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Abstract Purpose To compare ovulation rates between Letrozole and Clomiphene Citrate (CC) using a stair-step protocol to achieve ovulation induction in women with Polycystic Ovarian Syndrome (PCOS). Methods This is a retrospective cohort of predominantly Hispanic PCOS women of reproductive age who completed ovulation induction (OI) comparing women who underwent Letrozole stair-step protocol to those who underwent OI with CC stair-step. All women had a diagnosis of PCOS based on the 2003 Rotterdam criteria. For both protocols, sequentially higher doses of Letrozole or CC were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. The primary outcome was ovulation rate (determined by presence of a dominant follicle) between the two treatment groups. Secondary outcomes included time to ovulation, clinical pregnancy rates and side effects. Results 49 PCOS patients completed a Letrozole stair-step cycle and 43 completed a CC stair-step cycle for OI. Overall, demographics were comparable between both groups. Ovulation rates with the Letrozole stair-step protocol were equivalent to CC stair-step protocol (96% vs 88%, p = 0.17). Although the mean time (days) to ovulation was shorter in the Letrozole group (19.5 vs 23.1, p = 0.027), the pregnancy rates were similar for both groups. Conclusions This is the first study to date that has compared the efficacy of the stair-step protocol in PCOS patients using Letrozole and CC. Both Letrozole and CC can be prescribed in a stair-step fashion. Letrozole stair-step was as efficacious as CC stair-step; patients achieved comparable rates of ovulation and clinical pregnancy. Time to ovulation was shorter in the Letrozole protocol.

Introduction Incidence for depression increases during the perinatal period. Risk factors for depression may differentially affect each time period. Objectives To assess demographic, psychological and obstetric risk factors that differentially affect prenatal and postpartum depression Methods A total of 169 subjects participated. Assessment was conducted during the first trimester, second trimester, third trimester, within a month after childbirth, and a month after childbirth. Demographic and obstetric measures, as well as psychological measures, including the Edinburgh Postnatal Depression Scale were conducted. Multiple regression and the Mann-Whitney U test were performed to examine the association between variables and depression scores. Results Depression score was higher during the postpartum period than the prenatal period. Younger age was associated with depression during the first trimester. In the second trimester, less education, a history of depression and having stress within a year significantly affected depression scores. Smoking, artificial abortion and lack of support from family and parents correlated with depression during the third trimester. Within a month after childbirth, psychiatric and depression history, smoking, stress level within a year and lack of family support were associated with depression. At a month after childbirth, those who were primiparous and not breastfeeding had significantly higher depression scores. Conclusions This study identifies various risk factors for each gestational and postpartum period and suggests differential interventions for different perinatal periods.

Abstract Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease. Recognizing the difficulty in navigating these options, we developed a machine learning model trained on 1005 patient records from Columbia University Irving Medical Center to recommend appropriate genetic tests based on the phenotype information. The model achieved a remarkable performance with an AUROC of 0.823 and AUPRC of 0.918, aligning closely with decisions made by genetic specialists, and demonstrated strong generalizability (AUROC:0.77, AUPRC: 0.816) in an external cohort, indicating its potential value for general pediatricians to expedite rare disease diagnosis by enhancing genetic test ordering.

Autism is heterogeneous at many levels, including clinical symptoms and etiology. A key strategy in studying heterogeneous conditions is having large enough sample sizes to stratify into smaller groups that are more homogeneous. SPARK and Simons Searchlight are large and growing research cohorts of individuals with autism in the United States and individuals with genetically defined neurodevelopmental conditions around the world, respectively. They both provide freely available phenotypic and genotypic data with the ability to re-contact participants through the research match program. Deep dives into each gene in Searchlight provide comprehensive natural history data to understand the differing clinical courses to inform proper clinical care, and work toward treatment for each condition. Moreover, pilots of genetically based newborn screening programs for neurogenetic disorders can provide opportunities for equitable and early diagnosis to try to improve outcomes with earlier interventions.

Abstract Liver fibrosis and cirrhosis have limited therapeutic options and represent a serious unmet patient need. Recent use of single‐cell RNA sequencing (scRNAseq) has identified enriched cell types infiltrating cirrhotic livers but without defining the microanatomical location of these lineages thoroughly. To assess whether fibrotic liver regions specifically harbor enriched cell types, we explored whether whole‐tissue spatial transcriptomics combined with scRNAseq and gene deconvolution analysis could be used to localize cell types in cirrhotic explants of patients with end‐stage liver disease (total n = 8; primary sclerosing cholangitis, n = 4; primary biliary cholangitis, n = 2, alcohol‐related liver disease, n = 2). Spatial transcriptomics clearly identified tissue areas of distinct gene expression that strongly correlated with the total area (Spearman r = 0.97, p = 0.0004) and precise location (parenchyma, 87.9% mean congruency; range, 73.1%–97.1%; fibrosis, 68.5% mean congruency; range, 41.0%–91.7%) of liver regions classified as parenchymal or fibrotic by conventional histology. Deconvolution and enumeration of parenchymal and fibrotic gene content as measured by spatial transcriptomics into distinct cell states revealed significantly higher frequencies of ACTA2+ FABP4+ and COL3A1+ mesenchymal cells, IL17RA+ S100A8+ and FCER1G+ tissue monocytes, VCAM1+ SDC3+ Kupffer cells, CCL4+ CCL5+ KLRB1+ and GZMA+ IL17RA+ T cells and HLA‐DR+, CD37+ CXCR4+ and IGHM+ IGHG+ B cells in fibrotic liver regions compared with parenchymal areas of cirrhotic explants. Conclusion: Our findings indicate that spatial transcriptomes of parenchymal and fibrotic liver regions express unique gene content within cirrhotic liver and demonstrate proof of concept that spatial transcriptomes combined with additional RNA sequencing methodologies can refine the localization of gene content and cell lineages in the search for antifibrotic targets.

The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.

Circulatory system diseases and nervous system disorders often co-occur in patients. Here the authors use eMERGE and UK BioBank data to identify genomic regions associated with both phenotypes, providing insight into the relationship between these conditions.

Abstract Understanding the factors that facilitate or constrain establishment of populations in novel environments is crucial for conservation biology and the study of adaptive radiation. Important questions include: (1) Does the timing of colonization relative to stochastic events, such as climatic perturbations, impact the probability of successful establishment? (2) To what extent does community context (e.g., the presence of competitors) change the probability of establishment? (3) How do sources of intrapopulation variance, such as sex differences, affect success at an individual level during the process of establishment? Answers to these questions are rarely pursued in a field‐experimental context or on the same time scales (months to years) as the processes of colonization and establishment. We introduced slender anole lizards (Anolis apletophallus) to eight islands in the Panama Canal and tracked them over multiple generations to investigate the factors that mediate establishment success. All islands were warmer than the mainland (ancestral) environment, and some islands had a native competitor. We transplanted half of these populations only 4 months before the onset of a severe regional drought and the other half 2 years (two generations) before the drought. We found that successful establishment depended on both the intensity of interspecific competition and the timing of colonization relative to the drought. The islands that were colonized shortly before the drought went functionally extinct by the second generation, and regardless of time before the drought, the populations on islands with interspecific competition declined continuously over the study period. Furthermore, the effect of the competitor interacted with sex, with males suffering, and females benefitting, from the presence of a native competitor. Our results reveal that community context and the timing of colonization relative to climactic events can combine to determine establishment success and that these factors can generate opposite effects on males and females.

Abdominal aortic aneurysms (AAA) have been rigorously investigated to understand when their risk of rupture - which is the 13th leading cause of death in the US – exceeds the risks associated with repair. Clinical intervention occurs when an aneurysm diameter exceeds 5.5 cm, but this “one-size fits all” criterion is insufficient, as it has been reported thatup to a quarter of AAA smaller than 5.5 cm do rupture. Therefore, there is a need for a more reliable, patient-specific, clinical tool to aide in the management of AAA. Biomechanical assessment of AAA is thought to provide critical physical insights to rupture risk, but clinical translataion of biomechanics-based tools has been limited due to the expertise, time, and computational requirements. It was estimated that through 2015, only 348 individual AAA cases have had biomechanical stress analysis performed, suggesting a deficient sample size to make such analysis relevant in the clinic. Artificial intelligence (AI) algorithms offer the potential to increase the throughput of AAA biomechanical analyses by reducing the overall time required to assess the wall stresses in these complex structures using traditional methods. This can be achieved by automatically segmenting regions of interest from medical images and using machine learning models to predict wall stresses of AAA. In this study, we present an automated AI-based methodology to predict the biomechanical wall stresses for individual AAA. The predictions using this approach were completed in a significantly less amount of time compared to a more traditional approach (∼4 hours vs 20 seconds).

Urbanization is rapidly altering Earth’s environments, demanding investigation of the impacts on resident wildlife. Here, we show that urban populations of coyotes (Canis latrans), crested anole lizards (Anolis cristatellus), and white-crowned sparrows (Zonotrichia leucophrys) acquire gut microbiota constituents found in humans, including gut bacterial lineages associated with urbanization in humans. Comparisons of urban and rural wildlife and human populations revealed significant convergence of gut microbiota among urban populations relative to rural populations. All bacterial lineages overrepresented in urban wildlife relative to rural wildlife and differentially abundant between urban and rural humans were also overrepresented in urban humans relative to rural humans. Remarkably, the bacterial lineage most overrepresented in urban anoles was a Bacteroides sequence variant that was also the most significantly overrepresented in urban human populations. These results indicate parallel effects of urbanization on human and wildlife gut microbiota and suggest spillover of bacteria from humans into wildlife in cities.

OBJECTIVES:. The Seraph100 Microbind Affinity Blood Filter (Seraph 100) (ExThera Medical, Martinez, CA) is an extracorporeal therapy that can remove pathogens from blood, including severe acute respiratory syndrome coronavirus 2. The aim of this study was to evaluate safety and efficacy of Seraph 100 treatment for COVID-19. DESIGN:. Retrospective cohort study. SETTING:. Nine participating ICUs. PATIENTS:. COVID-19 patients treated with Seraph 100 (n = 53) and control patients matched by study site (n = 53). INTERVENTION:. Treatment with Seraph 100. MEASUREMENTS AND MAIN RESULTS:. At baseline, there were no differences between the groups in terms of sex, race/ethnicity, body mass index, and need for mechanical ventilation. However, patients in the Seraph 100 group were younger (median age, 54 yr; interquartile range [IQR], 41–65) compared with controls (median age, 64 yr; IQR, 56–69; p = 0.009). Charlson comorbidity index scores were lower in the Seraph 100 group (2; IQR, 0–3) compared with the control group (3; IQR, 2–4; p = 0.006). Acute Physiology and Chronic Health Evaluation II scores were also lower in Seraph 100 subjects (12; IQR, 9–17) compared with controls (16; IQR, 12–21; p = 0.011). The Seraph 100 group had higher vasopressor-free days with an incidence rate ratio of 1.30 on univariate analysis. This difference was not significant after adjustment. Seraph 100-treated subjects were less likely to die compared with controls (32.1% vs 64.2%; p = 0.001), a difference that remained significant after adjustment. However, no difference in mortality was observed in a post hoc analysis utilizing an external control group. In the full cohort of 86 treated patients, there were 177 total treatments, in which only three serious adverse events were recorded. CONCLUSIONS:. Although this study did not demonstrate consistently significant clinical benefit across all endpoints and comparisons, the findings suggest that broad spectrum, pathogen agnostic, blood purification can be safely deployed to meet new pathogen threats while awaiting targeted therapies and vaccines.

Abstract Background Research comparing sex differences in the effects of antipsychotic medications on acute ischemic heart disease (IHD) is limited and the findings ambiguous. This study aimed to investigate these associations within a primary care setting. Methods Hong Kong public general outpatient electronic records of patients aged 45+ during 2007–2010 were extracted, with the last consultation date as the baseline for a 4-year follow-up period to observe acute IHD hospitalizations (2011–2014). Antipsychotic use was defined as any prescription over the previous 12 months from a list of 16 antipsychotics, while acute IHD was defined by ICD-9: 410.00–411.89. Both sex-specific and sex-combined (both sexes) mixed-effects Cox models (random intercept across 74 clinics) were implemented to examine the association and test the interaction between antipsychotics and sex. Results Among 1,043,236 included patients, 17,780 (1.7%) were prescribed antipsychotics, and 8342 (0.8%) developed IHD. In sex-specific analyses, antipsychotic prescription was associated with a 32% increased hazard rate of acute IHD among women (95% CI 1.05–1.67) but not among men. A likelihood ratio test comparing sex-combined models with and without the interaction between antipsychotic use and sex suggested significant interaction (χ 2 = 4.72, P = 0.030). The association between antipsychotic use and IHD among women attenuated and became non-significant when haloperidol was omitted from the operationalization of antipsychotic use (HR = 1.23, 95% CI 0.95–1.60). Conclusion Our results suggest that antipsychotic prescription is moderately associated with an increased risk of acute IHD among women in primary care and this relationship may be explained by specific antipsychotics. Further research should observe and capture the potential intermediary mechanisms and the dose-response relationship of this association to provide more rigorous evidence to establish causality and inform clinical practices.

Summary Objective Noncoding alleles of the fat mass and obesity‐associated (FTO) gene have been associated with obesity risk, yet the underlying mechanisms remain unknown. Risk allele carriers show alterations in brain structure and function, but previous studies have not disassociated the effects of genotype from those of body mass index (BMI). Methods Differences in brain structure and function were examined in children without obesity grouped by their number of copies (0,1,2) of the FTO obesity‐risk single‐nucleotide polymorphism (SNP) rs1421085. One hundred five 5‐ to 10‐year‐olds (5th–95th percentile body fat) were eligible to participate. Usable scans were obtained from 93 participants (15 CC [homozygous risk], 31 CT [heterozygous] and 47 TT [homozygous low risk]). Results Homozygous C allele carriers (CCs) showed greater grey matter volume in the cerebellum and temporal fusiform gyrus. CCs also demonstrated increased bilateral cerebellar white matter fibre density and increased resting‐state functional connectivity between the bilateral cerebellum and regions in the frontotemporal cortices. Conclusions This is the first study to examine brain structure and function related to FTO alleles in young children not yet manifesting obesity. This study lends support to the notion that the cerebellum may be involved in FTO‐related risk for obesity, yet replication and further longitudinal study are required.

Abstract Background Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown. Main body In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19. Conclusion This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.

Abstract Background The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. Conclusions We estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.

Introduction: With personnel scattered throughout a continent 3 times larger than the United States, a lack of mature medical facilities necessitates a significant transportation network for medical evacuation in US Africa Command (AFRICOM). We describe medical evacuations analyzed from the US Air Force Transportation Command Regulating and Command & Control Evacuation System (TRAC2ES). Methods: We performed a retrospective review of all TRAC2ES medical records for medical evacuations from the AFRICOM theater of operations conducted between January 1, 2008 and December 31, 2018. We abstracted free text data entry in TRAC2ES for diagnostic and therapeutic interventions performed prior to the patient movement request. Results: During this time, there were 963 cases recorded in TRAC2ES originating within AFRICOM. 961 records were complete for analysis. Most patients were male (82%) and military personnel (92%). Most transports originated in Djibouti (72%), and Germany (93%) was the most common destination. Medical evacuations were largely routine (66%), and routine evacuations were proportionally highest amongst US military personnel compared to all other groups. A small portion of patients were evacuated for battle injuries (4%), compared to non-battle injury (33%) and disease (63%). Within disease, the largest proportion of patient complaints centered on gastrointestinal symptoms (13%), behavioral health (11%) and chest pain (8%). Prior to evacuation, only 55% of patients were document as receiving any medication. Pain control was documented in 21% of cases, most commonly being NSAIDs (7%). Discussion: Extremely low numbers of battle injuries highlight the unique nature of AFRICOM operations compared to areas with more intense combat operations. Limitations of the dataset highlight the need for a data collection mandate within AFRICOM as within other areas for optimization and performance improvement. Keywords: Medical, Evacuation, Military, Africa, Transport, Trauma

Abstract Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta‐analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow‐up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.

Background & Aims: The protective intestinal mucosal barrier consists of multiple elements including mucus and epithelial layers and immune defense; nonetheless, barrier dysfunction is common in various disorders. The imprinted and developmentally regulated long noncoding RNA H19 is involved in many cell processes and diseases. Here, we investigated the role of H19 in regulating Paneth and goblet cells and autophagy, and its impact on intestinal barrier dysfunction induced by septic stress. Methods: Studies were conducted in H19-deficient (H19-/-) mice, mucosal tissues from patients with sepsis, primary enterocytes, and Caco-2 cells. Septic stress was induced by cecal ligation and puncture (CLP), and gut permeability was detected by tracer fluorescein isothiocyanate–dextran assays. The function of Paneth and goblet cells was examined by immunostaining for lysozyme and mucin 2, respectively, and autophagy was examined by microtubule-associated proteins 1A/1B light chain 3 II immunostaining and Western blot analysis. Intestinal organoids were isolated from H19-/- and control littermate mice and treated with lipopolysaccharide (LPS). Results: Intestinal mucosal tissues in mice 24 hours after exposure to CLP and in patients with sepsis showed high H19 levels, associated with intestinal barrier dysfunction. Targeted deletion of the H19 gene in mice enhanced the function of Paneth and goblet cells and promoted autophagy in the small intestinal mucosa. Knockout of H19 protected Paneth and goblet cells against septic stress, preserved autophagy activation, and promoted gut barrier function after exposure to CLP. Compared with organoids from control littermate mice, intestinal organoids isolated from H19-/- mice had increased numbers of lysozyme- and mucin 2–positive cells and showed increased tolerance to LPS. Conversely, ectopic overexpression of H19 in cultured intestinal epithelial cells prevented rapamycin-induced autophagy and abolished the rapamycin-induced protection of the epithelial barrier against LPS. Conclusions: In investigations of mice, human tissues, primary organoids, and intestinal epithelial cells, we found that increased H19 inhibited the function of Paneth and goblet cells and suppressed autophagy, thus potentially contributing to barrier dysfunction in intestinal pathologies.