A neural network underlying circadian entrainment and photoperiodic adjustment of sleep and activity in Drosophila

A sensitivity of the circadian clock to light/dark cycles ensures that biological rhythms maintain optimal phase relationships with the external day. In animals, the circadian clock neuron network (CCNN) driving sleep/activity rhythms receives light input from multiple photoreceptors, but how these photoreceptors modulate CCNN components is not well understood. Here we show that the Hofbauer-Buchner eyelets differentially modulate two classes of ventral lateral neurons (LNvs) within the Drosophila CCNN. The eyelets antagonize Cryptochrome (CRY)- and compound-eye-based photoreception in the large LNvs while synergizing CRY-mediated photoreception in the small LNvs. Furthermore, we show that the large LNvs interact with subsets of “evening cells” to adjust the timing of the evening peak of activity in a day length-dependent manner. Our work identifies a peptidergic connection between the large LNvs and a group of evening cells that is critical for the seasonal adjustment of circadian rhythms. SIGNIFICANCE STATEMENT In animals, circadian clocks have evolved to orchestrate the timing of behavior and metabolism. Consistent timing requires the entrainment these clocks to the solar day, a process that is critical for an organism's health. Light cycles are the most important external cue for the entrainment of circadian clocks, and the circadian system uses multiple photoreceptors to link timekeeping to the light/dark cycle. How light information from these photorecptors is integrated into the circadian clock neuron network to support entrainment is not understood. Our results establish that input from the HB eyelets differentially impacts the physiology of neuronal subgroups. This input pathway, together with input from the compound eyes, precisely times the activity of flies under long summer days. Our results provide a mechanistic model of light transduction and integration into the circadian system, identifying new and unexpected network motifs within the circadian clock neuron network

Evaluating major anthropogenic VOC emission sources in densely populated Vietnamese cities

Volatile organic compounds (VOCs) play an important role in urban air pollution, both as primary pollutants and through their contribution to the formation of secondary pollutants, such as tropospheric ozone and secondary organic aerosols. In this study, more than 30 VOC species were continuously monitored in the two most populous cities in Vietnam, namely Ho Chi Minh City (HCMC, September-October 2018 and March 2019) and Hanoi (March 2019). In parallel with ambient VOC sampling, grab sampling was used to target the most prevalent regional-specific emission sources and estimate their emission factors (EFs). Emission ratios (ERs) obtained from ambient sampling were compared between Vietnamese cities and other cities across the globe. No significant differences were observed between HCMC and Hanoi, suggesting the presence of similar sources. Moreover, a good global agreement was obtained in the spatial comparison within a factor of 2, with greater ER for aromatics and pentanes obtained in the Vietnamese cities. The detailed analysis of sources included the evaluation of EF from passenger cars, buses, trucks, motorcycles, 3-wheeled motorcycles, waste burning, and coal-burning emissions. Our comparisons between ambient and near-source concentration profiles show that road transport sources are the main contributors to VOC concentrations in Vietnamese cities. VOC emissions were calculated from measured EF and consumption data available in Hanoi and compared with those estimated by a global emission inventory (EDGAR v4.3.2). The total VOC emissions from the road transport sector estimated by the inventory do not agree with those calculated from our observations which showed higher total emissions by a factor of 3. Furthermore, the inventory misrepresented the VOCs speciation, mainly for isoprene, monoterpenes, aromatics, and oxygenated compounds. Accounting for these differences in regional air quality models would lead to improved predictions of their impacts and help to prioritise pollution reduction strategies in the region

A proposal for a new PhD level curriculum on quantitative methods for drug development

This paper provides an overview of “Improving Design, Evaluation and Analysis of early drug development Studies” (IDEAS), a European Commission–funded network bringing together leading academic institutions and small‐ to large‐sized pharmaceutical companies to train a cohort of graduate‐level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early‐stage researchers for 36 months. IDEAS training activities are composed of a well‐rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development

The fingerprint of the summer 2018 drought in Europe on ground-based atmospheric CO2 measurements

During the summer of 2018, a widespread drought developed over Northern and Central Europe. The increase in temperature and the reduction of soil moisture have influenced carbon dioxide (CO2) exchange between the atmosphere and terrestrial ecosystems in various ways, such as a reduction of photosynthesis, changes in ecosystem respiration, or allowing more frequent fires. In this study, we characterize the resulting perturbation of the atmospheric CO2 seasonal cycles. 2018 has a good coverage of European regions affected by drought, allowing the investigation of how ecosystem flux anomalies impacted spatial CO2 gradients between stations. This density of stations is unprecedented compared to previous drought events in 2003 and 2015, particularly thanks to the deployment of the Integrated Carbon Observation System (ICOS) network of atmospheric greenhouse gas monitoring stations in recent years. Seasonal CO2 cycles from 48 European stations were available for 2017 and 2018.The UK sites were funded by the UK Department of Business, Energy and Industrial Strategy (formerly the Department of Energy and Climate Change) through contracts TRN1028/06/2015 and TRN1537/06/2018. The stations at the ClimaDat Network in Spain have received funding from the ‘la Caixa’ Foundation, under agreement 2010-002624

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

Do physiotherapy staff record treatment time accurately? An observational study

OBJECTIVE: To assess the reliability of duration of treatment time measured by physiotherapy staff in early-stage stroke patients. DESIGN: Comparison of physiotherapy staff's recording of treatment sessions and video recording. SETTING: Rehabilitation stroke unit in a general hospital. SUBJECTS: Thirty-nine stroke patients without trunk control or who were unable to stand with an erect trunk without the support of two therapists recruited to a randomized trial evaluating the Oswestry Standing Frame. Twenty-six physiotherapy staff who were involved in patient treatment. MAIN MEASURES: Contemporaneous recording by physiotherapy staff of treatment time (in minutes) compared with video recording. STATISTICAL ANALYSIS: Intraclass correlation with 95% confidence interval and the Bland and Altman method for assessing agreement by calculating the mean difference (standard deviation; 95% confidence interval), reliability coefficient and 95% limits of agreement for the differences between the measurements. RESULTS: The mean duration (standard deviation, SD) of treatment time recorded by physiotherapy staff was 32 (11) minutes compared with 25 (9) minutes as evidenced in the video recording. The mean difference (SD) was -6 (9) minutes (95% confidence interval (CI) -9 to -3). The reliability coefficient was 18 minutes and the 95% limits of agreement were -24 to 12 minutes. Intraclass correlation coefficient for agreement between the two methods was 0.50 (95% CI 0.12 to 0.73). CONCLUSIONS: Physiotherapy staff's recording of duration of treatment time was not reliable and was systematically greater than the video recording

Acoustic and articulatory characteristics of rhoticity in the North-West of England

We present a sociophonetic, acoustic, and articulatory analysis of coda rhoticity in East Lancashire, North-West England. We analysed data from 24 participants aged 8–73 recorded at a public engagement event in Blackburn Market (598 tokens). Auditory analysis shows coda rhoticity is declining across generations, with speakers born after 1990 being mostly non-rhotic. Audible rhoticity is realised by lowered F3 and raised F2. GAMMs fitted across the vowel(+rhoticity) interval show that audibly rhotic tokens have a significantly smaller distance between F3 and F2 than audibly non-rhotic tokens in all vowel contexts. Our ultrasound analysis compares minimal pairs e.g. ‘core’ and ‘caw’. Principal Component Analysis of tongue splines shows that speakers use different tongue shapes in auditorily rhotic tokens

Comparing the views of caseload midwives working with First Nations families in an all-risk, culturally responsive model with midwives working in standard caseload models, using a cross-sectional survey design

Problem: Little is known about midwives’ views and wellbeing when working in an all-risk caseload model. Background: Between March 2017 and December 2020 three maternity services in Victoria, Australia implemented culturally responsive caseload models for women having a First Nations baby. Aim: Explore the views, experiences and wellbeing of midwives working in an all-risk culturally responsive model for First Nations families compared to midwives in standard caseload models in the same services. Methods: A survey was sent to all midwives in the culturally responsive (CR) model six-months and two years after commencement (or on exit), and to standard caseload (SC) midwives two years after the culturally responsive model commenced. Measures used included the Midwifery Process Questionnaire and Copenhagen Burnout Inventory (CBI). Findings: 35 caseload midwives (19 CR, 16 SC) participated. Both groups reported positive attitudes towards their professional role, trending towards higher median levels of satisfaction for the culturally responsive midwives. Midwives valued building close relationships with women and providing continuity of care. Around half reported difficulty maintaining work-life balance, however almost all preferred the flexible hours to shift work. All agreed that a reduced caseload is needed for an all-risk model and that supports around the model (e.g. nominated social workers, obstetricians) are important. Mean CBI scores showed no burnout in either group, with small numbers of individuals having burnout in both groups. Discussion and conclusion: Midwives were highly satisfied working in both caseload models, but decreased caseloads and more organisational supports are needed in all-risk models