Impact of rituximab on humoral response to SARS-CoV-2 vaccination in previously vaccinated patients with autoimmune diseases.

SARS-CoV-2 infection is more severe in patients undergoing rituximab (RTX) treatment. Humoral response to vaccination is severely impaired in patients already treated with RTX, but data on antibody persistence in patients initiating RTX are lacking. We evaluated the impact of RTX initiation on humoral response to SARS-CoV-2 vaccination in previously vaccinated patients with immune-mediated inflammatory diseases. We performed a retrospective, multicenter study evaluating the evolution of anti-spike antibodies and breakthrough infections after initiation of RTX in previously vaccinated patients with protective levels of anti-SARS-CoV-2 antibodies. Threshold for anti-S antibodies positivity and protection were 30 and 264 BAU/mL, respectively. We included 31 previously vaccinated patients initiating RTX (21 female, median age 57 years). At first RTX infusion, 12 (39%) patients had received 2 doses of vaccine, 15 (48%) had received 3 doses, and 4 (13%) had received 4 doses. The most frequent underlying diseases were ANCA-associated vasculitis (29%) and rheumatoid arthritis (23%). Median anti-S antibody titers at RTX initiation, 3 months, and 6 months were 1620 (589-2080), 1055 (467-2080), and 407 (186-659) BAU/mL, respectively. Overall, antibody titers waned by almost two-fold at 3 months and four-fold at 6 months. Median antibody titers were significantly higher in patients who received ≥3 doses compared to those who received only 2 doses. Three patients developed SARS-CoV-2 infection without any severe symptom. Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after RTX initiation similarly to general population. Specific monitoring is useful to anticipate prophylactic strategies. Key Points • Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after rituximab initiation similarly to the general population. • The number of dose of vaccine before rituximab initiation is associated with higher antibody titers at month 3. • Monitoring antibody levels is mandatory to initiate prophylactic strategies in this population.

An interdisciplinary approach to controlling chikungunya outbreaks on French islands in the south-west Indian ocean.

The outbreak of chikungunya that occurred on French Island territories in the southwest Indian Ocean in 2005 and 2006 caused severe morbidity and mortality. In the aftermath, French authorities set up a scientific task force including experts in epidemiology, public health, entomology, virology, immunology, sociology, animal health, community and hospital medicine. The mission of the task force was to conceive and propose research programs needed to increase understanding of the disease and epidemic and to help public health officials in improving epidemic response measures. The purpose of this article is to describe the findings of the task force at the end of its two-year existence and initial outcomes in the the areas studied. Discussion emphasizes topics requiring further study.

Micro and macro population effects in disease transmission: the case of varicella.

Profiles of varicella-zoster virus (VZV) seroprevalence have shown large variability in European countries in which vaccination has not been implemented. Differences in micro and macro population structures (e.g. household and municipality, respectively) may explain such variability, which is the focus of a population-based study of varicella in 12,000 children from 7800 French households in Corsica. The cumulative incidence was 89% at age 11 years, as the median age at infection was 5 years in first-born children, but decreased to 3.9 years in younger siblings. Hazard of infection in households increased as the first-born child initially enrolled in primary school. Age at infection was higher in less populated areas. Household attack rates increased with age (55% in <6 months, >90% in >3 years) and household secondary attack rate was approximately 70%. Several levels of population structure independently affect age at varicella infection.

[Profile of active investigators involved in a clinical trial in general medical practice]. / Profil des investigateurs actifs au cours d'un essai clinique en médecine générale.

INTRODUCTION: Depiscan was the pilot phase of a large trial to evaluate low dose computed tomography as a screening method for lung cancer (GranDepiscan). The goal of the study presented in this manuscript was to predict the activity of general practitioners (GPs) involved as investigators in a clinical trial. METHODS: A questionnaire about GP's socio-demographic characteristics, initial involvement and perception of difficulties was sent to 189 GPs volunteers after enrollment into the Depiscan trial was complete. RESULTS: Among the 97 respondents, 61 were active investigators. Age lower than 50 years and presence during the initiation visit were significantly associated with the participation of investigators. Two other factors at the limit of significance were: the status and the type of initiation visit. The following factors: gender, type of practice, membership of a medical society, parallel activity in the public sector and knowledge of the referring pulmonary oncologist were not associated with the level of recruitment, as well as the difficulties mentioned by the investigators. CONCLUSIONS: These results will help for selection of investigators for future clinical trials in general medical practice, particularly for the GranDépiscan trial.

Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling.

We have assessed the possibility to build a prognosis predictor (PP), based on non-neoplastic mucosa microarray gene expression measures, for stage II colon cancer patients. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. Patients were repeatedly and randomly divided into 1000 training sets (TSs) of size 16 and validation sets (VS) of size 8. For each TS/VS split, a 70-gene PP, identified on the TS by selecting the 70 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Mean prognosis prediction performances of the 70-gene PP were 81.8% for accuracy, 73.0% for sensitivity and 87.1% for specificity. Informative genes suggested branching signal-transduction pathways with possible extensive networks between individual pathways. They also included genes coding for proteins involved in immune surveillance. In conclusion, our study suggests that one can build an accurate PP for stage II colon cancer patients, based on non-neoplastic mucosa microarray gene expression measures.

Dual infections by influenza A/H3N2 and B viruses and by influenza A/H3N2 and A/H1N1 viruses during winter 2007, Corsica Island, France.

BACKGROUND: The investigation of dual influenza infection human cases is of major interest specifically for the control of new emerging influenza strains. OBJECTIVES: Using RT-PCR assays, we retrospectively assessed the prevalence of dual influenza virus infections that occurred in patients during the 2006-2007 winter season in Corsica Island (France). STUDY DESIGN: One hundred and thirty-four nasal swabbing samples taken from patients suffering from influenza-like illness between February and March 2007 were analysed using a rapid influenza antigen detection test, cell culture and RT-PCR assays. RESULTS AND CONCLUSION: Influenza viruses were detected in 93 (69.4%) of 134 patients with influenza-like illness using the combination of classical and molecular assays. Dual respiratory infections by influenza viruses were detected in 3 (3.2%) of the 93 influenza positive patients, including two cases of infection by influenza A/H3N2 and B viruses and one case of dual infection by influenza A/H3N2 and A/H1N1 viruses. In the present report, human co-infection cases by two influenza viruses appeared as a rare event in symptomatic patients. However, the virological and epidemiological mechanisms that determine the occurrence of dual influenza infections remain to be fully investigated in further prospective multicentric studies.

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.

State of the fight against informal market of medicines in Togo: approaches and limitations.

The extent of medicines sales and consumption in the informal market in Togo raises many ethical and public health issues. In order to report on the situation of public action in the fight against this practice, we conducted a qualitative survey from 15 to 25 February 2016 in the commune of Lomé and in the Maritime Region among the actors of control system and resource people in the general population. This was supplemented by an analysis of Togo's pharmaceutical and health policy documents and a literature review on the illicit drug market issues relating to public health, political science, the social sciences applied to health. In spite of the existence of national and international tools, household poverty, cultural self-medication, ignorance of the population concerning the health risks of informal market medicines, weak political commitment, weakness regulation and enforcement, corruption, constitute obstacles to the success of actions to combat this practice.

[Systemic corticosteroid therapy: patients' adherence to dietary advice and relationship between food intake and corticosteroid-induced lipodystrophy]. / Corticothérapie systémique et alimentation: suivi des recommandations diététiques et relation entre apports alimentaires et apparition d'une lipodystrophie.

PURPOSE: No data is available about: 1) the adherence of corticosteroid-treated patients to dietary advice provided by physicians; 2) the relationship between food intake and the corticosteroid-induced lipodystrophy (CIL). METHODS: We conducted a cohort study in 2 French tertiary centers between June 2003 and May 2005 and enrolled all consecutive patients starting long-term systemic corticosteroid therapy. They received individual dietary advice from a qualified dietetician and were asked to record on a standardized questionnaire everything they ate during one week of the first and third months of treatment, including details of each meal. Each questionnaire was analysed by two qualified dieteticians for daily calorie, carbohydrate, fat, protein and sodium intake. Moreover, 3 investigators assessed the development of CIL from standardized patients' photographs. The relationship between food intake and CIL was investigated by a multiple logistic regression model. RESULTS: Eighty-eight patients were included and 80 were monitored until at least month 3 (women: 76%, mean age: 59.1+/-18.7 years). Most patients (65%) had giant-cell arteritis or connective tissue disease. The mean initial dosage of prednisone was 54+/-17 mg/day and the mean M3 dosage was 31+/-15 mg/day. Most patients were adherent to dietary advice during the first 3 months of therapy except for protidic ration which was below expected value. Sodium restriction was more strictly followed by women than by men. Multivariate analysis showed independent relationship between CIL and higher calorie intake (>30 kcal/kg/day). No relationship was evidenced between carbohydrate, protein, fat or sodium intake and the risk of CIL. CONCLUSION: During the first 3 months of therapy, corticosteroid-treated patients are adherent to dietary advice. A calorie-controlled alimentation could be beneficial to limit the risk of CIL.

[Natural history of corticosteroid-induced lipodystrophy: a prospective follow-up of 37 patients]. / Histoire naturelle de la lipodystrophie cervicofaciale cortico-induite: suivi prospectif d'une cohorte de 37 patients.

PURPOSE: No data is available about the natural history of the corticosteroid-induced lipodystrophy. The purpose of this study is to describe the natural history of corticosteroid-induced lipodystrophy in a selected and homogenous population. METHODS: We conducted a cohort study between June 2003 and September 2005 and enrolled all consecutive patients starting long-term systemic corticosteroid therapy for giant cell arteritis (because of a standardized therapeutic schedule). After enrollment, patients were seen every month until the end of the corticosteroid therapy. After the drug withdrawal, they consulted every 3 months during 6 months. At each consultation, they were photographed in a standardized way. At the end of the study, the development of lipodystrophy was assessed by analyzing these photographs. We evaluated the incidence of corticosteroid-induced lipodystrophy during the course of giant cell arteritis therapy and the time between initiation of therapy and its apparition. Lastly, we evaluated the time between the prednisone withdrawal and the disappearance of lipodystrophy (or the mean prednisone dosage if the disappearance was observed under treatment). RESULTS: Thirty-seven patients were included (women: 73%; mean age: 75+/-7 years; mean initial daily prednisone dosage: 44+/-13 mg). The mean duration of follow-up was 23.6+/-7.4 months. Incidence of corticosteroid-induced lipodystrophy was 48% after 3 months and 60% after 12 months of therapy. The median time between treatment initiation and appearance of lipodystrophy was short (3 months [1-4]). During the decrease of the therapy or the 6 months following its end, we observed a regression of lipodystrophy in 71% of the patients. The median time between corticosteroids initiation and disappearance of lipodystrophy was 19 months [16-22] (concomitant median daily dosage of prednisone: 4 mg [0-7]). CONCLUSION: Lipodystrophy is frequently observed in corticosteroid-treated old patients. It appears precociously after the initiation of therapy and is usually reversible.

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.

[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.

[Overmedicalization: When too much medicine harms]. / La surmédicalisation: quand trop de médecine nuit à la santé.

Overmedicalization refers to non-validated medical practices, with no clear benefits, potentially harmful and therefore unnecessarily costly. Awareness is growing with respect to this serious public health problem. Permanent expansion of diagnostic or therapeutic interventions, disease mongering, inadequate management of diagnostic uncertainty, conflict of interest or lack of commitment by physicians and patients in shared decision making. Overmedicalization is made possible by a lack of training of health professionals and users on medical decision process. Only a multidisciplinary research program, involving medical and non-medical worlds, will allow the implementation of corrective actions.

Public Health and Epidemiology Informatics.

OBJECTIVES: The aim of this manuscript is to provide a brief overview of the scientific challenges that should be addressed in order to unlock the full potential of using data from a general point of view, as well as to present some ideas that could help answer specific needs for data understanding in the field of health sciences and epidemiology. METHODS: A survey of uses and challenges of big data analyses for medicine and public health was conducted. The first part of the paper focuses on big data techniques, algorithms, and statistical approaches to identify patterns in data. The second part describes some cutting-edge applications of analyses and predictive modeling in public health. RESULTS: In recent years, we witnessed a revolution regarding the nature, collection, and availability of data in general. This was especially striking in the health sector and particularly in the field of epidemiology. Data derives from a large variety of sources, e.g. clinical settings, billing claims, care scheduling, drug usage, web based search queries, and Tweets. CONCLUSION: The exploitation of the information (data mining, artificial intelligence) relevant to these data has become one of the most promising as well challenging tasks from societal and scientific viewpoints in order to leverage the information available and making public health more efficient.

p53 gene status as a predictor of tumor response to induction chemotherapy of patients with locoregionally advanced squamous cell carcinomas of the head and neck.

PURPOSE: To determine whether p53 gene status predicts tumor responses to platinum- and fluorouracil-based induction chemotherapy in locoregionally advanced squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Tumor responses of 105 patients were measured at the primary tumor site. Objective response and major response were defined by a 50% and 80% reduction in tumor size, respectively. All coding parts of p53 gene were directly sequenced. p53 expression in tumor cells was determined by immunohistochemistry. Human papillomavirus infection was detected by polymerase chain reaction. Odd ratios were adjusted by stepwise logistic regression analysis. RESULTS: p53 mutations, p53 expression, and tumor stage were sufficient to explain the variation in tumor responses to chemotherapy in multivariate models. p53 mutation was the only variable to significantly predict objective response (odds ratio, 0. 23; 95% confidence interval, 0.10 to 0.57; P =.002) and was the strongest predictor of major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P =.006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98) and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also predicted major response. Specific mutations (contact mutations) accounted for much of the reduction in the risk of major response associated with overall mutations. In complementary analyses, p53 expression was weakly predictive of major response in the subgroup with wild-type p53, and p53 mutations also predicted histologic response. CONCLUSION: p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.

[Evaluation of the prevalence and management of normocholesterolaemic and non coronary hypertensives in France]. / Evaluation de la prévalence et de la prise en charge des hypertendus normo-cholestérolémiques et non coronariens en France.

We performed a study amongst hypertensive patients who consulted French general practitioners in the Sentinelles network. Firstly, the significance of this population in mainland France was quantified by keeping a register of all hypertensive patients aged over 40 years seen in a general practice consultation, and secondly the distribution of risk factors and management of normocholesterolaemic (total cholesterol < or = 2.5 g/l) without lipid lowering treatment and non coronary patients was described more precisely. Analysis of the population of 7864 hypertensives from this register showed that on average one doctor saw 3 hypertensive patients a day and that about half of them (54%) were normocholesterolaemic, non coronary patients. Analysis of this sub-population of 2519 patients showed that 19.9% of them had at least 3 of the other cardiovascular risk factors described in the ASCOT study (Anglo-Scandinavian Cardiac Outcomes Trial) and that 39.5% had controlled hypertension according to the New York Heart Association classification. The extrapolated number of hypertensive, non coronary patients who were normocholesterolaemic without lipid lowering treatment was estimated as 4.6 million (4.1:5.1) for the whole of France.

[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.

Forecasting disease risk for increased epidemic preparedness in public health.

Emerging infectious diseases pose a growing threat to human populations. Many of the world's epidemic diseases (particularly those transmitted by intermediate hosts) are known to be highly sensitive to long-term changes in climate and short-term fluctuations in the weather. The application of environmental data to the study of disease offers the capability to demonstrate vector-environment relationships and potentially forecast the risk of disease outbreaks or epidemics. Accurate disease forecasting models would markedly improve epidemic prevention and control capabilities. This chapter examines the potential for epidemic forecasting and discusses the issues associated with the development of global networks for surveillance and prediction. Existing global systems for epidemic preparedness focus on disease surveillance using either expert knowledge or statistical modelling of disease activity and thresholds to identify times and areas of risk. Predictive health information systems would use monitored environmental variables, linked to a disease system, to be observed and provide prior information of outbreaks. The components and varieties of forecasting systems are discussed with selected examples, along with issues relating to further development.

The geographical spread of influenza.

How infectious diseases spread in space within one cycle of an epidemic is an important question that has received considerable theoretical attention. There are, however, few empirical studies to support theoretical approaches, because data are scarce. Weekly reports obtained since 1984 from a network of general practitioners spanning the entire French territory allows the analysis of the spatio-temporal dynamics of influenza over a fine spatial scale. This analysis indicates that diffusion over long distances, possibly due to global transportation systems, is so quick that homogeneous global mixing occurs before the epidemic builds up within infected patches. A simple model in which the total number of cases is given by the empirical time-series and cases are randomly assigned to patches according to the population weight of the patches exhibits the same spatio-temporal properties as real epidemic cycles: homogeneous mixing models constitute appropriate descriptions, except in the vicinity of the epidemic's peak, where geographic heterogeneities play a role.