METHODS: Outpatient hemodialysis facilities report BSI events to NHSN. Pooled mean rates with 95% CI were calculated overall and for each type of vascular access (arteriovenous (AV) fistula, AV graft, or a central venous catheter (CVC)). Standardized infection ratios were calculated as observed BSI events divided by the predicted number of events based on national aggregate data. Median facility-level standardized infection ratios and 95% confidence intervals (CIs) were stratified by state and US territory. RESULTS: During 2020, 7,183 outpatient hemodialysis facilities reported data for 5,235,234 patient months with 15,181 BSI events. Pooled mean rates per 100 person-months were 0.29 (95% CI, 0.29-0.30) overall, 0.80 (95% CI, 0.78-0.82) for CVC, 0.12 (95% CI, 0.12-0.12) for AV fistula, 0.21 (95% CI, 0.20-0.22) for AV graft, and 0.28 (95% CI, 0.19-0.40) for other access types. The national standardized infection ratio was 0.40 (95% CI, 0.39-0.41). South Dakota had a standardized infection ratio significantly higher than one (1.34; 95% CI, 1.11 - 1.62). Fifty-one of 54 states and territories had BSI standardized infection ratio significantly lower than one. CONCLUSIONS: In 2020, the median standardized infection ratio for BSI in US outpatient hemodialysis facilities was lower than predicted overall and in almost all states and territories. An elevated standardized infection ratio was identified in South Dakota.

Monitoring trachoma transmission with antibody data requires characterization of decay in IgG to Chlamydia trachomatis antigens. In a three-year longitudinal cohort in a high transmission setting, we estimated a median IgG half-life of 3 years and a seroreversion rate of 2.5 (95% CI: 1.6, 3.5) per 100 person-years.

PURPOSE: Population-based prevalence surveys are essential for decision-making on interventions to achieve trachoma elimination as a public health problem. This paper outlines the methodologies of Tropical Data, which supports work to undertake those surveys. METHODS: Tropical Data is a consortium of partners that supports health ministries worldwide to conduct globally standardised prevalence surveys that conform to World Health Organization recommendations. Founding principles are health ministry ownership, partnership and collaboration, and quality assurance and quality control at every step of the survey process. Support covers survey planning, survey design, training, electronic data collection and fieldwork, and data management, analysis and dissemination. Methods are adapted to meet local context and needs. Customisations, operational research and integration of other diseases into routine trachoma surveys have also been supported. RESULTS: Between 29(th) February 2016 and 24(th) April 2023, 3373 trachoma surveys across 50 countries have been supported, resulting in 10,818,502 people being examined for trachoma. CONCLUSION: This health ministry-led, standardised approach, with support from the start to the end of the survey process, has helped all trachoma elimination stakeholders to know where interventions are needed, where interventions can be stopped, and when elimination as a public health problem has been achieved. Flexibility to meet specific country contexts, adaptation to changes in global guidance and adjustments in response to user feedback have facilitated innovation in evidence-based methodologies, and supported health ministries to strive for global disease control targets.

Persons receiving maintenance dialysis are at increased risk for SARS-CoV-2 infection and its severe outcomes, including death. However, rates of SARS-CoV-2 infection and COVID-19-related deaths in this population are not well described. Since November 2020, CDC's National Healthcare Safety Network (NHSN) has collected weekly data monitoring incidence of SARS-CoV-2 infections (defined as a positive SARS-CoV-2 test result) and COVID-19-related deaths (defined as the death of a patient who had not fully recovered from a SARS-CoV-2 infection) among maintenance dialysis patients. This analysis used NHSN dialysis facility COVID-19 data reported during June 30, 2021-September 27, 2022, to describe rates of SARS-CoV-2 infection and COVID-19-related death among maintenance dialysis patients. The overall infection rate was 30.47 per 10,000 patient-weeks (39.64 among unvaccinated patients and 27.24 among patients who had completed a primary COVID-19 vaccination series). The overall death rate was 1.74 per 10,000 patient-weeks. Implementing recommended infection control measures in dialysis facilities and ensuring patients and staff members are up to date with recommended COVID-19 vaccination is critical to limiting COVID-19-associated morbidity and mortality.

Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. Certain areas, particularly in Africa, pose persistent challenges to elimination of trachoma as a public health problem. Efficiently identifying communities with high infection burden could help target more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. We used measurements from 40 communities in the hyperendemic Amhara region of Ethiopia. Median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment to 29% by month 36. At baseline, correlation between seroprevalence and Ct infection was stronger among children 0-5 years old (ρ = 0.77) than children 6-9 years old (ρ = 0.48), and stronger than the correlation between clinical trachoma and Ct infection (0-5y ρ = 0.56; 6-9y ρ = 0.40). Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be an objective, programmatic tool for identifying communities with high levels of active ocular Ct infections, but accurate, future prediction in the context of changing transmission remains an open challenge.SIGNIFICANCE STATEMENT Trachoma is targeted for elimination as a public health problem by 2030. District-level estimates of clinical disease among children 1-9 years old are currently used to guide control programs and assess elimination. However, clinical trachoma is a subjective indicator. Serological markers present an objective, scalable alternative that could be measured in integrated platforms. In a hyperendemic region, community-level seroprevalence aligned more closely with concurrent infection prevalence than clinical trachoma. The correlation between seroprevalence and infection prevalence was stronger among 0–5-year-olds compared to 6–9-year-olds and was consistent over a three-year period of increasing transmission. Serosurveillance among children 0-5 years old may be a promising monitoring strategy to identify communities with the highest burdens of ocular chlamydial infection.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT02754583Funding StatementWe would like to thank the WUHA study participants and field team without whom this research would not be possible. This work was supported by the National Institute of Allergy and Infectious Diseases (R03 AI147128 to BFA) and the National Eye Institute (U10 EY023939 to JDK). This work was also made possible in part by an Unrestricted Grant from Research to Prevent Blindness. We would also like to thank Abbott for its donation of the m2000 RealTime molecular diagnostics system and consumables.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:Approval for the study was obtained from the University of California, San Francisco Institutional Review Board (14-14004).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.YesDe-identified data and code to replicate this work is available on Github. https://github.com/ctedijanto/swift-spatial-prediction

Background The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality. Additional endpoints in the trial have attempted to elucidate the mechanisms for mortality reduction. In this pre-specified secondary analysis, we assessed the effect of azithromycin compared with placebo on IgG- based measures of infectious disease exposure with a multiplex bead assay that included antigens to malaria parasites (Plasmodium falciparum, P. vivax, P. malariae, P. ovale), bacterial pathogens (Campylobacter spp., enterotoxigenic Escherichia coli, Vibrio cholerae, Salmonella enterica, Streptococcus pyogenes) and protozoans (Cryptosporidium parvum, Giardia duodenales).Methods and Findings Thirty communities in rural Niger were randomized 1:1 to biannual distributions of azithromycin or placebo among children ages 1-59 months. The analysis included 5,642 blood specimens collected from 3,814 children ages 1-59 months, measured at 6, 12, 24, and 36 months of follow-up in a repeated cross-sectional design. Campylobacter spp. seroprevalence averaged over all study visits was lower in azithromycin communities compared to placebo (91% vs 94%, difference = –3%, 95% CI: –5%, –1%; P=0.03), which corresponded to a 29% lower seroconversion rate (1.30 versus 1.84 seroconversions per year, hazard ratio = 0.71, 95% CI: 0.56, 0.89; P=0.004). Antibody-based measures of infection with P. falciparum and group A streptococcus were consistently lower in azithromycin communities, but were not statistically different from placebo, and there were no other differences across pathogens. Strengths of the study included masking of participants, investigators, and analysts, high treatment coverage, large sample size, and objective outcomes. Principal limitations included the timing of blood collection with respect to treatment (approximately 6 months later, which could have missed transient effects in the weeks immediately following treatment), and the durability of IgG response following clearance of infection. Both limitations would lead the trial to under-estimate effects on antibody-based measures of infection.Conclusions The reduction in Campylobacter spp. despite these limitations suggests an effect on carriage, findings which align with an independent metagenomic analysis of rectal swabs collected in the same villages and with previously reported reductions in dysentery-associated mortality. Given significant sequelae of Campylobacter infection among preschool aged children, our results support at least one possible mechanism through which biannual mass distribution of azithromycin likely reduced mortality in this study population.Competing Interest StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data analysis, data interpretation, or writing of the report. The authors declare no competing interests. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services. Clinical TrialNCT02048007Funding StatementThis work was supported by the Bill & Melinda Gates Foundation (award no. OPP1032340 to TML) and was supported in part by an unrestricted grant from Research to Prevent Blindness and by the National Institute of Allergy and Infectious Diseases (award no. K01-AI119180 to BFA). The Gates Foundation approved the study design, but had no role in data collection, data nalysis, data interpretation, or writing of the report.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:The trial protocol was reviewed and approved by the Committee on Human Research at the University of California, San Francisco, and the Niger Ministry of Health's Ethical Committee. Parents or guardians of enrolled children provided oral consent before each azithromycin or placebo treatment and at each specimen collection visit. Parents or guardians were instructed to report any adverse event within 7 days of treatment by contacting their village representative, who then reported events to the site coordinator and UCSF. An independent Data and Safety Monitoring Committee provided additional oversight. CDC researchers had access to de-identified samples for analysis (no personally identifying information).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).Yes I 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.YesData and computational notebooks used to conduct the analyses are available through the Open Science Framework (https://osf.io/954bt) and Dryad (xx DOI forthcoming xx). Analyses used R statistical software, version 4.0.2. https://osf.io/954bt

Background The transmission of trachoma, caused by repeat infections with Chlamydia trachomatis, and many enteropathogens are linked to water quantity. We hypothesized that children living further from a water source would have higher exposure to C. trachomatis and enteric pathogens as determined by antibody responses.Methods We used a multiplex bead assay to measure IgG antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in eluted dried blood spots collected from 2267 children ages 1–9 years in 40 communities in rural Ethiopia in 2016. Linear distance from the child’s house to the nearest water source was calculated. We derived seroprevalence cutoffs using external negative control populations, if available, or by fitting finite mixture models. We used targeted maximum likelihood estimation to estimate differences in seroprevalence according to distance to the nearest water source.Results Seroprevalence among 1–9-year-olds was 43% for C. trachomatis, 28% for S. enterica, 70% for E. histolytica, 54% for G. intestinalis, 96% for C. jejuni, 76% for ETEC and 94% for C. parvum. Seroprevalence increased with age for all pathogens. Median distance to the nearest water source was 473 meters (IQR 268, 719). Children living furthest from a water source had a 12% (95% CI: 2.6, 21.6) higher seroprevalence of S. enterica and a 12.7% (95% CI: 2.9, 22.6) higher seroprevalence of G. intestinalis compared to children living nearest.Conclusion Seroprevalence for C. trachomatis and enteropathogens was high, with marked increases for most enteropathogens in the first two years of life. Children living further from a water source had higher seroprevalence of S. enterica and G. intestinalis indicating that improving access to water in the Ethiopia’s Amhara region may reduce exposure to these enteropathogens in young children.AUTHOR SUMMARY Trachoma, and infection of the eye caused by the bacteria Chlamydia trachomatis, and many diarrhea-causing infections are associated with access to water for washing hands and faces. Measuring these different pathogens in a population is challenging and rarely are multiple infections measured at the same time. Here, we used an integrated approach to simultaneously measure antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae among young children residing in rural Ethiopia. We found that the seroprevalence of all pathogens increased with age and that seropositivity to more than one pathogen was common. Children living further from a water source were more likely to be exposed to S. enterica and G. intestinalis. Integrated sero-surveillance is a promising avenue to explore the complexities of multi-pathogen exposure as well as to investigate the relationship water, sanitation and hygiene related exposures disease transmission.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by the National Institutes of Health, National Eye Institute (NEI U10 EY016214)Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll 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 adva ce).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.YesAssociated data will be available on OSF upon publication

Monitoring trachoma transmission with antibody data requires characterization of decay in IgG to Chlamydia trachomatis antigens. In a three-year longitudinal cohort in a high transmission setting, we estimated a median IgG half-life of 3 years and a seroreversion rate of 2.5 (95% CI: 1.6, 3.8) per 100 person-years. 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.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.88, 95% CI: 0.77, 0.93). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any infection at high sensitivity (>90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination. 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.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.

Streptococcus pneumoniae can produce a wide breadth of antigenically diverse capsule types, a fact that poses a looming threat to the success of vaccines that target pneumococcal polysaccharide (PS) capsule. Yet, many pneumococcal capsule types remain undiscovered and/or uncharacterized. Prior sequence analysis of pneumococcal capsule synthesis (cps) loci suggested the existence of capsule subtypes among isolates identified as "serotype 36" according to conventional capsule typing methods. We discovered these subtypes represent two antigenically similar but distinguishable pneumococcal capsule serotypes, 36A and 36B. Biochemical analysis of their capsule PS structure reveals that both have the shared repeat unit backbone [→5)-α-d-Galf-(1→1)-d-Rib-ol-(5→P→6)-β-d-ManpNAc-(1→4)-β-d-Glcp-(1→] with two branching structures. Both serotypes have a β-d-Galp branch to Ribitol. Serotypes 36A and 36B differ by the presence of a α-d-Glcp-(1→3)-β-d-ManpNAc or α-d-Galp-(1→3)-β-d-ManpNAc branch, respectively. Comparison of the phylogenetically distant serogroup 9 and 36 cps loci, which all encode this distinguishing glycosidic bond, revealed that the incorporation of Glcp (in types 9N and 36A) versus Galp (in types 9A, 9V, 9L, and 36B) is associated with the identity of four amino acids in the cps-encoded glycosyltransferase WcjA. Identifying functional determinants of cps-encoded enzymes and their impact on capsule PS structure is key to improving the resolution and reliability of sequencing-based capsule typing methods and discovering novel capsule variants indistinguishable by conventional serotyping methods.

IMPORTANCE: Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources. OBJECTIVE: To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022. INTERVENTIONS: Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months. MAIN OUTCOMES AND MEASURES: Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens. RESULTS: At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07). CONCLUSIONS AND RELEVANCE: The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02048007.

Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. Efficient identification of communities with high infection burden could help target more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. We used measurements from 40 communities in the hyperendemic Amhara region of Ethiopia to assess this hypothesis. Median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment, in the context of recent mass drug administration (MDA), to 29% by month 36, following three years without MDA. At baseline, correlation between seroprevalence and Ct infection was stronger among children 0-5 years old (ρ = 0.77) than children 6-9 years old (ρ = 0.48), and stronger than the correlation between active trachoma and Ct infection (0-5y ρ = 0.56; 6-9y ρ = 0.40). Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be an objective tool for identifying communities with high levels of ocular Ct infections, but accurate, future prediction in the context of changing transmission remains an open challenge.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

BACKGROUND: WHO promotes the SAFE strategy for the elimination of trachoma as a public health programme, which promotes surgery for trichiasis (ie, the S component), antibiotics to clear the ocular strains of chlamydia that cause trachoma (the A component), facial cleanliness to prevent transmission of secretions (the F component), and environmental improvements to provide water for washing and sanitation facilities (the E component). However, little evidence is available from randomised trials to support the efficacy of interventions targeting the F and E components of the strategy. We aimed to determine whether an integrated water, sanitation, and hygiene (WASH) intervention prevents the transmission of trachoma. METHODS: The WASH Upgrades for Health in Amhara (WUHA) was a two-arm, parallel-group, cluster-randomised trial in 40 rural communities in Wag Hemra Zone (Amhara Region, Ethiopia) that had been treated with 7 years of annual mass azithromycin distributions. The randomisation unit was the school catchment area. All households within a 1·5 km radius of a potential water point within the catchment area (as determined by the investigators) were eligible for inclusion. Clusters were randomly assigned (at a 1:1 ratio) to receive a WASH intervention either immediately (intervention) or delayed until the conclusion of the trial (control), in the absence of concurrent antibiotic distributions. Given the nature of the intervention, participants and field workers could not be masked, but laboratory personnel were masked to treatment allocation. The WASH intervention consisted of both hygiene infrastructure improvements (namely, construction of a community water point) and hygiene promotion by government, school, and community leaders, which were implemented at the household, school, and community levels. Hygiene promotion focused on two simple messages: to use soap and water to wash your or your child's face, and to always use a latrine for defecation. The primary outcome was the cluster-level prevalence of ocular chlamydia, measured annually using conjunctival swabs in a random sample of children aged 0-5 years from each cluster at 12, 24, and 36 month timepoints. Analyses were done in an intention-to-treat manner. This trial is ongoing and is registered at ClinicalTrials.gov, NCT02754583. FINDINGS: Between Nov 9, 2015, and March 5, 2019, 40 of 44 clusters assessed for eligibility were enrolled and randomly allocated to the trial groups (20 clusters each, with 7636 people from 1751 households in the intervention group and 9821 people from 2211 households in the control group at baseline). At baseline, ocular chlamydia prevalence among children aged 0-5 years was 11% (95% CI 6 to 16) in the WASH group and 11% (5 to 18) in the control group. At month 36, ocular chlamydia prevalence had increased in both groups, to 32% (24 to 41) in the WASH group and 31% (21 to 41) in the control group (risk difference across three annual monitoring visits, after adjustment for prevalence at baseline: 3·7 percentage points; 95% CI -4·9 to 12·4; p=0·40). No adverse events were reported in either group. INTERPRETATION: An integrated WASH intervention addressing the F and E components of the SAFE strategy did not prevent an increase in prevalence of ocular chlamydia following cessation of antibiotics in an area with hyperendemic trachoma. The impact of WASH in the presence of annual mass azithromycin distributions is currently being studied in a follow-up trial of the 40 study clusters. Continued antibiotic distributions will probably be important in areas with persistent trachoma. FUNDING: National Institutes of Health-National Eye Institute. TRANSLATION: For the Amharic translation of the abstract see Supplementary Materials section.

Multiplex bead assays (MBAs) for serologic testing have become more prevalent in public health surveys, but few studies have assessed their test performance. As part of a trachoma study conducted in a rural part of Ethiopia in 2016, dried blood spots (DBS) were collected from a random sample of 393 children aged 0 to 9 years, with at least two separate 6-mm DBS collected on a filter card. Samples eluted from DBS were processed using an MBA on the Luminex platform for antibodies against 13 antigens of nine infectious organisms: Chlamydia trachomatis, Vibrio cholera, enterotoxigenic Escherichia coli, Cryptosporidium parvum, Entamoeba histolytica, Camplyobacter jejuni, Salmonella typhimurium Group B, Salmonella enteritidis Group D, and Giardia lamblia. Two separate DBS from each child were processed. The first DBS was run a single time, with the MBA set to read 100 beads per well. The second DBS was run twice, first at 100 beads per well and then at 50 beads per well. Results were expressed as the median fluorescence intensity minus background (MFI-BG), and classified as seropositive or seronegative according to external standards. Agreement between the three runs was high, with intraclass correlation coefficients of > 0.85 for the two Salmonella antibody responses and > 0.95 for the other 11 antibody responses. Agreement was also high for the dichotomous seropositivity indicators, with Cohen's kappa statistics exceeding 0.87 for each antibody assay. These results suggest that serologic testing on the Luminex platform had strong test performance characteristics for analyzing antibodies using DBS.

Programs seeking to eliminate the eye disease trachoma use prevalence of the clinical sign trachomatous inflammation–follicular (TF) in 1- to 9-year-olds as a proxy for population-level transmission of ocular Chlamydia trachomatis (Ct). TF prevalence determines the need for the A, F, and E components of the “SAFE” (surgery, antibiotics, facial cleanliness, environmental improvement) strategy. Ocular Ct infection, like its associated signs of conjunctival inflammation, is most common and most intense in young children [1, 2] who are repeatedly infected in areas of active transmission [3]: a model suggests that people can be infected more than 150 times in their lifetime [4]. Repeated infection leads to multiple episodes of TF plus more intense conjunctival inflammation and eventually conjunctival scarring (trachomatous scarring [TS])[5, 6]. Contraction of conjunctival scar can, over a period of years or decades, cause the upper eyelid to turn in and the eyelashes to rub against the eyeball (trachomatous trichiasis [TT]), which can lead to corneal opacity (CO) and blindness.

The transmission of trachoma, caused by repeat infections with Chlamydia trachomatis, and many enteropathogens are linked to water quantity. We hypothesized that children living further from a water source would have higher exposure to C. trachomatis and enteric pathogens as determined by antibody responses. We used a multiplex bead assay to measure IgG antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in eluted dried blood spots collected from 2267 children ages 0-9 years in 40 communities in rural Ethiopia in 2016. Linear distance from the child's house to the nearest water source was calculated. We derived seroprevalence cutoffs using external negative control populations, if available, or by fitting finite mixture models. We used targeted maximum likelihood estimation to estimate differences in seroprevalence according to distance to the nearest water source. Seroprevalence among 1-9-year-olds was 43% for C. trachomatis, 28% for S. enterica, 70% for E. histolytica, 54% for G. intestinalis, 96% for C. jejuni, 76% for ETEC and 94% for C. parvum. Seroprevalence increased with age for all pathogens. Median distance to the nearest water source was 473 meters (IQR 268, 719). Children living furthest from a water source had a 12% (95% CI: 2.6, 21.6) higher seroprevalence of S. enterica and a 12.7% (95% CI: 2.9, 22.6) higher seroprevalence of G. intestinalis compared to children living nearest. Seroprevalence for C. trachomatis and enteropathogens was high, with marked increases for most enteropathogens in the first two years of life. Children living further from a water source had higher seroprevalence of S. enterica and G. intestinalis indicating that improving access to water in the Ethiopia's Amhara region may reduce exposure to these enteropathogens in young children.

During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.

Streptococcus pneumoniae (pneumococcus) is a major human pathogen producing structurally diverse capsular polysaccharides. Widespread use of highly successful pneumococcal conjugate vaccines (PCVs) targeting pneumococcal capsules has greatly reduced infections by the vaccine types but increased infections by nonvaccine serotypes. Herein, we report a new and the 100th capsule type, named serotype 10D, by determining its unique chemical structure and biosynthetic roles of all capsule synthesis locus (cps) genes. The name 10D reflects its serologic cross-reaction with serotype 10A and appearance of cross-opsonic antibodies in response to immunization with 10A polysaccharide in a 23-valent pneumococcal vaccine. Genetic analysis showed that 10D cps has three large regions syntenic to and highly homologous with cps loci from serotype 6C, serotype 39, and an oral streptococcus strain (S. mitis SK145). The 10D cps region syntenic to SK145 is about 6 kb and has a short gene fragment of wciNalpha at the 5' end. The presence of this nonfunctional wciNalpha fragment provides compelling evidence for a recent interspecies genetic transfer from oral streptococcus to pneumococcus. Since oral streptococci have a large repertoire of cps loci, widespread PCV usage could facilitate the appearance of novel serotypes through interspecies recombination.IMPORTANCE The polysaccharide capsule is essential for the pathogenicity of pneumococcus, which is responsible for millions of deaths worldwide each year. Currently available pneumococcal vaccines are designed to elicit antibodies to the capsule polysaccharides of the pneumococcal isolates commonly causing diseases, and the antibodies provide protection only against the pneumococcus expressing the vaccine-targeted capsules. Since pneumococci can produce different capsule polysaccharides and therefore reduce vaccine effectiveness, it is important to track the appearance of novel pneumococcal capsule types and how these new capsules are created. Herein, we describe a new and the 100th pneumococcal capsule type with unique chemical and serological properties. The capsule type was named 10D for its serologic similarity to 10A. Genetic studies provide strong evidence that pneumococcus created 10D capsule polysaccharide by capturing a large genetic fragment from an oral streptococcus. Such interspecies genetic exchanges could greatly increase diversity of pneumococcal capsules and complicate serotype shifts.

BACKGROUND: Biannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger. METHODS: Markers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1-5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence. RESULTS: Antibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference - 0.39, 95% CI - 0.05 to - 0.72). CONCLUSIONS: Targeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution. Trial Registration Clinicaltrials.gov NCT00792922.

BACKGROUND: Program decision-making for trachoma elimination currently relies on conjunctival clinical signs. Antibody tests may provide additional information on the epidemiology of trachoma, particularly in regions where it is disappearing or elimination targets have been met. METHODS: A cluster-randomized trial of mass azithromycin distribution strategies for trachoma elimination was conducted over three years in a mesoendemic region of Niger. Dried blood spots were collected from a random sample of children aged 1-5 years in each of 24 study communities at 36 months after initiation of the intervention. A multiplex bead assay was used to test for antibodies to two Chlamydia trachomatis antigens, Pgp3 and CT694. We compared seropositivity to either antigen to clinical signs of active trachoma (trachomatous inflammation-follicular [TF] and trachomatous inflammation-intense [TI]) at the individual and cluster level, and to ocular chlamydia prevalence at the community level. RESULTS: Of 988 children with antibody data, TF prevalence was 7.8% (95% CI 6.1 to 9.5) and TI prevalence was 1.6% (95% CI 0.9 to 2.6). The overall prevalence of antibody positivity to Pgp3 was 27.2% (95% CI 24.5 to 30), and to CT694 was 23.7% (95% CI 21 to 26.2). Ocular chlamydia infection prevalence was 5.2% (95% CI 2.8 to 7.6). Seropositivity to Pgp3 and/or CT694 was significantly associated with TF at the individual and community level and with ocular chlamydia infection and TI at the community level. Older children were more likely to be seropositive than younger children. CONCLUSION: Seropositivity to Pgp3 and CT694 correlates with clinical signs and ocular chlamydia infection in a mesoendemic region of Niger. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922.

Importance: Mild traumatic brain injury (mTBI), or concussion, in children is a rapidly growing public health concern because epidemiologic data indicate a marked increase in the number of emergency department visits for mTBI over the past decade. However, no evidence-based clinical guidelines have been developed to date for diagnosing and managing pediatric mTBI in the United States. Objective: To provide a guideline based on a previous systematic review of the literature to obtain and assess evidence toward developing clinical recommendations for health care professionals related to the diagnosis, prognosis, and management/treatment of pediatric mTBI. Evidence Review: The Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, established the Pediatric Mild Traumatic Brain Injury Guideline Workgroup. The workgroup drafted recommendations based on the evidence that was obtained and assessed within the systematic review, as well as related evidence, scientific principles, and expert inference. This information includes selected studies published since the evidence review was conducted that were deemed by the workgroup to be relevant to the recommendations. The dates of the initial literature search were January 1, 1990, to November 30, 2012, and the dates of the updated literature search were December 1, 2012, to July 31, 2015. Findings: The CDC guideline includes 19 sets of recommendations on the diagnosis, prognosis, and management/treatment of pediatric mTBI that were assigned a level of obligation (ie, must, should, or may) based on confidence in the evidence. Recommendations address imaging, symptom scales, cognitive testing, and standardized assessment for diagnosis; history and risk factor assessment, monitoring, and counseling for prognosis; and patient/family education, rest, support, return to school, and symptom management for treatment. Conclusions and Relevance: This guideline identifies the best practices for mTBI based on the current evidence; updates should be made as the body of evidence grows. In addition to the development of the guideline, CDC has created user-friendly guideline implementation materials that are concise and actionable. Evaluation of the guideline and implementation materials is crucial in understanding the influence of the recommendations.

Importance: In recent years, there has been an exponential increase in the research guiding pediatric mild traumatic brain injury (mTBI) clinical management, in large part because of heightened concerns about the consequences of mTBI, also known as concussion, in children. The CDC National Center for Injury Prevention and Control's (NCIPC) Board of Scientific Counselors (BSC), a federal advisory committee, established the Pediatric Mild TBI Guideline workgroup to complete this systematic review summarizing the first 25 years of literature in this field of study. Objective: To conduct a systematic review of the pediatric mTBI literature to serve as the foundation for an evidence-based guideline with clinical recommendations associated with the diagnosis and management of pediatric mTBI. Evidence Review: Using a modified Delphi process, the authors selected 6 clinical questions on diagnosis, prognosis, and management or treatment of pediatric mTBI. Two consecutive searches were conducted on PubMed, Embase, ERIC, CINAHL, and SportDiscus. The first included the dates January 1, 1990, to November 30, 2012, and an updated search included December 1, 2012, to July 31, 2015. The initial search was completed from December 2012 to January 2013; the updated search, from July 2015 to August 2015. Two authors worked in pairs to abstract study characteristics independently for each article selected for inclusion. A third author adjudicated disagreements. The risk of bias in each study was determined using the American Academy of Neurology Classification of Evidence Scheme. Conclusion statements were developed regarding the evidence within each clinical question, and a level of confidence in the evidence was assigned to each conclusion using a modified GRADE methodology. Data analysis was completed from October 2014 to May 2015 for the initial search and from November 2015 to April 2016 for the updated search. Findings: Validated tools are available to assist clinicians in the diagnosis and management of pediatric mTBI. A significant body of research exists to identify features that are associated with more serious TBI-associated intracranial injury, delayed recovery from mTBI, and long-term sequelae. However, high-quality studies of treatments meant to improve mTBI outcomes are currently lacking. Conclusions and Relevance: This systematic review was used to develop an evidence-based clinical guideline for the diagnosis and management of pediatric mTBI. While an increasing amount of research provides clinically useful information, this systematic review identified key gaps in diagnosis, prognosis, and management.

The intent of this study was to assess passerine eastern equine encephalitis virus (EEEv) seroprevalence during the breeding season in southern Maine by testing songbird species identified in the literature as amplifying hosts of this virus. In 2013 and 2014, we collected serum samples from songbirds at a mainland site and an offshore island migratory stopover site, and screened samples for EEEv antibodies using plaque reduction neutralization tests. We compared seasonal changes in EEEv antibody seroprevalence in young (hatched in year of capture) and adult birds at the mainland site, and also compared early season seroprevalence in mainland versus offshore adult birds. EEEv seroprevalence did not differ significantly between years at either site. During the early season (May), EEEv antibody seroprevalence was substantially lower (9.6%) in the island migrant adults than in mainland adults (42.9%), 2013-2014. On the mainland, EEEv antibody seroprevalence in young birds increased from 12.9% in midseason (June-August) to 45.6% in late season (September/October), 2013-2014. Seroprevalence in adult birds did not differ between seasons (48.8% vs. 53.3%). EEEv activity in Maine has increased in the past decade as measured by increased virus detection in mosquitoes and veterinary cases. High EEEv seroprevalence in young birds-as compared to that of young birds in other studies-corresponded with two consecutive active EEEv years in Maine. We suggest that young, locally hatched songbirds be sampled as a part of long-term EEEv surveillance, and provide a list of suggested species to sample, including EEEv "superspreaders."

Twenty-four Ethiopian communities were randomized to receive either (1) quarterly mass azithromycin distributions for trachoma for 1 year or (2) delayed treatment. Nasopharyngeal swabs collected from separate cross-sectional population-based samples of children were processed for Streptococcus pneumoniae Mass azithromycin did not significantly alter the pneumococcal serotype distribution, and hence it would not be expected to alter vaccine coverage.

BACKGROUND: The WHO seeks to control trachoma as a public health problem in endemic areas. Achham District in western Nepal was found to have TF (trachoma follicular) above 20% in a 2006 government survey, triggering 3 annual mass drug administrations finishing in 2010. Here we assess the level of control that has been achieved using surveillance for clinical disease, ocular chlamydia trachomatis infection, and serology for antibodies against chlamydia trachomatis protein antigens. METHODS: We conducted a cross-sectional survey of children aged 1-9 years in communities in Achham District in early 2014 including clinical examination validated with photographs, conjunctival samples for Chlamydia trachomatis (Amplicor PCR), and serological testing for antibodies against chlamydia trachomatis protein antigens pgp3 and CT694 using the Luminex platform. FINDINGS: In 24 randomly selected communities, the prevalence of trachoma (TF and/or TI) in 1-9 year olds was 3/1124 (0.3%, 95% CI 0.1 to 0.8%), and the prevalence of ocular chlamydia trachomatis infection was 0/1124 (0%, 95% CI 0 to 0.3%). In 18 communities selected because they had the highest prevalence of trachoma in a previous survey, the prevalence of TF and/or TI was 7/716 (1.0%, 95% CI 0.4 to 2.0%) and the prevalence of ocular chlamydia trachomatis infection was 0/716 (0%, 95% CI 0 to 0.5%). In 3 communities selected for serological testing, the prevalence of trachoma was 0/68 (0%, 95% CI 0 to 5.3%), the prevalence of ocular chlamydia trachomatis infection was 0/68 (0%, 95% CI 0 to 0.5%), the prevalence of antibodies against chlamydia trachomatis protein antigen pgp3 was 1/68 (1.5%, 95% CI 0.04% to 7.9%), and the prevalence of antibodies against chlamydia trachomatis protein antigen CT694 was 0/68 (0%, 95% CI 0 to 5.3%). CONCLUSION/SIGNIFICANCE: This previously highly endemic district in Nepal has little evidence of recent clinical disease, chlamydia trachomatis infection, or serological evidence of trachoma, suggesting that epidemiological control has been achieved.

BACKGROUND: A clinical trial of mass azithromycin distributions for trachoma created a convenient experiment to test the hypothesis that antibiotic use selects for clonal expansion of pre-existing resistant bacterial strains. METHODS: Mass azithromycin was distributed to 12 communities in Ethiopia every 3 months for 1 year. A random sample of 10 children aged 0-9 years from each community was monitored with nasopharyngeal swabs before mass azithromycin distributions and after 4 mass treatments; S. pneumoniae was isolated and multilocus sequence typing performed. RESULTS: Of 82 pneumococcal isolates identified before treatment, 4 (5%) exhibited azithromycin resistance, representing 3 different sequence types (STs): 177, 6449, and 6494. The proportion of isolates that were classified as one of these 3 STs and were resistant to azithromycin increased after 4 mass azithromycin treatments (14 of 96 isolates; 15%; P=0.04). Using a classification index, we found evidence for a relationship between ST and macrolide resistance after mass treatments (P<0.0001). The diversity of STs-as calculated by the unbiased Simpson's index-decreased significantly after mass azithromycin treatment (P=0.045). CONCLUSIONS: Resistant clones present before mass azithromycin treatments increased in frequency after treatment, consistent with the theory that antibiotic selection pressure results in clonal expansion of existing resistant strains.

Bacillus anthracis was identified in a 61-year-old man hospitalized in Minnesota, USA. Cooperation between the hospital and the state health agency enhanced prompt identification of the pathogen. Treatment comprising antimicrobial drugs, anthrax immune globulin, and pleural drainage led to full recovery; however, the role of passive immunization in anthrax treatment requires further evaluation.

Cardiovascular disease (CVD) is the leading cause of preventable death in the United States, a major contributor to adult disability, and one of the most expensive conditions treated in U.S. hospitals. Lipid disorders (e.g., high blood cholesterol and triglycerides) increase the risk for atherosclerosis, which can lead to coronary heart disease (CHD), which accounts for a substantial proportion of cardiovascular mortality. Screening for lipid abnormalities is essential in detecting and properly managing lipid disorders early in the atherogenic process, thereby preventing the development of atherosclerotic plaques and minimizing existing plaques. Based on evidence-based studies, the United States Preventive Services Task Force (USPSTF) concluded that lipid measurement can identify asymptomatic adults who are eligible for cholesterol-lowering therapy.