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BACKGROUND: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD. METHODS: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome. RESULTS: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality (P<0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality (P<0.05). CONCLUSIONS: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta-analysis was to evaluate the effects of high-repetition strength training (HRST) on performance in competitive endurance athletes. The methodology followed the Preferred Reporting Items for Systematic Review and Meta-Analysis protocol. A search of databases was performed until December 2020. Inclusion criteria were (a) competitive endurance athletes, (b) ≥4 weeks HRST intervention, (c) control or comparison group, (d) outcome measures of performance (either physiological or time trial performance), and (e) all experimental designs. Quality assessment was performed using the Physiotherapy Evidence Database (PEDro) scale. Of the 615 studies retrieved, 11 studies were included (216 subjects) and 9 studies provided sufficient data for the meta-analysis (137 subjects). The PEDro scale score had a mean of 5 of 10 points (range: 3-6). There was no significant difference between the HRST and control groups (g = 0.35; 95% confidence interval [CI] = -0.38 to 1.07; p = 0.35) or HRST and low-repetition strength training (LRST) groups (g = 0.24; 95% CI = -0.24 to 0.72; p = 0.33). The findings of this review and meta-analysis indicate that HRST does not result in improved performance over a 4-to 12-week period, and the results seem to be similar to LRST. The majority of studies involved recreational endurance athletes and had a mean duration of 8 weeks, which is a limitation of the findings. Future intervention studies should be > 12 weeks in duration and involve well-trained endurance athletes (maximal oxygen uptake [V̇o2max] of >65 ml·kg-1·min-2). [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: The timing and magnitude of antiretroviral therapy–associated weight change attributions are unclear. Setting: HIV Outpatient Study participants. Methods: We analyzed 2007–2018 records of virally suppressed (VS) persons without integrase inhibitor (INSTI) experience who switched to either INSTI-based or another non–INSTI-based ART, and remained VS. We analyzed BMI changes using linear mixed models, INSTI- and tenofovir alafenamide (TAF) contributions to BMI change by linear mixed models–estimated slopes, and BMI inflection points. Results: Among 736 participants (5316 person-years), 441 (60%) switched to INSTI-based ART; the remainder to non–INSTI-based ART. The mean follow-up was 7.15 years for INSTI recipients and 7.35 years for non-INSTI. Preswitch, INSTI and non-INSTI groups had similar median BMI (26.3 versus 25.9 kg/m2, P = 0.41). INSTI regimens included raltegravir (178), elvitegravir (112), and dolutegravir (143). Monthly BMI increases postswitch were greater with INSTI than non-INSTI (0.0525 versus 0.006, P < 0.001). A BMI inflection point occurred 8 months after switch among INSTI users; slopes were similar regardless of TAF use immediately postswitch. Among INSTI + TAF users, during 8 months postswitch, 87% of BMI slope change was associated with INSTI use, 13% with TAF use; after 8 months, estimated contributions were 27% and 73%, respectively. For non-INSTI+TAF, 84% of BMI gain was TAF-associated consistently postswitch. Persons switching from TDF to TAF had greater BMI increases than others (P < 0.001). Conclusion: Among VS persons who switched ART, INSTI and TAF use were independently associated with BMI increases. During 8 months postswitch, BMI changes were greatest and most associated with INSTI use; afterward, gradual BMI gain was largely TAF-associated. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH. [ABSTRACT FROM AUTHOR]

Background: Three-column osteotomies (3COs), usually in the form of pedicle subtraction or vertebral column resection, have become common in adult spinal deformity surgery. Although a powerful tool for deformity correction, 3COs can increase the risks of perioperative morbidity.Methods: Operative patients with adult spinal deformity (Cobb angle of >20°, sagittal vertical axis [SVA] of >5 cm, pelvic tilt of >25°, and/or thoracic kyphosis of >60°) with available baseline and 2-year radiographic and health-related quality-of-life (HRQoL) data were included. Patients were stratified into 2 groups by surgical year: Group I (2008 to 2013) and Group II (2014 to 2018). Patients with 3COs were then isolated for outcomes analysis. Severe sagittal deformity was defined by an SVA of >9.5 cm. Best clinical outcome (BCO) was defined as an Oswestry Disability Index (ODI) of <15 and Scoliosis Research Society (SRS)-22 of >4.5. Multivariable regression analyses were used to assess differences in surgical, radiographic, and clinical parameters.Results: Seven hundred and fifty-two patients with adult spinal deformity met the inclusion criteria, and 138 patients underwent a 3CO. Controlling for baseline SVA, PI-LL (pelvic incidence minus lumbar lordosis), revision status, age, and Charlson Comorbidity Index (CCI), Group II was less likely than Group I to have a 3CO (21% versus 31%; odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.4 to 0.97) and more likely to have an anterior lumbar interbody fusion (ALIF; OR = 1.6; 95% CI = 1.3 to 2.3) and a lateral lumbar interbody fusion (LLIF; OR = 3.8; 95% CI = 2.3 to 6.2). Adjusted analyses showed that Group II had a higher likelihood of supplemental rod usage (OR = 21.8; 95% CI = 7.8 to 61) and a lower likelihood of proximal junctional failure (PJF; OR = 0.23; 95% CI = 0.07 to 0.76) and overall hardware complications by 2 years (OR = 0.28; 95% CI = 0.1 to 0.8). In an adjusted analysis, Group II had a higher likelihood of titanium rod usage (OR = 2.7; 95% CI = 1.03 to 7.2). Group II had a lower 2-year ODI and higher scores on Short Form (SF)-36 components and SRS-22 total (p < 0.05 for all). Controlling for baseline ODI, Group II was more likely to reach the BCO for the ODI (OR = 2.8; 95% CI = 1.2 to 6.4) and the SRS-22 total score (OR = 4.6; 95% CI = 1.3 to 16).Conclusions: Over a 10-year period, the rates of 3CO usage declined, including in cases of severe deformity, with an increase in the usage of PJF prophylaxis. A better understanding of the utility of 3CO, along with a greater implementation of preventive measures, has led to a decrease in complications and PJF and a significant improvement in patient-reported outcome measures.Level Of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: More recent birth cohorts are at a higher depression risk than cohorts born in the early 20th century. We aimed to investigate to what extent changes in alcohol consumption, smoking, physical activity, and obesity contribute to these birth cohort variations.Methods: We analyzed panel data from US adults born 1916-1966 enrolled in the Health and Retirement Study (N = 163,760 person-years). We performed a counterfactual decomposition analysis by combining age-period-cohort models with g-computation. We thereby compared the predicted probability of elevated depressive symptoms (CES-D 8 score ≥3) in the natural course to a counterfactual scenario where all birth cohorts had the health behaviors of the 1945 birth cohort. We stratified analyses by sex and race-ethnicity.Results: We estimated that depression risk of the 1916-1949 and 1950-1966 birth cohort would be on average 2.0% (-2.3 to -1.7) and 0.5% (-0.9 to -0.1) higher with the alcohol consumption levels of the 1945 cohort. In the counterfactual with the 1945 BMI distribution, depression risk is on average 2.1% (1.8 to 2.4) higher for the 1916-1940 cohorts and 1.8% (-2.2 to -1.5) lower for the 1950-1966 cohorts. We find no cohort variations in depression risk for smoking and physical activity. The contribution of alcohol is more pronounced for Whites than for other race-ethnicity groups, and the contribution of BMI more pronounced for women than for men.Conclusion: Increased obesity levels were associated with exacerbated depression risk in recent birth cohorts in the United States, while drinking patterns only played a minor role. [ABSTRACT FROM AUTHOR]

Bile acid‐CoA: amino acid N‐acyltransferase (BAAT) catalyzes bile acid conjugation, the last step in bile acid synthesis. BAAT gene mutation in humans results in hypercholanemia, growth retardation, and fat‐soluble vitamin insufficiency. The current study investigated the physiological function of BAAT in bile acid and lipid metabolism using Baat−/− mice. The bile acid composition and hepatic gene expression were analyzed in 10‐week‐old Baat−/− mice. They were also challenged with a westernized diet (WD) for additional 15 weeks to assess the role of BAAT in bile acid, lipid, and glucose metabolism. Comprehensive lab animal monitoring system and cecal 16S ribosomal RNA gene sequencing were used to evaluate the energy metabolism and microbiome structure of the mice, respectively. In Baat−/− mice, hepatic bile acids were mostly unconjugated and their levels were significantly increased compared with wild‐type mice. Bile acid polyhydroxylation was markedly up‐regulated to detoxify unconjugated bile acid accumulated in Baat−/− mice. Although the level of serum marker of bile acid synthesis, 7α‐hydroxy‐4‐cholesten‐3‐one, was higher in Baat−/− mice, their bile acid pool size was smaller. When fed a WD, the Baat−/− mice showed a compromised body weight gain and impaired insulin secretion. The gut microbiome of Baat−/− mice showed a low level of sulfidogenic bacteria Bilophila. Conclusion: Mouse BAAT is the major taurine‐conjugating enzyme. Its deletion protected the animals from diet‐induced obesity, but caused glucose intolerance. The gut microbiome of the Baat−/− mice was altered to accommodate the unconjugated bile acid pool. [ABSTRACT FROM AUTHOR]