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Background: Bloodstream infections are linked to heightened morbidity and mortality rates. The consequences of delayed antibiotic treatment can be detrimental. Effective management of bacteraemia hinges on rapid antimicrobial susceptibility testing., Objectives: This retrospective study examined the influence of the VITEK® REVEAL™ Rapid AST system on positive blood culture (PBC) management in a French tertiary hospital., Materials and Methods: Between November 2021 and March 2022, 79 Gram-negative monomicrobial PBC cases underwent testing with both VITEK®REVEAL™ and VITEK®2 systems., Results: The study found that VITEK®REVEAL™ yielded better results than the standard of care, significantly shortening the time to result (7.0 h compared to 9.6 h) as well as the turnaround time (15 h compared to 31.1 h) when applied for all isolates., Conclusions: This study implies that the use of VITEK®REVEAL™ enables swift adaptations of antibiotic treatment strategies. By considerably minimizing the turnaround time, healthcare professionals can promptly make necessary adjustments to therapeutic regimens. Notably, these findings underscore the potential of VITEK®REVEAL™ in expediting appropriate antibiotic interventions, even in less ideal conditions. Further studies in varied laboratory contexts are required to validate these encouraging outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Motivation: Lipid nanoparticles (LNPs) are the most widely used vehicles for mRNA vaccine delivery. The structure of the lipids composing the LNPs can have a major impact on the effectiveness of the mRNA payload. Several properties should be optimized to improve delivery and expression including biodegradability, synthetic accessibility, and transfection efficiency., Results: To optimize LNPs, we developed and tested models that enable the virtual screening of LNPs with high transfection efficiency. Our best method uses the lipid Simplified Molecular-Input Line-Entry System (SMILES) as inputs to a large language model. Large language model-generated embeddings are then used by a downstream gradient-boosting classifier. As we show, our method can more accurately predict lipid properties, which could lead to higher efficiency and reduced experimental time and costs., Availability and Implementation: Code and data links available at: https://github.com/Sanofi-Public/LipoBART., (© The Author(s) 2024. Published by Oxford University Press.)

Background: A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®)., Methods: This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection., Results: Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines., Conclusions: In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines., Clinical Trials Registration: NCT03965962., Competing Interests: Potential conflicts of interest. A. C. P. P., Q. J., C. P., J. K. P., V. B., S. B., S. P., F. G. M., and A. M. M. are employees of Sanofi and may hold shares and/or stock options in the company. Y. D. reports other financial or nonfinancial interests as investigator and CEO of 1 of the investigation sites. All other authors report no potential conflicts. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Collaboration between surveillance programmes is the keystone of One Health surveillance and international organizations call for integrated surveillance systems to manage antibiotic resistance (ABR). In France, the ABR surveillance system covers human, animal, food and the environment sectors, but appears to be fragmented, questioning its level of integration. This study aimed to evaluate collaboration within this system and to formulate recommendations towards more integration., Methods: ECoSur, a semi-quantitative tool, was used to evaluate collaboration between surveillance programmes. A total of 31 attributes were evaluated using information from the literature and 52 interviews with surveillance actors from all four sectors. Evaluation results were visualized via three output figures displaying aspects related to governance and functionality of collaboration. Results were validated by an expert committee., Results: Overall, the French collaborative strategy for ABR surveillance was well formalized and relevant to its objectives. However, a cross-sectoral coordination body was lacking to help with its practical implementation. The environmental sector was largely uncovered, but its integration appeared necessary to meet the strategy objectives. Data sharing and joint data analyses between programmes were insufficient, mainly due to limited resources and data interoperability issues. Collaboration was operational for internal and external communication of the results. Twelve recommendations were suggested to decision makers to foster collaboration within the French surveillance system and feed future strategies against ABR., Conclusions: This first evaluation of collaboration within the French ABR surveillance system produced concrete recommendations to move towards One Health integrated surveillance. Both the approach and the findings could be of interest to other countries., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science., Competing Interests: Conflicts of interest statement The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Intra-Abdominal Candidiasis (IAC) is frequent and associated with high mortality in intensive care unit (ICU) patients. Antifungal treatments may be overused due to a lack of diagnostic tools to rule out IAC. Serum 1,3-Beta-D-Glucan (BDG) concentrations are used to diagnose Candida infections, its concentration in peritoneal fluid (PF) may help to confirm or invalidate the diagnosis of IAC. We performed a non-interventional, prospective, multicenter study, at the Hospices Civils de Lyon, France, in seven ICU located in three different hospitals from December 2017 to June 2018. IAC was defined as the isolation of Candida in a sample collected from the intra-abdominal cavity under sterile conditions in patients displaying clinical evidence of intra-abdominal infection. Among the 113 included patients, 135 PF samples corresponding to 135 intra-abdominal infection episodes were collected and BDG concentrations were assessed. IAC accounted for 28 (20.7%) of the intra-abdominal infections. Antifungals were administered empirically to 70 (61.9%) patients; among them, 23 (32.9%) had an IAC. The median [IQR] BDG value was significantly higher in IAC (8100 [3000;15000] pg/mL) than in non-IAC samples (1961 [332;10650] pg/mL). BDG concentrations were higher in PF with Fecaloid aspect and in case of positive bacterial culture. For a BDG threshold of 125 pg/mL, the negative predictive value to assess IAC was 100%. In conclusion, low BDG PF concentrations could be used to rule out IAC. https://clinicaltrials.gov/ct2/show/NCT03469401., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Avian influenza virus subtype H9N2 is endemic in Bangladesh's poultry population. The subtype affects poultry production and poses a potential zoonotic risk. Insufficient understanding of how the poultry trading network shapes the dissemination of avian influenza viruses has hindered the design of targeted interventions to reduce their spread. Here, we use phylodynamic analyses of haemagglutinin sequences to investigate the spatial spread and dispersal patterns of H9N2 viruses in Bangladesh's poultry population, focusing on its two largest cities (Dhaka and Chattogram) and their poultry production and distribution networks. Our analyses suggest that H9N2 subtype avian influenza virus lineage movement occurs relatively less frequently between Bangladesh's two largest cities than within each city. H9N2 viruses detected in single markets are often more closely related to viruses from other markets in the same city than to each other, consistent with close epidemiological connectivity between markets. Our analyses also suggest that H9N2 viruses may spread more frequently between chickens of the three most commonly sold types (sunali-a cross-bred of Fayoumi hen and Rhode Island Red cock, deshi-local indigenous, and exotic broiler) in Dhaka than in Chattogram. Overall, this study improves our understanding of how Bangladesh's poultry trading system impacts avian influenza virus spread and should contribute to the design of tailored surveillance that accommodates local heterogeneity in virus dispersal patterns., Competing Interests: We declare that we have no competing interests of any kind, including financial., (© The Author(s) 2023. Published by Oxford University Press.)

Ultrasensitive, quantitative Clostridioides difficile stool toxin measurement demonstrated significantly higher concentrations of toxins A and B in patients infected with the North American pulsed-field gel electrophoresis type 1/ribotype 027 (NAP-1/027) strain compared with other strains, providing in vivo confirmation of the in vitro association between NAP-1/027 and elevated toxin production., Competing Interests: Potential conflicts of interest . C. D. A. has received grant support from Merck (investigator-initiated award, paid to their institution) and an NIH Loan Repayment Award, outside the submitted work. C. P. K. reports stock ownership options with First Light; has served as an investigator for a Pfizer-sponsored research study; has served as an investigator for a Merck-sponsored research study; has served as an investigator for a Janssen-sponsored research study; has acted as a paid consultant to Artugen (scientific advisor on clinical and clinical research aspects of Clostridioides difficile infection [CDI]), Facile Therapeutics (scientific advisor on clinical and clinical research aspects of CDI), Ferring (scientific advisor on clinical and clinical research aspects of CDI), First Light Biosciences (scientific advisor on clinical and clinical research aspects of diagnosis of CDI), Finch (scientific advisor on clinical and clinical research aspects of CDI), Janssen (J&J) (scientific advisor on clinical and research aspects of CDI), Matrivax (scientific advisor on C. difficile vaccine development), Merck (scientific advisor on clinical and research aspects of CDI), Seres, Pfizer (scientific advisor on C. difficile vaccine development), and Vedanta (scientific advisor on clinical and clinical research aspects of CDI). K. W. G. has received grant support from Acurx, Paratek, Summit, and Tetraphase Pharmaceuticals (research grants paid to the university) and has received consulting fees from Acurx and Summit Pharmaceuticals. M. M., A. F., A. L., and A. B. are employees of bioMérieux. All other authors report no potential conflicts. 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 the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Penicillin allergy, the most frequently reported drug allergy, has been associated with suboptimal antibiotic therapy, increased antimicrobial resistance, increased rates of Clostridioides difficile colonization and infection, as well as extended hospital length of stay and increased cost. Although up to 10% of all patients may report penicillin allergy, most penicillin allergies are not confirmed. As such, most patients with a penicillin allergy can still safely use penicillin and related drugs following a more precise assessment. Herein, we review the current practices and unmet needs in penicillin allergy testing. The diagnostic algorithm is mostly based on a clinical history assessment followed by in vivo testing, i.e. skin test and/or drug challenge. As these tests are labour and resource intensive, there is increased interest in point-of-care penicillin allergy de-labelling solutions incorporated into Antimicrobial Stewardship Programmes including digital assessment tools. These can be locally parameterized on the basis of characteristics of target populations, incidence of specific allergies and local antibiotic usage to perform clinical risk stratification. Safely ruling out any residual risk remains essential and in vivo drug challenge and/or skin testing should be systematically encouraged. Gradual understanding and convergence of the risk stratification of the clinical presentation of penicillin allergy is enabling a wider implementation of this essential aspect of antimicrobial stewardship through digitalized decision tools and in vivo testing. More research is needed to deliver point of care in vitro diagnostic tools to democratize this de-labelling practice, which would be highly beneficial to patient care. This progress, together with better education of patients and clinicians about the availability, efficacy and safety of penicillin allergy testing, will increase the dissemination of penicillin allergy assessment as an important component of Antimicrobial Stewardship Programmes., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

In a prospective cohort study, stools from children <3 years with and without diarrhea who were Clostridioides difficile nucleic acid amplification test-positive underwent ultrasensitive and quantitative toxin measurement. Among 37 cases and 46 controls, toxin concentration distributions overlapped substantially. Toxin concentration alone does not distinguish C. difficile infection from colonization in young children., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Stool toxin concentrations may impact Clostridioides difficile infection (CDI) severity and outcomes. We correlated fecal C difficile toxin concentrations, measured by an ultrasensitive and quantitative assay, with CDI baseline severity, attributable outcomes, and recurrence., Methods: We enrolled 615 hospitalized adults (≥18 years) with CDI (acute diarrhea, positive stool nucleic acid amplification testing, and decision to treat). Baseline stool toxin A and B concentrations were measured by single molecule array. Subjects were classified by baseline CDI severity (4 scoring methods) and outcomes within 40 days (death, intensive care unit stay, colectomy, and recurrence)., Results: Among 615 patients (median, 68.0 years), in all scoring systems, subjects with severe baseline disease had higher stool toxin A+B concentrations than those without (P < .01). Nineteen subjects (3.1%) had a severe outcome primarily attributed to CDI (group 1). This group had higher median toxin A+B (14 303 pg/mL [interquartile range, 416.0, 141 967]) than subjects in whom CDI only contributed to the outcome (group 2, 163.2 pg/mL [0.0, 8423.3]), subjects with severe outcome unrelated to CDI (group 3, 158.6 pg/mL [0.0, 1795.2]), or no severe outcome (group 4, 209.5 pg/mL [0.0, 8566.3]) (P = .003). Group 1 was more likely to have detectable toxin (94.7%) than groups 2-4 (60.5%-66.1%) (P = .02). Individuals with recurrence had higher toxin A+B (2266.8 pg/mL [188.8, 29411]) than those without (154.0 pg/mL [0.0, 5864.3]) (P < .001) and higher rates of detectable toxin (85.7% versus 64.0%, P = .004)., Conclusions: In CDI patients, ultrasensitive stool toxin detection and concentration correlated with severe baseline disease, severe CDI-attributable outcomes, and recurrence, confirming the contribution of toxin quantity to disease presentation and clinical course., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Embryo lipid profile is affected by in vitro culture conditions that lead to an increase in lipids. Efforts have been made to optimize embryo lipid composition as it is associated with their quality. The objective of this study was to evaluate whether the diet supplementation of donor cows (n-3 or n-6 polyunsaturated fatty acids), or the slow freezing protocols (ethylene glycol sucrose vs. glycerol-trehalose), or the physiological stage of the donor (nulliparous heifers vs. primiparous lactating cows) may impact the bovine embryo lipid profile. Lipid extracts of 97 embryos were individually analyzed by liquid chromatography-high resolution mass spectrometry, highlighting 246 lipids, including 85% being overabundant in cow embryos compared to heifer embryos. Among 105 differential lipids, 72 were overabundant after ethylene glycol sucrose protocol, including a single glycerophosphate PA(32:1) representing 27.3% of the significantly modulated lipids, suggesting that it is degraded when glycerol-trehalose protocol is used. No lipids were different according to the n-3 or n-6 supplementation of the donor cows. In conclusion, the embryonic lipid profile was mainly affected by the physiological stage of the donors and the slow freezing protocols. The overabundance of lipids in lactating cow embryos and the resulting lower quality of these embryos are consistent with the lower pregnancy rate observed in cows compared to heifers. Unlike glycerol-trehalose protocol, ethylene glycol sucrose freezing allowed to preserve glycerophospholipids, potentially improving the slow freezing of in vitro-produced embryos. Further studies are required to modulate embryo quality and freezability by modulating the lipidome and by integrating all stages of embryonic production., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antimicrobial susceptibility testing (AST) is classically performed using growth-based techniques that essentially require viable bacterial matter to become visible to the naked eye or a sophisticated densitometer., Content: Technologies based on the measurement of bacterial density in suspension have evolved marginally in accuracy and rapidity over the 20th century, but assays expanded for new combinations of bacteria and antimicrobials have been automated, and made amenable to high-throughput turn-around. Over the past 25 years, elevated AST rapidity has been provided by nucleic acid-mediated amplification technologies, proteomic and other "omic" methodologies, and the use of next-generation sequencing. In rare cases, AST at the level of single-cell visualization was developed. This has not yet led to major changes in routine high-throughput clinical microbiological detection of antimicrobial resistance., Summary: We here present a review of the new generation of methods and describe what is still urgently needed for their implementation in day-to-day management of the treatment of infectious diseases., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post hoc analysis assessed hospitalized and severe virologically confirmed dengue (VCD) over the complete 6-year follow-up of 3 CYD-TDV efficacy studies (CYD14, CYD15, and CYD23/CYD57)., Methods: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to 5 years after the last injection., Results: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over 6 years compared to placebo (HR [95% confidence interval] multiple imputation from month 0 method, .19 [.12-.30] and .15 [.06-.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups., Conclusions: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire 6-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year-olds. Clinical Trials Registration: NCT00842530, NCT01983553, NCT01373281, NCT01374516., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The GENE-UP® EHEC assay (Performance Tested MethodSM 121806) is a real-time PCR molecular detection method that utilizes fluorescence resonance energy transfer proprietary hybridization probes for the rapid detection of enterohemorrhagic Escherichia coli (EHEC) in select foods., Objective: The purpose of this validation was to evaluate the method's interlaboratory performance and submit the results to AOAC INTERNATIONAL for adoption as a First Action Official Method of AnalysisSM for the detection of EHEC in select foods., Method: The GENE-UP method was evaluated in a multi-laboratory study as part of the MicroVal VALIDATION certification process using unpaired test portions for one food matrix, raw ground beef (85% lean). Collaborators evaluated the candidate method using either an automated or manual lysis procedure. The candidate method was compared to the ISO/TS 13136:2012 method. Data from 17 participants from 15 laboratories throughout the European Union were evaluated. Three levels of contamination were evaluated: a non-inoculated control level (0 CFU/test portion), a low contamination level (∼1 CFU/test portion), and a high contamination level (∼10 CFU/test portion). Data from the study were analyzed according to the probability of detection (POD) statistical model., Results: The difference in laboratory probability of detection (dLPODC) values with 95% confidence interval between the candidate and reference method results were -0.01 (-0.04, 0.02), 0.23 (0.07, 0.39), and 0.06 (0.01, 0.12) for the non-inoculated, low, and high contamination levels, respectively., Conclusions: For the candidate method, values obtained for repeatability and reproducibility were similar to the reference method and indicated minimal variation between samples or between laboratories. No discrepant results (false positive or false negative) were observed for each contamination. A statistical difference was calculated between the candidate and reference method at the low and high inoculation levels, with the candidate method detecting a higher number of positive samples indicating a higher sensitivity than the reference method. No differences in the recovery of the target analyte were observed between the manual and automated lysis procedures., Highlights: The GENE-UP EHEC Detection Method provides end users a rapid, easy-to-use workflow for the detection of EHEC in food matrixes., (© AOAC INTERNATIONAL 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The recombinant tetravalent live-attenuated dengue vaccine based on the YF 17D vaccine virus backbone (CYD-TDV) demonstrated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype from month 13 to month 25 (VCD-DENV-AnyM13→M25) in the CYD14 (2-14-y-olds) and CYD15 (9-16-y-olds) phase 3 trials. Fifty percent plaque reduction neutralization test (PRNT50) titers are a potential surrogate for immunobridging VE to adults., Methods: Using PRNT50 calibration datasets, we applied immunobridging approaches using baseline and/or M13 PRNT50 titers to estimate VE against VCD-DENV-AnyM0→M25 and against hospitalized VCD (HVCD)-DENV-AnyM0→M72 in hypothetical 18-45-y-old and 46-50-y-old CYD14 and CYD15 cohorts., Results: Baseline and M13 geometric mean PRNT50 titers were greater in 18-45-y-olds and in 46-50-y-olds vs 9-16-y-olds for most comparisons. Estimated VE (95% CIs against VCD-DENV-AnyM0→M25 ranged from 75.3% to 90.9% (52.5% to 100%) for 18-45-y-olds and 74.8% to 92.0% (53.4% to 100%) for 46-50-y-olds. Estimated VE (95% CIs) against HVCD-DENV-AnyM0→M72 ranged from 58.8% to 78.1% (40.9 to 98.9%) for 18-45-y-olds and 57.2% to 78.4% (40.5 to 97.6%) for 46-50-y-olds. Corresponding predictions among baseline-seropositive individuals yielded comparable or higher VE estimates., Conclusions: VE M0→M25 against DENV-Any and VE against HVCD-DENV-AnyM0→M72 are both expected to be higher in 18-45 and 46-50-y-olds vs CYD14 and CYD15 9-16-y-olds., (© The Author(s) 2020. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: The immune profile of dengue-experienced individuals is a determinant of dengue reinfection severity risk. Individuals with a single prior dengue infection (monotypic) are at highest risk for severe disease, while individuals with ≥ 2 prior dengue infections (multitypic) are at lower risk. The tetravalent dengue vaccine (CYD-TDV) has shown efficacy in the prevention of dengue in individuals with prior dengue infection. We estimated efficacy in individuals with monotypic or multitypic immune profiles., Methods: Participants enrolled in the immunogenicity subsets of 2 randomized placebo-controlled phase 3 studies (CYD14, NCT01373281; CYD15, NCT01374516) were classified as either monotypic or multitypic, based on measured baseline dengue plaque reduction neutralization test. Vaccine efficacy (VE) against symptomatic virologically confirmed dengue (VCD) was assessed over 25 months and against VCD hospitalization over 6 years., Results: Of 3927 participants in the immunogenicity subsets, 496 and 257 in the CYD-TDV and placebo groups, respectively, were classified as monotypic immune, and 1227 and 612, respectively, as multitypic immune. VE against symptomatic VCD was 77.4% (95% CI, 56.4%-88.2%) for monotypic and 89.2% (95% CI, 71.5%-95.9%) for multitypic profiles, with corresponding absolute risk reductions (ARRs) of 4.48% (95% CI, 2.32%-6.65%) for monotypics and 1.67% (95% CI, .89%-2.46%) for multitypics. VE against hospitalized VCD was 75.3% (95% CI, 42.7%-90.2%) in monotypics and 81.2% (95% CI, 21.7%-96.8%) in multitypics, with ARRs of 0.95% (95% CI, .37%-1.53%) for monotypics and 0.18% (95% CI, .02%-.34%) for multitypics., Conclusions: CYD-TDV benefits individuals with monotypic and multitypic immune profiles. Larger public health benefit is expected to derive from the protection of individuals with a monotypic immune profile., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Chemosensory neurons translate perception of external chemical cues, including odorants, tastants, and pheromones, into information that drives attraction or avoidance motor programs. In the laboratory, robust behavioral assays, coupled with powerful genetic, molecular and optical tools, have made Caenorhabditis elegans an ideal experimental system in which to dissect the contributions of individual genes and neurons to ethologically relevant chemosensory behaviors. Here, we review current knowledge of the neurons, signal transduction molecules and regulatory mechanisms that underlie the response of C. elegans to chemicals, including pheromones. The majority of identified molecules and pathways share remarkable homology with sensory mechanisms in other organisms. With the development of new tools and technologies, we anticipate that continued study of chemosensory signal transduction and processing in C. elegans will yield additional new insights into the mechanisms by which this animal is able to detect and discriminate among thousands of chemical cues with a limited sensory neuron repertoire., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Background: The GENE-UP®  Listeria spp. 2 (LIS 2) assay (Performance Tested MethodSM 121803) is a real-time PCR molecular detection method for the rapid detection of Listeria species (Listeria monocytogenes, L. innocua, L. ivanovii, L. seeligeri, and L. welshimeri) in a variety of foods and environmental surfaces., Objective: The purpose of this validation was to evaluate the method's interlaboratory performance and submit the results to AOAC INTERNATIONAL for adoption as First Action Official MethodSM for the detection of Listeria species in a variety of foods and select environmental surfaces., Method: The GENE-UP method was evaluated in a multi-laboratory study as part of the AFNOR NF VALIDATION certification process using unpaired test portions for one food matrix, full-cream goat milk cottage cheese (8.4% fat). The candidate method was compared to the ISO 11290-1/Amd.1 reference method. Sixteen participants from 15 laboratories throughout the European Union participated. Three levels of contamination were evaluated: a non-inoculated control level (0 CFU/test portion), a low contamination level (∼2 CFU/test portion), and a high contamination level (∼10 CFU/test portion). Data from that study were analyzed according to the probability of detection (POD) statistical model., Results: The dLPODC values with 95% confidence intervals between the candidate and reference method results were -0.02 (-0.07, 0.03), -0.08 (-0.31, 0.16), and 0.00 (-0.03, 0.03) for the non-inoculated, low, and high contamination levels, respectively., Conclusions: The dLPODC results demonstrate no difference in performance between the candidate method and reference method for the matrix evaluated., Highlights: Data from a singular collaborative study was used to achieve adoption as an AOAC First Action Official Method for the detection of Listeria species in a variety of foods and select environmental surfaces., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The GENE-UP®  Listeria monocytogenes 2 (LMO 2) assay (Performance Tested MethodSM 121804) uses real-time PCR technology and a proprietary detection platform, the GENE-UP Thermocycler, to detect Listeria monocytogenes in a variety of foods and environmental surfaces., Objective: The purpose of this validation was to evaluate the method's interlaboratory performance and submit the result to AOAC INTERNATIONAL for adoption as First Action Official MethodSM for the detection of Listeria monocytogenes in a variety of foods and select environmental surfaces., Method: The GENE-UP method was evaluated in a multi-laboratory study as part of the AFNOR NF VALIDATION certification process using unpaired test portions for one food matrix, full-cream goat milk cottage cheese (8.4% fat). The candidate method was compared to the ISO 11290-1/Amd.1:2004 reference method. Sixteen participants from 15 laboratories throughout the European Union participated. Three levels of contamination were evaluated: a non-inoculated control level (0 CFU/test portion), a low inoculum level (∼2 CFU/test portion), and a high inoculum level (∼10 CFU/test portion). Data from the study were analyzed according to the Probability of Detection (POD) statistical model as presented in the AOAC validation guidelines., Results: The dLPODC values with 95% confidence interval for each comparison were; -0.02 (-0.07, 0.03), -0.08 (-0.31, 0.16), and 0.00 (-0.03, 0.03) for the non-inoculated, low, and high contamination levels, respectively., Conclusions: The dLPODC results demonstrate no difference in performance between the candidate method and reference method for the matrix evaluated., Highlights: The GENE-UP LMO method demonstrated accuracy and precision in detecting and discerning L. monocytogenes from other Listeria species., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Recent years have witnessed the development of several k-mer-based approaches aiming to predict phenotypic traits of bacteria on the basis of their whole-genome sequences. While often convincing in terms of predictive performance, the underlying models are in general not straightforward to interpret, the interplay between the actual genetic determinant and its translation as k-mers being generally hard to decipher., Results: We propose a simple and computationally efficient strategy allowing one to cope with the high correlation inherent to k-mer-based representations in supervised machine learning models, leading to concise and easily interpretable signatures. We demonstrate the benefit of this approach on the task of predicting the antibiotic resistance profile of a Klebsiella pneumoniae strain from its genome, where our method leads to signatures defined as weighted linear combinations of genetic elements that can easily be identified as genuine antibiotic resistance determinants, with state-of-the-art predictive performance., Conclusions: By enhancing the interpretability of genomic k-mer-based antibiotic resistance prediction models, our approach improves their clinical utility and hence will facilitate their adoption in routine diagnostics by clinicians and microbiologists. While antibiotic resistance was the motivating application, the method is generic and can be transposed to any other bacterial trait. An R package implementing our method is available at https://gitlab.com/biomerieux-data-science/clustlasso., (© The Author(s) 2020. Published by Oxford University Press GigaScience.)

Background: The GENE-UP®E. coli O157:H7 2 (ECO 2) assay (Performance Tested MethodSM 121805) incorporates Fluorescence Resonance Energy Transfer hybridization probes into its proprietary PCR technology for the rapid detection of E. coli O157:H7 in select foods., Objective: The purpose of this validation was to evaluate the method's interlaboratory performance and submit the result to AOAC INTERNATIONAL for adoption as First Action Official MethodSM for the detection of E. coli O157:H7 in select foods., Method: The GENE-UP® method was evaluated in a multi-laboratory study as part of the MicroVal validation process using unpaired test portions for one food matrix, raw milk cheese (Comté, 34% fat, 0.8% salt). The candidate method was compared to the ISO 16654:2001 reference method. Fourteen participants from 13 laboratories throughout the European Union participated. Three levels of contamination were evaluated: a non-inoculated control level (0 colony-forming units (CFU)/test portion), a low contamination level (∼5 CFU/test portion), and a high contamination level (∼10 CFU/test portion). Data from that study were analyzed according to the Probability of Detection (POD) statistical model as presented in the AOAC validation guidelines. The difference in laboratory POD (dLPODC) values with 95% confidence interval across collaborators was calculated for each level between the candidate and reference method results, and between the candidate presumptive and confirmed results., Results: The dLPODC values with 95% confidence interval were; 0.00 (-0.04, 0.04), 0.27 (0.04, 0.49), and 0.17 (0.01, 0.33) for the non-inoculated, low and high contamination levels respectively., Conclusions: The dLPODC results indicate a significant difference between the candidate method and the reference method for both the low and high contamination levels, with the candidate method producing higher recovery of the target organism at both levels., Highlights: The GENE-UP E. coli O157:H7 assay provides industry with a rapid, accurate detection method for E. coli O157:H7 in a broad range of foods., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Most Clostridioides difficile toxinogenic strains produce both toxins A and B (A+B+), but toxin A-negative, toxin B-positive (A-B+) variants also cause disease. We report the identification of a series of pathogenic clinical C. difficile isolates that produce high amounts of toxin A with low or nondetectable toxin B., Methods: An ultrasensitive, quantitative immunoassay was used to measure toxins A and B in stool samples from 187 C. difficile infection (CDI) patients and 44 carriers. Isolates were cultured and assessed for in vitro toxin production and in vivo phenotypes (mouse CDI model)., Results: There were 7 CDI patients and 6 carriers who had stools with detectable toxin A (TcdA, range 23-17 422 pg/mL; 5.6% of samples overall) but toxin B (TcdB) below the clinical detection limit (<20 pg/mL; median TcdA:B ratio 17.93). Concentrations of toxin A far exceeded B in in vitro cultures of all 12 recovered isolates (median TcdA:B ratio 26). Of 8 toxin A>>B isolates tested in mice, 4 caused diarrhea, and 3 of those 4 caused lethal disease. Ribotyping demonstrated strain diversity. TcdA-predominant samples were also identified at 2 other centers, with similar frequencies (7.5% and 6.8%)., Conclusions: We report the discovery of clinical pathogenic C. difficile strains that produce high levels of toxin A but minimal or no toxin B. This pattern of toxin production is not rare (>5% of isolates) and is consistently observed in vitro and in vivo in humans and mice. Our study highlights the significance of toxin A in human CDI pathogenesis and has important implications for CDI diagnosis, treatment, and vaccine development., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: The occupational environment represents an important source of exposures to multiplehazards for workers' health. Although it is recognized that mixtures of agents may have differenteffects on health compared to their individual effects, studies generally focus on the assessment ofindividual exposures. Our objective was to identify occupational co-exposures occurring in the United States using the multi-industry occupational exposure databank of the Occupational Safety and Health Administration (OSHA)., Methods: Using OSHA's Integrated Management Information System (IMIS), measurement data from workplace inspections occurring from 1979 to 2015 were examined. We defined a workplace situation (WS) by grouping measurements that occurred within a company, within the same occupation (i.e. job title) within 1 year. All agents present in each WS were listed and the resulting databank was analyzed with the Spectrosome approach, a methodology inspired by network science, to determine global patterns of co-exposures. The presence of an agent in a WS was defined either as detected, or measured above 20% of a relevant occupational exposure limit (OEL)., Results: Among the 334 648 detected exposure measurements of 105 distinct agents collected from 14 513 US companies, we identified 125 551 WSs, with 31% involving co-exposure. Fifty-eight agents were detected with others in >50% of WSs, 29 with a proportion >80%. Two clusters were highlighted, one for solvents and one for metals. Toluene, xylene, acetone, hexone, 2-butanone, and N-butyl acetate formed the basis of the solvent cluster. The main agents of the metal cluster were zinc, iron, lead, copper, manganese, nickel, cadmium, and chromium. 68 556 WS were included in the analyses based on levels of exposure above 20% of their OEL, with 12.4% of co-exposure. In this analysis, while the metal cluster remained, only the combinations of toluene with xylene or 2-butanone were frequently observed among solvents. An online web application allows the examination of industry specific patterns., Conclusions: We identified frequent co-exposure situations in the IMIS databank. Using the spectrome approach, we revealed global combination patterns and the agents most often implicated. Future work should endeavor to explore the toxicological effects of prevalent combinations of exposures on workers' health to prioritize research and prevention efforts., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Background: Dengue is a global health problem requiring an effective, safe dengue vaccine., Methods: We report the results of a phase II, randomized, open-label, single-center trial in adults aged 18 to 45 years in the United States designed to explore the effects of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine (CYD-TDV, Dengvaxia) when administered on its designated schedule (months 0, 6, and 12) or on an accelerated dosing schedule (months 0, 2, and 6) and/or given before, or concomitantly with, a vaccine against Japanese encephalitis (JE)., Results: Based on dengue virus serotype-specific neutralizing antibody (NAb), the accelerated dosing schedule was comparable to the 0, 6, and 12-month schedule. Giving JE vaccine concurrently with CYD-TDV did not result in an increase in overall NAb titers. Immunophenotyping of peripheral blood mononuclear cells revealed an increase in activated CD8+ T cells after CYD-TDV vaccination, a phenomenon that was greatest for the JE vaccine primed., Conclusions: We conclude that an accelerated dosing schedule of CYD-TDV results in essentially equivalent dengue serotype-specific NAb titers as the currently used schedule, and there may be an early benefit in antibody titers and activated CD8+ T cells by the administration of the JE vaccine before CYD-TDV vaccination., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Recent data indicate that Clostridioides difficile toxin concentrations in stool do not differentiate between C. difficile infection (CDI) and asymptomatic carriage. Thus, we lack a method to distinguish a symptomatic patient with CDI from a colonized patient with diarrhea from another cause. To address this, we evaluated markers of innate and adaptive immunity in adult inpatients with CDI (diagnosed per US guidelines), asymptomatic carriage, or non-CDI diarrhea., Methods: CDI-NAAT patients had clinically significant diarrhea and positive nucleic acid amplification testing (NAAT) and received CDI treatment. Carrier-NAAT patients had positive stool NAAT but no diarrhea. NAAT-negative patients (with and without diarrhea) were also enrolled. A panel of cytokines and anti-toxin A and B immunoglobulin (Ig) were measured in serum; calprotectin and anti-toxin B Ig A/G were measured in stool. NAAT-positive stool samples were tested by an ultrasensitive toxin assay (clinical cutoff, 20 pg/mL)., Results: Median values for interleukin (IL)-4, IL-6, IL-8, IL-10, IL-15, granulocyte colony-stimulating factor (GCSF), MCP-1, tumor necrosis factor α (TNF-α), and IgG anti-toxin A in blood and IgA/G anti-toxin B in stool were significantly higher in CDI patients compared with all other groups (P < .05). Concentration distributions for IL-6, GCSF, TNF-α, and IgG anti-toxin A in blood, as well as IgA and IgG anti-toxin B in stool, separated CDI patients from all other groups., Conclusions: Specific markers of innate and adaptive immunity distinguish CDI from all other groups, suggesting potential clinical utility for identifying which NAAT- and toxin-positive patients with diarrhea truly have CDI., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The GENE-UP®Cronobacter assay (Performance Tested MethodSM 081801) is a real-time PCR technology for the rapid detection of Cronobacter species in select foods and environmental surfaces., Objective: The purpose of this validation was to evaluate the method's interlaboratory performance and submit the result to AOAC INTERNATIONAL for adoption as a First Action Official MethodSM for the detection of Cronobacter species in select foods and environmental surfaces., Method: The GENE-UP method was evaluated in a multilaboratory study as part of the AFNOR NF VALIDATION certification process (NF102) following ISO 16140-2:2016 using unpaired test portions for one food matrix, reconstituted infant formula containing probiotics. The candidate method was compared to the ISO 22964:2017 reference method. Sixteen participants from fifteen laboratories throughout the European Union participated. Three levels of contamination were evaluated: a noninoculated control level (0 CFU/target test portion), a low contamination level (approximately 2 CFU/target test portion), and a high contamination level (approximately 10 CFU/target test portion). Data from that study were analyzed according to the probability of detection (POD) statistical model as presented in the AOAC validation guidelines. The difference in laboratory POD (dLPODC) values with 95% confidence intervals across collaborators was calculated for each level between the candidate and reference method results and between the candidate presumptive and confirmed results., Results: The dLPODC values with 95% confidence intervals were 0.00 (-0.03, 0.03), -0.08 (-0.19, 0.02), and 0.00 (-0.03, 0.03) for the noninoculated, low, and high contamination levels, respectively., Conclusions: The dLPODC results indicate no significant difference between the candidate method and the reference method or between presumptive and confirmed results for all three levels of contamination., Highlights: The GENE-UP Cronobacter assay provides industry with a rapid, easy to use method for the rapid detection of Cronobacter in a wide range of products and environmental samples., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In September 2018, the World Health Organization recommended that prevaccination screening be used with the tetravalent dengue vaccine (CYD-TDV), to ensure that only individuals with evidence of prior dengue infection (PDI) are vaccinated. Dengue rapid diagnostic tests (RDTs) would offer a potential solution for prevaccination screening at the point-of-care, but data on performance of available RDTs for identifying PDI are limited. We determined the suitability of four dengue RDTs and two conventional enzyme-linked immunosorbent assays (ELISAs) to identify PDI and evaluated cross-reactivity with co-circulating flaviviruses., Methods: Specificity was assessed using 534 dengue-negative [determined by 50% plaque reduction neutralization test (PRNT50)] serum samples from USA (n = 229) and dengue-endemic regions (n = 305). Sensitivity was assessed using 270 samples from recent (n = 90) or remote (n = 90) virologically confirmed prior dengue cases, and dengue PRNT50-positive samples (n = 90). Cross-reactivity was assessed in dengue-seronegative samples that were seropositive for yellow fever (n = 57), Japanese encephalitis (n = 37), West Nile (n = 59) or Zika (n = 41)., Results: Dengue IgG RDTs and the Panbio ELISA exhibited favourable specificities (99-100%), higher than the Focus ELISA (95%). The RDTs had variable sensitivities (40-70%) that were lower than those of the ELISAs (≥90%). Cross-reactivity to other flaviviruses was low with RDTs (≤7%), but more significant with ELISAs (up to 51% for West Nile and 34% for Zika). No cross-reactivity to any of the four closely related flaviviruses was observed with the CTK Biotech RDT. For each SeroTest, sensitivity appeared similar in samples from individuals with recent (<13 months) vs remote (3-4 years) virologically confirmed PDI., Conclusions: In general, dengue IgG RDTs were found to be more specific and less cross-reactive than the ELISAs, but the latter were more sensitive for identifying PDI cases. Currently available RDTs could be temporizing tools for rapid and safe prevaccination screening until improved RDTs with increased sensitivity become available., (© International Society of Travel Medicine 2019. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

cGMP plays a role in sensory signaling and plasticity by regulating ion channels, phosphodiesterases, and kinases. Studies that primarily used genetic and biochemical tools suggest that cGMP is spatiotemporally regulated in multiple sensory modalities. FRET- and GFP-based cGMP sensors were developed to visualize cGMP in primary cell culture and Caenorhabditis elegans to corroborate these findings. While a FRET-based sensor has been used in an intact animal to visualize cGMP, the requirement of a multiple emission system limits its ability to be used on its own as well as with other fluorophores. Here, we demonstrate that a C. elegans codon-optimized version of the cpEGFP-based cGMP sensor FlincG3 can be used to visualize rapidly changing cGMP levels in living, behaving C. elegans We coexpressed FlincG3 with the blue-light-activated guanylyl cyclases BeCyclOp and bPGC in body wall muscles, and found that the rate of change in FlincG3 fluorescence correlated with the rate of cGMP production by each cyclase. Furthermore, we show that FlincG3 responds to cultivation temperature, NaCl concentration changes, and sodium dodecyl sulfate in the sensory neurons AFD, ASEL/R, and PHB, respectively. Intriguingly, FlincG3 fluorescence in ASEL and ASER decreased in response to a NaCl concentration upstep and downstep, respectively, which is opposite in sign to the coexpressed calcium sensor jRGECO1a and previously published calcium recordings. These results illustrate that FlincG3 can be used to report rapidly changing cGMP levels in an intact animal, and that the reporter can potentially reveal unexpected spatiotemporal landscapes of cGMP in response to stimuli., (Copyright © 2019 Woldemariam et al.)

Summary: The exploration and comparison of genome organization is routinely used in the frame of genomic and phylogenomic analyses. As a consequence, in the past few years, various tools allowing visualizing genomic contexts have been developed. However, their use is often hampered by a lack of flexibility, particularly concerning associated databases input formats and figure customization. Here we present GeneSpy, a graphical user interface that allows the visualization and dynamic exploration of eukaryotic and prokaryotic annotated genomes. GeneSpy relies on user-friendly manageable local databases and allows the easy customization and production of figures in a multitude of formats., Availability and Implementation: GeneSpy is freely available at https://lbbe.univ-lyon1.fr/GeneSpy/ for Linux, Mac OS and Windows under CeCILL license (http://www.cecill.info/licences/). It is written in Python 2.7 and depends on Matplotlib, Tkinter and Sqlite libraries., Supplementary Information: Supplementary data are available at Bioinformatics online.

Background: Japanese encephalitis virus (JEV) is a zoonotic, mosquito-borne flavivirus, distributed across Asia. Infections are mostly mild or asymptomatic, but symptoms include neurological disorders, sequelae, and fatalities. Data to inform control strategies are limited due to incomplete case reporting., Methods: We used JEV serological data from a multicountry Asian dengue vaccine study in children aged 2-14 years to describe JEV endemicity, measuring antibodies by plaque reduction neutralization test (PRNT50)., Results: A total 1479 unvaccinated subjects were included. A minimal estimate of pediatric JEV seroprevalence in dengue-naive individuals was 8.1% in Indonesia, 5.8% in Malaysia, 10.8% in the Philippines, and 30.7% in Vietnam, translating to annual infection risks varying from 0.8% (in Malaysia) to 5.2% (in Vietnam). JEV seroprevalence and annual infection estimates were much higher in children with history of dengue infection, indicating cross-neutralization within the JEV PRNT50 assay., Conclusions: These data confirm JEV transmission across predominantly urban areas and support a greater emphasis on JEV case finding, diagnosis, and prevention.

Background: We used an ultrasensitive, quantitative single molecule array (Simoa) immunoassay to test whether concentrations of Clostridioides (formerly Clostridium) difficile toxins A and/or B in the stool of adult inpatients with C. difficile infection (CDI) were higher than in asymptomatic carriers of toxinogenic C. difficile., Methods: Patients enrolled as CDI-NAAT had clinically significant diarrhea and a positive nucleic acid amplification test (NAAT), per US guidelines, and received CDI treatment. Potential carriers had recently received antibiotics and did not have diarrhea; positive NAAT confirmed carriage. Baseline stool samples were tested by Simoa for toxin A and B., Results: Stool toxin concentrations in both CDI-NAAT (n = 122) and carrier-NAAT (n = 44) cohorts spanned 5 logs (0 pg/mL to >100000 pg/mL). Seventy-nine of 122 (65%) CDI-NAAT and 34 of 44 (77%) carrier-NAAT had toxin A + B concentration ≥20 pg/mL (clinical cutoff). Median toxin A, toxin B, toxin A + B, and NAAT cycle threshold (Ct) values in CDI-NAAT and carrier-NAAT cohorts were similar (toxin A, 50.6 vs 60.0 pg/mL, P = .958; toxin B, 89.5 vs 42.3 pg/mL, P = .788; toxin A + B, 197.2 vs 137.3 pg/mL, P = .766; Ct, 28.1 vs 28.6, P = .354). However, when CDI/carrier cohorts were limited to those with detectable toxin, respective medians were significantly different (A: 874.0 vs 129.7, P = .021; B: 1317.0 vs 81.7, P = .003, A + B, 4180.7 vs 349.6, P = .004; Ct, 25.8 vs 27.7, P = .015)., Conclusions: Toxin concentration did not differentiate an individual with CDI from one with asymptomatic carriage. Median stool toxin concentrations in groups with CDI vs carriage differed, but only when groups were defined by detectable stool toxin (vs positive NAAT).

The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients.

Background: We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments., Methods: We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples., Results: There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline., Conclusions: Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries., Clinical Trials Registration: NCT01373281 and NCT01374516.

Clinical Trials Registration: NCT01190228., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We assessed replication and excretion of the live attenuated tetravalent dengue vaccine (CYD-TDV) into biological fluids following vaccination in dengue-naive adults in Australia., Methods: Vaccinal viremia/shedding was assessed in a subset of participants enrolled in a lot-to-lot consistency study; 95 participants received 3 subcutaneous doses of CYD-TDV from phase 2/3 lots of the vaccine, and 8 received placebo; doses were administered 6 months apart. Quantitative reverse-transcription polymerase chain reaction (qR-PCR) analysis was used to initially detect the yellow fever virus (YFV) core protein gene in the backbone of CYD-TDV in serum, saliva and urine, followed by serotype-specific qRT-PCR analysis of samples positive for YFV by qRT-PCR (lower limit of detection, 5.16 GEq/mL)., Results: YFV viremia was detected by qRT-PCR in 69.5% of participants (66 of 95) who received CYD-TDV, mainly 6-14 days after injection 1. The serotypes detected were serotype 4 (in 68.2% of participants [45 of 95]), serotype 3 (in 19.7% [13 of 95]), and serotype 1 (in 12.1% [8 of 95]); serotype 2 was not detected. None of the placebo recipients had vaccinal viremia/shedding. No participants had detectable viral shedding into saliva at levels above the lower limit of quantitation. Two participants had low-level viral shedding (serotype 3) in urine (5.47 and 5.77 GEq/mL). None of the participants with viremia or shedding experienced concomitant fever., Conclusions: Low-level vaccinal viremia may occur following vaccination with CYD-TDV, but this is not associated with any symptom or adverse event., Clinical Trials Registration: NCT01134263., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Similar exposure groups (SEGs) are needed to reliably assess occupational exposures and health risks. However, the construction of SEGs can turn out to be rather challenging because of the multifactorial variability of exposures., Objectives: The objective of this study is to put forward a semi-empirical approach developed to construct and implement a SEG database for exposure assessments. An occupational database of airborne levels of polycyclic aromatic hydrocarbons (PAHs) was used as an illustrative and working example., Methods: The approach that was developed consisted of four steps. The first three steps addressed the construction and implementation of the occupational Exporisq-HAP database (E-HAP). E-HAP was structured into three hierarchical levels of exposure groups, each of which was based on exposure determinants, along 16 dimensions that represented the sampled PAHs. A fourth step was implemented to identify and generate SEGs using the geometric standard deviation (GSD) of PAH concentrations., Results: E-HAP was restructured into 16 (for 16 sampled PAHs) 3 × 3 matrices: three hierarchical levels of description versus three degrees of dispersion, which included low (the SEG database: GSD ≤ 3), medium (3 < GSD ≤ 6), and high (GSD > 6). Benzo[a]pyrene (BaP) was the least dispersed particulate PAH with 41.5% of groups that could be considered as SEGs, 48.5% of groups of medium dispersion, and only 8% with high dispersion. These results were comparable for BaP, BaP equivalent toxic, or the sum of all carcinogenic PAHs but were different when individual gaseous PAHs or ∑PAHG were chosen., Conclusion: Within the framework of risk assessment, such an approach, based on groundwork studies, allows for both the construction of an SEG database and the identification of exposure groups that require improvements in either the description level or the homogeneity degree toward SEG., (© The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Guttural pouch mycosis (GPM) is a rare but potentially life-threatening condition in horses. GPM is caused by a fungal invasion into the mucosal lining of the guttural pouches and, frequently, the associated neurovascular structures. Although several species of fungi have been associated with this disease, Aspergillus spp. appear to be the most common isolated from the guttural pouches. However, it remains unclear which are the predisposing factors leading to the development of the infection. The objectives of the present study were to experimentally reproduce an infection by Aspergillus fumigatus and to follow the natural evolution of the mycosis. Eight guttural pouches from four horses were experimentally infected by endoscopy-guided intrapouch inoculation of A. fumigatus culture. Horses were monitored for clinical signs and development of fungal plaques through endoscopic examination. Mycotic lesions were observed in all the horses and a spontaneous regression was observed within 15-28 days. No development of clinical signs was noticed. In conclusion, we were able to induce the development of mycotic lesions and to observe a natural regression of these lesions without clinical signs., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The live-attenuated Japanese encephalitis (JE) vaccine (JE-CV; IMOJEV) induces a protective response in children. A shift in circulating JE virus strains suggests that a genotype shift phenomenon may occur throughout Southeast Asia. We assessed the neutralization of wild-type (WT) JE virus isolates at distal time points after vaccination., Methods: We analyzed serum samples from a subset of 47 children who had received a JE-CV booster after an inactivated JE vaccine primary immunization. We measured antibody titers (50% plaque reduction neutralization test) using a panel of WT JE strains at baseline, then after the booster at 28 days and 6 months in all subjects present at the time points and in a subset at year 5. Three additional recent isolates were tested at year 5., Results: Of 47 subjects, 43 (91.5%) subjects had JE neutralizing antibody titers ≥10 (reciprocal serum dilution) against the homologous strain before JE-CV boost; all were seroprotected up to year 5 after the JE-CV boost. Baseline WT seroprotection ranged between 78.7% and 87.2%; all subjects were seroprotected against the 4 WT strains at 28 days and 6 months; year 5 seroprotection ranged between 95.7% and 97.9%. Similar rates of protection against 3 additional WT isolates were observed at year 5., Conclusions: The long-term immune responses induced after a JE-CV booster dose in toddlers were able to neutralize WT viruses from various genotypes circulating in Southeast Asia and India., Clinical Trials Registration: NCT00621764., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America)