Pediatric Prescriptions of Proton Pump Inhibitors in France (2009-2019): A Time-Series Analysis of Trends and Practice Guidelines Impact.

OBJECTIVE: To describe the ambulatory proton pump inhibitor (PPI) prescription in French children, its trends, and the impact of French (2014) and international (2018) clinical guidelines. STUDY DESIGN: We described PPI prescription rates based on national dispensation data in French children (IQVIA's Xponent database, 2009-2019). Using a segmented linear regression, we assessed the impact of clinical guidelines on PPI prescription rates. Analyses were performed for the overall pediatric population and by age subgroups (infants <2 years old, children 2-11 years old, adolescents 12-17 years old). RESULTS: During the study period, 8 060 288 pediatric PPI prescriptions were filled, with a mean PPI prescription rate of 52.5 per 1000 inhabitants per year. Between 2009 and 2019, the PPI prescription rate increased by 41% in the overall pediatric population (+110% in infants). The PPI prescription rate showed seasonal patterns with peaks in winter. After the release of French guidelines, significant decreases in trends of prescription rates occurred overall (change in trend -0.28, 95% CI -0.34;-0.23) and across all age groups. In infants, this change in trend was not sufficient to reverse the PPI prescription rate that was still increasing over time. In children, the PPI prescription rate slightly decreased and in adolescents, it was stable. After the release of international guidelines, a significant decrease in trend occurred in adolescents only (change in trend -0.26, 95% CI -0.47; -0.04). CONCLUSIONS: The pediatric PPI prescription rate in France was high, displayed a major increase over the last decade, mainly among infants, and was modestly affected by clinical guidelines.

Effects of the COVID-19 pandemic on head lice and scabies infestation dynamics: a population-based study in France.

BACKGROUND: Lockdowns and physical distancing have dramatically limited the circulation of SARS-CoV-2 and other common communicable infections. However, little is known about their impact on head lice and scabies. AIM: To assess the impact of the 2020 French National lockdowns (17 March-11 May 2020, and 30 October-15 December 2020) and physical distancing recommendations (from February 2020) on the dynamics of head lice and scabies infestations. METHODS: The weekly sales of topical head lice treatments, topical scabies treatments and oral ivermectin were extracted from the database of the healthcare science company IQVIA (60% of all French retail pharmacies) and analysed over a 5-year period (March 2016-December 2020). A periodic regression model was fitted to drug sales before the COVID-19 period (2016-2019) and extrapolated to compare the observed sales in 2020 to the expected sales. RESULTS: A decrease of the sales of tracer topical treatments for head lice and scabies was observed from March 2020, synchronously with the first French national lockdown. For the period March-December 2020, the mean reduction in observed vs. expected sales for head lice and scabies topical treatments was 44% and 14%, respectively. By contrast, although there was an observed decrease in oral ivermectin sales after March 2020, it was much lower (4%), probably because of studies reporting the potential positive effects of this drug on COVID-19 infection. CONCLUSION: COVID-19 lockdown and physical distancing reduce circulation of head lice and scabies in France. Further studies are needed to assess the long-term impact of these social behaviour changes.

Monitoring outpatient antibiotic utilization using reimbursement and retail sales data: a population-based comparison in France, 2012-17.

OBJECTIVES: To assess whether a retail sales database could be used to monitor antibiotic utilization in the outpatient setting at the national level. METHODS: We extracted 2012-17 outpatient antibiotic extrapolated retail sales (IQVIA's Xponent) and reimbursement data from the National Health Insurance (SNDS) in metropolitan France. We compared estimates of antibiotic use and consumption [number of antibiotic drug deliveries (DrID) and defined daily doses (DID) per 1000 inhabitants per day]. We relied on relative differences, Pearson's r statistics and time series using autoregressive integrated moving average (ARIMA) modelling to study: (i) differences in point estimates, (ii) correlation, and (iii) consistency in time trends between Xponent and SNDS. The analysis was conducted overall and in subgroups (age groups, therapeutic classes, major antimicrobial agents and regions). RESULTS: We analysed approximately 377 million antibiotic drug deliveries, comprising nearly 3.4 billion DDDs. Overall, Xponent slightly overestimated SNDS point estimates with yearly relative differences of +3.5% for DrID and +3.3% for DID. Peaks in relative differences were observed for July and August months. Relative differences were <5% in most subgroups, except for fosfomycin and three French regions. Overall and across most subgroups, the correlation between Xponent and SNDS monthly aggregated estimates was almost perfect (r ≥ 0.992 for all subgroups, except for one region). ARIMA modelling showed high consistency between Xponent's and SDNS's DrID time series, but detected timepoints where the series significantly diverged. CONCLUSIONS: IQVIA's Xponent and SNDS data were highly consistent. Xponent database seems suitable for monitoring outpatient antibiotic utilization in France.

Community antibiotic prescribing for children in France from 2015 to 2017: a cross-sectional national study.

OBJECTIVES: To assess recent community antibiotic prescribing for French children and identify areas of potential improvement. METHODS: We analysed 221 768 paediatric (<15 years) visits in a national sample of 680 French GPs and 70 community paediatricians (IQVIA's EPPM database), from March 2015 to February 2017, excluding well-child visits. We calculated antibiotic prescription rates per 100 visits, separately for GPs and paediatricians. For respiratory tract infections (RTIs), we described broad-spectrum antibiotic use and duration of treatment. We used Poisson regression to identify factors associated with antibiotic prescribing. RESULTS: GPs prescribed more antibiotics than paediatricians [prescription rate 26.1 (95% CI 25.9-26.3) versus 21.6 (95% CI 21.0-22.2) per 100 visits, respectively; P < 0.0001]. RTIs accounted for more than 80% of antibiotic prescriptions, with presumed viral RTIs being responsible for 40.8% and 23.6% of all antibiotic prescriptions by GPs and paediatricians, respectively. For RTIs, antibiotic prescription rates per 100 visits were: otitis, 68.1 and 79.8; pharyngitis, 67.3 and 53.3; sinusitis, 67.9 and 77.3; pneumonia, 80.0 and 99.2; bronchitis, 65.2 and 47.3; common cold, 21.7 and 11.6; bronchiolitis 31.6 and 20.1; and other presumed viral RTIs, 24.1 and 11.0, for GPs and paediatricians, respectively. For RTIs, GPs prescribed more broad-spectrum antibiotics [49.8% (95% CI 49.3-50.3) versus 35.6% (95% CI 34.1-37.1), P < 0.0001] and antibiotic courses of similar duration (P = 0.21). After adjustment for diagnosis, antibiotic prescription rates were not associated with season and patient age, but were significantly higher among GPs aged ≥50 years. CONCLUSIONS: Future antibiotic stewardship campaigns should target presumed viral RTIs, broad-spectrum antibiotic use and GPs aged ≥50 years.

Association between National Treatment Guidelines for Upper Respiratory Tract Infections and Outpatient Pediatric Antibiotic Use in France: An Interrupted Time-Series Analysis.

OBJECTIVE: To test whether updated clinical practice guidelines for managing upper respiratory tract infections released in France in November 2011 were associated with changes in national outpatient pediatric antibiotic use. STUDY DESIGN: We performed an interrupted time-series analysis using national antibiotic dispensation data in French children from January 2009 to December 2017 (IQVIA Suivi de la Dispensation Médicale database). We described the overall evolution of antibiotic prescription rates and modeled the changes in the proportion of amoxicillin and the proportion of broad-spectrum antibiotics following the guidelines in 2 age groups (0-5 and 6-14 years old). RESULTS: We analyzed 123 million pediatric antibiotic prescriptions. The most commonly prescribed individual antibiotic agent was amoxicillin (37.7%). Over the study period, the annual antibiotic prescription rate decreased by 33.1% (from 1387 to 928 per 1000 pediatric inhabitants per year), consistently across age groups and major antibiotic agents except for amoxicillin (+14.4%). After the release of the guidelines, we observed a gradual increase in the proportion of amoxicillin (relative change 5 years postintervention of +64.3% [95% CI 51.6-80.1] and +28.4% [21.1-36.2] for children 0-5 and 6-14 years, respectively) concomitantly with a gradual decrease in the proportion of broad-spectrum antibiotics (relative change 5 years postintervention of -26.1% [-29.3, -23.7] and -19.8% [-22.1, -16.0] for children 0-5 and 6-14 years old, respectively). CONCLUSIONS: The 2011 guidelines for upper respiratory tract infections preceded changes in outpatient pediatric antibiotic use at the national level, with a replacement of broad-spectrum antibiotics by amoxicillin.

Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: The risk of infection associated with tumor necrosis factor antagonists (anti-TNF) and thiopurines (combination therapy) is uncertain. We assessed the risk of serious and opportunistic infections in patients with inflammatory bowel disease (IBD) treated with thiopurine monotherapy, anti-TNF monotherapy, or combination therapy in a large cohort of patients in France. METHODS: We performed a nationwide population-based study of patients (18 years or older) with a diagnosis of IBD in the French national health insurance database; we collected data from January 1, 2009 until December 31, 2014. The risks of serious and opportunistic infections associated with exposure to combination therapy, anti-TNF, and thiopurine monotherapies were compared using marginal structural Cox proportional hazard models adjusted for baseline and time-varying sociodemographic characteristics, medications, and comorbidities. RESULTS: Among the 190,694 patients with IBD included in our analysis, 8561 serious infections and 674 opportunistic infections occurred. Compared with anti-TNF monotherapy, combination therapy was associated with increased risks of serious infection (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.05-1.45) and opportunistic infection (HR, 1.96; 95% CI, 1.32-2.91). Compared with thiopurine monotherapy, anti-TNF monotherapy was associated with increased risks of serious infection (HR, 1.71; 95% CI, 1.56-1.88), mycobacterial infection (HR, 1.98; 95% CI, 1.15-3.40), and bacterial infection (HR, 2.38; 95% CI, 1.23-4.58, respectively). Conversely, anti-TNF monotherapy was associated with decreased risk of opportunistic viral infection compared with thiopurine monotherapy (HR, 0.57; 95% CI, 0.38-0.87). CONCLUSIONS: In a nationwide cohort study of patients with IBD in France, we found heterogeneity in risks of serious and opportunistic infections in patients treated with immune-suppressive regimens. These should be carefully considered and weighed against potential benefits for IBD treatment in patient management.

Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease.

IMPORTANCE: An increased risk of lymphoma has been reported among patients receiving thiopurines for inflammatory bowel disease (IBD). The risk of lymphoma associated with anti-tumor necrosis factor (TNF) agents either alone or in combination with thiopurines is uncertain. OBJECTIVE: To assess the risk of lymphoma associated with thiopurines and anti-TNF agents, used alone or in combination, for the management of IBD. DESIGN, SETTING, AND PARTICIPANTS: Nationwide cohort study based on French National Health Insurance databases. Patients aged 18 years or older identified with IBD were included from January 1, 2009, through December 31, 2013, and followed up until December 31, 2015. EXPOSURES: At each time of the follow-up, patients were categorized as being exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed. MAIN OUTCOMES AND MEASURES: The primary outcome was incident lymphoma. RESULTS: Among the 189 289 patients included (54% women; median age, 43 years [interquartile range, 32-56 years]) and followed up for a median of 6.7 years, 123 069 were never exposed during follow-up, 50 405 were exposed to thiopurine monotherapy, 30 294 to anti-TNF monotherapy, and 14 229 to combination therapy. Overall, 336 lymphoma cases occurred: 220 in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% CI, 0.23-0.29), 70 in patients exposed to thiopurine monotherapy (IR, 0.54; 95% CI, 0.41-0.67), 32 in patients exposed to anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27-0.55), and 14 in patients exposed to combination therapy (IR, 0.95; 95% CI, 0.45-1.45). In a multivariable Cox model, compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96-3.44; P < .001), anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60-3.64; P < .001), or combination therapy (aHR, 6.11; 95% CI, 3.46-10.8; P < .001). The risk was higher in patients exposed to combination therapy vs those exposed to thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31-4.22; P < .001) or anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35-4.77; P < .001). CONCLUSIONS AND RELEVANCE: Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment.

Hospital Burden of All-Cause Pneumonia and Nonbacteremic Pneumococcal Pneumonia in Adults in France Between 2013 and 2019.

Background: Community-acquired pneumonia (CAP) is associated with significant morbidity and mortality. The study objective was to describe the hospital burden of pneumonia in the adult population in France. Methods: This retrospective study was conducted from the National Health Insurance Database. All hospitalizations for pneumonia (all-cause) between 2013 and 2019 were included. Different risk categories for patients were established based on pneumococcal vaccine recommendations by French health authorities. Results: A total of 2 199 240 episodes of CAP were registered over the study period (annual mean, 314 177 [standard deviation, 17 818.6]); 75% occurred in patients aged ≥65 years, among whom 47% were not classified in the moderate- or high-risk categories recommended for French pneumococcal vaccination. The incidence of CAP increased with age (117.9, 395.3, and 1916.7 per 100 000 for the age groups 18-49, 50-64, and ≥65 years, respectively, in 2019). Furthermore, being at risk of pneumococcal disease resulted in more severe outcomes, including longer episode duration (mean, 14 days in low-risk vs 17 days in high-risk patients) and higher risk of referral to critical care units (from 20% to 27%), of rehospitalization up to 180 days (from 39% to 67%), of in-hospital death (from 12% to 19%), and of 1-year mortality (from 26% to 49%). Conclusions: This study establishes the incidence of CAP in adults in France, describes the significant burden of disease, and highlights the need for better prevention policies.

Estimating the burden of influenza-related and associated hospitalizations and deaths in France: An eight-season data study, 2010-2018.

BACKGROUND: In France, each year, influenza viruses are responsible for seasonal epidemics leading to 2-6 million cases. Influenza can cause severe disease that may lead to hospitalization or death. As severe disease may be due to the virus itself or to disease complications, estimating the burden of severe influenza is complex. The present study aimed at estimating the epidemiological and economic burden of severe influenza in France during eight consecutive influenza seasons (2010-2018). METHODS: Influenza-related hospitalization and mortality data and patient characteristics were taken from the French hospital information database, PMSI. An ecological approach using cyclic regression models integrating the incidence of influenza syndrome from the Sentinelles network supplemented the PMSI data analysis in estimating excess hospitalization and mortality (CépiDc-2010-2015) and medical costs. RESULTS: Each season, the average number of influenza-related hospitalizations was 18,979 (range: 8627-44,024), with an average length of stay of 8 days. The average number of respiratory hospitalizations indirectly related with influenza (i.e., influenza associated) was 31,490 (95% confidence interval [CI]: 24,542-39,012), with an average cost of €141 million (range: 54-217); 70% of these hospitalizations and 77% of their costs concerned individuals ≥65 years of age (65+). More than 90% of excess mortality was in 65+ subjects. CONCLUSIONS: The combination of two complementary approaches allowed estimation of both influenza-related and associated hospitalizations and deaths and their burden in France, showing the substantial impact of complications. The present study highlighted the major public health burden of influenza and its severe complications, especially in 65+ subjects.

Impact of extending direct antiviral agents (DAA) availability in France: an observational cohort study (2015-2019) of data from French administrative healthcare databases (SNDS).

BACKGROUND: Direct antiviral agents (DAAs) became available in France in 2014 for the treatment of chronic hepatitis C (CHC) in patients with severe fibrosis (prioritized access); in 2017, DAAs became available to all CHC patients (universal access). We evaluated the impact of extending DAA availability on CHC patient care, especially on screening and time to treatment. METHODS: Adult patients affiliated with the national health insurance system (SNDS) who were screened or treated for CHC between 2015 and 2019 were included. Algorithms were developed to identify at-risk subpopulations. FINDINGS: The proportion of screened patients increased by 1% between 2015 and 2019, from 4·6% to 5·6%. The main nonexclusive risk factors for CHC were psychiatric conditions (27%), drug use (21%) and HIV positivity (11%); more than 50% of psychiatric patients had additional risk factors, mainly drug use with a 38% to 52% overlap.The median interval between the last screening test and treatment initiation decreased from 64 days in 2015 to 37 days in 2019.During the study period, 71,466 patients began CHC treatment (median age 55 [48-62]; 59% male), including 46% of "at-risk" patients with an increase in treatment initiation by 44% between 2015 and 2017 and a decrease of 46% between 2017 and 2019. Only 2,212 (3%) patients were treated at least twice.Among treated patients, the proportion of HIV+ patients decreased from 19% to 8% (prioritization consequence), while the proportions increased in the other at-risk subpopulations. INTERPRETATION: we showed that policies extending DAA availability are associated with a screening increase and a decrease in the time to treatment initiation, while universal access led to a surge in treatment initiations in 2017. This study may also contribute to improving the cascade of care in the at-risk subpopulations. For instance, by pointing out their relative importance, especially for the psychiatric subpopulation, it highlights the importance to address them with tailored policies.

Refracture and mortality following hospitalization for severe osteoporotic fractures: The Fractos Study.

Severe osteoporotic fractures (hip, proximal humerus, pelvic, vertebral and multiple rib fractures) carry an increased risk of mortality. This retrospective cohort study in the French national healthcare database aimed to estimate refracture and mortality rates after severe osteoporotic fractures at different sites, and to identify mortality-related variables. A total of 356,895 patients hospitalized for severe osteoporotic fracture between 2009 and 2014 inclusive were analyzed. The cohort was followed for 2 to 8 years up to the study end or until the patient died. Data were extracted on subsequent hospitalizations, refracture events, treatments, comorbidities of interest and survival. Time to refracture and survival were described using Kaplan-Meier analysis by site of fracture and overall. Mortality risk factors were identified using a Cox model. Hip fractures accounted for 60.4% of the sample (N = 215,672). In the 12 months following fracture, 58,220 patients (16.7%) received a specific osteoporosis treatment, of whom 21,228 were previously treatment-naïve. The 12-month refracture rate was 6.3% (95% confidence interval [CI], 6.2%-6.3%), ranging from 4.0% (95% CI, 3.7%-4.3%) for multiple rib fractures to 7.8% (95% CI, 7.5%-8.1%) for pelvic fractures. Twelve-month all-cause mortality was 12.8% (95% CI, 12.7%-12.9%), ranging from 5.0% (95% CI, 4.7%-5.2%) for vertebral fractures to 16.6% (95% CI, 16.4%-16.7%) for hip fractures. Osteoporosis-related mortality risk factors included fracture site, previous osteoporotic fracture (hazard ratio 1.21; 95% CI, 1.18-1.23), hip refracture (1.74; 95% CI, 1.71-1.77), and no prior osteoporosis treatment (1.24; 95% CI, 1.22-1.26). Comorbid cancer (3.15; 95% CI, 3.09-3.21) and liver disease (2.54; 95% CI, 2.40-2.68) were also strongly associated with mortality. In conclusion, severe osteoporotic fractures, including certain non-hip nonvertebral fractures, carry a high burden in terms of mortality and refracture risk. However, most patients received no anti-osteoporotic treatment. The findings emphasize the importance of better management of patients with severe fractures, and of developing effective strategies to reduce fracture risk in patients with osteoporosis. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Common communicable diseases in the general population in France during the COVID-19 pandemic.

In France, social distancing measures have been adopted to contain the spread of COVID-19, culminating in national Lockdowns. The use of hand washing, hydro-alcoholic rubs and mask-wearing also increased over time. As these measures are likely to impact the transmission of many communicable diseases, we studied the changes in common infectious diseases incidence in France during the first year of COVID-19 circulation. We examined the weekly incidence of acute gastroenteritis, chickenpox, acute respiratory infections and bronchiolitis reported in general practitioner networks since January 2016. We obtained search engine query volume for French terms related to these diseases and sales data for relevant drugs over the same period. A periodic regression model was fit to disease incidence, drug sales and search query volume before the COVID-19 period and extrapolated afterwards. We compared the expected values with observations made in 2020. During the first lockdown period, incidence dropped by 67% for gastroenteritis, by 79% for bronchiolitis, by 49% for acute respiratory infection and 90% for chickenpox compared to the past years. Reductions with respect to the expected incidence reflected the strength of implemented measures. Incidence in children was impacted the most. Reduction in primary care consultations dropped during a short period at the beginning of the first lockdown period but remained more than 95% of the expected value afterwards. In primary care, the large decrease in reported gastroenteritis, chickenpox or bronchiolitis observed during the period where many barrier measures were implemented imply that the circulation of common viruses was reduced and informs on the overall effect of these measures.

Comparative age distribution of influenza morbidity and mortality during seasonal influenza epidemics and the 2009 H1N1 pandemic.

BACKGROUND: Several studies have shown a relatively high mortality rate among young people infected by the 2009 pandemic influenza A (H1N1) virus. Here we compared the age distributions of morbidity and mortality during two seasonal influenza epidemics (H1N1 and H3N2) in France and the United States with those of the 2009 H1N1 pandemic waves in the same countries. METHODS: Age-standardized ratios were used to compare the age distribution of morbidity and mortality due to influenza between the two countries and across the different years. Non parametric analysis of variance was used to compare these ratios between epidemic and pandemic influenza. RESULTS: Age distribution of morbidity was similar between the 2009 pandemic and seasonal epidemics due to H1N1 (p = 0.72) and H3N2 viruses (p = 0.68). In contrast, the proportion of under-60s among influenza deaths was markedly higher during the 2009 pandemic (peak <20 years) than during the seasonal epidemics (respectively p = 0.007 and p = 0.0008). CONCLUSIONS: Young age was a principal mortality risk factor due to the 2009 H1N1 pandemic.

Association Between Acute Gastroenteritis and Continuous Use of Proton Pump Inhibitors During Winter Periods of Highest Circulation of Enteric Viruses.

Importance: An increased risk of acute bacterial enteric infections has been reported among patients receiving proton pump inhibitor (PPI) therapy. The risk of acute gastroenteritis (AGE) of viral origin associated with continuous PPI exposure has been less studied. Objective: To investigate the association between continuous PPI therapy and AGE occurrence during winter epidemic periods when the circulation of enteric viruses is the highest. Design, Setting, and Participants: A matched cohort study was performed using a prospectively collected drug dispensing database from a large panel of community pharmacies in continental France. All patients recorded in the database during the 2015 to 2016 winter season, with documented age, sex, and use of an identifiable regular panel pharmacy, were eligible for the study. Each patient exposed to continuous PPI therapy was matched to 3 unexposed patients, according to year of birth, sex, and identifiable regular panel pharmacy. Analyses were performed between January 2017 and December 2018. Exposure: Continuous PPI use during the 2015 to 2016 AGE winter epidemic. Main Outcomes and Measures: The occurrence of at least 1 AGE episode during the 2015 to 2016 AGE winter epidemic was the main outcome. Episodes of AGE were identified using a previously validated algorithm based on drug dispensing data. Relative risks of AGE were estimated using a multivariable log-binomial model adjusted for age, sex, and treatments for chronic conditions. Results: There were 233 596 patients receiving PPI therapy (median [interquartile range] age, 71 [62-81] years; 55.8% female) and 626 887 matched patients not receiving PPI therapy (median [interquartile range] age, 70 [61-80] years; 56.3% female) included in the analyses. At least 1 AGE epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy. The adjusted relative risk of AGE for those receiving PPI therapy was 1.81 (95% CI, 1.72-1.90) for all ages considered, 1.66 (95% CI, 1.54-1.80) among those aged 45 to 64 years, 2.19 (95% CI, 1.98-2.42) among those aged 65 to 74 years, and 1.98 (95% CI, 1.82-2.15) among those aged 75 years and older. Conclusions and Relevance: Continuous PPI therapy was associated with an increased risk of developing AGE during periods of highest circulation of enteric viruses. These findings support the hypothesis that PPI use is associated with an increased risk of enteric viral infections.

Time lines of infection and disease in human influenza: a review of volunteer challenge studies.

The dynamics of viral shedding and symptoms following influenza virus infection are key factors when considering epidemic control measures. The authors reviewed published studies describing the course of influenza virus infection in placebo-treated and untreated volunteers challenged with wild-type influenza virus. A total of 56 different studies with 1,280 healthy participants were considered. Viral shedding increased sharply between 0.5 and 1 day after challenge and consistently peaked on day 2. The duration of viral shedding averaged over 375 participants was 4.80 days (95% confidence interval: 4.31, 5.29). The frequency of symptomatic infection was 66.9% (95% confidence interval: 58.3, 74.5). Fever was observed in 37.0% of A/H1N1, 40.6% of A/H3N2 (p = 0.86), and 7.5% of B infections (p = 0.001). The total symptoms scores increased on day 1 and peaked on day 3. Systemic symptoms peaked on day 2. No such data exist for children or elderly subjects, but epidemiologic studies suggest that the natural history might differ. The present analysis confirms prior expert opinion on the duration of viral shedding or the frequency of asymptomatic influenza infection, extends prior knowledge on the dynamics of viral shedding and symptoms, and provides original results on the frequency of respiratory symptoms or fever.

Association Between Oral Fluoroquinolone Use and Retinal Detachment.

IMPORTANCE: Several studies have focused on the current use of oral fluoroquinolones and the risk for retinal detachment (RD), but the existence of this association is under debate. Given the widespread fluoroquinolone use, investigation of this association is essential. OBJECTIVE: To assess the association between oral fluoroquinolone use and the risk for RD, including the rhegmatogenous and exudative types. DESIGN, SETTING, AND PARTICIPANTS: This case-crossover study included 27,540 adults with RD from French health care databases from July 1, 2010, through December 31, 2013. Patients with a history of RD or retinal break, endophthalmitis, intravitreal injection, choroidal retinal vitreal biopsy, and human immunodeficiency virus infection or those hospitalized within 6 months of RD were excluded. The risk period of primary interest was current use, defined as exposure to fluoroquinolones within 10 days immediately before RD surgery, according to previous findings. Oral fluoroquinolone use was assumed to start on the day the prescription was dispensed. MAIN OUTCOMES AND MEASURES: Exposure to fluoroquinolones during the risk period (1-10 days) compared with the control period (61-180 days). The association was also assessed regarding use in the recent (11-30 days) and past (31-60 days) intermediate risk period, type of fluoroquinolone, and type of RD. RESULTS: Of the 27,540 eligible patients (57% men; mean [SD] age, 61.5 [13.6] years), 663 patients with RD were exposed to fluoroquinolones during the observation period, corresponding to 80 cases exposed during the 10-day risk period (≤10 days before RD) and 583 cases exposed during the control period (61-180 days). We found a significant increased risk for RD during the 10-day period after the dispensing of oral fluoroquinolones, with an adjusted odds ratio of 1.46 (95% CI, 1.15-1.87). The risk was significantly increased for rhegmatogenous and exudative RD, with adjusted odds ratios of 1.41 (95% CI, 1.04-1.92) and 2.57 (95% CI, 1.46-4.53), respectively. Recent and past use of fluoroquinolones were not associated with a higher risk for RD, with adjusted odds ratios of 0.94 (95% CI, 0.78-1.14) and 1.06 (95% CI, 0.91-1.24), respectively. CONCLUSIONS AND RELEVANCE: Current oral fluoroquinolone use was associated with an increased risk for RD, including the rhegmatogenous and exudative types. These findings, along with the available literature, suggest an association between fluoroquinolone use and the risk for RD. The nature of this association should be further investigated in future studies.

Applications of Extreme Value Theory in Public Health.

OBJECTIVES: We present how Extreme Value Theory (EVT) can be used in public health to predict future extreme events. METHODS: We applied EVT to weekly rates of Pneumonia and Influenza (P&I) deaths over 1979-2011. We further explored the daily number of emergency department visits in a network of 37 hospitals over 2004-2014. Maxima of grouped consecutive observations were fitted to a generalized extreme value distribution. The distribution was used to estimate the probability of extreme values in specified time periods. RESULTS: An annual P&I death rate of 12 per 100,000 (the highest maximum observed) should be exceeded once over the next 30 years and each year, there should be a 3% risk that the P&I death rate will exceed this value. Over the past 10 years, the observed maximum increase in the daily number of visits from the same weekday between two consecutive weeks was 1133. We estimated at 0.37% the probability of exceeding a daily increase of 1000 on each month. CONCLUSION: The EVT method can be applied to various topics in epidemiology thus contributing to public health planning for extreme events.

Impact of the 2013 French Pill Crisis on Women's Behaviour Regarding Contraception.

CONTEXT: In the last decade, several epidemiological studies have shown the increased risk of venous thromboembolism associated with third- and fourth-generation oral contraceptives (C3Gs and C4Gs) versus older combined first- and second-generation oral contraceptives (C1Gs and C2Gs). In France, in December 2012, a lawsuit filed against the National Agency for the Safety of Medicines and Health Products (ANSM) by a patient who had experienced a stroke, possibly due to the use of a C3G, triggered a national 'pill crisis'. Consequently, a 'crisis cell' was set up and pre-existing health recommendations were reinforced. The main aim of this study was to evaluate, in real time, the impact of the French health authorities' recommendations and communications on French women's behaviour regarding contraception. METHODS: Real-time monthly sales data reported during 2013 were compared with monthly sales data reported in 2012. Analyses were stratified according to the type of contraceptive and age. An index corresponding to the number of months of contraception sold was developed to facilitate comparison of the different contraceptives despite their distinct features and to assess the overall trend of contraception. RESULTS: After a 2-year analysis (2013 versus 2012), a significant 45 % decrease (p < 0.0001) in C3G-4G sales was observed, compared with a significant increase of 30 % (p < 0.0001) in C1G-2G sales. The sharp increase in C1G-2G sales focused specifically on C2Gs with an oestrogen concentration below 20 µg. Moreover, a large (47 %) increase was reported in sales of intrauterine devices (p < 0.0001). Finally, taking all types of contraceptive sales into account, a slight decrease (1 %) in overall sales was identified. CONCLUSION: Thanks to an effective national communication plan, real-time monitoring of drug sales and favourable reactions from physicians and patients, French women changed their behaviour regarding contraception. However, this study was conducted over a short period following the crisis. A longitudinal analysis is required in order to assess any real long-term changes.

Antibody persistence and serological protection among seasonal 2007 influenza A(H1N1) infected subjects: Results from the FLUREC cohort study.

INTRODUCTION: Haemagglutination-inhibition (HI) antibody titer is a correlate of protection against influenza; its persistence after infection or vaccination is important to determining susceptibility to subsequent infection. Few studies, however, have reported longitudinal data regarding the magnitude and duration of HI protection following natural seasonal influenza A infection. METHODS: Using French influenza cohort study data collected from 2008 to 2010, we investigated persistence of serological protection among subjects according to influenza-like illness (ILI) and laboratory-confirmed seasonal 2007 influenza A(H1N1) infection status at inclusion in 2008 (ILI-A(H1N1) positive, ILI-A(H1N1) negative, or no-ILI). Antibody titers against seasonal 2007 A(H1N1) were determined using the HI technique for sera. Regression models for interval-censored data were used to estimate geometric mean titers (GMT) for HI assays. A logistic regression model adjusted for age group (subjects <30, 30-50 and >50 years old) was used to quantify the association between HI titer and protection against infection. RESULTS: Based on 310 total subjects, influenza A(H1N1) infection was confirmed in 39 of 115 ILI subjects at inclusion. GMT associated with 50% probability of protection among ILI subjects decreased with age group (subjects <30 yo: GMT of 40.8 was associated with 50% [95CI: 29.3%; 70.7%] probability of protection, subjects 30-50 yo: 26.8 [95CI: 34.4%; 65.6%] and subjects >50 yo: 8.9 [95CI: 15.3%; 84.7%]). GMT declined after the first annual study visit among ILI-A(H1N1) positive subjects but remained higher compared to inclusion at the 2010 study visit (41.5 [95CI: 34.8; 49.5], p=0.0157). GMT remained stable among ILI-A(H1N1) negative subjects (p=0.7502), but decreased among no-ILI subjects (p<0.0001). CONCLUSION: Our results confirm the positive relationship between HI titer and probability of protection among naturally infected subjects, and provides evidence that protection associated with HI titer varies with age. This longitudinal analysis suggests the rise in HI titers following seasonal 2007 influenza A(H1N1) infection may persist into subsequent influenza seasons.

Coinfection with Plasmodium falciparum and Schistosoma haematobium: additional evidence of the protective effect of Schistosomiasis on malaria in Senegalese children.

Parasitic infections are associated with high morbidity and mortality in developing countries. Several studies focused on the influence of helminth infections on malaria but the nature of the biological interaction is under debate. Our objective was to undertake a study to explore the influence of the measure of excreted egg load caused by Schistosoma haematobium on Plasmodium falciparum parasite densities. Ten measures of malaria parasite density and two measures of schistosomiasis egg urinary excretion over a 2-year follow-up period on 178 Senegalese children were considered. A linear mixed-effect model was developed to take data dependence into account. This work showed that children with a light S. haematobium infection (1-9 eggs/mL of urine) presented lower P. falciparum parasite densities than children not infected by S. haematobium (P < 0.04). Possible changes caused by parasite coinfections should be considered in the anti-helminth treatment of children and in malaria vaccination development.