Daytime Sleepiness Is Associated with Lower Cognitive Scores: The Look AHEAD Study.

Background: Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may be associated with cognition in older adults. Objectives: We investigated the association between self-reported daytime sleepiness and cognitive function in the Look AHEAD clinical trial. Design: Observational follow-up of a randomized clinical trial of an intensive lifestyle intervention. Setting: Clinic. Participants: Participants (n=1,778) aged 45-76 years at baseline with type 2 diabetes and overweight or obesity. Interventions: Participants were randomized to an intensive lifestyle intervention for weight loss or a control condition of diabetes support and education. Measurements: Participants provided self-reported levels of daytime sleepiness at baseline and years 12-13. Cognitive function was assessed with a neurocognitive battery at years 12-13 and 18-20. Results: Participants who reported having frequent daytime sleepiness (often or always) performed significantly worse than others on the cognitive composite (-0.35; p-value=0.014) after controlling for covariates. When stratified by intervention arm, participants assigned to the intensive lifestyle intervention who reported often/always having daytime sleepiness performed worse on Digit Symbol Coding (-0.63; p-value=0.05) and Trail Making Part-B (-0.56; p-value=0.02) after controlling for covariates. Statistical interactions revealed associations between daytime sleepiness and the following covariates: race and ethnicity, APOE ε4 carrier status, baseline history of cardiovascular disease, and depression. Conclusions: Daytime sleepiness over ~13 years predicted poorer cognitive performance in older individuals who, by virtue of having diabetes and overweight/obesity, are at high risk for sleep disorders and cognitive impairment.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Prediabetes and deprivation: A couple at high risk of diabetes.

AIM: The higher prevalence of diabetes in deprived populations is well documented but little is known about the risk of diabetes associated with deprivation among pre-diabetic subjects. The aim of the study was to evaluate the risk of diabetes in a population of deprived pre-diabetic patients. METHODS: 2743 pre-diabetic subjects identified using the American Diabetes Association (ADA) criteria, 16 to 85 years old, 1656 non-deprived and 1087 deprived, had at least two health check-ups at an interval of 4.95 (2.04) vs 3.20 (1.71) years, P<0.0001, respectively. At the first visit, socioeconomic status was assessed using the EPICES score to differentiate deprived and non-deprived subjects. RESULTS: At the second visit, the prevalence of overt diabetes was 9.5% among deprived vs 5.1% in the non-deprived group (P<0.001). After adjustment on confounding factors, deprivation was found independently associated with occurrence of diabetes [1.70 (1.15-2.51), P=0.01]. Beyond social deprivation, Fasting Plasma Glucose and waist circumference were the main independent predictors of new-onset diabetes. CONCLUSION: After 4 years of follow-up, among subjects with prediabetes, prevalence of diabetes was twice as high among deprived compared with non-deprived subjects. Deprived populations with pre-diabetes may require specific public health approaches to avoid the occurrence of overt diabetes.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Transcriptomic changes in the nasal epithelium associated with diesel engine exhaust exposure.

BACKGROUND: Diesel engine exhaust (DEE) exposure causes lung cancer, but the molecular mechanisms by which this occurs are not well understood. OBJECTIVES: To assess transcriptomic alterations in nasal epithelium of DEE-exposed factory workers to better understand the cellular and molecular effects of DEE. METHODS: Nasal epithelial brushings were obtained from 41 diesel engine factory workers exposed to relatively high levels of DEE (17.2-105.4 µg/m3), and 38 unexposed workers from factories without DEE exposure. mRNA was profiled for gene expression using Affymetrix microarrays. Linear modeling was used to identify differentially expressed genes associated with DEE exposure and interaction effects with current smoking status. Pathway enrichment among differentially expressed genes was assessed using EnrichR. Gene Set Enrichment Analysis (GSEA) was used to compare gene expression patterns between datasets. RESULTS: 225 genes had expression associated with DEE exposure after adjusting for smoking status (FDR q < 0.25) and were enriched for genes in pathways related to oxidative stress response, cell cycle pathways such as MAPK/ERK, protein modification, and transmembrane transport. Genes up-regulated in DEE-exposed individuals were enriched among the genes most up-regulated by cigarette smoking in a previously reported bronchial airway smoking dataset. We also found that the DEE signature was enriched among the genes most altered in two previous studies of the effects of acute DEE on PBMC gene expression. An exposure-response relationship was demonstrated between air levels of elemental carbon and the first principal component of the DEE signature. CONCLUSIONS: A gene expression signature was identified for workers occupationally exposed to DEE that was altered in an exposure-dependent manner and had some overlap with the effects of smoking and the effects of acute DEE exposure. This is the first study of gene expression in nasal epithelial cells of workers heavily exposed to DEE and provides new insights into the molecular alterations that occur with DEE exposure.

Association of sleep characteristics with suicidal ideation and suicide attempt among adults aged 50 and older with depressive symptoms in low- and middle-income countries.

OBJECTIVES: Investigate the association of sleep characteristics with suicidal ideation and suicide attempt among middle-aged and older adults with depressive symptoms in five low- and middle-income countries (LMICs). DESIGN: Cross-sectional. SETTING: China, Ghana, India, Russia, and South Africa. PARTICIPANTS: Adults aged ≥50 years with depressive symptoms from the World Health Organization (WHO) Study on Global AGEing and Adult Health (n=2,040). MEASUREMENTS: Predictors were self-reported average sleep duration for the past 2 nights (<7 hours (shorter), 7 to <9 hours (reference), ≥9 hours (longer)), sleep quality for the past 2 nights (moderate/good/very good [both nights], poor/very poor [≥1 night]), past-month insomnia symptoms (none/mild, moderate, severe/extreme), and past-day daytime sleepiness. Outcomes were past-year suicidal ideation and suicide attempt. Analyses were adjusted for age, sex, household wealth, marital status, self-rated health, cognitive performance, number of depressive symptoms, and country of residence. RESULTS: Participants with poor/very poor sleep quality ≥1 night had greater odds of suicidal ideation (vs. moderate/good/very good sleep quality both nights). Participants with moderate and severe/extreme insomnia symptoms had greater odds of suicidal ideation and suicide attempt (vs. none/mild insomnia symptoms). In moderation analyses, greater insomnia symptoms were associated with higher odds of suicidal ideation among women only and those aged 60-60 years and ≥80 years only. CONCLUSIONS: Among middle-aged and older adults with depressive symptoms in LMICs, sleep characteristics are markers of-and potential contributors to-suicidal ideation and suicide attempt, and there was evidence of moderation by age and sex. Interventions aimed at preventing suicide-related outcomes in these populations should consider the role of sleep.

Quality of Life and Mental Health in Older Adults with Obesity and Frailty: Associations with a Weight Loss Intervention.

OBJECTIVE: To examine the bi-directional associations of a weight loss intervention with quality of life and mental health in obese older adults with functional limitations. DESIGN: Combined-group analyses of secondary variables from the MEASUR-UP randomized controlled trial. SETTING: Academic medical center. PARTICIPANTS: Obese community-dwelling men and women (N = 67; age ≥60; BMI ≥30) with functional limitations (Short Physical Performance Battery [SPPB] score of 4-10 out of 12). INTERVENTION: Six-month reduced calorie diet at two protein levels. MEASUREMENTS: Weight, height, body composition, physical function, medical history, and mental health and quality of life assessments (Center for Epidemiologic Studies Depression Scale [CES-D]; Profile of Mood States [POMS], Pittsburgh Sleep Quality Index [PSQI]; Perceived Stress Scale [PSS]; Satisfaction with Life Scale [SWLS]; and Short Form Health Survey [SF-36]) were acquired at 0, 3 and 6 months. RESULTS: Physical composite quality of life (SF-36) improved significantly at 3 months (ß = 6.29, t2,48 = 2.60, p = 0.012) and 6 months (ß = 10.03, t2,48 = 4.83, p < 0.001), as did several domains of physical quality of life. Baseline depression symptoms (CES-D and POMS) were found to predict lower amounts of weight loss; higher baseline sleep latency (PSQI) and anger (POMS) predicted less improvement in physical function (SPPB). CONCLUSION: The significant bi-directional associations found between a weight loss intervention and mental health/quality of life, including substantial improvements in physical quality of life with obesity treatment, indicate the importance of considering mental health and quality of life as part of any weight loss intervention for older adults.

Impact of acute exposure to cigarette smoke on airway gene expression.

BACKGROUND: Understanding effects of acute smoke exposure (ASE) on airway epithelial gene expression and their relationship with the effects of chronic smoke exposure may provide biological insights into the development of smoking-related respiratory diseases. METHODS: Bronchial airway epithelial cell brushings were collected from 63 individuals without recent cigarette smoke exposure and before and 24 h after smoking three cigarettes. RNA from these samples was profiled on Affymetrix Human Gene 1.0 ST microarrays. RESULTS: We identified 91 genes differentially expressed 24 h after ASE (false discovery rate < 0.25). ASE induced genes involved in xenobiotic metabolism, oxidative stress, and inflammation and repressed genes related to cilium morphogenesis and cell cycle. While many genes altered by ASE are altered similarly in chronic smokers, metallothionein genes are induced by ASE and suppressed in chronic smokers. Metallothioneins are also suppressed in current and former smokers with lung cancer relative to those without lung cancer. CONCLUSIONS: Acute exposure to as little as three cigarettes and chronic smoking induce largely concordant changes in airway epithelial gene expression. Differences in short-term and long-term effects of smoking on metallothionein expression and their relationship to lung cancer requires further study given these enzymes' role in the oxidative stress response.

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results: Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. Trial registration number: NCT00940225.

A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.

BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. METHODS: Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. RESULTS: Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

[Requests for assisted reproduction formulated by same-sex couples consulting physicians in France]. / Demandes d'aide à la procréation formulées par les couples de même sexe auprès de médecins en France.

BACKGROUND, MATERIAL AND METHODS: In order to determine the characteristic features of requests for assisted reproduction formulated by same-sex couples consulting physicians in France, we conducted a study in collaboration with professional organizations, general practitioners, gynecologists and obstetricians who distributed an email questionnaire among their recruitment. RESULTS: In our sample, 191 physicians (71% of responders) reported that 1040 homosexual couples expressed desire to become parents in 2011-2012. Nearly all of the physicians (94%) reported that the couples sought assistance before participating in an assisted reproduction technology (ART) program in a foreign country, but 35% reported that advice was solicited concerning natural reproduction and 48.5% reported requests for advice concerning inseminations performed by the woman herself. Most of the physicians responded to all or part of the requests and 61% of those who had been consulted reported they had directly participated in preparing an ART program in a foreign country. Among the 270 physicians who participated in this study, 162 (60%) believed that ART should be assessable to homosexual couples in France, but less than half of them were in favor of reimbursement by the national health insurance fund. DISCUSSION: Although biased and non-representative, this study shows that assisted reproduction, with or without medical intervention, is a real-life phenomenon for many homosexual couples, and for many physicians, even before same-sex marriage became legal.

Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab.

This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.

Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer.

BACKGROUND: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. PATIENTS AND METHODS: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). RESULTS: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. CONCLUSION: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.

[Measure of premature mortality: comparison of deaths before age 65 and expected years of life lost]. / La mesure de la mortalité prématurée: comparaison des décès avant 65 ans et des années espérées de vie perdues.

BACKGROUND: For many years in France, premature mortality (i.e., deaths before 65 years old) and avoidable deaths have generally been used to monitor health of the population and help to elaborate policies in this area. This paper aims to examine the utility of another indicator of premature mortality, which makes it possible to take into account the impact of deaths, the expected years of life lost (EYLL). METHODS: Mortality data for France in the years 2000 to 2002 were obtained from the Centre for Epidemiology of the Medical Causes of Death. Premature mortality was defined as death before 65 years of age. For the calculation of EYLL, the mortality norm chosen was French-life expectancy for the years 2001 to 2003. In order to study the spatial distribution of the indicators above defined, standardized ratios were calculated for each administrative area, taking France as the reference population. RESULTS: Irrespective of the gender and indicator considered, ranking of the causes emphasized three major groups of pathological conditions, which are strongly distinguished from the others: cardiovascular diseases, malignant neoplasm and injuries. The ranking of causes varied considerably according to the indicator used. The spatial representation of standardized ratios of expected years of life lost and deaths before 65 showed a strong North-South trend. CONCLUSION: The concept of premature mortality is difficult to define and discussions persist on the age limit to use for its quantification. The choice of an indicator strongly depends on the use which one wishes to make. The simple analysis of deaths before 65 years currently used to describe premature mortality in France makes it possible to describe its frequency. The use of a summary measure as EYLL allows to quantify the impact of premature mortality by giving different weights to deaths depending on the age of occurrence. EYLL, thus, seems to be an indicator, which is particularly adapted to decision-making in public health, depending on choices and values one wishes to give preference to.

Reproductive life events in the population living in the vicinity of a nuclear waste reprocessing plant.

OBJECTIVE: There is concern about the health of populations living close to nuclear waste reprocessing plants. A comparative study was conducted on reproductive life events in the general population living near the nuclear waste reprocessing plant in Beaumont-Hague, France and a reference area in Brittany. DESIGN, SETTING AND PARTICIPANTS: Women were randomly selected and retrospectively questioned on reproductive life events occurring between 1985 and 2000. The monthly probability of pregnancy (assessed by time to pregnancy for pregnancy attempts leading or not to a live birth), occurrence of involuntary infertility, miscarriage and birth weight were compared between both areas using regression models with random effect. RESULTS: Compared with the reference area (326 couples) and after adjustment for sociodemographic and behavioural factors, couples from Beaumont-Hague (857 couples) had an estimated hazard ratio of pregnancy of 1.19 (95% CI 0.89 to 1.58). The prevalence ratio of 12-month involuntary infertility was 0.99 (95% CI 0.64 to 1.55) and the odds ratio of miscarriage was 0.86 (95% CI 0.85 to 1.33) for Beaumont-Hague, compared with the reference area. Mean birth weight was similar in both areas (95% CI of difference -85 g to 53 g). CONCLUSION: No increased risk of adverse reproductive life events was highlighted in the population living in the vicinity of the French nuclear waste reprocessing plant, compared with the reference area. Reproductive health is unlikely to be strongly altered in the general population of Beaumont-Hague.