A Compact Beam Stop for a Rare Kaon Decay Experiment

We describe the development and testing of a novel beam stop for use in a rare kaon decay experiment at the Brookhaven AGS. The beam stop is located inside a dipole spectrometer magnet in close proximity to straw drift chambers and intercepts a high-intensity neutral hadron beam. The design process, involving both Monte Carlo simulations and beam tests of alternative beam-stop shielding arrangements, had the goal of minimizing the leakage of particles from the beam stop and the resulting hit rates in detectors, while preserving maximum acceptance for events of interest. The beam tests consisted of measurements of rates in drift chambers, scintilation counter hodoscopes, a gas threshold Cherenkov counter, and a lead glass array. Measurements were also made with a set of specialized detectors which were sensitive to low-energy neutrons, photons, and charged particles. Comparisons are made between these measurements and a detailed Monte Carlo simulation.Comment: 39 pages, 14 figures, submitted to Nuclear Instruments and Method

A straw drift chamber spectrometer for studies of rare kaon decays

We describe the design, construction, readout, tests, and performance of planar drift chambers, based on 5 mm diameter copperized Mylar and Kapton straws, used in an experimental search for rare kaon decays. The experiment took place in the high-intensity neutral beam at the Alternating Gradient Synchrotron of Brookhaven National Laboratory, using a neutral beam stop, two analyzing dipoles, and redundant particle identification to remove backgrounds

How Coupling Determines the Entrainment of Circadian Clocks

Autonomous circadian clocks drive daily rhythms in physiology and behaviour. A network of coupled neurons, the suprachiasmatic nucleus (SCN), serves as a robust self-sustained circadian pacemaker. Synchronization of this timer to the environmental light-dark cycle is crucial for an organism's fitness. In a recent theoretical and experimental study it was shown that coupling governs the entrainment range of circadian clocks. We apply the theory of coupled oscillators to analyse how diffusive and mean-field coupling affects the entrainment range of interacting cells. Mean-field coupling leads to amplitude expansion of weak oscillators and, as a result, reduces the entrainment range. We also show that coupling determines the rigidity of the synchronized SCN network, i.e. the relaxation rates upon perturbation. %(Floquet exponents). Our simulations and analytical calculations using generic oscillator models help to elucidate how coupling determines the entrainment of the SCN. Our theoretical framework helps to interpret experimental data

Community psychiatric nurses and the care co-ordinator role: squeezed to provide ‘limited nursing’.

Background: The Care Programme Approach (CPA) is the key policy underpinning community-focused mental health services but has been unevenly implemented and is associated with increased inpatient bed use. The care co-ordinator role is central to the CPA and is most often held by Community Psychiatric Nurses (CPNs), but there has been little research into how this role is conducted or how it impacts on the work of CPNs and their ability to meet the needs of service users. Aim: The study aimed to identify and illuminate the factors that either facilitated or constrained the ability of CPNs, in their role as care co-ordinators, to meet service users’ and carers’ needs. Methods: A multiple case study of seven sectorised community mental health teams was employed over two years using predominantly qualitative methods of participant observation, semi-structured interviews and document review. Findings: Additional duties and responsibilities specifically associated with the care co-ordinator role and multidisciplinary working, combined with heavy workloads, combined to produce ‘limited nursing’, whereby CPNs are unable to provide evidence-based psychosocial interventions that are recognised to reduce relapse amongst people with severe mental illness. Conclusions: The role of the CPA care co-ordinator was not designed to support the provision of psychosocial interventions. Consequently, CPNs in the co-ordinator role faced with competing demands are unable to provide the range of structured, evidence-based interventions required. This may partially account for the increased inpatient bed use associated with the CPA

Acceptance and Use of E-Learning Based on Cloud Computing: The Role of Consumer Innovativeness

Cloud computing and E-learning are the inevitable trend of computational science in general, and information systems and technologies in specific.However, there are not many studies on the adoption of cloud-based E-learning systems. Moreover, while there are many papers on information system adoption as well as customer innovativeness, the innovativeness and adoption in the same model seems to be rare in the literature. The study combines the extended Unified Theory of Acceptance and Use of Technology (UTAUT2) and consumer innovativeness on the adoption of E-learning systems based on cloud computing. A survey was conducted among 282 cloud-based E-learning participants and analyzed by structural equation modeling (SEM). The findings indicate that the adoption of cloud-based E-learning is influenced by performance expectancy, social influence, hedonic motivation, and habit. Interestingly, although innovativeness is not significant to use intention, it has a positive effect on E-learning usage which is relatively new in Vietnam

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury