Background/Objectives: To examine if head injury (HI) is associated with age at ALS diagnosis in the United States. Methods: In this cross-sectional populationf-based analysis, we identified patients with ALS who were registered from 2015 to 2023 who completed the Registry's head trauma survey module. The association between HI and age at ALS diagnosis was assessed using multivariate analysis. Results: Of the 3424 respondents, 56.6% had experienced a HI. The adjusted odds ratio (aOR) for an ALS diagnosis before age 60 years for patients with a HI was 1.24 (95% CI, 1.07-1.45). One or two HIs had an aOR of 1.15 (95% CI, 0.97-1.36), and five or more HIs had an aOR of 1.58 (95% CI, 1.19-2.09). HI before age 18 years yielded an aOR of 2.03 (95% CI, 1.53-2.70) as well as HI between the ages of 18 and 30 years (aOR = 1.48, 95% CI: 1.06-2.06)). When narrowing the analysis to patients with HI before age 18 compared with patients with no HI, we found an association with HI that led to an emergency department or hospital visit (aOR = 1.50 (95% CI: 1.21-1.86)). Conclusions: In this cross-sectional analysis of ALS patients, HIs occurring in childhood and early adulthood and the number of HIs increased the odds of being diagnosed before age 60 years. These results suggest that HI continues to be a risk factor for ALS and could be associated with a younger age of diagnosis.

Kalamari is a resource that supports genomic epidemiology and pathogen surveillance. It consists of representative genomes and common contaminants. Kalamari also contains a custom taxonomy and software for downloading and formatting the data.

There is limited research on associations of per- and polyfluoroalkyl substances (PFAS) with areal bone mineral density (aBMD) through adolescence and whether bone-strengthening factors ameliorate effects. In the Project Viva cohort (N = 484; 50% female), we used sex-stratified linear regression and quantile g-computation mixture models to examine associations of mid-childhood (median: 7.8 years; 2007-2010) plasma PFAS concentrations with a dual-energy X-ray absorptiometry total-body aBMD Z-score in early and late adolescence (median: 12.9 and 17.6 years, respectively). We explored stratum-specific estimates by parent/self-reported physical activity and dairy intake. Using linear mixed models, we evaluated associations with aBMD accrual from mid-childhood through late adolescence. Females with higher perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) had lower early adolescent aBMD Z-score [e.g., β(95%CI)] per doubling PFOA: -0.19(-0.41, 0.03)]. Youth with higher PFOA and PFDA had lower late adolescent aBMD Z-score, but CIs were wide [e.g., PFOA: females, -0.12(-0.40, 0.16); males, -0.10(-0.42, 0.21)]. Mixture models generally corroborated single PFAS results, and in linear mixed models, females with higher PFAS concentrations, and males with higher PFOA, had slower aBMD accrual. Less active males with higher PFOA, PFDA, and the PFAS mixture had lower late adolescent aBMD Z-score. Some PFAS appeared more negatively associated with the aBMD Z-score among those who consumed less dairy, but there was not consistent evidence of effect modification. Exposure to select PFAS may affect bone accrual through adolescence, with possible resilience conferred by greater physical activity and dairy intake.

BACKGROUND: Individual immune responses to SARS-CoV-2 are well-studied, while the combined effect of these responses on population-level immune dynamics remains poorly understood. Given the key role of population immunity on pathogen transmission, delineation of the factors that drive population immune evolution has critical public health implications. METHODS: We enrolled individuals 5 years and older selected using a multistage cluster survey approach in the Northwest and Southeast of the Dominican Republic. Paired blood samples were collected mid-pandemic (Aug 2021) and late pandemic (Nov 2022). We measured serum pan-immunoglobulin antibodies against the SARS-CoV-2 spike protein. Generalized Additive Models (GAMs) and random forest models were used to analyze the relationship between changes in antibody levels and various predictor variables. Principal component analysis and partial dependence plots further explored the relationships between predictors and antibody changes. FINDINGS: We found a transformation in the distribution of antibody levels from an irregular to a normalized single peak Gaussian distribution that was driven by titre-dependent boosting. This led to the convergence of antibody levels around a common immune setpoint, irrespective of baseline titres and vaccination profile. INTERPRETATION: Our results suggest that titre-dependent kinetics driven by widespread transmission direct the evolution of population immunity in a consistent manner. These findings have implications for targeted vaccination strategies and improved modeling of future transmission, providing a preliminary blueprint for understanding population immune dynamics that could guide public health and vaccine policy for SARS-CoV-2 and potentially other pathogens. FUNDING: The study was primarily funded by the Centers for Disease Control and Prevention grant U01GH002238 (EN). Salary support was provided by Wellcome Trust grant 206250/Z/17/Z (AK) and the Australian National Health and Medical Research Council Investigator grant APP1158469 (CLL).

The ultimate goal of value-based laboratory medicine is maximizing the effectiveness of laboratory tests in improving patient outcomes, optimizing resources and minimizing unnecessary costs. This approach abandons the oversimplified notion of test volume and cost, in favor of emphasizing the clinical utility and quality of diagnostic tests in the clinical decision-making. Several key elements characterize value-based laboratory medicine, which can be summarized in some basic concepts, such as organization of in vitro diagnostics (including appropriateness, integrated diagnostics, networking, remote patient monitoring, disruptive innovations), translation of laboratory data into clinical information and measurable outcomes, sustainability, reimbursement, ethics (e.g., patient empowerment and safety, data protection, analysis of big data, scientific publishing). Education and training are also crucial, along with considerations for the future of the profession, which will be largely influenced by advances in automation, information technology, artificial intelligence, and regulations concerning in vitro diagnostics. This collective opinion paper, composed of summaries from presentations given at the two-day European Federation of Laboratory Medicine (EFLM) Strategic Conference "A vision to the future: value-based laboratory medicine" (Padova, Italy; September 23-24, 2024), aims to provide a comprehensive overview of value-based laboratory medicine, projecting the profession into a more clinically effective and sustainable future.

BACKGROUND: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. OBJECTIVES: To estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. METHODS: In 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters - adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. RESULTS: We collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity - compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. CONCLUSION: Early pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

BACKGROUND: Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance. METHODS: Data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics. RESULTS: This dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014. DISCUSSION (CONCLUSION): The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

OBJECTIVES: The Multi-State EHR-Based Network for Disease Surveillance (MENDS) is a population-based chronic disease surveillance distributed data network that uses institution-specific extraction-transformation-load (ETL) routines. MENDS-on-FHIR examined using Health Language Seven's Fast Healthcare Interoperability Resources (HL7(®) FHIR(®)) and US Core Implementation Guide (US Core IG) compliant resources derived from the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) to create a standards-based ETL pipeline. MATERIALS AND METHODS: The input data source was a research data warehouse containing clinical and administrative data in OMOP CDM Version 5.3 format. OMOP-to-FHIR transformations, using a unique JavaScript Object Notation (JSON)-to-JSON transformation language called Whistle, created FHIR R4 V4.0.1/US Core IG V4.0.0 conformant resources that were stored in a local FHIR server. A REST-based Bulk FHIR $export request extracted FHIR resources to populate a local MENDS database. RESULTS: Eleven OMOP tables were used to create 10 FHIR/US Core compliant resource types. A total of 1.13 trillion resources were extracted and inserted into the MENDS repository. A very low rate of non-compliant resources was observed. DISCUSSION: OMOP-to-FHIR transformation results passed validation with less than a 1% non-compliance rate. These standards-compliant FHIR resources provided standardized data elements required by the MENDS surveillance use case. The Bulk FHIR application programming interface (API) enabled population-level data exchange using interoperable FHIR resources. The OMOP-to-FHIR transformation pipeline creates a FHIR interface for accessing OMOP data. CONCLUSION: MENDS-on-FHIR successfully replaced custom ETL with standards-based interoperable FHIR resources using Bulk FHIR. The OMOP-to-FHIR transformations provide an alternative mechanism for sharing OMOP data.

BACKGROUND: The global campaign for "Undetectable equals Untransmittable" (U = U) seeks to spread awareness of HIV treatment as prevention, aiming to enhance psychological well-being and diminish stigma. Despite its potential benefits, U = U faces challenges in Sub-Saharan Africa, with low awareness and hesitancy to endorse it. We sought to develop a U = U communications intervention to support HIV counselling in primary healthcare settings in South Africa. METHODS: We used Intervention Mapping (IM), a theory-based framework to develop the "Undetectable and You" intervention for the South African context. The six steps of the IM protocol were systematically applied to develop the intervention including a needs assessment consisting of a systematic review and qualitative research including focus group discussions (FGD) and key informant (KI) interviews. Program objectives and target population were determined before designing the intervention components and implementation plan. RESULTS: The needs assessment indicated low global U = U awareness, especially in Africa, and scepticism about its effectiveness. Lay counsellors and clinic managers stressed the need for a simple and standardized presentation of U = U addressing both patients' needs for encouragement and modelling of U = U success but also clear guidance toward ART adherence behaviour. Findings from each step of the process informed successive steps. Our final intervention consisted of personal testimonials of PLHIV role models and their partners, organized as an App to deliver U = U information to patients in primary healthcare settings. CONCLUSIONS: We outline an intervention development strategy, currently in evaluation stage, utilizing IM with formative research and input from key U = U stakeholders and people living with HIV (PLHIV).

INTRODUCTION: ultimately detected in 2016, wild poliovirus (WPV) transmission continued undetected after 2011 in Northeast Nigeria Borno and Yobe States in security-compromised areas, inaccessible due to armed insurgency. Varying inaccessibility prevented children aged <5 years in these areas from polio vaccination interventions and surveillance, while massive population displacements occurred. We examined progress in access over time to provide data supporting a very low probability of undetected WPV circulation within remaining trapped populations after 2016. METHODS: to assess the extent of inaccessibility in security-compromised areas, we obtained empirical historical data in 2020 on a quarterly and annual basis from relevant polio eradication staff for the period 2010-2020. The extent of access to areas for immunization by recall was compared to geospatial data from vaccinator tracking. Population estimates over time in security-compromised areas were extracted from satellite imagery. We compared the historical access data from staff with tracking and population esimates. RESULTS: access varied during 2010-2020, with inaccessibility peaking during 2014-2016. We observed concurrent patterns between historical recalled data on inaccessibility and contemporaneous satellite imagery on population displacements, which increased confidence in the quality of recalled data. CONCLUSION: staff-recalled access was consistent with vaccinator tracking and satellite imagery of population displacments. Despite variability in inaccessibility over time, innovative immunization initiatives were implemented as access allowed and surveillance initiatives were initiated to search for poliovirus transmission. Along with escape and liberation of residents by the military in some geographic areas, these initiatives resulted in a massive reduction in the size of the unvaccinated population remaining resident.

Newborn screening (NBS), a comprehensive system that includes testing, diagnosis, follow-up, treatment, education, and evaluation, was recently named one of the Top 10 Great Public Health Achievements by the Centers for Disease Control and Prevention (CDC).1 Each year, approximately 10,000 infants are identified with NBS conditions, which frequently go unnoticed at birth.2 NBS is administered by state public health programs across the country and provides for early identification of newborns with certain congenital, metabolic, endocrine, hematologic, and other genetic conditions. Early identification of these conditions in newborns facilitates timely interventions that result in significant decreases in morbidity, mortality, and disability.1 | | Screening begins by pricking a newborn's heel to get enough blood to fill a few circles on a filter paper card. The specimen, referred to as a dried blood spot, is collected by a health-care provider—typically at the birthing facility—during the first 24–48 hours of life. Some states are required to collect two specimens, in which case the second specimen is collected between seven and 15 days of life. The specimens are then sent to a state-designated NBS laboratory for analysis. When a test result is out of normal range, laboratory or follow-up personnel contact the birthing facility and the newborn's physician to ensure the child receives the appropriate diagnostic work-up and treatment. NBS goes beyond blood-spot screening to include point-of-care testing for hearing and, in some states, critical congenital heart disease. These tests are performed at the hospital shortly after birth, and the state NBS program performs follow-up testing. Although there is some variability in protocols among states, most NBS programs have similar components, including specimen collection, laboratory testing, follow-up, education of providers and the public, verification of a diagnosis, treatment, and ongoing program evaluation.3

PURPOSE: We evaluated a template for molecular genetic test reports that was developed as a strategy to reduce communication errors between the laboratory and ordering clinician. METHODS: We surveyed 1,600 primary care physicians to assess satisfaction, ease of use, and effectiveness of genetic test reports developed using our template and reports developed by clinical laboratories. Mean score differences of responses between the reports were compared using t-tests. Two-way analysis of variance evaluated the effect of template versus standard reports and the influence of physician characteristics. RESULTS: There were 396 (24%) respondents. Template reports had higher scores than the standard reports for each survey item. The gender and specialty of the physician did not influence scores; however, younger physicians gave higher scores regardless of report type. There was significant interaction between report type and whether physicians ordered or reviewed any genetic tests (none versus at least one) in the past year, P = 0.005. CONCLUSION: For each survey item assessing satisfaction, ease of use, and effectiveness, physicians gave higher ratings to genetic test reports developed with the template than standard reports used by clinical laboratories. Physicians least familiar with genetic test reports, and possibly having the greatest need for better communication, were best served by the template reports.

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.

CONTEXT: Electronic health records (EHRs) are an emerging chronic disease surveillance data source and facilitating this data sharing is complex. PROGRAM: Using the experience of the Multi-State EHR-Based Network for Disease Surveillance (MENDS), this article describes implementation of a governance framework that aligns technical, statutory, and organizational requirements to facilitate EHR data sharing for chronic disease surveillance. IMPLEMENTATION: MENDS governance was cocreated with data contributors and health departments representing Texas, New Orleans, Louisiana, Chicago, Washington, and Indiana through engagement from 2020 to 2022. MENDS convened a governance body, executed data-sharing agreements, and developed a master governance document to codify policies and procedures. RESULTS: The MENDS governance committee meets regularly to develop policies and procedures on data use and access, timeliness and quality, validation, representativeness, analytics, security, small cell suppression, software implementation and maintenance, and privacy. Resultant policies are codified in a master governance document. DISCUSSION: The MENDS governance approach resulted in a transparent governance framework that cultivates trust across the network. MENDS's experience highlights the time and resources needed by EHR-based public health surveillance networks to establish effective governance.

Identification of enteric bacteria species by whole genome sequence (WGS) analysis requires a rapid and an easily standardized approach. We leveraged the principles of average nucleotide identity using MUMmer (ANIm) software, which calculates the percent bases aligned between two bacterial genomes and their corresponding ANI values, to set threshold values for determining species consistent with the conventional identification methods of known species. The performance of species identification was evaluated using two datasets: the Reference Genome Dataset v2 (RGDv2), consisting of 43 enteric genome assemblies representing 32 species, and the Test Genome Dataset (TGDv1), comprising 454 genome assemblies which is designed to represent all species needed to query for identification, as well as rare and closely related species. The RGDv2 contains six Campylobacter spp., three Escherichia/Shigella spp., one Grimontia hollisae, six Listeria spp., one Photobacterium damselae, two Salmonella spp., and thirteen Vibrio spp., while the TGDv1 contains 454 enteric bacterial genomes representing 42 different species. The analysis showed that, when a standard minimum of 70% genome bases alignment existed, the ANI threshold values determined for these species were ≥95 for Escherichia/Shigella and Vibrio species, ≥93% for Salmonella species, and ≥92% for Campylobacter and Listeria species. Using these metrics, the RGDv2 accurately classified all validation strains in TGDv1 at the species level, which is consistent with the classification based on previous gold standard methods.

Urinary and intestinal schistosomiasis are endemic in Senegal, with prevalence heterogeneous throughout the country. Because of their way of life, nomadic pastoralists are not typically included in epidemiological surveys, and data on the prevalence of schistosomiasis in Senegalese nomadic populations are largely non-existent. The purpose of this study was to determine the seroprevalence of schistosomiasis in Senegalese nomadic pastoralists. A modified snowball sampling survey was conducted among 1,467 nomadic pastoralists aged 6 mo and older in 5 districts in northern Senegal. Dried blood spots from participants of all ages and data regarding demographics were collected to assess IgG antibody responses against Schistosoma mansoni soluble egg antigen (SEA) using a bead-based multiplex assay. Out of 1,467 study subjects, 1,464 (99.8%) provided IgG serological data that cleared quality assurance. Of the participants with appropriate data, 56.6% were male, the median age was 22 yr, and 31.6% were under 15 yr of age. The overall anti-SEA IgG seroprevalence was 19.1% (95% confidence interval [CI]: 17.1-21.1%) with the highest estimates observed in Dagana (35.9%) and the lowest observed in Podor nomadic groups (3.4%). Antibody responses increased significantly with age except for the oldest age groups (>40 yr of age), which saw lower levels of antibody response compared to younger adults. When controlling for age and location by multivariate regression, the male sex was associated with a 2-fold greater odds of anti-SEA IgG seropositivity (aPOR: 2.0; 95% CI: 1.5-2.7). Serosurveys for anti-SEA IgG among nomadic peoples in northern Senegal found a substantial percentage of individuals with evidence for current or previous Schistosoma spp. infection with the highest levels of exposure in the district adjacent to the Diama dam along the Senegal River. With IgG prevalence increased by age except in the older adults, and the male sex significantly associated with seropositivity, these data point toward sex-associated behavioral practices and human environmental modification as risk factors for Schistosoma exposure.

We here analyze data from the first year of an ongoing nationwide program of genetic surveillance of Plasmodium falciparum parasites in Senegal. The analysis is based on 1097 samples collected at health facilities during passive malaria case detection in 2019; it provides a baseline for analyzing parasite genetic metrics as they vary over time and geographic space. The study's goal was to identify genetic metrics that were informative about transmission intensity and other aspects of transmission dynamics, focusing on measures of genetic relatedness between parasites. We found the best genetic proxy for local malaria incidence to be the proportion of polygenomic infections (those with multiple genetically distinct parasites), although this relationship broke down at low incidence. The proportion of related parasites was less correlated with incidence while local genetic diversity was uninformative. The type of relatedness could discriminate local transmission patterns: two nearby areas had similarly high fractions of relatives, but one was dominated by clones and the other by outcrossed relatives. Throughout Senegal, 58% of related parasites belonged to a single network of relatives, within which parasites were enriched for shared haplotypes at known and suspected drug resistance loci and at one novel locus, reflective of ongoing selection pressure.

Salmonella enterica is a leading cause of bacterial foodborne and zoonotic illnesses in the United States. For this study, we applied four different whole genome sequencing (WGS)-based subtyping methods: high quality single-nucleotide polymorphism (hqSNP) analysis, whole genome multilocus sequence typing using either all loci [wgMLST (all loci)] and only chromosome-associated loci [wgMLST (chrom)], and core genome multilocus sequence typing (cgMLST) to a dataset of isolate sequences from 9 well-characterized Salmonella outbreaks. For each outbreak, we evaluated the genomic and epidemiologic concordance between hqSNP and allele-based methods. We first compared pairwise genomic differences using all four methods. We observed discrepancies in allele difference ranges when using wgMLST (all loci), likely caused by inflated genetic variation due to loci found on plasmids and/or other mobile genetic elements in the accessory genome. Therefore, we excluded wgMLST (all loci) results from any further comparisons in the study. Then, we created linear regression models and phylogenetic tanglegrams using the remaining three methods. K-means analysis using the silhouette method was applied to compare the ability of the three methods to partition outbreak and sporadic isolate sequences. Our results showed that pairwise hqSNP differences had high concordance with cgMLST and wgMLST (chrom) allele differences. The slopes of the regressions for hqSNP vs. allele pairwise differences were 0.58 (cgMLST) and 0.74 [wgMLST (chrom)], and the slope of the regression was 0.77 for cgMLST vs. wgMLST (chrom) pairwise differences. Tanglegrams showed high clustering concordance between methods using two statistical measures, the Baker's gamma index (BGI) and cophenetic correlation coefficient (CCC), where 9/9 (100%) of outbreaks yielded BGI values ≥ 0.60 and CCCs were ≥ 0.97 across all nine outbreaks and all three methods. K-means analysis showed separation of outbreak and sporadic isolate groups with average silhouette widths ≥ 0.87 for outbreak groups and ≥ 0.16 for sporadic groups. This study demonstrates that Salmonella isolates clustered in concordance with epidemiologic data using three WGS-based subtyping methods and supports using cgMLST as the primary method for national surveillance of Salmonella outbreak clusters.

OBJECTIVE: A 2015 survey of primary care providers (PCPs) found that while many believed that milliliter (mL)-only dosing was safest for oral liquid medications, few would use mL alone in dosing instructions. Since 2015, many recommendations have promoted "mL-only" dosing. In 2019, a follow-up survey was conducted to assess if PCP perceptions and practices have changed. METHODS: Pediatricians, family medicine physicians, nurse practitioners, and internists participating in the 2015 and 2019 DocStyles cross-sectional, web-based surveys were asked about their perceptions and practices regarding dosing units for oral liquid medications. RESULTS: In 2019, among 1392 respondents, the proportion of PCPs who reported they believed using mL-only is the safest dosing instruction ranged from 55.1% of internists to 80.8% of pediatricians. While fewer PCPs believed patients/caregivers prefer dosing instructions in mL-only (23.9% of nurse practitioners to 48.4% of pediatricians), more held this belief in 2019 compared to 2015; pediatricians had the greatest absolute increase (+14.4%) and family medicine physicians had the smallest increase (+1.3%). While 61.6% of pediatricians reported they would use mL-only dosing, only 36.0% of internists, 36.6% of nurse practitioners, and 42.5% of family medicine physicians reported they would do so. After controlling for age, gender, region, and specialty, 2019 PCP survey participants were more likely to report that they would use mL-only dosing compared to 2015 participants (adjusted odds ratio 1.51, 95% confidence interval 1.29-1.77). CONCLUSIONS: Broader educational efforts may be necessary to reach non-pediatricians, to encourage prescribing and communication with patients/caregivers using mL-only dosing.

The goal of this article is to describe an integrated parallel process for the co-development of written and computable clinical practice guidelines (CPGs) to accelerate adoption and increase the impact of guideline recommendations in clinical practice. From February 2018 through December 2021, interdisciplinary work groups were formed after an initial Kaizen event and using expert consensus and available literature, produced a 12-phase integrated process (IP). The IP includes activities, resources, and iterative feedback loops for developing, implementing, disseminating, communicating, and evaluating CPGs. The IP incorporates guideline standards and informatics practices and clarifies how informaticians, implementers, health communicators, evaluators, and clinicians can help guideline developers throughout the development and implementation cycle to effectively co-develop written and computable guidelines. More efficient processes are essential to create actionable CPGs, disseminate and communicate recommendations to clinical end users, and evaluate CPG performance. Pilot testing is underway to determine how this IP expedites the implementation of CPGs into clinical practice and improves guideline uptake and health outcomes.

Clinical practice guidelines (CPGs) support individual and population health by translating new, evidence-based knowledge into recommendations for health practice. CPGs can be provided as computable, machine-readable guidelines that support the translation of recommendations into shareable, interoperable clinical decision support and other digital tools (eg, quality measures, case reports, care plans). Interdisciplinary collaboration among guideline developers and health information technology experts can facilitate the translation of written guidelines into computable ones. The benefits of interdisciplinary work include a focus on the needs of end-users who apply guidelines in practice through clinic decision support systems as part of the Centers for Disease Control and Prevention's (CDC's) Adapting Clinical Guidelines for the Digital Age (ACG) initiative, a group of interdisciplinary experts proposed a process to facilitate the codevelopment of written and computable CPGs, referred to as the "integrated process (IP)."1 This paper presents a framework for evaluating the IP based on a combination of vetted evaluation models and expert opinions. This framework combines 3 types of evaluations: process, product, and outcomes. These evaluations assess the value of interdisciplinary expert collaboration in carrying out the IP, the quality, usefulness, timeliness, and acceptance of the guideline, and the guideline's health impact, respectively. A case study is presented that illustrates application of the framework.

Most efforts to understand the biology of Vibrio cholerae have focused on a single group, the pandemic-generating lineage harbouring the strains responsible for all known cholera pandemics. Consequently, little is known about the diversity of this species in its native aquatic environment. To understand the differences in the V. cholerae populations inhabiting in regions with varying history of cholera cases and how that might influence the abundance of pandemic strains, a comparative analysis of population composition was performed. Little overlap was found in lineage compositions between those in Dhaka (cholera endemic) located in the Ganges delta, and of Falmouth (no known history of cholera), a small coastal town on the US East Coast. The most striking difference was the presence of a group of related lineages at high abundance in Dhaka which was completely absent from Falmouth. Phylogenomic analysis revealed that these lineages form a cluster at the base of the phylogeny of V. cholerae species, sufficiently differentiated genetically and phenotypically to form a novel species. Strains from this species have been anecdotally isolated from around the world and were isolated as early as 1916 from a British soldier in Egypt suffering from choleraic diarrhoea. In 1935 Gardner and Venkatraman unofficially referred to a member of this group as Vibrio paracholerae. In recognition of this earlier designation, we propose the name Vibrio paracholerae, sp. nov. for this bacterium. Genomic analysis suggests a link with human populations for this novel species and substantial interaction with its better-known sister species.Importance Cholera continues to remain a major public health threat around the globe. Understanding the ecology, evolution and environmental adaptation of the causative agent Vibrio cholerae and tracking the emergence of novel lineages with pathogenic potential are essential to combat the problem. In this study, we investigated the population dynamics of Vibrio cholerae in an inland locality which is known as endemic for cholera and compared with that of a cholera free coastal location. We found the consistent presence of the pandemic generating V. cholerae in cholera-endemic Dhaka and an exclusive presence of a lineage phylogenetically distinct from other V. cholerae. Our study suggests that this lineage represents a novel species having pathogenic potential and a human link to its environmental abundance. The possible association with human population, co-existence and interaction with toxigenic V. cholerae in the natural environment make this potential human pathogen an important subject for future studies.Competing Interest StatementThe authors have declared no competing interest.

Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.Competing Interest StatementThe authors have declared no competing interest.Funding StatementClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: U41HG006834, U41HG009649, U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the following three grants: U24HD093483, U24HD093486, U24HD093487.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study did not involve human subjects and therefore no IRB was required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is included in the figures, tables and supplement included in the manuscript.

The design and execution of rigorous, fast, and ethical vaccine efficacy trials can be challenging during epidemics of emerging pathogens, such as the 2014-2016 Ebola virus and 2015-2016 Zika virus epidemics. Response to an urgent public health crisis requires accelerated research even as emerging epidemics themselves change rapidly and are inherently less well understood than well-established diseases. As part of the World Health Organization Research and Development Blueprint, we designed a web-based interactive decision support system (InterVax-Tool) to help diverse stakeholders navigate the epidemiological, logistical, and ethical decisions involved in designing a vaccine efficacy trial during a public health emergency. In contrast to existing literature on trial design, InterVax-Tool offers high-level visual and interactive assistance through a set of four decision trees, guiding users through selection of 1) the Primary Endpoint, (2) the Target Population, (3) Randomization, and (4) the Comparator. Guidance is provided on how each of fourteen key considerations–grouped as Epidemiological, Vaccine-related, Infrastructural, or Sociocultural–should be used to inform each decision in the trial design process. The tool is not intended to provide a black box decision framework for identifying an optimal trial design, but rather to facilitate transparent, collaborative and comprehensive discussion of the relevant decisions, while recording the decision process. The tool can also assist capacity building by providing a cross-disciplinary picture of trial design using concepts from epidemiology, study design, vaccinology, biostatistics, mathematical modeling and clinical research ethics. Here, we describe the goals and features of InterVax-Tool as well as its application to the design of a Zika vaccine efficacy trial.One Sentence Summary An interactive web-based decision support tool was developed to assist in the design of vaccine efficacy trials during emerging outbreaks.

The global SARS-CoV-2 immune landscape and population protection against emerging variants is largely unknown. We assessed SARS-CoV-2 antibody changes in the Dominican Republic and implications for immunological protection against variants of concern. Between March 2021 and August 2022, 2,300 patients with undifferentiated febrile illnesses were prospectively enrolled. Sera was tested for total anti-spike antibodies and simultaneously collected nasopharyngeal samples for acute SARSCoV-2 infection with RT-PCR. Geometric mean anti-spike titers increased from 6.6 BAU/ml (95% CI 5.1-8.7) to 1,332 BAU/ml (1055-1,682). Multivariable binomial odds ratios for acute SARS-CoV-2 infection were 0.55 (0.40-0.74), 0.38 (0.27-0.55), and 0.27 (0.18-0.40) for the second, third, and fourth versus the first anti-S quartile, with similar findings by viral strain. Integrated serological and virological screening can leverage existing acute fever surveillance platforms to monitor population-level immunological markers and concurrently characterize implications for emergent variant transmission in near real-time. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. We analyzed data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasite strains in Senegal to determine how historical changes in drug administration policy may have affected parasite evolution. We profiled several known drug resistance markers and their surrounding haplotypes using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole-genome sequence (WGS) based population genomics. We observed rapid changes in drug resistance markers associated with the withdrawal of chloroquine and introduction of sulfadoxine-pyrimethamine in 2003. We also observed a rapid increase in Pfcrt K76T and decline in Pfdhps A437G starting in 2014, which we hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC). Parasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Over 230,000 COVID-19 cases and over 2,200 deaths have been reported in Mozambique though May 2023. Understanding community members' knowledge of SARS-CoV-2 transmission and prevention is essential for directing public health interventions to reduce disease spread and improve vaccination coverage. Here, we describe knowledge of COVID-19 transmission, prevention, and symptoms among community residents in Mozambique. We conducted a cross-sectional survey among 33,087 households in a Health and Demographic Surveillance System in Manhica, Mozambique. Participants were recruited at the tail end of the Delta variant wave in September 2021 to the peak of Omicron cases in January 2022. Principal components analysis was used to create scores representing knowledge of COVID-19 symptoms, transmission, and prevention. Multiple imputation and quasi-Poisson regression were used to examine associations between demographic characteristics and sources of COVID-19 information, and knowledge of COVID-19 symptoms, transmission, and prevention. We examined whether sources of COVID-19 information mediated the relationship between educational attainment and knowledge of symptoms, transmission, and prevention. Across this rural community, 98.2%, 97.0%, and 85.1% of respondents reported knowing how COVID-19 could be prevented, that SARS-CoV-2 can cause disease, and how SARS-CoV-2 is transmitted, respectively. Most cited symptoms were cough (51.2%), headaches (44.9%), and fever (44.5%); transmission mechanisms were droplets (50.5%) or aerosol (<5 microm diameter) (46.9%) from an infected person; and prevention measures were handwashing (91.9%) and mask-wearing (91.8%). Characteristics associated with greater knowledge of symptoms, transmission, and prevention included having at least primary education, older age, employment, higher wealth, and Christian religion. Respondents who had had COVID-19 symptoms were also more likely to have knowledge of symptoms, transmission, and prevention. Gathering information from TV, WhatsApp, radio, and hospital mediated the relationship between educational attainment and knowledge scores. These findings support the need for outreach and for community-engaged messaging to promote prevention measures, particularly among people with low education. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

A number of bacteria with close resemblance to Vibrio cholerae has been isolated over the years by the Centers for Disease Control and Prevention (CDC), which could not be assigned a proper taxonomic designation based on preliminary identification methods. Nine such isolates have been found to share 16S rRNA gene identity exceeding 99% with V. cholerae, yet DNA-DNA hybridization (60.4-62.1%) and average nucleotide identity values (94.4-95.1%) were below the species cut-off, indicating a potentially novel species. Phylogenetic analysis of core genomes places this group of isolates in a monophyletic clade, within the "Cholerae clade," but distinct from any other species. Extensive phenotypic characterization reveals unique biochemical properties that distinguish this novel species from V. cholerae. Comparative genomic analysis reveals a unique set of siderophore genes, suggesting that iron acquisition strategies could be vital for the divergence of the novel species from a common ancestor with V. cholerae. Based on genetic, phylogenetic, and phenotypic differences observed, we propose these isolates represent a novel species of the genus Vibrio, for which the name Vibrio tarriae sp. nov. is proposed. Strain 2521-89 (= DSM 112461 = CCUG 75318), isolated from lake water, is the type strain. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Parasite genetic surveillance has the potential to play an important role in malaria control. We describe here an analysis of data from the first year of an ongoing, nationwide program of genetic surveillance of Plasmodium falciparum parasites in Senegal, intended to provide actionable information for malaria control efforts. Looking for a good proxy for local malaria incidence, we found that the best predictor was the proportion of polygenomic infections (those with multiple genetically distinct parasites), although that relationship broke down at very low incidence. The proportion of closely related parasites in a site was more weakly correlated with incidence while the local genetic diversity was uninformative. Study of related parasites indicated their potential for discriminating local transmission patterns: two nearby study areas had similarly high fractions of relatives, but one area was dominated by clones and the other by outcrossed relatives. Throughout the country, most related parasites proved to belong to a single network of relatives, within which parasites were enriched for shared haplotypes at known and suspected drug resistance loci as well as at one novel locus, reflective of ongoing selection pressure. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.