Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Synthesis of anti-depressant molecules via metal-catalyzed reactions: a review.

Depression is one of the most mutilating conditions in the world today. It has been difficult to make advancements toward better, more effective therapies since the introduction of antidepressant medicines in the late 1950s. One important field of medicinal chemistry is the synthesis of antidepressant molecules through metal-catalyzed procedures. The important role that different transition metals, including iron, nickel, ruthenium, and others, serve as catalysts in the synthesis of antidepressants is examined in this review. Key structural motifs included in antidepressant drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and others can be synthesized in a variety of effective ways using metal-catalyzed steps. This review examines current developments in the catalytic synthesis of antidepressants and their potential application over the previous thirteen years.

Predictors of Extubation Failure in Very Low Birth Weight Infants at a Tertiary Care Hospital in Al Ain: A Retrospective Study.

OBJECTIVES: To identify and analyze the factors leading to extubation failure among very low birth weight infants in a specific tertiary care setting in Al Ain, emphasizing clinical and demographic variables. The study used medical data of Very Low Birth Weight (VLBW) infants admitted to the Neonatal Intensive Care Unit (NICU) from 1st January 2015 to 31st December 2019, and evaluated the incidence and risk factors associated with extubation failure. METHODS: Data was collected from the hospital's electronic records and tabulated in Excel sheets, with extubation failure defined as reintubation due to deterioration of respiratory condition within seven days post-extubation. The data was collected from the period of 1st January 2015 to 31st December 2019. Inclusion criteria included babies admitted to the NICU with a gestational age of ≤ 32 weeks, or of birth weight ≤1500 grams who were intubated within the first seven days of life. Results were analyzed using SPSS software, version 9.0 (SPSS Inc., Chicago) to determine the risk factors for extubation failure and short-term outcomes. RESULTS: Gestational age, birth weight, antenatal steroids, mode of delivery, number of Survanta® (beractant intratracheal suspension) doses, Positive End-Expiratory Pressure (PEEP), Mean Airway Pressure (MAP), Mean Arterial Pressure (Blood Pressure (BP)), and Infectious Diseases (ID) (indicated by a positive blood culture) were found to be the key predictors of extubation failure in very low birth weight infants at a tertiary care hospital in Al Ain. The most common reasons for reintubation were FiO2 > 50% (23.53%), followed by Respiratory Acidosis (20.59%). Other factors, including maternal chorioamnionitis, Apgar scores, indication for intubation, caffeine, and pre-and post-extubation laboratory values, comorbidities, and hemoglobin (Hgb), creatinine and sodium levels were found to have no effect on the success of extubations. CONCLUSIONS: The results of this research indicate that factors such as gestational age, birth weight, prenatal steroid use, delivery method, the quantity of Survanta® doses, PEEP, MAP, MAP (BP), and ID (+ve blood culture) were the primary determinants of unsuccessful extubation in VLBW babies at a tertiary healthcare facility in Al Ain. The predominant cause for needing reintubation was a FiO2 level above 50%, followed by Respiratory Acidosis. Additional ®®investigations are required to validate these findings and pinpoint other potential predictors of extubation failure within this demographic.

Assessment of initial vancomycin trough levels and risk factors of vancomycin-induced nephrotoxicity in neonates.

OBJECTIVES: Vancomycin is a glycopeptide antibiotic commonly used in neonatal intensive care units (NICUs) to treat late onset sepsis. It is recommended that vancomycin trough levels at steady state following intermittent dosing regimen be maintained at 10-20 mg/L, which is largely dependent on the type of infection. Our objective is to assess the ability of initial vancomycin dosing regimens to obtain target trough levels and to assess the percentage and risk factors associated with the development of acute kidney injury (AKI) while on vancomycin. METHODS: This is a retrospective review of all NICU patients admitted between January 2016 and December 2017 who received vancomycin according to the NeoFax at either 10 mg/kg/dose (low-dose group, LDG) or 15 mg/kg/dose (high-dose group, HDG), with a frequency based on the postmenstrual age (PMA) and postnatal age (PNA). Both regimens were compared by their ability to attain target trough levels and the episodes of vancomycin-induced AKI. Other outcomes included identification of risk factors associated with the development of vancomycin-induced nephrotoxicity. RESULTS: Of 182 patients evaluated, 44 (24%) were in the LDG and 138 patients (76%) were in the HDG. Ninety-one patients (50%) attained target trough levels of 10-20 mg/L. Among these and according to patients' PMA, 48% in the HDG versus 7% in the LDG in PMA ≤29 weeks and 69% in the HDG versus 18% in the LDG in PMA 30-36 weeks attained target trough levels (p=0.006 and p<0.001, respectively). According to PNA, 47% in the HDG versus none in the LDG in patients <7 days old and 61% in the HDG versus 10% in the LDG in patients aged 8-14 days attained target trough levels (p=0.025 and p=0.016, respectively). A total of 14% developed AKI in the LDG vs 7% in the HDG (p=0.225). Only PMA ≤29 weeks (OR, 4.5, 95% CI 1.5 to 13), vancomycin trough levels >20 mg/L (OR 5.1, 95% CI 1.5 to 17), hypotension (OR 11.02, 95% CI 3.5 to 34) and furosemide (OR 4.4, 95% CI 1.4 to 13.5) were significantly associated with vancomycin-induced AKI in our NICU. CONCLUSION: Vancomycin dosing in neonates according to the NeoFax did not provide sufficient attainment of target trough levels (10-20 mg/L). However, using the higher dosing range at 15 mg/kg/dose was more likely to reach target levels, with no measured increased risk of nephrotoxicity. Extreme premature neonates, supratherapeutic vancomycin trough levels, hypotension and furosemide use are associated with an increased incidence of vancomycin-induced nephrotoxicity.

Health informatics to optimize complex laboratory developed test configurations.

BACKGROUND: Configuration of complex Laboratory Developed Tests (LDTs) is a time-consuming and complicated task, potentially leading to inconsistent LDTs in which features constraints remain unresolved and important features could remain unselected. OBJECTIVE: Our objective is to address these issues by presenting an automated, health informatics solution which autonomously optimizes feature selection in complex LDTs through Particle Swarm Optimization (PSO). The optimization goal is to minimize inconsistencies and configuration time, and maximize the number of selected features. METHODS: We implemented our technology in a local, secondary-care hospital in Pakistan which configures LDT for a local epidemic disease. First, a list of inconsistent LDT configurations is generated. This is used to initially estimate optimal PSO parameters, which are then used for optimization process. RESULTS: Results show that PSO is able to minimize 91% inconsistencies between 9 and 11 seconds. The number of selected critical features also increases by 100% in the optimized LDT configuration. CONCLUSIONS: We present a novel and the first application of computational optimization to solve LDT configuration issues.

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.

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk.

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Precision of SPECT/CT Allows the Diagnosis of a Hidden Brodie's Abscess of the Talus in a Patient with Sickle Cell Disease.

Brodie's abscess is a rare subacute osteomyelitis that can be found in sickle cell disease along with other bone complications. A 21-year-old female with sickle cell disease was presenting frequently to the medical casualty department for painful vasoocclusive crises and for persistent ankle pain and swelling. Hybrid imaging with single-photon emission computed tomography-computed tomography (SPECT-CT) incidentally revealed Brodie's abscess in the talus bone of the ankle, causing persisting long-standing pain. SPECT-CT is a modern technology used to scan bone to detect both anatomical and functional abnormalities with high specificity. Brodie's abscess is a rare bone inflammation that could be a hidden cause of pain and infection in sickle cell disease. Although rare, this lesion requires more attention in patients with sickle cell disease because their immunocompromised status renders them prone to this infection.

A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies.

DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.

BACKGROUND: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. METHODS: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. FINDINGS: 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)). INTERPRETATION: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. FUNDING: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

The South Asian genome.

The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.

A case of dupable duple duplicity and duplexity.

Duplication anomalies are quite common with ureteral duplication anomalies being the most frequent. Despite the relatively frequent incidence of a horseshoe kidney and duplication anomalies in any individual patient, the combination of horseshoe kidney and bilateral ureteric duplication is a very rare entity and very few cases have been reported to date. We present a case of a patient with a novel combination of a horseshoe kidney and multiple rare congenital renal anomalies and their sequelae.