Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Vancomycin-Induced Thrombocytopenia in a 35-Year-Old Female With Pneumonia: A Case Report.

Vancomycin is one of the most empirically used antibiotics in severely ill patients in hospitalized settings. Vancomycin-induced thrombocytopenia (VITP) is a rare and potentially life-threatening complication that requires immediate recognition. Platelet destruction is largely immune-mediated and results in a precipitous drop in the platelet count over a short period of time. Most cases of VITP are drug-dependent, as discontinuation of the offending agent frequently results in a timely return to baseline to pre-exposure platelet levels. Here, we present a case of severe vancomycin-induced thrombocytopenia in a 35-year-old female with a history of multiple comorbidities who presented with pneumonia. She was undergoing treatment with vancomycin and piperacillin-tazobactam and developed thrombocytopenia within 24 hours of hospitalization. The patient was on a loading dose of 1250 mg intravenous vancomycin every 24 hours and piperacillin-tazobactam 3.375 g intravenously every six hours for presumed community-acquired pneumonia. Her other medications included ondansetron, bupropion, sertraline, tamsulosin, pantoprazole, ergocalciferol, and insulin glargine. Additionally, the patient was placed on a prophylactic dose of enoxaparin while in-patient. The patient's thrombocytopenia resolved with discontinuation of vancomycin. Clinicians should be well-informed about which medications can trigger thrombocytopenia whenever starting a medication in such cases.

Superior Mesenteric Artery Syndrome in Systemic Lupus Erythematosus.

Although the gastrointestinal (GI) manifestations of systemic lupus erythematosus (SLE) are relatively less reported, they are common and occur in approximately half of individuals with SLE. These symptoms vary and include, but are not limited to, oral ulceration, dysphagia, nausea, vomiting, diarrhea, abdominal pain, and intestinal perforation. Gastrointestinal manifestations are often triggered by an inciting event, such as an infection or the side effects of medication. This case report presents a rare GI-related SLE complication, namely superior mesenteric artery syndrome.

An Unusual Case of Candida albicans Empyema in Patient With Gastric Cancer and Colon Metastasis.

Candida empyema is a rare presentation seen in immunocompromised patients, with a high mortality rate if not treated appropriately. We present a rare case of Candida albicans empyema in a patient with gastric cancer undergoing chemotherapy who recently underwent cholecystectomy, successfully treated with fluconazole and drainage. This case not only highlights an unusual presentation of a common pathogen but stresses the fact that when patients with malignancy, present with pleural effusion, candida should be in the differential. Early detection is key in such cases, as outcomes are poor if diagnosis and treatment are delayed.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

A Rare Case of Phentermine-Induced Nonischemic Cardiomyopathy.

Obesity is a global epidemic with steadily increasing prevalence in most countries. Weight loss is generally challenging for patients to tackle in the face of the temptation to overeat and avoid physical activity. Hence, clinicians and patients alike are likely to steer toward the use of anorexigens. We report the case of a 33-year-old female with no significant cardiac history who presented with dyspnea, productive cough, and chest pressure for one month and was diagnosed with new-onset heart failure with a reduced ejection fraction secondary to prolonged phentermine use. The authors aim to highlight phentermine's potential for precipitating heart failure, even in a young, relatively healthy person, especially with a growing obese population. Ultimately, healthy weight loss can be achieved by implementing dietary changes and encouraging adequate physical activity, as the World Health Organization (WHO) recommended. Anorectic drugs may be employed for short-term use. Further research concerning the long-term side effects of phentermine may avert the prescriber and patient from abusing this drug.

Change in healthcare utilisation after surgical treatment: observational study of routinely collected patient data from primary and secondary care.

BACKGROUND: Most patients fully recover after surgery. However, high-risk patients may experience an increased burden of medical disease. METHODS: We performed a prospectively planned analysis of linked routine primary and secondary care data describing adult patients undergoing non-obstetric surgery at four hospitals in East London between January 2012 and January 2017. We categorised patients by 90-day mortality risk using logistic regression modelling. We calculated healthcare contact days per patient year during the 2 yr before and after surgery, and express change using rate ratios (RaR) with 95% confidence intervals. RESULTS: We included 70 021 patients, aged (mean [standard deviation, sd]) 49.8 (19) yr, with 1238 deaths within 2 yr after surgery (1.8%). Most procedures were elective (51 693, 74.0%), and 20 441 patients (29.1%) were in the most deprived national quintile for social deprivation. Elective patients had 12.7 healthcare contact days per patient year before surgery, increasing to 15.5 days in the 2 yr after surgery (RaR, 1.22 [1.21-1.22]), and those at high-risk of 90-day mortality (11% of population accounting for 80% of all deaths) had the largest increase (37.0 days per patient year before vs 60.8 days after surgery; RaR, 1.64 [1.63-1.65]). Emergency patients had greater increases in healthcare burden (13.8 days per patient year before vs 24.8 days after surgery; RaR, 1.8 [1.8-1.8]), particularly in high-risk patients (28% of patients accounting for 80% of all deaths by day 90), with 21.6 days per patient year before vs 49.2 days after surgery; RaR, 2.28 [2.26-2.29]. DISCUSSION: High-risk patients who survive the immediate perioperative period experience large and persistent increases in healthcare utilisation in the years after surgery. The full implications of this require further study.

Role of Sex in Atherosclerosis: Does Sex Matter?

PURPOSE OF REVIEW: Atherosclerosis is the largest cause of death in the western world with the role of sex yet to be determined. The purpose of this review is to investigate the role sex may play in the development of atherosclerosis. RECENT FINDINGS: Differences in plaque burden play a role in atherosclerotic outcome. Men have a higher prevalence of plaque burden, while women have less plaque rupture, necrotic core, and calcium. Differences in hormones, vascular anatomy, and overall lifestyle all play a role. Estrogen's cardioprotective effect is well known, but there is a lack of consensus on testosterone's role. There are varying rates of atherosclerosis between the sexes. Studies have also shown varying differences in the progression of plaque and the type of plaques between sexes. Further investigations need to be done to solidify the role sex may play as a variable in the development of atherosclerosis and how that may impact future treatment goals.

A Case Report on Rare Presentation of Sporadic Disease: Dermatomyositis Sine Dermatitis-Diagnosis and Management.

Dermatomyositis sine dermatitis (DMSD) is one of the rare idiopathic inflammatory myopathies. Based on predominant symptoms faced by patients, it is classified into 3 types: (1) classic dermatomyositis (DM), where patients have both muscle and skin symptoms; and (2) amyopathic DM, when only skin symptoms present with no muscle involvement. Whereas (3) DMSD has mainly muscle symptoms with muscle antibodies but no skin rashes. There have been only nearly 10 published articles about DMSD proving this disease's scarcity. At the same time, it shows the importance of discussing the unusual presentation of such a rare disease. Here we present, a 28-year-old woman with worsening proximal muscle weakness. The decreased muscle strength on physical examination and elevated creatinine kinase required more work up for autoimmune disease. Interestingly, on muscle biopsy, anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody returned positive, and the patient responded well to 3 days course of steroids. The lack of skin involvement, the predominance of muscle symptoms, and positive anti-MDA5 antibody indispensably diagnosed patients with DMSD. The previously published articles have proved the association between anti-NXP-2 antibody and DMSD, which was not seen in our case. The systemic involvement of DMSD can lead to interstitial lung disease, where due to diffuse alveolar damage and pulmonary fibrosis, patients end up requiring intubation and may be associated with higher-level mortality. In our case, chest X-rays and computed tomography (CT) scans were unremarkable for lung involvement, so as no paraneoplastic syndromes were present, which has also been reported in DMSD patients previously.

Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals.

Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry individuals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Another Sherlock Holmes Mystery: Abdominal Pain Explained by Median Arcuate Ligament Syndrome.

Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, is a rare gastrointestinal condition with an estimated incidence of 2 per 100 000 population. Predominantly in female patients, this syndrome is characterized by the compression of the celiac artery at its origin from the aorta by the median arcuate ligament, which at the same time is entrapping the celiac plexus, causing upper abdominal pain, notably postprandial pain, as well as nausea, vomiting, food aversion, and weight loss. We present a case of abdominal pain secondary to MALS that was appropriately diagnosed after requiring narcotic medication, which responded to surgical therapy.

The power of genetic diversity in genome-wide association studies of lipids.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Psychosocial and Behavioral Effects of the COVID-19 Pandemic in the Indian Population: Protocol for a Cross-sectional Study.

BACKGROUND: During the year 2020, the COVID-19 pandemic spread from China to the rest of the world, which prompted the world to implement a widespread mandated quarantine or social isolation. The impending uncertainty of the pandemic must have resulted in a variety of widespread mental health maladies. There has been documentation in the literature about a lot of these in small populations of the world but limited studies have been conducted in India, leading to limited evidence in the literature. OBJECTIVE: The main objective of our study is to investigate the mental health effects that the COVID-19 pandemic has had on the general population in India both quantitatively and qualitatively. These results will help contribute to reducing the knowledge gap that is recognized in the literature, which is the result of the unprecedented and novel nature of the pandemic. METHODS: We designed and validated our own questionnaire and used the method of circulating the questionnaire via WhatsApp (Facebook Inc). WhatsApp is a social media app that is very popularly used in India; hence, it turned out to be an effective medium for gathering pilot data. We analyzed the pilot data and used them to validate the questionnaire. This was done with the expertise of our mentor, Nilima Shah, MD (psychiatry). We gathered pilot data on 545 subjects and used the results to determine the changes that were needed for the questionnaire while simultaneously validating the questionnaire. RESULTS: The study protocol was approved in September 2020 by the institutional review board at Vadilal Sarabhai General Hospital, Ahmedabad, Gujarat, India. CONCLUSIONS: The following preliminary assumptions can be made about the study based on the pilot data: the majority of the survey respondents were male (289/545, 53%), most of them were educated and employed as health care workers (199/545, 36.5%). The majority of the responders were self-employed (185/545, 33.9%), single (297/545, 54.5%), and stayed with their families (427/541, 79%) for the lockdown, which helped them psychologically. Findings that are specific to mental health have been elaborated upon in the manuscript. It is evident from the data collected in previous literature that the pandemic has had significant detrimental effects on the mental health of a vast proportion of the Indian population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29896.

Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia.

BACKGROUND: The COVID-19 pandemic has strained healthcare systems and how best to address post-COVID health needs is uncertain. Here we describe the post-COVID symptoms of 675 patients followed up using a virtual review pathway, stratified by severity of acute COVID infection. METHODS: COVID-19 survivors completed an online/telephone questionnaire of symptoms after 12+ weeks and a chest X-ray. Dependent on findings at virtual review, patients were provided information leaflets, attended for investigations and/or were reviewed face-to-face. Outcomes were compared between patients following high-risk and low-risk admissions for COVID pneumonia, and community referrals. RESULTS: Patients reviewed after hospitalisation for COVID pneumonia had a median of two ongoing physical health symptoms post-COVID. The most common was fatigue (50.3% of high-risk patients). Symptom burden did not vary significantly by severity of hospitalised COVID pneumonia but was highest in community referrals. Symptoms suggestive of depression, anxiety and post-traumatic stress disorder were common (depression occurred in 24.9% of high-risk patients). Asynchronous virtual review facilitated triage of patients at highest need of face-to-face review. CONCLUSION: Many patients continue to have a significant burden of post-COVID symptoms irrespective of severity of initial pneumonia. How best to assess and manage long COVID will be of major importance over the next few years.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Antiepileptic Drugs-induced Stevens-Johnson syndrome: A case Series.

Stevens-Johnson syndrome (SJS) is an acute life-threatening mucocutaneous reaction, characterized by extensive necrosis and detachment of the epidermis from the skin. The overall incidence of SJS is seen in five cases per million people per year. SJS is typically caused by drugs and is a kind of idiosyncratic reaction. Adverse drug reactions such an SJS have a remarkable effect on patient's safety issues. We encountered nine cases of antiepileptic drug (AED)-induced SJS, specifically with carbamazepine, oxcarbazepine, and phenytoin. To manage the reaction, the clinician withdrew the drug in all 8 cases, and in 1 case, the patient was shifted to valproate and symptomatic treatment was provided. There is still a controversy whether or not all AEDs can cause SJS. Recent studies have investigated the role of genetic factors - HLAB*502 allele in the development of AED-induced SJS in patients of Asian ancestry.