Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels

Arteriovenous (AV) malformation (AVM) is a devastating condition characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. AVMs can form anywhere in the body and can cause debilitating ischemia and life-threatening hemorrhagic stroke. The mechanisms that underlie AVM formation remain poorly understood. Here, we examined the cellular and hemodynamic changes at the earliest stages of brain AVM formation by time-lapse two-photon imaging through cranial windows of mice expressing constitutively active Notch4 (Notch4*). AVMs arose from enlargement of preexisting microvessels with capillary diameter and blood flow and no smooth muscle cell coverage. AV shunting began promptly after Notch4* expression in endothelial cells (ECs), accompanied by increased individual EC areas, rather than increased EC number or proliferation. Alterations in Notch signaling in ECs of all vessels, but not arteries alone, affected AVM formation, suggesting that Notch functions in the microvasculature and/or veins to induce AVM. Increased Notch signaling interfered with the normal biological control of hemodynamics, permitting a positive feedback loop of increasing blood flow and vessel diameter and driving focal AVM growth from AV connections with higher blood velocity at the expense of adjacent AV connections with lower velocity. Endothelial expression of constitutively active Notch1 also led to brain AVMs in mice. Our data shed light on cellular and hemodynamic mechanisms underlying AVM pathogenesis elicited by increased Notch signaling in the endothelium.American Heart Association (Grant 0715062Y)Tobacco-Related Disease Research Program (Predoctoral Fellowship 18DT-0009

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Psychosocial interventions for supporting women to stop smoking in pregnancy

Background: Tobacco smoking remains one of the few preventable factors associated with complications in pregnancy, and has serious long-term implications for women and babies. Smoking in pregnancy is decreasing in high-income countries, but is strongly associated with poverty and is increasing in low- to middle-income countries. Objectives: To assess the effects of smoking cessation interventions during pregnancy on smoking behaviour and perinatal health outcomes. Search methods: In this sixth update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 November 2015), checked reference lists of retrieved studies and contacted trial authors. Selection criteria: Randomised controlled trials, cluster-randomised trials, and quasi-randomised controlled trials of psychosocial smoking cessation interventions during pregnancy. Data collection and analysis: Two review authors independently assessed trials for inclusion and trial quality, and extracted data. Direct comparisons were conducted in RevMan, with meta-regression conducted in STATA 14. Main results: The overall quality of evidence was moderate to high, with reductions in confidence due to imprecision and heterogeneity for some outcomes. One hundred and two trials with 120 intervention arms (studies) were included, with 88 trials (involving over 28,000 women) providing data on smoking abstinence in late pregnancy. Interventions were categorised as counselling, health education, feedback, incentives, social support, exercise and dissemination. In separate comparisons, there is high-quality evidence that counselling increased smoking cessation in late pregnancy compared with usual care (30 studies; average risk ratio (RR) 1.44, 95% confidence interval (CI) 1.19 to 1.73) and less intensive interventions (18 studies; average RR 1.25, 95% CI 1.07 to 1.47). There was uncertainty whether counselling increased the chance of smoking cessation when provided as one component of a broader maternal health intervention or comparing one type of counselling with another. In studies comparing counselling and usual care (largest comparison), it was unclear whether interventions prevented smoking relapse among women who had stopped smoking spontaneously in early pregnancy. However, a clear effect was seen in smoking abstinence at zero to five months postpartum (11 studies; average RR 1.59, 95% CI 1.26 to 2.01) and 12 to 17 months (two studies, average RR 2.20, 95% CI 1.23 to 3.96), with a borderline effect at six to 11 months (six studies; average RR 1.33, 95% CI 1.00 to 1.77). In other comparisons, the effect was unclear for most secondary outcomes, but sample sizes were small. Evidence suggests a borderline effect of health education compared with usual care (five studies; average RR 1.59, 95% CI 0.99 to 2.55), but the quality was downgraded to moderate as the effect was unclear when compared with less intensive interventions (four studies; average RR 1.20, 95% CI 0.85 to 1.70), alternative interventions (one study; RR 1.88, 95% CI 0.19 to 18.60), or when smoking cessation health education was provided as one component of a broader maternal health intervention. There was evidence feedback increased smoking cessation when compared with usual care and provided in conjunction with other strategies, such as counselling (average RR 4.39, 95% CI 1.89 to 10.21), but the confidence in the quality of evidence was downgraded to moderate as this was based on only two studies and the effect was uncertain when feedback was compared to less intensive interventions (three studies; average RR 1.29, 95% CI 0.75 to 2.20). High-quality evidence suggests incentive-based interventions are effective when compared with an alternative (non-contingent incentive) intervention (four studies; RR 2.36, 95% CI 1.36 to 4.09). However pooled effects were not calculable for comparisons with usual care or less intensive interventions (substantial heterogeneity, I2 = 93%). High-quality evidence suggests the effect is unclear in social support interventions provided by peers (six studies; average RR 1.42, 95% CI 0.98 to 2.07), in a single trial of support provided by partners, or when social support for smoking cessation was provided as part of a broader intervention to improve maternal health. The effect was unclear in single interventions of exercise compared to usual care (RR 1.20, 95% CI 0.72 to 2.01) and dissemination of counselling (RR 1.63, 95% CI 0.62 to 4.32). Importantly, high-quality evidence from pooled results demonstrated that women who received psychosocial interventions had a 17% reduction in infants born with low birthweight, a significantly higher mean birthweight (mean difference (MD) 55.60 g, 95% CI 29.82 to 81.38 g higher) and a 22% reduction in neonatal intensive care admissions. However the difference in preterm births and stillbirths was unclear. There did not appear to be adverse psychological effects from the interventions. The intensity of support women received in both the intervention and comparison groups has increased over time, with higher-intensity interventions more likely to have higher-intensity comparisons, potentially explaining why no clear differences were seen with increasing intervention intensity in meta-regression analyses. Among meta-regression analyses: studies classified as having 'unclear' implementation and unequal baseline characteristics were less effective than other studies. There was no clear difference between trials implemented by researchers (efficacy studies), and those implemented by routine pregnancy staff (effectiveness studies), however there was uncertainty in the effectiveness of counselling in four dissemination trials where the focus on the intervention was at an organisational level. The pooled effects were similar in interventions provided for women classified as having predominantly low socio-economic status, compared to other women. The effect was significant in interventions among women from ethnic minority groups; however not among indigenous women. There were similar effect sizes in trials with biochemically validated smoking abstinence and those with self-reported abstinence. It was unclear whether incorporating use of self-help manuals or telephone support increased the effectiveness of interventions. Authors' conclusions: Psychosocial interventions to support women to stop smoking in pregnancy can increase the proportion of women who stop smoking in late pregnancy and the proportion of infants born low birthweight. Counselling, feedback and incentives appear to be effective, however the characteristics and context of the interventions should be carefully considered. The effect of health education and social support is less clear. New trials have been published during the preparation of this review and will be included in the next update

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe