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We collected social contact data in Greece to measure contact patterns before (January 2020) and during the COVID-19 pandemic (March 2020-October 2021) and assess the effects of social distancing over time. During lockdowns, mean daily contacts decreased to 2.8-5.9 (mean prepandemic 20.4). Persons >65 years of age retained the fewest contacts during the pandemic (2.1-4.1). Compared with the first lockdown (March-April 2020), the second lockdown (November-December 2020) and third lockdown (April 2021) showed higher numbers of contacts (incidence rate ratio 1.50 [95% CI 1.27-1.76] in second lockdown and 2.19 [95% CI 1.86-2.58] in third lockdown). In 2021, an increase in contacts was apparent, which persisted during the April 2021 lockdown among persons 18-64 years of age. Our study provides evidence of the waning observance of physical distancing. Effective risk communication alongside targeted social distancing could offer alternatives to repeated lockdowns.

Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality. Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34-0.45) infections per dose of vaccine and 1.74 (1.16-3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5-16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52-0.81) infections per dose and 1.95 (1.28-3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50-64-y-olds) would prevent only 0.43 (0.35-0.52) infections per dose and 1.77 (1.15-3.14) deaths per 1,000 doses. This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults. Please see later in the article for the Editors' Summary.

The results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible → Exposed → Infectious → Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.

Malaria constitutes an important cause of human mortality. After 2009 Greece experienced a resurgence of malaria. Here, we develop a model-based framework that integrates entomological, geographical, social and environmental evidence in order to guide the mosquito control efforts and apply this framework to data from an entomological survey study conducted in Central Greece. Our results indicate that malaria transmission risk in Greece is potentially substantial. In addition, specific districts such as seaside, lakeside and rice field regions appear to represent potential malaria hotspots in Central Greece. We found that appropriate maps depicting the basic reproduction number, R0, are useful tools for informing policy makers on the risk of malaria resurgence and can serve as a guide to inform recommendations regarding control measures.

Background The gut microbiome is implicated as a marker of response to  immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. Methods Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. Discussion There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes. Trial registration NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021).

IntroductionHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a progressive movement disorder along with cognitive and psychiatric problems. It is caused by a Cytosine-adenin-guanine (CAG) expansion in exon 1 of the huntingtin gene which codes for mutant huntingtin (mHTT) that over time accumulates in cells, causing dysfunction and then death through new toxic gain-of-function mechanisms. Autophagy has been shown to be critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative disease, including mHTT. From a screen of a library enriched in approved drugs, felodipine was selected as the most suitable candidate showing strong autophagy-inducing effects in preclinical models of HD. We are, therefore, conducting a trial to assess the safety and tolerability of felodipine in people with early HD.Methods and analysisFELL-HD is a phase II, single-centre, open-label, dose-finding trial in people with early HD. 18 participants with early clinical features of the disease will be treated with felodipine for 58 weeks, with a further 4-week follow-up. The primary outcome measure is the number of adverse events attributable to felodipine. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life scales, as well as peripheral and central disease biomarkers assessed through brain MRI. Analysis of blood and cerebrospinal fluid will also be performed through an associated sample study, FELL HD-s.Ethics and disseminationThe study was approved by the London-Brent Research Ethics Committee (reference 22/LO/0387) and has been accepted by the Medicines and Healthcare products Regulatory Agency for clinical trials authorisation (reference CTA 12854/0256/001-0001). A lay summary of the results of the trial will be uploaded to our research group website which is publicly accessible. A webinar or in-person open day, to present results of the trial to participants and our wider cohort of patients who attend our centre, will be held once the trial is completed. The results of the trial will also be published in scientific journals and presented at national and international conferences.Trial registration numbersEudraCT-2021-000897-27, ISRCTN56240656.

The potential for asymptomatic infection from Ebola viruses has long been questioned. Knowing the proportion of infections that are asymptomatic substantially changes the predictions made by mathematical models and alters the corresponding decisions based upon these models. To assess the degree of asymptomatic infection occurring during an Ebola virus disease (EVD) outbreak, we carried out a serological survey in the Djera district of the Equateur province of the Democratic Republic of the Congo affected by an Ebola outbreak in 2014. We sampled all asymptomatic residents (n = 182) of 48 households where at least one case of EVD was detected. To control for potential background seroprevalence of Ebola antibodies in the population, we also sampled 188 individuals from 92 households in an unaffected area with a similar demographic background. We tested the sera collected for anti-Ebola IgG and IgM antibodies at four different dilutions. We then developed a mixture model to estimate the likely number of asymptomatic patients who developed IgM and IgG responses to Ebola antigens in both groups. While we detected an association between medium to high titres and age, we did not detect any evidence of increased asymptomatic infection in the individuals who resided in the same household as cases. This article is part of the themed issue ‘The 2013–2016 West African Ebola epidemic: data, decision-making and disease control’.

Background: Dietary interventions are powerful tools for disease prevention and health promotion, yet the molecular mechanisms by which diet influences health remain incompletely understood. Investigating the effects of diet in healthy individuals enables characterization of molecular and physiological responses in the absence of disease-related confounders and facilitates the identification of diet-responsive pathways underlying physiological regulation. Methods: We investigated the metabolic and immune effects of short-term dietary restriction of animal products in a unique group of apparently healthy individuals (N = 200) who alternate between omnivory and animal product restriction for religious reasons. We profiled clinical biomarkers and immune parameters during both dietary states, alongside a control group of continuously omnivorous individuals (N = 211). Results: Short-term restriction is associated with reductions in total and non-high-density lipoprotein cholesterol, urea, creatinine, alanine aminotransferase, and gamma-glutamyltransferase, and a concurrent 73% reduction of normal-range C-reactive protein levels. Immune profiling reveals reductions in frequencies of non-classical monocytes, CD56⁺ natural killer cells, and CD8⁺ memory T cells, accompanied by an increased response of cytokine IL-10, suggesting enhanced immune regulation against inflammation. Although most changes are in a direction suggesting beneficial health effects, levels of alkaline phosphatase increase upon restriction, implying possible negative effects on bone turnover or liver function. Conclusions: Short-term animal product restriction mostly improves systemic metabolic and immune health markers and may lower chronic inflammatory disease risk. Our findings highlight the value of studying diet in the absence of disease to reveal adaptive molecular changes and emphasize the translational potential of short-term dietary interventions in altering health-related risks. Plain language summary Changing what we eat, even for a short time, can have important effects on our health. In this study, we looked at healthy individuals who regularly switch between being omnivorous and avoiding animal products for religious reasons. We compared their health markers and immune system activity during both diets and to a continuously omnivorous group. When animal products were restricted, we found improvements in cholesterol, liver and kidney markers, and signs of lower inflammation. These changes suggest that even short periods of avoiding animal products may support better health, although further work is necessary to explore potential negative effects. Studying healthy people helps us understand how diet alone can influence the body before disease develops. Loizidou, Palaiokrassa, Asiedu, et al. study individuals who alternate between being omnivorous and avoiding animal products for religious reasons. Results reveal widespread changes in health-related biomarkers in a direction suggesting positive effects on health, along with signs of lower inflammation during animal product restriction.

Recent studies of (cost-) effectiveness in cardiothoracic transplantation have required estimation of mean survival over the lifetime of the recipients. In order to calculate mean survival, the complete survivor curve is required but is often not fully observed, so that survival extrapolation is necessary. After transplantation, the hazard function is bathtub-shaped, reflecting latent competing risks which operate additively in overlapping time periods. The poly-Weibull distribution is a flexible parametric model that may be used to extrapolate survival and has a natural competing risks interpretation. In addition, treatment effects and subgroups can be modelled separately for each component of risk. We describe the model and develop inference procedures using freely available software. The methods are applied to two problems from cardiothoracic transplantation.