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Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

International audience; Importance: Acute chest syndrome (ACS) is one of the leading acute severe complications of sickle-cell disease (SCD). Although Streptococcus pneumoniae (S pneumoniae) is highly prevalent in children with SCD, its precise role in ACS is unclear. The efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) implementation on ACS is still unknown.Objective: To assess the association of PCV13 implementation in the general pediatric population with the incidence of ACS in children with SCD.Design, setting, and participants: This cohort study used an interrupted time-series analysis of patient records from a national hospital-based French surveillance system. All children younger than 18 years with SCD (based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision definition) hospitalized in France between January 2007 and December 2019 were included.Exposures: PCV13 implementation.Main outcomes and measures: Monthly incidence of ACS per 1000 children with SCD over time as analyzed by segmented linear regression with autoregressive error; monthly incidence of hospitalization for vaso-occlusive crisis, asthma crisis, and acute pyelonephritis per 1000 children with SCD over the same period as the control outcomes.Results: Among the 107 694 hospitalizations of children with SCD, 4007 episodes of ACS were included (median [IQR] age, 8 [4-12] years; 2228 [55.6%] boys). PCV13 implementation in 2010 was followed by a significant decrease in the incidence of ACS (-0.9% per month; 95% CI, -1.4% to -0.4%; P < .001), with an estimated cumulative change of -41.8% (95% CI, -70.8% to -12.7%) by 2019. Sensitivity analyses yielded the same results, including the incidence of ACS adjusted for that of vaso-occlusive crisis over time. The results were similar among different age groups. By contrast, no change was found for the 3 control outcomes over the study period.Conclusions and relevance: PCV13 implementation was associated with an important reduction in the incidence of ACS in children with SCD. This vaccine benefit provides new evidence of the key role of S pneumoniae in ACS and should be considered when estimating outcomes associated with current PCVs and the potential benefit of next-generation PCVs in children.

International audience; Coxsackievirus A6 (CVA6) emerged as the most common enterovirus of seasonal outbreaks of hand-foot-and-mouth disease (HFMD). We investigated CVA6 genetic diversity among the clinical phenotypes reported in the paediatric population during sentinel surveillance in France between 2010 and 2018. CVA6 infection was confirmed in 981 children (mean age 1.52 years [IQR 1.17–2.72]) of whom 564 (58%) were males. Atypical HFMD was reported in 705 (72%) children, followed by typical HFMD in 214 (22%) and herpangina in 57 (6%) children. Throat specimens of 245 children were processed with a target-enrichment new-generation sequencing approach, which generated 213 complete CVA6 genomes. The genomes grouped within the D1 and D3 clades (phylogeny inferred with the P1 genomic region). In total, 201 genomes were classified among the recombinant forms (RFs) A, B, F, G, H, and N, and 12 genomes were assigned to 5 previously unreported RFs (R–V). The most frequent RFs were A (58%), H (19%), G (6.1%), and F (5.2%). The yearly number of RFs ranged between 1 (in 2012 and 2013) and 6 (2018). The worldwide CVA6 epidemic transmission began between 2005 and 2007, which coincided with the global spread of the recombinant subclade D3/RF-A.

Background Platelet transfusions are used to prevent or control bleeding in patients with thrombocytopenia or platelet dysfunction. The pretransfusion platelet count threshold has been studied extensively in multiple patient settings yielding high-quality evidence that has been summarized in several comprehensive evidence-based platelet guidelines. Study design and methods A prospective 12-week audit of consecutive platelet transfusions using validated and evidence-based adjudication criteria was conducted. Patient demographic, laboratory, and transfusion details were collected with an electronic audit tool. Each order was adjudicated either electronically or independently by two transfusion medicine physicians. The aim was to determine platelet transfusion appropriateness and common scenarios with deviations from guidelines. Results Fifty-seven (38%) of 150 hospitals provided data on 1903 platelet orders, representing 90% of platelet usage in the region during the time period. Overall, 702 of 1693 adult (41.5%) and 133 of 210 pediatric orders (63.3%) were deemed inappropriate. The most common inappropriate platelet order was for prophylaxis in the absence of bleeding or planned procedure in patients with hypoproliferative thrombocytopenia and a platelet count over 10 x 109 /L (53% of inappropriate orders in adults and 45% in pediatrics). Platelet transfusions ordered with either a preprinted transfusion order set (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.44-2.73) or technologist prospective screening (OR, 1.40; 95% CI, 1.10-1.78) were more likely to be appropriate. Conclusion There is a discrepancy between clinical practice and evidence-based platelet guidelines. Broad educational and system changes will be needed to align platelet transfusion practice with guideline recommendations.

Background Alloimmunization can impact both the fetus and neonate. Study objectives (a) calculate the incidence of clinically significant RBC isoimmunization during pregnancy, (b) review maternal management and neonatal outcomes, (c) assess the value of prenatal and postnatal serological testing in predicting neonatal outcomes. Study design and methods A retrospective audit of consecutive alloimmunized pregnancies was conducted. Data collected included demographics, clinical outcomes, and laboratory results. Outcomes included: incidence of alloimmunization; outcomes for neonates with and without the cognate antigen; and sensitivity and specificity of antibody titration testing in predicting hemolytic disease of the fetus and newborn (HDFN). Results Over 6 years, 128 pregnant women (0.4%) were alloimmunized with 162 alloantibodies; anti-E was the most common alloantibody (51/162; 31%). Intrauterine transfusions (IUTs) were employed in 2 (3%) of 71 mothers of cognate antigen positive (CoAg+) neonates. Of 74 CoAg+ neonates, 58% required observation alone, 23% intensive phototherapy, 9% top up transfusion, and 3% exchange transfusion; no fetal or neonatal deaths occurred. HDFN was diagnosed in 28% (21/74) of neonates; anti-D was the most common cause. The sensitivity and specificity of the critical gel titer >32 in predicting HDFN were 76% and 75%, respectively (negative predictive value 95%; positive predictive value 36%). The sensitivity and specificity of a positive direct antiglobulin test (DAT) in predicting HDFN were 90% and 58%, respectively (NPV 97%; PPV 29%). Conclusion Morbidity and mortality related to HDFN was low; most alloimmunized pregnancies needed minimal intervention. Titers of >32 by gel warrant additional monitoring during pregnancy.

Background Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. Methods The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. Discussion The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.

Background Prenatal antibody titers for alloimmunized patients are subject to multiple sources of variation. A parallel titer on the previous sample at the same time as the current sample is recommended. The purpose of this study was to determine the added value of parallel titers. Study design and methods This is a retrospective study of samples from consecutive prenatal patients with at least two prenatal antibody titers performed in the same pregnancy at a single institution between October 2010 and March 2017. Prenatal titers were performed using gel technology. Data were collected to determine the sensitivity and specificity of a clinically significant increase (twofold or greater) in serial titers compared with the gold standard of using parallel titers. Results There were 155 serial prenatal titers performed in 59 alloimmunized pregnant women. Nineteen samples (12%) had a serial titer increase of twofold or greater with eight false positive samples (increase less than twofold when using parallel titers). Thirty-six samples (23%) had a serial titer increase of onefold with two false negative samples (increase of twofold or greater using parallel titers). One hundred samples (65%) had no increase (or a decrease) in serial titer with none having an increase of twofold or greater using parallel titers. The sensitivity of a twofold or greater increase in serial titers was 84.6% (95% CI 55-98%) and the specificity was 94.4% (95% CI 89-98%) when compared with parallel titers. Conclusion This study questions the value of parallel titers on every prenatal titer performed. When no increase in serial titers was observed, parallel titers added no new information.

BACKGROUND & OBJECTIVES Serologic testing after transfusion reactions (TRs) aims to find accountable immune haemolytic incompatibility. Our hospital policies recommend serologic testing in all TR, except for low-risk fevers (subclinical temperature

A multi-partner effort in Uganda and Zambia employed a districtwide health systems strengthening approach, with supply- and demand-side interventions, to address timely use of appropriate, quality maternity care. Between 2012 and 2016, maternal mortality declined by approximately 40% in both partnership-supported facilities and districts in each country. This experience has useful lessons for other low-resource settings., Background: Ending preventable maternal and newborn deaths remains a global health imperative under United Nations Sustainable Development Goal targets 3.1 and 3.2. Saving Mothers, Giving Life (SMGL) was designed in 2011 within the Global Health Initiative as a public–private partnership between the U.S. government, Merck for Mothers, Every Mother Counts, the American College of Obstetricians and Gynecologists, the government of Norway, and Project C.U.R.E. SMGL's initial aim was to dramatically reduce maternal mortality in low-resource, high-burden sub-Saharan African countries. SMGL used a district health systems strengthening approach combining both supply- and demand-side interventions to address the 3 key delays to accessing effective maternity care in a timely manner: delays in seeking, reaching, and receiving quality obstetric services. Implementation: The SMGL approach was piloted from June 2012 to December 2013 in 8 rural districts (4 each) in Uganda and Zambia with high levels of maternal deaths. Over the next 4 years, SMGL expanded to a total of 13 districts in Uganda and 18 in Zambia. SMGL built on existing host government and private maternal and child health platforms, and was aligned with and guided by Ugandan and Zambian maternal and newborn health policies and programs. A 35% reduction in the maternal mortality ratio (MMR) was achieved in SMGL-designated facilities in both countries during the first 12 months of implementation. Results: Maternal health outcomes achieved after 5 years of implementation in the SMGL-designated pilot districts were substantial: a 44% reduction in both facility and districtwide MMR in Uganda, and a 38% decrease in facility and a 41% decline in districtwide MMR in Zambia. Facility deliveries increased by 47% (from 46% to 67%) in Uganda and by 44% (from 62% to 90%) in Zambia. Cesarean delivery rates also increased: by 71% in Uganda (from 5.3% to 9.0%) and by 79% in Zambia (from 2.7% to 4.8%). The average annual rate of reduction for maternal deaths in the SMGL-supported districts exceeded that found countrywide: 11.5% versus 3.5% in Uganda and 10.5% versus 2.8% in Zambia. The changes in stillbirth rates were significant (−13% in Uganda and −36% in Zambia) but those for pre-discharge neonatal mortality rates were not significant in either Uganda or Zambia. Conclusion: A district health systems strengthening approach to addressing the 3 delays to accessing timely, appropriate, high-quality care for pregnant women can save women's lives from preventable causes and reduce stillbirths. The approach appears not to significantly impact pre-discharge neonatal mortality.

The authors examined associations between different forms of children's friendship nomination reciprocity (mutual, unilateral given, unilateral received) and other measures of children's peer social competence (liking, loneliness, overt aggression, perceived popularity) for 501 Chinese third- to sixth-grade students. Using a multigroup path analysis (with gender as group), for both boys and girls, all three forms of friendship nominations were negatively related to self-reported loneliness. Mutual friendship nominations and unilateral received friendship nominations were positively related to peer nominations for liking and to peer nominations of perceived popularity. The path between unilateral received friendship nominations and perceived popularity was higher for boys than for girls. Also, for boys only, mutual friendship nominations and unilateral received friendship nominations were each negatively related to peer nominations of overt aggression. These patterns are somewhat different from research examining the association of forms of friendships to peer social competence for children in Western cultures. Findings are discussed in terms of the importance of the relation of different forms of friendship nominations to children's peer social competence as well as the broad association of culture for these relations.

International audience; Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P =.008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P =.004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design..

BACKGROUND: Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution. METHODS: We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement. RESULTS: We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children CONCLUSIONS: In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children

Background: This study aimed to evaluate whether the high frequency of reported statin adverse effects (AEs) may be associated with the nocebo effect. We compared nocebo-related subjective AEs with objective AEs and investigated factors potentially associated with the nocebo effect. Methods: A retrospective cohort study was conducted using the Food and Drug Administration Adverse Event Reporting System between January 2010 and December 2019 for statins, including, atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Subjective AEs included fatigue, subjective muscular, and nervous system AEs. Objective AEs were defined as hepatic and objective muscular AEs. We compared the number of subjective and objective AEs using the Mann-Whitney U test and examined trends in the frequency of subjective versus objective reports over time using linear regression with interaction terms. We evaluated the association between AEs and gender and country using linear regression. Quantitative detection of signals was estimated using proportional reporting ratio and reporting odds ratio for simvastatin. Results: Of 2 994 487 overall AE reports, more subjective than objective AEs were reported per quarter (mean±SD: 4777±1375.45 versus 999±276.95; P P P =0.035; subjective muscular AE: 417.95, P P P Conclusions: This study found that significantly more subjective than objective AEs are reported for statins. Subjective statin AEs, potentially related to the nocebo effect are reported more often by women than by men, and in the United States than in other countries.

International audience; Primary infection with varicella-zoster virus (VZV) causes chickenpox, a benign and self-limited disease in healthy children. In patients with primary or acquired immunodeficiencies, primary infection can be life-threatening, due to rapid dissemination of the virus to various organs [lung, gastrointestinal tract, liver, eye, central nervous system (CNS)]. We retrospectively described and compared the clinical presentations and outcomes of disseminated varicella infection (DV) in patients with acquired (AID) (n= 7) and primary (PID) (n= 12) immunodeficiencies. Patients with AID were on immunosuppression (mostly steroids) for nephrotic syndrome, solid organ transplantation or the treatment of hemopathies, whereas those with PID had combined immunodeficiency (CID) or severe CID (SCID). The course of the disease was severe and fulminant in patients with AID, with multiple organ failure, no rash or a delayed rash, whereas patients with CID and SICD presented typical signs of chickenpox, including a rash, with dissemination to other organs, including the lungs and CNS. In the PID group, antiviral treatment was prolonged until immune reconstitution after bone marrow transplantation, which was performed in 10/12 patients. Four patients died, and three experienced neurological sequelae. SCID patients had the worst outcome. Our findings highlight substantial differences in the clinical presentation and course of DV between children with AID and PID, suggesting differences in pathophysiology. Prevention, early diagnosis and treatment are required to improve outcome.

Objective: Nearly half of children who undergo tympanostomy tube (TT) insertion may experience otorrhea following surgery. We sought to review the evidence for the role of bacterial biofilms in post-tympanostomy tube otorrhea (PTTO) and the accumulated experience regarding the preventive measures for biofilm formation/adhesion on TTs. Methods: English literature search for relevant MeSH keywords was conducted in the following databases: MEDLINE (via PubMed), Ovid Medline, Google Scholar, and Clinical Evidence (BMJ Publishing) between January 1, 1995, and December 31, 2019. Subsequently, articles were reviewed and included if biofilm was evident in PTTO. Results: There is an increased evidence supporting the role of biofilms in PTTO. Studies on TT design and material suggest that nitinol and/or silicone TTs had a lower risk for PTTO and that biofilms appeared in specific areas, such as the perpendicular junction of the T-tubes and the round rims of the Paparella-type tubes. Biofilm-component DNAB-II protein family was present in half of children with PTTO, and targeting this protein may lead to biofilm collapse and serve as a potential strategy for PTTO treatment. Novel approaches for the prevention of biofilm-associated PTTO include changing the inherent tube composition; tube coating with antibiotics, polymers, plant extracts, or other biofilm-resistant materials; impregnation with antimicrobial compounds; and surface alterations by ion-bombardment or surface ionization, which are still under laboratory investigation. Conclusions: Currently, there is no type of TT on which bacteria will not adhere. The challenges of treating PTTO indicate the need for further research in optimization of TT design, composition, and coating.

International audience; The objective of this study was to determine the number of cases of pediatric meningitis or purpura fulminans associated with an incorrect vaccination status from 2011 to 2013 in France. A total of 48 children with vaccine-preventable meningitis or purpura fulminans, including three deaths, had an incorrect vaccination status: 26 cases were due to Neisseria meningitidis group C (54.2%), 19 to Streptococcus pneumoniae (39.6%), and three to Haemophilus influenzae type b (6.3%). The majority of patients (n = 35, 72.9%) had received no injection of the vaccine concerned. Over a 3-year period, 48 cases of bacterial meningitis or purpura fulminans in children could have been avoided if the French immunization schedule had been followed.

Many ambulatory networks in several countries have established syndromic surveillance systems to detect outbreaks of different illnesses. Here, we describe a new Pediatric and Ambulatory Research in Infectious diseases network that combined automated data extraction from the computers of primary care pediatricians.Pediatricians who used the same software, AxiSanté 5-Infansoft for electronic medical records were specially trained in infectious diseases, encouraged to comply with French treatments' recommendations, use of point-of-care tests and vaccination guidelines. Infectious disease diagnoses in children16 years old in the records triggered automatic data extraction of complete records. A quality control process and external validation were developed.From September 2017 to February 2020, 107 pediatricians enrolled 57,806 children (mean age 2.9 ± 2.6 years at diagnosis) with at least one infectious disease diagnosis among those followed by the network. Among the 118,193 diagnoses, the most frequent were acute otitis media (n = 44,924, 38.0%), tonsillopharyngitis (n = 13,334, 11.3%), gastroenteritis (n = 12,367, 10.5%), influenza (n = 11,062, 9.4%), bronchiolitis (n = 10,531, 8.9%), enteroviral infections (n = 8474, 7.2%) and chickenpox (n = 6857, 5.8%). A rapid diagnostic test was performed in 84.7% of cases of tonsillopharyngitis and was positive in 44%. The antibiotic recommendations from French guidelines were strictly followed: amoxicillin was the most prescribed antibiotic and less than 10% of presumed viral infections were treated.This "tailor-made" network set up with quality controls and external validation represents a new approach to the surveillance of pediatric infectious diseases in the digital era and could highly optimize pediatric practices.

Papillomavirus (HPV), the first sexually transmitted disease in the world, is the main infectious agent responsible for cancer (6300 per year, in France). The cycle of HPV infection - precancerous lesions -cancer is well documented with regard to the cervix (cf. Nobel Prize in 2008). While this area is the most frequent (3000), it is far from being the only one. Other cancers include the anus, oropharyngeal sphere, glans and vulva. The sum of these other induced HPV cancers is greater than the total number of cervical cancers and also concerns boys. Screening is essential but insufficient and only concerns the cervix. Only vaccination can provide primary and general prevention. Since 2007, there have been many studies demonstrating its excellent efficacy and tolerance. However, France lags behind other countries with a vaccination coverage (30 %) that does not allow for an epidemiological impact.

Objectives To assess time trends of outpatient antibiotic utilization using different measures and explore their discrepancies. Methods Based on French sales data from the IQVIA SDM database, 2009-16, we assessed time trends in outpatient antibiotic utilization using PrID, DID, PID and SID (defined as the number of prescriptions, DDDs, packages and standard units per 1000 inhabitants per day, respectively). We explored discrepancies between trends in PrID and DID by modelling the number of DDDs per prescription. Results Outpatient antibiotic utilization (n = 538.2 million projected prescriptions) decreased in terms of PrID, PID and SID (-10%, -8% and -8%, respectively; negative regression slopes; P

Hypothermia (36°C) exacerbates trauma-induced coagulopathy and worsens morbidity and mortality among severely injured trauma patients; there is a paucity of published data describing how well trauma centres adhere to standards regarding measurement of temperature, and best practices for preventing and treating hypothermia.We completed a retrospective quality audit of all severely injured trauma patients (Injury Severity Score (ISS≥20)) who had urgent surgery at Sunnybrook Health Sciences Centre (SHSC) between 2010 and 2014. Information regarding temperature monitoring was evaluated over the course of the initial resuscitation and admission. Independent risk factors for in-hospital mortality were elucidated through a multivariable regression analysis.Out of a total of 4492 trauma patients, 495 were severely-injured and went to the operating room (OPR) after being treated in the trauma bay (TB) at SHSC between 2010 and 2014. The majority of the patients were male (n=384, 77.6%) and had a blunt mechanism of injury (n=391, 79.0%). The median ISS score was 29 (interquartile range (IQR) 26, 35). Eighty-nine (17.9%) patients died; 26 (5.2%) of these patients died intra-operatively. Less than one fifth of patients (n=82,16.6%) received a temperature measurement during pre-hospital transport phase. Upon arrival to the TB, almost two-thirds (n=301, 60.8%) of patients had their temperature recorded and a similar proportion (n=175, 58.1%) of those patients were hypothermic (36°C). In the OPR, close to 80% (n=389, 78.6%) of patients had their temperature measured on both arrival; almost 60% (n=223, 57.3%) were hypothermic on arrival. Almost all patients had their temperature measured upon arrival to the ICU or specialized ward (n=450, 98.3%). Warming initiatives were documented in only 36 (7.3%) patients in the TB, yet documented in almost all patients in OR (n=464, 93.7%). An increased risk of in-hospital mortality was correlated with not taking a temperature measurement in the TB (Odds Ratio (OR) 2.86 (95% Confidence Interval (CI) [1.64-4.99]) or OPR (OR 4.66 (95% CI [2.50-8.69]).A majority of severely injured trauma patients are hypothermic well into the perioperative period after initial admission. An absence of having temperature measurement during initial hospitalization is associated with increased in-hospital mortality amongst this patient group. Quality improvement initiatives should aim to strive for ongoing temperature measurement as a key performance indicator and early prevention and treatment of hypothermia during initial resuscitation.

The occurrence of meningitis in children5 years old may be associated with specific predisposing factors that can be anatomic, such as cerebrospinal fluid fistula or breach, or related to genetic susceptibility or N inborn or acquired immunologic defect. This study aimed to assess the anatomical and immunologic risk factors in children5 years old with pneumococcal meningitis and prospectively enrolled in the French national meningitis network.We analyzed all data for children who were 5-15 years old with a diagnosis of pneumococcal meningitis between 2001 and 2013. We describe the frequency and typology of the anatomic or immunologic risk factors, the clinical features and the pneumococcal serotypes.Among the 316 patients with pneumococcal meningitis, the mortality rate was 9.5% and 23.1% of cases presented complications (abscess, coma, hemodynamic failure, thrombophlebitis cerebral or deafness). In total, 108 children (34%) showed risk factors, the most frequent being anatomic: 70 cases (22.8%) were related to a cerebrospinal fluid breach or fistula and 55 (17.9%) to immunodeficiency, primary or acquired. Serotype data were available for 207 pneumococcal isolates (65.5%). The most frequent serotypes were as follows: 3, 18C, 19A and 19F between 2001 and 2009 and 19F, 3, 19A, 12F, 22F, 17F and 24F after 2009.We describe the largest cohort of children5 years old with pneumococcal meningitis. One third of the children had risk factors justifying a complete immunologic and radiologic work-up.

Supplemental Digital Content is available in the text., Background: Acute otitis media (AOM) is an important cause of childhood morbidity and antibiotic prescriptions. However, the relative importance of the well-known otopathogens, Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hflu), remains unclear because of a limited number of tympanocentesis-based studies that vary significantly in populations sampled, case definitions and heptavalent pneumococcal conjugate vaccine use. Methods: We conducted a pooled analysis of results from 10 AOM etiology studies of similar design, the protocols of which were derived from a common protocol and conducted in children 3 months to 5 years of age in different countries. Generalized estimating equations were used to account for within-study correlations. Results: The majority, 55.5% (95% confidence interval: 47.0%–65.7%) of 1124 AOM episodes, were bacterial pathogen positive: 29.1% (24.8%–34.1%) yielded Hflu and 23.6% (19.0%–29.2%) Spn. Proportions of Hflu and Spn were higher and lower, respectively, in heptavalent pneumococcal conjugate vaccine–vaccinated children. Hflu and Spn were each isolated from 20% to 35% of children in every 1-year age range. Hflu was less likely to be isolated from first (vs. subsequent) episodes [relative risk (RR): 0.71 (0.60–0.84)]. Spn was more often isolated from sporadic (vs. recurrent) cases [RR: 0.76 (0.61–0.97)]; the opposite was true for Hflu [RR: 1.4 (1.00–1.96)]. Spn cases were more likely to present with severe (vs. mild) symptoms [RR: 1.42 (1.01–2.01)] and Hflu cases with severe tympanic membrane inflammation [RR: 1.35 (1.06–1.71)]. Conclusions: Spn and Hflu remain the leading otopathogens in all populations examined. While associated with overlapping symptoms and severity, they exhibit some differences in their likelihood to cause disease in specific subpopulations.

Objective Vaccination of pregnant women against seasonal influenza is recommended in France since 2010. We currently do not have any vaccination coverage (VC) data to assess the implementation of this recommendation. Methods Vaccinoscopie ® is an annual study conducted online using a self-administered questionnaire. A section dedicated to parents’ vaccination was included in 2014 and aimed at interviewing 300 mothers of infants aged Results While 56% of mothers reported to have been informed of the importance of vaccination by a healthcare professional (HCP) during their last pregnancy, only 11% reported having been informed of the importance of influenza vaccination. Overall, 49% of mothers reported willing to be vaccinated during their next pregnancy to protect their baby, if the vaccination were to be recommended by a HCP. However, this rate was only 32% for influenza vaccination. In contrast, 52% of mothers reported willing to be vaccinated against pertussis during pregnancy if the vaccination were to be recommended by a HCP. The influenza VC estimates in pregnant women was 7%. Conclusion Although influenza vaccination has been recommended for all French pregnant women for the past five years, HCPs rarely recommend this vaccination – hence, the low VC. Informing and raising awareness among HCPs seems to be crucial to improve this coverage.

Outbreaks can be detected by syndromic surveillance, rapid enterovirus testing, and genotyping., The clinical impact of enteroviruses associated with hand, foot and mouth disease (HFMD) is unknown outside Asia, and the prevalence of enterovirus A71 (EV-A71) in particular might be underestimated. To investigate the prevalence of enterovirus serotypes and the clinical presentations associated with HFMD in France, we conducted prospective ambulatory clinic–based surveillance of children during April 2014–March 2015. Throat or buccal swabs were collected from children with HFMD and tested for the enterovirus genome. Physical examinations were recorded on a standardized form. An enterovirus infection was detected in 523 (79.3%) of 659 children tested. Two epidemic waves occurred, dominated by coxsackievirus (CV) A6, which was detected in 53.9% of enterovirus-infected children. CV-A6 was more frequently related to atypical HFMD manifestations (eruptions extended to limbs and face). Early awareness and documentation of HFMD outbreaks can be achieved by syndromic surveillance of HFMD by ambulatory pediatricians and rapid enterovirus testing and genotyping.

Objectives The vaccine schedule was changed in 2013 in France, which resulted in fewer vaccinations. However, to maintain disease protection, both vaccine timeliness and high coverage should be respected. In the context of growing vaccine hesitancy, we aimed to describe compliance with the immunization program according to the age recommended for each dose for non-preterm children less than 2 years old. Methods Between May 2013 and April 2016, we used automated electronic data capture of electronic medical records for non-preterm children less than 2 years old. Children were followed up by 92 randomly selected pediatricians from the French ambulatory pediatricians group. Delayed immunization was defined as more than 15 days after the recommended age for the primary series of diphtheria-tetanus-pertussis-polio-Haemophilus influenzae b-hepatitis B (DTaP-IPV-Hib±HB) and 13-valent pneumococcal vaccine (PCV13), 2 months for boosters, 1 month for measles-mumps-rubella (MMR)/meningococcal C conjugate (Men-C), and 6 months for the second dose of MMR. An association between delayed first dose and other doses delayed were described with odds ratios (ORs) and their 95% confidence intervals (CIs). Results Data for 22,097 children in France with 124,702 vaccinations were analyzed: 21.8%, 20.4%, and 30.7% of children had one or more delayed doses of DTaP-IPV-Hib±HB, PCV13, and MMR vaccines, respectively. For 47.6% of children, the single-dose Men-C vaccination was delayed. A delayed first dose of DTaP-IPV-Hib±HB, PCV13, and MMR was associated with a delayed second dose of the same vaccine (OR 7.5 [95% CI 6.6–8.6], 39.0 [34.1–44.8], and 23.5 [19.1–29.0], respectively) and with a third dose of DTaP-IPV-Hib±HB and PCV13 (14.7 [13.3–17.7] and 3.7 [3.1–4.5]). Conclusion This large study shows that the proportion of children with delayed vaccination in France was globally high and substantial for Men-C and the first MMR vaccination. Risk of a delayed second and third dose was increased with a delayed first dose, which may reflect vaccine hesitancy.

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P

BackgroundChanges in serotype distribution have been induced after pneumococcal conjugate vaccines (PCV) implementation, and non-vaccine serotypes are now circulating. Among these latter serotypes, we aimed to distinguish those with high invasive disease potential before (2008–2009) and after PCV13 implementation (2012–2013).MethodsInvasive pneumococcal disease (IPD) serotypes isolated from children 6 to 24 months were compared with nasopharyngeal-colonizing serotypes in healthy children. To assess the invasive potential of a given serotype, odds ratios (ORs) were calculated. For each serotype, OR >1 indicated increased probability of association with IPD and OR

We collected cases of pneumococcal meningitis vaccine breakthrough (VBT) and vaccine failure (VF) from 2003 to 2013 after the implementation of pneumococcal conjugate vaccines (PCVs) in France. VBT accounted for 3.2% of the cases (PCV7 era: 24 of 943, PCV13 era: 15 of 290) and VF 0.6% (PCV7 era: 6 of 943, PCV13 era: 2 of 290). VBT and VF are rare and occur in most cases in children younger than 2 years. The serotype 19F was the most frequent cause even after the introduction of PCV13.

International audience;

Lyme neuroborreliosis is a bacterial infection caused by the dissemination and proliferation of a Borrelia species in the central nervous system. Neuroborreliosis occurs after transmission of the pathogen from an infected tick to a human host during a tick bite. We report nine cases of pediatric neuroborreliosis collected by the National Observatory of Pediatric Bacterial Meningitis in France between 2001 and 2012. The nine children, aged 4-13 years, were identified in northern and eastern France and had the following clinical features: meningeal irritation alone or with facial palsy, or isolated facial palsy. All cases showed anti-Borrelia antibodies in cerebrospinal fluid or serum, or with a positive Borrelia PCR in the CSF. The outcome was favorable in all cases after a 2- to 3-week course of third-generation cephalosporin. On the basis of these nine pediatric cases, this study provides an update on the epidemiology, pathophysiology, diagnostic strategy, and treatment of neuroborreliosis, with insight into the specific features of pediatric neuroborreliosis and the difficulties encountered in the diagnosis of this infection.

Despite the increased understanding of surgical best practices, capsular contracture remains the most commonly reported complication and reason for reoperation following breast implant surgery. This study provides a long-term update to a previous investigation of potential contributing risk factors for capsular contracture in primary augmentation patients.The data used for this analysis include 5,122 implants in 2,565 primary augmentation patients implanted by 34 surgeons based on long-term results from Sientra's clinical study. Potential risk factors, including patient and implant attributes, surgery characteristics, pocket irrigation, and postsurgery characteristics, were analyzed using frequency and multivariate models.A total of 333 capsular contracture events in 224 patients were reported. The overall Kaplan-Meier rate for capsular contracture was 10.8% by device through 10 years. Results from the multivariate analysis found 8 factors to be independently associated with capsular contracture (implant placement, implant surface, incision site, hematoma or seroma development, device size, surgical bra, steroid, and antibiotic pocket irrigation; all P values0.05). Results from correlation analysis found 2 of the 8 factors to be more strongly associated with early onset capsular contracture events, compared with those occurring after 2 and 5 years of implantation (implant surface and steroid pocket irrigation).The results of this large-scale, multivariate analysis identified several significant risk factors for capsular contracture, including device features (smooth surface, smaller size), surgical factors (periareolar incision, subglandular placement, antibiotic irrigation), the development of hematoma/seroma, and the use of a surgical bra.

International audience; Background: The incidence of meningitis caused by Klebsiella pneumoniae (Kp) and Klebsiella oxytoca (Ko) in high-income countries is unknown, and no series have been published to date.Methods: We conducted a nationwide multicenter observational study in France between 2006 and 2016. All children from the French national registry for paediatric bacterial meningitis under the age of 1 year and hospitalized for Kp or Ko meningitis were included. Virulence factors of four Klebsiella spp. strains were explored by whole genome sequencing.Results: Of 1859 cases of meningitis in children under the age of 1 year, 13 cases (0.7%) of Klebsiella spp. meningitis (nine for Kp meningitis and four for Ko meningitis) were registered in the French national registry. Three of the patients died and 50% of the survivors had developmental delays.Conclusions: Prematurity, low birth weight, and congenital anomalies of the urinary tract appear to be risk factors for Klebsiella spp. meningitis as well as virulence factors of the strain.

Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. In regard to TACO, little is known regarding biomarkers as a predictor, their most informative timing, or thresholds of significance or differentiation from other reactions.In this study of inpatients at risk for TACO (age ≥ 50 years) receiving 1 red blood cell unit, cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high-sensitivity troponin were measured at baseline, 6 to 12 hours (except troponin) posttransfusion, and 18 to 24 hours posttransfusion. Primary outcome was a critical increase in biomarkers (1.5-fold increase and supranormal) at 18 to 24 hours.Fifty-one patients were analyzed; 29% had cardiovascular disease, 73% had one or more cardiac risk factors, and 50% took cardiac or antihypertensive therapies. Although eight (16%) developed an increase in systolic pressure of at least 30 mmHg and four (8%) reported dyspnea and/or cough, none had TACO. At baseline, BNP level was more than 100 ng/L in 59% and NT-proBNP was more than 300 pg/mL in 83%. A total of 25% had a BNP critical increase, 33% had a NT-proBNP critical increase, and 2% had a troponin critical increase at 18 to 24 hours. Overall, 38% had at least one biomarker critical increase and NT-proBNP/BNP concordance was 84%. An increase in the NT-proBNP (1.5-fold increase and300 pg/mL) at 18 to 24 hours was the commonest biomarker change.An increase of the NT-proBNP at 18 to 24 hours may be the preferred surrogate marker for identifying a patient experiencing physiologic difficulty in handling the volume challenge. Larger studies are needed to clarify the risk of TACO for a given pretransfusion biomarker profile and the correlation between TACO and increase in biomarkers after transfusion.

Objectives To assess the management of febrile urinary-tract infection (FUTIs) due to extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E) in children, the Pediatric Infectious Diseases Group of the French Pediatric Society set up an active surveillance network in pediatric centers across France in 2014. Materials and methods We prospectively analysed data from 2014 to 2016 for all children < 18 years old who received antibiotic treatment for FUTI due to ESBL-E in 24 pediatric centers. Baseline demographic, clinical features, microbiological data and antimicrobials prescribed were collected. Results 301 children were enrolled in this study. The median age was 1 year (IQR 0.02–17.9) and 44.5% were male. These infections occurred in children with history of UTIs (27.3%) and urinary malformations (32.6%). Recent antibiotic use was the main associated factor for FUTIs due to ESBL-E, followed by a previous hospitalization and travel history. Before drug susceptibility testing (DST), third-generation cephalosporins (3GC) PO/IV were the most-prescribed antibiotics (75.5%). Only 13% and 24% of children received amikacine alone for empirical or definitive therapy, respectively, whereas 88.7% of children had isolates susceptible to amikacin. In all, 23.2% of children received carbapenems in empirical and/or definitive therapy. Cotrimoxazole (24.5%), ciprofloxacin (15.6%) and non-orthodox clavulanate–cefixime combination (31.3%) were the most frequently prescribed oral options after obtaining the DST. The time to apyrexia and length of hospital stay did not differ with or without effective empirical therapy. Conclusions We believe that amikacin should increasingly take on a key role in the choice of definitive therapy of FUTI due to ESBL-E in children by avoiding the use of carbapenems.

BACKGROUND AND OBJECTIVES Approaches to preventing transfusion-associated circulatory overload (TACO) include the use of diuretics. The purpose of this study was to determine how commonly diuretics are prescribed in patients receiving a red-blood-cell (RBC) transfusion. MATERIALS AND METHODS This was a retrospective study of 200 adult inpatient RBC transfusion orders, 50 consecutive at each of four academic institutions. Only the first transfusion order for each patient was included. Only 1 or 2 unit orders were included. The primary outcome was the percentage of patients receiving furosemide peri-transfusion. Secondary objectives included the dose, route, and timing of furosemide and the association of clinical factors with ordering furosemide. RESULTS The median age was 62·5 years (IQR 53, 73), and 52% were female. Peri-transfusion furosemide was ordered in 16% (95% CI 11-21%). The most common dose was 20 mg (55%), the route intravenous (90%) and timing post-transfusion (74%). At least one risk factor for TACO was present in 55% of patients: renal dysfunction (33%), older than 70 years (28%), history of congestive heart failure (18%), ejection fraction

OBJECTIVE Race, sex, and socioeconomic status (SES) are associated with childhood obesity. The present research longitudinally examines these factors with 12,674 White and Black children from kindergarten through 8th grade. METHODS Body mass index (BMI) data were collected and standardized at six time points (zBMI). Using Latent Growth Curve Modeling, race and sex were evaluated as moderators for the relation between SES and initial zBMI and rate of zBMI change. RESULTS Higher SES significantly predicted higher initial zBMI for Black males and lower initial zBMI and rate of change for White males. A nonlinear relation between SES and zBMI was found for White females. CONCLUSIONS SES has a differential impact on adiposity for different demographic groups. The longitudinal nature of the study and the focus on younger school-aged children provide important information regarding the complex interplay of race, sex, and SES for the prediction of childhood adiposity.

The purpose of this study was to test an integrative model in which peer relations at different levels of social complexity (friendship quality, social preference, and proximity prestige) are associated with children's loneliness, with children's self-perceived social competence acting as a mediator of these associations. A middle childhood sample of 509 Chinese children (233 girls and 276 boys; 3rd to 6th grade) completed a battery of sociometric and self-report questionnaires. Bootstrap analysis showed that self-perceived social competence mediated the relations between each peer variable and loneliness. In the integrative model tested with SEM, the mediating effect of self-perceived social competence in the relation between friendship quality and loneliness and between social preference and loneliness remained significant. However, self-perceived social competence no longer mediated the association between proximity prestige and loneliness, when considering the simultaneous influences of the three peer variables (friendship quality, social preference, and proximity prestige). The whole model accounted for 56% of the variance in loneliness. These findings suggest that self-perceived social competence played an important role in children's loneliness, that the quality and the quantity of direct peer relations (friendship quality, social preference, and part of proximity prestige) were associated with loneliness, and that indirect friends had a relatively lower but significant influence on children's loneliness. The results are discussed in terms of their implications for preventing children's loneliness.

The Department of Santa Rosa, Guatemala, is targeted for malaria elimination. However, compared with 2011, a 13‐fold increase in cases was reported in 2012. To describe the epidemiology of malaria in Santa Rosa in the setting of the apparent outbreak, demographic and microscopic data from 2008 to 2013 were analyzed. In April 2012, a new surveillance strategy, funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, was introduced involving more active case detection, centralized microscopy, increased community engagement, and expanded vector control. Interviews with vector control personnel and site visits were conducted in June 2013. From 2008 to 2013, 337 cases of malaria were reported. The increase in cases occurred largely after the new surveillance strategy was implemented. Most (137/165; 83%) 2012 cases came from one town near a lake. Plasmodium vivax was the malaria species detected in all cases. Cases were detected where malaria was not previously reported. Monthly rainfall or/and temperature did not correlate with cases. Interviews with public health personnel suggested that the new funding, staffing, and strategy were responsible for improved quality of malaria detection and control and thus the increase in reported cases. Improvements in surveillance, case detection, and funding appear responsible for the temporary increase in cases, which thus may paradoxically indicate progress toward elimination.

Increasing incidence of whooping cough (pertussis) has been reported in many countries, attributed to a switch from whole-cell pertussis-containing vaccine (wPV) to acellular PV (aPV) and circulation of the pertactin non-producing Bordetella pertussis. The present study aimed to estimate the duration of immunity conferred by PVs in children in France with data from an ongoing pediatric ambulatory surveillance of pertussis.A total of 64 pediatricians throughout France enrolled children with suspected pertussis. A standardized data form was used to collect data on age sex, vaccination status, brand of wPV or aPV and source of infection. Confirmed cases were positive on culture and/or real-time Polymerase Chain Reaction (for B.-non-classified or B. pertussis or B. parapertussis) and/or pertussis serology.Between October 2006 and December 2015, 149 cases of confirmed Bordetella infections were reported, 86 infected with B. pertussis and 55 B. non-classified. Fifteen children (10.1%) were not vaccinated, and 26 (17.4%) were partially vaccinated. The mean age was greater for children who received 4 doses of wPV (11.3±2.2, p0.001) or a combination of wPV and aPV (10.5±3.3, p0.001) than only aPV (7.2±2.4years). The mean duration of cough before a visit to a pediatrician was longer for children with wPV or a combination of wPV and aPV than only aPV (23.8±10.1 and 25.0±25.6vs 13.6±10.0days).Despite the use of a more sensitive diagnostic method and emergence of pertactin non producing B. pertussis, in France context, aPV-induced immunity still protects against pertussis; however, the mean duration of immunity is about 6 to 7years, compared to 9years for wPV vaccine, after the primary vaccination and one booster (3+1 doses).

Febrile nonhemolytic transfusion reactions (FNHTRs) are characterized by a post-transfusion temperature rise (of ≥ 1°C, to ≥ 38°C) or chills/rigors unrelated to the underlying condition. FNHTRs are provoked by inflammatory cytokines in the product or by host antileukocyte antibodies against residual donor leukocytes. FNHTRs are among the most commonly reported transfusion disturbances and are generally deemed nonserious events. However, their impact on patients and hospitals may be underestimated.A search through two hemovigilance databases identified all known possible-to-definite FNHTRs over 3 years (2013-2015) at four academic hospitals using prestorage leukoreduced components. FNHTRs were assessed for frequency by product (red blood cells [RBCs], platelets [PLTs], intravenous immunoglobulin), diagnostics (bedside, chest imaging, serology, microbiology), and management (medications, disposition change). The definition of FNHTR was derived from Canada's Transfusion-Transmitted Injuries Surveillance System.For 437 FNHTRs, the overall per-product rate across all sites was 0.24%, or 0.17% with RBCs alone and 0.25% with PLTs alone. One-third of patients had significant fevers (≥ 39.0°C or a rise by ≥ 2.0°C). Approximately one-quarter underwent chest imaging within 48 hours, and 79% had blood cultures. A hospital admission directly attributable to the FNHTR, to exclude other causes of fever, occurred in 15% of FNHTR outpatients.An analysis of FNHTRs reveals a substantial burden of postreaction clinical activity in addition to the disturbance itself. Efforts to avoid this adverse event may save resources, reduce patient distress, and encourage compliance with more restrictive transfusion strategies.

Objective Examine unique forms of peer relations (i.e., peer group vs. friendships) in relation to patterns of youth's resilience and challenge-related growth in the context of cancer. Methods In all, 279 youth (cancer, n = 156; control, n = 123) completed measures of posttraumatic stress, depression, anxiety, posttraumatic growth (PTG), and perceived positive changes. Youth also reported on their peer relations. Latent profile analysis (LPA) was used to examine patterns of youth's adjustment. Peer relations were examined as predictors of youth's adjustment. Results LPA revealed three profiles (42.1% resilient high growth, 21.4% resilient low growth, and 36.5% mild distress with growth). Youth's peer relations, demographic factors, and disease-related factors predicted assignment to profiles. Differences in adjustment emerged depending on youth's connection with their peers versus their friends. Summary Peer relations serve an important role in youth's adjustment to stressful life events. Assessment of peer and friend support may provide a more nuanced understanding of adjustment processes.

Several underlying conditions increase the risk of pneumococcal meningitis (PM) in childhood. Patients with these diseases are initially considered as an important target of pneumococcal conjugate vaccines (PCVs). Limited data are available for PM in children with underlying conditions. To understand the benefits of PCV7 followed by PCV13 in this vulnerable population, we analyzed the data for a large cohort of pediatric patients with PM in France from 2001 to 2014.We conducted hospital-based active surveillance with 227 pediatric wards working with 168 microbiology departments throughout France. Standardized inclusion criteria for PM were used and data were analyzed by a pre-PCV7, post-PCV7 and post-PCV13 period.From 2001 to 2014, among the 1582 cases of PM, 62.5% were reported in children less than 2years old. Underlying conditions (n=255, 16.1%) accounted for 7.3% of the cases in these young children versus 30.8% for children ⩾2-18years old (p0.001). After PCV13 implementation, PM cases decreased by 44.0% from 2009 to 2014, mainly in children without underlying conditions. Though the number of children with underlying conditions remained stable, their proportion among overall PM cases increased by 79.1%. Among children with underlying conditions, PCV7 serotypes, 6 additional PCV13 serotypes, additional 11 serotypes in PPV23 and other serotypes accounted for 24.5%, 14.7%, 25.0% and 35.8%, respectively (p0.001). After PCV13 implementation, 50.0% of PM cases with underlying conditions and 37.9% without underlying conditions were caused by serotypes included in neither PCV13 nor PPV23.Besides the reduced numbers of PM, its profile has changed, with an increase in cases in proportion of children with underlying conditions accompanied by a striking change in serotype distribution. This underlines the importance of detecting underlying conditions in children with PM in the PCV13 era.

Rotavirus is the main cause of severe gastroenteritis and diarrhea in infants and young children less than 5 years of age. Potential impact of breast-feeding on the efficacy and immunogenicity of human rotavirus G1P[8] vaccine was examined in this exploratory analysis.Healthy infants (N = 3994) aged 6-14 weeks who received 2 doses of human rotavirus vaccine/placebo according to a 0-1 or 0-2 month schedule were followed for rotavirus gastroenteritis during 2 epidemic seasons. Rotavirus IgA seroconversion rate (anti-IgA antibody concentration ≥ 20 mIU/mL) and geometric mean concentrations were measured prevaccination and 1-2 months post-dose 2. Vaccine efficacy against any and severe rotavirus gastroenteritis was analyzed according to the infants being breast-fed or exclusively formula-fed at the time of vaccination.Antirotavirus IgA seroconversion rate was 85.5% (95% confidence interval [CI]: 82.4-88.3) in breast-fed and 89.2% (95% CI: 84.2-93) in exclusively formula-fed infants; geometric mean concentrations in the respective groups were 185.8 U/mL (95% CI: 161.4-213.9) and 231.5 U/mL (95% CI: 185.9-288.2). Vaccine efficacy was equally high in breast-fed and exclusively formula-fed children in the first season but fell in breast-fed infants in the second rotavirus season. During the combined 2-year efficacy follow-up period, vaccine efficacy against any rotavirus gastroenteritis was 76.2% (95% CI: 68.7-82.1) and 89.8% (95% CI: 77.6-95.9) and against severe rotavirus gastroenteritis 88.4% (95% CI: 81.6-93) and 98.1% (95% CI: 88.2-100) in the breast-fed and exclusively formula-fed infants, respectively.The difference in immunogenicity of human rotavirus vaccine in breast-fed and exclusively formula-fed infants was small. Vaccine efficacy was equally high in breast-fed and exclusively formula-fed children in the first season. Breast-feeding seemed to reduce slightly the efficacy in the second season.

This observational study was designed to evaluate the acceptability of oral antibiotics (including generics) commonly prescribed to children by community practitioners in France. Between February and July 2006, the parents of 953 children enrolled by 46 pediatricians completed a questionnaire, including a taste assessment based on representations of five facial expressions. The proportions of "satisfactory" taste judgments showed a significant difference between amoxicillin-clavulanate reference product and its generics (77.9% vs. 65%, p = 0.01). The amoxicillin-clavulanate generics were more likely than the reference product to be spat out at least once (28.7% vs. 19%, p = 0.05). The full treatment course was taken by 91.7% and 82.3% of children prescribed the amoxicillin-clavulanate reference product and its generics, respectively (p = 0.02). The proportions of "satisfactory" taste judgments showed no significant difference between amoxicillin reference product and generics (64.3% vs. 72.5%, p = 0.3). The amoxicillin generics were not different from the reference product to be spat out at least once (8.6% vs. 14.3%, p = 0.2). The full treatment course was taken by 90.7% and 94.6% of children prescribed the amoxicillin reference product and its generics, respectively (p = 0.3). This study suggests the role of the active substance in the taste, and calls for the evaluation of palatability of future drugs (generics and references) before granting of the marketing authorization, particularly for active substances of poor taste; this palatability plays a significant role in the compliance of the treatment, notably in children. Poor compliance increases the risk of therapeutic failures and the emergence of resistance.

In the last 15 years, reduction mammaplasty has been increasingly performed on an outpatient basis. Despite this evolution, few outcome studies have been published regarding outpatient breast reduction surgery.The authors documented clinical outcomes of reduction mammaplasty performed in an outpatient setting over an 11-year period and compared these results with published normative values in the plastic surgery literature.A retrospective review was undertaken of 884 reduction mammaplasties in 444 patients at a single outpatient surgical center performed by the senior author (W.G.S.) from 1995 through 2006. In all cases, a laser-assisted, inferior pedicle, Wise pattern, reduction mammaplasty was performed. In addition to demographic and surgical data, complication frequency and type were recorded. Complication data were further stratified into minor and major categories. Potential minor complications included seroma, hematoma, soft tissue infection, dog-ears requiring revision, and small incisional breakdowns or delayed healing of less than 2 cm. Potential major complications included large incisional breakdowns or delayed healing of greater than 2 cm, nipple/areolar necrosis, need for blood transfusion, deep vein thrombosis, pulmonary embolus, myocardial infarction, and death.The mean patient age was 38 years (range, 16 to 73 years). Mean body-mass index was 27 (range 17 to 47). The reported preoperative brassiere cup sizes ranged from a 34 C to a 38 K, with a DD being the most common size. The mean preoperative sternal notch-to-nipple distance was 29 cm (range 22 to 54 cm). Forty patients smoked (9%). Mean clinical follow-up was 13 months. Mean total resection weight of breast tissue was 1228 g (range 100 to 5295 g). Mean operative time for reduction mammaplasty was 115 minutes (range 50 to 195 minutes). Nineteen percent of patients underwent multiple procedures, including abdominoplasty, lipoplasty, and facial procedures, with a mean operative time of 132 minutes (range 75 to 345 minutes). The overall complication rate was 14%, with 70 minor complications occurring in 62 patients. Specific minor complications included one seroma, four hematomas, eight soft tissue infections, two of which required a short course of intravenous antibiotics, one patient with dog-ears requiring surgical revision, and 56 small incisional wound breakdowns (2 cm). The small incisional breakdowns, which represented the largest group of complications, were further subdivided into 44 minor T-zone wounds, 3 nipple-areolar complex wounds, and 9 wounds of the vertical and horizontal incisions. Three major complications (0.67%) were recorded. Two patients had development of partial nipple/areolar necrosis. A third patient required anticoagulation for a pulmonary embolus diagnosed 10 days after surgery. Statistical analysis of the complication data revealed one significant relationship. Patients with a body mass index above the mean had a 21% complication rate as compared with a 12% rate for those below the mean. Of note, there was no increase in complication rate in the context of multiple procedures.This retrospective series is the largest to date involving outpatient reduction mammaplasty. Complication data derived from this series are comparable to previously published studies and thus support the safety and efficacy of outpatient reduction mammaplasty performed in an accredited facility.

This nasopharyngeal (NP) carriage surveillance study was requested by the European Agency for the Evaluation of Medicinal Products as a post-licensing commitment to determine whether the use of the pneumococcal conjugate vaccines (PCVs) including 7 then 13 valents (introduced in 2001 and 2010, respectively) caused a shift in the distribution of Streptococcus pneumoniae serotypes in children with acute otitis media and modified the resistance of this bacterial species to antibiotics.Between 2001 and 2014, 121 pediatricians obtained nasopharyngeal swabs from children with acute otitis media aged 6-24 months. The swabs were analyzed by the French National Reference Centre for Pneumococci. Demographics, medical history and physical examination findings were recorded.Over the 13 years, among the 7991 enrolled patients, the proportion of PCV-vaccinated children (≥1 dose) increased (54.3-99.7%, p0.001). Overall, pneumococcal carriage was reduced from 71.2% to 56.2% from 2001 to 2014 (p0.001) and carriage of PCV7 serotypes (STs) from 44.5% to 1.2% (p0.001). The carriage of 6 additional STs plus 6C increased from 17.2% to 24.3% from 2001 to 2010 (p0.001) and decreased after PCV13 implementation (21.4-3.5%, p0.001). The proportion of ST 19A carriage increased from 8.6% to 15.8% from 2001 to 2010 (p0.001) and decreased to 1.2% in 2014. After PCV13 implementation, the most frequently carried non-PCV13 STs were ST 15B/C, 11A, 15A, and 35B. Penicillin non-susceptible pneumococcal strains decreased from 67.1% in 2001 to 33.1% in 2014 (p0.001).By the number of patients enrolled and the duration, this study is the largest performed to date. It allows to demonstrate a strong impact of PCVs and to describe the complex dynamics of pneumococcal carriage during AOM. As pneumococcal carriage decreased during AOM, a reduction in the incidence of pneumococcal AOM could be expected.

A panel of board-certified plastic surgeons chaired by Dr Grant Stevens convened to discuss their respective experiences with the Sientra High-Strength Cohesive (HSC) Textured Round silicone gel breast implants. The authors have implanted a combined total of approximately 2100 patients. Surgical pearls, complication avoidance, and practice integration tips are among the topics reviewed. The surgeons also present challenging cases and describe how the HSC textured implants helped them achieve a successful outcome. Level of Evidence 5![Graphic][1] Therapeutic [1]: /embed/inline-graphic-1.gif

Objective We have previously described a breaking bad news (BBN) training program for primary care physicians [Ungar L, Alperin M, Amiel GE, Beharier Z, Reis S. Breaking bad news: structured training for family medicine residents. Patient Educ Couns 2002;48:63–68]. In this paper, we present the assessment of an educational intervention aimed at improving this important skill. Methods The assessment tool was an eight station objective structured clinical examination (OSCE) utilizing standardized patients (SPs). Intervention and control groups of 17 general practitioners (GP) each were evaluated before and after an educational intervention, or a Balint group (control). Results Intervention group GPs significantly increased their average grade on the post-test as compared to the pre-test (58.5, S.D. 12.7 versus 68.4, S.D. 9.2), effect size 0.94. Improvement in the control group was minimal (pre-test 57, S.D. 10.4 versus 58.1, S.D. 9.5 for the post-test), effect size 0.23. Reliability of the OSCE was α = 0.81. Conclusion The performance assessment used in this study proved to be a reliable and valid tool to assess the ability of physicians to break bad news. It provided evidence of the effectiveness of the intervention. Practice implications BBN training can and should be evaluated by valid and reliable measures. SPs can serve as reliable evaluators of BBN training.

Background Bioethics education has been recommended as a formal component of surgical residency training. The best method for teaching bioethics to residents is unclear. We compared the effectiveness of a standardized patient (SP)-based seminar to a traditional seminar format for teaching bioethics to surgical residents. Methods We randomized 31 first- and second-year surgical residents to either a SP-based seminar or a traditional seminar on informed consent. Immediately after the seminars, we evaluated resident performance in patient encounters on informed consent by using an objective structured clinical examination. Their knowledge of informed consent was also evaluated by using a 20-question short-answer written examination immediately after the seminars and then 3 weeks later. Results Twenty-nine residents completed the study; two withdrew because of an emergency. The SP seminar group had lower SP interview scores on the 22 item checklist compared with the traditional seminar group (57% versus 66%; difference −9%; 95% confidence interval [CI], −17% to −1%, P = .03). The SP seminar group also had lower knowledge scores on the questionnaire immediately after the seminar (60% versus 73%; difference −13%; 95% CI, −21% to −4%, P = .003). The difference in knowledge scores persisted at 3 weeks (41% for the SP group, 59% for the traditional seminar group; difference −18%; 95% CI, −29% to −7%; P = .002). Conclusions A traditional seminar was superior to an SP-based seminar for teaching informed consent to surgical residents.