Economic and disease burden of RSV-associated hospitalizations in young children in France, from 2010 through 2018.

BACKGROUND: Respiratory syncytial virus (RSV) is the main cause of infant and child hospitalizations. The study objective is to estimate the RSV-associated hospitalizations and economic burden in young children in France to inform future preventive strategies. METHODS: We conducted a retrospective analysis of RSV-associated hospitalizations data from the French Hospital database (PMSI-MCO) which covers the entire French population. All children aged < 5 years hospitalized with RSV ICD-10 codes (J210, J219, J45, J121, J205, R062) from 2010 to 2018, were included. Descriptive analyses were conducted by RSV seasons (Oct to March), by respiratory years (July to June) and per age groups. RESULTS: On average 45,225 RSV-associated hospitalizations (range: 43,715 - 54,616) per season was reported in France, 69% among children < 1 year old. This represents 28% of all-cause hospitalizations that occurred among children < 1 year old, and less than 10% of all-cause hospitalizations in older children. Number of RSV-associated hospitalizations were similar for infants born during (Oct-March) or outside (April-September) their first RSV season. The highest risk being reported for infants born from September through November. The associated hospitalization cost increased between 2010 - 11 and 2017-18, from €93.2 million to €124.1 million, respectively, and infants < 1 year old represented 80% of the economic burden. CONCLUSION: RSV is an important cause of child hospitalization in France. The burden on healthcare system is mainly driven by < 1 year olds, and preventive strategies should be implemented before the first RSV season.

Hospitalisations with infections related to antimicrobial-resistant bacteria from the French nationwide hospital discharge database, 2016.

Massive use of antibiotics has led to increased bacterial resistance to these drugs, making infections more difficult to treat. Few studies have assessed the overall antimicrobial resistance (AMR) burden, and there is a paucity of comprehensive data to inform health policies. This study aims to assess the overall annual incident number of hospitalised patients with AMR infection in France, using the National Hospital Discharge database. All incident hospitalisations with acute infections in 2016 were extracted. Infections which could be linked with an infecting microorganism were first analysed. Then, an extrapolation of bacterial species and resistance status was performed, according to age class, gender and infection site to estimate the total number of AMR cases. Resistant bacteria caused 139 105 (95% CI 127 920-150 289) infections, resulting in a 12.3% (95% CI 11.3-13.2) resistance rate. ESBL-producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus were the most common resistant bacteria (>50%), causing respectively 49 692 (95% CI 47 223-52 142) and 19 493 (95% CI 15 237-23 747) infections. Although assumptions are needed to provide national estimates, information from PMSI is comprehensive, covering all acute bacterial infections and a wide variety of microorganisms.

[The use of administrative health databases in infectious disease epidemiology and public health]. / Apport des bases médico-administratives en épidémiologie et santé publique des maladies infectieuses.

BACKGROUND: The public health burden resulting from infectious diseases requires efforts in surveillance and evaluation of health care. The use of administrative health databases (AHD) and in particular the French national health insurance database (SNIIRAM) is an opportunity to improve knowledge in this field. The SNIIRAM data network (REDSIAM) workshop dedicated to infectious diseases conducted a narrative literature review of studies using French AHD. From the results, benefits and limits of these new tools in the field of infectious diseases are presented. METHODS: Publications identified by the members of the workgroup were collected using an analytical framework that documented the pathology of interest, the aim of the study, the goal of the developed algorithm, the kind of data, the study period, and the presence of an evaluation or a discussion of the performance of the performed algorithm. RESULTS: Fifty-five articles were identified. A majority focused on the field of vaccination coverage and joint infections. Excluding vaccine coverage field, the aim of 28 studies was epidemiological surveillance. Twenty-six studies used hospital databases exclusively, 18 used ambulatory databases exclusively and 4 used both. Validation or discussion of the performed algorithm was present in 18 studies. CONCLUSIONS: The literature review confirmed the interest of the French AHD in the infectious diseases field. The AHD are additional tools of the existing surveillance systems and their use will probably be more frequent in the coming years given their advantage and reliability. However, incoming users need to be assisted. Thus, the workgroup will contribute to a reasonable use of AHD and support future developments.

Prevalence of traumatic brain injury and epilepsy among prisoners in France: Results of the Fleury TBI study.

OBJECTIVE: The first aim of this study was to estimate the prevalence of TBI and epilepsy in a French prison population and to study variables known to be associated with TBI. The second aim was to compare prisoners with and without a history of TBI. PARTICIPANTS: All offenders (females, males and juveniles) admitted consecutively to Fleury-Mérogis prison over a period of 3 months were included in the study. DESIGN: During the admission procedure, offenders were interviewed by healthcare staff using a self-reported questionnaire. RESULTS: In all, 1221 prisoners were included. The rates of TBI and epilepsy were high, with a prevalence of 30.6% and 5.9%, respectively. Psychiatric care, anxiolytic and antidepressant treatment, use of alcohol and cannabis were all significantly higher among offenders with a history of TBI. Moreover, the number of times in custody and the total time spent in jail over the preceding 5 years were significantly higher among offenders with a history of TBI. CONCLUSIONS: These results provide further evidence that specific measures need to be developed such as, first of all, screening for TBI upon arrival in prison.

The Bayesian microbial subtyping attribution model: robustness to prior information and a proposition.

Attributing foodborne illnesses to food sources is essential to conceive, prioritize, and assess the impact of public health policy measures. The Bayesian microbial subtyping attribution model by Hald et al. is one of the most advanced approaches to attribute sporadic cases; it namely allows taking into account the level of exposure to the sources and the differences between bacterial types and between sources. This step forward requires introducing type and source-dependent parameters, and generates overparameterization, which was addressed in Hald's paper by setting some parameters to constant values. We question the impact of the choices made for the parameterization (parameters set and values used) on model robustness and propose an alternative parameterization for the Hald model. We illustrate this analysis with the 2005 French data set of non-typhi Salmonella. Mullner's modified Hald model and a simple deterministic model were used to compare the results and assess the accuracy of the estimates. Setting the parameters for bacterial types specific to a unique source instead of the most frequent one and using data-based values instead of arbitrary values enhanced the convergence and adequacy of the estimates and led to attribution estimates consistent with the other models' results. The type and source parameters estimates were also coherent with Mullner's model estimates. The model appeared to be highly sensitive to parameterization. The proposed solution based on specific types and data-based values improved the robustness of estimates and enabled the use of this highly valuable tool successfully with the French data set.

PfEMP1 A-Type ICAM-1-Binding Domains Are Not Associated with Cerebral Malaria in Beninese Children.

PfEMP1 is the major antigen involved in Plasmodium falciparum-infected erythrocyte sequestration in cerebrovascular endothelium. While some PfEMP1 domains have been associated with clinical phenotypes of malaria, formal associations between the expression of a specific domain and the adhesion properties of clinical isolates are limited. In this context, 73 cerebral malaria (CM) and 98 uncomplicated malaria (UM) Beninese children were recruited. We attempted to correlate the cytoadherence phenotype of Plasmodium falciparum isolates with the clinical presentation and the expression of specific PfEMP1 domains. Cytoadherence level on Hbec-5i and CHO-ICAM-1 cell lines and var genes expression were measured. We also investigated the prevalence of the ICAM-1-binding amino acid motif and dual receptor-binding domains, described as a potential determinant of cerebral malaria pathophysiology. We finally evaluated IgG levels against PfEMP1 recombinant domains (CIDRα1.4, DBLß3, and CIDRα1.4-DBLß3). CM isolates displayed higher cytoadherence levels on both cell lines, and we found a correlation between CIDRα1.4-DBLß1/3 domain expression and CHO-ICAM-1 cytoadherence level. Endothelial protein C receptor (EPCR)-binding domains were overexpressed in CM isolates compared to UM whereas no difference was found in ICAM-1-binding DBLß1/3 domain expression. Surprisingly, both CM and UM isolates expressed ICAM-1-binding motif and dual receptor-binding domains. There was no difference in IgG response against DBLß3 between CM and UM isolates expressing ICAM-1-binding DBLß1/3 domain. It raises questions about the role of this motif in CM pathophysiology, and further studies are needed, especially on the role of DBLß1/3 without the ICAM-1-binding motif.IMPORTANCE Cerebral malaria pathophysiology remains unknown despite extensive research. PfEMP1 proteins have been identified as the main Plasmodium antigen involved in cerebrovascular endothelium sequestration, but it is unclear which var gene domain is involved in Plasmodium cytoadhesion. EPCR binding is a major determinant of cerebral malaria whereas the ICAM-1-binding role is still questioned. Our study confirmed the EPCR-binding role in CM pathophysiology with a major overexpression of EPCR-binding domains in CM isolates. In contrast, ICAM-1-binding involvement appears less obvious with A-type ICAM-1-binding and dual receptor-binding domain expression in both CM and UM isolates. We did not find any variations in ICAM-1-binding motif sequences in CM compared to UM isolates. UM and CM patients infected with isolates expressing the ICAM-1-binding motif displayed similar IgG levels against DBLß3 recombinant protein. Our study raises interrogations about the role of these domains in CM physiopathology and questions their use in vaccine strategies against cerebral malaria.

[Behavior difficulties, attention difficulties and learning problems in children aged from 3.5 to 8 years: a longitudinal school study]. / Comportement perturbateur, difficultés d'attention et apprentissages entre 3,5 ans et 8 ans: une étude longitudinale en milieu scolaire.

AIM: To evaluate the long term impact of teacher's report of behavior difficulties in children aged 3.5 years. METHOD: Teachers assessed behavior and attention difficulties in 2054 children by questionnaire; reading performance, and behavior and attention difficulties were re-assessed in 695 of these children at second grade (7-8 years). RESULTS: Reading delay was not significantly associated with behavior and attention assessment at 3.5 years. Children with behavior problems according to the teacher were most often different at 3.5 years and at 7-8 years. CONCLUSION: Reading delay at second grade was not related to teacher's report of behavior problems at 3.5 years of age in this french longitudinal school study. These observations are discussed in relation to DSM-IV criteria of disruptive behavior and attention deficit in children.

[Language and behavioral difficulties at age 3 and half and reading delay in grade 2]. / Difficultés de langage et de comportement à 3 ans et demi et retard en lecture au cours élémentaire.

BACKGROUND: Early detection of specific language impairment and dyslexia in children is an important public health problem. Longitudinal studies are needed for the distinction of real impairments from simple transitory delays. METHODS: Teachers filled a 29-item questionnaire on language and behavior for 695 children aged 3.5 years. Four years later (at second grade of primary school) the same children were evaluated for reading and writing. Statistical analysis focused on the relationships between teacher's early observations and reading delay 4 years later. Associated factors were age, sex, educational level and bilinguism of the parents, and area of the school. RESULTS: The delay in written language acquisition (8.5% of the children) was significantly associated with low educational level (but not bilinguism) of the parents and to the area of the school. In univariate analysis, most of the teacher's early negative assessments were significantly related to reading/writing delay, with the exception of some behavioral problems. However, when the effect of associated factors was taken into account only a few items, mainly concerning language expression, remained significantly associated with later reading/writing delay. CONCLUSION: These data show a major role of associated factors (educational level of the parents, area of the school) in reading delay, and help to select specific teacher's observations for an early prediction of this delay.

[Screening by teachers for language and behavior difficulties in 2059 children aged 3,5 years]. / Repérage par les enseignants des difficultés de langage et de comportement chez 2,059 enfants de 3 ans et demi.

BACKGROUND: Several tools have been proposed for screening for specific language impairment and behavioral problems in pre-school children. These disorders are risk factors for later poor school achievement and social life. However, presence of real disorders must be differentiated from environmental factors, such as low educational level of the parents or bilingual family. METHODS: A 29-item teachers'questionnaire was used for screening for language and behavioral disorders in 2059 nursery-school children aged 3.5 years from 200 nursery-schools of different areas in France. RESULTS: According to the teachers, difficulties were clearly more frequent in boys than girls, in children from low educational level families, and in children with not-french-speaking parents. CONCLUSION: The gender of the child and the characteristics of the family play a very important role in the teachers'assessment of a young pre-school child's language and behavior. Longitudinal studies would be required to differentiate the presence of specific disorders, requiring individual intervention, from simple delays due to environmental factors.

Influence of renal biomarker variability on the design and interpretation of occupational or environmental studies.

OBJECTIVES: To quantify and identify sources of within- and between-subject variability of microalbumin, N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP), three biomarkers used for early detection of renal injury, and to assess the consequences of this variability for the design and power of epidemiological studies. METHODS: Urinary excretion of microalbumin, NAG, AAP and creatinine as well as blood pressure (BP) were measured three times over a 2-year period among 142 healthy male workers. To minimise physiopathological and analytical sources of variation, standardised methods were used for urine collection and assays, and severe exclusion criteria were applied. At the first and third examinations, subjects completed the same questionnaire, providing information about their personal characteristics, tobacco and alcohol consumption, and health. A linear mixed model was used to estimate the within- and between-subject variance components and to analyse the relation between subjects' characteristics and the biomarkers. RESULTS: No change in the mean value of any of the biomarkers was observed over the 2-year period. Intra-class correlation coefficients between repeated measurements were 0.53, 0.57 and 0.56 for microalbumin, NAG and AAP, respectively; the between-subject variance was slightly higher than the within-subject variance. Subjects' age, BP, body mass index and smoking and drinking habits explained 7.2%, 12.5% and 4.2% of the total variance of microalbumin, NAG and AAP, respectively. CONCLUSIONS: In this healthy population of male workers, day-to-day differences in biomarker values appeared to be nearly as great as differences between subjects. The within-subject variance of these biomarkers is not high enough to justify systematic repeated measurements in epidemiological surveys. But, in some situations where the number of subjects is limited, measuring the subjects twice may improve study power by reducing the total variance by about 25% for each biomarker. Taking the above covariates into account would slightly improve study power and the accuracy of parameter estimates for NAG, but would add little to the analysis of microalbumin and AAP.

[A methodological review of specific techniques of time series analysis in epidemiology and public health]. / Revue méthodologique de quelques techniques spécifiques à l'analyse des séries temporelles en épidémiologie et santé publique.

Time series analysis of health indicator can contribute to the improvement of knowledge in epidemiology and public health. It is necessary to use models and methods appropriate to the time domain. A class of models proposed by Box & Jenkins are presented together with the necessary tools for identifying such models. Two useful generalisations are also discussed. To study the link between two time series, regression models need to include autocorrelated error terms while to evaluate the effect of an intervention, the use of intervention models are appropriate. This paper presents basic concepts of such analyses in a simple way to encourage the use of those methods.

[Time series analysis of non-typhoid salmonella infections]. / Analyse des séries temporelles des infections à salmonelles non typhiques.

The use of time series modeling for non-typhoidal salmonella infections is important for improving epidemiological surveillance. Specific techniques which were necessary for our objectives are detailed in an accompanying paper. For each series analysed, we discuss how to choose an appropriate statistical model taking into account both the data structure and the specific objectives. For salmonella infections, we have quantified a "media coverage effect", constructed and alert threshold and estimated a link between two series. We have thus shown that the analysis of temporal variations is of relevance in public health and can contribute to epidemiological knowledge.

Attribution of the French human Salmonellosis cases to the main food-sources according to the type of surveillance data.

Salmonella are the most common bacterial cause of foodborne infections in France and ubiquitous pathogens present in many animal productions. Assessing the relative contribution of the different food-animal sources to the burden of human cases is a key step towards the conception, prioritization and assessment of efficient control policy measures. For this purpose, we considered a Bayesian microbial subtyping attribution approach based on a previous published model (Hald et al., 2004). It requires quality integrated data on human cases and on the contamination of their food sources, per serotype and microbial subtype, which were retrieved from the French integrated surveillance system for Salmonella. The quality of the data available for such an approach is an issue for many countries in which the surveillance system has not been designed for this purpose. In France, the sources are monitored simultaneously by an active, regulation-based surveillance system that produces representative prevalence data (as ideally required for the approach) and a passive system relying on voluntary laboratories that produces data not meeting the standards set by Hald et al. (2004) but covering a broader range of sources. These data allowed us to study the impact of data quality on the attribution results, globally and focusing on specific features of the data (number of sources and contamination indicator). The microbial subtyping attribution model was run using an adapted parameterization previously proposed (David et al., 2012). A total of 9076 domestic sporadic cases were included in the analyses as well as 9 sources among which 5 were common to the active and the passive datasets. The greatest impact on the attribution results was observed for the number of sources. Thus, especially in the absence of data on imported products, the attribution estimates presented here should be considered with caution. The results were comparable for both types of surveillance, leading to the conclusion that passive data constitute a potential cost-effective complement to active data collection, especially interesting because the former encompass a greater number of sources. The model appeared robust to the type of surveillance, and provided that some methodological aspects of the model can be enhanced, it could also serve as a risk-based guidance tool for active surveillance systems.

Is hand-rub consumption correlated with hand hygiene and rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-acquired infections?

A retrospective investigation was conducted to determine whether the consumption of alcohol-based hand rub (ABHR) used was correlated with the incidence of acquired nosocomial infection due to meticillin-resistant Staphylococcus aureus or to extended-spectrum beta lactamase (ESBL)-producing strains. Between 2005 and 2008, the use of ABHRs increased significantly by 8 L per 1000 patient-days of hospitalization per year. During the same period, adherence to hand hygiene increased significantly from 55.6% to 70.9% (P < 0.0001). Despite these improvements there was a steady increase in the incidence of ESBL-producing strains in the past three years and no correlation was found between ABHR consumption and either nosocomially acquired ESBL or adherence to hand hygiene.

Primary glomerulonephritis: an update on renal survival and determinants of progression.

BACKGROUND: Few epidemiological studies have investigated the long-term outcome of primary glomerulonephritis (GN) and its determinants in the decade since angiotensin-converting enzyme inhibitors entered widespread use. AIM: To study several traditional and less traditional risk factors for kidney disease progression in a cohort of patients with primary GN. DESIGN: Retrospective cohort study. METHODS: We included 536 patients with primary GN first diagnosed between 1994 and 2001: 283 IgA nephropathy (IgA), 129 membranous nephropathy (MN), and 124 focal and segmental glomerulosclerosis (FSGS). Adjusted hazard ratios (HR) or dialysis or preemptive transplantation for end-stage renal disease (ESRD) according to various characteristics were estimated with Cox proportional-hazard models. RESULTS: At diagnosis, mean patient age was 43 +/- 17 years, 74% were men, and the mean estimated glomerular filtration rate (eGFR) was 69 +/- 31 mL/mn/1.73m(2). After a mean follow-up of 7-years, 104 patients had started ESRD treatment and 14 had died before reaching ESRD. The 7-year renal survival rate was 69% for FSGS, 88% for MN, and 82% for IgAN (p < 0.01). In patients with FSGS, younger age was associated with a higher risk of ESRD. Baseline proteinuria, diabetes, and haemoglobin (Hb) concentration were strongly associated with shorter time to ESRD independent of baseline eGFR, but gender, hypertension and smoking were not. Adjusted HRs for ESRD were 2.6 [95% confidence interval, 1.2-5.8] for diabetes and 2.4 [1.3-4.5] for the lowest and 1.9 [1.0-3.6] for the intermediate Hb tertiles versus the highest. DISCUSSION: In patients with primary GN, renal survival is clearly lower for FSGS than for IgAN and MN. Independent predictors for progression were baseline diabetes and anaemia, as well as proteinuria, for all GN types, and younger age, for FSGS.

Evaluation of the impact on human salmonellosis of control measures targeted to Salmonella Enteritidis and Typhimurium in poultry breeding using time-series analysis and intervention models in France.

In France, salmonellosis is the main cause of foodborne bacterial infection with serotypes Enteritis (SE) and Typhimurium (ST) accounting for 70% of all cases. French authorities implemented a national control programme targeting SE and ST in poultry and eggs from October 1998 onwards. A 33% decrease in salmonellosis has been observed since implementation. We designed an evaluation of the impact of this control programme on SE and ST human infections in France. Using monthly Salmonella human isolate reports to the National Reference Centre we defined two intervention series (SE and ST) and one control series comprising serotypes not know to be associated with poultry or eggs. The series, from 1992 to 2003, were analysed using autoregressive moving average models (ARMA). To test the hypothesis of a reduction of SE and ST human cases >0 after the programme started and to estimate its size, we introduced an intervention model to the ARMA modelling. In contrast to the control series, we found an annual reduction of 555 (95% CI 148-964) SE and of 492 (95% CI 0-1092) ST human infections, representing respectively a 21% and 18% decrease. For SE, the decrease occurred sharply after implementation while for ST, it followed a progressive decrease that started early in 1998. Our study, suggests a true relation between the Salmonella control programme and the subsequent decrease observed for the two targeted serotypes. For ST, however, the decrease prior to the intervention may also reflect control measures implemented earlier by the cattle and milk industry.

Influence of anxiety and reported stressful life events on relapses in multiple sclerosis: a prospective study.

OBJECTIVE: Self-reported stressful life events and infections have been associated with relapses in multiple sclerosis. Also, anxiety has been reported to influence other diseases of unpredictable course. To study relation of self-reported stressful life events, levels of anxiety, and episodes of infection, with relapses of the disease in women with multiple sclerosis. METHODS: This is a one-year prospective study. Thirty seven women with multiple sclerosis were regularly seen every four weeks, for one year. They were keeping diaries of events they considered stressful. These events were ranked according to the Holmes and Rahe Social Readjustment Rating Scale. Their anxiety levels were assessed with the Hamilton rating scale for anxiety. Relapses and episodes of infection were verified at additional visits. Results were studied using a survival analysis model adapted for several recurrent events. RESULTS: A total of 291 stressful events, 37 episodes of infection, and 48 relapses, were registered. High level of anxiety were stongly related to the number and the severity of reported stressful events during the preceding period and with the advent of a relapse in the following period (Hamilton score greater than 18 is associated with 4.2 times the rate of relapsing and three or more reported stressful events with 5.7 times the rate of relapsing). CONCLUSIONS: Anxiety and self-reported stressful events may in fact be two measures of the same underlying emotional factor, which plays an important role on the course of the disease, in addition to episodes of infection.

A time series construction of an alert threshold with application to S. bovismorbificans in France.

Epidemiological surveillance can be used to initiate preventive measures and Salmonella infection is a prime example of application. It is important that any unusual increase of reported cases should be detected as rapidly as possible. Reliable forecasts based on a suitable model of the temporal structure of a pathological indicator are necessary for the elaboration of an alert threshold. We first discuss the specific problems associated with the identification and the estimation of the temporal structure of indicators of infectious diseases when they present both epidemic peaks and an underlying stationary structure. Then we consider how an alert threshold can be defined. Our application concerns infections caused by S. bovismorbificans in France for which an alert threshold is constructed and tested both retrospectively and prospectively.

Accounting for pregnancy dependence in epidemiologic studies of reproductive outcomes.

The aim of this paper is to evaluate the contribution of hierarchical mixed models to the analysis of epidemiologic studies of environmental exposure and reproductive outcomes. We have re-analyzed, with a logistic-normal mixed model, four studies investigating the relation between the frequency of spontaneous abortions and paternal or maternal environmental exposures. The data include multiple pregnancies for some women. The fitted models allow for between-woman variation of the propensity for spontaneous abortion, by including a random intercept in the logistic model to adjust for within-woman correlations on pregnancy outcomes. We have discussed and implemented two estimation methods, maximum likelihood and Bayesian inference. We found similar values in the various epidemiologic studies of the between-woman variance of the intrinsic risk of spontaneous abortion. The size of this variance corresponds to a substantial variability in risk between women. Indeed, the risk of spontaneous abortion calculated for "nonexposed" pregnancies, that is, with mother's age, birth order, tobacco consumption, and maternal environmental exposure equal to the referent class, can vary, according to this model, from 2% to 17%.