Age at death during the Covid-19 lockdown in French metropolitan regions: a non parametric quantile regression approach.

BACKGROUND: Lockdowns have been implemented to limit the number of hospitalisations and deaths during the first wave of 2019 coronavirus disease. These measures may have affected differently death characteristics, such age and sex. France was one of the hardest hit countries in Europe with a decreasing east-west gradient in excess mortality. This study aimed at describing the evolution of age at death quantiles during the lockdown in spring 2020 (17 March-11 May 2020) in the French metropolitan regions focusing on 3 representatives of the epidemic variations in the country: Bretagne, Ile-de-France (IDF) and Bourgogne-Franche-Comté (BFC). METHODS: Data were extracted from the French public mortality database from 1 January 2011 to 31 August 2020. The age distribution of mortality observed during the lockdown period (based on each decile, plus quantiles 1, 5, 95 and 99) was compared with the expected one using Bayesian non-parametric quantile regression. RESULTS: During the lockdown, 5457, 5917 and 22 346 deaths were reported in Bretagne, BFC and IDF, respectively. An excess mortality from + 3% in Bretagne to + 102% in IDF was observed during lockdown compared to the 3 previous years. Lockdown led to an important increase in the first quantiles of age at death, irrespective of the region, while the increase was more gradual for older age groups. It corresponded to fewer young people, mainly males, dying during the lockdown, with an increase in the age at death in the first quantile of about 7 years across regions. In females, a less significant shift in the first quantiles and a greater heterogeneity between regions were shown. A greater shift was observed in eastern region and IDF, which may also represent excess mortality among the elderly. CONCLUSIONS: This study focused on the innovative outcome of the age distribution at death. It shows the first quantiles of age at death increased differentially according to sex during the lockdown period, overall shift seems to depend on prior epidemic intensity before lockdown and complements studies on excess mortality during lockdowns.

Modeling the impact of national and regional lockdowns on the 2020 spring wave of COVID-19 in France.

Several countries have implemented lockdowns to control their COVID-19 epidemic. However, questions like "where" and "when" still require answers. We assessed the impact of national and regional lockdowns considering the French first epidemic wave of COVID-19 as a case study. In a regional lockdown scenario aimed at preventing intensive care units (ICU) saturation, almost all French regions would have had to implement a lockdown within 10 days and 96% of ICU capacities would have been used. For slowly growing epidemics, with a lower reproduction number, the expected delays between regional lockdowns increase. However, the public health costs associated with these delays tend to grow with time. In a quickly growing pandemic wave, defining the timing of lockdowns at a regional rather than national level delays by a few days the implementation of a nationwide lockdown but leads to substantially higher morbidity, mortality, and stress on the healthcare system.

A cross-sectional study on infectious health risks regarding freshwater sports practice in Brittany, France.

Freshwater sports expose practitioners to pathogens in the water environment and may result in infection. In French Brittany, these infections are particularly worrying, especially since 2016 with an increase in the incidence of leptospirosis reaching 1 case per 100,000 inhabitants, which represents the highest incidence observed since 1920. We aimed to estimate the prevalence of infectious diseases related to freshwater sports practice and to identify the factors associated with these infections among freshwater sports licensees in Brittany, France. From March 18, 2019, to May 8, 2019, we interviewed freshwater sports licensees (online study) and club presidents and instructors (phone study) in Brittany. Licensee participants were 18 years old or more and practiced at least one freshwater sport in one of the 79 Brittany clubs. We used logistic regression models to study the association between our variables of interest and potential risk factors. In total, 551 licensees (20.3% of the total number of licensees) and 38 clubs (48.1%) were surveyed. Among the licensees, 29 (5.3%) reported being diagnosed with leptospirosis, of which 12 (41.3%) occurred in the last 5 years. The most reported symptoms were skin irritation/itchy skin (24.3%) and 39 individuals (7.1%) reported at least one hospitalization in their lifetime for a disease related to freshwater sports. The occurrence of leptospirosis was negatively associated with boarding from a pontoon (odds ratio (OR)=0.20, 95% confidence interval (95% CI) 0.06-0.56), practicing for less than 4 years (OR=0.17, 95% CI 0.04-0.56) compared to more than 10 years, and the occurrence of leptospirosis was positively associated with taking a soapy shower after practice (OR=4.38, 95% CI 1.90-10.51). Eskimo roll was positively associated with the occurrence of otitis and conjunctivitis (OR=3.22, 95% CI 1.82-6.03), and skin irritation/itchy skin (OR=1.66, 95% CI 0.99-2.84). Otitis, conjunctivitis, and skin irritation/itchy skin are the most commonly reported freshwater sport-related diseases in French Brittany. Despite a good level of knowledge of prevention measures, their implementation by licensees and clubs remains low. Further studies are needed to identify practices associated with infectious risk in freshwater sports.

Evaluating COVID-19 Booster Vaccination Strategies in a Partially Vaccinated Population: A Modeling Study.

BACKGROUND: Several countries are implementing COVID-19 booster vaccination campaigns. The objective of this study was to model the impact of different primary and booster vaccination strategies. METHODS: We used a compartmental model fitted to hospital admission data in France to analyze the impact of primary and booster vaccination strategies on morbidity and mortality, assuming waning of immunity and various levels of virus transmissibility during winter. RESULTS: Strategies prioritizing primary vaccinations were systematically more effective than strategies prioritizing boosters. Regarding booster strategies targeting different age groups, their effectiveness varied with immunity and virus transmissibility levels. If the waning of immunity affects all adults, people aged 30 to 49 years should be boosted in priority, even for low transmissibility levels. CONCLUSIONS: Increasing the primary vaccination coverage should remain a priority. If a plateau has been reached, boosting the immunity of younger adults could be the most effective strategy, especially if SARS-CoV-2 transmissibility is high.

Agent-based modelling of reactive vaccination of workplaces and schools against COVID-19.

With vaccination against COVID-19 stalled in some countries, increasing vaccine accessibility and distribution could help keep transmission under control. Here, we study the impact of reactive vaccination targeting schools and workplaces where cases are detected, with an agent-based model accounting for COVID-19 natural history, vaccine characteristics, demographics, behavioural changes and social distancing. In most scenarios, reactive vaccination leads to a higher reduction in cases compared with non-reactive strategies using the same number of doses. The reactive strategy could however be less effective than a moderate/high pace mass vaccination program if initial vaccination coverage is high or disease incidence is low, because few people would be vaccinated around each case. In case of flare-ups, reactive vaccination could better mitigate spread if it is implemented quickly, is supported by enhanced test-trace-isolate and triggers an increased vaccine uptake. These results provide key information to plan an adaptive vaccination rollout.

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.

Time-series modelling for the quantification of seasonality and forecasting antibiotic-resistant episodes: application to carbapenemase-producing Enterobacteriaceae episodes in France over 2010-20.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) cause resistant healthcare-associated infections that jeopardize healthcare systems and patient safety worldwide. The number of CPE episodes has been increasing in France since 2009, but the dynamics are still poorly understood. OBJECTIVES: To use time-series modelling to describe the dynamics of CPE episodes from August 2010 to December 2016 and to forecast the evolution of CPE episodes for the 2017-20 period. METHODS: We used time series to analyse CPE episodes from August 2010 to November 2016 reported to the French national surveillance system. The impact of seasonality was quantified using seasonal-to-irregular ratios. Seven time-series models and three ensemble stacking models (average, convex and linear stacking) were assessed and compared with forecast CPE episodes during 2017-20. RESULTS: During 2010-16, 3559 CPE episodes were observed in France. Compared with the average yearly trend, we observed a 30% increase in the number of CPE episodes in the autumn. We noticed a 1 month lagged seasonality of non-imported episodes compared with imported episodes. Average stacking gave the best forecasts and predicted an increase during 2017-20 with a peak up to 345 CPE episodes (95% prediction interval = 124-1158, 80% prediction interval = 171-742) in September 2020. CONCLUSIONS: The observed seasonality of CPE episodes sheds light on potential factors associated with the increased frequency of episodes, which need further investigation. Our model predicts that the number of CPE episodes will continue to rise in the coming years in France, mainly due to local dissemination, associated with bacterial carriage by patients in the community, which is becoming an immediate challenge with regard to outbreak control.

Teriflunomide-exposed pregnancies in a French cohort of patients with multiple sclerosis.

OBJECTIVE: To describe pregnancies exposed to teriflunomide (TERIF) in women with multiple sclerosis (MS) in France over the period 2014-2016. METHODS: All 15- to 49-year-old women with MS in the national health insurance database were included. Pregnancies that had started between August 2014 and March 2016 were identified from their outcomes. Three groups according to treatment exposure were compared: TERIF, interferons (IFNs) or glatiramer acetate, and no medication. RESULTS: Among the 44,008 women with MS followed 24.5 months on average, 2,639 pregnancies were identified. There were 1,538 pregnancies (58.3%) that were not exposed to any MS treatment in accordance with the guidelines. A total of 673 pregnancies (25.5%) were exposed to IFN and/or glatiramer acetate, and possible or probable exposure to contra-indicated treatments was observed in 428 pregnancies (16.2%), of whom 47 pregnancies were exposed to TERIF. The annual incidence rate of pregnancies exposed to TERIF was 1.4 per 100 patient-years; i.e., 3 times less than the 2 control groups (5.6 and 4.7, respectively). The median exposure duration to TERIF was 45 days after conception. The outcomes comprised 23 live births, 22 abortions (3 times more than the 2 other groups), and 2 miscarriages. All newborns were healthy at birth. CONCLUSIONS: Despite specific TERIF guidelines for pregnancy-related issues and the availability of alternative therapies, some pregnancies exposed to TERIF were identified. Most of the cases were because of the absence of the recommended accelerated elimination procedure and appeared to be mostly unplanned pregnancies that probably reflect a lack of effective contraception.

Prevalence of mental disorders is higher in patients with multiple sclerosis than in the general population or in patients with rheumatoid arthritis in France.

BACKGROUND: Mental disorders (MDs) in multiple sclerosis (MS) patients decreases treatment adherence and quality of life, and increases the risk of disability progression and care consumption. OBJECTIVE: This study was to assess the prevalence of MDs in MS patients compared with healthy controls (HC) of the French general population and rheumatoid arthritis (RA) patients. METHODS: The 2015 prevalence of MDs for MS patients, RA patients and general population was estimated using a random population-based data sample from 'National Inter-Scheme Information System on Health Insurance' in the 2011-2015 period. Two control groups (1:5 ratio for the HC and 1:1 for the RA group) were matched to the MS group for year of birth, gender, area of residence and health insurance scheme. RESULTS: A total of 1145 MS patients were identified (sex ratio of 2.5 (F/M); median age 50 years). The prevalence of MDs was higher in the population of patients with MS (37.3%) than in the French general population (13.6%), and to a lesser extent in the RA group (21.1%) leading to the prevalence ratios of 2.8 (95% confidence intervals (CIs) 2.5-3.0) and 1.9 (95% CI 1.7-2.3), respectively. CONCLUSIONS: This study confirmed that MS patients are at a higher risk of MDs than the French general population or RA patients.

Use of state sequence analysis for care pathway analysis: The example of multiple sclerosis.

The concept of care pathways is increasingly being used to enhance the quality of care and to optimize the use of resources for health care. We here propose an innovative method in epidemiology that is derived from social sciences: state sequence analysis (SSA). This method takes into account the chronology of care consumption and allows for identification of specific patterns. A process for using SSA in the health area is proposed and discussed. The main steps are: data coding, measurement of dissimilarities between sequences (focusing on optimal matching methods and the choice of related costs), and application of a clustering method to obtain a typology of sequence patterns. As an example of its use in the health area, SSA was employed to analyse care pathways of a random sample of patients with multiple sclerosis. This sample has been selected from the main French healthcare database covering the period 2007 to 2013 (n = 1 000). A five-cluster typology was obtained which allowed distinction of care consumption groups. Overall, about half of the patients had low care consumption, about one quarter had medium to high consumption, and another quarter had high consumption. We conclude that state sequence analysis is an innovative and flexible methodology that is worth considering in health care research.

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.

Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses.

BACKGROUND: Seasonal variation of relapses in multiple sclerosis (MS) suggests that season-dependent factors, such as ambient air pollution, may trigger them. However, only few studies have considered possible role of air pollutants as relapse's risk factor. OBJECTIVE: We investigated the effect of particulate matter of aerodynamic diameter smaller than 10µm (PM10) on MS relapses. METHODS: In total, 536 relapsing MS patients from Strasbourg city (France) were included, accounting for 2052 relapses over 2000-2009 period. A case-crossover design was used with cases defined as the days of relapse and controls being selected in the same patient at plus and minus 35 days. Different lags from 0 to 30 days were considered. Conditional logistic regressions, adjusted on meteorological parameters, school and public holidays, were used and exposure was considered first as a quantitative variable and second, as a binary variable. RESULTS: The natural logarithm of the average PM10 concentration lagged from 1 to 3 days before relapse onset was significantly associated with relapse risk (OR =1.40 [95% confidence interval 1.08-1.81]) in cold season. Consistent results were observed when considering PM10 as a binary variable, even if not significant. CONCLUSION: With an appropriate study design and robust ascertainment of neurological events and exposure, the present study highlights the effect of PM10 on the risk of relapse in MS patients, probably through oxidative stress mechanisms.

DEEP CLUSTERING AND CONVENTIONAL NETWORKS FOR MUSIC SEPARATION: STRONGER TOGETHER.

Deep clustering is the first method to handle general audio separation scenarios with multiple sources of the same type and an arbitrary number of sources, performing impressively in speaker-independent speech separation tasks. However, little is known about its effectiveness in other challenging situations such as music source separation. Contrary to conventional networks that directly estimate the source signals, deep clustering generates an embedding for each time-frequency bin, and separates sources by clustering the bins in the embedding space. We show that deep clustering outperforms conventional networks on a singing voice separation task, in both matched and mismatched conditions, even though conventional networks have the advantage of end-to-end training for best signal approximation, presumably because its more flexible objective engenders better regularization. Since the strengths of deep clustering and conventional network architectures appear complementary, we explore combining them in a single hybrid network trained via an approach akin to multi-task learning. Remarkably, the combination significantly outperforms either of its components.

Efficacy of hepatitis B sero-vaccination in newborns of African HBsAg positive mothers.

BACKGROUND: Maternal-infant transmission of hepatitis B virus (HBV) during birth carries a high risk of chronic HBV infection in infants. Appropriate neonatal prophylaxis is effective in preventing perinatal transmission of HBV. The purpose of this study was to evaluate the protective efficacy of anti-HBV sero-vaccination in newborns of HBsAg positive mothers from Mayotte, French island in the Mozambican canal. PATIENTS AND METHODS: One-hundred newborns of HBsAg positive mothers were identified retrospectively on the basis of hospital medical record and hepatitis B immune globulin (HBIG) prescriptions review from 1994 to 2007. To determine the rate of protective efficacy of neonatal prophylaxis defined by anti HBs antibodies >10 IU/mL with negative HBsAg, anti HBc and HBV DNA testing, HBV serological markers were performed in vaccinated children. RESULTS: Eighty-three of 100 newborns (83%) were given a complete sero-vaccination. Maternal HBe Ag status at delivery (available in 93%) was positive in 56 (60%) of cases and HBV viral load (available in 57%) was <5 logIU/mL, between 5 and 7 logsIU/mL and >7 logsIU/mL in 23 (40.4%), 12 (21%) and 22 (38.6%), respectively. HBV markers in all children at a median age of 5 years [IQR 2-8] showed that 76% were protected with anti HBs >10 IU/mL, despite incomplete sero-vaccination in 12 infants; 6% of infants had anti-HBs and anti-HBc positivity with undetectable HBV DNA, 1% had isolated anti HBc while 14% were seronegative. Only 3% had evidence of immunoprophylaxis failure: 1 infant was HBsAg carrier and 2 had detectable HBV DNA without HBsAg (occult HBV infection). The only factor associated with sustained protective efficacy was on time serological control performed within one year of life, whereas maternal age, HBeAg status and HBV viral load on delivery were not. CONCLUSION: The anti-HBV sero-vaccination of newborns of HBsAg-positive mothers is fairly done in Mayotte and allows a high protection of mother-to-child transmission in a mean endemic area with fair safety. Screening of sero-vaccination failures has to be reinforced in order either to revaccinate or to treat infected children.