SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Introduction-The long-term complications of catheter ablation within the pulmonary veins are unknown. The development of pulmonary vein stenosis has recently been described after catheter ablation to treat either chronic or paroxysmal atrial fibrillation. The purpose of this study was to examine the pathological and hemodynamic effects of radiofrequency (RF) energy application within the pulmonary veins. Methods and Results-Right heart and transseptal catheterization were performed in 9 anesthetized mongrel dogs. The pulmonary vein ostia were cannulated and pulmonary venous pressure was measured before RF energy application in up to 4 separate pulmonary veins. Animals were euthanized at intervals of 2 to 4 weeks (nϭ3), 6 to 8 weeks (nϭ3), or 10 to 14 weeks (nϭ3) after ablation. Repeat catheterization before euthanasia demonstrated statistically significant differences in pulmonary capillary wedge pressure, cardiac output, pulmonary vascular resistance, and systemic vascular resistance (PϽ0.05) compared with the baseline. Luminal narrowing was observed in 22 of 33 pulmonary veins to which RF energy was applied. Of these, 7 were totally occluded, 7 had severe stenosis, and 8 were only minimally narrowed. Histological examination revealed intimal proliferation with organizing thrombus, necrotic myocardium in various stages of collagen replacement, endovascular contraction, and a proliferation of elastic lamina. Conclusions-Applications of RF current within the pulmonary veins may result in pulmonary vein narrowing or complete occlusion. These observations should be considered in treatment of arrhythmias originating within the pulmonary veins.
The 21Na(p,gamma)22Mg reaction is expected to play an important role in the nucleosynthesis of 22Na in oxygen-neon novae. The decay of 22Na leads to the emission of a characteristic 1.275 MeV gamma-ray line. This report provides the first direct measurement of the rate of this reaction using a radioactive 21Na beam, and discusses its astrophysical implications. The energy of the important state was measured to be E(c.m.)=205.7+/-0.5 keV with a resonance strength omegagamma=1.03+/-0.16(stat)+/-0.14(sys) meV.
Conduction block usually occurred when continuous transmural necrosis was present, and conduction usually persisted when continuous transmural necrosis was absent. However, important exceptions were observed, including block when the ablation zone was wide but nontransmural, and conduction despite a thin line of continuous transmural necrosis.
Peripheral carcinoid tumours (PCT) of the lung are a distinct entity. These tumours arise from subsegmental or distal bronchioles, are usually well circumscribed and encapsulated, and contain varying amounts of spindle cells. Their histogenesis is from the Kultchitsky or neurosecretory type of cells. Of 52 patients with carcinoid tumours of the lung, 11 (21.1%) had PCT. The mean age was 60.2 years, 9 out of 11 patients were females, and about two-thirds of tumours were in the left lung (8 out of 13). No patient developed carcinoid syndrome, but three patients had nonspecific respiratory symptoms. Bronchoscopy was not helpful in diagnosing any of these cases. Four patients required a wedge resection of the lung; the other six underwent lobectomy. One patient had tumours detected incidentally at autopsy. Mean tumour size was 2.39 cm (range 1.0-5.0 cm); four tumours were 3.0 cm or larger in diameter. Three cases (27.3%) had regional lymph node metastases, but no systemic metastasis was discovered. Apart from the patient who was discovered to have carcinoid tumours at autopsy, all others are alive and disease-free from 1 to 6 years after surgery.
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