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An editorial is presented on confirming the contemporary existence of worker inequality within the field of nephrology. Topics include physician qualities are humanistic, and practices being accountable to peer and societal expectations; and female first authors of the abstracts during the time, although proportionately fewer female presenters of basic science research.

Anxiety and depression are common psychiatric conditions associated with significant morbidity and healthcare costs. Sleep is an evolutionarily conserved health state. Anxiety and depression have a bidirectional relationship with sleep. This study reports on the use of analysis of polysomnographic data using deep learning methods to detect the presence of anxiety and depression. Polysomnography data on 940 patients performed at an academic sleep center during the 3-year period from 01/01/2016 to 12/31/2018 were identified for analysis. The data were divided into 3 subgroups: 205 patients with Anxiety/Depression, 349 patients with no Anxiety/Depression, and 386 patients with likely Anxiety/Depression. The first two subgroups were used for training and testing of the deep learning algorithm, and the third subgroup was used for external validation of the resulting model. Hypnograms were constructed via automatic sleep staging, with the 12-channel PSG data being transformed into three-channel RGB (red, green, blue channels) images for analysis. Composite patient images were generated and utilized for training the Xception model, which provided a validation set accuracy of 0.9782 on the ninth training epoch. In the independent test set, the model achieved a high accuracy (0.9688), precision (0.9533), recall (0.9630), and F1-score (0.9581). Classification performance of most other mainstream deep learning models was comparable. These findings suggest that machine learning techniques have the potential to accurately detect the presence of anxiety and depression from analysis of sleep study data. Further studies are needed to explore the utility of these techniques in the field of psychiatry. [ABSTRACT FROM AUTHOR]

Background: Prolonged length of stay (LOS) and post‐acute care after percutaneous coronary intervention (PCI) is common and costly. Risk models for predicting prolonged LOS and post‐acute care have limited accuracy. Our goal was to develop and validate models using artificial neural networks (ANN) to predict prolonged LOS > 7days and need for post‐acute care after PCI. Methods: We defined prolonged LOS as ≥7 days and post‐acute care as patients discharged to: extended care, transitional care unit, rehabilitation, other acute care hospital, nursing home or hospice care. Data from 22 675 patients who presented with ACS and underwent PCI was shuffled and split into a derivation set (75% of dataset) and a validation dataset (25% of dataset). Calibration plots were used to examine the overall predictive performance of the MLP by plotting observed and expected risk deciles and fitting a lowess smoother to the data. Classification accuracy was assessed by a receiver‐operating characteristic (ROC) and area under the ROC curve (AUC). Results: Our MLP‐based model predicted prolonged LOS with an accuracy of 90.87% and 88.36% in training and test sets, respectively. The post‐acute care model had an accuracy of 90.22% and 86.31% in training and test sets, respectively. This accuracy was achieved with quick convergence. Predicted probabilities from the MLP models showed good (prolonged LOS) to excellent calibration (post‐acute care). Conclusions: Our ANN‐based models accurately predicted LOS and need for post‐acute care. Larger studies for replicability and longitudinal studies for evidence of impact are needed to establish these models in current PCI practice. [ABSTRACT FROM AUTHOR]

Background: In low resource settings recall of the date of the mother's last menstrual period may be unreliable and due to limited availability of prenatal ultrasound, gestational age of newborns may not be assessed reliably. Preterm babies are at high risk of morbidity and mortality so an alternative strategy is to identify them soon after birth is needed for early referral and management. Objective: The objective of this study was to assess the accuracy in assessing prematurity of newborn, over and above birthweight, using a pictorial Simplified Gestational Age Score adapted for use as a Tablet App. Methods: Two trained nurse midwives, blinded to each other's assessment and the actual gestational age of the baby used the app to assess gestational age at birth in 3 hospitals based on the following 4 parameters—newborn's posture, skin texture, breast and genital development. Inter-observer variation was evaluated and the optimal scoring cut-off to detect preterm birth was determined. Sensitivity and specificity of gestational age score using the tablet was estimated using combinations of last menstrual period and ultrasound as reference standards to assess preterm birth. The predictive accuracy of the score using the area under a receiver operating characteristic curve was also determined. To account for potential reference standard bias, we also evaluated the score using latent class models. Results: A total of 8,591 live singleton births whose gestational age by last menstrual period and ultrasound was within 1 weeks of each other were enrolled. There was strong agreement between assessors (concordance correlation coefficient 0.77 (95% CI 0.76–0.78) and Fleiss' kappa was 0.76 (95% CI 0.76–0.78). The optimal cut-off for the score to predict preterm was 13. Irrespective of the reference standard, the specificity of the score was 90% and sensitivity varied from 40–50% and the predictive accuracy between 74%–79% for the reference standards. The likelihood ratio of a positive score varied between 3.75–4.88 while the same for a negative likelihood ratio consistently varied between 0.57–0.72. Latent class models showed similar results indicating no reference standard bias. Conclusion: Gestational age scores had strong inter-observer agreement, robust prediction of preterm births simplicity of use by nurse midwives and can be a useful tool in resource-limited scenarios. Trial registration: The Tablet App for the Simplified Gestational Age Score (T-SGAS) study was registered at ClinicalTrials.gov NCT02408783; [ABSTRACT FROM AUTHOR]

Objective: To assess the performance of fine needle aspiration cytology (FNAC) in the diagnosis of tuberculosis mastitis. Materials and Methods: Diagnostic test performance evaluation using two methods--as compared to an alloyed gold standard as well as in the absence of a gold standard. Alloyed gold standard combined the results of acid fast bacilli in cytology smears, histopathological confirmation, and response to treatment. Bayesian estimation of test parameters was done in the absence of the gold standard. Results: FNAC was carried out in 6,496 consecutive cases of breast lump and 104 cases of granulomatous mastitis were detected. Both methods of test parameter estimation identified a high specificity of FNAC for the diagnosis of tuberculosis mastitis (98.9% and 98.4%, respectively). Estimation of sensitivity was falsely high (100%) using the alloyed gold standard because of a workup bias and falsely low (8.41%) using the Bayesian estimation because of low prevalence. Likelihood ratios by both methods suggested that FNAC has good discriminatory capability. Conclusion: In situations where prevalence of tuberculosis is high and where facilities for histopathological evaluation do not exist, FNAC can offer an optional alternative to base the therapeutic decision for starting antitubercular treatment. [ABSTRACT FROM AUTHOR]

Background: Myocardial relaxation is impaired in almost all cases with left ventricular diastolic dysfunction (LVDD) and is a strong predictor of cardiovascular and all-cause mortality.Objectives: This study investigated the feasibility of signal-processed surface electrocardiography (spECG) as a diagnostic tool for predicting the presence of abnormal cardiac muscle relaxation.Methods: A total of 188 outpatients referred for coronary computed tomography (CT) angiography underwent an echocardiogram for assessment of LVDD. The use of 12-lead spECG for predicting myocardial relaxation abnormalities as identified using tissue Doppler echocardiography was validated with machine-learning approaches.Results: A total of 188 subjects underwent diagnostic testing, with 133 (70%) showing abnormal myocardial relaxation on tissue Doppler imaging. A 12-lead spECG showed an area under the curve of 91% (95% confidence interval: 86% to 95%) for prediction of abnormal myocardial mechanical relaxation with a sensitivity and specificity of 80% and 84%, respectively. The spECG demonstrated more accurate diagnostic performance in individuals age ≥60 years as well as those with obesity or hypertension, compared with their respective counterparts. Prediction of low early diastolic relaxation velocity (e') also correctly identified concomitant significant underlying coronary artery disease in 23 of 28 cases (82%). Furthermore, a superior integrated discrimination and net reclassification improvement was observed for spECG over clinical features and traditional ECG.Conclusions: The spECG provides a robust prediction of abnormal myocardial relaxation. These data suggest a potential role for spECG as a novel screening strategy for identifying patients at risk for LVDD who would benefit undergoing echocardiographic evaluations. [ABSTRACT FROM AUTHOR]

Background: Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits. Results: We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment -- insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits. Conclusions: Our results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D. [ABSTRACT FROM AUTHOR]

SLC30A8 encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association of SLC30A8 variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) around SLC30A8 for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of the SLC30A8 locus tested the association with eight T2D-related traits at four levels: (i) each SNP using measured genotype approach (MGA); (ii) interaction of SNPs with age and sex; (iii) combinations of SNPs using Bayesian Quantitative Trait Nucleotide (BQTN) analyses; and (iv) entire gene locus using the gene burden test. Only one SNP (rs7817754) was significantly associated with incident T2D but a summary statistic based on all T2D-related traits identified 11 novel SNPs. Three SNPs and one SNP were weakly but interactively associated with age and sex, respectively. BQTN analyses could not demonstrate any informative combination of SNPs over MGA. Lastly, gene burden test results showed that at best the SLC30A8 locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of the SLC30A8 SNPs with T2D in Mexican American families. [ABSTRACT FROM AUTHOR]

Background: Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening. Methods: Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The LRS derived from SAFHS as well as its recalibrated version were validated in an independent cohort from Australia - the AusDiab cohort. The participants were T2D-free at baseline and followed for 9197 person-years in the SAFHS cohort (n = 771) and 5930 person-years in the AusDiab cohort (n = 644). Statistically and clinically improved T2D prediction was evaluated with established statistical parameters in both cohorts. Modeling studies were conducted to determine whether the use of LRS would be cost-effective for T2D screening. The main outcome measures included accuracy and incremental value of the LRS over routinely used clinical predictors of T2D risk; validation of these results in an independent cohort and cost-effectiveness of including LRS in screening/intervention programs for T2D. Results: The LRS was based on plasma concentration of dihydroceramide 18:0, lysoalkylphosphatidylcholine 22:1 and triacyglycerol 16:0/18:0/18:1. The score predicted future T2D independently of prediabetes with an accuracy of 76 %. Even in the subset of initially euglycemic individuals, the LRS improved T2D prediction. In the AusDiab cohort, the LRS continued to predict T2D significantly and independently. When combined with risk-stratification methods currently used in clinical practice, the LRS significantly improved the model fit (p < 0.001), information content (p < 0.001), discrimination (p < 0.001) and reclassification (p < 0.001) in both cohorts. Modeling studies demonstrated that LRS-based risk-stratification combined with metformin supplementation for high-risk individuals was the most cost-effective strategy for T2D prevention. Conclusions: Considering the novelty, incremental value and cost-effectiveness of LRS it should be used for risk-stratification of future T2D. [ABSTRACT FROM AUTHOR]

Objective: While the role of type 2 diabetes (T2D) in inducing endothelial dysfunction is fairly well-established the etiological role of endothelial dysfunction in the onset of T2D is still a matter of debate. In the light of conflicting evidence in this regard, we conducted a prospective study to determine the association of circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) with incident T2D. Methods: Data from this study came from 1,269 Mexican Americans of whom 821 initially T2D-free individuals were longitudinally followed up in the San Antonio Family Heart Study. These individuals were followed for 9752.95 person-years for development of T2D. Prospective association of sICAM-1 and sVCAM-1 with incident T2D was studied using Kaplan-Meier survival plots and mixed effects Cox proportional hazards modeling to account for relatedness among study participants. Incremental value of adhesion molecule biomarkers was studied using integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indexes. Results: Decreasing median values for serum concentrations of sICAM-1 and sVCAM-1 were observed in the following groups in this order: individuals with T2D at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal glucose tolerant (NGT) individuals who remained T2D-free during follow-up. Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment—insulin resistance (HOMA-IR). Mixed effects Cox proportional hazards modeling revealed that after correcting for important clinical confounders, high sICAM-1 and sVCAM-1 concentrations were associated with 2.52 and 1.99 times faster progression to T2D as compared to low concentrations, respectively. Individuals with high concentrations for both sICAM-1 and sVCAM-1 progressed to T2D 3.42 times faster than those with low values for both sICAM-1 and sVCAM-1. The results were similar in women in reproductive age group and the remainder of the cohort. Inclusion of sICAM-1 and sVCAM-1 in predictive models significantly improved reclassification and discrimination. The majority of these results were seen even when the analyses were restricted to NGT individuals. Conclusion: Serum concentrations of sICAM-1 and sVCAM-1 independently and additively predict future T2D and represent important candidate biomarkers of T2D. [ABSTRACT FROM AUTHOR]

Background: There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (=95 cm in males and =80 cm in females) combined with high serum triglyceride concentration (=2.0 mmol/L in males and =1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively. Results: Data for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26% of these individuals had HTGW. This phenotype was significantly heritable (h²r = 0.52, p = 1.1 × 10-5) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism. Conclusions: Our results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype. [ABSTRACT FROM AUTHOR]

Background Mexican Americans are at an increased risk of both thyroid dysfunction and metabolic syndrome (MS). Thus it is conceivable that some components of the MS may be associated with the risk of thyroid dysfunction in these individuals. Our objective was to investigate and replicate the potential association of MS traits with thyroid dysfunction in Mexican Americans. Methods We conducted association testing for 18 MS traits in two large studies on Mexican Americans - the San Antonio Family Heart Study (SAFHS) and the National Health and Nutrition Examination Survey (NHANES) 2007-10. A total of 907 participants from 42 families in SAFHS and 1633 unrelated participants from NHANES 2007-10 were included in this study. The outcome measures were prevalence of clinical and subclinical hypothyroidism and thyroid function index (TFI) - a measure of thyroid function. For the SAFHS, we used polygenic regression analyses with multiple covariates to test associations in setting of family studies. For the NHANES 2007-10, we corrected for the survey design variables as needed for association analyses in survey data. In both datasets, we corrected for age, sex and their linear and quadratic interactions. Results TFI was an accurate indicator of clinical thyroid status (area under the receiver-operating-characteristic curve to detect clinical hypothyroidism, 0.98) in both SAFHS and NHANES 2007-10. Of the 18 MS traits, waist circumference (WC) showed the most consistent association with TFI in both studies independently of age, sex and body mass index (BMI). In the SAFHS and NHANES 2007-10 datasets, each standard deviation increase in WC was associated with 0.13 (p < 0.001) and 0.11 (p < 0.001) unit increase in the TFI, respectively. In a series of polygenic and linear regression models, central obesity (defined as WC ⩾ 102 cm in men and ⩾88 cm in women) was associated with clinical and subclinical hypothyroidism independent of age, sex, BMI and type 2 diabetes in both datasets. Estimated prevalence of hypothyroidism was consistently high in those with central obesity, especially below 45y of age. Conclusions WC independently associates with increased risk of thyroid dysfunction. Use of WC to identify Mexican American subjects at high risk of thyroid dysfunction should be investigated in future studies. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 49 year old female patient who presented to physicians with symptoms of severe myalgia, proximal weakness and dark urine. A discussion of diagnostic testing which was conducted on the patient, and led to a diagnosis of rhabdomyolysis linked to a combined tetanus, diphtheria and acellular pertussis (Tdap) vaccine, is presented.

Several studies have identified effects of genetic variation on DNA methylation patterns and associated heritability, with research primarily focused on Caucasian individuals. In this paper, we examine the evidence for genetic effects on DNA methylation in a Mexican American cohort, a population burdened by a high prevalence of obesity. Using an Illumina-based platform and following stringent quality control procedures, we assessed a total of 395 CpG sites in peripheral blood samples obtained from 183 Mexican American individuals for evidence of heritability, proximal genetic regulation and association with age, sex and obesity measures (i.e. waist circumference and body mass index). We identified 16 CpG sites (∼4%) that were significantly heritable after Bonferroni correction for multiple testing and 27 CpG sites (∼6.9%) that showed evidence of genetic effects. Six CpG sites (∼2%) were associated with age, primarily exhibiting positive relationships, including CpG sites in two genes that have been implicated in previous genome-wide methylation studies of age (FZD9 and MYOD1). In addition, we identified significant associations between three CpG sites (∼1%) and sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. Although we did not identify any significant associations between DNA methylation and the obesity measures, several nominally significant results were observed in genes related to adipogenesis, obesity, energy homeostasis and glucose homeostasis (ARHGAP9, CDKN2A, FRZB, HOXA5, JAK3, MEST, NPY, PEG3 and SMARCB1). In conclusion, we were able to replicate several findings from previous studies in our Mexican American cohort, supporting an important role for genetic effects on DNA methylation. In addition, we found a significant influence of age and sex on DNA methylation, and report on trend-level, novel associations between DNA methylation and measures of obesity. [ABSTRACT FROM AUTHOR]

Purpose: The role of v-ATPases in cancer biology is being increasingly recognized. Yeast studies indicate that the tyrosine kinase inhibitor imatinib may interact with the v- ATPase genes and alter the course of cancer progression. Data from humans in this regard are lacking. Methods: We constructed 55 lymphoblastoid cell lines from pedigreed, cancer-free human subjects and treated them with IC20 concentration of imatinib mesylate. Using these cell lines, we (i) estimated the heritability and differential expression of 19 genes encoding several subunits of the v-ATPase protein in response to imatinib treatment; (ii) estimated the genetic similarity among these genes; and (iii) conducted a high-density scan to find cis-regulating genetic variation associated with differential expression of these genes. Results: We found that the imatinib response of the genes encoding v-ATPase subunits is significantly heritable and can be clustered to identify novel drug targets in imatinib therapy. Further, five of these genes were significantly cis-regulated and together represented nearly half-log fold change in response to imatinib ( p = 0.0107) that was homogenous ( p = 0.2598). Conclusions: Our results proffer support to the growing view that personalized regimens using proton pump inhibitors or v-ATPase inhibitors may improve outcomes of imatinib therapy in various cancers. [ABSTRACT FROM AUTHOR]

Objective: In spite of the growing recognition of the specific association of waist circumference (WC) with type 2 diabetes (T2D) and insulin resistance (IR), current guidelines still use body mass index (BMI) as a tool of choice. Our objective was to determine whether WC is a better T2D predictor than BMI in family-based settings. Research Design and Methods: Using prospectively collected data on 808 individuals from 42 extended Mexican American families representing 7617.92 person-years follow-up, we examined the performance of WC and BMI as predictors of cumulative and incident risk of T2D. We used robust statistical methods that accounted for the kinships and included polygenic models, discrete trait modeling, Akaike information criterion, odds ratio (OR), relative risk (RR) and Kullback-Leibler R2. SOLAR software was used to conduct all the data analyses. Results: We found that in multivariate polygenic models, WC was an independent predictor of cumulative (OR = 2.76, p = 0.0002) and future risk of T2D (RR = 2.15, p = 3.56×10−9) and outperformed BMI when compared in a head-to-head fashion. High WC (≥94.65 cm after adjusting for age and sex) was also associated with high fasting glucose, insulin and triglyceride levels and low high-density lipoprotein levels indicating a potential association with IR. Moreover, WC was specifically and significantly associated with insulin resistant T2D (OR = 4.83, p = 1.01×10−13). Conclusions: Our results demonstrate the value of using WC as a screening tool of choice for future risk of T2D in Mexican American families. Also, WC is specifically associated with insulin resistant T2D. [ABSTRACT FROM AUTHOR]

Objective. Bisphenol A (BPA) is being increasingly associated with adverse health effects. Our objective was to determine whether urinary BPA concentration is associated with allergic asthma in a representative US population. Methods. Data for this analysis were obtained from the National Health and Nutrition Examination Survey 2005-2006 survey and included asthma-related questions, total immunoglobulin E (IgE), 19 allergen-specific IgE levels, and urinary environmental phenol measurements. Allergic asthma was defined as a history of asthma ever, high eosinophil count, and high total IgE or atopy. Association analyses included dichotomous and polychotomous logistic regression, receiver operating characteristic curves, Akaike information criterion, and likelihood ratio χ2. Results. We found that 10-fold increase in BPA was independently associated with a higher likelihood of allergic asthma in females [odds ratio (OR)  =  2.21, p = .032] but not in males (OR =  0.83, p = .474). These findings were reaffirmed when allergic asthma was defined based on atopy rather than total IgE (OR  = 2.45, p = .001 in females and OR  =  0.83, p = .605 in males). Urinary BPA was significantly associated with sensitization to various specific allergens in a dose-response manner. Lastly, urinary BPA independently predicted an asthma episode in the past 12 months in females but not in males. Conclusions. Urinary BPA is significantly associated with allergic asthma in females. [ABSTRACT FROM AUTHOR]

Background: Imatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime. Methods: We conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure. Results: Cytotoxicity within cell lines was highly heritable following imatinib treatment (h2 = 0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly >10). Conclusions: Induction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background. [ABSTRACT FROM AUTHOR]

The relationship between CD4+ T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown.Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4+ T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4+ T-cell count was determined after adjustment for other relevant covariates.A higher baseline CD4+ T-cell count predicted a greater post-HAART CD4+ T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4+ count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/baseline count ratio was consistently ≥0.6.Among viral load suppressing seroconverters, the absolute CD4+ T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4+ T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. [ABSTRACT FROM AUTHOR]

The Duffy-null trait and ethnic neutropenia are highly prevalent in Africa. The authors found that the trait of Duffy-null–associated low neutrophil counts associated with increased HIV-1 susceptibility. The possible contribution of this trait to the high prevalence of HIV-1 in Africa requires further investigationBackground. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)–1 infection among Africans is unknown.Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity.Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC −46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10−11). DARC −46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null–associated low neutrophil counts, compared with all other study participants.Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null–associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa. [ABSTRACT FROM AUTHOR]

A response by Weijing He and colleagues to a letter to the editor on their articles regarding the methodological concerns of C-C chemokine ligand-3-like-1 (CCL3L1) gene quantitative Polymerase Chain Reaction (qPCR) assay is presented.

Background. Despite suppression of the human immunodeficiency virus type1 (HIV-1)load by highly active antiretroviral therapy (HAART), recovery of CD4+ Tcell counts can be impaired. We investigated whether this impairment may be associated with hyporesponsiveness of T cells to γ-chain (γc) cytokines known to influence T cell homeostasis. Methods. The responsiveness of T cells to interleukin (IL)-2, IL-7, and IL-15 was determined by assessing cytokine-induced phosphorylation of the signal transducer and activator of transcription 5 (STAT5) in peripheral T cells obtained from 118 HIV-positive subjects and 13 HIV-negative subjects. Results. The responsiveness of T cells to interleukin (IL)-7 but not to IL-2 or IL-15 was lower among HIV-positive subjects than among HIV-negative subjects. Among subjects with viral load suppression, the degree of IL-7 responsiveness (1) correlated with naive CD4+ T cell counts and was a better immune correlate of the prevailing CD4+ T cell count than were levels of human leukocyte antigen-DR1 or programmed death-1, which are predictors of T cell homeostasis during HIV infection; and (2) was greater in subjects with complete (i.e., attainment of ⩾500 CD4+ T cells/mm³ ⩾5 years after initiation of HAART) versus incomplete immunologic responses. The correlation between plasma levels of IL-7 and CD4+ T cell counts during HAART was maximal in subjects with increased IL-7 responsiveness. Conclusions. Responsiveness of T cells to IL-7 is associated with higher CD4+ T cell counts during HAART and thus may be a determinant of the extent of immune reconstitution. [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention. Methods and Results: Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV2 partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1- CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of .70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of ∼12% from the true vaccine efficacy. Conclusions: CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. Methods and Findings: In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1- CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. Conclusions: The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1- CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine. [ABSTRACT FROM AUTHOR]

Iron chelators have dramatically prolonged the life expectancy of patients with transfusion-dependent thalassaemia, but their precise clinical benefit in reducing the myocardial iron burden and improving cardiac function is unknown. This systematic review and meta-analysis included published clinical trials that assessed the efficacy of iron chelators in regularly transfused patients of thalassaemia major for two commonly reported outcomes – myocardial iron content and left ventricular ejection fraction (LVEF). The meta-analysis of 392 patients for myocardial iron content and 291 patients for LVEF showed that (i) iron chelators reduced cardiac iron content by 23·9% (95% confidence interval 17·3–29·8%); (ii) there was no significant difference between the amount of iron reduced by deferoxamine and deferiprone ( P = 0·9504); and (iii) LVEF was not significantly influenced by iron chelators – summary Hedge’s g 0·13 (95% confidence interval −0·10–0·36). A significant publication bias existed for LVEF (Egger’s P = 0·049) but not for myocardial iron (Egger’s P = 0·871). Our results indicate that iron chelators significantly reduce myocardial iron content. Further, the choice of deferoxamine versus deferiprone may rest on factors other than their efficacy to reduce cardiac iron load. [ABSTRACT FROM AUTHOR]

The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4+ T cells/mm3. The CCL3L1-CCR5 genotypes favoring CD4+ T cell recovery are similar to those that blunted CD4+ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4+ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution. [ABSTRACT FROM AUTHOR]

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry–independent mechanisms. [ABSTRACT FROM AUTHOR]

Background: In spite of several available anthropometric indexes, the relative merit of these indexes for the prediction of type 2 diabetes remains unknown. Considering that obesity and diabetes commonly coexist as co-morbidities, our objective was to directly compare the performance of measures of central and general obesity to predict the risk of type 2 diabetes. Methods: We conducted a case-control study of type 2 diabetes on 150 cases and 150 age- and gender-matched controls. We directly compared the predictive performance of five anthropometric indexes: four related to central obesity—waist circumference (WC), waist/hip ratio (WHR), abdominal volume index (AVI) and conicity index (CI); and one related to general obesity—body mass index (BMI). We used various statistical approaches like area under (AUC) receiver-operating characteristic (ROC) curves, likelihood ratios, logistic regression and Shannon''s entropy to compare the performance of the indexes in the study sample as well as bootstrapped samples. Results: WC had the highest overall predictive accuracy that was gender insensitive (AUC=0.77 in males and 0.74 in females); a comparable information content as that of AVI (Shannon''s entropy=1.81 for WC and 1.84 for AVI) and was a better predictor of the risk of type 2 diabetes than all the remaining indexes. WC also correlated strongly with the biochemical markers of diabetes like blood sugar and lipid profile. Conclusions: WC is a simple, non-invasive and accurate predictor of the risk of type 2 diabetes that can potentially be used in screening programs in developing countries. [Copyright &y& Elsevier]

Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1αP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases. [ABSTRACT FROM AUTHOR]

This first comprehensive serological analysis of an haemolytic uraemic syndrome (HUS) outbreak in which a wide range of ‘O’ group Escherichia coli antibody responses in patients and controls provided a unique insight into the epidemiology of such epidemics. Possible answers to clinical aspects related to severity of disease and complications were revealed. A microagglutination assay was used to examine E. coli ‘O’ group serological responses in 49 serum samples of 21 children hospitalised with HUS and 14 single samples from contemporaneous age-matched controls. A total of 51 O serogroup strains were used, including those reported to be associated with cases of HUS, with six isolates from patients associated with the Adelaide outbreak, environmental verocytotoxigenic/shiga-toxin producing E. coli (VTEC/STEC) strains and common human commensal strains. Amongst the 21 patients, there were 226 instances of seroreactivity (titre ≥100) against 34 E. coli serogroups while six instances of seroreactivity against four serogroups occurred in controls. There were 128 instances in patients and one instance in controls in which titres ≥400 were observed. All 21 patients were seroreactive (titre ≥100 and <400) to one or more of the 17 HUS-associated serogroups included in the study. Titres ranged from 100 to 6400, some of the highest in three patients were against O157, whose faeces yielded only EHEC O111, and only one developed O111 antibody. Mixed infection was demonstrated serologically by microagglutination (confirmed by western blot) and was consistent with the multiple serogroups of VTEC found in the mettwurst incriminated as the source, and suggests further strains (not found in the source or in patients’ faeces) were probably involved. In HUS-associated EHEC infection, multiple strain infection may be the rule rather than the exception. Analysis of 34 of the 51 serogroup antibody responses in the HUS patients revealed clues to possible relationships with clinical severity and complications. Patients with severe renal failure tended to develop antibodies to a larger number of serogroups than those with moderate or mild impairment. The same was true for central nervous system complications. Other associations were observed. While VTEC O157 remains an important causal serogroup in HUS, non-O157 serogroups also appear to play a significant role and therefore the latter should always be sought in all future HUS cases as new insights into pathogenicity may be discovered. This study indicates that co-infection with different VTEC serogroups may affect clinical outcome. [ABSTRACT FROM AUTHOR]

Whether weather plays a part in the transmissibility of the novel Coronavirus Disease-19 (COVID-19) is still not established. We tested the hypothesis that meteorological factors (air temperature, relative humidity, air pressure, wind speed and rainfall) are independently associated with transmissibility of COVID-19 quantified using the basic reproduction rate (R 0). We used publicly available datasets on daily COVID-19 case counts (total n = 108,308), three-hourly meteorological data and community mobility data over a three-month period. Estimated R 0 varied between 1.15 and 1.28. Mean daily air temperature (inversely), wind speed (positively) and countrywide lockdown (inversely) were significantly associated with time dependent R 0 , but the contribution of countrywide lockdown to variability in R 0 was over three times stronger as compared to that of temperature and wind speed combined. Thus, abating temperatures and easing lockdown may concur with increased transmissibility of COVID-19 in India. Unlabelled Image • We tested association of geo-socio-meteorological factors with COVID-19 in India. • Air temperature, wind speed and lockdown were independently associated with R 0. • Countrywide lockdown contributed to COVID-19 more strongly than weather factors. [ABSTRACT FROM AUTHOR]

Complex genetic traits are often characterized by multiple quantitative phenotypes. Because values of such phenotypes vary over time, it is thought that analyses of longitudinal data on the phenotypes may lead to increased power in detecting genetic association. In this paper, we extend a transmission-based association test applying quasi-likelihood that has been developed by us to the longitudinal framework and to carry out a genome-wide association analysis of triglyceride levels based on the data provided in GAW20. We consider different phenotype definitions based on administration of fenofibrate and obtain significant association findings within genes involved in heart diseases. [ABSTRACT FROM AUTHOR]

Background Parenteral iron is integral in the treatment of anaemia of chronic kidney disease patients on haemodialysis (HD). However, increased liver iron concentration (LIC) can result from such treatment, and this correlates poorly with serum ferritin or transferrin saturation values. It is unclear whether increased cardiac iron concentration also occurs in this setting. We aimed to evaluate the relationship of intravenous iron supplementation to hepatic and cardiac iron deposition in chronic HD subjects. Methods A cohort of 10 patients on chronic HD for at least 1 year underwent MRI-based quantitation of hepatic and cardiac iron content to evaluate the relationship between intravenous iron supplements and hepatic and cardiac iron deposition. The results were compared against the cumulative parenteral iron dose and serum iron markers. Results The median age was 61 years (95% confidence interval (CI) 50-71), HD time 2.5 years (95%CI 2.0-5.3) and cumulative iron dose 4300 mg (95%CI 2110-9045). Hepatic iron concentration was elevated in eight of 10 subjects (median 46 mmol/kg, range 31-76). Cardiac iron levels were within the reference range in all subjects. There was poor correlation between conventional haematinic values and either LIC or cardiac iron levels. None of the study subjects exhibited elevated cardiac iron concentration. Conclusion Whilst HD patients receiving standard parenteral iron therapy have elevated LICs, this is not associated with cardiac iron deposition. Transferrin saturation and serum ferritin levels are poor markers of either liver or cardiac iron deposition in HD subjects. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex metabolic derangement that has a strong genetic basis. There is substantial population-specificity in the association of genetic variants with T2D. The Indian urban Sindhi population is at a high risk of T2D. The genetic basis of T2D in this population is unknown. We interrogated 28 pooled whole blood genomes of 1402 participants from the Diabetes In Sindhi Families In Nagpur (DISFIN) study using Illumina's Global Screening Array. From a total of 608,550 biallelic variants, 140 were significantly associated with T2D after adjusting for comorbidities, batch effects, pooling error, kinship status and pooling variation in a random effects multivariable logistic regression framework. Of the 102 well-characterized genes that these variants mapped onto, 70 genes have been previously reported to be associated with T2D to varying degrees with known functional relevance. Excluding open reading frames, intergenic non-coding elements and pseudogenes, our study identified 22 novel candidate genes in the Sindhi population studied. Our study thus points to the potential, interesting candidate genes associated with T2D in an ethnically endogamous population. These candidate genes need to be fully investigated in future studies. [ABSTRACT FROM AUTHOR]

Background: Routine use of adjunctive devices to percutaneous coronary intervention (PCI) for the treatment of patients of ST-segment elevation myocardial infarction (STEMI) is questionable. Also, the clinical characteristics of STEMI patients that can modulate the treatment benefits of adjunctive devices are not fully understood. Objective: To synthesize the existing literature to summarize the therapeutic benefit of the adjunctive devices and to identify the patient characteristics which relate to this therapeutic benefit. Methods: We conducted (i) meta-analyses of the randomized controlled trials (RCT) comparing the performance of the adjunctive devices with PCI for three reperfusion-related outcomes: myocardial blush grade (MBG) < 3, failed ST-segment resolution (STR), and Thrombolysis In Myocardial Infarction (TIMI) flow grade < 3; (ii) stepwise meta-regressions of the effect of trial characteristics on between-trial heterogeneity; and (iii) analyses to examine whether the reperfusion-related end-points explained the between-trial difference in cardiac death and major adverse cardiac events (MACE). Results: Our meta-analyses represent data from 23 RCT and 5,728 subjects. The overall therapeutic benefit attributable ranged from 32 to 35% for the reperfusion-related outcomes, and thrombectomy devices were more beneficial than the distal protection devices. Meta-regression identified gender, receipt of glycoprotein (GP) IIb/IIIa inhibitor, and baseline TIMI flow grade as significant predictors of improved reperfusion across trials. The available clinical trials were individually underpowered and not designed to detect the influence of adjunctive devices on death or MACE. Conclusions: Routine use of adjunctive devices cannot be recommended. Thrombus burden, treatment with GP IIb/IIIa inhibitors, and gender may modify the reperfusion benefit of adjunctive devices. [ABSTRACT FROM AUTHOR]

Background. The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)-1 infection and AIDS is unknown. Methods. A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL. Results. Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the -221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4+ T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand. Conclusions. MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection. [ABSTRACT FROM AUTHOR]

Abstract: In this study of 167 neonates who demonstrated a total of 1010 transitions between arousal states, we considered whether specific state transitions were associated with umbilical cord blood lead levels. We found that the arousal patterns of neonates with varying levels (<1, 1–10 and >10 μg/dL) of lead exposure could not be distinguished based on the NBAS scoring system alone, but their transition state patterns revealed striking differences. Specifically, the neonates with the highest lead levels were more fidgety, had more state transitions from state 5 or 6, and were least likely to fall from awake states back into lower states. Arousal state transition pattern is thus a novel correlate of umbilical cord blood lead that may be useful for risk stratification of the neonates. [Copyright &y& Elsevier]

Considering the multigenic and multifactorial nature of the disease, we argue that a generalized bone marrow hyperplasia—and not merely erythroid hyperplasia—will occur in sickle cell disease. Consequently, we expect the hematological parameters to depict erythroid, myeloid as well as megakaryocyte hyperplasia. In the light of this expectation, we hypothesized that platelet distribution width (PDW) will increase in sickle cell disease. Here, we report the results from a cross-sectional study of 216 children admitted with complaints suggestive of vaso-occlusive crisis. We observed a strong association between PDW and sickle cell disease as compared to children who had HbAA genotype. Our findings bridge previous inconsistencies relating to the role of platelets in sickle cell disease. Implications of this finding are discussed. [ABSTRACT FROM AUTHOR]

Background: Ethnically endogamous populations can shed light on the genetics of type 2 diabetes. Such studies are lacking in India. We conducted this study to determine the genetic and environmental contributions of anthropometric traits to type 2 diabetes risk in the Sindhi families in central India. Methods: We conducted a family study in Indian Sindhi families with at least one case of type 2 diabetes. Variance components methods were used to quantify the genetic association of 18 anthropometric traits with eight type 2 diabetes related traits. Univariate and bivariate polygenic models were used to determine the heritability, genetic and environmental correlation of anthropometric traits with type 2 diabetes related traits. Results: We included 1,152 individuals from 112 phenotyped families. The ascertainment-bias corrected prevalence of type 2 diabetes was 35%. Waist circumference, hip circumference and the biceps, triceps, subscapular and medial calf skinfold thicknesses were polygenically and significantly associated with type 2 diabetes. The range of heritability of the anthropometric traits and type 2 diabetes related traits was 0.27–0.73 and 0.00–0.39, respectively. Heritability of type 2 diabetes as a discrete trait was 0.35. Heritability curves demonstrated a substantial local influence of type 2 diabetes related traits. Bivariate trait analyses showed that biceps and abdominal skinfold thickness and all waist-containing indexes were strongly genetically correlated with type 2 diabetes. Conclusions: In this first study of Sindhi families, we found evidence for genetic and environmental concordance of anthropometric traits with type 2 diabetes. Future studies need to probe into the genetics of type 2 diabetes in this population. [ABSTRACT FROM AUTHOR]

Background: Impella was approved for mechanical circulatory support (MCS) in 2008, but large-scale, real-world data on its use are lacking. Our objective was to describe trends and variations in Impella use, clinical outcomes, and costs across US hospitals in patients undergoing percutaneous coronary intervention (PCI) treated with MCS (Impella or intra-aortic balloon pump).Methods: From the Premier Healthcare Database, we analyzed 48 306 patients undergoing PCI with MCS at 432 hospitals between January 2004 and December 2016. Association analyses were performed at 3 levels: time period, hospital, and patient. Hierarchical models with propensity adjustment were used for association analyses. We examined trends and variations in the proportion of Impella use, and associated clinical outcomes (in-hospital mortality, bleeding requiring transfusion, acute kidney injury, stroke, length of stay, and hospital costs).Results: Among patients undergoing PCI treated with MCS, 4782 (9.9%) received Impella; its use increased over time, reaching 31.9% of MCS in 2016. There was wide variation in Impella use across hospitals (>5-fold variation). Specifically, among patients receiving Impella, there was a wide variation in outcomes of bleeding (>2.5-fold variation), and death, acute kidney injury, and stroke (all ≈1.5-fold variation). Adverse outcomes and costs were higher in the Impella era (years 2008-2016) versus the pre-Impella era (years 2004-2007). Hospitals with higher Impella use had higher rates of adverse outcomes and costs. After adjustment for the propensity score, and accounting for clustering of patients by hospitals, Impella use was associated with death: odds ratio, 1.24 (95% CI, 1.13-1.36); bleeding: odds ratio, 1.10 (95% CI, 1.00-1.21); and stroke: odds ratio, 1.34 (95% CI, 1.18-1.53), although a similar, nonsignificant result was observed for acute kidney injury: odds ratio, 1.08 (95% CI, 1.00-1.17).Conclusions: Impella use is rapidly increasing among patients undergoing PCI treated with MCS, with marked variability in its use and associated outcomes. Although unmeasured confounding cannot be ruled out, when analyzed by time periods, or at the hospital level or the patient level, Impella use was associated with higher rates of adverse events and costs. More data are needed to define the appropriate role of MCS in patients undergoing PCI. [ABSTRACT FROM AUTHOR]

Background: Presently, preterm birth is globally the leading cause of neonatal mortality. Prompt community based identification of women at high risk for preterm births (HRPB) can either help to avert preterm births or avail effective interventions to reduce neonatal mortality due to preterm births. We evaluated the performance of a package to train community workers to detect the presence of signs or symptoms of HRPB.Methods: Pregnant women enrolled in the intervention arm of a cluster randomized trial of Antenatal Corticosteroids (ACT Trial) conducted at Nagpur, India were informed about 4 directly observable signs and symptoms of preterm labor. Community health workers actively monitored these women from 24 to 36 weeks of gestation for these signs or symptoms. If they were present (HRPB positive) the identified women were brought to government health facilities for assessment and management. HRPB positive could also be determined by the provider if the woman presented directly to the facility. Risk stratification was based on the number of signs or symptoms present. The outcome of preterm birth was based on the clinical assessment of gestational age < 37 weeks at delivery or a birth weight of <2000 g.Results: Between July 1, 2012 and 30 November, 2013, 686 of 7050 (9.7%) pregnant women studied, delivered preterm. 732 (10.4%) women were HRPB positive, of whom 333 (45.5%) delivered preterm. Of the remaining 6318(89.6%) HRPB negative women 353 (5.6%) delivered preterm. The likelihood ratio (LR) of a preterm birth in the HRPB positives was 8.14 (95% confidence interval 7.16-9.26). The LR of a preterm birth increased in women who had more signs or symptoms of HRBP (p < 0.00001). More signs or symptoms of HRPB were also associated with a shorter time to delivery, lower birth weight and higher rates of stillbirths, neonatal deaths and postnatal complications. Addition of risk stratification improved the prediction of preterm delivery (Integrated Discrimination Improvement 17% (95% CI 15-19%)).Conclusions: The package for detection of signs and symptoms of HRPB is feasible, promising and likely to improve management of preterm labor.Trial Registration: NCT01073475 on February 21, 2010 and NCT01084096 on March 9, 2010. [ABSTRACT FROM AUTHOR]

Background. An epidemiological association between exposure to phthalates and type 2 diabetes (T2D) is known. However, the potential role of environmental phthalates in the complications of T2D is unknown. Methods. Using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2010, we studied the association of 12 urinary phthalate metabolites with self-reported eye affliction/retinopathy in 1,004 participants with diabetes. Data from retinal imaging was used to validate this outcome. Independence of the phthalates→T2D association was studied by adjusting for age, sex, race, marital status, educational attainment, poverty income ratio, physical activity, glycated hemoglobin levels, total serum cholesterol, serum high-density lipoprotein cholesterol, serum triglycerides, blood pressure, duration of diabetes, total calorie intake, and obesity. Results. Self-reported eye affliction/retinopathy had 82% accuracy with Cohen’s kappa of 0.31 (p<0.001). Urinary mono-n-octyl phthalate (MOP) was independently associated with the likelihood of self-reported eye affliction/retinopathy in subjects with T2D after accounting for all the confounders. This significance of this association was robust to the potential misclassification in cases and controls of retinopathy. Further, a significant dose-response relationship between MOP and self-reported eye affliction/retinopathy was demonstrable. Conclusions. We show a novel epidemiological link between the environment and diabetic complications in NHANES 2001–2010 participants. [ABSTRACT FROM AUTHOR]

Background. An epidemiological association between exposure to phthalates and type 2 diabetes (T2D) is known. However, the potential role of environmental phthalates in the complications of T2D is unknown. Methods. Using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2010, we studied the association of 12 urinary phthalate metabolites with self-reported eye affliction/retinopathy in 1,004 participants with diabetes. Data from retinal imaging was used to validate this outcome. Independence of the phthalates→T2D association was studied by adjusting for age, sex, race, marital status, educational attainment, poverty income ratio, physical activity, glycated hemoglobin levels, total serum cholesterol, serum high-density lipoprotein cholesterol, serum triglycerides, blood pressure, duration of diabetes, total calorie intake, and obesity. Results. Self-reported eye affliction/retinopathy had 82% accuracy with Cohen’s kappa of 0.31 (p<0.001). Urinary mono-n-octyl phthalate (MOP) was independently associated with the likelihood of self-reported eye affliction/retinopathy in subjects with T2D after accounting for all the confounders. This significance of this association was robust to the potential misclassification in cases and controls of retinopathy. Further, a significant dose-response relationship between MOP and self-reported eye affliction/retinopathy was demonstrable. Conclusions. We show a novel epidemiological link between the environment and diabetic complications in NHANES 2001–2010 participants. [ABSTRACT FROM AUTHOR]

Purpose: There is a burgeoning recognition and interest in the potential of probiotics in the treatment and prevention of oral candidiasis associated with the use of dentures. Our aim was to investigate if commercially available over-the-counter probiotics can influence the ability of Candida albicans to form biofilms, which is considered a hallmark of the initiation and progression of oral candidiasis. Methods: We conducted a 2x5 factorial in vitro study to culture C. albicans on denture strips and challenge with one of the following four commercially available probiotics in bacterial or cell-free supernatant form: Accuflora®, Align®, Culturelle® and Sustenex®. C. albicans biofilm formation was studied in triplicates in all factorial combinations of the study and assessed qualitatively with fluorescence microscopy and quantitatively with tetrazolium salt (XTT) reduction assay. Quality control measures included determination of coefficient of variation, Bland Altman plots and Pittman's test. Results were analyzed using two-way analysis of variance (ANOVA) with pairwise post-hoc Scheffe's tests. Results: Our experimental conditions passed the quality control checks. Two-way ANOVA results indicated that cell-free supernatants provided a stronger and significant inhibitory effect on biofilm formation than their bacterial counterparts (2-way ANOVA p=3.8×10-6). Further, Lactobacillus-containing probiotic formulations (Accuflora® and Culturelle®) significantly reduced biofilm formation especially in supernatant form. Conclusion: Commercially available probiotics that contain Lactobacilli species interfere with the in vitro ability of C. albicans to form biofilms on dentures. The mechanistic and clinical implications of our results need to be addressed by larger in vivo studies. [ABSTRACT FROM AUTHOR]

Malakoplakia is an unusual granulomatous inflammatory disorder associated with diminished bactericidal action of leucocytes that occurs in immunosuppressed hosts. Cases of renal allograft malakoplakia are generally associated with a poor graft and patient survival. We present the case of a 56-year-old female with allograft and bladder malakoplakia occurring two years after renal transplantation complicated by an early antibody mediated rejection. Following a number of symptomatic urinary tract infections caused by resistant Gram-negative bacilli, a diagnosis of malakoplakia was made by biopsy of a new mass lesion of the renal allograft. Cystoscopy also revealed malakoplakia of the bladder wall. Immunosuppressant regimen was modified. Mycophenolate mofetil was ceased, prednisolone reduced to 5 mg/day and tacrolimus concentrations were carefully monitored to maintain trough serum concentrations of 2-4 μg/L. Concurrently, she received a prolonged course of intravenous antibiotics followed by 13 months of dual oral antibiotic therapy with fosfomycin and faropenem. This joint approach resulted in almost complete resolution of allograft malakoplakia lesions and sustained regression of bladder lesions on cystoscopy with histological resolution in bladder lesions. Her renal function has remained stable throughout the illness. If treated with sustained antimicrobial therapy and reduction of immunosuppression, cases of allograft malakoplakia may not necessarily be associated with poor graft survival. [ABSTRACT FROM AUTHOR]

Sex selection, a gender discrimination of the worst kind, is highly prevalent across all strata of Indian society. Physicians have a crucial role in this practice and implementation of the Indian Government's Pre-Natal Diagnostic Techniques Act in 1996 to prevent the misuse of ultrasound techniques for the purpose of prenatal sex determination. Little is known about family preferences, let alone preferences among families of physicians. We investigated the sex ratios in 946 nuclear families with 1,624 children, for which either one or both parents were physicians. The overall child sex ratio was more skewed than the national average of 914. The conditional sex ratios decreased with increasing number of previous female births, and a previous birth of a daughter in the family was associated with a 38 % reduced likelihood of a subsequent female birth. The heavily skewed sex ratios in the families of physicians are indicative of a deeply rooted social malady that could pose a critical challenge in correcting the sex ratios in India. [ABSTRACT FROM AUTHOR]