Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.

Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Neo-Fregean accounts of the complex numbers and some reflections on Frege's applications constraint

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A systematic review to determine the presence and effectiveness of shared decision making interventions for airway clearance techniques in adults with bronchiectasis

BackgroundBronchiectasis is a chronic lung disorder, impaired muco-ciliary clearance and sputum retention are core elements in bronchiectasis pathophysiology. Airway clearance is regarded as the cornerstone of therapy in bronchiectasis. There is currently a lack of randomised controlled trials (RCTs) proving the efficacy of one specific airway clearance technique (ACT) over another. Shared decision-making (SDM) interventions are usually designed for situations where there is some uncertainty about the best treatment option and provide information about the advantages and disadvantages in as balanced a way as possible.AimsTo determine if and how SDM is used when choosing ACTs for adults with bronchiectasis. To determine the effectiveness of SDM when choosing ACTs for adults with bronchiectasis. Effectiveness will be measured using clinical and patient outcomesincluding: exacerbation frequency, hospitalisation, adverse events and mortality, patient adherence, health related quality of life, patient preference and acceptance. ObjectivesTo systematically search and identify all studies that include the use of SDM in ACTs in adults with bronchiectasis. To critically appraise and synthesise studies to provide a summary of the effectiveness on the use of SDM in ACTs in adults with bronchiectasis. Search criteria The following electronic databases were searched: CINAHL, EMBASE, Medline, PsycINFO, Google Scholar, Web of Science and the Cochrane Library. No limit was set for publication date. The review was limited to English language publications only. ResultsNo studies were identified for inclusion in the review.LimitationsWith no studies meeting criteria for inclusion, it may appear to offer no conclusions or offer conclusions not based on evidence and may seem disappointing among some clinicians and policymakers. We argue that this empty review remains important and highlights a major research gap and has identified the state of the evidence at this point in time in SDM for ACTs in bronchiectasis. ConclusionsBronchiectasis is an increasingly prevalent disease. ACTs are the cornerstone of bronchiectasis management. We have presented clear justification for further research for development of a SDM intervention for ACTs in adults with bronchiectasis

Rbm24a and Rbm24b Are Required for Normal Somitogenesis

<div><p>We recently demonstrated that the gene encoding the RNA binding motif protein 24 (RBM24) is expressed during mouse cardiogenesis, and determined the developmental requirement for its zebrafish homologs Rbm24a and Rbm24b during cardiac development. We demonstrate here that both Rbm24a and Rbm24b are also required for normal somite and craniofacial development. Diminution of <i>rbm24a</i> or <i>rbm24b</i> gene products by morpholino knockdown resulted in significant disruption of somite formation. Detailed <i>in situ</i> hybridization-based analyses of a spectrum of somitogenesis-associated transcripts revealed reduced expression of the cyclic muscle pattering genes <i>dlc</i> and <i>dld</i> encoding Notch ligands, as well as their respective target genes <i>her7</i>, <i>her1</i>. By contrast expression of the Notch receptors <i>notch1a</i> and <i>notch3</i> appears unchanged. Some RBM-family members have been implicated in pre-mRNA processing. Analysis of affected Notch-pathway mRNAs in <i>rbm24a</i> and <i>rbm24b</i> morpholino-injected embryos revealed aberrant transcript fragments of <i>dlc</i> and <i>dld</i>, but not <i>her1</i> or <i>her7</i>, suggesting the reduction in transcription levels of Notch pathway components may result from aberrant processing of its ligands. These data imply a previously unknown requirement for Rbm24a and Rbm24b in somite and craniofacial development. Although we anticipate the influence of disrupting RBM24 homologs likely extends beyond the Notch pathway, our results suggest their perturbation may directly, or indirectly, compromise post-transcriptional processing, exemplified by imprecise processing of <i>dlc</i> and <i>dld</i>.</p></div

<i>rbm24a</i> and <i>rbm24b</i> are expressed throughout somitogenesis.

<p><i>ISH</i> images of uninjected AB embryos using <i>rbm24a</i> or <i>rbm24b</i> riboprobes individually marking spatial and temporal RNA expression. Tailbud expression of bud stage embryos in lateral-slightly ventral facing (A, C) and dorsal (B, D) orientations. 8 somite embryos in dorsal facing orientations show all segmented somites (E, G) and PSM (F, H) marked by <i>rbm24a</i> and <i>rbm24b</i> riboprobes. Trunk images of embryos at 24 hpf show spatial expression of <i>rbm24a</i> in the somites concentrated at the posterior, while <i>rbm24b</i> is uniformly expressed in somites along the A-P axis (I–J). Inset of (I–J) highlights expression of <i>rbm24a</i> and <i>rbm24b</i> in the PSM. Embryos at 48 hpf show no somite <i>rbm24a</i> expression, while somite expression of <i>rbm24b</i> remains uniform thought the somites (K–L). som, somites; hpf, hours post fertilization; arrows, tailbud expression; A, anterior of embryo; P, posterior of embryo; bracket, PSM expression.</p

Number of embryos with somite defects.

<p>The number of embryos examined and number observed to have somite defects is listed for embryos at 13 somites and 24 hpf. Statistical significance and p-values were determined at a 95% confidence interval.</p><p>* = p<0.05 compared to ctrlMO.</p><p>** = p<0.01 compared to ctrlMO0.</p><p>*** = p<0.001 compared to ctrlMO.</p><p>+ = p<0.05 compared to respective MO.</p><p>++ = p<0.01 compared to respective MO.</p><p>+++ = p<0.001 compared to respective MO.</p><p>Number of embryos with somite defects.</p