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Sex effect on the incubation period of variant Creutzfeldt-Jakob disease (vCJD) disease in human and ME-7 murine models was investigated. In the 167 vCJD cases reported in the United Kingdom as of January 2009, age at onset was significantly lower in female patients (by 2 years) than in male patients after stratification on birth cohort. In C57/Bl6N mice infected with ME-7 scrapie strain, incubation was shorter in female than in male mice. The incubation period increased in castrated male mice after intraperitoneal infection but not after intracerebral inoculation. In the absence of androgen receptors, the incubation period for prion disease increased after intraperitoneal inoculation. In ovariectomized or estrogen receptor alpha-defective female mice, no effect was observed on the incubation period of mouse prion disease. These results show that androgens influence the prion diseases incubation period after inoculation at a peripheral site. [ABSTRACT FROM AUTHOR]

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

Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T-cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV- patients, offering potential opportunities for future T-cell-based immune therapies.

Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Nirsevimab, an RSV-neutralising monoclonal antibody, was approved for use in the EU in 2022, and a national immunisation campaign began in France in September, 2023. We aimed to assess the effectiveness of nirsevimab in reducing paediatric emergency department visits (and subsequent hospitalisations) for all-cause bronchiolitis and RSV-associated bronchiolitis., Methods: In this case-control study in a paediatric emergency department in Paris, France, we included all infants aged 12 months or younger who attended the department between Oct 14, 2023, and Feb 29, 2024, and whose nirsevimab status was known. Infants were classed as cases if they had all-cause bronchiolitis; all other infants were classed as controls. The primary outcome was the effectiveness of nirsevimab against paediatric emergency department visits for all-cause bronchiolitis during the 2023-24 RSV season. Secondary outcomes were paediatric emergency department visits for RSV-associated bronchiolitis; hospitalisations for all-cause bronchiolitis, RSV-associated bronchiolitis, and severe RSV-associated bronchiolitis requiring supplemental oxygen or feeding by nasogastric tube; and severe RSV-associated bronchiolitis requiring admission to the paediatric intensive care unit. Effectiveness estimates were adjusted for age, week of paediatric emergency department visit, and sex., Findings: Our study included 2786 infants, 864 with all-cause bronchiolitis (cases) and 1922 without bronchiolitis (controls). 178 (21%) of the 864 cases had received nirsevimab, and 305 (35%) cases were hospitalised for all-cause bronchiolitis. 200 (72%) of the 277 cases tested for RSV were positive, of whom 22 (11%) had received nirsevimab. 701 (36%) of 1922 infants in the control group had received nirsevimab. The effectiveness of nirsevimab against paediatric emergency department visits for all-cause bronchiolitis was 47% (95% CI 33-58). Nirsevimab effectiveness was 83% (71-90) against paediatric emergency department visits for RSV-associated bronchiolitis, 59% (42-71) against hospitalisations for all-cause bronchiolitis, 83% (72-90) against hospitalisations for RSV-associated bronchiolitis (91% [78-96] against those necessitating supplement oxygen and 88% [74-95] against those necessitating feeding via a nasogastric tube). Nirsevimab did not significantly reduce admissions to the paediatric intensive care unit (67% [95% CI -100 to 95])., Interpretation: During the first French national immunisation campaign, a single dose of nirsevimab effectively reduced paediatric emergency department visits (both all-cause visits and visits related to RSV-associated bronchiolitis) and subsequent hospitalisations., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Corticosteroids have become standard of care for COVID-19 but their effect on the systemic immune-inflammatory response has been little investigated., Methods: Multicenter prospective cohort, including critically ill COVID-19 patients between March and November 2020. C-reactive protein (CRP), lymphocyte count and fibrinogen levels were collected upon hospital admission before initiation of steroid treatment and at ICU admission, three days and seven days later, along with interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha (TNF-α) plasma levels., Results: A hundred and fifty patients were included, 47 received corticosteroids, 103 did not. Median age was 62 [53-70], and 96 (65%) patients were mechanically ventilated. Propensity score matching rendered 45 well-balanced pairs of treated and non-treated patients, particularly on pre-treatment CRP levels. Using a mixed model, CRP (P=0.019), fibrinogen (P=0.003) and lymphocyte counts (P=0.006) remained lower in treated patients over ICU stay. Conversely, there was no significant difference over the ICU stay for Il-6 (P=0.146) and IL-10 (0.301), while TNF- α levels were higher in the treated group (P=0.013). Among corticosteroid-treated patients, CRP (P=0.012), fibrinogen (P=0.041) and lymphocyte count (P=0.004) over time were associated with outcome, whereas plasma cytokine levels were not., Conclusions: Steroid treatment was associated with an early and sustained decrease in the downstream IL-6-dependent inflammatory signature but an increase in TNF-α levels. In corticosteroid-treated patients, CRP and lymphocyte count were associated with outcome, conversely to plasma cytokine levels. Further research on using these biomarker's kinetics to individualize immunomodulatory treatments is warranted.

Background: The impact of chemoprophylaxis targeting Plasmodium falciparum on Plasmodium vivax and Plasmodium ovale, which may remain quiescent as hypnozoites in the liver, is debated., Methods: We conducted a nested case-control analysis of the outcomes of P. vivax and P. ovale infections in imported malaria cases in France among civilian travelers from 1 January 2006, to 31 December 2017. Using adjusted logistic regression, we assessed the effect of chemoprophylaxis on the incubation period, time from symptoms to diagnosis, management, blood results, symptoms, and hospitalization duration. We analyzed the effect of blood-stage drugs (doxycycline, mefloquine, chloroquine, chloroquine-proguanil) or atovaquone-proguanil on the incubation period. We used a counterfactual approach to ascertain the causal effect of chemoprophylaxis on postinfection characteristics., Results: Among 247 P. vivax- and 615 P. ovale-infected travelers, 30% and 47%, respectively, used chemoprophylaxis, and 7 (3%) and 8 (1%) were severe cases. Chemoprophylaxis users had a greater risk of presenting symptoms >2 months after returning for both species (P. vivax odds ratio [OR], 2.91 [95% confidence interval {CI}, 1.22-6.95], P = .02; P. ovale OR, 2.28 [95% CI, 1.47-3.53], P < .001). Using drugs only acting on the blood stage was associated with delayed symptom onset after 60 days, while using atovaquone-proguanil was not., Conclusions: Civilian travelers infected with P. vivax or P. ovale reporting chemoprophylaxis use, especially of blood-stage agents, had a greater risk of delayed onset of illness. The impact of chemoprophylaxis on the outcomes of infection with relapse-causing species calls for new chemoprophylaxis acting against erythrocytic and liver stages., Competing Interests: Potential conflicts of interest. M. L. G. reports support for attending meetings and/or travel from the European Congress of Clinical Microbiology and Infectious Diseases. M. T. reports payment or honoraria as a speaker at the Colloque Experts Praticiens Infectiologie on 4 February 2022 in Paris for Pfizer. S. J. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Alfa Sigma expert board; participation on a data and safety monitoring board or advisory board for Artesunate; and data safety surveillance on behalf of the French National Agency for the Safety of Medicines and Health Products. All other authors report no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Capillary refill time (CRT) is a valuable tool for triage and to guide resuscitation. However, little is known about CRT kinetics after fluid infusion., Methods: We conducted a prospective observational study in a tertiary teaching hospital. First, we analyzed the intra-observer variability of CRT. Next, we monitored fingertip CRT in sepsis patients during volume expansion within the first 24 h of ICU admission. Fingertip CRT was measured every 2 min during 30 min following crystalloid infusion (500 mL over 15 min)., Results: First, the accuracy of repetitive fingertip CRT measurements was evaluated on 40 critically ill patients. Reproducibility was excellent, with an intra-class correlation coefficient of 99.5% (CI 95% [99.3, 99.8]). A CRT variation larger than 0.2 s was considered as significant. Next, variations of CRT during volume expansion were evaluated on 29 septic patients; median SOFA score was 7 [5-9], median SAPS II was 57 [45-72], and ICU mortality rate was 24%. Twenty-three patients were responders as defined by a CRT decrease  > 0.2 s at 30 min after volume expansion, and 6 were non-responders. Among responders, we observed that fingertip CRT quickly improved with a significant decrease at 6-8 min after start of crystalloid infusion, the maximal improvement being observed after 10-12 min (-0.7 [-0.3;-0.9] s) and maintained at 30 min. CRT variations significantly correlated with baseline CRT measurements (R = 0.39, P = 0.05)., Conclusions: CRT quickly improved during volume expansion with a significant decrease 6-8 min after start of fluid infusion and a maximal drop at 10-12 min., (© 2022. The Author(s).)

Background: The extent to which very young children contribute to the transmission of SARS-CoV-2 is unclear. We aimed to estimate the seroprevalence of antibodies against SARS-CoV-2 in daycare centres that remained open for key workers' children during a nationwide lockdown in France., Methods: Children and staff who attended one of 22 daycare centres during a nationwide lockdown in France (between March 15 and May 9, 2020) were included in this cross-sectional, multicentre, seroprevalence study. Hospital staff not occupationally exposed to patients with COVID-19, or to children, were enrolled in a comparator group. The primary outcome was SARS-CoV-2 seroprevalence in children, daycare centre staff, and the comparator group. The presence of antibodies against SARS-CoV-2 in capillary whole blood was measured with a rapid chromatographic immunoassay. We computed raw prevalence as the percentage of individuals with a positive IgG or IgM test, and used Bayesian smoothing to account for imperfect sensitivity and specificity of the assay. This study is registered with ClinicalTrials.gov, NCT04413968., Findings: Between June 4 and July 3, 2020, we enrolled 327 children (mean age 1·9 [SD 0·9] years; range 5 months to 4·4 years), 197 daycare centre staff (mean age 40 [12] years), and 164 adults in the comparator group (42 [12] years). Positive serological tests were observed for 14 children (raw seroprevalence 4·3%; 95% CI 2·6-7·1) and 14 daycare centre staff (7·7%; 4·2-11·6). After accounting for imperfect sensitivity and specificity of the assay, we estimated that 3·7% (95% credible interval [95% CrI] 1·3-6·8) of the children and 6·8% (3·2-11·5) of daycare centre staff had SARS-CoV-2 infection. The comparator group fared similarly to the daycare centre staff; nine participants had a positive serological test (raw seroprevalence 5·5%; 95% CI 2·9-10·1), leading to a seroprevalence of 5·0% (95% CrI 1·6-9·8) after accounting for assay characteristics. An exploratory analysis suggested that seropositive children were more likely than seronegative children to have been exposed to an adult household member with laboratory-confirmed COVID-19 (six [43%] of 14 vs 19 [6%] of 307; relative risk 7·1 [95% CI 2·2-22·4])., Interpretation: According to serological test results, the proportion of young children in our sample with SARS-CoV-2 infection was low. Intrafamily transmission seemed more plausible than transmission within daycare centres. Further epidemiological studies are needed to confirm this exploratory hypothesis., Funding: Assistance Publique-Hôpitaux de Paris; Mairie de Paris, Conseil Départemental de Seine Saint Denis., Translations: For the French translation of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs; 1 had negative RT-PCR but typical COVID-19 signs on a CT scan; and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9-60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes ( n = 19, 61.3%), and a mild lung disease ( n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV 1 ) > 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever ( n = 22, 78.6%), fatigue ( n = 14, 50%), and increased cough ( n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.

France has been heavily affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and went into lockdown on 17 March 2020. Using models applied to hospital and death data, we estimate the impact of the lockdown and current population immunity. We find that 2.9% of infected individuals are hospitalized and 0.5% of those infected die (95% credible interval: 0.3 to 0.9%), ranging from 0.001% in those under 20 years of age to 8.3% in those 80 years of age or older. Across all ages, men are more likely to be hospitalized, enter intensive care, and die than women. The lockdown reduced the reproductive number from 2.90 to 0.67 (77% reduction). By 11 May 2020, when interventions are scheduled to be eased, we project that 3.5 million people (range: 2.1 million to 6.0 million), or 5.3% of the population (range: 3.3 to 9.3%), will have been infected. Population immunity appears to be insufficient to avoid a second wave if all control measures are released at the end of the lockdown., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Context: Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants., Objective: To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes., Design and Patients: A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD., Results: Genome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate < 0.1) and the genome-wide significant variants was associated with CFRD in a replication population., Conclusions: CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite improvements in intermittent hemodialysis management, intradialytic hemodynamic instability (IHI) remains a common issue that could account for increased mortality and delayed renal recovery. However, predictive factors of IHI remain poorly explored. The objective of this study was to evaluate the relationship between baseline macrohemodynamic, tissue hypoperfusion parameters and IHI occurrence., Methods: Prospective observational study conducted in a 18-bed medical ICU of a tertiary teaching hospital. Cardiovascular SOFA score, index capillary refill time (CRT) and lactate level were measured just before (T0) consecutive intermittent hemodialysis sessions performed for AKI. The occurrence of IHI requiring a therapeutic intervention was recorded., Results: Two hundred eleven sessions, corresponding to 72 (34%) first sessions and 139 (66%) later sessions, were included. As IHI mostly occurred during first sessions (43% vs 12%, P < 0.0001), following analyses were performed on the 72 first sessions. At T0, cardiovascular SOFA score ≥1 (87% vs 51%, P = 0.0021) was more frequent before IHI sessions, as well as index CRT ≥ 3 s (55% vs 15%, P = 0.0004), and hyperlactatemia > 2 mmol/L (68% vs 29%, P = 0.0018). Moreover, the occurrence of IHI increased with the number of macrohemodynamic and tissue perfusion impaired parameters, named SOCRATE score (cardiovascular SOFA, index CRT and lactATE): 10% (95% CI [3%, 30%]), 33% (95% CI [15%, 58%]), 55% (95% CI [35%, 73%]) and 80% (95% CI [55%, 93%]) for 0, 1, 2 and 3 parameters, respectively (AUC = 0.79 [0.69-0.89], P < 0.0001). These results were confirmed by analyzing the 139 later sessions included in the study., Conclusions: The SOCRATE score based on 3 easy-to-use bedside parameters correlates with the risk of IHI. By improving risk stratification of IHI, this score could help clinicians to manage intermittent hemodialysis initiation in critically ill AKI patients.

Purpose: ICU patient's care may require the use of onerous devices, which contributes to make this department one of the most expensive in the hospital. It seemed us relevant to assess healthcare workers' (HCWs) knowledge of the cost of the devices daily used in ICU., Materials and Methods: An anonymous questionnaire was administered on a voluntary basis to HCWs of 3 ICUs., Measurements and Main Results: Cost estimations were expressed as percentage of the real cost; an estimation was considered correct if it was ±50% of the true price. 107 HCWs (66 physicians and 41 nurses and nurse aids) answered the survey. Only 29% of estimations were within 50% of the real cost. The prices of the cheapest devices were overestimated, while the costs of the most expensive ones were underestimated. In multivariate analysis, cost less than50 euros [OR = 3.2; CI 95%(1.6-6.3)], professional experience <10 years [OR = 1.5; CI 95%(1.1-2.1)], being a medical student [OR = 2.0; CI 95%(1.3-3.0)], and working in a university affiliated hospital [OR = 0.6; CI 95%(0.4-0.9)] were associated with an incorrect estimation., Conclusions: ICU's HCWs have a poor knowledge of the price of devices they regularly use for the care of their patients., Competing Interests: Declaration of Competing Interest No conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer., Methods: We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90., Results: Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P<0.001, Se = 100%, Sp = 78%)., Conclusion: We show that regular measurement of sHER2, CA15.3, and CEA levels is useful for predicting the therapeutic response and for monitoring HER2-targeted therapy in patients with HER2-positive metastatic breast cancer. The average decrease of the three biomarkers with a threshold of > 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Interstitial lung disease in children (chILD) is a highly heterogeneous group of rare and severe respiratory disorders. The disease by itself, the burden of the treatments (oxygen therapy, corticosteroid pulses, nutritional support) and recurrent hospitalizations may impair the quality of life (QoL) of these children. The aim of the study was to compare the health-related QoL (HR-QoL) in chILD compared to a healthy population and to find out the predictive factors of an altered QoL., Methods: Patients aged 1 month to 18 years with ILD of known or unknown etiology were prospectively included. Parents and children over 8 years old were asked to fill the PedsQL 4.0 Generic Core Scale ranging from 0 to 100 points., Results: A total of 78 children were recruited in 13 French pediatric centers. Total scores were 11.94 points (P = 0.0003) less for child self-report and 14.08 points ( P < 0.0001) less for parent proxy-report with respect to the healthy population. The clinical factors associated with a lower total score were: extrapulmonary expression of the disease, higher Fan severity score, long-term oxygen therapy, nutritional support, and a number of oral treatments., Conclusion: Using a validated quality of life (QoL) scale, we showed that health-related-QoL is significantly impaired in chILD compared with a healthy population. Factors altering QoL score are easy to recognize and could help identify children at a heightened risk of low QoL., (© 2019 Wiley Periodicals, Inc.)

Background: Liver retransplantation (RLT) is the only life-saving treatment option for patients with a failing graft, but it remains a major challenge because of inferior outcomes and technical difficulties., Methods: This study aimed to evaluate the outcomes of and risk factors for adult RLT in a single center, focusing on the etiology of graft failure. Between 1987 and 2011, 1592 liver transplants (LTs) and 143 RLTs (9%) were performed at our institution., Results: The 1-, 5- and 10-year patient survival rates after RLT were 60%, 52% and 39%, and the graft survival rates were 55%, 46% and 32%. The 90-day mortality rate was 32%, mainly due to septic complications (45% of deaths). Ischemic-type biliary lesions (ITBL) were the leading indication for RLT (23%), and patient survival was significantly better in patients retransplanted for ITBL than for any other indication (P<0.02). Indications other than ITBL (P=0.015), the transfusion of more than 7 units (P=0.006) and preoperative dialysis (P=0.005) were the three parameters associated with poor survival after RLT., Conclusion: Patients with ITBL benefit the most from elective RLT., (Copyright © 2017. Published by Elsevier Masson SAS.)

Background: We aimed to evaluate the predictive value of the end-tidal CO2 (EtCO2) alone or combined with ventilation related parameters on Spontaneous Breathing Trial (SBT) outcome on mechanically ventilated patients., Methods: Prospective observational study in a medical Intensive Care Unit. Mechanically ventilated adult patients who met predefined criteria for weaning were included. Patients underwent a T-piece SBT for 30 minutes and the hemodynamic and respiratory clinical parameters including EtCO2 were recorded every five minutes., Results: The study included 280 patients, who were studied (age: 64±17 years, SAPS II: 44 [34-56]) during a first SBT and 76 patients during a second SBT. The Weaning Index, defined as the product of the respiratory rate and EtCO2, was a strong early predictive factor of SBT outcome; at 10 minutes, the area under the curve (AUC) was 86% ([80-90], P<0.0001) during the first SBT and 88% ([80-96], P<0.0001) during the second SBT. After 10 minutes of SBT, a Weaning Index >1100 identified patients that will not successfully complete the SBT at 30 minutes with a specificity of 98%., Conclusions: In unselected mechanically ventilated patients, the Weaning Index is helpful to early identify patients who will fail the SBT during a first and a second trial.

Objective: The contribution of environmental factors to spondyloarthritis (SpA) course remains poorly characterized. We previously reported a possible triggering of disease flares by stressful life events and vaccination. The objective of the present study was to specify the types of vaccine and life event that may influence disease activity., Methods: A prospective cohort of adult SpA was followed for two years. Patients logged on to a secured website every month to complete a standardized auto-questionnaire. They reported whether they had been exposed to stressful life events, vaccinations or other environmental factors. Patients were asked to rate the distress resulting from exposure to life events on a numerical rating scale (NRS: 0-10). Primary outcome variable was the variation of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measured on two consecutive connections. Months where an event occurred were compared to months without events. The cut-off value of 1 is defined as the minimal clinically important variation for the BASDAI., Results: The 272 enrolled SpA patients returned 3,388 questionnaires. Months where an abrupt and unexpected traumatic event occurred were associated with a significant increase of BASDAI of 0.57 [95%CI: 0.29; 0.85] (P<0.001). The higher the rating of distress, the larger the impact on BASDAI, reaching a clinically meaningful increase of 0.99 [0.17; 1.82] for a VNS≥9. The effect of stressful events on BASDAI persisted during a median of 3 months. No other environmental factor was significantly associated with BASDAI variations., Conclusion: Among stressful life events, abrupt and unexpected events were associated with transient worsening of disease activity in SpA, which reached a clinically meaningful increase for the highest rating of distress. Association between vaccines and disease flare was not confirmed., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

We aimed to assess the relationship between alterations of tissue perfusion parameters at admission (highly predictive of mortality in septic shock) and outcome in patients admitted to the intensive care unit (ICU) for acute pulmonary embolism (PE). We conducted a retrospective study to analyze the association between arterial lactate level, skin mottling and urinary output, and 28-day mortality.Over a 22-year period, 317 patients with PE were identified but we finally analyzed 108 patients whose main diagnosis for ICU admission was acute PE. At admission, the sequential organ failure assessment score was 2 (0-6) and the simplified acute physiology score II was 29 (16-43). Thirty patients (28%) received vasopressors and 37 patients (34%) received thrombolytic therapy. Day 28 mortality rate was 25% (n = 27). When compared to 28-day survivors, nonsurvivor patients had higher lactate level (4.5 [2.3-10.3] mmol/L vs 1.4 [1-2.9] mmol/L, P < .0001), more frequent mottling around the knee area (56% vs 25%, P = .003) and a lower urinary output (during the first 6 hours) (0.35 [0-1] mL/kg/h vs. 0.88 [0.62-1.677] mL/kg/h, P = .0002). Mortality increased with the number of tissue perfusion alterations present upon admission, 8% for none, 21% for 1, 28% for 2, and finally reached 85% for 3 tissue perfusion alterations (P < .0001). In a multivariate analysis, the relationship between the number of tissue perfusion alterations and 28-day mortality was maintained after adjustment on the presence of shock and right ventricular dilation at admission.In ICU patients admitted for acute PE, tissue perfusion alterations correlated with 28-day mortality independently of blood pressure and right ventricular dilation.

Objectives: Metabolic acidosis is commonly observed in critically ill patients. Experimental studies suggested that acidosis by itself could impair vascular function, but this has been poorly investigated in human., Design: Prospective observational study., Setting: Medical ICU in a tertiary teaching hospital., Patients: To assess the relationship between metabolic acidosis severity and microvascular reactivity, we included adult diabetic patients admitted in ICU for ketoacidosis. Microvascular response to acetylcholine iontophoresis was measured at admission (baseline) and after correction of metabolic acidosis (24 hr)., Interventions: None., Measurements and Main Results: Thirty-nine patients with diabetic ketoacidosis were included (68% male), with a median age of 43 (31-57) years. At admission, microvascular reactivity negatively correlated with acidosis severity (R = -0.53; p < 0.001). Microvascular response was strongly depressed at pH less than 7.20 (area under the curve, 1,779 [740-3,079] vs 12,944 [4,874-21,596] at pH > 7.20; p < 0.0001). In addition, acidosis severity was significantly correlated with capillary refill time (R = 0.50; p = 0.02). At H24, after rehydration and insulin infusion, clinical and biological disorders were fully corrected. After acidosis correction, microvascular reactivity increased more in patients with severe baseline acidosis (pH < 7.20) than in those with mild baseline acidosis (area under the curve, +453% [213%-1,470%] vs +121% [79%-312%]; p < 0.01)., Conclusions: We identified an alteration of microvascular reactivity during metabolic acidosis in critically ill patients with diabetic ketoacidosis. Microvascular hyporeactivity recovered after acidosis correction.

Background: While the prevalence of Stenotrophomonas maltophilia lung infection in cystic fibrosis (CF) patients has increased in the last decades, its pathogenicity remains controversial. The aim of this study was to investigate the effects of S. maltophilia initial infection on the progression of lung disease in CF children., Methods: This case-control retrospective study took place in a pediatric CF center. A total of 23 cases defined by at least one sputum culture positive for S. maltophilia, were matched for age, sex, and CFTR mutations to 23 never infected CF controls. The clinical data were collected for 2 years before and after S. maltophilia initial infection and comprised lung function analyses, rates of exacerbations and of antibiotic courses., Results: Compared with controls, cases had lower lung function (P = 0.05), more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02), and intravenous antibiotic courses (P = 0.04) before S. maltophilia acquisition. In the year following S. maltophilia initial infection, lung function decline was similar in cases and controls but cases remained more severe, with more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02) and intravenous antibiotic courses (P = 0.02)., Conclusions: S. maltophilia seems to be a marker of CF lung disease severity and international recommendations to reduce lung infection by this pathogen should rapidly emerge., (© 2018 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

Objective: In France, indications for pre-exposure prophylaxis (PrEP) for HIV prevention are based on individual-level risk factors for HIV infection. However, the risk of HIV infection may also depend on characteristics of sexual partnerships. Here we study how place-based selection of partners change transmission and the overall efficiency of PrEP., Methods: We used the PREVAGAY survey of sexual behavior and HIV serostatus in men who have sex with men (MSM) in a Parisian district to look for associations between sexual network characteristics and HIV infection. We then simulated HIV transmission in a high-risk MSM population. We used information about venues visited to meet casual sexual partners (clubs, backrooms or saunas) to define sexual networks. We then simulated HIV transmission in these networks and assessed the impact of PrEP in this population., Results: In the PREVAGAY study, we found that HIV serostatus changed with the type of venues visited, in addition to other individual risk factors. In simulations, we found similar differences in HIV incidence when the choice of venues visited was not random. The use of PrEP allowed reducing incidence, irrespective of the venues visited by PrEP users. However, with the same amount of PrEP, the number of infections adverted could almost double depending on network structure and venues visited by PrEP users., Conclusion: This study shows that characteristics of the sexual network structure can strongly impact the effectiveness of PrEP interventions. These should be considered further to refine individual risk assessment and maximize the effect of individual-based prevention policies.

Although extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae have become a worldwide public health concern, little is known regarding the clinical course of colonized or infected individuals. Our objective was to characterize the determinants of fatal outcomes related to ESBL-producing microorganisms at a large hospital in Paris, France. In 2012-2013, all consecutive patients with clinical samples testing positive for ESBL-producing Enterobacteriaceae at Saint-Antoine Hospital were identified. Patient clinical data were obtained at hospital entry, while information on intensive care unit (ICU) admissions and death were prospectively collected. Risk-factors for fatal 1-year outcomes were assessed using logistic regression. In total, 643/4684 (13%) ESBL-positive samples were observed, corresponding to 516 episodes (n = 206, 40% treated) among 330 patients. Most episodes were nosocomial-related (n = 347/516, 67%) involving Escherichia coli (n = 232/516, 45%) or Klebsiella pneumoniae (n = 164/516, 32%). Empirical antibiotic therapy was adequate in 89/206 (43%) infections, while the median length of hospital stay was 30 days [interquartile range (IQR) = 11-55] and 39/201 (19%) were admitted to the ICU. Overall, 104/241 patients (43%) with available data died within 1 year. In the multivariable analysis, 1-year death was associated with age >80 years (p = 0.01), concomitant comorbidity (p = 0.001), nosocomial-acquired infection (p = 0.002), and being infected rather than colonized (p < 0.001). In this series of patients with identified samples of ESBL-producing Enterobacteriaceae, hospital burden was large and 1-year mortality rates high. Understanding which patients in this setting would benefit from broad-spectrum empirical antibiotic therapy should be further examined.

Background: Elderly people are at risk of repeated hospitalizations, some of which may be drug related and preventable. In 2011, a group of French healthcare experts selected 5 iatrogenic alerts (IAs), based on criteria identified in a literature search and from their professional experience, to assess the appropriateness of medication in elderly patients., Objectives: Our objective was to examine the association between hospitalizations and IAs in elderly patients treated for Alzheimer disease who are particularly sensitive to adverse drug events., Design: A 2-year (January 1, 2011, to December 31, 2012) longitudinal national database study, with a study design similar to self-controlled case series, was performed to analyze data on drug prescriptions and hospitalization. IAs were defined as (1) long half-life benzodiazepine; (2) antipsychotic drugs in patients with Alzheimer disease; (3) co-prescription of 3 or more psychotropic drugs; (4) co-prescription of 2 or more diuretics; and (5) co-prescription of 4 or more antihypertensive drugs. Data were obtained by matching of 2 French National Health Insurance Databases., Setting: France., Participants: All affiliates, aged ≥75 years, receiving treatment for Alzheimer disease, alive on January 1, 2011 were included., Measurements: We calculated the relative increase in the number of hospitalizations in patients with IAs. The analysis was performed over four 6-month periods., Results: A total of 10,754 patients were included. During the periods with IAs, hospitalization rates increased by 0.36/year compared with 0.23/year in the periods without for the same patient, and the number of hospitalizations doubled [proportional fold change = 1.9, 95% confidence interval (1.8, 2.1)]. We estimated that 22% [95% confidence interval (20%, 23%)] of all hospitalizations were associated with IAs, 80% of which were due to psychotropic IAs., Conclusions: The IAs could be used as a simple and clinically relevant tool by prescribing physicians to assess the appropriateness of the prescription in elderly patients treated for Alzheimer disease., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Clusterin (CLU) is a sulfated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. Several studies have reported the overexpression of CLU in human neoplasm, examined by immunohistochemistry. However, there are no extensive data on its role in the thyroid. Here we investigate CLU expression in thyroid tumors, and the potential correlation between this expression and clinicopathological parameters. Immunohistochemistry with anti-CLU was performed on paraffin sections from 39 thyroid tumors. Only medullary thyroid carcinomas (MTCs) were positive (n = 5). To confirm these results, 130 further cases (including 4 C-cell hyperplasia), their matched lymph node metastases (46 cases), and lymph node recurrences (10 cases) were analyzed. All MTCs were subdivided according to World Health Organization classification. Cytoplasmic positivity was scored qualitatively (weak, moderate, strong) and quantitatively on a 5-tier scale from 0, 1+ (<10% of cells positive) to 5+ (>75%). Statistical analysis was performed. CLU was expressed in normal C cells, C-cell hyperplasia, all MTCs, their lymph node metastases, and recurrences. There was a strong association between CLU score and the cellular type (P < .004). CLU score was inversely correlated with the presence of lymph node metastases (P < .0001). There were no differences between primary and metastatic or recurrent tumors. CLU expression is related to the cellular type and inversely correlated with the presence of lymph node metastases, which could represent a new positive prognostic factor., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The oncogenic mechanisms driven by aberrantly expressed transcription factors in T-cell acute leukemia (T-ALL) are still elusive. MicroRNAs (miRNAs) play an important role in normal development and pathologies. Here, we examined the expression of 738 miRNA species in 41 newly diagnosed pediatric T-ALLs and in human thymus-derived cells. We found that expression of 2 clustered miRNAs, miR-125b/99a, peaks in primitive T cells and is upregulated in the T leukemia homeobox 3 (TLX3)-positive subtype of T-ALL. Using loss- and gain-of-function approaches, we established functional relationships between TLX3 and miR-125b. Both TLX3 and miR-125b support in vitro cell growth and in vivo invasiveness of T-ALL. Besides, ectopic expression of TLX3 or miR-125b in human hematopoietic progenitor cells enhances production of T-cell progenitors and favors their accumulation at immature stages of T-cell development resembling the differentiation arrest observed in TLX3 T-ALL. Ectopic miR-125b also remarkably accelerated leukemia in a xenograft model, suggesting that miR125b is an important mediator of the TLX3-mediated transformation program that takes place in immature T-cell progenitors. Mechanistically, TLX3-mediated activation of miR-125b may impact T-cell differentiation in part via repression of Ets1 and CBFβ genes, 2 regulators of T-lineage. Finally, we established that TLX3 directly regulates miR-125b production through binding and transactivation of LINC00478 , a long noncoding RNA gene, which is the host of miR-99a/Let-7c/miR-125b. Altogether, our results reveal an original functional link between TLX3 and oncogenic miR-125b in T-ALL development., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Background: Microcirculatory disorders leading to tissue hypoperfusion play a central role in the pathophysiology of organ failure in severe sepsis and septic shock. As microcirculatory disorders have been identified as strong predictive factors of unfavourable outcome, there is a need to develop accurate parameters at the bedside to evaluate tissue perfusion. We evaluated whether different body temperature gradients could relate to sepsis severity and could predict outcome in critically ill patients with severe sepsis and septic shock., Method: We conducted a prospective observational study in a tertiary teaching hospital in France. During a 10-month period, all consecutive adult patients with severe sepsis or septic shock who required ICU admission were included. Six hours after initial resuscitation (H6), we recorded the hemodynamic parameters and four temperature gradients: central-to-toe, central-to-knee, toe-to-room and knee-to-room., Results: We evaluated 40 patients with severe sepsis (40/103, 39 %) and 63 patients with septic shock (63/103, 61 %). In patients with septic shock, central-to-toe temperature gradient was significantly higher (12.5 [9.2; 13.8] vs 6.9 [3.4; 12.0] °C, P < 0.001) and toe-to-room temperature gradient significantly lower (1.2 [-0.3; 5.2] vs 6.0 [0.6; 9.5] °C, P < 0.001) than in patients with severe sepsis. Overall ICU mortality rate due to multiple organ failure (MOF) was 21 %. After initial resuscitation, toe-to-room temperature gradient was significantly lower in patients dead from MOF than in the survivors (-0.2 [-1.1; +1.3] °C vs +3.9 [+0.5; +7.2] °C, P < 0.001) and the difference in gradients increased during the first 24 h. Furthermore, toe-to-room temperature gradient was related to tissue perfusion parameters such as arterial lactate level (r = -0.54, P < 0.0001), urine output (r = 0.37, P = 0.0002), knee capillary refill time (r = -0.42, P < 0.0001) and mottling score (P = 0.001)., Conclusions: Toe-to-room temperature gradient reflects tissue perfusion at the bedside and is a strong prognosis factor in critically ill patients with severe infections.

Rationale: Expanding the use of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors for the treatment of cystic fibrosis (CF) requires precise and accurate biomarkers. Sweat chloride concentration provides an in vivo assessment of CFTR function, but it is unknown the degree to which CFTR mutations account for sweat chloride variation., Objectives: To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself., Methods: A total of 2,639 sweat chloride measurements were obtained in 1,761 twins/siblings from the CF Twin-Sibling Study, French CF Modifier Gene Study, and Canadian Consortium for Genetic Studies. Variance component estimation was performed by nested mixed modeling., Measurements and Main Results: Across the tested CF population as a whole, CFTR gene mutations were found to be the primary determinant of sweat chloride variability (56.1% of variation) with contributions from variation over time (e.g., factors related to testing on different days; 13.8%), environmental factors (e.g., climate, family diet; 13.5%), other residual factors (e.g., test variability; 9.9%), and unique individual factors (e.g., modifier genes, unique exposures; 6.8%) (likelihood ratio test, P < 0.001). Twin analysis suggested that modifier genes did not play a significant role because the heritability estimate was negligible (H 2  = 0; 95% confidence interval, 0.0-0.35). For an individual with CF, variation in sweat chloride was primarily caused by variation over time (58.1%) with the remainder attributable to residual/random factors (41.9%)., Conclusions: Variation in the CFTR gene is the predominant cause of sweat chloride variation; most of the non-CFTR variation is caused by testing variability and unique environmental factors. If test precision and accuracy can be improved, sweat chloride measurement could be a valuable biomarker for assessing response to therapies directed at mutant CFTR.

Background: Low-dose azithromycin has beneficial effects on severity of the lung disease in cystic fibrosis (CF) patients for a period of 6-12 months after initiation of the treatment. Although its impact in the longer term is uncertain, this treatment is frequently used chronically. The aim of this retrospective study was to investigate the effects of low-dose azithromycin treatment on the progression of CF lung disease in patients treated for more than 12 months., Methods: All of the CF patients followed in our pediatric center and who had been on low-dose azithromycin for more than 12 sequential months were included. The clinical data were collected for one year before and three years after the initiation of the azithromycin treatment. These data comprised lung function analyses, rates of exacerbations and of antibiotic courses, and changes in the airways' bacterial colonization., Results: A total of 68 patients were included (mean age: 9.95 yrs (3.61)). After 12 months, significant reductions in the numbers of pulmonary exacerbations and antibiotic courses were present. However, this effect was not maintained in the subsequent periods, during which increased rates of both pulmonary exacerbations and antibiotic courses were observed. The lung function decline was not modified during the treatment, and a decreasing time-dependent trend typical of CF was observed for the various parameters. No differences in the airway colonization by pathogens such as Pseudomonas aeruginosa and methicillin-sensitive and/or -resistant Staphyloccocus aureus were observed during the treatment. However, isolated Staphyloccocus aureus strains became resistant to macrolides after 6 months of azithromycin and remained resistant thereafter., Conclusions: No clinical benefits of low-doses azithromycin were present after one year of treatment in young CF patients. Selection for macrolide-resistant strains of bacteria occurred, which should lead to a reconsideration of the duration of azithromycin treatment in CF., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We have developed a culture model to assess antifibrotic drugs using normal human liver myofibroblasts (HLMFs) obtained from 31 subjects. Activation was evaluated in terms of α-smooth muscle actin (α-SMA) and collagen 1 (Coll1) expression using RT-PCR, and proliferation as the uptake of 5-ethynil-2'-deoxyuridine. Under analysis of variance, between-subject differences accounted for 70% of all variability and inter-experiment differences for 30%. The sensitivity of the model was determined by quantifying the effects in terms of relative expression, which were 0.74±0.03 for cyclosporine A (CsA) and 2.4±0.10 for transforming growth factor-beta (TGF-β) (P<0.0001 vs no treatment) for α-SMA expression. Inter-subject variations in α-SMA and Coll1 expression enabled the classification of subjects as potentially low or high fibrosers. Finally, we observed that pirfenidone (which has beneficial effects in vivo) significantly reduced the expressions of α-SMA and Coll1, whereas the angiotensin-converting enzyme inhibitor losartan (which has no effect in vivo) had no significant effect. Our model may thus detect the antifibrotic properties of drugs. Antifibrotic drugs with promising clinical relevance could possibly be selected using a bank of HLMFs from high fibrosers.

Unlabelled: Background The objective was to evaluate the effect of a HPV vaccination program on the incidence proportion of a proxy, genital warts (GW), in women in France., Methods: The number of primary GW cases was prospectively recorded over two 4-month periods before (T0: Dec 2008 to March 2009) and after (T1: Dec 2011 to March 2012) a HPV vaccination program. A total of 160 gynaecologists participated in T0 and 189 in T1. Primary genital herpes (HSV) infection was used as a control., Results: During T0, 39190 15- to 26 year-old women were seen, of whom 176 were diagnosed with GW (incidence proportion: 0.45%) and 155 with primary HSV infection (incidence proportion: 0.39%). During T1, 45628 females were seen [229 with GW (incidence proportion: 0.50%) and 202 with HSV (incidence proportion: 0.44%)]. In the 15-20 years age category, the incidence proportion of primary GW decreased from 0.41% to 0.30% (P=0.128) between T0 and T1, and the proportion of women newly diagnosed with primary genital herpes diseases slightly increased from 0.34% to 0.38% (P=0.620). In the 15-18 years age group, this decrease became significant (0.34% to 0.18%; P=0.048)., Conclusions: A trend for a non-significant decreased incidence proportion of GW was observed in young women below 20 years who are more frequently vaccinated. This may be the result of HPV vaccination and suggests that a substantial increase in vaccine coverage could lead to a more pronounced decreased incidence proportion of GW in the future.

Background: Viral infections such as influenza are thought to impact respiratory parameters and to promote infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF). However, the real morbidity of the influenza virus in CF needs to be further investigated because previous studies were only observational., Methods: CF patients were included in a case-control study (n = 44 cases and n = 371 controls) during the 2009 pandemic A/H1N1 influenza. Cases were patients with polymerase reaction chain-confirmed influenza A/H1N1 infection. Controls did not report any influenza symptoms during the same period. Sputum colonization and lung function were monitored during 1 year after inclusion., Results: Cases were significantly younger than controls (mean(SD) 14.9 years(11) versus 20.1 years (13.2) and significantly less frequently colonized with P. aeruginosa (34 % versus 53 %). During influenza infection, 74 % of cases had pulmonary exacerbation, 92 % had antibiotics adapted to their usual sputum colonization and 82 % were treated with oseltamivir. Two cases required lung transplantation after A/H1N1 infection (one had not received oseltamivir and the other one had been treated late). The cases received a mean number of antibiotic treatments significantly higher during the year after the influenza infection (mean(SD) 2.8 (2.4) for cases versus 1.8(2.1) for controls; p = 0.002). An age-matched comparison did not demonstrate any significant modification of bronchopulmonary bacterial colonization during the year after influenza infection nor any significant change in FEV1 at months 1, 3 and 12 after A/H1N1 infection., Conclusions: Our results do not demonstrate any change in sputum colonization nor significant lung disease progression after pandemic A/H1N1 influenza., Trial Registration: Clinical Trials.gov registration number: NCT01499914.

Background: Aspergillus colonisation is frequently reported after lung transplantation. The question of whether aspergillus colonisation is related to the hospital environment is crucial to prevention., Method: To elucidate this question, a prospective study of aspergillus colonisation after lung transplantation, along with a mycological survey of the patient environment, was performed., Results: Forty-four consecutive patients were included from the day of lung transplantation and then examined weekly for aspergillus colonisation until hospital discharge. Environmental fungal contamination of each patient was followed weekly via air and surface sampling. Twelve patients (27%) had transient aspergillus colonisation, occurring 1-13 weeks after lung transplantation, without associated manifestation of aspergillosis. Responsible Aspergillus species were A. fumigatus (6), A. niger (3), A. sydowii (1), A. calidoustus (1) and Aspergillus sp. (1). In the environment, contamination by Penicillium and Aspergillus was predominant. Multivariate analysis showed a significant association between occurrence of aspergillus colonisation and fungal contamination of the patient's room, either by Aspergillus spp. in the air or by A.fumigatus on the floor. Related clinical and environmental isolates were genotyped in 9 cases of aspergillus colonisation. For A. fumigatus (4 cases), two identical microsatellite profiles were found between clinical and environmental isolates collected on distant dates or locations. For other Aspergillus species, isolates were different in 2 cases; in 3 cases of aspergillus colonisation by A. sydowii, A. niger and A. calidoustus, similarity between clinical and environmental internal transcribed spacer and tubulin sequences was >99%., Conclusion: Taken together, these results support the hypothesis of environmental risk of hospital acquisition of aspergillus colonisation in lung transplant recipients.

Objectives: To relate socio-demographic and virological information to phylogenetic clustering in HIV infected patients in a limited geographical area and to evaluate the role of recently infected individuals in the spread of HIV., Methods: HIV-1 pol sequences from newly diagnosed and treatment-naive patients receiving follow-up between 2008 and 2011 by physicians belonging to a health network in Paris were used to build a phylogenetic tree using neighbour-joining analysis. Time since infection was estimated by immunoassay to define recently infected patients (very early infected presenters, VEP). Data on socio-demographic, clinical and biological features in clustered and non-clustered patients were compared. Chains of infection structure was also analysed., Results: 547 patients were included, 49 chains of infection containing 108 (20%) patients were identified by phylogenetic analysis. analysis. Eighty individuals formed pairs and 28 individuals were belonging to larger clusters. The median time between two successive HIV diagnoses in the same chain of infection was 248 days [CI = 176-320]. 34.7% of individuals were considered as VEP, and 27% of them were included in chains of infection. Multivariable analysis showed that belonging to a cluster was more frequent in VEP and those under 30 years old (OR: 3.65, 95 CI 1.49-8.95, p = 0.005 and OR: 2.42, 95% CI 1.05-5.85, p = 0.04 respectively). The prevalence of drug resistance was not associated with belonging to a pair or a cluster. Within chains, VEP were not grouped together more than chance predicted (p = 0.97)., Conclusions: Most newly diagnosed patients did not belong to a chain of infection, confirming the importance of undiagnosed or untreated HIV infected individuals in transmission. Furthermore, clusters involving both recently infected individuals and longstanding infected individuals support a substantial role in transmission of the latter before diagnosis.

BACKGROUND Staphylococcus aureus carriage among healthcare workers (HCWs) is a concern in hospital settings, where it may provide a reservoir for later infections in both patients and staff. Earlier studies have shown that the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) carriage in HCWs is highly variable, depending notably on location, hospital department type, MRSA prevalence among patients, and type of contacts with patients. However, MRSA incidence in HCWs and its occupational determinants have seldom been studied. METHODS A prospective, observational cohort study was conducted between May and October 2009 in a French rehabilitation center hospital. HCWs and patients were screened weekly for S. aureus nasal carriage. Methicillin-susceptible S. aureus and MRSA prevalence and incidence were estimated and factors associated with MRSA acquisition were identified using generalized estimating equation regression methods. RESULTS Among 343 HCWs included in the analysis, the average prevalence was 27% (95% CI, 24%-29%) for methicillin-susceptible S. aureus and 10% (8%-11%) for MRSA. We observed 129 MRSA colonization events. According to the multivariable analysis, high MRSA prevalence level among patients and HCW occupation were significantly associated with MRSA acquisition in HCWs, with assistant nurses being more at risk than nurses (odds ratio, 2.2; 95% CI, 1.4-3.6). CONCLUSIONS Our findings may help further our understanding of the transmission dynamics of MRSA carriage acquisition in HCWs, suggesting that it is notably driven by carriage among patients and by the type of contact with patients.

Background: Liver transplantation (LT) remains the best curative option for early hepatocellular carcinoma (HCC) but is limited by the ongoing graft shortage. The present study aimed at defining the population in which primary liver resection (LR) could represent the best alternative to LT., Methods: An exploration set of 357 HCC patients (LR n = 221 and LT n = 136) operated between 2000-2012 was used in order to identify factors associated with survival following LR and define a good prognosis (GP) group for which LR may challenge the results of upfront LT. These factors were validated in an external validation set of 565 HCC patients operated at another center (LR n = 287 LR and LT n = 278)., Results: In the exploration set, factors associated with survival on multivariate analysis were a solitary lesion, a diameter <50 mm, a well-moderately differentiated lesion, the absence of microvascular invasion, and preoperative AST level <2N. Thirty-nine patients (18%) displayed all these criteria and constituted the GP patients. Overall survivals at 1, 3, and 5 years did not significantly differ between GP resected patients, and the in Milan transplanted patients (93, 80.4, and 80.4% vs. 86.9, 82, and 78.8%, P = 0.79). In the validation cohort, patients with GP factors of survival still displayed better overall survivals than those without (P = 0.036) but also displayed better survivals than in Milan HCC transplanted patients (P = 0.005)., Conclusion: In a group of early HCC patients gathering all factors of GP, primary LR achieves at least similar survival as upfront LT and should be the approach of choice., (© 2015 Wiley Periodicals, Inc.)

Background: Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value., Objectives: To assess the predictive value of cTnI in patients with TTP for death or refractoriness., Patients/methods: The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission., Results: Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 μg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 μg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01)., Conclusions: A CTnI level of > 0.25 μg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP., (© 2014 International Society on Thrombosis and Haemostasis.)

Introduction: Studies provide evidence that reduced nurse staffing resources are associated to an increase in health care-associated infections in intensive care units, but tools to assess the contribution of the mechanisms driving these relations are still lacking. We present an agent-based model of pathogen spread that can be used to evaluate the impact on nosocomial risk of alternative management decisions adopted to deal with transitory nurse shortage., Materials and Methods: We constructed a model simulating contact-mediated dissemination of pathogens in an intensive-care unit with explicit staffing where nurse availability could be temporarily reduced while maintaining requisites of patient care. We used the model to explore the impact of alternative management decisions adopted to deal with transitory nurse shortage under different pathogen- and institution-specific scenarios. Three alternative strategies could be adopted: increasing the workload of working nurses, hiring substitute nurses, or transferring patients to other intensive-care units. The impact of these decisions on pathogen spread was examined while varying pathogen transmissibility and severity of nurse shortage., Results: The model-predicted changes in pathogen prevalence among patients were impacted by management decisions. Simulations showed that increasing nurse workload led to an increase in pathogen spread and that patient transfer could reduce prevalence of pathogens among patients in the intensive-care unit. The outcome of nurse substitution depended on the assumed skills of substitute nurses. Differences between predicted outcomes of each strategy became more evident with increasing transmissibility of the pathogen and with higher rates of nurse shortage., Conclusions: Agent-based models with explicit staff management such as the model presented may prove useful to design staff management policies that mitigate the risk of healthcare-associated infections under episodes of increased nurse shortage., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)