The Response Study: A French registry on pregnancy in women with MS and related disorders and their children up to 6 years-Protocol, recruitment status, and baseline characteristics.

BACKGROUND: Counseling on pregnancy is still challenging, particularly regarding the use of disease-modifying treatments (DMTs). We are lacking long-term outcomes in children exposed to DMTs. OBJECTIVES: This study aimed to set up a French pregnancy registry for women with multiple sclerosis (MS) and related disorders nested within the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. METHODS: Prospective, observational, multicentric, epidemiological study in France. Neurological visits are organized according to routine practice. Data are collected on the OFSEP minimal datasheet. Auto-questionnaires on pregnancy are completed by patients at Months 5-6 and 8 during pregnancy, and Months 3, 6, and 12 postpartum. A specific survey on analgesia is completed by anesthesiologists. Pediatric data are collected from the child's health book, where visits on Day 8, Month 9, and 24 are mandatory. Parents complete neurodevelopmental questionnaires at Year 1, Years 2 and 6. RESULTS: The RESPONSE study started in August 2019. On 7 April 2023, 515 women were included. Baseline demographics are presented. CONCLUSIONS: RESPONSE will provide rich information on the global management of pregnancy in France and prospective data on children until the age of 6 years, exposed or not to a DMT, including data on neurodevelopment that can be compared to the general population. STUDY FUNDING: EDMUS and ARSEP Foundation, Biogen, Roche.

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION: These recommendations propose a strategic approach to managing cancer risk in PwMS.

Low socioeconomic status was associated with a higher mortality risk in multiple sclerosis.

BACKGROUND: The relationship between socioeconomic status (SES) and mortality among persons with multiple sclerosis (PwMS) is poorly understood. OBJECTIVE: To investigate the association between SES and mortality risk in PwMS. METHODS: From health-administrative data, we identified 12,126 incident MS cases with a first demyelinating event (MS 'onset') occurring between 1994 and 2017. Cox proportional hazard model assessed the association between socioeconomic status quintiles (SES-Qs) at MS onset and all-cause mortality. RESULTS: Lower SES-Qs were associated with higher mortality risk; adjusted hazard ratios: SES-Q1 (most deprived) =1.61 (95% confidence interval (CI) = 1.36-1.91); SES-Q2 = 1.26 (95% CI = 1.05-1.50); SES-Q3 = 1.22 (95% CI = 1.02-1.46); SES-Q4 = 1.13 (95% CI = 0.94-1.35) versus SES-Q5 (least deprived). CONCLUSION: A lower SES was associated with higher mortality risk in PwMS.

Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society.

OBJECTIVE: The objective of this study was to develop evidence-based recommendations on pregnancy management for persons with multiple sclerosis (MS). BACKGROUND: MS typically affects young women in their childbearing years. Increasing evidence is available to inform questions raised by MS patients and health professionals about pregnancy issues. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and university databases (January 1975 through June 2021). The RAND/UCLA appropriateness method was developed to synthesise the scientific literature and expert opinions on healthcare topics; it was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 104 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, locoregional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses and disease-modifying treatments. CONCLUSION: The 2022 recommendations of the French MS society should be helpful to harmonise counselling and treatment practice for pregnancy in persons with MS, allowing for better and individualised choices.

Improving the decision to switch from first- to second-line therapy in multiple sclerosis: A dynamic scoring system.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression. OBJECTIVE: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy. METHODS: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs). RESULTS: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09-0.22) for the waiting group and 0.40 (95% CI 0.32-0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30-0.46) and 0.44 (95% CI 0.37-0.52), respectively. CONCLUSIONS: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.

Pregnancy and neuromyelitis optica spectrum disorders: 2022 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed. OBJECTIVES: To establish recommendations on pregnancy in women with NMOSD. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments. CONCLUSION: Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.

Care consumption of people with multiple sclerosis: A multichannel sequence analysis in a population-based setting in British Columbia, Canada.

BACKGROUND: Persons with multiple sclerosis (PwMS) typically require complex multidisciplinary care, which is rarely formally assessed. OBJECTIVES: We applied multichannel sequence analysis (MCSA) to identify care consumption patterns by PwMS in British Columbia, Canada. METHODS: We created two cohorts, comprising incident and prevalent MS cases, using linked clinical and administrative data. We applied MCSA to quantify and compare the care pathways of PwMS, based on all-cause hospitalizations and physician visits (divided into five specialities). Care consumption clusters were characterized using demographic and clinical features. RESULTS: From 1048 incident and 3180 prevalent PwMS, the MCSA identified 12 and 6 distinct care consumption clusters over a median follow-up of 9.6 and 13.0 years, respectively. Large disparities between clusters were observed; the median number of annual consultations ranged from 5.6 to 21.3 for general practitioners, 1.2 to 4.6 for neurologists and 0 to 5.3 for psychiatrists in the incident cohort. Characteristics at MS symptom onset associated with the highest care consumption included high comorbidity burden and older age. There were similar disparities and associations for prevalent PwMS. CONCLUSION: The distinct patterns of care consumption, which were reminiscent of the heterogeneity of MS itself, may facilitate health service planning and evaluation, and provide a novel outcome measure in health research.

Pregnancy in women with multiple sclerosis in France from 2010 to 2015: Incidence, outcomes, and exposure to disease-modifying therapies.

BACKGROUND: Multiple sclerosis (MS) is usually diagnosed between 20-40 years old, when women often plan to have children. OBJECTIVE: Our objectives were to estimate pregnancy incidence rates in women with multiple sclerosis (MS), and to describe the use of disease-modifying therapies (DMTs) before conception and during pregnancy, and pregnancy outcomes. METHODS: This retrospective cohort study included all 15- to 49-year-old women with MS in the French national health insurance database over 2010-2015. A pregnancy was exposed if a DMT reimbursement claim occurred during pregnancy or in the 14 preceding days. We used zero-inflated negative binomial (ZINB) regression models to estimate incidence rates and ordinal and multinomial regression models to estimate DMT exposure and pregnancy outcomes. RESULTS: The pregnancy incidence rate was 4.5 per 100 person-years. The probability of having a DMT-exposed pregnancy increased from 0.22 in 2010 to 0.30 in 2015. The probability of live birth was 0.72 (95% CI = 0.70-0.74) for exposed pregnancies (varied considerably among DMTs), 0.77 (95% CI = 0.76-0.79) without treatment, and 0.81 (95% CI = 0.79-0.83) if treatment was stopped within the previous year. CONCLUSION: In this population-based study, we showed an increase of exposed pregnancies over time, beta-interferon and glatiramer acetate being the most used DMTs and associated with the highest probabilities of live birth. Interrupted exposed pregnancies may reflect undesired pregnancies or fear of an adverse outcome, while recent DMT stop probably reflects pregnancy planning.

Disability Progression in Multiple Sclerosis Patients using Early First-line Treatments.

BACKGROUND: Therapeutic management of relapsing-remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression among RRMS first-line treated patients. METHODS: This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1996/01/01 to 2012/31/12 (N=5,279) from ten MS expert OFSEP centers (Observatoire Français de la Sclérose en Plaques). The delay from treatment start to attain an irreversible Expanded Disability Status Scale score of 3.0 were compared between "Early" group (N= 1,882; treated within 12 months following MS clinical onset) and "Later" group using propensity score weighted Kaplan-Meier methods, overall and stratified by age. RESULTS: Overall, the restricted mean time before reaching EDSS 3.0 (RMST) from treatment start was 11 years and two months for patients treated within the year following MS clinical onset and 10 years and seven months for patients treated later. Thus, early treated patients gained 7 months (95% CI: [4-11] months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in RMST was respectively six months (95% CI: [1-10] months) and 14 months (95% CI: [4-24] months) in the "≤40 years" age group and in the ">40 years" age group, in favour of early group. . CONCLUSIONS: Early treatment initiation resulted in a significant reduction of disability progression among patients with RRMS, and also among older patients.

Cumulative effects of therapies on disability in relapsing multiple sclerosis.

BACKGROUND: Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far. OBJECTIVE: Explore the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function. RESULTS: At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT). CONCLUSION: Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS.

Determinants of therapeutic lag in multiple sclerosis.

BACKGROUND: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. OBJECTIVES: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. METHODS: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. RESULTS: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5). CONCLUSIONS: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Assessing environmental epidemiology questions in practice with a causal inference pipeline: An investigation of the air pollution-multiple sclerosis relapses relationship.

When addressing environmental health-related questions, most often, only observational data are collected for ethical or practical reasons. However, the lack of randomized exposure often prevents the comparison of similar groups of exposed and unexposed units. This design barrier leads the environmental epidemiology field to mainly estimate associations between environmental exposures and health outcomes. A recently developed causal inference pipeline was developed to guide researchers interested in estimating the effects of plausible hypothetical interventions for policy recommendations. This article illustrates how this multistaged pipeline can help environmental epidemiologists reconstruct and analyze hypothetical randomized experiments by investigating whether an air pollution reduction intervention decreases the risk of multiple sclerosis relapses in Alsace region, France. The epidemiology literature reports conflicted findings on the relationship between air pollution and multiple sclerosis. Some studies found significant associations, whereas others did not. Two case-crossover studies reported significant associations between the risk of multiple sclerosis relapses and the exposure to air pollutants in the Alsace region. We use the same study population as these epidemiological studies to illustrate how appealing this causal inference approach is to estimate the effects of hypothetical, but plausible, environmental interventions.

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

Decreasing impact of late relapses on disability worsening in secondary progressive multiple sclerosis.

BACKGROUND: Changes in relapse activity during secondary progressive multiple sclerosis (SPMS) need to be accurately characterized in order to identify patients who might benefit from continuing disease-modifying therapies. OBJECTIVE: To describe relapse occurrence in patients with SPMS during long-term follow-up and assess its impact on disability worsening. METHODS: This retrospective cohort study included 506 patients. We assessed the influence of relapses on time from SPMS onset to an Expanded Disability Status Scale score of 6 (EDSS 6), and on irreversible worsening of EDSS scores across different periods. RESULTS: The annualized relapse rate (ARR) decreased with patient's age (mean reduction of 43% per decade) and SPMS duration (mean reduction of 46% every 5 years). Post-progression relapses were associated with shorter time from secondary progressive (SP) phase onset to EDSS 6 (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = (1.01, 1.64)). Relapse occurrence during the first 3 years and 3-5 years after SP onset was associated with an increased risk of irreversible EDSS worsening (OR = 3.12 (1.54, 6.31) and 2.04 (1.16, 3.58)). This association was no longer significant after 5 years. CONCLUSION: The occurrence of relapses was a marker of short-term disability progression during early SPMS, but did not have decisive impact in later SPMS.

High-dose biotin in progressive multiple sclerosis: A prospective study of 178 patients in routine clinical practice.

BACKGROUND: A recent controlled trial suggested that high-dose biotin supplementation reverses disability progression in patients with progressive multiple sclerosis. OBJECTIVE: To analyze the impact of high-dose biotin in routine clinical practice on disability progression at 12 months. METHODS: Progressive multiple sclerosis patients who started high-dose biotin at Nantes or Rennes Hospital between 3 June 2015 and 15 September 2017 were included in this prospective study. Disability outcome measures, patient-reported outcome measures, relapses, magnetic resonance imaging (MRI) data, and adverse events were collected at baseline, 6, and 12 months. RESULTS: A total of 178 patients were included. At baseline, patients were 52.0 ± 9.4 years old, mean Expanded Disability Status Scale (EDSS) score was 6.1 ± 1.3, mean disease duration was 16.9 ± 9.5 years. At 12 months, 3.8% of the patients had an improved EDSS score. Regarding the other disability scales, scores either remained stable or increased significantly. In total, 47.4% of the patients described stability, 27.6% felt an improvement, and 25% described a worsening. Four patients (2.2%) had a relapse. Of the 74 patients (41.6%) who underwent an MRI, 20 (27.0%) had new T2 lesions, 8 (10.8%) had gadolinium-enhancing lesions. Twenty-five (14%) reported adverse event. CONCLUSION: In this study, high-dose biotin did not seem to be associated with a clear improvement in disability.

Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition.

BACKGROUND: High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts. OBJECTIVES: The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels. METHODS: Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis. Regional analyses and comparisons with 2013 data were conducted. RESULTS: A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population). MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist. The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years. Females are twice as likely to live with MS as males. CONCLUSIONS: The global prevalence of MS has risen since 2013, but good surveillance data is not universal. Action is needed by multiple stakeholders to close knowledge gaps.

Multiple sclerosis: effect of beta interferon treatment on survival.

Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the 'real-world' setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980-2004) or Rennes, France (1976-2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure ('low', 6 months to 3 years; and 'high', >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53-0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30-0.66), but not between 6 months and 3 years exposure (1.00; 0.73-1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe.

Long-term effect of first-line injectable multiple sclerosis treatments: Input of a time-dependent propensity score.

PURPOSE: The long-term effect of beta-interferon and glatiramer acetate on multiple sclerosis (MS) disability progression has resulted in controversial results, probably due to a lack of appropriate control of biases as raised in observational studies. In particular, the time of the therapeutic decision is difficult to define when the controls are not treated. METHODS: This retrospective observational study was based on a series of patients from the MS expert center in Rennes, France. We used a time-dependent propensity score defined as the linear predictor of a Cox model estimating the hazard of being treated at each time from MS onset. The matching procedure resulted in two groups: patients matched as treated and as not yet treated. The restricted mean times (RMST) to reach a moderate level of disability or worsening of the disability were compared between the two groups in an intention-to-treat analysis. RESULTS: Of the 2383 patients included in the study, 556 were matched as treated. The matching procedure provided a good balance of both the time-fixed and the time-dependent covariates. A slight difference was observed for the time to reach a moderate level of disability, in favor of the "not yet treated" group (difference in the RMST: -0.62 [-0.91; -0.33]) while no difference was found in terms of worsening of the disability (-0.03 [-0.24; 0.33]). CONCLUSION: This unexpected result is probably due to unmeasured confounders. However, this time-dependent PS warrants consideration in long-term effectiveness studies.

Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses.

BACKGROUND: Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM10 exposure has recently been associated with an increased risk of relapses. OBJECTIVES: We further explore the short-term associations between PM10, NO2, benzene (C6H6), O3, and CO exposures, and the odds of MS relapses' occurrence. METHODS: Using a case-crossover design, we studied 424 MS patients living in the Strasbourg area, France between 2000 and 2009 (1783 relapses in total). Control days were chosen to be ± 35 days relative to the case (relapse) day. Exposure was modeled through ADMS-Urban software at the census block scale. We consider single-pollutant and multi-pollutant conditional logistic regression models coupled with a distributed-lag linear structure, stratified by season ("hot" vs. "cold"), and adjusted for meteorological parameters, pollen count, influenza-like epidemics, and holidays. RESULTS: The single-pollutant analyses indicated: 1) significant associations between MS relapse incidence and exposures to NO2, PM10, and O3, and 2) seasonality in these associations. For instance, an interquartile range increase in NO2 (lags 0-3) and PM10 exposure were associated with MS relapse incidence (OR = 1.08; 95%CI: [1.03-1.14] and OR = 1.06; 95%CI: [1.01-1.11], respectively) during the "cold" season (i.e., October-March). We also observed an association with O3 and MS relapse incidence during "hot" season (OR = 1.16; 95%CI: [1.07-1.25]). C6H6 and CO were not significantly related to MS relapse incidence. However, using multi-pollutant models, only O3 remained significantly associated with the odds of relapse triggering during "hot" season. CONCLUSION: We observed significant single-pollution associations between the occurrence of MS relapses and exposures to NO2, O3 and PM10, only O3 remained significantly associated with occurrence of MS relapses in the multi-pollutant model.

Factors Associated with Parent-Child Discrepancies in Reports of Mental Health Disorders in Young Children.

The study compares parent and child reports of child mental health to determine the relationship between parent-child disagreement and parental psychological and attitudinal factors, and to determine how parent-child disagreement is associated with the use of specialized services. A cross-sectional study was conducted with 1268 children aged 6-11 years using the Dominic Interactive and the Strengths and Difficulties Questionnaire. Psychological distress and negative parental attitudes were associated with greater reporting of mental health problems, leading to greater parent-child agreement on symptom presence, and to parental over-reporting of symptoms. Parent/child agreement was associated with 43.83% of contact with a mental health provider for externalizing and 33.73% for internalizing problems. The contribution of key parental psychological and attitudinal factors in parent-child disagreement on child mental health status may prove helpful in improving the identification of children in need of specialized services.