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Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

PurposeTo test the effectiveness of a central venous catheter (CVC) insertion strategy and a hand hygiene (HH) improvement strategy to prevent central venous catheter-related bloodstream infections (CRBSI) in European intensive care units (ICUs), measuring both process and outcome indicators.MethodsAdult ICUs from 14 hospitals in 11 European countries participated in this stepped-wedge cluster randomised controlled multicentre intervention study. After a 6 month baseline, three hospitals were randomised to one of three interventions every quarter: (1) CVC insertion strategy (CVCi); (2) HH promotion strategy (HHi); and (3) both interventions combined (COMBi). Primary outcome was prospective CRBSI incidence density. Secondary outcomes were a CVC insertion score and HH compliance.ResultsOverall 25,348 patients with 35,831 CVCs were included. CRBSI incidence density decreased from 2.4/1000 CVC-days at baseline to 0.9/1000 (p < 0.0001). When adjusted for patient and CVC characteristics all three interventions significantly reduced CRBSI incidence density. When additionally adjusted for the baseline decreasing trend, the HHi and COMBi arms were still effective. CVC insertion scores and HH compliance increased significantly with all three interventions.ConclusionsThis study demonstrates that multimodal prevention strategies aiming at improving CVC insertion practice and HH reduce CRBSI in diverse European ICUs. Compliance explained CRBSI reduction and future quality improvement studies should encourage measuring process indicators.

Land application has become a widely applied method for treating wastewater. However, it is not always clear which soil–plant systems should be used, or why. The objectives of our study were to determine if four contrasting soils, from which the pasture is regularly cut and removed, varied in their ability to assimilate nutrients from secondary‐treated domestic effluent under high hydraulic loadings, in comparison with unirrigated, fertilized pasture. Grassed intact soil cores (500 mm in diameter by 700 mm in depth) were irrigated (50 mm wk−1) with secondary‐treated domestic effluent for two years. Soils included a well‐drained Allophanic Soil (Typic Hapludand), a poorly drained Gley Soil (Typic Endoaquept), a well‐drained Pumice Soil formed from rhyolitic tephra (Typic Udivitrand), and a well‐drained Recent Soil formed in a sand dune (Typic Udipsamment). Effluent‐irrigated soils received between 746 and 815 kg N ha−1 and 283 and 331 kg P ha−1 over two years of irrigation, and unirrigated treatments received 200 kg N ha−1 and 100 kg P ha−1 of dissolved inorganic fertilizer over the same period. Applying effluent significantly increased plant uptake of N and P from all soil types. For the effluent‐irrigated soils plant N uptake ranged from 186 to 437 kg N ha−1 yr−1, while plant P uptake ranged from 40 to 88 kg P ha−1 yr−1 for the effluent‐irrigated soils. Applying effluent significantly increased N leaching losses from Gley and Recent Soils, and after two years ranged from 17 to 184 kg N ha−1 depending on soil type. Effluent irrigation only increased P leaching from the Gley Soil. All P leaching losses were less than 49 kg P ha−1 after two years. The N and P leached from effluent treatments were mainly in organic form (69–87% organic N and 35–65% unreactive P). Greater N and P leaching losses from the irrigated Gley Soil were attributed to preferential flow that reduced contact between the effluent and the soil matrix. Increased N leaching from the Recent Soil was the result of increased leaching of native soil organic N due to the higher hydraulic loading from the effluent irrigation.

Background Multimodal analgesic strategies that reduce perioperative opioid consumption are well-supported in Enhanced Recovery After Surgery (ERAS) literature. However, the optimal analgesic regimen has not been established, as the contributions of each individual agent to the overall analgesic efficacy with opioid reduction remains unknown. Perioperative ketamine infusions can decrease opioid consumption and opioid-related side effects. However, as opioid requirements are drastically minimized within ERAS models, the differential effects of ketamine within an ERAS pathway remain unknown. We aim to pragmatically investigate through a learning healthcare system infrastructure how the addition of a perioperative ketamine infusion to mature ERAS pathways affects functional recovery. Methods The IMPAKT ERAS trial (IMpact of PerioperAtive KeTamine on Enhanced Recovery after Abdominal Surgery) is a single center, pragmatic, randomized, blinded, placebo-controlled trial. 1544 patients undergoing major abdominal surgery will be randomly allocated to receive intraoperative and postoperative (up to 48 h) ketamine versus placebo infusions as part of a perioperative multimodal analgesic regimen. The primary outcome is length of stay, defined as surgical start time until hospital discharge. Secondary outcomes will include a variety of in-hospital clinical end points derived from the electronic health record. Discussion We aimed to launch a large-scale, pragmatic trial that would easily integrate into routine clinical workflow. Implementation of a modified consent process was critical to preserving our pragmatic design, permitting an efficient, low-cost model without reliance on external study personnel. Therefore , we partnered with leaders of our Investigational Review Board to develop a novel, modified consent process and shortened written consent form that would meet all standard elements of informed consent, yet also allow clinical providers the ability to recruit and enroll patients during their clinical workflow. Our trial design has created a platform for subsequent pragmatic studies at our institution. Trial registration NCT04625283, Pre-results.

A micromachined specimen with a test section only 150-μm thick was developed for investigating subcritical crack growth in silicon. Crack growth rates in the range 10−4–10−10 m/s were measured as a function of applied stress intensity (v–K curves) during tests in humid air and dry nitrogen lasting up to 24 h. The fracture toughness, KIc of {110} silicon was also measured at 1.15 ± 0.08 MPa m1/2. While some evidence MPa-m1/2 of subcritical crack growth appeared to occur in the region 0.9 KIc < K > 0.98 KIc, the extremely high crack growth exponent (n 100) and the high ratio of the apparent stress corrosion threshold, KIscc, to the fracture toughness, KIscc/KIc > 0.9, suggests that no clear evidence exists for a stress corrosion process in silicon exposed to humid air.

Although crystalline silicon is not generally considered susceptible to fatigue crack growth, recent studies suggest that there may be fatigue processes in silicon micro-machined structures. In the present study, a micro-machined fracture specimen geometry was used to examine stable crack growth under fatigue loading. Crack length and loads were carefully monitored throughout the test to distinguish between environmentally assisted crack growth (stress corrosion) and mechanically induced fatigue-crack growth. Results revealed similar steplike crack extension versus time for the cyclic and monotonic tests. The fatigue crack-growth curve extracted from the crack extension data exhibited a nearly vertical slope with no evidence of accelerated crack-growth rates. Fracture surfaces for the monotonic and cyclic tests were similar, further suggesting that a true mechanical fatigue crack-growth mechanism did not occur. Explanations for the observed lack of fatigue crack growth are presented and discussed with respect to reported stress-life behavior.

Habituation as an index of the intrasensory and intersensory integration of form was investigated in nine-year-old children. In Habituation Period One, Ss were habituated to either a visual or a haptic 14″-perimeter standard stimulus. During Habituation Period Two, groups were subdivided and presented with one of the following stimuli: (a) 14″ visual, (b) 16″ visual, (c) 14″ haptic, or (d) 16″ haptic. The dependent variables were GSR frequency and amplitude, visual fixation time, and touching time. Subjects required more trials to habituate to the different stimulus presented in Habituation Period Two than Ss who received repeated presentations of the same stimulus. GSR frequency and amplitude habituated more consistently than did fixation and touching response measures. The results supported the use of the habituation paradigm for the study of intersensory and intrasensory integration, as well as providing support for extending Sokolov's theory to intersensory functions.