Femtosecond laser-assisted versus phacoemulsification cataract surgery (FEMCAT): a multicentre participant-masked randomised superiority and cost-effectiveness trial.

BACKGROUND: Cataract surgery is one of the most common operations in health care. Femtosecond laser-assisted cataract surgery (FLACS) enables more precise ocular incisions and lens fragmentation than does phacoemulsification cataract surgery (PCS). We hypothesised that FLACS might improve outcomes in cataract surgery compared with PCS despite having higher costs. METHODS: We did a participant-masked randomised superiority clinical trial comparing FLACS and PCS in two parallel groups (permuted block randomisation stratified on centres via a centralised web-based application, allocation ratio 1:1, block size of 2 or 4 for unilateral cases and 2 or 6 for bilateral cases). Five French University Hospitals enrolled consecutive patients aged 22 years or older who were eligible for unilateral or bilateral cataract surgery. Participants, outcome assessors, and technicians carrying out examinations were masked to the surgical treatment allocation until the last follow-up visit and a sham laser procedure was set up for participants randomly assigned to the PCS arm. The primary clinical endpoint was the success rate of surgery, defined as a composite of four outcomes at a 3-month postoperative visit: absence of severe perioperative complication, a best-corrected visual acuity (BCVA) of 0·0 LogMAR (logarithm of the minimum angle of resolution) or better, an absolute refractive error of 0·75 dioptres or less, and unchanged postoperative corneal astigmatism power (≤0·5 dioptres) and axis (≤20°). The primary economic endpoint was the incremental cost per additional patient who had treatment success at 3 months. Primary outcomes were assessed in all randomly assigned patients who met all eligibility criteria (missing data considered as failure). We used mixed logistic regression models or mixed linear regression models for statistical comparisons, adjusted on centres and whether cataract surgery was bilateral or unilateral. The study is registered with ClinicalTrials.gov, NCT01982006. FINDINGS: Of the 907 patients (1476 eyes) randomly assigned between Oct 9, 2013, and Oct 30, 2015, 870 (704 eyes in FLACS group and 685 eyes in the PCS group) were analysed. We identified no significant difference in the success rate of surgery between the FLACS and PCS groups (FLACS: 41·1% [289 eyes]; PCS: 43·6% [299 eyes]); adjusted odds ratio 0·85, 95% CI 0·64-1·12, p=0·250). The incremental cost-effectiveness ratio was €10 703 saved per additional patient who had treatment success with PCS compared with FLACS. We observed no severe adverse events during the femtosecond laser procedure, and most of the complications in the FLACS group related to the primary outcome measures occurred during the phacoemulsification phase or postoperatively. INTERPRETATION: Despite its advanced technology, femtosecond laser was not superior to phacoemulsification in cataract surgery and, with higher costs, did not provide an additional benefit over phacoemulsification for patients or health-care systems. FUNDING: French Ministry of Social Affairs and Health.

A Phase 2 Randomized Trial of Asleep versus Awake Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Asleep deep brain stimulation (DBS) for Parkinson's disease (PD) is being performed more frequently; however, motor outcomes and safety of asleep DBS have never been assessed in a prospective randomized trial. METHODS: We conducted a prospective, randomized, noncomparative trial to assess the motor outcomes of asleep DBS. Leads were implanted in the subthalamic nucleus (STN) according to probabilistic stereotactic coordinates with a surgical robot under O-arm© imaging guidance under either general anesthesia without microelectrode recordings (MER) (20 patients, asleep group) or local anesthesia with MER and clinical testing (9 patients, awake group). RESULTS: The mean motor improvement rates on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-3) between OFF and ON stimulation without medication were 52.3% (95% CI: 45.4-59.2%) in the asleep group and 47.0% (95% CI: 23.8-70.2%) in the awake group, 6 months after surgery. Except for a subcutaneous hematoma, we did not observe any complications related to the surgery. Three patients (33%) in the awake group and 8 in the asleep group (40%) had at least one side effect potentially linked with neurostimulation. CONCLUSIONS: Owing to its randomized design, our study supports the hypothesis that motor outcomes after asleep STN-DBS in PD may be noninferior to the standard awake procedure.

Maintenance of occupational therapy (OT) for dementia: protocol of a multi-center, randomized controlled and pragmatic trial.

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 .

Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.

BACKGROUND: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. OBJECTIVE: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission. STUDY DESIGN: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. RESULTS: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine. CONCLUSION: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis.

Association of the ANRS-12126 male circumcision project with HIV levels among men in a South African township: evaluation of effectiveness using cross-sectional surveys.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Susceptibility-weighted angiography for the detection of high-flow intracranial vascular lesions: preliminary study.

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.

Cost Utility and Value of Information Analysis of Femtosecond Laser-Assisted Cataract Surgery.

Importance: The efficacy and safety of femtosecond laser-assisted cataract surgery is well documented. An important requirement for decision makers is the evaluation of the cost-effectiveness of femtosecond laser-assisted cataract surgery (FLACS) over a sufficiently long horizon. Evaluating the cost-effectiveness of this treatment was a preplanned secondary objective of the Economic Evaluation of Femtosecond Laser Assisted Cataract Surgery (FEMCAT) trial. Objective: To estimate the cost utility of FLACS compared with phacoemulsification cataract surgery (PCS) on a 12-month time horizon. Design, Setting, and Participants: This multicenter randomized clinical trial compared FLACS with PCS in parallel groups. All FLACS procedures were performed using the CATALYS precision system. Participants were recruited and treated in ambulatory surgery settings in 5 university-hospital centers in France. All consecutive patients eligible for a unilateral or bilateral cataract surgery 22 years or older with written informed consent were included. Data were collected from October 2013 to October 2018, and data were analyzed from January 2020 to June 2022. Interventions: FLACS or PCS. Main Outcomes and Measures: Utility was measured through the Health Utility Index questionnaire. Costs of cataract surgery were estimated by microcosting. All inpatient and outpatient costs were collected from the French National Health Data System. Results: Of 870 randomized patients, 543 (62.4%) were female, and the mean (SD) age at surgery was 72.3 (8.6) years. A total of 440 patients were randomized to receive FLACS and 430 to receive PCS; the rate of bilateral surgery was 63.3% (551 of 870). The mean (SD) costs of cataract surgery were €1124.0 (€162.2; US $1235) for FLACS and €565.5 (€61.4; US $621) for PCS. The total mean (SD) cost of care at 12 months was €7085 (€6700; US $7787) in participants treated with FLACS and €6502 (€7323; US $7146) in participants treated with PCS. FLACS yielded a mean (SD) of 0.788 (0.009) quality-adjusted life-years (QALYs), and PCS yielded 0.792 (0.009) QALYs. The difference in mean costs was €545.9 (95% CI, -434.1 to 1525.8; US $600), and the difference in QALYs was -0.004 (95% CI, -0.028 to 0.021). The incremental cost-effectiveness ratio (ICER) was -€136 476 (US $150 000) per QALY. The cost-effectiveness probability of FLACS compared with PCS was 15.7% for a cost-effectiveness threshold of €30 000 (US $32 973) per QALY. At this threshold, the expected value of perfect information was €246 139 079 (US $270 530 231). Conclusions and Relevance: The ICER of FLACS compared with PCS was not within the $50 000 to $100 000 per QALY range frequently cited as cost-effective. Additional research and development on FLACS is needed to improve its effectiveness and lower its price. Trial Registration: ClinicalTrials.gov Identifier: NCT01982006.

Effects of job strain on fatigue: cross-sectional and prospective views of the job content questionnaire and effort--reward imbalance in the GAZEL cohort.

OBJECTIVES: The 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. METHODS: The 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. RESULTS: By 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. CONCLUSIONS: These 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.

Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE).

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

The effect of heterogeneity on HIV prevention trials.

BACKGROUND: Randomized controlled trials (RCTs) for the prevention of HIV heterosexual acquisition are usually conducted among adult African populations with high heterogeneity in individual risk of infection. PURPOSE: The objectives were to (a) review how this heterogeneity has been considered when designing and interpreting such RCTs, (b) evaluate its effect on the findings and the statistical power of these trials, and (c) assess the potential advantages of using the crossover design with single failure-time endpoint. METHODS: Individual-level HIV prevention RCTs conducted in Africa and published in the period 1998-2008 were reviewed. Using Monte Carlo simulations and statistical calculations, we assessed the effect of heterogeneity on the findings and the statistical power of HIV prevention RCTs. RESULTS: All reviewed RCTs used the parallel design. The heterogeneity in individual risk of infection within study sites was not used for stratification nor generally considered in the design and interpretation of RCTs. Simulations showed that in the context of high HIV incidence, high heterogeneity can lead to a substantial underestimation of the impact of an intervention and reduced statistical power. Calculations demonstrated that the crossover design allowed for similar or better estimation and statistical power. The crossover design has the ethical advantage of sharing the potential benefits and risks of the intervention between participants. LIMITATIONS: Only trials with two treatment arms and two follow-up periods were modeled. The baseline risk of infection of each participant was assumed to be constant over time and HIV status was assessed at the end of each follow-up period. CONCLUSIONS: The heterogeneity in individual risk of HIV infection is an underestimated problem which should be taken into account when designing and interpreting RCTs that test prevention methods of HIV heterosexual acquisition in adult African populations with high HIV incidence. When the effects of tested interventions are rapidly reversible, the use of the crossover design should be considered.

HIV-positive men who have sex with men: biography, diversity in lifestyles, common experience of living with HIV. ANRS-EN12 VESPA Study, 2003.

The conceptualisation of male who have sex with male (MSM) to account for male homosexual behaviour has been developed to facilitate the endorsement of prevention message since the advent of HIV infection. Population studies performed to understand and monitor sexual and preventive behaviour usually recruit respondents through gay-friendly channels such as media, sexual venues or festivals, leading to recruitment bias. Few studies question possible differences according to varying sexual biography and current behaviour within the MSM population. The random sample of HIV+ individuals treated in specialised outpatient clinics (ANRS-EN12-VESPA study, 2003) provides the opportunity to question the MSM conceptualisation regarding sexual biography, social characteristics, current sexual behaviour, use of condom, living with HIV (quality of life, discrimination and participation in NGOs). Among the 2932 respondents, 1309 men reported a lifetime male sexual partner. Information regarding sexual biography (lifetime and current numbers of male and female sexual partners, lifetime number of male and female stable couples) was computed using cluster analysis and identified five profiles: exclusive gay (53.7%), gay with some bisexuality (21.8%), gay with mixed sexual history (8.1%), bisexual (7.8%) and heterosexual with male-to-male sex (8.6%). The profiles matched self-identification better among the most exclusive homosexuals than among men with current bisexuality. These five subgroups differed regarding demographic and social characteristics (except migration status), their period of diagnosis, age and CD4 count at diagnosis. Sexual activity, steady partnership, number of male and female partners, use of sexual venues and illegal substance use were different across subgroups. Reversely, these groups are homogenous regarding experience of discrimination and involvement in People living with HIV/AIDS (PLWHA) activities. These findings among men living with HIV support the MSM conceptualisation and underscore the role of medicine and HIV activism in shaping the experience of HIV infection.

The CONSTANCES cohort: an open epidemiological laboratory.

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: 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.

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

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 8th, 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 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 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 15th, 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 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 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).

Childhood sexual abuse and adult binge drinking among Kanak women in New Caledonia.

The long-term consequences of violence against women are poorly documented within the context of political domination, economic inequalities and rapid social change of indigenous communities. Using data from the first population study on violence against women and their consequences on health in New Caledonia, South Pacific, this article investigates the association between childhood sexual abuse and binge drinking among 441 adult Kanak women. Face-to-face standardised interviews were conducted in 2002-2003, among women aged 18-54 years drawn from the electoral rolls. Childhood sexual abuse before 15 years of age was reported by 11.6% of respondents. Nearly all the perpetrators (96%) were known to the victims (63% being a close relative). The rate of frequent binge drinking amongst the women within the last 12 months was 34%. After controlling for social and demographic factors, an independent association was found between childhood sexual abuse and current binge drinking. This study is the first to analyse the contribution of childhood sexual abuse to the likelihood of later heavy alcohol use in an indigenous population in the South Pacific. The findings call for improving and giving priority to care for children who are victims of violence to prevent long-term health consequences and to develop prevention programs aimed at alcohol-related behaviour in women, while taking into account simultaneous individual and collective factors.

Reproductive choice in men and women living with HIV: evidence from a large representative sample of outpatients attending French hospitals (ANRS-EN12-VESPA Study).

BACKGROUND: In France, the third decade of the HIV epidemic is characterized by a lower age among women who have been recently infected with HIV. This study analysed factors associated with the desire for a child in a sample of heterosexual women and men of reproductive age living with HIV. METHODS: Individuals of reproductive age within the VESPA study were included in the analysis. Desire for a child was analysed according to reproductive potential, cultural aspects and HIV-related health condition (CD4 cell count, plasma HIV load and being on treatment). RESULTS: A total of 555 women and 699 men who self-identified as heterosexual and did not report a medical diagnosis of infertility, were included in the analysis. Among them, 33% of the women and 20% of the men stated that they expected to have children in the future. In multivariate analysis, significant predictors of the desire for a child included factors associated with reproductive potential (younger age, already being a parent, regular relationship), the HIV status of the regular partner and ethnicity (African origin). HIV-related health status did not affect reproductive intentions among men and women. CONCLUSIONS: For both men and women, reproductive potential, ethnicity and partner's HIV status influenced the desire for a child, whereas the person's own clinical condition in relation to HIV had low impact. Reproductive counselling integrated into HIV care should take into account cultural aspects in order to help people living with HIV examine issues of parenthood.

Factors correlated with disclosure of HIV infection in the French Antilles and French Guiana: results from the ANRS-EN13-VESPA-DFA Study.

OBJECTIVES: To determine the rate, patterns and predictors of HIV disclosure in the French Antilles and French Guiana. METHODS: A cross-sectional survey was carried out among a 15% random sample (n=398) of the hospital caseload in hospitals providing HIV care. Determinants of disclosure to a steady partner and other members of the individual's social network were analysed using logistic regression. RESULTS: From the time of diagnosis, 84.6% of those in a couple (n=173) disclosed their HIV-positive status to their steady partner, 55.6% disclosed to others, and 30.3% did not tell their status to anyone. Disclosure within a steady partnership was less likely among non-French individuals [Haitians: adjusted odds ratio (AOR) 0.11, 95% confidence interval (CI) 0.02-0.72; other nationalities: AOR 0.13, 95% CI 0.02-0.68]; and among those diagnosed with HIV after 1997 (AOR 0.21, 95% CI 0.05-0.86). Determinants of disclosure to others were found to be sex (women: AOR 2.04, 95% CI 1.24-3.36), age at diagnosis (>or=50 versus<30 years: AOR 0.42, 95% CI 0.19-0.90), nationality (Haitians versus French: AOR 0.39, 95% CI 0.19-0.77), transmission route (non-sexual versus sexual: AOR 3.38, 95% CI 1.12-10.23) and hospital inpatients (hospitalized versus non-hospitalized patients: AOR 1.98, 95% CI 1.17-3.37). After disclosing, social and emotional support from confidants was common and discrimination was infrequent. CONCLUSION: One third of PLWHA had kept their HIV status secret. Interventions targeting the general population and social institutions, and support for PLWHA by healthcare staff are needed to improve the situation.

Effects of Maternal Supplementation With Omega-3 Precursors on Human Milk Composition.

BACKGROUND: Long-chain polyunsaturated fatty acids (LC-PUFAs) are important for newborn neurosensory development. Supplementation of breastfeeding mothers' diets with omega-3 PUFAs, such as alpha-linolenic acid (ALA), may increase their concentration in human milk. Research aim: This study aimed to assess human milk composition after 15-day supplementation regimens containing either omega-3 PUFAs or olive oil, which does not provide ALA. METHODS: A multicenter factorial randomized trial was conducted with four groups of breastfeeding women, with each group containing 19 to 22 women. After a 15-day ALA washout period, three groups received supplementation with omega-3 precursors for 15 days: an enriched margarine (M), a rapeseed oil (R), and a margarine and rapeseed oil (MR). The fourth was unexposed to omega-3 precursors (olive oil control diet, O). After 15 days, blind determination of human milk fatty acid (FA) composition was assessed by gas chromatography, and the FA composition was compared among groups using variance analyses. RESULTS: Alpha-linolenic acid content, expressed as the mean (standard deviation) total human milk FA percentage, was significantly higher after diet supplementation with omega-3 PUFAs, with values of 2.2% (0.7%) (MR), 1.3% (0.5%) (R), 1.1% (0.4%) (M), and 0.8% (0.3%) (O at D30) ( p < .003 for each comparison). The lowest LA-ALA ratio (5.5) was found in the MR group ( p < .001). Docosahexaenoic acid and trans FA concentrations did not differ among groups. CONCLUSION: In lactating women, omega-3 supplementation via the combination of enriched margarine and rapeseed oil increased the ALA content of human milk and generated the most favorable LA-ALA ratio for LC-PUFA synthesis.

Development and validation of hospital information system-generated indicators of the appropriateness of oral anticoagulant prescriptions in hospitalised adults: the PACHA study protocol.

INTRODUCTION: The appropriateness of oral anticoagulant prescriptions is a major challenge to improve quality and safety of care. As indicators of the appropriateness of oral anticoagulant prescriptions are lacking, the aim of the study is to develop and validate a panel of such indicators, in hospitalised adults, from the hospital information system of two university hospitals in France. METHODS AND ANALYSIS: The study will be carried out in four steps: (1) a literature review to identify indicators of the appropriateness of oral anticoagulant prescriptions and their conditions of appropriateness; (2) a Delphi consensus method to assess the potential utility and operational implementation of the selected indicators; (3) techniques of medical data search to implement indicators from the hospital information system and; (4) a cross-sectional study to assess the ability of indicators to detect inappropriate oral anticoagulant prescriptions, performance of medical data search techniques for tracking or retrieving information and the ability of tools to be transferred into other institutions. The fourth step will include up to 80 patient hospital stays for each indicator, depending on the prevalence of inappropriate prescriptions estimated in interim analyses. ETHICS AND DISSEMINATION: This work addresses the current lack of quality indicators of the appropriateness of oral anticoagulant prescriptions. We aim to develop and validate such indicators for integrating them into hospital clinical practice, as part of a structured approach to improve quality and safety of care. As each hospital information system is different, we will propose tools transferable to other healthcare institutions to allow an automated construction of these indicators. The PACHA study protocol was approved by institutional review boards and ethics committees (CPP Sud-Ouest et Outre Mer III-DC 2016/119; CPP Ile-de-France II-CDW_2016_0014). REGISTRATION DETAILS: Clinical Trial.gov registration: NCT02898090.

Phase I study of axitinib and everolimus in metastatic solid tumours and extension to metastatic renal cell carcinoma: Results of EVAX study.

PURPOSE: Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. EXPERIMENTAL DESIGN: Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. RESULTS: 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. CONCLUSION: The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.

Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial.

BACKGROUND: 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. METHODS AND FINDINGS: 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%). CONCLUSION: 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.).