Replicative history marks transcriptional and functional disparity in the CD8+ T cell memory pool.

Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8+ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically 'record' the replicative history of different CD8+ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (TCM) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the TCM compartment. Specifically, we demonstrate that lowly divided TCM cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8+ T cell effector pool upon reinfection is marked by prior quiescence.

Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19.

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood1-4. Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genes including Toll-like receptors in monocytes. Male individuals who had recovered from COVID-19 had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared with healthy male individuals and female individuals who had recovered from COVID-19, in part because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated prevaccination frequencies of 'virtual memory'-like CD8+ T cells poised to produce more IFNγ after IL-15 stimulation. Moreover, the expression of the repressed innate immune genes in monocytes increased by day 1 to day 28 after vaccination in recoverees, therefore moving towards the prevaccination baseline of the healthy control individuals. By contrast, these genes decreased on day 1 and returned to the baseline by day 28 in the control individuals. Our study reveals sex-dimorphic effects of previous mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points that affect future immune responses in an antigen-agnostic manner.

A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Pompe disease ascertained through The Lantern Project, 2018-2021: Next-generation sequencing and enzymatic testing to overcome obstacles to diagnosis.

The Lantern Project is an ongoing complimentary diagnostic program for patients in the United States sponsored by Sanofi and implemented by PerkinElmer Genomics. It combines specific enzymatic, biomarker, and genetic testing to facilitate rapid, accurate laboratory diagnosis of Pompe disease and several other lysosomal storage diseases, and a multigene next-generation sequencing panel including Pompe disease, LGMD, and other neuromuscular disorders. This article reports data for Pompe disease collected from October 2018 through December 2021, including acid α-glucosidase (GAA) enzyme assay and GAA sequencing (standard or expedited for positive newborn screening [NBS] to rule out infantile-onset Pompe disease [IOPD]) and the Focused Neuromuscular Panel, which includes GAA. One hundred forty patients (12 received only GAA enzyme testing, 128 had GAA sequencing alone or in addition to enzyme assay) have been confirmed with Pompe disease in this project. Eight of the 140 had a variant of unknown significance, but GAA activity ≤2.10 µmol/L/h, thus were confirmed with Pompe disease. Three diagnosed patients 0-2 years old had cross-reactive immunologic material (CRIM)-negative GAA variants and thus IOPD. One additional infant with presumptive IOPD had a homozygous frameshift c.1846del, likely CRIM-negative; symptoms were not provided. Among the 128 patients with molecular results, the c.-32-13T>G splice variant was homozygous in 11, compound-heterozygous in 98, and absent in 19. Proximal muscle weakness (58 patients) was the most common sign reported at testing; elevated creatine kinase (29 patients) was the most common laboratory result. The most common symptom categories were muscular (73 patients), musculoskeletal (13 patients), and respiratory (23 patients). Clinical information was not available for 42 samples, and 17 infants had only "abnormal NBS" or "low GAA" reported. Cardiac symptoms in 7 included potentially age-related conditions in five c.-32-13T>G-compound-heterozygous adults (myocardial infarction, heart murmur/palpitations, congestive heart failure: 1 each; 2 with atrial fibrillation) and hypertrophic cardiomyopathy in 2 children (1 and 2 years old) with presumptive IOPD. One novel GAA variant was observed in a patient with enzyme activity 0.31 µmol/L/h: c.1853_1854ins49, a frameshift pathogenic variant. The Lantern Project demonstrates the combinatorial utility of enzyme assay, targeted single-gene testing, and a focused neuromuscular next-generation sequencing panel in diagnosing Pompe disease.

Bacterial co-infection and antibiotic stewardship in patients with COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Understanding the proportion of patients with COVID-19 who have respiratory bacterial co-infections and the responsible pathogens is important for managing COVID-19 effectively while ensuring responsible antibiotic use. OBJECTIVE: To estimate the frequency of bacterial co-infection in COVID-19 hospitalized patients and of antibiotic prescribing during the early pandemic period and to appraise the use of antibiotic stewardship criteria. METHODS: Systematic review and meta-analysis was performed using major databases up to May 5, 2021. We included studies that reported proportion/prevalence of bacterial co-infection in hospitalized COVID-19 patients and use of antibiotics. Where available, data on duration and type of antibiotics, adverse events, and any information about antibiotic stewardship policies were also collected. RESULTS: We retrieved 6,798 studies and included 85 studies with data from more than 30,000 patients. The overall prevalence of bacterial co-infection was 11% (95% CI 8% to 16%; 70 studies). When only confirmed bacterial co-infections were included the prevalence was 4% (95% CI 3% to 6%; 20 studies). Overall antibiotic use was 60% (95% CI 52% to 68%; 52 studies). Empirical antibiotic use rate was 62% (95% CI 55% to 69%; 11 studies). Few studies described criteria for stopping antibiotics. CONCLUSION: There is currently insufficient evidence to support widespread empirical use of antibiotics in most hospitalised patients with COVID-19, as the overall proportion of bacterial co-infection is low. Furthermore, as the use of antibiotics during the study period appears to have been largely empirical, clinical guidelines to promote and support more targeted administration of antibiotics in patients admitted to hospital with COVID-19 are required.

Correlates of cannabis use in a sample of mental health treatment-seeking Canadian armed forces members and veterans.

OBJECTIVE: Canadian Armed Forces (CAF) members and Veterans are more likely to experience mental health (MH) conditions, such as posttraumatic stress disorder (PTSD), than the general Canadian population. Previous research suggests that an increasing number of individuals are employing cannabis for MH symptom relief, despite a lack of robust evidence for its effectiveness in treating PTSD. This research aimed to: (1) describe the prevalence of current cannabis use among MH treatment-seeking CAF members and Veterans; and (2) estimate the association between current cannabis use and a number of sociodemographic, military, and MH-related characteristics. METHOD: Using cross-sectional intake data from 415 CAF members and Veterans attending a specialized outpatient MH clinic in Ontario, Canada, between January 2018 and December 2020, we estimated the proportion of CAF members and Veterans who reported current cannabis use for either medical or recreational purposes. We used multivariable logistic regression to estimate adjusted odds ratios for a number of sociodemographic, military, and MH-related variables and current cannabis use. RESULTS: Almost half of the study participants (n = 187; 45.1%) reported current cannabis use. Respondents who reported current cannabis use for medical purposes had a higher median daily dose than those who reported current cannabis use for recreational purposes. The multivariable logistic regression identified younger age, lower income, potentially hazardous alcohol use, and increased bodily pain as statistically significant correlates of current cannabis use among our MH treatment-seeking sample. PTSD severity, depressive severity, sleep quality, and suicide ideation were not statistically associated with current cannabis use. CONCLUSIONS: Almost half of our treatment-seeking sample reported current cannabis use for medical or recreational purposes, emphasizing the importance of screening MH treatment-seeking military members and Veterans for cannabis use prior to commencing treatment. Future research building upon this study could explore the potential impact of cannabis use on MH outcomes.

Dose modification for haematological toxicity: a survey of Australian medical oncologists.

BACKGROUND: Evidence supporting dose modifications to reduce serious treatment-related adverse events of antineoplastic therapy is limited and frequently based on clinical trial protocols, which are not always generalisable to community patients. eviQ is an online resource with treatment protocols and recommendations for dose modification formulated by expert opinion and evidence-based review. Original recommended haematological thresholds to delay treatment were: neutrophil count <1.5 × 109 /L and platelet count <100 × 109 /L. AIMS: To evaluate the current practices of Australian medical oncologists with regard to haematological dose modifications for antineoplastic treatments, and to determine rates of adherence to eviQ recommendations. METHODS: An online survey regarding haematological dose modifications was distributed to over 400 Medical Oncology Group of Australia members and eviQ medical oncology reference committee members via email. Responses were collated on 18 December 2017. RESULTS: Of 153 respondents, 67% indicated that they did not follow the eviQ haematological dose modification guidelines; 8% delayed curative intent treatment at neutrophil counts <1.5 × 109 /L, compared with 36% for palliative treatment; most delayed treatment at neutrophil counts <1.0 × 109 /L (94% curative and 97% palliative respectively). 70% of clinicians delayed palliative treatment at platelet counts <100 × 109 /L, compared to 34% with curative treatment. No respondents indicated the original haematological cut-off levels were too aggressive. CONCLUSION: The majority of responding medical oncologists indicated that they did not follow the eviQ haematological dose modification guidelines, which were viewed as too conservative. Subsequent to this survey, eviQ reviewed and updated haematological dose modification recommendations.

Targeted vaccination campaigns of teenagers after two clusters of B invasive meningococcal disease in Brittany, France, 2017.

BACKGROUND: In December 2016, three cases of serogroup B invasive meningococcal disease, including two children from the same middle school (11 to 15 years old pupils), occurred in the department (administrative district) Côtes-d'Armor (Brittany, France). They were infected by a rare strain (B:P1.7-2,4:F5-9:cc162), covered by the 4CMenB vaccine (Bexsero®). Four months later, two cases due to the same strain occurred in a high school in the same area (15 to 19 years old students). In accordance with French recommendations, vaccination was proposed to students of both schools and to all individuals aged 11-19 years living or studying in the hyperendemic area. We describe these vaccination campaigns, from the alert to the impact evaluation. METHODS: The target population included 8884 people: 579 in the middle school, 2007 in the high school and 6298 in the community. In both schools, vaccination sessions were organized directly on site. In the community, teenagers were vaccinated by general practitioners. The vaccination campaign took place from May to October 2017. An active pharmacovigilance follow-up was set up to document adverse effects of the vaccine. RESULTS: Considering the whole target population, the vaccination coverage was estimated at 43% for 1 dose and 34% for 2 doses. Higher vaccination coverage was observed in the schools (79% in the middle school and 42% in the high school for 2 doses) than in the community (27% for 2 doses). The reported adverse effects were consistent with the safety profile of the vaccine and no severe adverse effect was reported. CONCLUSIONS: This vaccination campaign was the third one implemented with Bexsero® in France and constitutes a reproducible approach for future targeted vaccination campaigns. No additional cases of the same strain have occurred since the end of the campaigns in the area.

Comorbidity Patterns of Psychiatric Conditions in Canadian Armed Forces Personnel.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is often accompanied by other mental health conditions, including major depressive disorder (MDD), substance misuse disorders, and anxiety disorders. The objective of the current study is to delineate classes of comorbidity and investigate predictors of comorbidity classes amongst a sample of Canadian Armed Forces (CAF) Regular Force personnel. METHODS: Latent class analyses (LCAs) were applied to cross-sectional data obtained between April and August 2013 from a nationally representative random sample of 6700 CAF Regular Force personnel who deployed to the mission in Afghanistan. RESULTS: MDD was the most common diagnosis (8.0%), followed by PTSD (5.3%) and generalized anxiety disorder (4.7%). Of those with a mental health condition, LCA revealed 3 classes of comorbidity: a highly comorbid class (8.3%), a depressed-only class (4.6%), and an alcohol use-only class (3.1%). Multinomial logit regression showed that women (adjusted relative risk ratio [ARRR] = 2.77; 95% CI, 2.13 to 3.60; P < 0.01) and personnel reporting higher trauma exposure (ARRR = 4.18; 95% CI, 3.13 to 5.57; P < 0.01) were at increased risk of membership in the comorbid class compared to those without a mental health condition. When compared to those with no mental health condition, experiencing childhood abuse increased the risk of being in any comorbidity class. CONCLUSIONS: Results provide further evidence to support screening for and treatment of comorbid mental health conditions. The role of sex, childhood abuse, and combat deployment in determining class membership may also prove valuable for clinicians treating military-related mental health conditions.

Defining and Measuring Moral Injury: Rationale, Design, and Preliminary Findings From the Moral Injury Outcome Scale Consortium.

In the current paper, we first describe the rationale for and methodology employed by an international research consortium, the Moral Injury Outcome Scale (MIOS) Consortium, the aim of which is to develop and validate a content-valid measure of moral injury as a multidimensional outcome. The MIOS Consortium comprises researchers and clinicians who work with active duty military service members and veterans in the United States, the United Kingdom, the Netherlands, Australia, and Canada. We describe the multiphase psychometric development process being conducted by the Consortium, which will gather phenomenological data from service members, veterans, and clinicians to operationalize subdomains of impact and to generate content for a new measure of moral injury. Second, to illustrate the methodology being employed by the Consortium in the first phase of measure development, we present a small subset of preliminary results from semistructured interviews and questionnaires conducted with care providers (N = 26) at three of the 10 study sites. The themes derived from these initial preliminary clinician interviews suggest that exposure to potentially morally injurious events is associated with broad psychological/behavioral, social, and spiritual/existential impacts. The early findings also suggest that the outcomes associated with acts of commission or omission and events involving others' transgressions may overlap. These results will be combined with data derived from other clinicians, service members, and veterans to generate the MIOS.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Definiendo y midiendo el daño moral: fundamentos, diseño y resultados preliminares de la escala consorcio de consecuencias del daño moral DEFINIENDO Y MIDIENDO EL DAÑO MORAL En el documento actual, describimos en primer lugar los fundamentos y la metodología empleados por un consorcio internacional de investigación, la Escala Consorcio de consecuencias del daño moral (MIOS en sus siglas en inglés), cuyo objetivo es desarrollar y validar una medida de daño moral con contenido válido y como consecuencias multidimensionales. El Consorcio MIOS está compuesto por investigadores y clínicos que trabajan con miembros del servicio militar activos y veteranos en los Estados Unidos, el Reino Unido, los Países Bajos, Australia y Canadá. Describimos el proceso de desarrollo psicométrico multifase que está llevando a cabo el Consorcio, que recopilará datos fenomenológicos de miembros del servicio, veteranos y clínicos para poner en práctica subdominios de impacto y generar contenido para una nueva medida de daño moral. En segundo lugar, para ilustrar la metodología empleada por el Consorcio en la primera fase de desarrollo de la medida, presentamos un pequeño subconjunto de resultados preliminares de entrevistas semiestructuradas y cuestionarios realizados con proveedores de atención (N = 26) en tres de los 10 sitios de estudio. Los temas derivados de estas primeras entrevistas clínicas preliminares sugieren que la exposición a eventos potencialmente dañinos moralmente está asociada con amplios impactos psicológicos / conductuales, sociales y espirituales / existenciales. Los primeros hallazgos también sugieren que los resultados asociados con actos de comisión u omisión y eventos que involucran las transgresiones de otros pueden superponerse. Estos resultados se combinarán con datos derivados de otros clínicos, miembros del servicio y veteranos para generar el MIOS.

Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016.

IntroductionHaemolytic uraemic syndrome (HUS) related to Shiga toxin-producing Escherichia coli (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged < 15 years was implemented starting from 1996.AimWe present the results of this surveillance between 2007 and 2016.MethodsA voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation.ResultsOver the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26).ConclusionsNo major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.

Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency.

Neuroendocrine control of reproduction by brain-secreted pulses of gonadotropin-releasing hormone (GnRH) represents a longstanding puzzle about extracellular signal decoding mechanisms. GnRH regulates the pituitary gonadotropin's follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are heterodimers specified by unique ß subunits (FSHß/LHß). Contrary to Lhb, Fshb gene induction has a preference for low-frequency GnRH pulses. To clarify the underlying regulatory mechanisms, we developed three biologically anchored mathematical models: 1) parallel activation of Fshb inhibitory factors (e.g. inhibin α and VGF nerve growth factor-inducible), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. growth differentiation factor 9). Simulations with all three models recapitulated the Fshb expression levels obtained in pituitary gonadotrope cells perifused with varying GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration, and pulse frequency revealed that the apparent frequency-dependent pattern of Fshb expression in model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed "true" pulse frequency sensing. To resolve which components of this GnRH signal induce Fshb, we developed a high-throughput parallel experimental system. We analyzed over 4,000 samples in experiments with varying near-physiological GnRH concentrations and pulse patterns. Whereas Egr1 and Fos genes responded only to variations in average GnRH concentration, Fshb levels were sensitive to both average concentration and true pulse frequency. These results provide a foundation for understanding the role of multiple regulatory factors in modulating Fshb gene activity.

Depression and the relationship between sleep disturbances, nightmares, and suicidal ideation in treatment-seeking Canadian Armed Forces members and veterans.

BACKGROUND: Research on the relationship between insomnia and nightmares, and suicidal ideation (SI) has produced variable findings, especially with regard to military samples. This study investigates whether depression mediated the relationship between: 1) sleep disturbances and SI, and 2) trauma-related nightmares and SI, in a sample of treatment-seeking Canadian Armed Forces (CAF) personnel and veterans (N = 663). METHOD: Regression analyses were used to investigate associations between sleep disturbances or trauma-related nightmares and SI while controlling for depressive symptom severity, posttraumatic stress disorder (PTSD) symptom severity, anxiety symptom severity, and alcohol use severity. Bootstrapped resampling analyses were used to investigate the mediating effect of depression. RESULTS: Approximately two-thirds of the sample (68%; N = 400) endorsed sleep disturbances and 88% (N = 516) reported experiencing trauma-related nightmares. Although sleep disturbances and trauma-related nightmares were both significantly associated with SI on their own, these relationships were no longer significant when other psychiatric conditions were included in the models. Instead, depressive symptom severity emerged as the only variable significantly associated with SI in both equations. Bootstrap resampling analyses confirmed a significant mediating role of depression for sleep disturbances. CONCLUSIONS: The findings suggest that sleep disturbances and trauma-related nightmares are associated with SI as a function of depressive symptoms in treatment-seeking CAF personnel and veterans. Treating depression in patients who present with sleep difficulties may subsequently help mitigate suicide risk.

An outbreak of leptospirosis among kayakers in Brittany, North-West France, 2016.

In September 2016, a cluster of seven kayakers with clinical symptoms of leptospirosis with onset since July 2016 was reported to French health authorities. Human and animal investigations were undertaken to describe the outbreak, identify the likely place and source of infection and implement necessary control measures. We identified 103 patients with clinical symptoms of leptospirosis between 1 June and 31 October 2016 who lived in the Ille-et-Vilaine district in Brittany. Of these, 14 (including the original seven) reported contacts with the river Vilaine during the incubation period and were defined as outbreak cases: eight were confirmed by serology tests or PCR and six were probable without a laboratory confirmation for leptospirosis. All 14 cases were kayakers. Three distinct contamination sites were identified on a 30 km stretch of the river Vilaine. Nine cases reported having skin wounds while kayaking. None were vaccinated against leptospirosis. The outbreak was attributed to Leptospira kirschneri serogroup Grippotyphosa. Animal investigations did not allow identifying the possible reservoir. Leptospirosis outbreaks associated with freshwater sports are rare in temperate climates. The prevention of such outbreaks requires control of potential animal reservoirs in zones such as the Vilaine valley and that kayakers adopt the recommended individual prevention measures.

Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy.

BACKGROUND: Changes in adaptive immune cells after chemotherapy in adult acute myeloid leukemia (AML) may have implications for the success of immunotherapy. This study was designed to determine the functional capacity of the immune system in adult patients with AML who have completed chemotherapy and are potential candidates for immunotherapy. METHODS: We used the response to seasonal influenza vaccination as a surrogate for the robustness of the immune system in 10 AML patients in a complete remission post-chemotherapy and performed genetic, phenotypic, and functional characterization of adaptive immune cell subsets. RESULTS: Only 2 patients generated protective titers in response to vaccination, and a majority of patients had abnormal frequencies of transitional and memory B-cells. B-cell receptor sequencing showed a B-cell repertoire with little evidence of somatic hypermutation in most patients. Conversely, frequencies of T-cell populations were similar to those seen in healthy controls, and cytotoxic T-cells demonstrated antigen-specific activity after vaccination. Effector T-cells had increased PD-1 expression in AML patients least removed from chemotherapy. CONCLUSION: Our results suggest that while some aspects of cellular immunity recover quickly, humoral immunity is incompletely reconstituted in the year following intensive cytotoxic chemotherapy for AML. The observed B-cell abnormalities may explain the poor response to vaccination often seen in AML patients after chemotherapy. Furthermore, the uncoupled recovery of B-cell and T-cell immunity and increased PD-1 expression shortly after chemotherapy might have implications for the success of several modalities of immunotherapy.

Beyond rescue: Implementation and evaluation of revised naloxone training for law enforcement officers.

OBJECTIVE: This study describes the implementation and evaluation of revised opioid overdose prevention and education of naloxone training for law enforcement officers (LEOs) that added: (1) a recovery testimony and (2) the process for deputy-initiated referrals postnaloxone administration. DESIGN AND SAMPLE: Evaluation regarding the naloxone training included a pre- and postopioid overdose knowledge surveys (N = 114) and subsequent 1-year postnaloxone training outcomes. RESULTS: Pre- and posttest scores for all knowledge outcome measures were statistically significant (p < .001) with favorable comments pertaining to the recovery testimony. Out of 31 individuals who received naloxone, 6 individuals (19.4%) continue to be in treatment or received some treatment services. The most common symptoms reported were unconsciousness/unresponsiveness (40.5%), abnormal breathing patterns (24.3%), and blue lips (16.2%). The majority of the calls (65.6%) were to a residential area, and the time for naloxone revival ranged <1-10 min (M = 3.48; SD = 2.27). CONCLUSION: As nearly 20% of individuals sought treatment after a LEO-initiated referral, it is recommended that other agencies consider the referral process into the training. Future research will investigate the impact of the recovery testimony in reducing the stigma of addiction.

High Proportion of Asymptomatic Infections in an Outbreak of Hepatitis E Associated With a Spit-Roasted Piglet, France, 2013.

BACKGROUND: On 11 December 2013, 3 clustered cases of hepatitis E were reported on a French coastal island. Individuals had taken part in a wedding meal that included a spit-roasted piglet. The piglet had been stuffed with a raw stuffing partly made from the liver. Investigations were carried out to identify the vehicle of contamination and evaluate the dispersion of the hepatitis E virus (HEV) in the environment. METHODS: A questionnaire was administered to 98 wedding participants who were asked to give a blood sample. Cases were identified by reverse transcription-polymerase chain reaction and serological tests. A retrospective cohort study was conducted among 38 blood-sampled participants after the exclusion of 14 participants with evidence of past HEV infection. Relative risks (RR) and 95% confidence intervals were calculated based on food consumed at the wedding meal using univariate and multivariable Poisson regressions. Phylogenetic analyses were performed to compare the clinical HEV strains. Strains were detected in the liquid manure sampled at the farm where the piglet was born and in the untreated island wastewater. RESULTS: Seventeen cases were identified, 70.6% were asymptomatic. Acute HEV infection was independently associated with piglet stuffing consumption (RR = 1.69 [1.04-2.73], P = .03). Of clinical strains from the index cases, veterinary and environmental HEV strains were identical. CONCLUSIONS: Our investigation attributed this large HEV outbreak to the consumption of an undercooked pig liver-based stuffing. After infection, the cases became a temporary reservoir for HEV, which was detected in the island's untreated wastewater.

Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody.

Affinity maturation refines a naive B-cell response by selecting mutations in antibody variable domains that enhance antigen binding. We describe a B-cell lineage expressing broadly neutralizing influenza virus antibodies derived from a subject immunized with the 2007 trivalent vaccine. The lineage comprises three mature antibodies, the unmutated common ancestor, and a common intermediate. Their heavy-chain complementarity determining region inserts into the conserved receptor-binding pocket of influenza HA. We show by analysis of structures, binding kinetics and long time-scale molecular dynamics simulations that antibody evolution in this lineage has rigidified the initially flexible heavy-chain complementarity determining region by two nearly independent pathways and that this preconfiguration accounts for most of the affinity gain. The results advance our understanding of strategies for developing more broadly effective influenza vaccines.

Community Incidence of Campylobacteriosis and Nontyphoidal Salmonellosis, France, 2008-2013.

Community incidence estimates are necessary to assess the burden and impact of infections on health and to set priorities for surveillance, research, prevention, and control strategies. The current study was performed to estimate the community incidence of campylobacteriosis and nontyphoidal salmonellosis in France from the number of laboratory-confirmed cases reported to the national reference center (NRC). The probabilities of a case in the community visiting a doctor, having a stool sample requested, having a positive laboratory test, and having the case reported to the NRC were estimated using data of national surveillance systems, national hospitalization and health insurance databases, and specific surveys informing about these parameters. Credible intervals (CrI) were calculated using Monte Carlo simulation. In addition, we estimated the number of hospitalizations for both infections in France. The annual community incidence rate in France is estimated at 842 cases per 100,000 (90%CrI 525-1690) for campylobacteriosis and 307 cases per 100,000 (90%CrI 173-611) for salmonellosis. The annual number of hospitalizations is estimated at 5182 for campylobacteriosis and 4305 for salmonellosis. The multiplication factors between cases ascertained by the surveillance system and cases in the community were 115 for campylobacteriosis and 20 for salmonellosis. They are consistent with estimates reported in other countries, indicating a high community incidence of campylobacteriosis and salmonellosis in France.