6-minute walk test and Young Men's Christian Association (YMCA) submaximal cycle test during midpregnancy. J Strength Cond Res 35(11): 3236-3242, 2021-Submaximal exercise testing can be a feasible alternative to maximal testing within special populations to safely predict fitness levels; however, submaximal exercise testing has not been well-validated for use during pregnancy. The purpose of this study was to determine the concurrent validity of the 6-minute walk test (6MWT) and the YMCA submaximal cycle test (YMCAT) to predict V̇o2max in physically active women during midpregnancy. Thirty-seven (n = 37) pregnant women (22.1 ± 1.4 weeks' gestation) and 10 (n = 10) nonpregnant women participated in the study. Subjects completed a graded maximal treadmill test at 1 visit to measure maximal oxygen consumption (V̇o2max), and then subjects completed the 6MWT and YMCAT in randomized order during a separate visit. The predicted V̇o2max from each submaximal test were compared with the measured V̇o2max from the treadmill test to assess the validity of these tests during pregnancy. Among pregnant women, predicted V̇o2max from the YMCAT was not correlated to the measured V̇o2max (r = 0.14, p = 0.42), and the predicted V̇o2max from the 6MWT was only moderately correlated (r = 0.40, p = 0.016) to the measured V̇o2max. Among nonpregnant women, the predicted V̇o2max values from both the YMCAT and the 6MWT had strong correlations with the measured V̇o2max values (YMCAT: r = 0.71, p = 0.02; 6MWT: r = 0.80, p = 0.006). Neither test demonstrated concurrent validity among the pregnant sample. The main finding is that the YMCAT is not a valid method to estimate V̇o2max during midpregnancy (likely due to physiological changes in heart rate [HR] during pregnancy). The 6MWT has potential to be used clinically for estimating fitness as actual and predicted values did positively correlate, and it is not dependent on HR responses to exercise. However, if a precise measure of fitness is needed, then neither test appears to have strong validity for use during midpregnancy., (Copyright © 2019 National Strength and Conditioning Association.)

Background: Deviations from gestational weight gain (GWG) recommendations are associated with unfavorable maternal and neonatal outcomes. There is a need to understand how maternal substrate metabolism, independent of weight status, may contribute to GWG and neonatal outcomes. The purpose of this study was to explore the potential link between maternal lipid oxidation rate, GWG, and neonatal anthropometric outcomes., Methods: Women (N = 32) with a lean pre-pregnancy BMI were recruited during late pregnancy and substrate metabolism was assessed using indirect calorimetry, before and after consumption of a high-fat meal. GWG was categorized as follows: inadequate, adequate, or excess. Shortly after delivery (within 48 h), neonatal anthropometrics were obtained., Results: Using ANOVA, we found that fasting maternal lipid oxidation rate (grams/minute) was higher (p = 0.003) among women with excess GWG (0.1019 ± 0.0416) compared to women without excess GWG (inadequate = 0.0586 ± 0.0273, adequate = 0.0569 ± 0.0238). Findings were similar when lipid oxidation was assessed post-meal and also when expressed relative to kilograms of fat free mass. Absolute GWG was positively correlated to absolute lipid oxidation expressed in grams/minute at baseline (r = 0.507, p = 0.003), 2 h post-meal (r = 0.531, p = 0.002), and 4 h post-meal (r = 0.546, p = 0.001). Fasting and post-meal lipid oxidation (grams/minute) were positively correlated to neonatal birthweight (fasting r = 0.426, p = 0.015; 2-hour r = 0.393, p = 0.026; 4-hour r = 0.540, p = 0.001) and also to neonatal absolute fat mass (fasting r = 0.493, p = 0.004; 2-hour r = 0.450, p = 0.010; 4-hour r = 0.552, p = 0.001)., Conclusions: A better understanding of the metabolic profile of women during pregnancy may be critical in truly understanding a woman's risk of GWG outside the recommendations. GWG counseling during prenatal care may need to be tailored to women based not just on their weight status, but other metabolic characteristics., (© 2021. The Author(s).)

Background: Muscle weakness and exercise intolerance contribute to reduced quality of life (QOL) in Barth syndrome (BTHS). Our group previously found that 12 weeks of resistance exercise training (RET) improved muscle strength, however, did not increase muscle (lean) mass or QOL in n = 3 young adults with BTHS. The overall objective of this pilot study was to examine the safety and effectiveness of RET plus daily protein supplementation (RET + protein) on muscle strength, skeletal muscle mass, exercise tolerance, cardiac function, and QOL in late adolescents/young adults with BTHS., Methods: Participants with BTHS (n = 5, age 27 ± 7) performed 12 weeks of supervised RET (60 minutes per session, three sessions/week) and consumed 42 g/day of whey protein. Muscle strength, muscle mass, exercise capacity, cardiac function, and health-related QOL were assessed pre-post intervention., Results: RET + protein was safe, increased muscle strength and quality of life, and tended to increase lean mass., Conclusions: RET + protein appears safe, increases muscle strength and quality of life and tends to increase lean mass. Larger studies are needed to confirm these findings and to fully determine the effects of RET + protein in individuals with BTHS., Competing Interests: All authors declare that they have no conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function., Methods/results: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15 O-water and 1- 11 C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31 P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 μmol·g -1 ·min -1 , P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g -1 ·min -1 , P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS., Conclusions: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663., (© 2019. American Society of Nuclear Cardiology.)

Importance: Difficulty maintaining balance is common among individuals aged 40 years or older and increases the risk of falls. However, little is known about the association of balance function with long-term mortality outcomes in adults., Objective: To investigate the association of balance function with all-cause and cause-specific mortality among US adults., Design, Setting, and Participants: A prospective, population-based cohort study of a nationally representative sample of 5816 adults (weighted population, 92 260 641) from the US National Health and Nutrition Examination Survey was conducted from 1999 to 2004. Individuals aged 40 years or older who completed the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces were included. Participants were linked to mortality data from the test date through December 31, 2015. Data analysis was conducted from February 1 to June 1, 2020., Exposures: The modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces was used to measure balance function and define balance disorder according to sensory input., Main Outcomes and Measures: Mortality associated with all causes, cardiovascular disease (CVD), and cancer., Results: A total of 5816 adults (weighted mean [SE] age, 53.6 [0.2] years; 2897 [49.8%] women) were included in this cohort study. During up to 16.8 years of follow-up (median, 12.5 years; 68 919 person-years), 1530 deaths occurred, including 342 associated with CVD and 364 associated with cancer. Participants with balance disorder were at a higher risk of death from all causes, CVD, and cancer. After adjusting for sociodemographic characteristics, lifestyle factors, and chronic conditions, the hazard ratios (HRs) among participants with balance disorder compared with those without balance disorder were 1.44 (95% CI, 1.23-1.69) for all-cause mortality, 1.65 (95% CI, 1.17-2.31) for CVD mortality, and 1.37 (95% CI, 1.03-1.83) for cancer mortality. Furthermore, vestibular balance disorder was associated with increased mortality from all causes (HR, 1.31; 95% CI, 1.08-1.58), CVD (HR, 1.59; 95% CI, 1.12-2.27), and cancer (HR, 1.39; 95% CI, 1.04-1.86)., Conclusions and Relevance: In this nationally representative sample of US adults, balance disorder was associated with an increased risk of all-cause, CVD, and cancer mortality. Further studies are needed to confirm these findings and evaluate whether the observed associations represent a causal biological phenomenon and, if so, whether the effect is modifiable with a multicomponent exercise program.

The aim of this study was to determine the relationships between maternal metabolic flexibility during pregnancy and neonatal health outcomes. Percent change in lipid oxidation (before and after a high-fat meal) was calculated as the measure of "metabolic flexibility". Neonatal adiposity was assessed within 48 h of delivery by skinfold anthropometry. Metabolic flexibility ( r = -0.271, p = 0.034), maternal HOMA-IR ( r = 0.280, p = 0.030), and maternal body mass index ( r = 0.299, p = 0.018) were correlated with neonatal subscapular skinfold (i.e., measure of neonatal adiposity). Clinical Trail Registration Number: NCT03504319. Novelty: This is the first study to link maternal metabolic flexibility, body mass index, and insulin resistance during pregnancy to neonatal adiposity at parturition.

Introduction: Prediabetes is a major risk factor for type 2 diabetes and cardiovascular diseases. Although resistance exercise (RE) is recommended for individuals with prediabetes, the effects of RE on postprandial glucose metabolism in this population are poorly understood. Therefore, the purpose of this study was to elucidate how RE affects postprandial glucose kinetics, insulin sensitivity, beta cell function, and glucose oxidation during the subsequent meal in sedentary men with obesity and prediabetes., Methods: We studied 10 sedentary men with obesity (body mass index, 33 ± 3 kg·m-2) and prediabetes by using a randomized, cross-over study design. After an overnight fast, participants completed either a single bout of whole-body RE (seven exercises, 3 sets of 10-12 repetitions at 80% one-repetition maximum each) or an equivalent period of rest. Participants subsequently completed a mixed meal test in conjunction with an intravenous [6,6-2H2]glucose infusion to determine basal and postprandial glucose rate of appearance (Ra) and disappearance (Rd) from plasma, insulin sensitivity, and the insulinogenic index (a measure of beta cell function). Skeletal muscle biopsies were obtained 90 min postmeal to evaluate pyruvate-supported and maximal mitochondrial respiration. Whole-body carbohydrate oxidation was assessed using indirect calorimetry., Results: RE significantly reduced the postprandial rise in glucose Ra and plasma glucose concentration. Postprandial insulin sensitivity was significantly greater after RE, whereas postprandial plasma insulin concentration was significantly reduced. RE had no effect on the insulinogenic index, postprandial pyruvate respiration, or carbohydrate oxidation., Conclusion/interpretation: A single bout of RE has beneficial effects on postprandial glucose metabolism in men with obesity and prediabetes by increasing postprandial insulin sensitivity, reducing the postprandial rise in glucose Ra, and reducing postprandial plasma insulin concentration., (Copyright © 2020 by the American College of Sports Medicine.)

Cardiorespiratory fitness (CRF) is routinely investigated in diverse populations, including in older adults of varying physical activity levels. Commonly performed maximal exercise testing protocols might be contraindicated and/or inadequate for older individuals who have physical or cognitive impairment. Moreover, early termination of an attempted maximal exercise test could result in underestimation of CRF in this population. The goal of the current study was to compare CRF estimates using the Ekblom-Bak (EB) submaximal exercise test - previously validated in a cohort of Scandinavian adults - versus a subsequent maximal exercise test in a diverse, Midwestern United States cohort. Fifteen generally healthy individuals were included in this study who were either "Young" (25-34 years old) or "Older" (55-75 years old) as well as either sedentary or highly active. Participants completed the EB submaximal exercise test, followed immediately by a maximal exercise test. We found that all 15 individuals were able to successfully perform the EB submaximal testing method. Across the wide range of volumes of maximal oxygen consumption (VO 2 max; 12-52 ml/kg/min), the EB submaximal estimates of VO 2 max correlated highly with the maximal test based values (Pearson's r = 0.98), but with a small bias (6 ml/kg/min, 95% limits of agreement -1.06 and -11.29). Our results suggest that the EB submaximal testing method may be useful in identifying wide differences in CRF among a diverse cohort of older adults in the United States, but larger studies will be needed to determine the degree of its accuracy and precision in identifying smaller differences., (Copyright © 2020 Schultz, Byers, Benzinger, Reeds, Vlassenko, Cade and Goyal.)

Barth syndrome (BTHS) is a rare, X-linked cardiomyopathy that is characterized by abnormalities in glucose and lipid metabolism, with less known regarding amino acid metabolism. This pilot study characterized whole-body arginine kinetics and found lower arginine rate of appearance into plasma (0.69 ± 0.09 vs. 0.88 ± 0.06 μmol/kgFFM/min, p  < 0.01) and arginine non-oxidative disposal rate (0.64 ± 0.11 vs. 0.80 ± 0.03 μmol/kgFFM/min, p  < 0.02) in adolescents and young adults with BTHS compared to Controls. This study provides a foundation for more in-depth studies on how arginine and potentially other amino acid abnormalities contribute to the pathology and clinical manifestations of BTHS., Competing Interests: W. Todd Cade, Kathryn L. Bohnert, Bruce W. Patterson, Adam J. Bittel, Shaji K. Chacko, Christina A. Pacak, Barry J. Byrne, Hilary J Vernon, and Dominic N. Reeds declare that they have no conflict of interest., (© 2020 The Authors. Published by Elsevier Inc.)

Background: Increased mortality associated with low cardiorespiratory fitness has shown to take effect during late adulthood in previous generations. A recent rise in early death was observed in the United States. We investigated the impact of low cardiorespiratory fitness during young and middle adulthood on premature death in healthy adults from recent generations., Methods: A prospective cohort study of a nationally representative sample of US Baby Boomers and Generation Xers (born 1945-1980). Between 1999 and 2004, 3242 adults ages 20 to 49 years (weighted N = 59,888,450; mean age, 33.8 ± 0.2 years) underwent submaximal treadmill exercise test in the National Health and Nutrition Examination Survey study. Weighted Cox proportional hazards regression were used to evaluate the association of cardiorespiratory fitness with premature death at 65 years or younger., Results: During a mean follow-up of 13.8 years, 104 deaths (weighted deaths N =1,326,808) occurred. Low cardiorespiratory fitness was associated with an increased risk of premature death as a result of all-cause (hazard ratio [HR], low vs high: 2.26; 95% confidence interval [CI], 1.10 to 4.64, P for trend = 0.036) and cancer mortality (HR low vs moderate/high: 6.53; 95% CI, 2.38 to 17.9). Further, this association was stronger in adults ages 35 to 49 years at baseline (HR, 4.17 [95% CI, 1.19 to 9.11])., Conclusion: We observed an inverse association between cardiorespiratory fitness during middle adulthood and premature death, which was not detected in preceding generations. These findings suggested that low cardiorespiratory fitness might be emerging as a new risk factor for early death among US Baby Boomers and Generation Xers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hypertension (HTN) affects nearly 1 billion people globally and is a major cause of morbidity and mortality. In low- and middle-income countries (LMICs), HTN represents an unmet health care gap that can be addressed by strengthening national health care systems. The National Heart, Lung, and Blood Institute recently funded the T4 Translation Research Capacity Building Initiative in Low Income Countries (TREIN) program to build capacity in dissemination and implementation (D&I) research in HTN in LMICs. The Special Programme for Research and Training in Tropical Diseases (TDR) at the World Health Organization (WHO) recently developed a massive open online course (MOOC) to train in D&I. Herein, we report on the use of the TDR WHO MOOC in D&I for the TREIN program in Rwanda, assessing feasibility of the MOOC and D&I competencies after MOOC training., Methods: Participants in one-group MOOC training completed pre- and post-training questionnaires to assess dissemination and implementation (D&I) competency outcomes and feasibility. D&I competencies were measured by use of a scale developed for a US-based training program, with the change in competency scores assessed by paired t test. Feasibility was measured by completion of homework and final project assignment and analyzed using descriptive statistics., Results: Of the 92 trainees enrolled, 35 (38%) completed all MOOC components. D&I competency scores showed strong evidence of improvements from pre- to post-test. The full-scale average score improved by an average of 1.09 points, representing an effect size of 1.25 (CI 0.48-2.00); all four subscales also showed strong evidence of improvements. Trainees reported challenges to MOOC course completion that included technological issues (i.e., limited internet access) and competing demands (i.e., work, family)., Conclusions: In the context of LMIC training, the MOOC course was feasible and course completion showed improvement in D&I competency scores. While the program was designed with a focus on training for tropical diseases, there is potential for scalability to a wider audience of health care researchers, workers, administrators, and policymakers in LMIC interested in D&I research in non-communicable diseases., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Aims/hypothesis: Prediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes., Methods: We evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10-12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m 2 ), sedentary men with prediabetes (HbA 1c >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [( 13 C 4 ) 3 ]tripalmitin, i.v. [U- 13 C 16 ]palmitate and [ 2 H 5 ]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation., Results: The single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue., Conclusions/interpretation: A single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.

Context: Maternal obesity is a significant public health concern that contributes to unfavorable outcomes such as inflammation and insulin resistance. Women with obesity may have impaired metabolic flexibility (i.e. an inability to adjust substrate metabolism according to fuel availability). Impaired metabolic flexibility during pregnancy may mediate poor pregnancy outcomes in women with obesity., Purpose: The purposes of this study were to: 1) compare metabolic flexibility between overweight/obese and lean women; and 2) determine the relationships between metabolic flexibility, inflammation following a high-fat meal, and maternal metabolic health outcomes (i.e. gestational weight gain and insulin resistance)., Procedures: This interventional physiology study assessed lipid oxidation rates via indirect calorimetry before and after consumption of a high-fat meal. The percent change in lipid metabolism was calculated to determine 'metabolic flexibility.' Maternal inflammatory profiles (CRP, IL-6, IL-8, IL-10, IL-12, TNF-α) and insulin resistance (HOMA-IR) were determined via plasma analyses., Main Findings: 64 women who were pregnant (lean = 35, overweight/obese = 29) participated between 32 and 38 weeks gestation. Lean women had significantly higher metabolic flexibility compared to overweight/obese women (lean 48.0 ± 34.1% vs overweight/obese 29.3 ± 34.3%, p = .035). Even when controlling for pre-pregnancy BMI, there was a negative relationship between metabolic flexibility and percent change in CRP among the overweight/obese group (r = -0.526, p = .017). Metabolic flexibility (per kg fat free mass) was negatively correlated with postprandial HOMA-IR (2 h: r = -0.325, p = .016; 4 h: r = -0.319, p = .019)., Conclusions: Overweight and obese women who are pregnant are less 'metabolically flexible' than lean women, and this is related to postprandial inflammation and insulin resistance., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To examine the communication between obstetric providers and their socioeconomically disadvantaged, African American patients who are overweight and obese during pregnancy, and whether this communication relates to outcomes. Pregnant patients and their obstetric providers were surveyed between October 2012 and March 2016 at Washington University School of Medicine in St. Louis, MO. Percent agreement between patients' and obstetric providers' survey responses was analyzed and measured (κ coefficient). Descriptive and multilevel logistic regression analyses aimed at identifying the relation of perceived communication between providers and patients to gestational weight gain, diet, and exercise during pregnancy. A total of 99 pregnant women and 18 obstetric providers participated in the study. Significant lack of agreement was observed between patients and obstetric providers regarding communication about weight gain recommendations, risk factors associated with excessive weight gain, what constitutes adequate exercise per week, exercise recommendations, dietary recommendations, and risk factors associated with a poor diet. Our findings suggest patients were not receiving intended messages from their obstetric providers. Thus, more effective patient-obstetric provider communication is needed regarding gestational weight gain, exercise and dietary recommendations among overweight/obese, socioeconomically disadvantaged, African American women.

Objective: This study aimed to investigate the potential antiobesity benefits of hot tea consumption at the population level., Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006, the association between hot tea consumption and dual-energy x-ray-measured body fat was examined in a large representative sample of US adults (n = 5,681, 51.9% women)., Results: Compared with non-tea drinkers, men who consumed 0.25 to 1 cup per day of hot tea had 1.5% (95% CI: 0.4% to 2.6%) and 1.7% (95% CI: 0.4% to 3.0%) less total and trunk body fat, respectively. The associations were stronger among men 45 to 69 years old compared with younger men (20-44 years). For men who consumed 1 or more cups per day of hot tea, lower total (-1.2%, 95% CI: -2.3% to -0.2%) and trunk body fat (-1.3%, 95% CI: -2.6 to -0.1%) was observed among men 45 to 69 years old only. In women, those who drank 1 or more cups per day had 1.5% lower (95% CI: -2.7% to -0.3%) trunk body fat compared with non-tea drinkers., Conclusions: Consumption of hot tea might be considered as part of a healthy diet in order to support parameters associated with metabolic health and may be particularly important in older male age groups in supporting reduced central adiposity., (© 2020 The Obesity Society.)

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome., Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment., Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups., Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting. Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Barth syndrome (BTHS) is a rare, X-linked, mitochondrial disorder caused by mutations in the gene encoding tafazzin. BTHS results in cardiomyopathy, muscle fatigue, and neutropenia in patients. Tafazzin is responsible for remodeling cardiolipin, a key structural lipid of the inner mitochondrial membrane. As symptoms can vary in severity amongst BTHS patients, we sought to compare mtDNA copy numbers, mitochondrial fragmentation, and functional parameters between primary dermal BTHS fibroblasts isolated from patients with two different mutations in the TAZ locus. To confirm cause‒effect relationships and further support the development of gene therapy for BTHS, we also characterized the BTHS cells following adeno-associated virus (AAV)- TAZ transduction. Our data show that, in response to AAV- TAZ transduction, these remarkably dynamic organelles show recovery of mtDNA copy numbers, mitochondrial structure, and mitochondrial function, providing additional evidence to support the therapeutic potential of AAV-mediated gene delivery for BTHS. This study also demonstrates the direct relationship between healthy mitochondrial membrane structure and maintenance of proper levels of mtDNA copy numbers.

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and in low- and middle-income countries, and hypertension (HTN) is a major risk factor for CVD. Although effective evidence-based interventions for control of HTN in high-income countries exist, implementation of these in low- and middle-income countries has been challenging due to limited capacity and infrastructure for late-phase translational research. In Rwanda, the 2015 STEPS NCD (STEPwise Approach to Surveillance of Noncommunicable Diseases) risk survey reported an overall prevalence of HTN of 15% (95% confidence interval [CI]: 13.8 to 16.3) for those ages 15 to 64 years; prevalence increased with increasing age to 39% (95% CI: 35.7 to 43.1) for those ages 55 to 64 years; CVD was the third most common cause of mortality (7%). Suboptimal infrastructure and capacity in Rwanda hinders research and community knowledge for HTN control., Objectives: To address the issue of suboptimal capacity to implement evidence-based interventions in HTN, this project was designed with the following objectives: 1) to develop a regional needs assessment of infrastructure for dissemination and implementation (D & I) strategies for HTN-CVD control; 2) to develop HTN-CVD research capacity through creation of countrywide resources such as core research facilities and training in the fields of HTN-CVD, D & I, and biostatistics; and 3) to engage and train multiple stakeholders in D & I and HTN-CVD evidence-based interventions., Methods: A weeklong training program in HTN-CVD, biostatistics, and D & I was conducted in Rwanda in August 2018, and pre- and post-D & I training competency questionnaires were administered., Results: Questionnaire results show a statistically significant increase in D & I knowledge and skills as a result of training (full scale pre- to post-test scores: 2.12 ± 0.78 vs. 3.94 ± 0.42; p < 0.0001)., Conclusions: Using principles of community engagement and train-the-trainer methods, we will continue to adapt guidelines and treatments for HTN-CVD developed in high-income countries to the context of Rwanda with the goal of establishing a sustainable platform to address the burden of disease from HTN-CVD., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Determine the validity and reliability of an exercise testing protocol to evaluate cardiorespiratory measures in manual wheelchair users (MWUs) with spinal cord injury (SCI) using a roller-based (RS) wheelchair system., Design: Repeated measures within-subject design., Setting: Community-based research laboratory., Participants: Ten adults with SCI requiring the use of a manual wheelchair., Interventions: Not applicable., Outcome Measures: Cardiorespiratory measures (peak oxygen consumption [VO 2 peak], respiratory exchange ratio [RER], pulmonary ventilation [VE], energy expenditure [EE], heart rate [HR], accumulated kilocalories [AcKcal]) and perceived exertion (RPE) were measured during three separate maximal exercise tests using an arm crank ergometer (ACE) and an RS., Results: At maximal exertion, there were no significant differences in variables between groups, with moderate-to-strong correlations (P < 0.05, r = 0.79-0.90) for VO 2 , HR, RPE, AcKcal, and rate of EE between RS and ACE trials. Significant moderate-to-strong correlations existed between RS trials for VO 2 , AcKcal, rate of EE, and peak power output (P < 0.01, r = 0.77-0.97)., Conclusions: VO 2peak was highly correlated between ACE and RS trials and between the two RS trials, indicating the RS protocol to be reliable and valid for MWUs with SCI. Differences in perceived exertion and efficiency at submaximal workloads and maximal pulmonary ventilation at peak workloads indicated potential advantages to using the RS.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U- 13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% V ˙ O 2 peak ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS., (© 2019 SSIEM.)

Objective: This study aimed to assess the efficacy of a home-based lifestyle intervention delivered through Parents as Teachers (PAT), a national home-visiting organization, designed to minimize excessive weight gain through 12 months post partum in socioeconomically disadvantaged (SED) African American women with overweight or obesity., Methods: This randomized controlled trial was conducted at a single center as part of the Lifestyle Interventions for Expectant Moms (LIFE-Moms) consortium. Analysis was conducted with 185 SED African American women (BMI 25.0-45.0 kg/m 2 at pregnancy onset) retained from an original sample of 267 randomized to standard PAT or PAT+Lifestyle, which embedded lifestyle therapy within standard PAT delivered prenatally and for 12 months post partum., Results: Compared with standard PAT, the PAT+Lifestyle group gained less weight (2.5 kg vs. 5.7 kg; P = 0.01) and were more likely to return to their baseline weight (38.0% vs. 21.5%; P = 0.01) from baseline to 12 months post partum. There were no differences between groups in cardiometabolic outcomes, indices of glycemic control and insulin sensitivity, and plasma lipid profile. The estimated cost of PAT+Lifestyle was $81 more to deliver per family than standard PAT., Conclusions: PAT+Lifestyle decreases weight gain during pregnancy through 12 months post partum in SED African American women with overweight or obesity at the start of pregnancy with minimal additional cost., (© 2019 The Obesity Society.)

Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 10 13 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age). At 5 months of age, evaluations of biodistribution and TAZ expression levels, mouse activity assessments, fatigue in response to exercise, muscle strength, cardiac function, mitochondrial structure, oxygen consumption, and electron transport chain complex activity assays were performed to measure the extent of improvement in treated mice. Each promoter was scored for significant improvement over untreated control mice and significant improvement compared with the other two promoters for every measurement and within each age of administration. All three of the promoters resulted in significant improvements in a majority of the assessments compared with untreated BTHS controls. When scored for overall effectiveness as a gene therapy, the Des promoter was found to provide improvement in the most assessments, followed by the CMV promoter, and finally Taz regardless of injection age. This study provides substantial support for translation of an adeno-associated virus serotype 9-mediated TAZ gene replacement strategy using a Des promoter for human BTHS patients in the clinic.

Barth syndrome (BTHS) is a rare mitochondrial disease that causes severe cardiomyopathy and has no disease-modifying therapy. It is caused by recessive mutations in the gene tafazzin ( TAZ ), which encodes tafazzin-an acyltransferase that remodels the inner mitochondrial membrane lipid cardiolipin. To identify novel mechanistic pathways involved in BTHS and evaluate the effects of gene therapy on proteomic profiles, we performed a multiplex tandem mass tagging (TMT) quantitative proteomics analysis to compare protein expression profiles from heart lysates isolated from BTHS, healthy wild-type (WT), and BTHS treated with adeno-associated virus serotype 9 (AAV9)- TAZ gene replacement as neonates or adults. 197 proteins with ≥2 unique peptides were identified. Of these, 91 proteins were significantly differentially expressed in BTHS compared to WT controls. Cause-effect relationships between tafazzin deficiency and altered protein profiles were confirmed through demonstrated significant improvements in expression levels following administration of AAV9- TAZ . The importance of TMEM65 in Cx43 localization to cardiac intercalated discs was revealed as a novel consequence of tafazzin deficiency that was improved following gene therapy. This study identifies novel mechanistic pathways involved in the pathophysiology of BTHS, demonstrates the ability of gene delivery to improve protein expression profiles, and provides support for clinical translation of AAV9- TAZ gene therapy.

Background: Pediatric short bowel syndrome (SBS) is a malabsorptive state placing patients at risk for malnutrition, dehydration, and bacterial overgrowth. These patients are often dependent on parenteral nutrition (PN) while intestinal adaptation is underway. The aim of this study was to characterize the effect of remnant small bowel length on the gut microbiome. Further, we sought to examine the contribution of clinical and nutritional variables to the gut microbiota and anthropometric growth., Study Design: Clinical data, anthropometrics, and fecal samples were collected from 14 SBS patients and 10 age- and sex-matched controls. Fecal bacterial DNA composition was analyzed using 16s ribosomal RNA gene sequencing. Statistical analysis was completed using the Mann-Whitney or Fisher's exact tests when applicable and linear mixed effect modeling., Results: Distinct microbiota changes were found among those with the least remaining small bowel (<35 cm) compared with those with longer remaining bowel and controls. Those with <35 cm small bowel displayed an increased relative abundance of Proteobacteria, while those with longer remaining small bowel had a higher proportion of Firmicutes. Further, patients with less remaining bowel required more PN (p < 0.01), with a tendency to be shorter in height (p = 0.05) and with a higher BMI (p = 0.05)., Conclusions: Remnant small bowel length appears to be a predictor of stunting with diminished linear growth, parenteral nutrition dependency, and a greater relative abundance of Proteobacteria in the gut. These findings suggest an integrated adaptive response predicted by remnant intestinal length. Further research is necessary to examine the effects of intestinal dysbiosis on clinical outcomes., (Copyright © 2018 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The role of mitochondria in the development of skeletal muscle insulin resistance has been an area of intense investigation and debate for over 20 years. The mitochondria is a multifaceted organelle that plays an integral part in substrate metabolism and cellular signalling. This article aims to summarize the current findings and thought regarding the relationship between mitochondria and insulin resistance in skeletal muscle., Recent Findings: Skeletal muscle insulin resistance was earlier thought to result from deficiency in mitochondrial oxidative capacity and ectopic lipid accumulation. Recent evidence suggests that skeletal muscle insulin resistance in high-energy intake models (i.e. obesity) results primarily from disrupted mitochondrial bioenergetics and alterations in mitochondrial-associated cell signalling. These signalling pathways include reactive oxygen species and redox balance, fatty acid β-oxidation intermediates, mitochondrial derived peptides, sirtuins, microRNAs and novel nuclear-encoded, mitochondria-acting peptides., Summary: The pathophysiology of skeletal muscle insulin resistance is likely multifactorial involving many coordinated physiological processes. However, it is apparent that the mitochondria play an essential role in skeletal muscle insulin sensitivity in health, ageing and in numerous metabolic diseases. Deciphering the manifold functions of the mitochondria will allow us to understand the complex relationship between mitochondria and skeletal muscle insulin resistance.

Background: Currently 20-35% of pregnant women are obese, posing a major health risk for mother and fetus. It is postulated that an abnormal maternal-fetal nutritional environment leads to adverse metabolic programming, resulting in altered substrate metabolism in the offspring and predisposing to risks of obesity and diabetes later in life. Data indicate that oocytes from overweight animals have abnormal mitochondria. We hypothesized that maternal obesity is associated with altered mitochondrial function in healthy neonatal offspring., Methods: Overweight and obese (body mass index, (BMI) ≥ 25 kg/m 2 , n = 14) and lean (BMI < 25 kg/m 2 , n = 8), African-American pregnant women carrying male fetuses were recruited from the Barnes Jewish Hospital obstetric clinic. Maternal and infant data were extracted from medical records. Infants underwent body composition testing in the first days of life. Circumcision skin was collected for isolation of fibroblasts. Fibroblast cells were evaluated for mitochondrial function, metabolic gene expression, nutrient uptake, and oxidative stress., Results: Skin fibroblasts of infants born to overweight mothers had significantly higher mitochondrial respiration without a concurrent increase in ATP production, indicating mitochondrial inefficiency. These fibroblasts had higher levels of reactive oxygen species and evidence of oxidative stress. Evaluation of gene expression in offspring fibroblasts revealed altered expression of multiple genes involved in fatty acid and glucose metabolism and mitochondrial respiration in infants of overweight mothers., Conclusions: This study demonstrates altered mitochondrial function and oxidative stress in skin fibroblasts of infants born to overweight mothers. Future studies are needed to determine the long-term impact of this finding on the metabolic health of these children.

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS., Methods and Materials: VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least two exercise tests over a span of 2-9 years., Results: VO2peak relative to body weight (ml/kgBW/min), fat-free mass (FFM) and by percent of predicted VO2peak obtained were not significantly different between children, adolescents and young adults. VO2peak did not longitudinally change over a mean time of ~5 years in late adolescent and young adult participants with repeated tests. A model including both cardiac and skeletal muscle variables best predicted VO2peak., Conclusions: In conclusion, VO2peak relative to body weight and fat-free mass demonstrates short- and long-term stability from childhood to young adulthood in BTHS with some variability among individuals., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to evaluate the efficacy of a home-based lifestyle intervention delivered through Parents as Teachers (PAT) to reduce excessive gestational weight gain (GWG)., Methods: This was a single-blinded randomized controlled trial conducted as part of the LIFE-Moms consortium at a single university-based tertiary care institution from October 2012 to March 2016. There were 267 socioeconomically disadvantaged (SED) African American women with overweight or obesity (BMI 25.0-45.0 kg/m 2 before pregnancy. Participants were randomized to therapy with standard PAT alone (n = 134) or PAT plus a lifestyle intervention program embedded within the standard PAT program (PAT+) (n = 133). Both interventions were delivered in 10 biweekly home visits during pregnancy. The primary outcome was the percentage of women whose GWG exceeded the Institute of Medicine guidelines, and secondary outcomes included both weekly and total GWG., Results: Compared with the standard PAT group in the intent-to-treat analysis, the PAT + group gained less weekly (0.4 kg vs. 0.5 kg/wk; P = 0.04) and total (8.0 kg vs. 9.6 kg; P = 0.02) weight during gestation. Fewer participants in the PAT + group had excessive total GWG (36.1% vs. 45.9%), but the difference between groups was not statistically significant (P = 0.11)., Conclusions: PAT + reduced the weekly and total GWG in SED African American women with overweight or obesity at the start of pregnancy., (© 2018 The Obesity Society.)