Polygenic Risk Score Assessment for Coronary Artery Disease in Asian Indians.

We evaluated the performance of various polygenic risk score (PRS) models derived from European (EU), South Asian (SA), and Punjabi Asian Indians (AI) studies on 13,974 subjects from AI ancestry. While all models successfully predicted Coronary artery disease (CAD) risk, the AI, SA, and EU + AI were superior predictors and more transportable than the EU model; the predictive performance in training and test sets was 18% and 22% higher in AI and EU + AI models, respectively than in EU. Comparing individuals with extreme PRS quartiles, the AI and EU + AI captured individuals with high CAD risk showed 2.6 to 4.6 times higher efficiency than the EU. Interestingly, including the clinical risk score did not significantly change the performance of any genetic model. The enrichment of diversity variants in EU PRS improves risk prediction and transportability. Establishing population-specific normative and risk factors and inclusion into genetic models would refine the risk stratification and improve the clinical utility of CAD PRS.

Assessing the prediction of type 2 diabetes risk using polygenic and clinical risk scores in South Asian study populations.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRSAI) and Europeans (PRSEU) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRSAI and PRSEU) successfully predicted the T2D risk. However, the PRSAI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63-1.97; p = 1.6 × 10-152] and 12.2% OR 1.38 (95% CI 1.30-1.46; p = 7.1 × 10-237) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRSAI showed about two-fold OR 20.73 (95% CI 10.27-41.83; p = 2.7 × 10-17) and 1.4-fold OR 3.19 (95% CI 2.51-4.06; p = 4.8 × 10-21) higher predictability to identify subgroups with higher genetic risk than the PRSEU. Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRSAI and 0.72 to 0.75 in PRSEU. Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium.

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

Vascular access complications in patients undergoing veno-arterial ecmo and their impact on survival in patients with refractory cardiogenic shock: A retrospective 8-year study.

Introduction: Veno-arterial extracorporeal membrane oxygenation (ECMO) is well-recognized treatment modality for patients with refractory cardiogenic shock. Uncomplicated cannulation is a prerequisite and basis for achieving a successful outcome in ECMO. Vascular access is obtained either by surgical cut-down. Common vascular access complications are bleeding and limb ischemia. Objective: To evaluate cannulation technique, the incidence of vascular complications, and their impact on the outcome. Methods: A retrospective data analysis conducted on 95 patients receiving ECMO from 2013 to 2020 was done. The patients were divided into two groups: no vascular access complications (non-VAC group) and vascular access complications (VAC group). The groups were compared related to the hospital and ICU stays and blood transfusion. Results: The patients in both groups were demographically and clinically comparable. The Non-VAC group had 75 patients, whereas the VAC group had a total of 20 patients. The main complication observed in the VAC group was bleeding from the cannulation site which required more blood transfusion than the non-VAC group (6.8 ± 1.02 vs 4.2 ± 1.26). Limb ischemia was another complication seen in the VAC group (4.2%, n = 4). Two patients had delayed bleeding after decannulation. The overall average length of stay in the hospital was statistically similar in both the groups (22 days in the VAC group vs 18 days in the non-VAC group), but the average ICU stay was more in the VAC group compared to the non-VAC group (18 days vs 12.06 days). Conclusion: Bleeding and limb ischemia are the important vascular access site complications, which increase blood transfusion requirements, ICU stay, and overall hospital stay.

Effect of anti-platelet therapy on peri-operative blood loss in patients undergoing off-pump coronary artery bypass grafting.

Purpose: The purpose of this study was to review the effect of the pre-operative use of clopidogrel and aspirin on peri-operative bleeding, blood product transfusion, and resource utilization after coronary artery bypass grafting (CABG). Materials and Methods: A total of 1200 patients who underwent off-pump CABG (OPCABG) between 2010 and 2012 were retrospectively studied. Patients were divided into three groups: group 1: discontinued aspirin and clopidogrel 6 days prior to surgery (n = 468), group 2: discontinued both drugs 3 to 5 days prior to surgery (n = 621), and group 3: discontinued both drugs 2 days prior to surgery (n = 111). The bleeding pattern and blood product transfusion were studied and compared between the groups. Patients having history of other drugs affecting the coagulation profile, other organ dysfunction, on-pump CABG, and the combined procedure were excluded from the study. Results: Group 2 patients had a higher rate of bleeding and a reduced mean value of hemoglobin (Hb) as compared to other groups. The same results were seen in blood and blood product transfusion. Patients of group 2 and group 3 were associated with higher blood loss in terms of drainage at 12 and 24 hours. Post-operatively, this was statistically significant. Re-exploration was statisitically significant in group 3 patients (9.01%) than in group 2 (2.58%) and group 1 (1.07%) patients. Conclusion: The pre-operative use of clopidogrel and aspirin in patients undergoing OPCABG showed limited clinical benefits; however, its use significantly increased the risk of bleeding and blood transfusion, thus increasing morbidity and resource utilization. Hence, clopidogrel and aspirin should be stopped at least 6 days prior to surgery.

Analysis of anticoagulation therapy related complications in patients with prosthetic valves: Our experience.

PURPOSE: The aim of this study is to analyze anticoagulation-related complications in patients following mechanical valve replacement and factors influencing the outcome. MATERIALS AND METHODS: A total of 250 patients were analyzed during OPD follow-up for anticoagulation-related complications and various factors influencing outcome. Patients received prosthetic valve at mitral and/or aortic or both. RESULTS: Out of 250 patients, 48% were male and 52% were female. The mean age was 41.9 ± 14.4. A total of 139 had mitral valve replacement (MVR), 70 had aortic valve replacement (AVR), 40 had double valve replacement (DVR), and 1 patient had triple valve replacement. Valves implanted were mechanical bileaflet valve. The mean international normalization ratio (INR) in the study was 2.4 ± 0.56. A total of 49 events occurred during follow-up, of which 4.5% per patient years were anticoagulation-related hemorrhagic events and 4.8% per patient years were thromboembolic events. Among thromboembolic events, valve thrombosis occurred in 10 patients and cerebrovascular accidents occurred in 11 patients. Mean INR for thromboembolic events was 1.46 ± 0.25 and anticoagulation-related hemorrhagic events was 4.4 ± 1.03. Mortality rate was 1.6% in AVR, 4% in MVR, and 0.4% in DVR groups; about 34% of patients needed dose modification of Acenocoumarol and reason for derangement of INR was associated with infectious process and poor compliance; 85% of cases showed good compliance for daily anticoagulation therapy. CONCLUSION: Anticoagulation for mechanical valve replacement can be managed with INR range of 2.0 to 2.5 in MVR and 1.5 to 2.0 in AVR with acceptable hemorrhagic and thromboembolic events. We must educate and counsel the patients during follow-up for better compliance to optimal anticoagulation.

Managing patients of shock and acute kidney injury in tertiary care cardiac ICU: Experience with continuous renal replacement therapy.

BACKGROUND: Clinical experience on details of CRRT initiation and outcomes in cardiac intensive care unit (CICU) patients is not available from developing countries like India. This study shares the 5-year clinical experience of managing CICU patients requiring CRRT in a tertiary care cardiac center of North India. MATERIALS AND METHODS: Medical records of all CICU patients with acute kidney injury (AKI) managed by CRRT from October 2011 to September 2016 at tertiary referral center in North India were retrospectively reviewed. Multiple logistic regression analysis was used to identify predictors of post-CRRT mortality. RESULTS: A total of 630 patients received CRRT during the study period. Most commonly AKI developed in patients with acute coronary syndrome (30.2 %) with cardiogenic shock. 55.9 % of the CRRT patients were >60 years of age, and/or on multiple supports in ICU including, mechanical ventilation, high doses of inotropes & vasopressors and other cardiovascular support. Of those on CRRT, 130 (20.6 %) patients had died, 215 (34.1 %) were discharged and 285 (45.2 %) could not complete the desired course. Multivariate regression analysis showed independent association of mortality with high vasoactive-inotropic score, single CRRT cycle and low mean arterial pressure in CRRT patients. CONCLUSION: About 34.1 % of patients receiving CRRT were alive at discharge, emphasizing the feasibility and utility of CRRT as a promising modality in this population for improving outcomes.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

Do anti-platelet drugs improve duration of continuous renal replacement therapy? A retrospective cohort study in cardiac ICU patients.

OBJECTIVE: The objective of this study was to investigate the impact of anti-platelet drug/s on duration of continuous renal replacement therapy (CRRT) in those patients where anti-coagulants were not used due to certain contraindications and in cases where patients were on anti-platelet drugs and were given anti-coagulant during CRRT. METHOD: This single-center, retrospective cohort study was conducted using the medical records patients treated with CRRT in the cardiac ICU of the inpatient urban facility, located in North India. Data was collected from only those patients who received CRRT for the duration of at least 12 h. Patient's in NAC group were not on any anti-platelet/s and did not receive anti-coagulant during CRRT. AC and AP group patients received anti-coagulant alone or were already on anti-platelet/s and did not receive anti-coagulant respectively while ACAP group patients were on anti-platelet drug/s and also received anti-coagulant during CRRT. RESULT: Patients in AC, AP, or ACAP group showed significantly (p < 0.001) higher CRRT filter life compared to NAC group. The median CRRT filter life was significantly higher in the ACAP group compared to AC (p < 0.05) and AP (p < 0.001) groups. CONCLUSION: This study indicates that systemic anti-platelet therapy can provide additional support in critical patients undergoing CRRT even with or without anti-coagulant therapy. However, the increase in CRRT filter life was more profound in patients who were on anti-platelet/s and also received anti-coagulant drug/s during CRRT.

Cardiothoracic surgery during COVID-19: Our experience with different strategies.

Background: An acute respiratory disease (COVID-19), caused by a novel coronavirus (SARS-CoV-2,), has been declared a pandemic by WHO. A surgery on COVID-19 patients not only involves a risk of spread of the disease but also there is a serious concern for the patient's surgical outcomes and resources requirement. Aim: The retrospective study is aimed to provide a protocol for pre-operative testing of SARS CoV-2 using RT-PCR in the patient undergoing cardio-thoracic surgeries. Material and Methods: To analyze the impact of pre-operative testing of SARS- CoV-2 using RT-PCR in the patient undergoing elective cardio-thoracic surgeries. The patient who underwent surgical interventions during the COVID-19 lockdown period was divided into two phases. Phase I (without COVID-19 RT-PCR testing) and Phase II (with pre-operative COVID-19 RT-PCR testing). The retrospective comparison between the two study groups was done using Student t-test, Mann-Whitney U, and Chi square (χ2) test depending upon the clinical variable to be analyzed. Results: During the early phase (phase I), 26 patients underwent cardio-thoracic surgery without COVID-19 RT-PCR test. Whereas, during phase II, all patients were tested for COVID-19 using RT-PCR, preoperatively and a total of 64 surgeries were performed during this phase. One patient planned for CABG was positive on RT-PCR for COVID-19 and was sent to the quarantine ward. The difference in the pre-operative hospital stay between two groups was found to be statistically significant and a significant decrease in the number of PPE kits used, during the phase I. Conclusion: All asymptomatic patients should be tested for COVID-19 using RT-PCR prior to cardio-thoracic surgeries not only to contain the disease but to avoid potential implications of COVID-19 on the perioperative course, without added financial implications.

Impact of extra-corporeal membrane oxygenation on outcome of aluminium phosphide poisoning complicated with myocardial dysfunction.

Background: Aluminium phosphide (AlP) poisoning is associated with a high mortality rate when patients are complicated with myocardial dysfunction and refractory shock or severe metabolic acidosis. We studied the role of veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) in patients of AlP poisoning induced myocardial dysfunction. Methods and results: This is a tertiary care, single-centre, retrospective study. Between January 2011 and June 2016, total of 107 patients with AlP poisoning were identified and of those 67 were categorised in high-risk category as per the criteria. The in-hospital mortality of patients who received ECMO (n = 35) was compared to those who received conventional treatment (n = 32) only. The use of ECMO in addition to conventional treatment has reduced the in-hospital mortality from 84.4% to 40% (odds ratio: 0.47; 95% confidence interval 0.31-0.73). Among survivors, the ECMO group had a significantly lower baseline left ventricular ejection fraction (LVEF; median: 24%; IQR: 22-29 vs. median: 32%; IQR: 32-33.5; p < .003) but a non-significantly higher LVEF at the time of discharge (median: 52%; IQR: 48-60 vs. median: 48%; IQR: 47-49; p: .064) than did the conventional group. On logistic regression analysis the higher sequential organ failure assessment (SOFA) score, lower pH and the non-usage of ECMO were found to be the independent predictors of mortality. Conclusion: The use of ECMO in high-risk patient of AlP poisoning has resulted in a significant reduction in the mortality. A high baseline SOFA score has been found to be the independent predictor of mortality.

Complete transection of the right main bronchus: case report.

Tracheobronchial injuries (TBIs) have a high mortality rate unless aggressive treatment is used. The clinical presentation is variable depending on the presence of associated injuries and on whether the peribronchial tissues remain intact. High index of clinical suspicion and accurate interpretation of radiological findings are necessary to diagnose the injury at presentation and allow prompt surgical intervention with primary repair of the airway. Herein, we describe a case of complete right main bronchus rupture in a 10-year-old boy diagnosed by chest computed tomography.

Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin.

Diversity in drug response is attributed to both genetic and non-genetic factors. However, there is paucity of pharmacogenetics information across ethnically and genetically diverse populations of India. Here, we have analyzed 21 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Indian origin (N = 1,616), as part of the Sikh Diabetes Study (SDS). We compared the allele frequency of poor metabolism (PM) phenotype among Sikhs across other major global populations from the Exome Aggregation Consortium and 1000 Genomes. The PM phenotype of CYP1A2*1 F for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 42%, GIH [Gujarati] 51%, SAS [Pakistani] 45%) compared to Europeans 29% (pgenotype = 5.3E-05). Similarly, South Asians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH, 11% SAS) vs. 7% in Europeans (pgenotype = <1.0E-05) and 'T' allele of CYP4F2 (36%) SDS, (43%) GIH, 40% (SAS) vs. (29%) in Europeans (pgenotype = <1.0E-05); both associated with a higher risk of bleeding with warfarin. All South Asians -the Sikhs (0.36), GIH (0.34), and SAS (0.36) had a higher frequency of the NAT2*6 allele (linked with slow acetylation of isoniazid) compared to Europeans (0.29). Additionally, the prevalence of the low activity 'C' allele of MTHFR (rs1801131) was highest in Sikhs compared to all other ethnic groups [SDS (44%), GIH (39%), SAS (42%) and European (32%) (pgenotype = <1.0E-05)]. SNPs in MTHFR affect metabolism of statins, 5-fluorouracil and methotrexate-based cancer drugs. These findings underscore the need for evaluation of other endogamous ethnic groups of India and beyond for establishing a global benchmark for pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention.

Outcome of patients supported by extracorporeal membrane oxygenation for aluminum phosphide poisoning: An observational study.

INTRODUCTION: Aluminum phosphide (AlP) poisoning has a high mortality rate despite intensive care management, primarily because it causes severe myocardial depression and severe acute respiratory distress syndrome. The purpose of this study was to evaluate the impact of the novel use of extracorporeal membrane oxygenation (ECMO), a modified "heart-lung" machine, in a specific subset of AlP poisoning patients who had profound myocardial dysfunction along with either severe metabolic acidosis and/or refractory cardiogenic shock. METHODS: Between January 2011 and September 2014, 83 patients with AlP poisoning were enrolled in this study; 45 patients were classified as high risk. The outcome of the patients who received ECMO (n=15) was compared with that of patients who received conventional treatment (n=30). RESULTS: In the high-risk group (n=45), the mortality rate was significantly (p<0.001) lower in patients who received ECMO (33.3%) compared to those who received conventional treatment (86.7%). Compared with the conventional group, the average hospital stay was longer in the ECMO group (p<0.0001). In the ECMO group, non-survivors had a significantly (p=0.01) lower baseline LV ejection fraction (EF) and a significantly longer delay in presentation (p=0.01). CONCLUSION: Veno-arterial ECMO has been shown to improve the short-term survival of patients with AlP poisoning having severe LV myocardial dysfunction. A low baseline LVEF and longer delay in hospital presentation were found to be predictors of mortality even after ECMO usage. Large, adequately controlled and standardized trials with long-term follow-up must be performed to confirm these findings.

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians.

South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.

Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P<10(-4)) using an independent replication sample (n=2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [ß=-0.13, p=4.47×10(-9)] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [ß=0.90; p=1.36×10(-6)] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p=0.007) and CYP2R1 (p=0.019) reported in Europeans and the DAB1 (p=0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities.

Role of Extracorporeal Membrane Oxygenation in Aluminum Phosphide Poisoning-Induced Reversible Myocardial Dysfunction: A Novel Therapeutic Modality.

BACKGROUND: Aluminum phosphide (AlP) poisoning carries a high rate of mortality despite intensive care management, primarily because of refractory myocardial depression, resistant hypotension, and severe metabolic acidosis as well as acute respiratory distress syndrome. Extracorporeal membrane oxygenation (ECMO) is a modified "heart-lung" machine to provide temporary cardiorespiratory support. We studied the novel use of ECMO in the management of a subset of patients with AlP poisoning. CASE REPORT: In this case series, seven patients with AlP poisoning suffering from severe metabolic acidosis and refractory cardiogenic shock with a reduced left ventricular ejection fraction (<35%) received ECMO treatment. The acidosis and hemodynamic status improved within 6-12 h and 12-24 h, respectively, in five patients. Two patients did not survive because of a long delay in presentation after ingestion. The majority of the patients developed dysrhythmias, ECMO cannulation site bleeding, and thrombocytopenia. Two patients required surgical exploration of the femoral artery. At 9 months of follow-up, all five surviving patients were doing well, with the near normalization of ventricular function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We have found that timely intervention with ECMO in patients with AlP poisoning-induced severe metabolic acidosis and refractory cardiogenic shock may lead to a significant improvement in overall survival. Therefore, ECMO might be considered as a bridge therapy for patients with intractable cardiorespiratory failure caused by AlP poisoning who are not responding to conventional treatment. ECMO, however, also is associated with significant complication rates, which must be incorporated into the risk-benefit analysis while considering treatment options.