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Background Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home ‘kits’ for peer administration (take-home naloxone). Aim To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings. Design We used Welsh routine data (2015–21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes. Setting This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area. Participants At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training. Interventions Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration. Results Discriminant function With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. Randomised controlled trial Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: ‘forgot’ (n = 136); ‘too busy’ (n = 15); suspected intentional overdose (n = 3). Qualitative interviews Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users. Health economics We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met – fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales. Future work The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods. Limitations The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease. Conclusions This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. Trial registration This trial is registered as ISRCTN13232859. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information. Plain language summary Emergency ambulance staff and doctors in the emergency department regularly administer naloxone to people who have overdosed, reversing effects of the opioid – so-called ‘take-home naloxone’ – to administer to others in an emergency. We don’t know whether take-home naloxone saves lives. We carried out this feasibility study to see whether: we could identify a high-risk population to include in a trial to determine whether take-home naloxone reduces deaths from overdose ambulance paramedics and emergency department staff could be trained, and would then give out take-home naloxone kits to drug users they see. We included four areas in the study. We randomly selected two for distribution of take-home naloxone to patients at risk of or following an overdose by emergency department clinicians and local ambulance paramedics. We attempted to identify people at high risk of death from opioid overdose. We collected data about patients that were eligible and received take-home naloxone in the two intervention areas. We carried out interviews to find out about the views of patients and staff who gave out the kits. At the start, we agreed criteria that should be met for us to recommend that a full evaluation be carried out. We could not reliably identify people at high risk of death from opioid overdose, as deaths were rare in the population, and previous health service usage was variable. Less than half of eligible staff were trained to supply take-home naloxone (299/687, 44%), and less than half of eligible patients were given take-home naloxone (60/277, 21.7%) over 1 year. Patients were not offered take-home naloxone because staff forgot, were too busy or suspected an intentional overdose. Other patients left before receiving a kit. Service users liked the idea of take-home naloxone kits being provided in the emergency setting but reported resistance to attending hospital following an overdose. Service providers were supportive of providing take-home naloxone in the emergency setting but reported challenges in consent and training. Conclusion This study found that it was not feasible to deliver or evaluate this form of take-home naloxone, using this study design, in emergency care. Scientific summary Parts of this summary have been reproduced from Jones M, Bell F, Benger J, Black S, Buykx P, Dixon S, et al. Protocol for Take-home naloxone In Multicentre Emergency (TIME) settings: feasibility study. Pilot Feasib Stud 2020;6(1):1–10. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Background Opioids, such as heroin, kill more people worldwide by overdose than any other type of drug, and death rates associated with opioid poisoning in the United Kingdom (UK) are at record levels. Naloxone is an opioid antagonist which can be distributed in ‘kits’ for administration by witnesses in an overdose emergency. This intervention is known as take-home naloxone (THN). We know that THN can save lives on an individual level, but there is currently limited evidence about the effectiveness of THN distribution on an aggregate level, in specialist drug service settings or in emergency service (ES) settings. Notably, we do not know whether THN kits reduce deaths from opioid overdose in at-risk populations, if there are unforeseen harms associated with THN distribution or if THN is cost-effective. To address this research gap, we aimed to determine the feasibility of a fully powered cluster randomised controlled trial (RCT) of THN distribution in emergency settings. Aim To determine the feasibility of carrying out a definitive RCT of THN in emergency settings. Objectives To determine: the best form of THN kit, training and delivery whether a trial clustered by emergency department (ED) catchment area and the associated ambulance service (AS) is deliverable, as assessed against predefined progression criteria related to intervention, trial design and methods. Design We assessed feasibility of intervention and trial methods based upon the following predetermined progression criteria. Intervention feasibility Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site. Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period. THN kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites. Serious adverse event rate [to be defined in agreement with Data Monitoring and Ethics Committee (DMEC)] of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment. Trial methods feasibility Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to Office of National Statistics (ONS) mortality data (previous ONS data suggest between 140 and 180 such deaths across the 4 participating sites during the study period). Matching and data linkage in ≥ 90% of cases not dissented at the conclusion of quantitative data collection. Retrieval of primary and secondary outcomes from National Health Service (NHS) Digital and National Welsh Informatics Service within 6 months of projected timeline. As the intervention tested is for administration to recipients of the THN kits and peers who may suffer an overdose, we needed to find a way to identify cohorts to include in outcome comparisons. We therefore analysed Welsh routine data to test the feasibility of developing a discriminant function to identify a high-risk population for fatal opioid overdose. We scoped anonymised routine retrospective data from 1 January 2015 to 30 November 2021, sourced from the Welsh Demographic Service Dataset (WDSD) to define the study population. To categorise death associated with an opioid overdose, the annual district death extract (ADDE) dataset was used in conjunction with the WDSD to calculate an individual-level study end date. Finally, we considered critical care, ED and hospital admissions as well as substance misuse treatment for the 36 months up to the end of the study period. We carried out a RCT clustered by site in the emergency environment with a qualitative study to examine processes of implementation, patient safety, costs of training NHS staff and experiences of service users and providers. Two intervention sites (paired ED and local AS catchment area) were randomly selected from the four participating sites. Usual practice was continued in the other two sites, acting as controls. Alongside the RCT, we collected qualitative data via semistructured interviews with service users from substance use treatment centres and third-sector organisations. The interview questions were guided by literature around opioid overdose experience and emergency naloxone use, with the aim to explore how opioid users interact with the knowledge, behaviour and attitudes towards the use of THN kits and training to use the kits. Focus groups and interviews with service providers (paramedics and ED clinical staff) were conducted to discuss barriers in the provision of THN in the emergency setting as well as facilitators to this implementation. We assessed the feasibility of collecting costs associated with THN provision in the emergency setting by measuring the health service contacts and incorporating healthcare resource groups (HRGs) into the analysis to produce an overall cost. Setting This feasibility study was carried out in the emergency care environment, across study sites each centred on a receiving ED and defined geographically as the local AS catchment area for that receiving ED. Participants At intervention sites, we invited ED clinicians and paramedics to participate in the trial and recruited adult patients who arrived at the ED or were attended by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the THN and related training. Participants were to be identified for outcome comparison by application of the discriminant function, if completed, to the study site general populations. Interventions Usual care comprised administration of basic life support plus naloxone by paramedics or ED staff. The THN intervention was offered in addition to usual care and included a multi dose THN kit (Prenoxad) containing 2 mg naloxone hydrochloride 1 mg/1 ml solution for intramuscular (IM) injection, and instructions on the correct administration of the naloxone dose. Recipients also received guidance on: BLS; the importance of calling the ES; duration of effect; the safety of naloxone in terms of adverse events and overdose; and the legality of bystander administration of naloxone. Results TABLE S1Assessment against preset progression criteria Criteria Achieved Criteria met Sign-up of four sites, including ≥ 50% eligible staff to complete training in delivering the intervention at each intervention site Site 1: ED trained 81.1%, AS trained 54% of eligible staffSite 2: ED trained 8.1%, AS trained 33.8% of eligible staff No Identification of ≥ 75% of people who have presented to ED or AS with opioid overdose or an opioid use-related problem over a 12-month period Unable to assess Not known THN kits issued to ≥ 50% eligible patients over a 12-month period at intervention sites 21.7% of eligible patients were given kits No Serious adverse event rate (to be defined in agreement with the DMEC) of no more than 10% difference in intervention sites to control sites at the conclusion of recruitment No serious adverse events were reported Yes Identification and inclusion for follow-up of ≥ 75% of people who died of opioid poisoning in the following year in the study areas according to ONS mortality data (previous ONS data suggest between 140 and 180 such deaths across the four participating sites during the study period) We were able to identify decedents from opioid poisoning in Wales but were unable to produce a discriminant function which included this group in a sufficiently small section of the general population, or to test these methods in a second population No Matching and data linkage in ≥ 90% of cases not dissented at the conclusion of quantitative data collection Due to significant delays in permissions processes for routine- linked data retrieval from NHS Digital, and low administration of THN kits, we did not attempt to match and link records for patients recruited to the trial No Retrieval of routinely recorded primary and secondary outcomes from national repositories within six-months of projected timeline Again, due to significant delays in permissions processes for routine- linked data retrieval, and low administration of THN kits, we did not attempt to retrieve routinely recorded primary and secondary outcomes No Discriminant function With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion of them having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. RCT In total, 299 of 687 (43.5%) eligible staff were trained to supply THN kits to eligible patients at the two sites (Site 1: ED n = 107, AS n = 121; Site 2: ED n = 25, AS n = 46). Sixty THN kits were supplied to eligible patients during the recruitment period (Site 1: ED n = 36, AS n = 4; Site 2: ED n = 16, AS n = 4). Eligible patients were recorded as not being offered THN kits 164 times, with reasons reported for not offering eligible patients kits: staff forgot (n = 136); staff too busy (n = 15); and suspected intentional overdose (n = 3). Staff recorded 626 people as being considered for inclusion but found not to be eligible, with reasons listed as: uncooperative including being abusive towards staff (n = 55); lack of capacity (n = 35); reduced consciousness level (n = 41); patient in custody (n = 21); and patient absconded (n = 161). Qualitative interviews Service users had high levels of knowledge about THN, with variable previous access to kits. They generally supported the provision of THN kits and training in the emergency setting and felt that it should be expanded further to chemists and needle exchanges. They also noted the importance of including loved ones in training and felt that this gave them a sense of empowerment and motivation to help others in an overdose situation. They noted concerns with regards to opioid withdrawal and resistance to attending hospital for an overdose. The service users reported that the provision of THN kits and training to friends and family of opioid users would possibly be more beneficial and believed that incorporating THN provision into normal practice would help mitigate some of these barriers. Interviews and focus groups with service providers found that they were supportive about the provision of THN kits and training in the emergency setting. However, they also reported barriers including difficulties consenting and training opioid users, a high turnover of staff impacting the cascade of the intervention as well as negative attitudes towards the patient group and the coronavirus disease 2019 (COVID-19) pandemic. No adverse events were reported. Conclusion This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. There does appear to be appetite for THN kit provision and training in the emergency setting. We conclude that the THN intervention as defined and administered in the Take-home naloxone Intervention Multicentre Emergency setting (TIME) study was not feasible and should not therefore go forward to full trial. However, there may be space for further development of this complex intervention in emergency care – for example, for protocols to allow administration to family and friends of opioid users; as well as methods for definition and identification of study cohorts for outcome comparisons. Trial registration This trial is registered as ISRCTN13232859. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

Abstract Background Understanding and treating the harm caused by gambling is a growing international psychiatric and public health challenge. Treatment of gambling harm may involve psychological and pharmacological intervention, in conjunction with peer support. This scoping review was conducted to identify, for the first time, the characteristics and extent of United Kingdom (UK) based gambling treatment research. We reviewed studies conducted among people seeking treatment for disordered or harmful gambling in the UK, the settings, research designs, and outcome measures used, and to identify any treatment research gaps. Methods Systematic searches of PsycInfo, PsycArticles, Scopus, PubMed, and Web of Science databases were carried out for gambling treatment research or evaluation studies conducted in the UK. Studies were included if they evaluated the effectiveness of an intervention or treatment designed to improve symptoms of harmful or problematic gambling, reported outcomes of interventions on treatment adherence, gambling symptoms, or behaviours using standardised measures, were conducted in the UK, and were published since 2000. Results Eight studies met the inclusion criteria. Four were retrospective chart reviews, two were single-participant case reports, one described a retrospective case series, and one employed a cross-sectional design. None used an experimental design. Conclusion The limited number of studies included in this review highlights a relative paucity of gambling treatment research conducted in UK settings. Further work should seek to identify potential barriers and obstacles to conducting gambling treatment research in the UK.

Background: Patients with spinal cord injuries (SCIs) are at a greater risk for the development of cardiovascular diseases (CVDs) than able-bodied individuals due to the high risk of endothelial dysfunction. Summary: For instance, patients with SCIs lose autonomic control of the heart and vasculature, which results in severe fluctuations in blood pressure. These oscillations between hypotension and hypertension have been shown to damage blood vessel endothelial cells and may contribute to the development of atherosclerosis. Furthermore, the loss of skeletal muscle control results in skeletal muscle atrophy and inward remodeling of the conduit arteries. It has been shown that blood vessels in the legs are chronically exposed to high shear, while the aorta experiences chronically low shear. These alterations to shear forces may adversely impact endothelial vasodilatory capacity and promote inflammatory signaling and leukocyte adherence. Additionally, microvascular endothelial vasodilatory capacity is impaired in patients with an SCI, and this may precede changes in conduit artery endothelial function. Finally, due to immobility and a loss of skeletal muscle mass, patients with SCIs have a higher risk of metabolic disorders, inflammation, and oxidative stress. Key Messages: Collectively, these factors may impair endothelium-dependent vasodilatory capacity, promote leukocyte adhesion and infiltration, promote the peroxidation of lipids, and ultimately support the development of atherosclerosis. Therefore, future interventions to prevent CVDs in patients with SCIs should focus on the management of endothelial health to prevent endothelial dysfunction and atherosclerosis.

Abstract A method for methane emissions monitoring at industrial facility level was developed based on a high precision multi-open-path laser dispersion spectrometer combined with Bayesian analysis algorithms using Monte Carlo Markov Chain (MCMC) inference. From the methane path-averaged concentrations spatially distributed over the facility under study, together with the wind vector, the analysis allows detection, localization and quantification of fugitive methane emissions. This paper describes the very first long term (3 months), continuous (24 h/7 days) deployment of this monitoring system at an operational gas processing and distribution facility. The continuous monitoring system, made of the combination of the open-path high-precision (

Background: Whilst qualitative research has previously been conducted on older people’s personal resilience and wellbeing during COVID-19, there are fewer empirical studies on the impact it had on social connectedness for this age group. In this paper we seek to examine older people’s social connectedness to others during the pandemic, their personal experiences of seeking out those connections, and whether there are any identifiable pre-existing factors that enabled them to minimise the impact of enforced isolation. Methods: Using a phenomenological methodology, we conducted in-depth interviews with 13 older people between March and May 2021. These interviews explored the participant’s lived experiences of staying socially connected to others during the enforced lockdowns and various restrictions. Results: Our findings reveal strong themes of personal resilience, sense of coherence and other protective factors, but also highlight the benefits of establishing connections to friends, family, organised groups and community prior to the pandemic. Conclusion: Older people’s ability to stay socially connected is influenced by personal resilience and a positive mindset; pre-existing social ties to others and maintaining a personal sense of coherence and a sense of belonging to people or places. Our findings shed light on the importance of informal social interactions, what it means to feel lonely in older age and indicate that for some the pandemic restrictions may even have offered a welcome space in which to process significant life events.

Abstract Background Tobacco smoking during pregnancy is the most important preventable risk factor for pregnancy complications and adverse birth outcomes and can have lifelong consequences for infants. Smoking during pregnancy is associated with higher healthcare costs related to birth complications and during childhood. Psychosocial interventions to support pregnant women to quit are effective, yet provision of smoking cessation support has been inconsistent. The Midwives and Obstetricians Helping Mothers to Quit Smoking (MOHMQuit) intervention provides systems change, and leadership and clinician elements, to support clinicians to help women stop smoking in pregnancy. There have been few long-term analyses conducted of the cost-effectiveness of smoking cessation interventions for pregnant women that target healthcare providers. This protocol describes the economic evaluation of the MOHMQuit trial, a pragmatic stepped-wedge cluster-randomised controlled implementation trial in nine public maternity services in New South Wales (NSW), Australia, to ascertain whether MOHMQuit is cost-effective in supporting clinicians to help women quit smoking in pregnancy compared to usual care. Methods Two primary analyses will be carried out comparing MOHMQuit with usual care from an Australian health care system perspective: i) a within-trial cost-effectiveness analysis with results presented as the incremental cost per additional quitter; and ii) a lifetime cost-utility analysis using a published probabilistic decision analytic Markov model with results presented as incremental cost per quality-adjusted life-year (QALY) gained for mother and child. Patient-level data on resource use and outcomes will be used in the within-trial analysis and extrapolated and supplemented with national population statistics and published data from the literature for the lifetime analysis. Discussion There is increasing demand for information on the cost-effectiveness of implementing healthcare interventions to provide policy makers with critical information for the best value for money within finite budgets. Economic evaluation of the MOHMQuit trial will provide essential, policy-relevant information for decision makers on the value of evidence-based implementation of support for healthcare providers delivering services for pregnant women. Trial registrations ACTRN12622000167763, registered 2 February 2022.

Background: Stent implantation has become the preferred method of treatment for treating vessel stenosis in congenital heart diseases. The availability of covered stents may decrease complications and have an important role in the management of patients with complex anatomy. Aim: This study aims to evaluate the feasibility and safety of the pre-mounted cobalt–chromium stent-graft-covered ePTFE Aortic BeGraft in a broad spectrum of vascular lesions. Methods: This is a multicenter retrospective results analysis of 107 implanted BeGraft stents between 2016 and 2022 in six different European centers. Results: One hundred and four patients with a mean age of thirteen years (range 1–70 years) and with the body weight of 56.5 kg (range 11–115 kg) underwent the BeGraft stent implantation. Stents were implanted in the following conditions: aortic coarctation (74 patients), RVOT dysfunction (12 patients), Fontan circulation (7 patients), and miscellaneous (11 subjects with complex CHD). All the stents were implanted successfully. The median stent diameter was 16 mm (range 7–24 mm), and the median length was 39 mm (range 19–49 mm). Major complications occurred in five subjects (4.7%). During a median follow-up of fourteen (1–70) months, stents’ re-dilatation was performed in five patients. Conclusions: The BeGraft stent can be used safely and effectively in a wide spectrum of congenital heart diseases. Whether these good results will be stable in the longer term still needs to be investigated in a follow-up given its recent introduction into clinical practice, in particular regarding stent fracture or neointimal proliferation.

BackgroundThe Occlutech Atrial Flow Regulator (AFR) is a self-expandable double-disc nitinol device with a central fenestration. Its use has been approved in the adult population with heart failure and described for pulmonary hypertension (PH). Only case reports and small series have been published about its use in the paediatric population and for congenital heart disease (CHD).ObjectivesThe authors sought to investigate the feasibility, safety, and short-term follow-up of AFR implantation in patients with CHD or children with PH or cardiomyopathy.MethodsThis is a multicenter retrospective study involving 10 centers worldwide. Patients of any age with CHD or patients aged

Introduction: Prevention of tuberculosis disease through diagnosis and treatment of latent tuberculosis infection is critical for achieving tuberculosis elimination in the U.S. Diagnosis and treatment of latent tuberculosis infection in safety-net primary care settings that serve patients at risk for tuberculosis may increase uptake of this prevention effort and accelerate progress toward elimination. Optimizing tuberculosis prevention in these settings requires measuring the latent tuberculosis infection care cascade (testing, diagnosis, and treatment) and identifying gaps to develop solutions to overcome barriers. We used electronic health record data to describe the latent tuberculosis infection care cascade and identify gaps among a network of safety-net primary care clinics. Methods: Electronic health record data for patients seen in the OCHIN Clinical Network, the largest network of safety-net clinics in the U.S., between 2012 and 2019 were extracted. electronic health record data were used to measure the latent tuberculosis infection care cascade: patients who met tuberculosis screening criteria on the basis of current recommendations were tested for tuberculosis infection, diagnosed with latent tuberculosis infection, and prescribed treatment for latent tuberculosis infection. Outcomes were stratified by diagnostic test and treatment regimen. Results: Among 1.9 million patients in the analytic cohort, 43.5% met tuberculosis screening criteria, but only 21.4% were tested for latent tuberculosis infection; less than half (40.4%) were tested using an interferon-gamma release assay. Among those with a valid result, 10.5% were diagnosed with latent tuberculosis infection, 29.1% of those were prescribed latent tuberculosis infection treatment, and only 33.6% were prescribed a recommended rifamycin-based regimen. Conclusions: Electronic health record data can be used to measure the latent tuberculosis infection care cascade. A large proportion of patients in this safety-net clinical network are at high risk for tuberculosis infection. Addressing identified gaps in latent tuberculosis infection testing and treatment may have a direct impact on improving tuberculosis prevention in primary care clinics and accelerate progress toward elimination.

Abstract Investigative interviews (e.g., interrogations) are a critical component of criminal, military, and civil investigations. However, how levels of alertness (vs. sleepiness) of the interviewer impact outcomes of actual interviews is unknown. To this end, the current study tracked daily fluctuations in alertness among professional criminal investigators to predict their daily experiences with actual field interviews. Fifty law-enforcement investigators wore a sleep-activity tracker for two weeks while keeping a daily-diary of investigative interviews conducted in the field. For each interview, the investigators indicated how well they established rapport with the subject, how much resistance they encountered, how well they maintained their own focus and composure, and the overall utility of intelligence obtained. Daily alertness was biomathematically modeled from actigraphic sleep duration and continuity estimates and used to predict interview characteristics. Investigators consistently reported more difficulties maintaining their focus and composure as well as encountering more subject resistance during interviews on days with lower alertness. Better interview outcomes were also reported on days with subjectively better sleep, while findings were generally robust to inclusion of covariates. The findings implicate adequate sleep as a modifiable fitness factor for collectors of human intelligence.

Objectives. To identify the factors contributing to coronavirus disease 2019 (COVID-19) vaccine hesitancy in Grenada. Methods. A phenomenological study was conducted using semi-structured interviews at vaccination and pop-up testing clinics during a spike in COVID-19 cases on the island. Interview questions were developed using the health belief model related to perceived threat of COVID-19, perceived benefits of and barriers to COVID-19 vaccination, and cues to action. Data were analyzed using a deductive approach to identify themes, categories, and subcategories. Results. Twenty-five interviews were transcribed and coded. In all, 68% of participants were unvaccinated, 12% were partially vaccinated, and 20% were fully vaccinated. Data analysis revealed two main themes: facilitators and barriers. Factors more likely to encourage vaccination (facilitators) included trust in medical advice and vaccine efficacy, social responsibility, and vaccine mandates for travel, employment, and social activities. Factors hindering vaccination (barriers) included: perceived low threat of COVID-19; preference for natural remedies; concerns about contraindications because of underlying health conditions; fear; mistrust of vaccines and related messaging; vaccine accessibility; and the many different information sources. Conclusions. Overcoming vaccine hesitancy is key to combating the detrimental effects of COVID-19 in Grenada. Public health interventions and policies that address barriers and capitalize on facilitators can increase vaccine uptake.

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. In the present study, we first investigated the validity of a liver xenograft mouse model repopulated with primary hepatocytes using single-nucleus RNA sequencing (sn-RNA-seq) by studying the transcriptomic profile of human hepatocytes pre- and post-engraftment. Complementary immunofluorescence analyses performed in highly engrafted animals confirmed that the human hepatocytes organize and present appropriate patterns of zone-dependent enzyme expression in this model. Next, we tested a set of rationally designed HSPG de-targeted AAV-LK03 variants for relative transduction performance in human hepatocytes. We used immunofluorescence, next-generation sequencing, and single-nucleus transcriptomics data from highly engrafted FRG mice to demonstrate that the optimally HSPG de-targeted AAV-LK03 displayed a significantly improved lobular transduction profile in this model.

Abstract Objectives Some pregnant women are not ready or do not want to quit smoking completely, and currently there is no support provided for these women in the UK. Offering help to reduce smoking could reduce the health risks associated with smoking and increase the limited reach of the NHS Stop Smoking Services (SSS) for pregnant women. This study aimed to design and evaluate a hypothetical intervention aimed at pregnant women who are not yet ready or do not want to quit smoking entirely. Methods A hypothetical intervention, the Reduced Smoking During Pregnancy (RSDP) intervention, was conceptualised based on the best available evidence. The intervention was evaluated, using a decision-analytic model developed for SDP interventions. Two different scenarios, a base-case and a cautious-case were developed, and a cost-utility analysis and return on investment analysis were conducted. The uncertainty around the estimates was assessed, using deterministic and probabilistic sensitivity analyses. Results The RSDP intervention could prevent the loss of 13 foetuses and generate 43 quitters 1 year after delivery per 1000 women. In the lifetime analysis, the intervention was cost-effective in both scenarios, with an incremental cost of £363 (95% CI £29 to £672) and 0.44 (95% CI 0.32 to 0.53) QALYs gained in the base-case. Conclusions The study found that the hypothetical reduction intervention would produce significant health benefits, reduce smoking and be cost-effective. Offering pregnant smokers help to reduce smoking could reduce health inequalities, widen the reach of SSS and improve health. This economic evaluation of a novel, intensive intervention could inform the piloting of such interventions.

The distribution and transmission of Yersinia pestis, the bacterial agent of plague, responds dynamically to climate, both within wildlife reservoirs and human populations. The exact mechanisms mediating plague's response to climate are still poorly understood, particularly across large environmentally heterogeneous regions encompassing several reservoir species. A heterogeneous response to precipitation was observed in plague intensity across northern and southern China during the Third Pandemic. This has been attributed to the response of reservoir species in each region. We use environmental niche modelling and hindcasting methods to test the response of a broad range of reservoir species to precipitation. We find little support for the hypothesis that the response of reservoir species to precipitation mediated the impact of precipitation on plague intensity. We instead observed that precipitation variables were of limited importance in defining species niches and rarely showed the expected response to precipitation across northern and southern China. These findings do not suggest that precipitation–reservoir species dynamics never influence plague intensity but that instead, the response of reservoir species to precipitation across a single biome cannot be assumed and that limited numbers of reservoir species may have a disproportional impact upon plague intensity.

Consumption of contaminated produce remains a leading cause of foodborne illness. Increasingly, growers are altering agricultural practices and farm environments to manage food-safety hazards, but these changes often result in substantial economic, social, and environmental costs. Here, we present a comprehensive evidence synthesis evaluating the efficacy of soil, non-crop vegetation, animal, landscape, and irrigation water management strategies aimed at reducing produce-safety risk in North America. We systematically summarized findings from 78 peer-reviewed papers on the effect of 21 management practices on the prevalence, abundance, or survival of four foodborne pathogens (i.e., E. coli, Salmonella spp., Listeria spp., and Campylobacter spp.), resulting in 113 summaries. We then organized a 30-member expert panel, who used these summaries to evaluate the impact of each practice on food-safety outcomes. While more than half of the practices were too understudied to confidently evaluate their impact on food safety, the panel did identify several practices that were associated with reduced preharvest food-safety risks, including not using raw manure, separating crop and livestock production, and choosing low-risk irrigation sources. The panel also identified practices that appear ineffective at reducing food-safety risks, such as the removal of non-crop vegetation. Overall, these findings provide insights into the food-safety impacts of agricultural and land management practices that growers, auditors, and extension personnel can use to co-manage produce preharvest environments for food safety and other aims.

Strength-based technology clubs are thought to help autistic adolescents transition to adulthood by developing positive traits, enhancing technical skills, and creating supportive networks. A newly developed strength-based technology club was delivered to 25 autistic adolescents, with the feasibility tested via qualitative and quantitative methods. Autistic adolescents, their parents, and club facilitators participated in separate focus groups, with audio data transcribed and thematically analyzed. Quantitative data was collected via adolescent and parent-reported pretest-posttest measures following the 15-week program. Autistic adolescents were highly satisfied with the club (acceptability), the technology club satisfied an unmet need (demand), with the program demonstrating the potential to be integrated into the current therapy system in Australia (integration). Feasibility areas that could be improved in delivering future clubs are discussed.

Abstract A pathogen inactivation step during collection or processing of clinical samples has the potential to reduce infectious risks associated with diagnostic procedures. It is essential that these inactivation methods are demonstrated to be effective, particularly for non-traditional inactivation reagents or for commercial products where the chemical composition is undisclosed. This study assessed inactivation effectiveness of twenty-four next-generation (guanidine-free) nucleic acid extraction lysis buffers and twelve rapid antigen test buffers against SARS-CoV-2, the causative agent of COVID-19. These data have significant safety implications for SARS-CoV-2 diagnostic testing and support the design and evidence-based risk assessment of these procedures.

Building upon Wayne Modest’s work on the representation of Caribbean and enslaved people in the British Museum, this article examines the representation of Caribbean plantations in several British establishments, the Museum of London Docklands, the National Maritime Museum, the Mshed Museum, the Georgian House, and the International Slavery Museum. Drawing on Black feminist works on race, geography and identity, I argue that these museums create a homogenised vision of the Caribbean, which results in a homogenised depiction of enslaved peoples. Specifically, resistance to slavery is presented as a largely masculine endeavour and taking place only in terms of military conflict. Indeed, representations of enslaved women are largely absent in many of these museums. Only the International Slavery Museum achieves a complex rendering of the Caribbean by pushing against the limitations of abolitionist produced representations of the Caribbean and incorporating models and a multifaceted range of testimonies, including that of enslaved women.

Objective: The objective of the study was to assess the efficacy of the LapiCotton procedure on patients with hallux valgus (HV) combined with medial longitudinal arch collapse. Methods: Preoperative and postoperative weight-bearing computed tomography (WBCT) scans were obtained from patients with HV submitted to the LapiCotton procedure. Semi-automatic measurements were applied to 22 WBCT images across 11 patients enrolled in the study using a software package (Bonelogic, Disior™, Helsinki, Finland). Significance level was set at 0.05. Results: The hallux valgus angle (HVA) was significantly larger (p=0.026) in the preoperative group (Mdn = 27.52) than in the postoperative group (Mdn = 20). In addition, the Meary sagittal measurement was found to be significantly increased (p=0.033) in the preoperative group (Mdn = -14.28) when compared to the postoperative group (Mdn = -11.15). It was also observed that the intermetatarsal angle was significantly larger (p=0.003) in the preoperative group (Mdn = 15.68) compared to the postoperative group (Mdn = 11.26). Conclusion: The LapiCotton procedure effectively corrected radiographic parameters in patients with HV combined with the medial longitudinal arch collapse. Level of Evidence III; Therapeutic Studies; Comparative Retrospective Study.

Objective: This cadaveric pilot study was to develop a weight bearing computed tomography (WBCT) three-dimensional (3D) distance mapping algorithm that would allow for detection of syndesmotic instability. Methods: Pilot study, two cadaveric specimens. Syndesmotic instability was induced by release of all syndesmotic ligaments through a conventional lateral ankle approach. WBCT imaging under simulated weight bearing was acquired before and after syndesmotic destabilization. Syndesmotic incisura and ankle gutter distances were assessed using a 3D distance mapping WBCT algorithm. Results: We found increases in the overall mean syndesmotic distances in the injured syndesmosis when compared to pre-injury state, and color coded distance maps allowed easy interpretation of the syndesmotic widening following ligament sectioning and destabilization of the syndesmotic joint. Conclusion: The WBCT 3D distance mapping algorithm has the potential to allow detection of mild syndesmotic instability with a relatively ease of interpretation by using color-coded distance maps. Level of Evidence V; Cadaveric Study.

Research must be well designed, properly conducted and clearly and transparently reported. Our independent medical research institute wanted a simple, generic tool to assess the quality of the research conducted by its researchers, with the goal of identifying areas that could be improved through targeted educational activities. Unfortunately, none was available, thus we devised our own. Here, we report development of the Quality Output Checklist and Content Assessment (QuOCCA), and its application to publications from our institute’s scientists. Following consensus meetings and external review by statistical and methodological experts, 11 items were selected for the final version of the QuOCCA: research transparency (items 1–3), research design and analysis (items 4–6) and research reporting practices (items 7–11). Five pairs of raters assessed all 231 articles published in 2017 and 221 in 2018 by researchers at our institute. Overall, the results were similar between years and revealed limited engagement with several recommended practices highlighted in the QuOCCA. These results will be useful to guide educational initiatives and their effectiveness. The QuOCCA is brief and focuses on broadly applicable and relevant concepts to open, high-quality, reproducible and well-reported science. Thus, the QuOCCA could be used by other biomedical institutions and individual researchers to evaluate research publications, assess changes in research practice over time and guide the discussion about high-quality, open science. Given its generic nature, the QuOCCA may also be useful in other research disciplines.

Diabetic peripheral neuropathy (DPN) is a medical condition that is progressively becoming more prevalent. The underlying cause of DPN is still unknown, although there have been several hypothesized mechanisms. There are current pharmaceutical treatments used to manage the pain, but their efficacy is largely unsatisfactory and are often associated with serious adverse effects. This review will explore the evidence of a new potential target for treating DPN, the ligands for nicotinic acetylcholine receptors (nAChRs), specifically α4ꞵ2 agonists and α9α10 antagonists.

Background: Serology assays have the potential to support RT-PCR in the diagnosis of SARS-CoV-2 infection. We studied three commercially available immunoassays for their diagnostic accuracy from blood specimens collected from 93 patients. Methods: Blood samples from patients with confirmed COVID-19 infection were analysed using three different Immunoassays (Roche total antibody assay, Abbott IgG assay and Euroimmun IgG assay). Sensitivity, specificity, precision and time of seroconversion were evaluated. Results: The sensitivity of Roche, Abbott and Euroimmun assays was 38.7%, 35.5% and 25.0% respectively for specimens collected

Abstract Background Fever is a common symptom in children presenting to the Emergency Department (ED). We aimed to describe the epidemiology of systemic viral infections and their predictive values for excluding serious bacterial infections (SBIs), including bacteremia, meningitis and urinary tract infections (UTIs) in children presenting to the ED with suspected systemic infections. Methods We enrolled children who presented to the ED with suspected systemic infections who had blood cultures obtained at seven healthcare facilities. Whole blood specimens were analyzed by an experimental multiplexed PCR test for 7 viruses. Demographic and laboratory results were abstracted. Results Of the 1114 subjects enrolled, 245 viruses were detected in 224 (20.1%) subjects. Bacteremia, meningitis and UTI frequency in viral bloodstream-positive patients was 1.3, 0 and 10.1% compared to 2.9, 1.3 and 9.7% in viral bloodstream-negative patients respectively. Although viral bloodstream detections had a high negative predictive value for bacteremia or meningitis (NPV = 98.7%), the frequency of UTIs among these subjects remained appreciable (9/89, 10.1%) (NPV = 89.9%). Screening urinalyses were positive for leukocyte esterase in 8/9 (88.9%) of these subjects, improving the ability to distinguish UTI. Conclusions Viral bloodstream detections were common in children presenting to the ED with suspected systemic infections. Although overall frequencies of SBIs among subjects with and without viral bloodstream detections did not differ significantly, combining whole blood viral testing with urinalysis provided high NPV for excluding SBI.

Abstract Despite its epidemiological importance, the time Plasmodium parasites take to achieve development in the vector mosquito (the extrinsic incubation period, EIP) remains poorly characterized. A novel non-destructive assay designed to estimate EIP in single mosquitoes, and more broadly to study Plasmodium–Anopheles vectors interactions, is presented. The assay uses small pieces of cotton wool soaked in sugar solution to collect malaria sporozoites from individual mosquitoes during sugar feeding to monitor infection status over time. This technique has been tested across four natural malaria mosquito species of Africa and Asia, infected with Plasmodium falciparum (six field isolates from gametocyte-infected patients in Burkina Faso and the NF54 strain) and across a range of temperatures relevant to malaria transmission in field conditions. Monitoring individual infectious mosquitoes was feasible. The estimated median EIP of P. falciparum at 27 °C was 11 to 14 days depending on mosquito species and parasite isolate. Long-term individual tracking revealed that sporozoites transfer onto cotton wool can occur at least until day 40 post-infection. Short individual EIP were associated with short mosquito lifespan. Correlations between mosquito/parasite traits often reveal trade-offs and constraints and have important implications for understanding the evolution of parasite transmission strategies.

Rock climbing has evolved from a method for alpine mountaineering into a popular recreational activity and competitive sport. Advances in safety equipment and the rapid growth of indoor climbing facilities has enabled climbers to focus on the physical and technical movements needed to elevate performance. Through improved training methods, climbers can now achieve ascents of extreme difficulty. A critical aspect to further improve performance is the ability to continuously measure body movement and physiologic responses while ascending the climbing wall. However, traditional measurement devices (e.g., dynamometer) limit data collection during climbing. Advances in wearable and non-invasive sensor technologies have enabled new applications for climbing. This paper presents an overview and critical analysis of the scientific literature on sensors used during climbing. We focus on the several highlighted sensors with the ability to provide continuous measurements during climbing. These selected sensors consist of five main types (body movement, respiration, heart activity, eye gazing, skeletal muscle characterization) that demonstrate their capabilities and potential climbing applications. This review will facilitate the selection of these types of sensors in support of climbing training and strategies.

Objective To determine the feasibility of designing and conducting a definitive trial to evaluate the effectiveness of sacral fracture fixation compared with non-surgical management among older people admitted with a lateral compression pelvic fragility fracture (PFF).Design Single-site, parallel, two-arm randomised controlled feasibility trial.Setting A UK tertiary centre hospital.Participants Patients aged ≥70 years who were ambulating pre-injury requiring hospital admission (within 28 days of injury) with a type 1 lateral compression PFF.Interventions The intervention group received sacral fracture fixation (cement augmentation±screw fixation) within 7 days of randomisation. Routine preoperative and postoperative care followed each surgical intervention. The control group received usual care consisting of analgesia, and regular input from the medical and therapy team.Primary and secondary outcome measures The feasibility outcomes were the number of eligible patients, willingness to be randomised, adherence to allocated treatment, retention, data on the completeness and variability of the proposed definitive trial outcome measures, and reported adverse events.Results 241 patients were screened. 13 (5.4%) were deemed eligible to participate. Among the eligible participants, nine (69.2%) were willing to participate. Five participants were randomised to the intervention group and four to the control group. The clinicians involved were willing to allow their patients to be randomised and adhere to the allocated treatment. One participant in the intervention group and two participants in the control group received their allocated treatment. All participants were followed up until 12 weeks post-randomisation, and had an additional safety follow-up assessment at 12 months. Overall, the proportion of completeness of outcome measures was at least 75%. No adverse events were directly related to the trial.Conclusions There were significant challenges in recruiting sufficient participants which will need to be addressed prior to a definitive trial.Trial registration number ISRCTN16719542.

Objective: To assess the agreement between semiautomatic 3D measurements and manual measurements derived from WBCT images in patients with end-stage ankle osteoarthritis (AO) who underwent total ankle replacement (TAR). Methods: In this retrospective, IRB-approved study (ID #201904825), we evaluated patients who underwent TAR via the lateral trans-fibular approach for end-stage ankle OA. The study included 14 ankles from 14 patients. Raw multiplanar data were analyzed using CubeVue® software. Lateral talar station (LTS) was obtained in the sagittal plane, while hindfoot moment arm (HMA) and talar tilt angle (TTA) were calculated in the coronal view. Semiautomatic 3D measurements were performed using Disior® software. Intra-rater reliabilities were analyzed using the intraclass correlation coefficient (ICC). Agreement between methods was tested with Bland-Altman plots. Each measurement was assessed using the Wilcoxon signed-rank test. Alpha risk was set to 5% (α=0.05). P-values of ≤0.05 were considered significant. Results: ICC-measured reliabilities ranged from moderate to almost perfect for manual and semiautomatic WBCT measurements in the preoperative and postoperative groups for HMA and LTS. There was high correlation between parameters calculated from manual and semiautomatic measurements, and strong agreement between the readers and software in both groups. Conclusions: Manual (M) and semiautomatic (SA) 3D measurements expressed excellent agreement for pre- and postoperative groups, indicating a high correlation between the parameters calculated and strong agreement between the readers and the software in both groups. Level of Evidence III; Therapeutic Studies; Comparative Retrospective Study.

Abstract Background Opioids, such as heroin, kill more people worldwide by overdose than any other type of drug, and death rates associated with opioid poisoning in the UK are at record levels (World Drug Report 2018 [Internet]. [cited 2019 Nov 19]. Available from: http://www.unodc.org/wdr2018/ ; Deaths related to drug poisoning in England and Wales - Office for National Statistics [Internet]. [cited 2019 Nov 19]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2018registrations ). Naloxone is an opioid antagonist which can be distributed in ‘kits’ for administration by witnesses in an overdose emergency. This intervention is known as take-home naloxone (THN). We know that THN can save lives on an individual level, but there is currently limited evidence about the effectiveness of THN distribution on an aggregate level, in specialist drug service settings or in emergency service settings. Notably, we do not know whether THN kits reduce deaths from opioid overdose in at-risk populations, if there are unforeseen harms associated with THN distribution or if THN is cost-effective. In order to address this research gap, we aim to determine the feasibility of a fully powered cluster randomised controlled trial (RCT) of THN distribution in emergency settings. Methods We will carry out a feasibility study for a RCT of THN distributed in emergency settings at four sites, clustered by Emergency Department (ED) and catchment area within its associated ambulance service. THN is a peer-administered intervention. At two intervention sites, emergency ambulance paramedics and ED clinical staff will distribute THN to adult patients who are at risk of opioid overdose. At two control sites, practice will carry on as usual. We will develop a method of identifying a population to include in an evaluation, comprising people at risk of fatal opioid overdose, who may potentially receive naloxone included in a THN kit. We will gather anonymised outcomes up to 1 year following a 12-month ‘live’ trial period for patients at risk of death from opioid poisoning. We expect approximately 100 patients at risk of opioid overdose to be in contact with each service during the 1-year recruitment period. Our outcomes will include deaths, emergency admissions, intensive care admissions, and ED attendances. We will collect numbers of eligible patients attended by participating in emergency ambulance paramedics and attending ED, THN kits issued, and NHS resource usage. We will determine whether to progress to a fully powered trial based on pre-specified progression criteria: sign-up of sites (n = 4), staff trained (≥ 50%), eligible participants identified (≥ 50%), THN provided to eligible participants (≥ 50%), people at risk of death from opioid overdose identified for inclusion in follow-up (≥ 75% of overdose deaths), outcomes retrieved for high-risk individuals (≥ 75%), and adverse event rate (< 10% difference between study arms). Discussion This feasibility study is the first randomised, methodologically robust investigation of THN distribution in emergency settings. The study addresses an evidence gap related to the effectiveness of THN distribution in emergency settings. As this study is being carried out in emergency settings, obtaining informed consent on behalf of participants is not feasible. We therefore employ novel methods for identifying participants and capturing follow-up data, with effectiveness dependent on the quality of the available routine data. Trial registration ISRCTN13232859 (Registered 16/02/2018)

Abstract Background Single-cell RNA sequencing has been widely adopted to estimate the cellular composition of heterogeneous tissues and obtain transcriptional profiles of individual cells. Multiple approaches for optimal sample dissociation and storage of single cells have been proposed as have single-nuclei profiling methods. What has been lacking is a systematic comparison of their relative biases and benefits. Results Here, we compare gene expression and cellular composition of single-cell suspensions prepared from adult mouse kidney using two tissue dissociation protocols. For each sample, we also compare fresh cells to cryopreserved and methanol-fixed cells. Lastly, we compare this single-cell data to that generated using three single-nucleus RNA sequencing workflows. Our data confirms prior reports that digestion on ice avoids the stress response observed with 37 °C dissociation. It also reveals cell types more abundant either in the cold or warm dissociations that may represent populations that require gentler or harsher conditions to be released intact. For cell storage, cryopreservation of dissociated cells results in a major loss of epithelial cell types; in contrast, methanol fixation maintains the cellular composition but suffers from ambient RNA leakage. Finally, cell type composition differences are observed between single-cell and single-nucleus RNA sequencing libraries. In particular, we note an underrepresentation of T, B, and NK lymphocytes in the single-nucleus libraries. Conclusions Systematic comparison of recovered cell types and their transcriptional profiles across the workflows has highlighted protocol-specific biases and thus enables researchers starting single-cell experiments to make an informed choice.

Abstract Background Physical inactivity contributes to disability and falls in older adults. Falls prevention exercise (FaME) programmes improve physical activity and physical function and reduce falling rates. Improvements in physical function are reduced, and falls rates increase, if physical activity is not maintained. This research investigated the feasibility and acceptability of an intervention that aimed to maintain physical activity in older adults exiting FaME. Methods The Keeping Adults Physically Active (KAPA) intervention comprised of six group sessions of motivational interviewing, delivered monthly by trained and mentor-supported postural stability instructor’s after the FaME programme ceased. The KAPA intervention included participant manuals, illustrated exercise books, physical activity diaries and pedometers. A feasibility study was conducted in 8 FaME classes. The study design was a two-arm, cluster randomised, multi-site feasibility study comparing the KAPA intervention with usual care. A sample of 50 community-dwelling adults aged 65 years old or older were recruited. Recruitment, retention and attendance rates, self-reported physical activity and participant interviews were used to examine the feasibility and acceptability of the KAPA intervention. Results Fifty of the sixty-seven (74.6%) participants invited into the study agreed to take part, 94.2% of the available KAPA sessions were attended and 92.3% of the recruited participants provided outcome data. The KAPA participants expressed positive views about the venues and postural stability instructors and reported enjoying the group interactions. Intervention participants discussed increasing their physical activity in response to the peer-support, illustrated home exercise booklet, physical activity diaries and pedometers. Most discussed the written tasks to be the least enjoyable element of the KAPA intervention. The proportion of participants reporting at least 150 minutes of moderate to vigorous physical activity per week rose from 56.3 to 62.5% in the intervention arm and from 41.4 to 52.0% in the usual care arm. Conclusions The participants found the KAPA intervention acceptable. Participants reported the exercise booklet, peer support and the physical activity monitoring tools encouraged them to keep active. A full-scale trial is needed to assess whether physical activity can be significantly maintained in response to the KAPA intervention. Trial registration Retrospectively registered on ClinicalTrials.gov ( NCT03824015 ).

Methane is a powerful greenhouse gas, and a primary target for mitigating climate change in the short-term future due to its relatively short atmospheric lifetime and greater ability to trap heat in Earth’s atmosphere compared to carbon dioxide. Top-down observations of atmospheric methane are possible via drone and aircraft surveys as well as satellites such as the TROPOspheric Monitoring Instrument (TROPOMI). Recent work has begun to apply the divergence method to produce regional methane emission rate estimates. Here we show that when the divergence method is applied to spatially incomplete observations of methane, it can result in negatively biased time-averaged regional emission rates. We show that this effect can be counteracted by adopting a procedure in which daily advective fluxes of methane are time-averaged before the divergence method is applied. Using such a procedure with TROPOMI methane observations, we calculate yearly Permian emission rates of 3.1, 2.4 and 2.7 million tones per year for the years 2019 through 2021. We also show that highly-resolved plumes of methane can have negatively biased estimated emission rates by the divergence method due to the presence of turbulent diffusion in the plume, but this is unlikely to affect regional methane emission budgets constructed from TROPOMI observations of methane. The results from this work are expected to provide useful guidance for future implementations of the divergence method for emission rate estimation from satellite data—be it for methane or other gaseous species in the atmosphere.

Endoparasites of dogs and cats, play an important role in both veterinary medicine and public health. Untreated and stray dogs and cats, in particular, play an important role in contaminating the environment with important zoonotic parasites. Thus, the aim of this study was to estimate the prevalence of intestinal parasites in stray dogs and cats using highly sensitive and specific copro-antigen tests. Archive faecal samples from previous surveys conducted between 2016–2019 from dogs (n = 789) and cats (n = 241) were included in this study. The IDEXX Fecal Dx™ antigen panel was used for the detection of Toxocara, hookworms, Trichuris and the SNAP™ Giardia antigen assay was used for the detection of Giardia infection. Giardia duodenalis was the most common parasite (26%, n = 205) detected in the dogs, followed by ascarids (17.6%, n = 139) and hookworms (5.3%, n = 42). Trichuris vulpis was only detected in 1 dog. Ascarids (23.2%, n = 56) was the most common parasite detected in the cats, followed by Giardia (12.9%, n = 31) and hookworms (n = 7, 2.9%). No whipworms were detected in cats. Overall, there was little difference in the positivity between sexes in both dogs and cats. However, in terms of age, adolescent dogs (G. duodenalis and ascarids being the most prevalent. This study shows a high prevalence of parasite infection in untreated and stray dogs and cats in the greater Dublin area in Ireland. Since they live in synanthropic conditions and can roam over vast distances they can contaminate public areas and pose a risk to both humans and owned pets that utilise these spaces. It is therefore important to raise public awareness and increase the knowledge on zoonotic parasites.

BackgroundAntimicrobial resistance (AMR) is a globally important one health threat. The impact of resistant infections on companion animals, and the potential public health implications of such infections, has not been widely explored, largely due to an absence of structured population-level data.ObjectivesWe aimed to efficiently capture and repurpose antimicrobial susceptibility test (AST) results data from several veterinary diagnostic laboratories (VDLs) across the United Kingdom to facilitate national companion animal clinical AMR surveillance. We also sought to harness and genotypically characterize isolates of potential AMR importance from these laboratories.MethodsWe summarized AST results for 29,330 canine and 8,279 feline Enterobacteriaceae isolates originating from companion animal clinical practice, performed between April 2016 and July 2018 from four VDLs, with submissions from 2,237 United Kingdom veterinary practice sites.ResultsEscherichia coli (E. coli) was the most commonly isolated Enterobacteriaceae in dogs (69.4% of AST results, 95% confidence interval, CI, 68.7–70.0) and cats (90.5%, CI 89.8–91.3). Multi-drug resistance was reported in 14.1% (CI 13.5–14.8) of canine and 12.0% (CI 11.1–12.9) of feline E. coli isolates. Referral practices were associated with increased E. coli 3rd generation ≤ cephalosporin resistance odds (dogs: odds ratio 2.0, CI 1.2–3.4). We selected 95 E. coli isolates for whole genome analyses, of which seven belonged to sequence type 131, also carrying the plasmid-associated extended spectrum β-lactamase gene blaCTX–M–15. The plasmid-mediated colistin resistance gene mcr-9 was also identified for the first time in companion animals.ConclusionsLinking clinical AMR data with genotypic characterization represents an efficient means of identifying important resistance trends in companion animals on a national scale.

Summary: We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

Abstract Objective This two-site randomised trial compared the effectiveness of a voluntary sector-led, community-based diabetes prevention programme to a waiting-list control group at 6 months, and included an observational follow-up of the intervention arm to 12 months. Methods Adults aged 18–75 years at increased risk of developing type 2 diabetes due to elevated blood glucose and being overweight were recruited from primary care practices at two UK sites, with data collected in participants’ homes or community venues. Participants were randomised using an online central allocation service. The intervention, comprising the prototype “Living Well, Taking Control” (LWTC) programme, involved four weekly two-hour group sessions held in local community venues to promote changes in diet and physical activity, plus planned follow-up contacts at two, three, six, nine and 12 months alongside 5 hours of additional activities/classes. Waiting list controls received usual care for 6 months before accessing the programme. The primary outcome was weight loss at 6 months. Secondary outcomes included glycated haemoglobin (HbA1c), blood pressure, physical activity, diet, health status and well-being. Only researchers conducting analyses were blinded. Results The target sample of 314 participants (157 each arm) was largely representative of local populations, including 44% men, 26% from ethnic minorities and 33% living in deprived areas. Primary outcome data were available for 285 (91%) participants (141 intervention, 144 control). Between baseline and 6 months, intervention participants on average lost more weight than controls (− 1.7 kg, 95% CI − 2.59 to − 0.85). Higher attendance was associated with greater weight loss (− 3.0 kg, 95% CI − 4.5 to − 1.5). The prototype LWTC programme more than doubled the proportion of participants losing > 5% of their body weight (21% intervention vs. 8% control, OR 2.83, 95% CI 1.36 to 5.90) and improved self-reported dietary behaviour and health status. There were no impacts on HbA1c, blood pressure, physical activity and well-being at 6 months and, amongst intervention participants, few further changes from six to 12-months (e.g. average weight re-gain 0.36 kg, 95% CI − 0.20 to 0.91). There were no serious adverse events but four exercise-related injuries were reported in the intervention arm. Conclusions This voluntary sector-led diabetes prevention programme reached a broad spectrum of the population and had modest effects on weight-related outcomes, but limited impacts on other diabetes risk factors. Trial registration Trial registration number: ISRCTN70221670, 5 September 2014 Funder (National Institute for Health Research School for Public Health Research) project reference number: SPHR-EXE-PES-COM.

Abstract Background Smoking in pregnancy is a major international public health problem. Self-help support (SHS) increases the likelihood of women stopping smoking in pregnancy and delivering this kind of support by text message could be a cost-effective way to deliver SHS to pregnant women who smoke. SHS delivered by text message helps non-pregnant smokers to stop but the currently available message programmes are not appropriate for use in pregnancy. A randomised controlled trial (RCT) has demonstrated the feasibility and acceptability of using a programme called ‘MiQuit’ to text SHS support to pregnant women who smoke. Another pilot RCT has shown that it would be feasible to run a larger, multi-centre trial within the UK National Health Service (NHS). The aim of this third RCT is to complete MiQuit’s evaluation, demonstrating whether or not this is efficacious for smoking cessation in pregnancy. Methods/design This is a multi-centre, parallel-group RCT. Pregnant women aged over 16 years, of less than 25 weeks’ gestation who smoke one or more daily cigarettes but smoked at least five daily cigarettes before pregnancy and who understand written English and are being identified in 24 English antenatal care hospitals. Participants are randomised to control or intervention groups in a 1:1 ratio stratified by gestation (

Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

Known genetic variation, in conjunction with post-PCR melting curve analysis, can be leveraged to provide increased taxonomic detail for pathogen identification in commercial molecular diagnostic tests. Increased taxonomic detail may be used by clinicians and public health decision-makers to observe circulation patterns, monitor for outbreaks, and inform testing practices. We propose a method for expanding the taxonomic resolution of PCR diagnostic systems by incorporating a priori knowledge of assay design and sequence information into a genotyping classification model. For multiplexed PCR systems, this framework is generalized to incorporate information from multiple assays to increase classification accuracy. An illustrative hierarchical classification model for human adenovirus (HAdV) species was developed and demonstrated ~95% cross-validated accuracy on a labeled dataset. The model was then applied to a near-real-time surveillance dataset in which deidentified adenovirus detected patient test data from 2018 through 2021 were classified into one of six adenovirus species. These results show a marked change in both the predicted prevalence for HAdV and the species makeup with the onset of the COVID-19 pandemic. HAdV-B decreased from a pre-pandemic predicted prevalence of up to 40% to less than 5% in 2021, while HAdV-A and HAdV-F species both increased in predicted prevalence.

Wolbachia is an intracellular bacterium that blocks virus replication in insects and has been introduced into the mosquito, Aedes aegypti for the biocontrol of arboviruses including dengue, Zika, and chikungunya. Despite ongoing research, the mechanism of Wolbachia-mediated virus blocking remains unclear. We recently used experimental evolution to reveal that Wolbachia-mediated dengue blocking could be selected upon in the A. aegypti host and showed evidence that strong levels of blocking could be maintained by natural selection. In this study, we investigate the genetic variation associated with blocking and use these analyses to generate testable hypotheses surrounding the mechanism of Wolbachia-mediated dengue blocking. From our results, we hypothesize that Wolbachia may block virus replication by increasing the regeneration rate of mosquito cells via the Notch signaling pathway. We also propose that Wolbachia modulates the host’s transcriptional pausing pathway either to prime the host’s anti-viral response or to directly inhibit viral replication.

Objectives: We sought to explore the sociodemographics and primary care service utilization among people who died from opioid overdose and to assess the possibility of using this information to identify those at high risk of opioid overdose using routine linked data. Methods: Data related to decedents of opioid overdose between January 1, 2012 and December 31, 2015 were linked with general practitioner (GP) records over a period of 36 months prior to death. Results: Of n = 312 decedents of opioid overdose, 73% were male (n = 228). Average age at death was 40.72 (SD 11.92) years. A total of 63.8% of the decedents were living in the 2 most deprived quintiles according to the Welsh Index of Multiple Deprivation. Over 80% (n = 258) of the decedents were recorded as having at least 1 GP episode during the 36-month observation period prior to death. The median number of episodes per decedent was 75 [38-118]. Overall, 31.8% (n = 82) of decedents with at least 1 GP episode received a prescription for a proton pump inhibitor and 31% (n = 80) were prescribed a broad-spectrum antibiotic. According to their GP records, less than 10% were referred to or receiving specialist drug treatment (n = 24, 9.3%); or were known to be drug dependent (n = 21, 8.14%), or a drug user (n = 5, 1.94%). In all, 81% were recorded as smokers (n = 209) and 10.5% as ex-smokers (n = 27). Conclusions: The majority of decedents of opioid overdose were in contact with GP services prior to death. GPs are either often unaware of high-risk opioid use, or rarely record details of opioid use in patient notes. It is possible that GP awareness of high-risk opioid use could be increased. For example, awareness of the risks associated with opioid use, and the relationship between the sociodemographic and clinical characteristics of opioid overdose decedents could be raised using educational materials prominently displayed in waiting areas. Clinicians in primary care may be in an excellent position to intervene in problematic opioid use.

Influenza A viruses are amongst the most challenging viruses that threaten both human and animal health. Constantly evolving and crossing species barrier, the emergence of novel zoonotic pathogens is one of the greatest challenges to global health security. During the last decade, considerable attention has been paid to influenza virus infections in dogs, as two canine H3N8 and H3N2 subtypes caused several outbreaks through the United States and Southern Asia, becoming endemic. Cats, even though less documented in the literature, still appear to be susceptible to many avian influenza infections. While influenza epidemics pose a threat to canine and feline health, the risks to humans are largely unknown. Here, we review most recent knowledge of the epidemiology of influenza A viruses in dogs and cats, existing evidences for the abilities of these species to host, sustain intraspecific transmission, and generate novel flu A lineages through genomic reassortment. Such enhanced understanding suggests a need to reinforce surveillance of the role played by companion animals-human interface, in light of the “One Health” concept and the potential emergence of novel zoonotic viruses.

Background: Ambulance services have a vital role in the shift towards the delivery of health care outside hospitals, when this is better for patients, by offering alternatives to transfer to the emergency department. The introduction of information technology in ambulance services to electronically capture, interpret, store and transfer patient data can support out-of-hospital care. Objective: We aimed to understand how electronic health records can be most effectively implemented in a pre-hospital context in order to support a safe and effective shift from acute to community-based care, and how their potential benefits can be maximised. Design and setting: We carried out a study using multiple methods and with four work packages: (1) a rapid literature review; (2) a telephone survey of all 13 freestanding UK ambulance services; (3) detailed case studies examining electronic health record use through qualitative methods and analysis of routine data in four selected sites consisting of UK ambulance services and their associated health economies; and (4) a knowledge-sharing workshop. Results: We found limited literature on electronic health records. Only half of the UK ambulance services had electronic health records in use at the time of data collection, with considerable variation in hardware and software and some reversion to use of paper records as services transitioned between systems. The case studies found that the ambulance services’ electronic health records were in a state of change. Not all patient contacts resulted in the generation of electronic health records. Ambulance clinicians were dealing with partial or unclear information, which may not fit comfortably with the electronic health records. Ambulance clinicians continued to use indirect data input approaches (such as first writing on a glove) even when using electronic health records. The primary function of electronic health records in all services seemed to be as a store for patient data. There was, as yet, limited evidence of electronic health records’ full potential being realised to transfer information, support decision-making or change patient care. Limitations: Limitations included the difficulty of obtaining sets of matching routine data for analysis, difficulties of attributing any change in practice to electronic health records within a complex system and the rapidly changing environment, which means that some of our observations may no longer reflect reality. Conclusions: Realising all the benefits of electronic health records requires engagement with other parts of the local health economy and dealing with variations between providers and the challenges of interoperability. Clinicians and data managers, and those working in different parts of the health economy, are likely to want very different things from a data set and need to be presented with only the information that they need. Future work: There is scope for future work analysing ambulance service routine data sets, qualitative work to examine transfer of information at the emergency department and patients’ perspectives on record-keeping, and to develop and evaluate feedback to clinicians based on patient records. Study registration: This study is registered as Health and Care Research Wales Clinical Research Portfolio 34166. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 10. See the NIHR Journals Library website for further project information.

Methane is a strong greenhouse gas, with a higher radiative forcing per unit mass and shorter atmospheric lifetime than carbon dioxide. The remote sensing of methane in regions of industrial activity is a key step toward the accurate monitoring of emissions that drive climate change. Whilst the TROPOspheric Monitoring Instrument (TROPOMI) on board the Sentinal-5P satellite is capable of providing daily global measurement of methane columns, data are often compromised by cloud cover. Here, we develop a statistical model which uses nitrogen dioxide concentration data from TROPOMI to efficiently predict values of methane columns, expanding the average daily spatial coverage of observations of the Permian basin from 16% to 88% in the year 2019. The addition of predicted methane abundances at locations where direct observations are not available will support inversion methods for estimating methane emission rates at shorter timescales than is currently possible.

Abstract Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.

Abstract Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups. Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.