A potential role for adjunctive vitamin D therapy in the management of weight gain and metabolic side effects of second-generation antipsychotics

Second-generation antipsychotic (SGA) medications introduced about 20 years ago are increasingly used to treat psychiatric illnesses in children and adolescents. There has been a five-fold increase in the use of these medications in U.S. children and adolescents in the past decade. However, there has also been a parallel rise in the incidence of side effects associated with these medications, such as obesity, dyslipidemia, insulin resistance, and diabetes mellitus. Despite the severity of these complications and their financial impact on the national healthcare budget, there is neither a clear understanding of the mechanisms contributing to these side effects nor the best ways to address them. Studies that examined lifestyle modification and pharmaceutical agents have yielded mixed results. Therefore, clinical studies using agents, such as vitamin D, which are inexpensive, readily available, with low side effects profile, and have mechanisms to counteract the metabolic side effects of SGA agents, are warranted. Vitamin D is a prohormone with skeletal and extraskeletal properties that could potentially reduce the severity of these metabolic side effects. Its role as an adjunctive therapy for the management of metabolic side effects of SGA agents has not been adequately studied. Effective strategies to curb these side effects will improve the overall health of youths with psychiatric illnesses who receive SGAs. Herein we present a pilot study on the use of vitamin D in patients on treatment with SGAs

Effects of a multicomponent wellness intervention on dyslipidemia in an overweight adolescent population

Epidemiologic studies suggest that atherosclerotic processes begin in childhood and are associated with abnormal lipid levels. Behavioral changes are the first line of treatment for dyslipidemia in adolescents but outcome data on the effectiveness of this approach are inconsistent. This study aimed to assess the effect of a 13-week multicomponent wellness intervention program on dyslipidemia in lean and overweight/obese adolescents enrolled at a public high school in Boston, Massachusetts. The intervention was conducted at a university-based youth fitness center where 9 overweight/obese adolescents (body mass index [BMI]≥85th percentile for age and sex) and 9 lean adolescents (BMIsex) participated in weekly nutrition classes and structured cardiovascular, flexibility and strength training 2 times/week for 5 weeks, followed by up to 4 times/week for 8 weeks. Clinical measurements (BMI, percent body fat, blood pressure [BP]) and lipid profile assessment (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) were performed at baseline and at completion of the intervention. At the completion of the study, the overweight/obese adolescents demonstrated a 15% increase in HDL-C levels (mean, 47 mg/dL vs 54 mg/dL) while there was no improvement in BMI, percent body fat, BP,TG, TC and LDL-C. The participants in the lean group showed no change in their anthropometric and serum parameters. A multicomponent wellness intervention resulted in a significant increase of cardioprotective HDL-C levels which has been associated with coronary health in adulthood. The long-term effects of this intervention on indicators of cardiometabolic health and others like it require further study

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Increased Toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents

BACKGROUND: Metabolic syndrome (MetSyn) is diagnosed frequently in some but not all overweight adolescents. Chronic inflammation, as seen in obesity, is strongly associated with MetSyn. OBJECTIVES: The aim of this pilot study was to assess the correlation between activation of the innate immune system and MetSyn, independent of body mass index (BMI), in a young population. METHODS: We quantitatively measured both systemic pro-inflammatory cytokines and gene expression of Toll-like receptors (TLRs) and downstream cytokines in circulating monocytes obtained from nine adolescents with metabolic syndrome (Overwt-MetSyn) and eight BMI-matched controls (Overwt-Healthy). RESULTS: The Overwt-MetSyn group demonstrated a significant elevation in expression of TLR2, TLR4, tumour necrosis factor-a (TNF a) and interleukin-6 (IL6) in peripheral monocytes, and increased circulating levels of TNF a and IL6 when compared with the Overwt-Healthy group. TLR2 (r = 0.78, P \u3c 0.001), TLR4 (r = 0.57, P \u3c 0.01) and TNF a (r = 0.61, P \u3c 0.01) gene expression positively correlated with serum levels of TNF a. CONCLUSIONS: Our study suggests that activation of the innate immune pathway via TLRs may be partially responsible for the increased systemic inflammation seen in adolescents with MetSyn. the Study of Obesity

Effects of a multicomponent wellness intervention on dyslipidemia among overweight adolescents

Behavioral changes are the first line of treatment for dyslipidemia in adolescents, but outcome data on the effectiveness of this approach are inconsistent. This study aims to assess the effect of a 13-week multicomponent wellness intervention program, which included weekly nutrition classes and structured cardiovascular, flexibility, and strength training on dyslipidemia in nine overweight/obese [body mass index (BMI) \u3e or = 85th percentile] and nine lean (BMIpercentile) adolescents. Clinical measurements and lipid profile assessment were performed before and after the intervention. At the completion of the study, the overweight/obese adolescents demonstrated a 15% increase in high-density lipoprotein cholesterol (HDL-C) levels (mean, 47 +/- 8 vs. 54 +/- 5 mg/dL), whereas there was no improvement in BMI or other measurements. The participants in the lean group showed no change in their anthropometric and serum parameters. A multicomponent wellness intervention resulted in a significant increase of cardioprotective HDL-C levels, which have been associated with coronary health in adulthood

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept