Multinational survey of treatment practices of clinicians managing subclinical hypothyroidism in older people in 2019

Background: International societies have recommended that levothyroxine should not routinely be prescribed in older individuals for the management of mild subclinical hypothyroidism (SCH). However, it is unknown whether clinicians managing people with SCH are either aware of or adhere to these guidelines. Methods: A web-based survey of members of several international thyroid associations and general practitioners in North-East England was conducted. Respondents were presented with a vignette of an 80-year-old gentleman with mild persistent SCH experiencing tiredness. Multivariable logistic regression analyses were performed to evaluate predictors of awareness of guidelines and responses to treatment. Results: The survey response rate was 21.9% (565/2,583). Only 7.6% of clinicians were unaware of guidelines regarding management of SCH in older people. Twenty percent of clinicians stated that they would treat the older patient with mild SCH, whereas 13% were unsure. Clinicians from North America were more likely to treat the older person with mild SCH than clinicians from elsewhere (OR 2.24 [1.25–3.98]). Likewise, non-endocrinologists were also more likely than endocrinologists to treat the older person with mild SCH (OR 3.26 [1.45–6.47]). Conclusion: The majority of clinicians are aware of guidelines regarding management of SCH in older individuals. However, a considerable proportion of clinicians would still treat an older person with non-specific symptoms and mild SCH. These guidelines need to be disseminated more widely and more research is required to understand barriers to adherence to international recommendations

The People's Trial : supporting the public's understanding of randomised trials

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Simone Lepage, Aoife O’Shaughnessy, and Louise Foley for their support with the research project. We would also like to thank Rob & Paul Digital Design™, Galway, Ireland. In addition, we would like to thank Marina Zaki for her support of The People’s Trial, in particular her expertise in promoting The People’s Trial through social media channels. Funding This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award (grant reference KEDS-2018-012) 2018. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

Diarrhea, Pneumonia, and Infectious Disease Mortality in Children Aged 5 to 14 Years in India

Background: Little is known about the causes of death in children in India after age five years. The objective of this study is to provide the first ever direct national and sub-national estimates of infectious disease mortality in Indian children aged 5 to 14 years. Methods: A verbal autopsy based assessment of 3 855 deaths is children aged 5 to 14 years from a nationally representative survey of deaths occurring in 2001–03 in 1?1 million homes in India. Results: Infectious diseases accounted for 58 % of all deaths among children aged 5 to 14 years. About 18 % of deaths were due to diarrheal diseases, 10 % due to pneumonia, 8 % due to central nervous system infections, 4 % due to measles, and 12 % due to other infectious diseases. Nationally, in 2005 about 59 000 and 34 000 children aged 5 to 14 years died from diarrheal diseases and pneumonia, corresponding to mortality of 24?1 and 13?9 per 100 000 respectively. Mortality was nearly 50 % higher in girls than in boys for both diarrheal diseases and pneumonia. Conclusions: Approximately 60 % of all deaths in this age group are due to infectious diseases and nearly half of these deaths are due to diarrheal diseases and pneumonia. Mortality in this age group from infectious diseases, and diarrhea i

Study protocol of European Fans in Training (EuroFIT):a four-country randomised controlled trial of a lifestyle program for men delivered in elite football clubs

Background: Lifestyle interventions targeting physical activity, sedentary time and dietary behaviours have the potential to initiate and support behavioural change and result in public health gain. Although men have often been reluctant to engage in such lifestyle programs, many are at high risk of several chronic conditions. We have developed an evidence and theory-based, gender sensitised, health and lifestyle program (European Fans in Training (EuroFIT)), which is designed to attract men through the loyalty they feel to the football club they support. This paper describes the study protocol to evaluate the effectiveness and cost-effectiveness of the EuroFIT program in supporting men to improve their level of physical activity and reduce sedentary behaviour over 12 months. Methods: The EuroFIT study is a pragmatic, two-arm, randomised controlled trial conducted in 15 football clubs in the Netherlands, Norway, Portugal and the UK (England). One-thousand men, aged 30 to 65 years, with a self-reported Body Mass Index (BMI) ≥27 kg/m2 will be recruited and individually randomised. The primary outcomes are objectively-assessed changes in total physical activity (steps per day) and total sedentary time (minutes per day) at 12 months after baseline assessment. Secondary outcomes are weight, BMI, waist circumference, resting systolic and diastolic blood pressure, cardio-metabolic blood biomarkers, food intake, self-reported physical activity and sedentary time, wellbeing, self-esteem, vitality and quality of life. Cost-effectiveness will be assessed and a process evaluation conducted. The EuroFIT program will be delivered over 12 weekly, 90-minute sessions that combine classroom discussion with graded physical activity in the setting of the football club. Classroom sessions provide participants with a toolbox of behaviour change techniques to initiate and sustain long-term lifestyle changes. The coaches will receive two days of training to enable them to create a positive social environment that supports men in engaging in sustained behaviour change. Discussion: The EuroFIT trial will provide evidence on the effectiveness and cost-effectiveness of the EuroFIT program delivered by football clubs to their male fans, and will offer insight into factors associated with success in making sustained changes to physical activity, sedentary behaviour, and secondary outcomes, such as diet.Trial registration: ISRCTN: 81935608. Registered 16 June 2015.<br/

A primary care Web-based Intervention Modeling Experiment replicated behavior changes seen in earlier paper-based experiment

OBJECTIVES: Intervention Modeling Experiments (IMEs) are a way of developing and testing behavior change interventions before a trial. We aimed to test this methodology in a Web-based IME that replicated the trial component of an earlier, paper-based IME. STUDY DESIGN AND SETTING: Three-arm, Web-based randomized evaluation of two interventions (persuasive communication and action plan) and a "no intervention" comparator. The interventions were designed to reduce the number of antibiotic prescriptions in the management of uncomplicated upper respiratory tract infection. General practitioners (GPs) were invited to complete an online questionnaire and eight clinical scenarios where an antibiotic might be considered. RESULTS: One hundred twenty-nine GPs completed the questionnaire. GPs receiving the persuasive communication did not prescribe an antibiotic in 0.70 more scenarios (95% confidence interval [CI] = 0.17-1.24) than those in the control arm. For the action plan, GPs did not prescribe an antibiotic in 0.63 (95% CI = 0.11-1.15) more scenarios than those in the control arm. Unlike the earlier IME, behavioral intention was unaffected by the interventions; this may be due to a smaller sample size than intended. CONCLUSIONS: A Web-based IME largely replicated the findings of an earlier paper-based study, providing some grounds for confidence in the IME methodology

Allorecognition in the Tasmanian Devil (Sarcophilus harrisii), an Endangered Marsupial Species with Limited Genetic Diversity

Tasmanian devils (Sarcophilus harrisii) are on the verge of extinction due to a transmissible cancer, devil facial tumour disease (DFTD). This tumour is an allograft that is transmitted between individuals without immune recognition of the tumour cells. The mechanism to explain this lack of immune recognition and acceptance is not well understood. It has been hypothesized that lack of genetic diversity at the Major Histocompatibility Complex (MHC) allowed the tumour cells to grow in genetically similar hosts without evoking an immune response to alloantigens. We conducted mixed lymphocyte reactions and skin grafts to measure functional MHC diversity in the Tasmanian devil population. The limited MHC diversity was sufficient to produce measurable mixed lymphocyte reactions. There was a wide range of responses, from low or no reaction to relatively strong responses. The highest responses occurred when lymphocytes from devils from the east of Tasmania were mixed with lymphocytes from devils from the west of Tasmania. All of the five successful skin allografts were rejected within 14 days after surgery, even though little or no MHC I and II mismatches were found. Extensive T-cell infiltration characterised the immune rejection. We conclude that Tasmanian devils are capable of allogeneic rejection. Consequently, a lack of functional allorecognition mechanisms in the devil population does not explain the transmission of a contagious cancer

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine