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Observational studies suggest that male circumcision may provide protection against HIV-1 infection. A randomized, controlled intervention trial was conducted in a general population of South Africa to test this hypothesis. A total of 3,274 uncircumcised men, aged 18-24 y, were randomized to a control or an intervention group with follow-up visits at months 3, 12, and 21. Male circumcision was offered to the intervention group immediately after randomization and to the control group at the end of the follow-up. The grouped censored data were analyzed in intention-to-treat, univariate and multivariate, analyses, using piecewise exponential, proportional hazards models. Rate ratios (RR) of HIV incidence were determined with 95% CI. Protection against HIV infection was calculated as 1 - RR. The trial was stopped at the interim analysis, and the mean (interquartile range) follow-up was 18.1 mo (13.0-21.0) when the data were analyzed. There were 20 HIV infections (incidence rate = 0.85 per 100 person-years) in the intervention group and 49 (2.1 per 100 person-years) in the control group, corresponding to an RR of 0.40 (95% CI: 0.24%-0.68%; p < 0.001). This RR corresponds to a protection of 60% (95% CI: 32%-76%). When controlling for behavioural factors, including sexual behaviour that increased slightly in the intervention group, condom use, and health-seeking behaviour, the protection was of 61% (95% CI: 34%-77%). Male circumcision provides a degree of protection against acquiring HIV infection, equivalent to what a vaccine of high efficacy would have achieved. Male circumcision may provide an important way of reducing the spread of HIV infection in sub-Saharan Africa. (Preliminary and partial results were presented at the International AIDS Society 2005 Conference, on 26 July 2005, in Rio de Janeiro, Brazil.).

IntroductionIt has been reported that pregnant women used more cosmetics daily than non-pregnant women. Phenoxyacetic acid is the main metabolite of phenoxyethanol, the most frequent preservative in cosmetics used in Europe, previously associated with reproductive effects (longer time to conception, endocrine disruptors in newborns and poorer verbal comprehension in children). In France, specialised platforms (PREVention ENvIronment Reproduction (PREVENIR)) in university hospital maternity wards are dedicated to evaluating environmental and occupational exposures in patients with pregnancy-related pathologies and supporting targeted prevention efforts. These platforms are composed of occupational health physicians, obstetrician-gynaecologists, midwives, occupational health nurses, and occupational health and environmental engineers. To assess the efficacy of these platforms, we developed a randomised clinical trial, the protocol for which is presented in this paper. The primary objective of the PREVENIR-G Study is to compare the change in urinary phenoxyacetic acid concentrations from baseline to 3 months postintervention between an intervention group and a control group. To date, the intervention has been integrated into routine care in certain facilities; however, its efficacy remains unproven. It is therefore essential to assess the relevance of this intervention, considering both its potential benefits and any adverse effects, such as increased stress or anxiety.Methods and analysisThis study is an unblinded, randomised clinical superiority trial with two parallel groups (intervention vs no intervention) in four university maternity hospitals in France. We will include 300 pregnant women (aged 18 years or older) who are under 24 weeks of gestation (150 per group) referred to the participating PREVENIR platforms for management. The intervention will consist of clinical prevention management through the PREVENIR platforms, involving a consultation with an environmental health expert for an assessment of environmental and occupational exposures. During the consultation, targeted prevention messages will be provided based on identified exposures. The no intervention comparator will be a waiting-list control group. At the inclusion visit, patients will receive urine collection vials for samples to be collected at baseline and again at 3 months. Urine samples will be collected twice in a single day, on three separate days, during the collection week at home. In the week following the urine collection period, only participants in the intervention group will engage with the PREVENIR platforms. The primary outcome will be the difference in the urinary phenoxyacetic acid concentration between baseline and 3 months postintervention, compared between the intervention and control groups.Ethics and disseminationThe study has been approved by the hospital ethics committee (CCP Ouest 2, no. 2023-A00941-44). All participants will provide written informed consent. Results will be shared through presentations and publications.Trial registration numberNCT06642818

Randomized controlled trials have shown that voluntary medical male circumcision (VMMC) reduces HIV infection by 50% to 60% in sub-Saharan African populations; however, little is known about the population-level effect of adult male circumcision (MC) as an HIV prevention method. We assessed the effectiveness of VMMC roll-out on the levels of HIV in the South African township of Orange Farm where the first randomized controlled trial (RCT) to test the effect of VMMC on HIV acquisition was conducted in 2002-2005. The Bophelo Pele project is a community-based campaign against HIV, which includes the roll-out of free VMMC. A baseline cross-sectional biomedical survey was conducted in 2007-2008 among a random sample of 1,998 men aged 15 to 49 (survey response rate 80.7%). In 2010-2011, we conducted a follow-up random survey among 3,338 men aged 15 to 49 (survey response rate 79.6%) to evaluate the project. Participants were interviewed, blood samples were collected and tested for HIV and recent HIV infection (using the BED HIV incidence assay), and MC status was assessed through a clinical examination. Data were analyzed using multivariate and propensity statistical methods. Owing to the VMMCs performed in the context of the RCT and the Bophelo Pele project, the prevalence rate of adult MC increased from 0.12 (95% CI 0.10-0.14) to 0.53 (95% CI 0.51-0.55). Without these VMMCs, the HIV prevalence rate in 2010-2011 would have been 19% (95% CI 12%-26%) higher (0.147 instead of 0.123). When comparing circumcised and uncircumcised men, no association of MC status with sexual behavior was detected. Among circumcised and uncircumcised men, the proportion consistently using condoms with non-spousal partners in the past 12 months was 44.0% (95% CI 41.7%-46.5%) versus 45.4% (95% CI 42.2%-48.6%) with weighted prevalence rate ratio (wPRR) = 0.94 (95% CI 0.85-1.03). The proportion having two or more non-spousal partners was 50.4% (95% CI 47.9%-52.9%) versus 44.2% (95% CI 41.3%-46.9%) with wPRR = 1.03 (95% CI 0.95-1.10). We found a reduction of BED-estimated HIV incidence rate ranging from 57% (95% CI 29%-76%) to 61% (95% CI 14%-83%) among circumcised men in comparison with uncircumcised men. Findings suggest that the roll-out of VMMC in Orange Farm is associated with a significant reduction of HIV levels in the community. The main limitation of the study is that it was not randomized and cannot prove a causal association. The roll-out of VMMC among adults in sub-Saharan Africa should be an international priority and needs to be accelerated to effectively combat the spread of HIV. Please see later in the article for the Editors' Summary.

Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate ( e.g .: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. Intervention and comparator The four experimental treatments planned in protocol version 1.2 (April 8 th , 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. Main outcome The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. Randomisation Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan ( i.e .: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs . nursing home). Blinding (masking) This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. Numbers to be randomised (sample size) A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. Trial Status This describes the Version 1.2 (April 8 th , 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15 th , 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15 th , 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms < 3 days replaced by time since first symptoms < 5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. Trial registration The trial was registered on Clinical Trials.gov on April 22 nd , 2020 (Identifier: NCT04356495): and on EudraCT on April 10 th , 2020 (Identifier: 2020-001435-27). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background There is a growing interest in developing tailored non-pharmacological strategies to face patients’ needs in dementia. Occupational therapy (OT) may contribute to promote self-empowerment of both patients and caregivers. France has implemented nationwide OT over a short-term period of 3/4 months. The main objective of the MathéoAlz study is to measure the impact of maintaining OT over 4 supplementary months on patients’ neuropsychiatric symptoms. Methods/design The MatheoAlz trial (Maintenance of Occupational Therapy in Alzheimer’s disease) is a multi-center, pragmatic randomized controlled trial testing maintenance of OT over 4 supplementary months compared to routine OT delivered as recommended. This paper describes the study protocol. MatheoAlz plans to enroll 240 dyads, i.e. dementia patients and caregivers, whose main inclusion criteria are: prescription for routine OT, patients with mild or moderate dementia, living at home, receiving support from an informal caregiver. The study will compare a control group of patients benefiting from 12 to 15 initial sessions of OT over 3/4 months and an intervention group of patients benefiting from these initial sessions plus 8 extra home sessions over 4 supplementary months. The main outcome is the patient’s neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory at 8 months. Several clinical outcomes and economic consequences are measured at 4, 8 and 12 months. Discussion This is the first trial designed to assess the specific impact of the maintaining OT on the patients’ neuropsychiatric symptoms burden. The results will inform policymakers on strategies to implement in the near future. Trial registration This trial was registered at ClinicalTrials.gov on February 16, 2018, identifier: NCT03435705 .

Background Prospective cohorts represent an essential design for epidemiological studies and allow for the study of the combined effects of lifestyle, environment, genetic predisposition, and other risk factors on a large variety of disease endpoints. The CONSTANCES cohort is intended to provide public health information and to serve as an \"open epidemiologic laboratory\" accessible to the epidemiologic research community. Although designed as a \"general-purpose\" cohort with very broad coverage, it will particularly focus on occupational and social determinants of health, and on aging. Methods/Design The CONSTANCES cohort is designed as a randomly selected representative sample of French adults aged 18-69 years at inception; 200,000 subjects will be included over a five-year period. At inclusion, the selected subjects will be invited to fill a questionnaire and to attend a Health Screening Center (HSC) for a comprehensive health examination: weight, height, blood pressure, electrocardiogram, vision, auditory, spirometry, and biological parameters; for those aged 45 years and older, a specific work-up of functional, physical, and cognitive capacities will be performed. A biobank will be set up. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HSC. Social and work-related events and health data will be collected from the French national retirement, health and death databases. The data that will be collected include social and demographic characteristics, socioeconomic status, life events, behaviors, and occupational factors. The health data will cover a wide spectrum: self-reported health scales, reported prevalent and incident diseases, long-term chronic diseases and hospitalizations, sick-leaves, handicaps, limitations, disabilities and injuries, healthcare utilization and services provided, and causes of death. To take into account non-participation at inclusion and attrition throughout the longitudinal follow-up, a cohort of non-participants will be set up and followed through the same national databases as participants. A field-pilot was performed in 2010 in seven HSCs, which included about 3,500 subjects; it showed a satisfactory structure of the sample and a good validity of the collected data. Discussion The constitution of the full eligible sample is planned during the last trimester of 2010, and the cohort will be launched at the beginning of 2011.

To show how reweighting can correct for unit nonresponse bias in an occupational health surveillance survey by using data from administrative databases in addition to classic sociodemographic data. In 2010, about 10,000 workers covered by a French health insurance fund were randomly selected and were sent a postal questionnaire. Simultaneously, auxiliary data from routine health insurance and occupational databases were collected for all these workers. To model the probability of response to the questionnaire, logistic regressions were performed with these auxiliary data to compute weights for correcting unit nonresponse. Corrected prevalences of questionnaire variables were estimated under several assumptions regarding the missing data process. The impact of reweighting was evaluated by a sensitivity analysis. Respondents had more reimbursement claims for medical services than nonrespondents but fewer reimbursements for medical prescriptions or hospitalizations. Salaried workers, workers in service companies, or who had held their job longer than 6 months were more likely to respond. Corrected prevalences after reweighting were slightly different from crude prevalences for some variables but meaningfully different for others. Linking health insurance and occupational data effectively corrects for nonresponse bias using reweighting techniques. Sociodemographic variables may be not sufficient to correct for nonresponse.

ObjectivesThe objectives this study were (1) to investigate correlations between measures of psychosocial workplace stress as measured in separate years by the Job Content Questionnaire (JCQ) and Effort–Reward Imbalance (ERI) scales; (2) to establish a valid measure of psychosocial job stress with its components (by identifying the individual and interactive associations of job stress components) and (3) to use the component measures to assess the risk of psychosocial strain at work on fatigue.MethodsThe JCQ and ERI from the annual survey of the GAZEL cohort established in 1989 initially with 20 624 respondents were used to investigate the associations of workplace stress on mental and physical fatigue in two separate years (1998 and 2006). First, the JCQ measures from separate years (1997 and 1999) were combined to create a measure for the same year as ERI (1998). The new measure was validated for internal and external consistency. Using logistic regression, the subcomponents of stress (upper tertiles of psychological demands, physical demands, decision latitude, social support, effort, reward, ERI and overcommitment) were tested for associations with the highest reporting of mental and physical fatigue.ResultsBy combining JCQ responses from 1997 to 1999, we were able to increase the amount of information available on psychosocial factors in 1998. Psychometric properties of the workplace stress scales also showed expected factor loadings. Workplace psychosocial factors had greater associations with fatigue among men than women. Although psychosocial factors became less predictive of fatigue at 8 years of follow-up, associations between fatigue and psychosocial components (overcommitment, social support and rewards) remained significant.ConclusionsThese analyses continue to validate the various subcomponents scales of workplace stress as measured by the JCQ and effort–reward imbalance model in GAZEL. They also highlight the importance of psychosocial work factors in the experience of overall fatigue even after an 8-year follow-up.

Objectives Susceptibility-weighted magnetic resonance imaging (MRI) sequences may demonstrate various signal intensities of draining veins in cases of high-flow vascular malformation (HFVM), including arteriovenous malformation (AVM) and dural arteriovenous fistula (dAVF). Our objective was to evaluate susceptibility-weighted angiography (SWAN) for the detection of HFVM. Methods Fifty-eight consecutive patients with a suspected intracranial vascular malformation were explored with SWAN and post-contrast MRI sequences at 3 T. The diagnosis of slow-flow vascular malformation (SFVM), including developmental venous anomaly (DVA) or brain capillary telangiectasia (BCT), was based on MRI. Patients with suspected HFVM underwent digital subtraction angiography (DSA). SWAN images were analysed by three blinded readers according to a three-point scale of the venous signal. Results Thirty-one patients presented 35 SFVM (26 DVA and 9 BCT) that systematically appeared hypointense on SWAN images. In patients with atypical MRI findings, DSA revealed one patient with an atypical DVA and 26 patients with HFVM (22 AVM and 4 dAVF). SWAN revealed at least one venous hyperintensity in all patients with HFVM. Agreement between readers was excellent. Conclusions SWAN appears reliable for characterising blood flow dynamics in brain veins. In clinical practice, SWAN can routinely rule out HFVM in patients with atypical brain veins. Key Points • Susceptibility - weighted angiography (SWAN) offers new perspectives for detecting intracranial vascular malformations. • SWAN sequence provides non - invasive characterisation of blood flow dynamics. • SWAN can differentiate between high and slow flowing venous blood. • SWAN can routinely rule out high - flow vascular malformations.