Background Cardiovascular disease is currently the leading cause of death in patients with human immunodeficiency virus on combination antiretroviral therapy. Although the use of the protease inhibitor ritonavir has been associated with increased prevalence of cardiovascular disease, the underlying mechanisms remain ill-defined. Herein, we tested the hypothesis that ritonavir-mediated lipoatrophy causes endothelial dysfunction via reducing endothelial leptin signaling. Methods and Results Long-term (4 weeks) but not short-term (3 days) treatment with ritonavir reduced body weight, fat mass, and leptin levels and induced endothelial dysfunction in mice. Moreover, ritonavir increased vascular NADPH oxidase 1, aortic H2O2 levels as well as interleukin-1β, GATA3 (GATA binding protein 3), the macrophage marker (F4/80), and C-C chemokine receptor type 5 (CCR5) expression. Reactive oxygen species scavenging with tempol restored endothelial function, and both NADPH oxidase 1 and CCR5 deletion in mice protected from rprovide beneficial avenues for limiting human immunodeficiency virus infection.Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.Prior studies have reported white matter abnormalities associated with a history of cumulative concussion and/or repetitive head impacts (RHI) in contact sport athletes. Growing evidence suggests these abnormalities may begin as more subtle changes earlier in life in active younger athletes. We investigated the relationship between prior concussion and contact sport exposure with multi-modal white matter microstructure and macrostructure using magnetic resonance imaging. High school and collegiate athletes (n = 121) completed up to four evaluations involving neuroimaging. Linear mixed-effects models examined associations of years of contact sport exposure (i.e., RHI proxy) and prior concussion across multiple metrics of white matter, including total white matter volume, diffusion tensor imaging (DTI) metrics, diffusion kurtosis imaging (DKI) metrics, and quantitative susceptibility mapping (QSM). buy Lurbinectedin A significant inverse association between cumulative years of contact sport exposure and QSM was observed, F(1, 237.77) = 4.67, p = 0.032. Cumulative contact sport exposure was also associated with decreased radial diffusivity, F(1, 114.56) = 5.81, p = 0.018, as well as elevated fractional anisotropy, F(1, 115.32) = 5.40, p = 0.022, and radial kurtosis, F(1, 113.45) = 4.03, p = 0.047. In contrast, macroscopic white matter volume was not significantly associated with cumulative contact sport exposure (p > 0.05). Concussion history was not significantly associated with QSM, DTI, DKI, or white matter volume (all, p > 0.05). Cumulative contact sport exposure is associated with subtle differences in white matter microstructure, but not gross white matter macrostructure, in young active athletes. Longitudinal follow-up is required to assess the progression of these findings to determine their contribution to potential adverse effects later in life.Background Levothyroxine (LT4) as a medication is used by up to 5.3% of the adult population. For optimal efficacy, the traditional tablet formulation (LT4tab) requires that patients avoid concomitant ingestion with food, drinks, and certain medications, as well as excellent patient compliance. Some comorbidities influence bioavailability of LT4 and may mandate repeated dose adjustments. Summary New LT4 formulations (soft gel [LT4soft] and liquid [LT4liq]) containing predissolved LT4 are claimed to improve bioavailability, presumably by facilitating absorption. Thus, these formulations may well be more suitable than LT4tab for patients whose daily requirements are subjected to variations in bioavailability. Here, we review the evidence and indications for use of new LT4 formulations and highlight areas of uncertainty that are worthy of further investigation. While bioequivalence is established for LT4soft and LT4liq administered to healthy volunteers compared with LT4tab in pharmacokinetic (PK) studies, therapeutic equivalence of the new formulations seems to be different in several clinical settings. Some evidence suggests that new formulations of LT4 may mitigate against the strict requirements relating to concomitant ingestion with food, drinks, and certain medications, which apply to traditional LT4 tablets. The principal indication is in selected patients with disease fluctuations and intermittent therapies with interfering medications, where the need for frequent dose adjustments and office visits may be diminished. Whether the use of LT4soft or LT4liq in patients with impaired gastric acid secretion results in better control of hypothyroidism than LT4tab remains unclear. Conclusions The evidence in favor of using LT4soft and LT4liq in clinical practice over LT4tab is weak, and the underlying putative PK mechanisms unclear. Additional studies to investigate these potential benefits, define the cost-effectiveness, and understand the PK mechanisms involved with new LT4 formulations are needed.