Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

BACKGROUND: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. METHODS: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. RESULTS: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. CONCLUSIONS: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. TRIAL REGISTRATION: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.

Estimating influenza latency and infectious period durations using viral excretion data.

Influenza infection natural history is often described as a progression through four successive stages: Susceptible-Exposed/Latent-Infectious-Removed (SEIR). The duration of each stage determines the average generation time, the time between infection of a case and infection of his/her infector. Recently, several authors have justified somewhat arbitrary choices in stage durations by how close the resulting generation time distribution was to viral excretion over time after infection. Taking this reasoning one step further, we propose that the viral excretion profile over time can be used directly to estimate the required parameters in an SEIR model. In our approach, the latency and infectious period distributions are estimated by minimizing the Kullback-Leibler divergence between the model-based generation time probability density function and the normalized average viral excretion profile. Following this approach, we estimated that the latency and infectious period last respectively 1.6 and 1.0 days on average using excretion profiles from experimental infections. Interestingly, we find that only 5% of cases are infectious for more than 2.9 days. We also discuss the consequences of these estimates for the evaluation of the efficacy of control measures such as isolation or treatment. We estimate that, under a best-case scenario where symptoms appear at the end of the latency period, index cases must be isolated or treated at most within 16h after symptoms onset to avoid 50% of secondary cases. This study provides the first estimates of latency and infectious period for influenza based directly on viral excretion data. It provides additional evidence that isolation or treatment of cases would be effective only if adopted shortly after symptoms onset, and shows that four days of isolation may be enough to avoid most transmissions.

Louis-Rene Villerme (1782-1863), a pioneer in social epidemiology: re-analysis of his data on comparative mortality in Paris in the early 19th century.

BACKGROUND: During the early 19th century, contagionists' and anti-contagionists' explanations of disease causes opposed one another, and the Hippocratic miasma theory still predominated. According to that theory, geographic health disparities could be explained by topographical factors: differences in altitude, population density or proximity to a river. This article summarizes the life of Louis-René Villermé (1782-1863) and his major contributions to social epidemiology that proved the association between poverty and mortality. METHODS: In this study, data reported by Villermé to study the mortality-rate variations across the 12 districts (arrondissements) of Paris-that is, 1817-1826 Parisian death rates by district, population density and income indicators-are presented and reanalyzed. RESULTS: Results obtained with today's statistical techniques (correlation analysis) support Villermé's claims of a direct poverty-high death rate link: the three income indicators that he chose were significantly correlated with at-home mortality: taxation index (r=-0.83, p<0.002), average rent (r=-0.83, p<0.002), trade taxation index (r=-0.67, p<0.05), while population density variables were not associated with mortality. CONCLUSION: Villermé was not only a forerunner of social epidemiology, he was also a scientific pioneer by relying on data, not opinions, to challenge or support medical hypotheses.

Real-time comparative monitoring of the A/H1N1 pandemic in France.

The clinical burden of the A/H1NI influenza pandemic in the general population is comparable to those of previous seasonal influenza epidemics in terms of total numbers of clinical cases. It is higher in young, and virtually nil in older adults. These assertions can be made safely because of long-established clinical influenza surveillance systems. However, what characterizes this pandemic is that it may kill young patients without known risk factors. Surveillance systems dedicated to the most severely ill patients admitted to intensive care units have been implemented only recently. The present experience strongly supports the view that they should be made perennial.

The causes of cancer in France.

BACKGROUND: While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce. METHODS: We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985. RESULTS: In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers. CONCLUSIONS: While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

Enhancing global capacity in the surveillance, prevention, and control of chronic diseases: seven themes to consider and build upon.

BACKGROUND: Chronic diseases are now a major health problem in developing countries as well as in the developed world. Although chronic diseases cannot be communicated from person to person, their risk factors (for example, smoking, inactivity, dietary habits) are readily transferred around the world. With increasing human progress and technological advance, the pandemic of chronic diseases will become an even bigger threat to global health. METHODS: Based on our experiences and publications as well as review of the literature, we contribute ideas and working examples that might help enhance global capacity in the surveillance of chronic diseases and their prevention and control. Innovative ideas and solutions were actively sought. RESULTS: Ideas and working examples to help enhance global capacity were grouped under seven themes, concisely summarised by the acronym "SCIENCE": Strategy, Collaboration, Information, Education, Novelty, Communication and Evaluation. CONCLUSION: Building a basis for action using the seven themes articulated, especially by incorporating innovative ideas, we presented here, can help enhance global capacity in chronic disease surveillance, prevention and control. Informed initiatives can help achieve the new World Health Organization global goal of reducing chronic disease death rates by 2% annually, generate new ideas for effective interventions and ultimately bring global chronic diseases under greater control.

Investigating transmission in a two-wave epidemic of Chikungunya fever, Réunion Island.

An epidemic of Chikungunya fever, a mosquito-borne viral disease, spectacularly swept through Réunion Island (population 780,000) in 2005-2006. There were 3,000 cases in a first wave (March-June 2005) and more than 250,000 cases in a second (December 2005-April 2006). Adapting newly developed epidemiological tools to vector-borne diseases, we show that despite this massive difference in magnitude, the transmission potential as measured by the number of secondary cases per index case (or reproduction number), remained similar during the two consecutive waves. The best estimate for the initial reproduction number R(0) was 3.7, with a possible range from 2 to 11 depending on incubation duration and lifespan of the mosquito. We conclude that an increase in virulence between the two seasons was not necessary to explain the change in magnitude of the epidemics, and that the attack rate may be well over 50% in Chikungunya fever epidemics in the absence of intervention.

The rising impact of mathematical modelling in epidemiology: antibiotic resistance research as a case study.

Mathematical modelling of infectious diseases has gradually become part of public health decision-making in recent years. However, the developing status of modelling in epidemiology and its relationship with other relevant scientific approaches have never been assessed quantitatively. Herein, using antibiotic resistance as a case study, 60 published models were analysed. Their interactions with other scientific fields are reported and their citation impact evaluated, as well as temporal trends. The yearly number of antibiotic resistance modelling publications increased significantly between 1990 and 2006. This rise cannot be explained by the surge of interest in resistance phenomena alone. Moreover, modelling articles are, on average, among the most frequently cited third of articles from the journal in which they were published. The results of this analysis, which might be applicable to other emerging public health problems, demonstrate the growing interest in mathematical modelling approaches to evaluate antibiotic resistance.

sispread: A software to simulate infectious diseases spreading on contact networks.

OBJECTIVES: We present a simulation software which allows studying the dynamics of a hypothetic infectious disease within a network of connected people. The software is aimed to facilitate the discrimination of stochastic factors governing the evolution of an infection in a network. In order to do this it provides simple tools to create networks of individuals and to set the epidemiological parameters of the outbreaks. METHODS: Three popular models of infectious disease can be used (SI, SIS, SIR). The simulated networks are either the algorithm-based included ones (scale free, small-world, and random homogeneous networks), or provided by third party software. RESULTS: It allows the simulation of a single or many outbreaks over a network, or outbreaks over multiple networks (with identical properties). Standard outputs are the evolution of the prevalence of the disease, on a single outbreak basis or by averaging many outbreaks. The user can also obtain customized outputs which address in detail different possible epidemiological questions about the spread of an infectious agent in a community. CONCLUSIONS: The presented software introduces sources of stochasticity present in real epidemics by simulating outbreaks on contact networks of individuals. This approach may help to understand the paths followed by outbreaks in a given community and to design new strategies for preventing and controlling them.

Understanding the dynamics of Ebola epidemics.

Ebola is a highly lethal virus, which has caused at least 14 confirmed outbreaks in Africa between 1976 and 2006. Using data from two epidemics [in Democratic Republic of Congo (DRC) in 1995 and in Uganda in 2000], we built a mathematical model for the spread of Ebola haemorrhagic fever epidemics taking into account transmission in different epidemiological settings. We estimated the basic reproduction number (R0) to be 2.7 (95% CI 1.9-2.8) for the 1995 epidemic in DRC, and 2.7 (95% CI 2.5-4.1) for the 2000 epidemic in Uganda. For each epidemic, we quantified transmission in different settings (illness in the community, hospitalization, and traditional burial) and simulated various epidemic scenarios to explore the impact of control interventions on a potential epidemic. A key parameter was the rapid institution of control measures. For both epidemic profiles identified, increasing hospitalization rate reduced the predicted epidemic size.

Modelling outbreak control for pneumonic plague.

Although pneumonic plague is listed by the Centers of Disease Control in the leading 'critical biological agents', very few studies exist on this subject. In this study, a mathematical compartment model was used to describe the geographical and temporal spread of an epidemic of pneumonic plague following its use as a biological weapon. Univariate and multivariate analyses were performed in order to assess the key parameters for the control of an outbreak in France. If interventions were taken 10 days after an attack, a reference scenario of 1000 index cases in Paris would lead to 2500 deaths. The results of the study indicate that the rapidity of onset of interventions has the largest effect on the final size of the epidemic, followed by wearing masks, treating contacts preventively and quarantine. Limiting inter-regional mixing does little to reduce casualties, although it does confine them to a single region.

Virtual surveillance of communicable diseases: a 20-year experience in France.

Inserm has developed, since 1984, an information system based on a computer network of physicians in France. It allows for constitution of large databases on diseases, with individual description of cases, and to explore some aspects of the mathematical theory of communicable diseases. We developed user-friendly interfaces for remote data entry and GIS tools providing real-time atlas of the epidemiologic situation in any location. The continuous and ongoing surveillance network is constituted of about 1200 sentinel voluntary and unpaid investigators. We studied their motivation, reasons for either withdrawal or compliance using survival analyses. We implemented early warning systems for outbreak detection and for time-space forecasting. We conducted epidemiological surveys for investigating outbreaks. Large available time and space series allowed us to calibrate and explore synchronism of influenza epidemics, to test the assumption of panmixing in susceptibles-infectious-removed type models and to study the role of closing school in influenza morbidity and mortality in elderly. More than 250 000 cases of influenza, 150 000 cases of acute diarrheas, 35,000 patients for whom HIV tests have been prescribed by general practitioners and 25,000 cases of chickenpox have been collected. Detection of regional influenza or acute diarrhea outbreaks and forecasting of epidemic trends three weeks ahead are currently broadcasted to the French media and published on Sentiweb on a weekly basis. Age-cohort-period models assessed field effectiveness of mass immunization strategies against measles and influenza in the country. Case-control studies with more than 1200 sets of cases of acute diarrheas and their matched controls showed the role of calicivirus and rotavirus as probable major causes of gastroenteritis during recurrent widespread outbreaks in winter in France. An age-specific model for chickenpox showed the probable role of children in disease transmission to their susceptible parents or grandparents. High level of synchronism between influenza epidemics has been demonstrated, either at a regional level (in France) or between France and the USA. The designation of our lab as a WHO collaborating center for electronic disease surveillance stimulates the development of global monitoring of diseases. We developed operational systems that are now available for the global monitoring of influenza (FluNet), and human and animal rabies (RABNET). Extension of electronic syndromic surveillance is needed in the world for improving surveillance capacities and real-time response against emerging diseases.

[The evaluation of health care outcomes and hospital performance indicators]. / De l'évaluation de la qualité des soins à la performance des soins.

INTRODUCTION: The assessment of the performance of health care establishments has undergone a considerable development over the past 15 years in the United States and to a lesser extent in other developed countries. BACKGROUND: The aim of measurement of performance indicators is to improve the quality of care (outcomes), patient information and the contractual arrangements with purchasers. However, this approach poses numerous methodological problems in the choice of performance indicators as well as the collection and interpretation of data. Specific structural patterns such as social and geographic environment, research and educational assignments, are often inadequately considered. In terms of public health the impact of the publication of these measurements has not been well studied. Based on the data in the literature this revue defines the measures of hospital performance and describes the main studies, their impacts and limitations. VIEWPOINT: It seems likely that the French public authorities will, in the short term, ask health care establishments to undertake this approach. CONCLUSIONS: Complimentary studies are needed to clarify the links between performance indicators and health care outcomes.

Can a second wave of new variant of the CJD be discarded in absence of observation of clinical non Met-Met cases?

BACKGROUND: Presently, all patients with clinical variant Creutzfeldt-Jakob disease in the United Kingdom have been Met-Met at codon 129 of the PrP gene. There is much worry about the possibility of a second wave of the epidemic in the 60% of the United Kingdom population which are not Met-Met. METHODS: A mathematical model of a putative United Kingdom variant Creutzfeldt-Jakob disease epidemic that could occur in non Met-Met is derived. The risk of infection is assumed to parallel the Met-Met risk which has been previously modelled. The reason for the present absence of clinical non Met-Met cases is assumed to be a longer incubation period in these subjects than in others. The incubation period is assumed to be lognormally distributed. The means and coefficients of variation compatible with the present absence of clinical cases are systematically searched. RESULTS: We show that the present absence of clinical cases of variant Creutzfeldt-Jakob disease in the Met-Val or Val-Val population can be compatible with a second wave only if the mean incubation period is more than 25 years. The best estimates of the size of the second wave are always below 250. A fraction of these cases however will never be observed, as they will die from other causes before the onset of the new variant. CONCLUSION: The mean incubation period values compatible with the absence of non Met-Met clinical cases that we found are not implausible, and the possibility of a second wave cannot yet be ruled out. However, should this second wave occur, it would be below 250 in the worst hypothesis.

[Risk-benefit assessment of hepatitis B vaccination in France, 2006]. / Evaluer le rapport bénéfices/risques de la vaccination contre l'hépatite B en France en 2006.

PURPOSE: Rare and unexpected adverse events following hepatitis B immunization have been reported. This article aims to illustrate the risk-benefit assessment of hepatitis B immunization strategies, using the available evidence in medical literature. CURRENT EVENTS: i) Hepatitis B vaccination efficacy is high in infants, children and adolescents. It may be lower in adults and at risk populations; ii) Hepatitis B descriptive epidemiological data in France are scarce, fragmental, unprecise and changing according to the studied population strata. The incidence of symptomatic cases in the general population is below 5 per 100,000 since the year 2000. In France, it is estimated that about 300,000 adults are carriers of HBs antigen, and thus able to transmit the disease; iii) The actual French pharmacovigilance signal and the epidemiological studies may suggest the hypothesis of an association between the occurrence of central nervous system demyelinating diseases and hepatitis B vaccination. If this association exists, the relative risk is probably of less than 3. PERSPECTIVES: The lack of accuracy of risks estimates complicates the risk-benefit assessment of hepatitis B vaccination. Its perception is then influenced and distorted by subjective factors, underlying the need for research in communication about benefits and risks of immunizations. Although still debated, the hypothesis of a putative role of hepatitis B vaccine in the pathophysiology of demyelinating diseases should prompt to pursue experimental and epidemiological research to better understand the links between infectious environment and inflammatory chronic diseases.

[Prevalence and management of heart failure in France: national study among general practitioners of the Sentinelles network]. / Prévalence et prise en charge de l'insuffisance cardiaque en France: enquête nationale auprès des médecins généralistes du réseau Sentinelles.

BACKGROUND: Epidemiological data on heart failure's epidemiology in France are scarce and mostly hospital based. The present study's objective is to estimate the prevalence of heart failure (HF) and its management, in subjects aged 60 years and older seen by the French general practitioners (GP). METHODS: A standardised questionnaire was mailed to 900 GPs of the Sentinelles network, requiring answers for any patient aged 60 years and more, seen on a randomly assigned single day of year 2002. National census and health insurance data were used to estimate prevalence. RESULTS: 434 GPs answered, reporting data for 1797 patients aged 60 years and more. The 214 patients with HF, aged 79 years on average, had been seen by a cardiologist in 95% of cases. Results of an echocardiography was available for 58% of HF patients. Compared to non-HF patients, patients with HF were significantly more dependent, more frequently requiring home visit of the GP and more frequently hospitalised (p < 0.001, age adjusted). All the 42% HF patients with a reported left ventricle ejection fraction lower than 40% were treated with an angiotensin converting enzyme inhibitor or an angiotensin receptor inhibitor. The prevalence of HF among patients aged 60 years and older was estimated at 11.9% in general practice (95% confidence interval: 10.5-13.5), and at 2.19% (1.9-2.5) in the general population. The prevalence increased with age, over 20% in persons aged 80 years and more. CONCLUSION: HF in patients aged 60 years and more seen in general practice in France is characterised by a high prevalence and medical consumption in terms of required number of hospitalisation and GP's home visit. For the GP, the diagnosis of HF relies on the cardiologist more than on an echocardiography. The therapeutic management seems to fit the actual recommendations.

Penicillin-resistant pneumococcal meningitis: high antibiotic exposure impedes new vaccine protection.

The frequency of meningitis due to penicillin-resistant Streptococcus pneumoniae (PRP) has increased in recent years, making treatment failure more likely. It is currently expected that pneumococcal conjugate vaccines might curb this trend. We investigated this issue using a mathematical model applied to the current prevalence of resistance and antibiotic exposure in the United States and in France. Our main finding was that the level of antibiotic exposure may limit the effect of the vaccine. In relatively low antibiotic exposure environments such as the United States, large-scale vaccination prevents a large part of PRP meningitis cases, whereas in high antibiotic-exposure environments such as France, vaccination alone does not lead to a substantial reduction in PRP meningitis incidence. Our results suggest that antibiotic exposure reduction will remain of primary importance for the control of PRP meningitis despite wide scale use of pneumococcal conjugate vaccines.

A Bayesian MCMC approach to study transmission of influenza: application to household longitudinal data.

We propose a transmission model to estimate the main characteristics of influenza transmission in households. The model details the risks of infection in the household and in the community at the individual scale. Heterogeneity among subjects is investigated considering both individual susceptibility and infectiousness. The model was applied to a data set consisting of the follow-up of influenza symptoms in 334 households during 15 days after an index case visited a general practitioner with virologically confirmed influenza. Estimating the parameters of the transmission model was challenging because a large part of the infectious process was not observed: only the dates when new cases were detected were observed. For each case, the data were augmented with the unobserved dates of the start and the end of the infectious period. The transmission model was included in a 3-levels hierarchical structure: (i) the observation level ensured that the augmented data were consistent with the observed data, (ii) the transmission level described the underlying epidemic process, (iii) the prior level specified the distribution of the parameters. From a Bayesian perspective, the joint posterior distribution of model parameters and augmented data was explored by Markov chain Monte Carlo (MCMC) sampling. The mean duration of influenza infectious period was estimated at 3.8 days (95 per cent credible interval, 95 per cent CI [3.1,4.6]) with a standard deviation of 2.0 days (95 per cent CI [1.1,2.8]). The instantaneous risk of influenza transmission between an infective and a susceptible within a household was found to decrease with the size of the household, and established at 0.32 person day(-1) (95 per cent CI [0.26,0.39]); the instantaneous risk of infection from the community was 0.0056 day(-1) (95 per cent CI [0.0029,0.0087]). Focusing on the differences in transmission between children (less than 15 years old) and adults, we estimated that the former were more likely to transmit than adults (posterior probability larger than 99 per cent), but that the mean duration of the infectious period was similar in children (3.6 days, 95 per cent CI [2.3,5.2]) and adults (3.9 days, 95 per cent CI [3.2,4.9]). The posterior probability that children had a larger community risk was 76 per cent and the posterior probability that they were more susceptible than adults was 79 per cent.