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Abstract Objectives Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME. Methods Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5. Results These results strengthen the hypothesis that somatic variants in PI3K‐Akt‐mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation. Significance In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.

ABSTRACT Background Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched‐chain α‐keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1β, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. Methods This manuscript describes a cross‐sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. Results Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients. Conclusion If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype‐phenotype relationships more efficiently.

Abstract Identifying how species respond to system drivers such as weather, climate, habitat, and resource availability is critical for understanding population change. In coastal areas, the transfer of nutrients across the marine and terrestrial interface increases complexity. Nesting populations of bald eagles (Haliaeetus leucocephalus) along the Pacific coast of North America, although terrestrial, are largely dependent on marine resources during the breeding season and therefore represent a good focal species for understanding the linkages of nutrients between terrestrial and marine systems. Due to their location, coastal eagle populations are susceptible to a variety of climate‐induced perturbations, from both land and sea. The northeast Pacific Marine Heatwave (PMH) of 2014–2016 had wide‐ranging impacts on the marine ecosystem and provided an opportunity to explore how marine conditions can impact terrestrial wildlife populations. We used a spatially explicit multistate occupancy modeling framework to analyze >30 years of bald eagle nest occupancy data collected in four large national parks along a coastal interior gradient in Alaska, USA. We assessed occupancy state in relation to weather conditions, salmon abundance, access to alternate prey resources, and the PMH event to help elucidate the factors affecting bald eagle occupancy dynamics over time. We found that occupancy probability was higher in areas where prey resources were concentrated (e.g., near seabird colonies, where bears facilitate access to salmon carcasses). We also found that the probability of reproductive success was higher during warmer, drier springs with higher‐than‐average salmon abundance. After the onset of the PMH, success declined in the areas most dependent on non‐salmon marine resources. These findings confirm the importance of spring weather conditions and access to salmon resources during the critical chick‐rearing period, but also reveal that marine heatwaves may have important secondary effects through a reduction in the overall quantity or quality of prey available to bald eagles. Given ongoing warming at high latitudes and the expectation that marine heatwaves will become more common, our findings are useful for understanding ongoing and future changes in the transfer of nutrients from marine to terrestrial ecosystems and how such changes may impact terrestrial species such as bald eagles.

ABSTRACT Identifying neurometabolic disorders that lead to neonatal encephalopathy is difficult, and access to exome sequencing is a significant advantage in developing countries. We present a case of neonatal encephalopathy characterized by refractory seizures and significant apnea resulting from glutaminase deficiency, along with elevated levels of glutamine and glycine in the cerebrospinal fluid. Although the condition was fatal, it was possible to offer genetic counseling and recommendations for future pregnancies following exome sequencing.

Background Hospital‐ and physician‐level variation for selection of percutaneous coronary intervention versus coronary artery bypass grafting (CABG) for patients with coronary artery disease has been associated with outcome differences. However, most studies excluded patients treated medically. Methods and Results From 2010 to 2019, adults with 3‐vessel or left main coronary artery disease at 3 hospitals (A, B, C) in Alberta, Canada, were categorized by treatment with medical therapy, percutaneous coronary intervention, or CABG. Multilevel regression models determined the proportion of variation in treatment attributable to patient, physician, and hospital factors, and survival models assessed outcomes including death and major adverse cardiovascular events over 5 years. Of 22 580 patients (mean age, 67 years; 80% men): 6677 (29%) received medical management, 9171 (41%) percutaneous coronary intervention, and 6732 (30%) CABG. Hospital factors accounted for 10.8% of treatment variation. In adjusted models (site A as reference), patients at sites B and C had 49% (95% CI, 44%–53%) and 43% (95% CI, 37%–49%) lower rates of medical therapy, respectively, and 31% (95% CI, 24%–38%) and 32% (95% CI, 24%–40%) lower rates of CABG. During 5.0 years median follow‐up, 3287 (14.6%) patients died, with no intersite mortality differences. There were no between‐site differences in acute coronary syndromes or stroke; patients at sites B and C had 24% lower risk (95% CI, 13%–34% and 11%–35%, respectively) of heart failure hospitalization. Conclusions Hospital‐level variation in selection of percutaneous coronary intervention, CABG, or medical therapy for patients with complex coronary artery disease was not associated with differences in 5‐year mortality rates. Research and quality improvement initiatives comparing revascularization practices should include medically managed patients.

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

Background Frailty, a syndrome of physiologic vulnerability, increases cardiovascular disease (CVD) risk. Whether in person or automated frailty tools are ideal for identifying CVD risk remains unclear. We calculated 3 distinct frailty scores and examined their associations with mortality and CVD events in the Million Veteran Program, a prospective cohort of nearly 1 million US veterans. Methods and Results Veterans aged ≥50 years and enrolled from 2011 to 2018 were included. Two frailty indices (FI) based on the deficit accumulation theory were calculated: the questionnaire‐based 36‐item Million Veteran Program‐FI and 31‐item Veterans Affairs‐FI using claims data. We calculated Fried physical frailty using the self‐reported, 3‐item Study of Osteoporotic Fractures. Multivariable‐adjusted Cox models examined the association of frailty by each score with primary (all‐cause and CVD mortality) and secondary (myocardial infarction, stroke, and heart failure) outcomes. In 190 688 veterans (69±9 years, 94% male, 85% White), 33, 233 (17%) all‐cause and 10 115 (5%) CVD deaths occurred. Using Million Veteran Program‐FI, 29% were robust, 42% pre‐frail, and 29% frail. Frailty prevalence increased by age group (27% in 50‐59 to 42% in ≥90 years). Using the Million Veteran Program‐FI, over 6±2 years, frail veterans had a higher hazard of all‐cause (hazard ratio [HR], 3.05 [95% CI, 2.95–3.16]) and CVD mortality (HR, 3.65 [95% CI, 3.43–3.90]). Findings were concordant for the Veterans Affairs‐FI and Study of Osteoporotic Fractures frailty definitions, and remained significant even among younger veterans aged 50‐59 years. Conclusions Irrespective of frailty measure, frailty is associated with a higher risk of all‐cause mortality and adverse CVD events. Further study of frailty in veterans aged

Abstract Background Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first‐degree relatives (FDRs). Methods We performed a retrospective case–control study including cases with gender‐matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. Results In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001–3.79, p = 0.047) and prostate cancer (OR 2.72, 95% CI 1.07–7.01, p = 0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31–4.28, p = 0.004) and prostate cancer (OR 2.92, 95% CI 1.47–6.14, p = 0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08–4.39, p = 0.028), prostate cancer (OR 2.85, 95% CI 1.09–7.54, p = 0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31–4.29, p = 0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59–6.83, p = 0.001). Conclusions Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.