Learning to View Nonpharmacological Care as Equivalent to Medications in the Treatment of Babies Born with Neonatal Abstinence Syndrome

The new changes in hospitals that have come in reaction to an increase in maternal opioid use have positively changed the care of infants going through withdrawal. The positive change is for both the benefit of the infant and the benefit of the hospital. By training health care workers to view nonpharmacological treatment as equivalent to medication in the treatment of the infants born with NAS, these newborns will have a speedier recovery that decreases the length that they stay in the hospital. Therefore, by decreasing the infant’s hospital length of stay, hospital costs also decrease. The medical treatments that the infants should be receiving for the treatment of NAS are no longer based on medications themselves. Instead, they are based on a holistic approach allowing the physical and emotional needs of the infant to be met through approaches involving the environment, the quality of sleep and feedings and human contact. In the case of NAS, evidence has guided treatments to a more successful approach and supported the use of nonpharmacological treatment as a replacement for medication

Analyse biomécanique de la réductibilité de la scoliose idiopathique par rééducation posturale globale en physiothérapie

La scoliose idiopathique (SI) est une déformation tridimensionnelle (3D) du rachis évolutive et complexe sans cause exacte connue. La déformation crée une asymétrie de posture apparente qui peut affecter l’estime et la confiance en soi, limiter ou gêner la pratique de certaines activités et altérer la capacité respiratoire. Des 2-3 % de la population générale diagnostiquée avec une scoliose, 80 % des cas sont de type idiopathique et les cas évolutifs concernent majoritairement les jeunes filles en période de croissance. Le type de traitement prescrit est adapté selon la gravité de la déformation, qui se mesure selon l’angle de Cobb. Pour les scolioses légères (Cobb 45°) la chirurgie est préconisée. La Rééducation posturale globale (RPG) est une approche de physiothérapie développée dans les années 80 en France pour traiter les affectations musculo-squelettiques, et fait partie des exercices spécifiques à la scoliose. Cette approche de traitement est basée sur la pratique de postures actives d’étirement et d’exercices d’intégration sensorimotrice. Les principaux objectifs sont de freiner la progression de la courbure, améliorer la posture et éliminer les douleurs au dos. En RPG l’évaluation posturale qui guidera la suite de la prise en charge se fait par la photographie générale, l’évaluation des rétractions musculaires et la ré-équilibration. L’étape de ré-équilibration vise à déterminer la capacité de correction de la déformation et à évaluer la rigidité du tronc. Les postures de correction manuelle et d’autocorrection pratiquées debout en font partie et permettent d’évaluer le potentiel de réductibilité de la courbure du patient. La correction manuelle permet de vérifier qualitativement la rigidité du tronc et de voir l’impact de cette correction sur la posture générale. L’autocorrection vise à évaluer la capacité du patient à intégrer les corrections en sollicitant la musculature du tronc. Toutefois, la RPG appliquée à la scoliose est peu documentée dans la littérature scientifique. De plus, il n’y a pas d’outil permettant une évaluation quantitative de la rigidité du tronc du patient avec scoliose pendant la séance de traitement de physiothérapie. Un modèle par éléments finis (MEF) représentant les structures anatomiques du tronc humain a été précédemment développé pour simuler la correction immédiate de la scoliose obtenue dans le corset. Ce modèle a le potentiel de pouvoir être adapté et modifié pour simuler d’autres traitements conservateurs comme les manoeuvres de physiothérapie. L’objectif de cette étude était d’évaluer, par le biais de la modélisation par éléments finis, la réductibilité de la correction manuelle et de l’autocorrection selon l’approche RPG en physiothérapie sur la correction de la courbure pour la scoliose idiopathique. Une étude clinique avec 16 patients SI (2 SI juvénile et 14 SI de l’adolescence) a permis de mesurer expérimentalement les postures de ré-équilibration RPG. Pour chaque patient, le MEF a été reconstruit depuis la topographie de surface et les radiographies bi-planaires faibles doses en posture de référence debout. Des gants munis de capteurs de force portés par le thérapeute ont permis de mesurer la force exercée par ce dernier à l’interface main-tronc lors de la posture de correction manuelle. La correction manuelle a été simulée en reproduisant la force mesurée par la main droite par un vecteur force équivalent sur un noeud des côtes du modèle. Un indice de rigidité de la correction manuelle a été défini comme le rapport entre la force appliquée et la réduction de courbure résultante (forceΔ angle de Cobb). L’autocorrection a été mesurée par topographie de surface et radiographies afin d’être comparée avec les acquisitions en posture de référence. Elle a ensuite été simulée en fixant la position de la première vertèbre thoracique (T1) et des vertèbres apicales thoracique et lombaire à leur position autocorrigée telle que mesurée sur les radiographies sagittale et coronale en autocorrection. Un indice de rigidité de l’autocorrection a été défini comme la force de réaction à la vertèbre apicale thoracique divisée par la réduction de courbure en autocorrection (forceΔ angle de Cobb). L’analyse statistique a consisté en une ANOVA avec test post-hoc de Tukey pour comparer les angles de Cobb dans les différentes conditions testées et les corrélations ont été calculées avec le coefficient de Pearson. Lors de la pratique de la correction manuelle, une force de correction moyenne de 31 ± 6 N [23 N – 55 N] a été mesurée sous la main droite du thérapeute. La simulation de cette posture a généré une correction moyenne de 26 % (p < 0.05) de la courbure thoracique avec une augmentation non cliniquement significative de la contre-courbure. La cyphose thoracique a augmenté d’en moyenne 3˚ (p < 0.05) alors que la lordose lombaire est demeurée inchangée. L’indice de rigidité en correction manuelle variait de 2 à 10 N par degré de correction. L’autocorrection réelle a réduit la courbure thoracique en moyenne de 33 % (p < 0.05) sans aggraver la contre-courbure lombaire, alors que les courbures du plan sagittal ont été réduites d’en moyenne 6˚ pour la cyphose et 5˚ pour la lordose (p < 0.05). Une corrélation forte a été obtenue entre l’autocorrection réelle et simulée (r = 0.9), bien que la simulation de l’autocorrection ait tendance à sous-évaluer la correction réelle obtenue d’en moyenne 3˚ (p < 0.05). La force de réaction moyenne à la vertèbre apicale thoracique était de 45 N, résultant en un indice de rigidité allant de 0 à 21 N par degré de correction. Il n’y avait pas de corrélation entre la correction manuelle du thérapeute et l’autocorrection exercée par le patient. Le rapport entre la force appliquée et la réduction de courbure thoracique obtenue en correction manuelle permet de définir un indice de rigidité définissant un classement relatif de la souplesse des troncs des patients. L’indice de rigidité en autocorrection informe sur la capacité du patient à réduire de lui-même sa courbure. L’absence de corrélation entre les corrections des deux postures suggère des mécanismes de correction différents, soit une correction passive (correction manuelle) et active par sollicitation musculaire (autocorrection). Comme pour tout modèle de calcul, le MEF est une simplification de la réalité permettant de tester l’effet de paramètres contrôlés, et présente donc certaines limites. Comme condition limite l’orientation du bassin était fixée dans l’espace et une position prédéterminée de T1 devait être établie dans le plan transverse. La simulation de la correction manuelle n’a pu être vérifiée, car il était éthiquement impossible de prendre une radiographie dans cette posture, mais l’exploitation des topographies de surface permettrait éventuellement une première vérification. La rotation vertébrale n’a pas été mesurée dans cette étude ni implémentée dans la simulation. Cette modélisation présente la force générale permettant de maintenir la posture de correction manuelle et d’autocorrection; les différentes combinaisons de recrutement musculaire pour conserver ces postures ne sont pas représentées explicitement dans le modèle. Finalement, le nombre limité de patients n’a pas permis de distinguer l’effet du traitement prescrit (corset, physiothérapie en cours ou passé) sur les réductions de courbures mesurées et simulées dans l’une ou l’autre des postures. Cette étude est dans les premières à mesurer les forces de correction des mains du physiothérapeute lors d’un traitement RPG de la scoliose et a permis de calculer un indice de rigidité du tronc. Plus de travaux sont nécessaires pour compléter la validation complète du modèle pour simuler la correction manuelle et l’autocorrection. Cela permettrait à terme de quantifier la rigidité du tronc sans l’entremise de tests de flexibilité ionisants. De ce fait, le développement d’un indice de rigidité pour quantifier la résistance du tronc à la correction permettrait de faciliter la planification et le suivi du traitement de physiothérapie. De plus, l'évaluation du potentiel d’autocorrection trouve sa pertinence pour déterminer l'efficacité du traitement au niveau de l'intégration de la posture corrigée. La poursuite des recherches portant sur la biomécanique des mécanismes de correction en RPG permettrait de supporter la contribution de cette approche au traitement. ----------ABSTRACT Idiopathic scoliosis (IS) is a complex and evolutive three-dimensional (SD) deformation of the spine of unknown cause. It leads to a visible postural asymmetry, which may affect self-esteem and self-confidence, limit recreational activities and impact respiratory capacity. Up to 3 % of the general population suffers from a form of scoliosis; 80 % of the scoliosis cases are idiopathic and the evolutive cases affect primarily young girls during their growth period. The severity of the deformation, which is measured using the Cobb angle, is used to adapt the prescribed treatment. Patients diagnosed with mild scoliosis (Cobb 45°). Global postural re-education (GPR) is a physiotherapy approach developed in the 80’s in France to treat musculoskeletal disorders, and is part of the specific exercises for scoliosis. This treatment approach is based on active stretching postures and task-oriented exercises. Main treatment objectives are to decrease curve progression, improve posture and eliminate back pain. The postural evaluation in GPR to orient the choice of exercises is based on three steps: general photography, muscular retraction evaluation and re-equilibration. The goal of re-equilibration is to determine the correction capacity and trunk stiffness. More specifically, stand-up manual correction and self-correction postures aim to evaluate patient curve reducibility potential. Manual correction aims to qualitatively verify trunk stiffness and to evaluate the impact of this correction on the overall posture. Self-correction aims to evaluate patient’s ability to integrate the corrections by soliciting the muscles of the trunk. GPR applied to scoliosis is poorly documented in scientific literature. To our knowledge, there currently is no tool developed to quantitatively measure trunk stiffness during a physiotherapy treatment for scoliosis. A finite element model (FEM) representing the human trunk anatomical structures was previously developed to simulate immediate scoliosis correction in bracing. This model has the potential to be adapted and modified to simulate other conservative treatments such as physiotherapy manoeuvers. The objective of this study was to evaluate, using finite elements modeling, the curve reducibility of manual correction and self-correction of GPR physiotherapy approach in idiopathic scoliosis. A clinical study with 16 patients presenting with IS (2 juvenile IS and 14 adolescent IS) allowed to experimentally measure GPR re-equilibration postures. For each patient, a FEM was built from surface topography and biplanar low-dose radiographs of a standing reference posture. Gloves equipped with force sensors worn by the therapist allowed to measure the force applied at the hand-torso interface during manual correction. The manual correction was then simulated by reproducing the force measured under the right hand with an equivalent force vector on a node of the ribs in the FEM. A stiffness index was defined as the ratio between the force applied at thoracic apex over the thoracic Cobb angle reduction (forceΔ Cobb angle). In order to be compared to the standing reference posture, the self-correction was clinically measured through surface topography and biplannar radiographs. To simulate the self-correction, the positions of the first thoracic vertebra (T1) and the thoracic and lumbar apical vertebrae were imposed as measured on the self-corrected coronal and sagittal radiographs. The self-correction stiffness index was defined as the reaction force computed at thoracic apex over the thoracic curve reduction (forceΔ Cobb angle). The statistical analysis consisted of an ANOVA with Tukey post-hoc test to compare the Cobb angles in different postures. Correlations were evaluated using the Pearson coefficient. During manual correction, an average corrective force of 31 ± 6 N [23 N – 55 N] was measured under the therapist right hand. The simulation of this posture resulted in an average correction of 26 % (p < 0.05) of thoracic curvature with a non-significant clinical increase of the counter curvature. The thoracic kyphosis increased on average by 3˚ (p < 0.05) while the lumbar lordosis remained unchanged. Manual correction stiffness index varied from 2 to 10 N per degree of correction. Self-correction reduced on average by 33 % the thoracic curvature (p < 0.05) without affecting the lumbar counter curvature, while the sagittal curvatures flattened on average by 6˚ for the kyphosis and 5˚ for the lordosis (p < 0.05). Good correlation (r = 0.9) was obtained between the actual and simulated self-correction, despite the fact that the simulation tends to under-estimate the actual correction by 3˚ on average (p < 0.05). Average reaction force computed at thoracic apical vertebra was 45 N, which resulted in a stiffness index ranging between 0 and 21 N per degree of correction. There was no correlation between curve reduction obtained with manual correction and self-correction. The ratio between the force applied and the thoracic curve reduction in self-correction allowed to define a stiffness index for a relative ranking of patient trunk flexibility. Self-correction stiffness index informs on patient’s ability to correct by himself/herself the spine deformation. The lack of correlation between the corrections obtained in the two postures suggests that different correction mechanisms are at work: a passive correction (manual correction) and an active correction through muscular solicitation (self-correction). The FEM computational model is a simplification of reality that allows testing of the effects of controlled parameters. As boundary conditions, the pelvis orientation was fixed in space and a predetermined position of T1 had to be established in the transverse plane. Manual correction could not be verified because it was ethically impossible to take a radiography while maintaining the posture, however the future exploitation of surface topography could eventually lead to a preliminary verification. Vertebral rotation was not measured nor implemented in the simulation. This modeling presents the general force required to maintain the posture of self-correction and manual correction; the different combinations of muscular recruitment to retain these postures are not explicitly represented in the model. The limited number of patients did not allow to establish relationship between the prescribed treatment (bracing, physiotherapy prior to this study or in progress) and the curve reductions measured and simulated in the GPR postures. This study is one of the first to measure corrective force applied by physiotherapist hands during scoliosis GPR treatment and allowed to compute a stiffness index. More studies are required to complete the full validation of the model to simulate manual correction and self-correction. This would ultimately allow to quantify trunk stiffness without the necessity of ionised flexibility test. The definition of a stiffness index to quantify trunk resistance to correction would contribute to treatment planning and physiotherapy follow-up. In addition, the evaluation of self-correction potential finds its relevance in determining the effectiveness of the treatment regarding the integration of the corrected posture. Further research into the biomechanics of GPR correction mechanisms would support the contribution of this approach to treatment

InfraPhenoGrid: A scientific workflow infrastructure for Plant Phenomics on the Grid

International audiencePlant phenotyping consists in the observation of physical and biochemical traits of plant genotypes in response to environmental conditions. Challenges , in particular in context of climate change and food security, are numerous. High-throughput platforms have been introduced to observe the dynamic growth of a large number of plants in different environmental conditions. Instead of considering a few genotypes at a time (as it is the case when phenomic traits are measured manually), such platforms make it possible to use completely new kinds of approaches. However, the data sets produced by such widely instrumented platforms are huge, constantly augmenting and produced by increasingly complex experiments, reaching a point where distributed computation is mandatory to extract knowledge from data. In this paper, we introduce InfraPhenoGrid, the infrastructure we designed and deploy to efficiently manage data sets produced by the PhenoArch plant phenomics platform in the context of the French Phenome Project. Our solution consists in deploying scientific workflows on a Grid using a middle-ware to pilot workflow executions. Our approach is user-friendly in the sense that despite the intrinsic complexity of the infrastructure, running scientific workflows and understanding results obtained (using provenance information) is kept as simple as possible for end-users

Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

BACKGROUND: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. RESULTS: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at . CONCLUSION: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1); National Institutes of Health (HL064753, HL076784, AG028321, HL71039, 2 K24HL04334, 1K23 HL083102); Doris Duke Charitable Foundation; American Diabetes Association Career Developement Award; National Center for Research Resources (GCRC M01-RR01066); US Department of Agriculture Agricultural Research Service (58-1950-001, 58-1950-401); National Institute of Aging (AG14759

Compliance with Gluten Free Diet Is Associated with Better Quality of Life in Celiac Disease

The quality of life (QOL) of patients with celiac disease (CD) can be altered by both symptoms of the disease and by the restrictions of the gluten-free diet (GFD). The objective was to determine the factors associated with better QOL in a large cohort of CD patients. A link to an online survey was sent to the members of the French Association of Gluten Intolerant People (AFDIAG). The French-Celiac Disease Questionnaire (F-CDQ), scoring from 0 to 100, was used to measure the QOL. Other data collected were sociodemographic characteristics, information on CD, purchasing and consumption habits of gluten-free products, and a self-assessment scale (ranging from 0 to 10) to determine the compliance with the GFD. Among the 907 CD patients who returned the questionnaire, 787 were analyzed (638 women (81%); median age: 49 years; 71% with self-assessed GFD compliance &gt; 8). Their median F-CDQ was 73 (range: 59-82). In multivariate analysis, the main factors associated with a better quality of life were the long duration of the GFD, good compliance with the GFD, and the number of follow-up visits. Compliance with and duration of the GFD are associated with a better quality of life in patients with CD. Taking this into consideration would offset its restrictive aspect and improve its adherence

Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update.

PURPOSE To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients. METHODS The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered. RESULTS We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients. CONCLUSION The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Efficacy of antibiotic prophylaxis in patients with cancer and hematopoietic stem cell transplantation recipients : A systematic review of randomized trials

PURPOSE: To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia. RESULTS: Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified. CONCLUSIONS: Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes