Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Products liability.

The goal of this Products Liability IQP is to learn the basic concepts of products liability law. First, to gain this fundamental understanding, we watched nine videos and read two books pertaining to products liability. Using this solid foundation, we analyzed two liability cases and performed one accident reconstruction. This experience expanded our knowledge of safety, ethics, and good engineering practice

Integration of DADISP and TI DSK6711 for real-time digital signal processing

This project utilizes Texas Instruments' TMS320C6711 DSP Development Kit to implement a custom digital filtering package. Although very powerful DSP hardware and software exist, their integration is key to realizing the true power of DSP and the goal of this project. The digital filtering software created for the project allows for the stand-alone design of digital filters using a custom graphical user interface. A second goal of the project is to utilize the processing capabilities of DSP Development Corporation's DADiSP. This is accomplished by using Microsoft's ActiveX technology to transfer data between DADiSP and the custom interface. The outcome of this project is the creation of a highly versatile digital signal processing package

Les risques conchylicoles en Baie de Quiberon. Première partie : le risque de mortalité virale du naissain d’huître creuse Crassostra gigas. Rapport final du projet Risco 2010-2013

This study (“Risco”), implicating both industry, socio-economic experts and biologists, was funded by the Regional Council of Brittany, for 3 years (2010-2013), to investigate upon the origin of oysters (Crassostrea gigas) mortalities in the bay of Quiberon (South Brittany, France). Specific mortalities of adult oysters were recorded in this bay in 2006, whereas mortalities of one year old spat were observed since in 2008 in this bay as at a national scale. The experimental protocol in 2010, including a monthly survey of oyster batches at 15 experimental stations, allowed to assess the risk for one-year oysters, due to viral disease. A clear spatial distribution of this risk was evidenced, with a western area spared from contamination and mortality, and a central and north-east sector strongly affected. The virus analysis clearly demonstrate the responsibility of the OsHV-1 virus in the mortalities. The oysters on the bottom with a lower growth appear less sensitive to the viral disease than the surelevated ones. In order to interpret this spatial distribution, an epidemiological model has been tested : it is based on emission of virus from the stock of spat in surrounding farming areas, dispersion by the hydrodynamic conditions, and inactivation of the virus by solar radiation. The resulting simulations suggest that the contamination would be endogenous to the bay (from contaminated stocks of spat seeded nearby). A decrease of densities for rearing spat, as well as the seeding of non contaminated spat may be recommended.L’étude « Risco », labellisée Pôle Mer et financée par la Région Bretagne, mobilise à la fois des socio-économistes, des biologistes et des professionnels. Elle vise à comprendre et gérer les facteurs de mortalités massives d’huîtres creuses (Crassostrea gigas) enregistrées par les concessionnaires de baie de Quiberon (France, 56), à partir de 2006 sur les huîtres adultes et 2008 sur le naissain. Le protocole engagé en 2010, avec un volet expérimental basé sur le suivi mensuel de lots d’huîtres en 15 stations et des analyses pathologiques, a permis d’éclairer notamment le risque épizootique sur le naissain. Une spatialisation très marquée de ce risque a été mise en évidence, avec une zone à l’ouest relativement épargnée et une zone au centre et à l’est très affectée. Les analyses virales mettent clairement en évidence la responsabilité du virus OsHV-1 dans ces mortalités. Les huîtres élevées au sol, moins poussantes, seraient aussi moins sensibles à la mortalité virale que les huîtres élevées en surélévation. L’existence d’une zone quasi-indemne de contamination et de mortalité à cette échelle est inédite parmi les secteurs ostréicoles français, depuis 2008. Pour interpréter cette distribution spatiale de la contamination et des mortalités, un modèle épidémiologique a été testé : il s’appuie sur une émission de virus à partir des stocks de naissain estimés en 2010 (estran et eau profonde), une dispersion par les courants, et une inactivation du virus en fonction du rayonnement solaire. Avec le taux d’abattement viral retenu, les simulations suggèrent que la contamination serait majoritairement endogène à la baie (à partir de semis de naissain en place, contaminés). Les recommandations qui en découlent sont notamment d’introduire en baie du naissain non contaminé et de diminuer les densités de naissain

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss

Les risques conchylicoles en Baie de Quiberon. Troisième partie : le risque d’hypoxie pour l’huître creuse Crassostrea gigas. Rapport final du projet Risco 2010-2013

The project “Risco”, supported by the “Pôle Mer” and funded by the Regional Council of Brittany, deals with specific risks of mortality of oysters, Crassostrea gigas, cultivated on the bottom, in a subtidal bay of South Brittany : the bay of Quiberon (56, France). Massive mortalities of oysters were reported in summer 2006 in this bay, exclusively located in the deep muddy area with a positive gradient eastward. A validated biogeochemical model was applied in order to simulate the dissolved oxygen over 2000-2006 : it revealed several episodes of hypoxia, more or less intense according to years, but with the same spatial distribution. This approach proved 2006 to be the most hypoxic year since 2000. The hypoxia was due to a rare conjunction of 3 factors : (a) a local upwelling generated by north-west winds, during a neap tide; (b) an abnormal high temperature of coastal waters; (c) probably an intense phytoplankton bloom in summertime. Due to the stratification induced, oxygen consumption near the bottom exceeded its renewal. The hydrodynamism of Mor Bras, at a larger scale, excludes any import of hypoxic water from the nearby “Baie de Vilaine”, whatever the wind or tide regime. The simulated hypoxia area fitted fairly well to the 2006 mortalities. In 2010, experimental oysters deployed at 15 stations and monitored monthly, exhibited also a lower growth rate in the same area, in spite of higher chlorophyll concentration. The application of a Dynamic Energy Budget (DEB) model to growth data confirmed the responsibility of hypoxia in abnormally slow growth rates. So hypoxia may be considered as a stressful factor limiting growth prior to mortalities. It may be concluded from our study that hydro-climatic and trophic conditions have the capacity to deplete oxygen in bottom coastal zones with possible consequences on biotopes and cultivated species: farm yields may be severely affected. This study will allow to manage more closely the commercial risk of shellfish farming at spatial and temporal scale.L’étude « Risco », labellisée par le Pôle Mer et financée par la région Bretagne, a révélé un facteur insoupçonné d’altération des résultats d’élevage ostréicole en baie de Quiberon (France, 56): l’hypoxie. Elle a ainsi fourni une explication convaincante des mortalités anormales observées sur les huîtres adultes l’été 2006. Le modèle biogéochimique appliqué sur la période 2000-2006 a mis en évidence plusieurs épisodes d’hypoxie d’intensité variable selon les années, mais très géolocalisés. Parmi eux, celui de 2006 s’est avéré exceptionnel, tant par son emprise spatiale que par son intensité. L’hypoxie de 2006 résulte de la conjonction rare de plusieurs phénomènes : (a) un upwelling local généré par des vents de nord-ouest en période de morte-eau ; (b) des eaux côtières anormalement chaudes ; (c) probablement un fort bloom estival de phytoplancton. Du fait de la stratification induite, la consommation d’oxygène au niveau du fond excède alors son renouvellement. Le secteur profond et envasé, à l’est de la zone concédée, est particulièrement affecté en raison de la géomorphologie de la baie de Quiberon. L’analyse du fonctionnement hydrodynamique à l’échelle du Mor Bras montre par ailleurs qu’il n’y a pas d’importation d’eau hypoxique depuis la baie de Vilaine, ceci quel que soit le régime de vent et de marée. La diminution de la teneur en oxygène dissous apparaît responsable de ralentissements de croissance des huîtres même en année peu hypoxique (comme 2010). C’est probablement le facteur explicatif des déficits de croissance marqués chez les huîtres au sol (par rapport aux huîtres en surélévation). En situation d’hypoxie extrême (année 2006), les huîtres des deux classes d’âge subissent des mortalités. Les huîtres d’un an paraissent plus affectées par le déficit d’oxygène, tant en croissance qu’en mortalité (étude 2010). Cette étude permet d’évaluer le risque d’hypoxie (sa probabilité d’occurrence, sa répartition géographique) et d’orienter les mesures préventives applicables en conchyliculture telles que la répartition des stocks en élevage ou l’entretien des parcs. L’incidence sur les peuplements naturels et les ressources exploitées, peut également être mieux prise en compte, à l’échelle du Mor Bras. Plus généralement, une meilleure connaissance des effets de l’hypoxie fournit des arguments en faveur du contrôle de l’eutrophisation (limitation des apports en nutriments par les bassins versants…)