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Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.

BackgroundCo-use of alcohol and e-cigarettes (often called vaping) has been linked with long-term health outcomes, including increased risk for substance use disorder. Co-use may have been exacerbated by the COVID-19 pandemic. Social networking sites may offer insights into current perspectives on polysubstance use. ObjectiveThe aims of this study were to investigate concurrent mentions of vaping and alcohol on Twitter (subsequently rebranded X) during a time of changing vaping regulations in the United States and the emergence of the COVID-19 pandemic. MethodsTweets including both vape- and alcohol-related terms posted between October 2019 and September 2020 were analyzed using latent Dirichlet allocation modeling. Distinct topics were identified and described. ResultsThree topics were identified across 6437 tweets: (1) flavors and flavor ban (n=3334, 51.8% of tweets), (2) co-use discourse (n=1119, 17.4%), and (3) availability and access regulation (n=1984, 30.8%). Co-use discussions often portrayed co-use as positive and prosocial. Tweets focused on regulation often used alcohol regulations for comparison. Some focused on the perceived overregulation of vaping (compared to alcohol), while others supported limiting youth access but not at the expense of adult access (eg, stronger age verification over product bans). Across topics, vaping was typically portrayed as less harmful than alcohol use. The benefits of flavors for adult smoking cessation were also discussed. The distribution of topics across time varied across both pre– and post–regulatory change and pre– and post–COVID-19 pandemic declaration periods, suggesting shifts in topic focus salience across time. ConclusionsCo-use discussions on social media during this time of regulatory change and social upheaval typically portrayed both vaping and alcohol use in a positive light. It also included debates surrounding the differences in regulation of the 2 substances—particularly as it related to limiting youth access. Emergent themes from the analysis suggest that alcohol was perceived as more harmful but less regulated and more accessible to underage youth than vaping products. Frequent discussions and comparisons of the 2 substances as it relates to their regulation emphasize the still-evolving vaping policy landscape. Social media content analyses during times of change may help regulators and policy makers to better understand and respond to common concerns and potential misconceptions surrounding drug-related policies and accessibility.

Abstract Purpose To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. Method Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. Results Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6–16 h, p

Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) recapitulate numerous disease and drug response phenotypes, but cell immaturity may limit their accuracy and fidelity as a model system. Cell culture medium modification is a common method for enhancing maturation, yet prior studies have used complex media with little understanding of individual component contribution, which may compromise long-term hiPSC-CM viability. Here, we developed high-throughput methods to measure hiPSC-CM maturation, determined factors that enhanced viability, and then systematically assessed the contribution of individual maturation medium components. We developed a medium that is compatible with extended culture. We discovered that hiPSC-CM maturation can be sub-specified into electrophysiological/EC coupling, metabolism, and gene expression and that induction of these attributes is largely independent. In this work, we establish a defined baseline for future studies of cardiomyocyte maturation. Furthermore, we provide a selection of medium formulae, optimized for distinct applications and priorities, that promote measurable attributes of maturation.

IntroductionCigarette smoking is strongly associated with the development of cardiovascular disease (CVD). However, evidence is limited as to whether smokeless tobacco (ST) use is associated with CVD.Aims and methodsUsing data from 4347 adults in the Population Assessment of Tobacco and Health Study (2013-2014), we compared geometric mean concentrations of CVD-related harm biomarkers and biomarkers of exposure among exclusive ST users and exclusive cigarette smokers-in relation to recent nicotine exposure-and never tobacco users, adjusting for age, sex, race/ethnicity, income, body mass index, and CVD. Biomarker levels among exclusive ST users who were former established cigarette smokers were compared with exclusive cigarette smokers.ResultsCompared with cigarette smokers, ST users had significantly higher concentrations of total nicotine equivalents (TNE) but lower concentrations of inflammatory (high-sensitivity C-reactive protein, interleukin-6, intercellular adhesion molecule, fibrinogen) and oxidative stress (8-isoprostane) biomarkers (all p < .05). Biomarker levels among ST users were similar to never smokers. ST users who were former cigarette smokers had lower levels of inflammatory and oxidative stress biomarkers and biomarkers of exposure (cadmium, lead, 1-hydroxypyrene, acrylonitrile, and acrolein), compared with cigarettes smokers (p < .05), despite having higher TNE levels (p < .05). Among cigarette smokers, but not among ST users, inflammatory biomarkers and TNE were highly correlated.ConclusionsST use is not associated with increases in biomarkers of CVD-related harm and exposure, compared with never smokers, despite exposure to nicotine at levels higher than those observed among cigarette smokers. These findings support the concept that increases in CVD risk among cigarette smokers is caused primarily by constituents of tobacco smoke other than nicotine.ImplicationsDespite having higher levels of nicotine and compared with exclusive cigarette smokers, exclusive ST users (including those who were former cigarette smokers) had significantly lower concentrations of inflammatory and oxidative stress biomarkers, comparable to levels observed among never tobacco users. These findings suggest that increases in CVD risk among cigarette smokers is caused primarily by tobacco constituents other than nicotine and that switching to ST is likely associated with lower CVD risk.

Abstract Objective A systematic review was conducted to evaluate the use patterns, health perceptions, and cardiopulmonary health effects of cigars. Data sources PubMed and Google Scholar were searched for peer-reviewed articles published between June 2014 and February 2021. Search keywords included cigars, cigarillos, little cigars, and cardiopulmonary health outcomes. Study selection Of 782 papers identified, we excluded non-English articles, review articles, commentaries, and those without empirical data on cigars. Three coders independently reviewed all articles and compared codes to resolve discrepancies. 93 articles met the inclusion criteria and were included. Data synthesis Cigars have evolved from premium cigars to encompass little cigars and cigarillos (LCCs). LCCs are available in an array of flavors and at a price advantage, and as a result, are used by different groups compared to premium cigars. LCCs are more frequently used by youth, young adults, and those who identify as Black/African American. LCCs are often used in combination with other tobacco products, alcohol, and cannabis. Despite limited regulation, cigars generate smoke of a similar composition as cigarettes. Among the studies identified, evidence suggests that cigar use is associated with cardiovascular and pulmonary toxicity. Higher all-cause and cancer-related mortalities are associated with cigar use, particularly with more frequent and deeper inhalation, compared to non-tobacco users. Conclusions LCCs are used more frequently by at-risk groups compared to premium cigars. Recent studies evaluating cigar cardiopulmonary health effects are limited but suggest cigars have similar health risks as conferred by cigarette smoking. With the use of LCCs and targeted marketing on the rise among high-risk groups, there is a critical need for continued research in this area.

Abstract Background Leigh syndrome, an inherited neurometabolic disorder, is estimated to be the most common pediatric manifestation of mitochondrial disease. No treatments are currently available for Leigh syndrome due to many hurdles in drug discovery efforts. Leigh syndrome causal variants span over 110 different genes and likely lead to both unique and shared biochemical alterations, often resulting in overlapping phenotypic features. The mechanisms by which pathogenic variants in mitochondrial genes alter cellular phenotype to promote disease remain poorly understood. The rarity of cases of specific causal variants creates barriers to drug discovery and adequately sized clinical trials. Body To address the current challenges in drug discovery and facilitate communication between researchers, healthcare providers, patients, and families, the Boston University integrative Cardiovascular Metabolism and Pathophysiology (iCAMP) Lab and Cure Mito Foundation hosted a Leigh Syndrome Symposium. This symposium brought together expert scientists and providers to highlight the current successes in drug discovery and novel models of mitochondrial disease, and to connect patients to providers and scientists to foster community and communication. Conclusion In this symposium review, we describe the research presented, the hurdles ahead, and strategies to better connect the Leigh syndrome community members to advance treatments for Leigh syndrome.

Mitochondrial diseases are a heterogeneous group of disorders that can be caused by mutations in the nuclear or mitochondrial genome. Mitochondrial DNA (mtDNA) variants may exist in a state of heteroplasmy, where a percentage of DNA molecules harbor a variant, or homoplasmy, where all DNA molecules have the same variant. The relative quantity of mtDNA in a cell, or copy number (mtDNA-CN), is associated with mitochondrial function, human disease, and mortality. To facilitate accurate identification of heteroplasmy and quantify mtDNA-CN, we built a bioinformatics pipeline that takes whole genome sequencing data and outputs mitochondrial variants, and mtDNA-CN. We incorporate variant annotations to facilitate determination of variant significance. Our pipeline yields uniform coverage by remapping to a circularized chrM and by recovering reads falsely mapped to nuclear-encoded mitochondrial sequences. Notably, we construct a consensus chrM sequence for each sample and recall heteroplasmy against the sample's unique mitochondrial genome. We observe an approximately 3-fold increased association with age for heteroplasmic variants in non-homopolymer regions and, are better able to capture genetic variation in the D-loop of chrM compared to existing software. Our bioinformatics pipeline more accurately captures features of mitochondrial genetics than existing pipelines that are important in understanding how mitochondrial dysfunction contributes to disease.

Summary: Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.

Background The American Heart Association's framework “ideal cardiovascular health” (CVH) focuses on modifiable risk factors to reduce cardiovascular disease (CVD). Metabolomics provides important pathobiological insights into risk factors and CVD development. We hypothesized that metabolomic signatures associate with CVH status, and that metabolites, at least partially, mediate the association of CVH score with atrial fibrillation (AF) and heart failure (HF). Methods and Results We studied 3056 adults in the FHS (Framingham Heart Study) cohort to evaluate CVH score and incident outcomes of AF and HF. Metabolomics data were available in 2059 participants; mediation analysis was performed to evaluate the mediation of metabolites in the association of CVH score and incident AF and HF. In the smaller cohort (mean age, 54 years; 53% women), CVH score was associated with 144 metabolites, with 64 metabolites shared across key cardiometabolic components (body mass index, blood pressure, and fasting blood glucose) of the CVH score. In mediation analyses, 3 metabolites (glycerol, cholesterol ester 16:1, and phosphatidylcholine 32:1) mediated the association of CVH score with incident AF. Seven metabolites (glycerol, isocitrate, asparagine, glutamine, indole‐3‐proprionate, phosphatidylcholine C36:4, and lysophosphatidylcholine 18:2), partly mediated the association between CVH score and incident HF in multivariable‐adjusted models. Conclusions Most metabolites that associated with CVH score were shared the most among 3 cardiometabolic components. Three main pathways: (1) alanine, glutamine, and glutamate metabolism; (2) citric acid cycle metabolism; and (3) glycerolipid metabolism mediated CVH score with HF. Metabolomics provides insights into how ideal CVH status contributes to the development of AF and HF.

School-Wide Positive Behavioral Interventions and Supports (SWPBIS) is a broad set of evidence-based strategies designed to create school environments that promote and support appropriate behavior of all students. The "PBIS Cultural Responsiveness Field Guide" provides a foundation for designing a SWPBIS program that meets the needs of culturally and linguistically students in schools. The purpose of this case study is to describe the development and implementation of a SWPBIS program in a newly formed, urban, Spanish-language magnet elementary school. Data from the culturally-responsive SWPBIS Spanish-Language School Program during the first year of implementation indicated increases in implementation fidelity, as well as equitable student knowledge of behavioral expectations across both native Spanish speakers and native English Speakers when culturally responsive materials and procedures were used to teach and reinforce behavior expectations. Teachers also reported positive perceptions of the Program's goals, procedures, and outcomes. Implications for practice are discussed.

Abstract Lymphoblastoid cell lines (LCLs) provide an unlimited source of genomic DNA for genetic studies. Here, we compared mtDNA sequence variants, heteroplasmic or homplasmic, between LCL (sequenced by mitoRCA-seq method) and whole blood samples (sequenced through whole genome sequencing approach) of the same 130 participants in the Framingham Heart Study. We applied harmonization of sequence coverages and consistent quality control to mtDNA sequences. We identified 866 variation sites in the 130 LCL samples and 666 sites in the 130 blood samples. More than 94% of the identified homoplasmies were present in both LCL and blood samples while more than 70% of heteroplasmic sites were uniquely present either in LCL or in blood samples. The LCL and whole blood samples carried a similar number of homoplasmic variants (p = 0.45) per sample while the LCL carried a greater number of heteroplasmic variants than whole blood per sample (p

BackgroundHealth warnings in tobacco advertisements provide health information while also increasing the perceived risks of tobacco use. However, existing federal laws requiring warnings on advertisements for tobacco products do not specify whether the rules apply to social media promotions. ObjectiveThis study aims to examine the current state of influencer promotions of little cigars and cigarillos (LCCs) on Instagram and the use of health warnings in influencer promotions. MethodsInstagram influencers were identified as those who were tagged by any of the 3 leading LCC brand Instagram pages between 2018 and 2021. Posts from identified influencers, which mentioned one of the three brands were considered LCC influencer promotions. A novel Warning Label Multi-Layer Image Identification computer vision algorithm was developed to measure the presence and properties of health warnings in a sample of 889 influencer posts. Negative binomial regressions were performed to examine the associations of health warning properties with post engagement (number of likes and comments). ResultsThe Warning Label Multi-Layer Image Identification algorithm was 99.3% accurate in detecting the presence of health warnings. Only 8.2% (n=73) of LCC influencer posts included a health warning. Influencer posts that contained health warnings received fewer likes (incidence rate ratio 0.59, P

Pod-based electronic (e-) cigarettes more efficiently deliver nicotine using a protonated formulation. The cardiovascular effects associated with these devices are poorly understood. We evaluated whether pod-based e-liquids and their individual components impair endothelial cell function. We isolated endothelial cells from people who are pod users (n = 10), tobacco never users (n = 7), and combustible cigarette users (n = 6). After a structured use, pod users had lower acetylcholine-mediated endothelial nitric oxide synthase (eNOS) activation compared with never users and was similar to levels from combustible cigarette users (overall P = 0.008, P = 0.01 pod vs never; P = 0.96 pod vs combustible cigarette). The effects of pod-based e-cigarettes and their constituents on vascular cell function were further studied in commercially available human aortic endothelial cells (HAECs) incubated with flavored JUUL e-liquids or propylene glycol (PG):vegetable glycerol (VG) at 30:70 ratio with or without 60 mg/mL nicotine salt for 90 min. A progressive increase in cell death with JUUL e-liquid exposure was observed across 0.0001-1% dilutions; PG:VG vehicle with and without nicotine salt induced cell death. A23187-stimulated nitric oxide production was decreased with all JUUL e-liquid flavors, PG:VG and nicotine salt exposures. Aerosols generated by JUUL e-liquid heating similarly decreased stimulated nitric oxide production. Only mint flavored e-liquids increased inflammation and menthol flavored e-liquids enhanced oxidative stress in HAECs. In conclusion, pod e-liquids and their individual components appear to impair endothelial cell function. These findings indicate the potential harm of pod-based devices on endothelial cell function and thus may be relevant to cardiovascular injury in pod type e-cigarette users.