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Background Desmopressin is used to reduce bleeding after kidney biopsy but evidence supporting its use is weak, especially in patients with elevated creatinine. The present study was undertaken to evaluate efficacy of desmopressin in reducing bleeding after percutaneous kidney biopsy. Methods Retrospective cohort study. 269 of 322 patients undergoing percutaneous kidney biopsy between January 1, 2014 and January 31, 2018 were included. Patients had normal bleeding time, platelet count and coagulation profile. Primary outcome was defined as composite of hemoglobin drop ≥1 g/dL, hematoma on post biopsy ultrasound, gross hematuria, erythrocyte transfusion or angiography to stop bleeding. Association of desmopressin with outcomes was assessed using linear (for continuous variables) and logistic (for binary variables) regression models. Propensity score was used to minimize potential confounding. Results Desmopressin was administered to 100/269 (37.17%) patients. After propensity score adjustment patients who received desmopressin had increased odds of post biopsy bleeding [OR 3.88 (1.95–7.74), p p = 0.09] but increased bleeding risk when serum creatinine was p Conclusion Desmopressin should not be used routinely prior to percutaneous kidney biopsy in patients at low risk for bleeding but should be reserved for patients who are at high risk for bleeding.

The purpose of this study was to evaluate factors influencing the use of propofol-based total intravenous anaesthesia (TIVA) since despite TIVA being a well-established technique, it is used far less frequently than volatile anaesthesia. Questions were formulated after reviewing the literature for perceived disadvantages of TIVA and meeting with a focus group consisting of both senior and junior anaesthestists from our department. Once the survey had been formulated, specialist anaesthetists from professional colleges and societies from several countries were invited to complete the survey on an electronic web-based platform to allow evaluation of the respondent's rating of the importance of a range of factors in their decision not to use TIVA for a particular case. Basic descriptive statistics were determined using SPSS statistical software, while graphical depictions of data were handled using R for statistical analysis. A total of 763 survey responses were included in the final analysis and stratified according to the frequency of TIVA use. Among the infrequent users, issues such as additional effort, institutional preference, lack of real-time monitoring of propofol concentration, risk of missing drug delivery failure and increased turnaround time were among the top reasons mentioned. Interestingly, these issues were considered far less important among the frequent users when not choosing TIVA. We concluded that frequent and infrequent users respond quite differently to similar technical TIVA-related factors. Non-technical factors may play an important role in the infrequent user's decision not to use TIVA for a particular case.

Importance Interstitial fibrosis and tubular atrophy (IFTA) is a strong indicator of decline in kidney function and is measured using histopathological assessment of kidney biopsy core. At present, a noninvasive test to assess IFTA is not available. Objective To develop and validate a deep learning (DL) algorithm to quantify IFTA from kidney ultrasonography images. Design, Setting, and Participants This was a single-center diagnostic study of consecutive patients who underwent native kidney biopsy at John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, between January 1, 2014, and December 31, 2018. A DL algorithm was trained, validated, and tested to classify IFTA from kidney ultrasonography images. Of 6135 Crimmins-filtered ultrasonography images, 5523 were used for training (5122 images) and validation (401 images), and 612 were used to test the accuracy of the DL system. Kidney segmentation was performed using the UNet architecture, and classification was performed using a convolution neural network–based feature extractor and extreme gradient boosting. IFTA scored by a nephropathologist on trichrome stained kidney biopsy slide was used as the reference standard. IFTA was divided into 4 grades (grade 1, 0%-24%; grade 2, 25%-49%; grade 3, 50%-74%; and grade 4, 75%-100%). Data analysis was performed from December 2019 to May 2020. Main Outcomes and Measures Prediction of IFTA grade was measured using the metrics precision, recall, accuracy, and F1 score. Results This study included 352 patients (mean [SD] age 47.43 [14.37] years), of whom 193 (54.82%) were women. There were 159 patients with IFTA grade 1 (2701 ultrasonography images), 74 patients with IFTA grade 2 (1239 ultrasonography images), 41 patients with IFTA grade 3 (701 ultrasonography images), and 78 patients with IFTA grade 4 (1494 ultrasonography images). Kidney ultrasonography images were segmented with 91% accuracy. In the independent test set, the point estimates for performance matrices showed precision of 0.8927 (95% CI, 0.8682-0.9172), recall of 0.8037 (95% CI, 0.7722-0.8352), accuracy of 0.8675 (95% CI, 0.8406-0.8944), and an F1 score of 0.8389 (95% CI, 0.8098-0.8680) at the image level. Corresponding estimates at the patient level were precision of 0.9003 (95% CI, 0.8644-0.9362), recall of 0.8421 (95% CI, 0.7984-0.8858), accuracy of 0.8955 (95% CI, 0.8589-0.9321), and an F1 score of 0.8639 (95% CI, 0.8228-0.9049). Accuracy at the patient level was highest for IFTA grade 1 and IFTA grade 4. The accuracy (approximately 90%) remained high irrespective of the timing of ultrasonography studies and the biopsy diagnosis. The predictive performance of the DL system did not show significant improvement when combined with baseline clinical characteristics. Conclusions and Relevance These findings suggest that a DL algorithm can accurately and independently predict IFTA from kidney ultrasonography images.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12863-017-0515-5) contains supplementary material, which is available to authorized users.

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n= 628; age = 23.28–93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). Forn= 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρpheno= −0.119,p= 0.028), with evidence of shared genetic (ρgene= −0.463,p= 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging.SIGNIFICANCE STATEMENTEpigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging.

The classical transmission disequilibrium test (TDT) based on a trio design uses information only on the allele transmitted by a heterozygous parent at a marker locus as homozygous parents are non-informative about linkage. However, the phenotype of an offspring depends on the alleles transmitted by both parents, irrespective of whether the parents are homozygous or heterozygous, and hence carry useful information on association. In this article, we propose modifications to the TDT procedures by incorporating transmission data on both parents in an informative trio to explore possible gain in power in detecting association. For a binary trait, we use a goodness-of-fit χ2 test, whereas for a quantitative trait, we devise two tests: one based on a bivariate response logistic model and the other using a quasi-likelihood approach. We evaluate the type 1 errors and the powers of the proposed tests with those of the classical TDT procedures for both binary and quantitative traits based on extensive simulations. We find that the inclusion of transmission data on non-informative parents yields marginally higher power in the logistic regression approach but results in substantial gain in power in the quasi-likelihood approach. We apply our proposed methods to analyze a count phenotype related to alcoholism.

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.

We thank Dr. Kampaktsis and colleagues for their interest in our investigation. Although we agree that the 2016 guidelines may have made diastolic dysfunction (DD) more conceptually simple in a clinical approach; there are 2 problems with this apparent simplification. First, the large number of

Introduction: Fiberoptic flexible bronchoscopy(FB)is frequently performed to evaluate children with known or suspected airway and lung parenchymal disorders. Aims: To retrospectively collect information on indications, clinical outcomes and complications of all flexible bronchoscopies performed at Sheffield Children’s Hospital over one year period (2017). Method: The clinical files of 158 children (aged 16 years or less) were reviewed. Demographic data, types of procedure, operator findings, bronchoalveolar lavage (BAL) reports and complications were analysed. Results: 161 FB were done, 51% in children aged 3 years or less. 48(30%) were normal but 113 had positive findings (Figure 1). The incidence of airway abnormalities was lower (36.6%) compared to other studies (57%). BAL results are presented in Figure 2. Conclusions: FB is an important investigation in the assessment of complex respiratory problems in children, with good diagnostic yield and low complication rate. BAL results could have significant implications on the choice of antibiotics in the context of antibiotic stewardship. References: 1. A Faro et al, AJRCCM 2015, 191: 1066 2. F. De Baets et al, ERJ 2012, 39: 392

Acute coronary syndrome (ACS) admissions are common and costly. The association between comprehensive ACS care pathways, outcomes, and costs are lacking. From 434,172 low-risk, uncomplicated ACS patients eligible for early discharge (STEMI 35%, UA/NSTEMI 65%) from the Premier database, we identified ACS care pathways, by stratifying low-risk, uncomplicated STEMI and UA/NSTEMI patients by access site for PCI (trans-radial intervention [TRI] vs transfemoral intervention [TFI]) and by length of stay (LOS). Associations with costs and outcomes (death, bleeding, acute kidney injury, and myocardial infarction at 1-year) were tested using hierarchical, mixed-effects regression, and projections of cost savings with change in care pathways were obtained using modeling. In low-risk uncomplicated STEMI patients, compared with TFI and LOS ≥3 days, a strategy of TRI with LOS3 days and TFI with LOS3 days were associated with cost savings of $6,206 and $4,802, respectively. Corresponding cost savings for UA/NSTEMI patients were $7,475 and $6,169, respectively. These care-pathways did not show an excess risk of adverse outcomes. We estimated that$300 million could be saved if prevalence of the TRI with LOS3 days and TFI with LOS3 days strategies are modestly increased to 20% and 70%, respectively. In conclusion, we demonstrate the potential opportunity of cost savings by repositioning ACS care pathways in low-risk and uncomplicated ACS patients, toward transradial access and a shorter LOS without an increased risk of adverse outcomes.

Contrast-induced acute kidney injury (AKI) is a common and severe complication of percutaneous coronary intervention (PCI). Despite its substantial burden, contemporary data on the incremental costs of AKI are lacking. We designed this large, nationally representative study to examine: (1) the independent, incremental costs associated with AKI after PCI and (2) to identify the departmental components of cost contributing to the incremental costs associated with AKI. In this observational cross-sectional study from the Premier database, we analyzed 1,443,297 PCI patients at 518 US hospitals from 1/2006 to 12/2015. Incremental cost of AKI from a hospital perspective obtained by a microcosting approach, was estimated using mixed-effects, multivariable linear regression with hospitals as random effects. Costs were inflation-corrected to 2016 US$. AKI occurred in 82,683 (5.73%) of the PCI patients. Those with AKI had higher hospitalization cost than those without ($38,869, SD 42,583 vs $17,167 SD 13,994, p

Purpose Hyperglycemia (HG) in critically ill patients influences clinical outcomes and hospitalization costs. We aimed to describe association of HG with hospital mortality and length of stay in large scale, real-world scenario. Materials From The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) we included 739,152 intensive care unit (ICU) patients admitted during 2007–2016. Hyperglycemia was quatified using midpoint blood glucose level (MBGL). Association with outcomes (hospital mortality and length of stay (LOS)) was tested using multivariable, mixed effects, 2-level hierarchical regression. Results Degree of HG (defined using MBGL as a continuous variable) was significantly associated with hospital mortality and longer hospital stay in a dose-dependent fashion. The fourth, third and second MBGL (compared to the first) quartiles were associated with hospital mortality (odds ratio 1.34, 1.05 and 0.97, respectively) and longer hospital stay (1.56, 1.38 and 0.93 days, respectively). These associations were stronger associations in trauma (especially head injury), neurological disease and coma patients. Significant variation across ICUs was observed for all associations. Conclusions In this largest study of nondiabetic ICU patients, HG was associated with both study outcomes. This association was differential across ICUs and diagnostic categories.

Background Bleeding is a common, morbid, and costly complication of percutaneous coronary intervention. While bleeding avoidance strategies ( BAS ) are effective, they are used paradoxically less in patients at high risk of bleeding. Whether a patient‐centered approach to specifically increase the risk‐concordant use of BAS and, thus, reverse the risk‐treatment paradox is associated with reduced bleeding and costs is unknown. Methods and Results We implemented an intervention to reverse the bleeding risk‐treatment paradox at Barnes‐Jewish Hospital, St. Louis, MO, and examined: (1) the temporal trends in BAS use and (2) the association of risk‐concordant BAS use with bleeding and hospital costs of percutaneous coronary intervention. Among 3519 percutaneous coronary interventions, there was a significantly increasing trend ( P =0.002) in risk‐concordant use of BAS . The bleeding incidence was 2% in the risk‐concordant group versus 9% in the risk‐discordant group (absolute risk difference, 7%; number needed to treat, 14). Risk‐concordant BAS use was associated with a 67% (95% confidence interval, 52–78%; P P Conclusions In this study, patient‐centered care directly aimed to make treatment‐related decisions based on predicted risk of bleeding, led to more risk‐concordant use of BAS and reversal of the risk‐treatment paradox. This, in turn, was associated with a reduction in bleeding and hospitalization costs. Larger multicentered studies are needed to corroborate these results. As clinical medicine moves toward personalization, both patients and hospitals can benefit from a simple practice change that encourages objectivity and mitigates variability in care.

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 (R0). 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 R0 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 R0, but the contribution of countrywide lockdown to variability in R0 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., Graphical abstract Unlabelled Image, Highlights • We tested association of geo-socio-meteorological factors with COVID-19 in India. • Air temperature, wind speed and lockdown were independently associated with R0. • Countrywide lockdown contributed to COVID-19 more strongly than weather factors.

Respiratory syncytial virus (RSV) is a highly contagious pathogen with a huge global health impact. It is a major cause of hospital-acquired infection; a large number of those exposed develop infection. Those infected in hospital are at increased risk of a severe clinical course. Prevention of nosocomial spread currently focuses on spread by hand and large droplets. There is little research evidence to determine if aerosol spread of infectious RSV is possible.To determine if the air surrounding infants with RSV-positive bronchiolitis contains RSV in aerosolized particles that remain capable of causing infection.The amount of RSV contained in aerosolized particles produced by infants with bronchiolitis due to RSV was measured using viable impactor sampling. The ability of RSV contained in these particles to infect healthy and chronic obstructive pulmonary disease (COPD) human ciliated respiratory epithelium was determined.We showed for the first time that infants with RSV-positive bronchiolitis nursed in a ward setting or ventilated in intensive care produced large numbers of aerosol particles containing RSV that remained infectious and were capable of infecting healthy and COPD human ciliated epithelium. A significant amount of RSV was found in particles with aerodynamic diameters less than 5 μm.Many of the aerosolized particles that contained RSV in the air surrounding infants with bronchiolitis were sufficiently small to remain airborne for a significant length of time and small enough to be inhaled and deposited throughout the respiratory tract. It is likely that this leads to spread of infection to others, with dissemination of infection throughout the respiratory tract.

BackgroundIn 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.ObjectiveThe 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.MethodsTwo 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.ResultsA 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.ConclusionGestational 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 registrationThe Tablet App for the Simplified Gestational Age Score (T-SGAS) study was registered at ClinicalTrials.gov NCT02408783.

Importance\ud Same-day discharge (SDD) after elective percutaneous coronary intervention (PCI) is associated with lower costs and preferred by patients. However, to our knowledge, contemporary patterns of SDD after elective PCI with respect to the incidence, hospital variation, trends, costs, and safety outcomes in the United States are unknown.\ud \ud Objective\ud To examine (1) the incidence and trends in SDD; (2) hospital variation in SDD; (3) the association between SDD and readmissions for bleeding, acute kidney injury (AKI), acute myocardial infarction (AMI), or mortality at 30, 90, and 365 days after PCI; and (4) hospital costs of SDD and its drivers.\ud \ud Design, Setting, and Participants\ud This observational cross-sectional cohort study included 672 470 patients enrolled in the nationally representative Premier Healthcare Database who underwent elective PCI from 493 hospitals between January 2006 and December 2015 with 1-year follow-up.\ud \ud Exposures\ud Same-day discharge, defined by identical dates of admission, PCI procedure, and discharge.\ud \ud Main Outcomes and Measures\ud Death, bleeding requiring a blood transfusion, AKI and AMI at 30, 90, or 365 days after PCI, and costs from hospitals’ perspective, inflated to 2016.\ud \ud Results\ud Among 672 470 elective PCIs, 221 997 patients (33.0%) were women, 30 711 (4.6%) were Hispanic, 51 961 (7.7%) were African American, and 491 823 (73.1%) were white. The adjusted rate of SDD was 3.5% (95% CI, 3.0%-4.0%), which increased from 0.4% in 2006 to 6.3% in 2015. We observed substantial hospital variation for SDD from 0% to 83% (median incidence rate ratio, 3.82; 95% CI, 3.48-4.23), implying an average (median) 382% likelihood of SDD at one vs another hospital. Among SDD (vs non-SDD) patients, there was no higher risk of death, bleeding, AKI, or AMI at 30, 90, or 365 days. Same-day discharge was associated with a large cost savings of $5128 per procedure (95% CI, $5006-$5248), driven by reduced supply and room and boarding costs. A shift from existing SDD practices to match top-decile SDD hospitals could annually save $129 million in this sample and $577 million if adopted throughout the United States. However, residual confounding may be present, limiting the precision of the cost estimates.\ud \ud Conclusions and Relevance\ud Over 2006 to 2015, SDD after elective PCI was infrequent, with substantial hospital variation. Given the safety and large savings of more than $5000 per PCI associated with SDD, greater and more consistent use of SDD could markedly increase the overall value of PCI care.

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.

BACKGROUND Although rates of preterm birth continue to increase globally, identification of preterm from low birth weight infants remains a challenge. The burden of low birth weight vs preterm is greatest in resource-limited settings, where gestational age (GA) prior to delivery is frequently not known because ultrasound in early pregnancy is not available and estimates of the date of the mother’s last menstrual period (LMP) may not be reliable. An alternative option is to assess GA at birth to optimize referral and care of preterm newborns. We previously developed and pilot-tested a system to measure the simplified gestational age score (SGAS) based on 4 easily observable neonatal characteristics. OBJECTIVE The objective of this study is to adapt the scoring system as a tablet app (potentially scalable approach) to assess feasibility of use and to validate whether the scoring system accurately predicts prematurity by itself, over and above birth weight in a large sample of newborns. METHODS The study is based in Nagpur, India, at the Research Unit of the National Institute of Child Health and Human Development’s Global Network for Women’s and Children’s Health Research. The Android tablet app for the SGAS (T-SGAS) displays de-identified photographs of skin, breasts, and genitalia across a range of GAs and line drawings of infant posture. Each item is associated with a score. The user is trained to choose the photograph or line drawing that most closely matches the newborn being evaluated, and the app determines the neonate’s GA category (preterm or term) from the cumulative score. The validation study will be conducted in 3 second level care facilities (most deliveries in India occur in hospitals, and women known to be at risk of preterm birth are referred to second level care facilities). Within 24 hours of delivery, women and their babies who are stable will be enrolled in the study. Two auxiliary nurse midwives (ANMs) blinded to prior GA assessments will use the T-SGAS to estimate the GA status of the newborn. An independent data collector will abstract the GA from the ultrasound recorded in the hospital chart and record the date of the mother’s LMP. Eligibility for analysis is determined by the ultrasound and LMP data being collected within 1 week of each other to have a rigorous assessment of true GA. RESULTS Publication of the results of the study is anticipated in 2019. CONCLUSIONS Until GA dating by ultrasound is universally available and easy to use in resource-limited settings, and where there are restrictions on ultrasound use due to their use for sex determination and abortion of female fetuses, this study will determine whether the T-SGAS app can accurately assess GA in risk categories at birth. CLINICALTRIAL ClinicalTrials.gov NCT02408783; https://clinicaltrials.gov/ct2/show/NCT02408783 (Archived by Webcite at http://www.webcitation.org/75S2kmr3T) INTERNATIONAL REGISTERED REPORT DERR1-10.2196/11913

Aim Non-tuberculous mycobacteria (NTM) have emerged as an important pathogen in cystic fibrosis (CF). Early detection and treatment of NTM can preserve lung function and maintain good lung health. Many children with CF are not regular sputum producers and cough swabs cannot routinely be used to diagnose NTM. We aimed to test the hypothesis that performing sputum induction at routine annual review results in earlier identification of NTM in non-sputum producing children with CF. Method We conducted a 5-year prospective observational cohort study involving children with CF aged 5-17 years who had sputum induction with hypertonic saline for microbiological surveillance including NTM at their annual review. Results Forty-two children (19 males, mean age 11.4 years ± 3.6, mean FEV1 % predicted 94.7 ± 20.6) participated in the study. Forty-one induced sputum samples from 29 children yielded bacterial pathogens. Six samples from six children (14% of the cohort) yielded NTM never previously isolated from the patient. We also detected three isolates of Pseudomonas aeruginosa and one isolate each of Burkholderia cepacia complex and Meticillin resistant Staphylococcus aureus (MRSA), all of which were first time isolates. Conclusion We conclude that annual induced sputum for microbiological surveillance is useful for early detection of NTM and other important respiratory pathogens, particularly in non-expectorating children. This may lead to earlier identification and help inform initiation of eradication treatment in children with NTM. Children can also be cohorted earlier, before they potentially infect other children in the clinic.

Background Same‐day discharge ( SDD ) after elective percutaneous coronary intervention is safe, less costly, and preferred by patients, but it is usually performed in low‐risk patients, if at all. To increase the appropriate use of SDD in more complex patients, we implemented a “patient‐centered” protocol based on risk of complications at Barnes‐Jewish Hospital. Methods and Results Our objectives were as follows: (1) to evaluate time trends in SDD ; (2) to compare (a) mortality, bleeding, and acute kidney injury, (b) patient satisfaction, and (c) hospital costs by SDD versus no SDD ( NSDD ); and (3) to compare SDD eligibility by our patient‐centered approach versus Society for Cardiovascular Angiography and Interventions guidelines. Our patient‐centered approach was based on prospectively identifying personalized bleeding, mortality, and acute kidney injury risks, with a personalized safe contrast limit and mitigating those risks. We analyzed Barnes‐Jewish Hospital's National Cardiovascular Data Registry Cath PCI Registry data from July 1, 2009 to September 30, 2015 (N=1752). SDD increased rapidly from 0% to 77% ( P SDD patients were comparable to NSDD patients, SDD was not associated with adverse outcomes (0% mortality, 0% bleeds, and 0.4% acute kidney injury). Patient satisfaction was high with SDD . Propensity score–adjusted costs were $7331 lower/ SDD patient ( P SDD by Society for Cardiovascular Angiography and Interventions guidelines, implying our patient‐centered approach markedly increased SDD eligibility. Conclusions With a patient‐centered approach, SDD rapidly increased and was safe in 75% of patients undergoing elective percutaneous coronary intervention, despite patient complexity. Patient satisfaction was high, and hospital costs were lower. Patient‐centered decision making to facilitate SDD is an important opportunity to improve the value of percutaneous coronary intervention.

Background We tested the hypothesis that the results of the same test performed on point-of-care blood gas analysis (BGA) machine and automatic analyzer (AA) machine in central laboratory have high degree of concordance in critical care patients and that the two test methods could be used interchangeably. Methods We analyzed 9398 matched pairs of BGA and AA results, obtained from 1765 patients. Concentration pairs of the following analytes were assessed: hemoglobin, glucose, sodium, potassium, chloride, and bicarbonate. We determined the agreement using concordance correlation coefficient (CCC) and Bland-Altman analysis. The difference in results was also assessed against the United States Clinical Laboratory Improvement Amendments (US-CLIA) 88 rules. The test results were considered to be interchangeable if they were within the US-CLIA variability criteria and would not alter the clinical management when compared to each other. Results The median time interval between sampling for BGA and AA in each result pair was 5 minutes. The CCC values ranged from 0.89(95% CI 0.89-0.90) for chloride to 0.98(95% CI 0.98-0.99) for hemoglobin. The largest bias was for hemoglobin. The limits of agreement relative to bias were largest for sodium, with 3.4% of readings outside the US-CLIA variation rule. The number of readings outside the US-CLIA acceptable variation was highest for glucose (7.1%) followed by hemoglobin (5.9%) and chloride (5.2%). Conclusion We conclude that there is moderate to substantial concordance between AA and BGA machines on tests performed in critically ill patients. However, the two tests methods cannot be used interchangeably, except for potassium.

This study sought to explore the natural clustering of echocardiographic variables used for assessing left ventricular (LV) diastolic dysfunction (DD) in order to isolate high-risk phenotypic patterns and assess their prognostic significance.Assessment of LV DD is important in the management and prognosis of cardiovascular diseases. Data-driven approaches such as cluster analysis may be useful in segregating similar cases without the constraint of an a priori algorithm for risk stratification.The study included a convenience sample of 866 consecutive patients referred for myocardial function assessment (age 65 ± 17 years; 55.3% women; ejection fraction 60 ± 9%) for whom echocardiographic parameters of DD assessment were obtained per conventional guideline recommendations. Unsupervised, hierarchical cluster analysis of these parameters was conducted using the Ward linkage method. Major adverse cardiovascular events, hospitalization, and mortality were compared between conventional and cluster-based classifications.Clustering algorithms for screening the presence of DD in 559 of 866 patients identified 2 distinct groups and revealed modest agreement with conventional classification (kappa = 0.41, p 0.001). Further cluster analysis in 387 patients with DD helped to classify the severity of DD into 2 groups, with good agreement with conventional classification (kappa = 0.619, p 0.001). Survival analyses of patients assessed by both clustering algorithms for screening and grading DD showed improved prediction of event-free survival by clusters over conventional classification for all-cause mortality and cardiac mortality, even after accounting for a multivariable, balanced propensity score.An unsupervised assessment of echocardiographic variables for assessing LV DD revealed unique patterns of grouping. These natural patterns of clustering may better identify patient groups who have similar risk, and their incorporation into clinical practice may help eliminate indeterminate results and improve clinical outcome prediction.

Background Tunneled central venous catheters (TCVCs) and peripherally inserted central catheters (PICC) are often used for the provision of home parenteral nutrition (HPN). There is no formal comparison being made to study the rate of catheter-related bloodstream infection (CRBSI) between TCVCs and PICC in HPN to recommend the use of 1 over the other. Methods An online MEDLINE, PubMed, and Scopus search was conducted. Studies reporting the rate of CRBSI in HPN patients were included. DerSimonian and Laird random effects meta-analyses were used to analyze comparative studies, whereas Begg and Pilote's random effects meta-analysis was used to pool and analyze single-arm studies. Results Seventeen studies (12 single-arm studies and 5 comparative studies) were included for analysis. Meta-analysis of comparative studies showed that PICC use was associated with a significantly lower rate of CRBSI (relative risk (RR) 0.40, 95% CI 0.19-0.83), whereas meta-analysis of single-arm studies revealed that the relative risk for CRBSI was not statistically significantly different from unity. Conclusion TCVC is more commonly used in long-term HPN. Our analysis of comparative studies showed a lower rate of CRBSI in HPN patients using PICC compared with TCVC; however, analysis of single-arm studies showed that the rate of CRBSI was comparable in PICC and TCVC use. The decision to which type of catheter is most suited for HPN patients should hence be based on the duration of treatment, level of care, patients' dexterity, as well patients' underlying comorbidities that may potentially contribute to other catheter-related complications.

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.

Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

Background— Cardiovascular disease (CVD) is the most common cause of death in the United States and is associated with a high economic burden. Prevention of CVD focuses on controlling or improving the lipid profile of patients at risk. The human lipidome is made up of thousands of ubiquitous lipid species. By studying biologically simple canonical lipid species, we investigated whether the lipidome is genetically redundant and whether its genetic influences can provide clinically relevant clues of CVD risk. Methods and Results— We performed a genetic study of the human lipidome in 1212 individuals from 42 extended Mexican American families. High-throughput mass spectrometry enabled rapid capture of precise lipidomic profiles, providing 319 unique species. Using variance component–based heritability analyses and bivariate trait analyses, we detected significant genetic influences on each lipid assayed. Median heritability of the plasma lipid species was 0.37. Hierarchical clustering based on complex genetic correlation patterns identified 12 genetic clusters that characterized the plasma lipidome. These genetic clusters were differentially but consistently associated with risk factors of CVD, including central obesity, obesity, type 2 diabetes mellitus, raised serum triglycerides, and metabolic syndrome. Also, these clusters consistently predicted occurrence of cardiovascular deaths during follow-up. Conclusions— The human plasma lipidome is heritable. Shared genetic influences reduce the dimensionality of the human lipidome into clusters that are associated with risk factors of CVD.

The entire gamut of changes in the lipid profile that precede, predict, and correlate with hypertension in metabolic syndrome is unknown. The power, resolution, and accuracy of lipidomic assay technologies have brought us to the threshold of another information explosion. Understanding of hypertension and its pathophysiology especially within the setting of metabolic syndrome has been greatly improved by recent lipidomic studies. Hypertension in metabolic syndrome differs from other forms of hypertension, and recent studies have highlighted this difference in many interesting ways. Mounting evidence points towards a derangement of the sphingolipid pathway that may trigger the precursor clinical conditions of hypertension as well as hypertension itself. In this review, we summarize the available published literature in this field and propose a unifying hypothesis based on the published evidence. Recent studies have created substantial interest and advances in the understanding of hypertension in metabolic syndrome. Studies that directly test these concepts within a lipidomic framework are urgently needed.

Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.

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.

Aims: There is an increasing recognition of the putative association between the use of biomass fuels and the risk of cataracts. However, the exact strength of this association is currently unknown. Our aim was to synthetically quantify the association between biomass fuel use and cataract. Study Design: Systematic review and meta-analysis. Methodology: Using results from the MEDLINE®, Scopus®, Web of Science® and Google® searches, we conducted a random-effects meta-analysis of the published studies. We also conducted subgroup meta-analyses, meta-regressions and sensitivity analyses to determine the contribution of potential confounders to between-study heterogeneity which was measured by the tau-squared and I statistics. Summary effect sizes (SES) were estimated using the DerSimonian and Laird method and the 95% Research Article British Journal of Medicine & Medical Research, 4(1): 382-394, 2014 383 confidence intervals (CI) and 95% prediction intervals (PI) were also estimated. Publication bias was examined using funnel plots and Egger’s test. Results: In spite of significant between-study heterogeneity (I 70%, p=8.1x10), biomass fuel use was associated with a significantly increased risk of cataract (SES 2.12; 95% CI 1.61-2.80; 95% PI 0.88-5.09). Age-, genderand other methodological differences did not significantly contribute to between-study heterogeneity but Indian studies showed a statistically significant association between biomass fuel use and cataract. Statistically homogeneous studies (n = 8) showed an SES of 2.01 (95% CI and PI 1.67-2.41). Conclusion: Synthetic evidence from observational studies indicates that biomass fuel use may increase the risk of cataract. Public health initiatives aimed at avoidance of biomass fuel use may reduce the burden of cataracts especially in settings where biomass fuels are commonly used.

6556 Background: Survival prediction models for lung cancer patients could help guide their care and therapy decisions. The objectives of this study were to predict probability of survival beyond 90, 180 and 360 days from any point in a lung cancer patient’s journey. Methods: We developed a Gradient Boosting model (XGBoost) using data from 55k lung cancer patients in the ASCO CancerLinQ database that used 3958 unique variables including Dx and Rx codes, biomarkers, surgeries and lab tests from ≤1 year prior to the prediction point, which was chosen at random for each patient. We used 40% data for training, 25% for hyper-parameter tuning, 20% for testing and 15% for holdout validation. Death date available in the Electronic Health Record was cross checked by linkage to death registries. Results: The model was validated on the holdout set of 8,468 patients. The Area Under the Curve (AUC) for the model was 0.79. The precision and recall for predicting survival beyond the three time points were between 0.7-0.8 and 0.8-0.9 respectively (see table). This compares favourably to other lung cancer survival models created using different machine learning techniques (Jochems 2017, Dekker 2009). A Cox-PH model created using the top 20 variables also had a significantly lower performance (see table). Analysis of input variables yielded distinctive patterns for patient subgroups and time points. Tumor status, medications, lab values and functional status were found to be significant in patient sub cohorts. Conclusions: An AI model to predict survival of lung cancer patients built using a large real world dataset yielded high accuracy. This general model can further be used to predict survival of sub cohorts stratified by variables such as stage or various treatment effects. Such a model could be useful for assessing patient risk and treatment options, evaluating cost and quality of care or determining clinical trial eligibility. [Table: see text]

Background: Influenza virus is a major human pathogen, yet surprisingly little data is available on the earliest stage of infection. We have developed a novel method to study natural transmission influenza infection by aerosol and to observe the effects of early infection on the ciliated airway epithelium using high-speed video microscopy. Methods: Primary human ciliated epithelial cultures were infected with influenza A (H1N1), delivered either by aerosol or by liquid immersion. Cells were stained for viral antigens and the level of inflammatory mediators, and the number of motile ciliated cells and ciliary beat frequency and pattern was measured. Results: Infection by aerosol and liquid inoculums of influenza virus was shown to be trophic for ciliated cells. Infection by both methods also led to a significant decrease in the number of cells with motile cilia over the first 24 hours; however, the ciliary beat frequency and beat pattern of the remaining cilia was maintained over 24 hours. Conclusions: Influenza virus aerosols readily infect human ciliated nasal epithelial cells resulting in early loss of motile ciliated cells. Delivery of the virus by aerosol elicited an anti-inflammatory Th2 response, which was distinct from cells exposed to virus by liquid immersion delivery. This suggests our aerosol model may provide a more clinically relevant model for studying the early effects of influenza infection.

Background Although rates of preterm birth continue to increase globally, identification of preterm from low birth weight infants remains a challenge. The burden of low birth weight vs preterm is greatest in resource-limited settings, where gestational age (GA) prior to delivery is frequently not known because ultrasound in early pregnancy is not available and estimates of the date of the mother’s last menstrual period (LMP) may not be reliable. An alternative option is to assess GA at birth to optimize referral and care of preterm newborns. We previously developed and pilot-tested a system to measure the simplified gestational age score (SGAS) based on 4 easily observable neonatal characteristics. Objective The objective of this study is to adapt the scoring system as a tablet app (potentially scalable approach) to assess feasibility of use and to validate whether the scoring system accurately predicts prematurity by itself, over and above birth weight in a large sample of newborns. Methods The study is based in Nagpur, India, at the Research Unit of the National Institute of Child Health and Human Development’s Global Network for Women’s and Children’s Health Research. The Android tablet app for the SGAS (T-SGAS) displays de-identified photographs of skin, breasts, and genitalia across a range of GAs and line drawings of infant posture. Each item is associated with a score. The user is trained to choose the photograph or line drawing that most closely matches the newborn being evaluated, and the app determines the neonate’s GA category (preterm or term) from the cumulative score. The validation study will be conducted in 3 second level care facilities (most deliveries in India occur in hospitals, and women known to be at risk of preterm birth are referred to second level care facilities). Within 24 hours of delivery, women and their babies who are stable will be enrolled in the study. Two auxiliary nurse midwives (ANMs) blinded to prior GA assessments will use the T-SGAS to estimate the GA status of the newborn. An independent data collector will abstract the GA from the ultrasound recorded in the hospital chart and record the date of the mother’s LMP. Eligibility for analysis is determined by the ultrasound and LMP data being collected within 1 week of each other to have a rigorous assessment of true GA. Results Publication of the results of the study is anticipated in 2019. Conclusions Until GA dating by ultrasound is universally available and easy to use in resource-limited settings, and where there are restrictions on ultrasound use due to their use for sex determination and abortion of female fetuses, this study will determine whether the T-SGAS app can accurately assess GA in risk categories at birth. Trial Registration ClinicalTrials.gov NCT02408783; https://clinicaltrials.gov/ct2/show/NCT02408783 (Archived by Webcite at http://www.webcitation.org/75S2kmr3T) International Registered Report Identifier (IRRID) DERR1-10.2196/11913

Contrast-induced acute kidney injury (AKI) is a common and serious complication after PCI. Despite the impact of AKI after PCI, the associated costs and its drivers are unknown. Using the nationally representative Premier Healthcare Database, we analyzed 1,443,297 PCI patients from 518 hospitals

Acute coronary syndrome (ACS) admissions are common and costly, amounting to $7 billion annually in the United States. The association between comprehensive ACS care strategies and outcomes are lacking. We identified 434,172 low-risk ACS patients (STEMI 35%, UA/NSTEMI 65%) enrolled in the Premier

Objective Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC. Methods Samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross-sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software. Results After adjusting for age and sex interactions, body mass index, homeostasis model of assessment—insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC. Conclusions Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D.

Respiratory syncytial virus is a major cause of respiratory disease. There are conflicting accounts of the response of human epithelial cells to respiratory syncytial virus and a lack of data on its effect on ciliary function. Our aim was to study the early stages of respiratory syncytial virus infection of primary human basal and ciliated cultures. Using high speed videomicroscopy, we found that ciliary beat frequency was unaffected by respiratory syncytial virus infection over 72 h; however, ciliary dyskinesia significantly increased within 24 h of infection (p

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. 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. 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). 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.

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.

Aims The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0173-x) contains supplementary material, which is available to authorized users.

SLC30A8encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association ofSLC30A8variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) aroundSLC30A8for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of theSLC30A8locus 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 theSLC30A8locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of theSLC30A8SNPs with T2D in Mexican American families.

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.

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.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.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.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.