OBJECTIVE: We investigated associations between per- and polyfluoroalkyl substances (PFAS) and changes in diabetes indicators from pregnancy to 12 years after delivery among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Eighty Hispanic women with GDM history were followed from the third trimester of pregnancy to 12 years after delivery. Oral and intravenous glucose tolerance tests were conducted during follow-up. Plasma PFAS concentrations were measured at the third trimester of pregnancy and first postpartum visit. A linear mixed-effects model was used to analyze associations between PFAS and trajectories of diabetes indicators, adjusted for age, breastfeeding status, daily total calorie intake, and body fat percentage. RESULTS: Increased 2-(N-methyl-perfluorooctane sulfonamido) acetate level was associated with faster increase in concentrations of fasting glucose (P = 0.003). Increased perfluorononanoate (PFNA) and linear perfluorooctanoate (n-PFOA) concentrations were associated with faster increase in fasting insulin concentrations (P = 0.04 for PFNA; P = 0.02 for n-PFOA) and faster decrease in acute insulin response to glucose (P = 0.04 for PFNA; P = 0.02 for n-PFOA). CONCLUSIONS: PFAS exposure is associated with glucose intolerance, insulin resistance, and β-cell dysfunction, thus increasing type 2 diabetes risk.

INTRODUCTION: We aim to assess HPV vaccine administration among privately insured populations before and during the COVID-19 pandemic in the United States and stratify the assessments by demographic and geographic characteristics. METHODS: Using the Merative MarketScan Commercial Claims and Encounters Database, we estimated monthly and yearly HPV vaccine administration among people aged 9-26 from 2019 to 2022, measured as the proportion of the enrolled population who received ≥ 1 dose of HPV vaccine during that month or year, and their relative percent change from 2020 to 2022, compared to the same period in 2019, overall and stratified by age group, sex, and urbanicity. RESULTS: HPV vaccine administration in 2020, 2021, and 2022 was lower than in 2019 and continued to decline for all age groups. The relative percent change in rate in 2022 relative to 2019 was -6.0% among children, -38.3% among adolescents, and -42.5% among young adults. The patterns were similar across subgroups, with certain disparities in magnitude. By subpopulations, the highest percent declines in 2022 relative to 2019 in each age group were observed among children in rural areas (-13.5%), male adolescents (-39.8%), and young adults in rural areas (-46.0%). CONCLUSION: During the COVID-19 pandemic, HPV vaccine administration dropped substantially and had not exceeded the pre-pandemic levels by the end of 2022, with larger declines seen among male adolescents and young adults in rural areas. Our results highlight the need for continuing monitoring and targeted intervention strategies to improve HPV vaccine administration.

BACKGROUND: Brain infections pose substantial challenges in diagnosis and management and carry high mortality and morbidity, especially in low-income and middle-income countries. We aimed to improve the diagnosis and early management of patients admitted to hospital (adults aged 16 years and older and children aged >28 days) with suspected acute brain infections at 13 hospitals in Brazil, India, and Malawi. METHODS: With hospital stakeholders, policy makers, and patient and public representatives, we co-designed a multifaceted clinical and laboratory intervention, informed by an evaluation of routine practice. The intervention, tailored for each setting, included a diagnostic and management algorithm, a lumbar puncture pack, a testing panel, and staff training. We used multivariable logistic regression and interrupted time series analysis to compare the coprimary outcomes-the percentage of patients achieving a syndromic diagnosis and the percentage achieving a microbiological diagnosis before and after the intervention. The study was registered at ClinicalTrials.gov (NCT04190303) and is complete. FINDINGS: Between Jan 5, 2021, and Nov 30, 2022, we screened 10 462 patients and enrolled a total of 2233 patients at 13 hospital sites connected to the four study centres in Brazil, India, and Malawi. 1376 (62%) were recruited before the intervention and 857 (38%) were recruited after the intervention. 2154 patients (96%) had assessment of the primary outcome (1330 [62%] patients recruited pre-intervention and 824 [38%] recruited post-intervention). The median age across centres was 23 years (IQR 6-44), with 1276 (59%) being adults aged 16 years or older and 888 (41%) children aged between 29 days and 15 years; 1264 (59%) patients were male and 890 (41%) were female. Data on race and ethnicity were not recorded. 1020 (77%) of 1320 patients received a syndromic diagnosis before the intervention, rising to 701 (86%) of 813 after the intervention (adjusted odds ratio [aOR] 1·81 [95% CI 1·40-2·34]; p<0·0001). A microbiological diagnosis was made in 294 (22%) of 1330 patients pre-intervention, increasing to 250 (30%) of 824 patients post-intervention (aOR 1·46 [95% CI 1·18-1·79]; p=0·00040). Interrupted time series analysis confirmed that these increases exceeded a modest underlying trend of improvement over time. The percentage receiving a lumbar puncture, time to appropriate therapy, and functional outcome also improved. INTERPRETATION: Diagnosis and management of patients with suspected acute brain infections improved following introduction of a simple intervention package across a diverse range of hospitals on three continents. The intervention is now being implemented in other settings as part of the WHO Meningitis Roadmap and encephalitis control initiatives. FUNDING: UK National Institute for Health and Care Research.

Rotavirus is a leading cause of severe diarrheal disease in infants and young children worldwide. Vaccination offers the best protection against this disease, and two rotavirus vaccines were developed in India and included in its routine immunization program. The Government of India's decision to adopt this intervention was supported by a solid base of evidence from clinical trials, as well as substantial research regarding rotavirus disease burden and the potential health and economic value of immunization. Following program implementation, multiple studies were initiated, including three evaluations of effectiveness and several investigations regarding intussusception. These additional data regarding vaccine impact, safety, and delivery from post-introduction evaluations in conditions of real-world use will further strengthen and sustain the immunization program. This manuscript evaluates the status of existing and forthcoming evidence regarding rotavirus vaccination in India through a literature review and consultation with relevant stakeholders. Studies evaluating vaccine impact, effectiveness, safety, health economics, and acceptability, as well as operational and programmatic research, were included in the review. Overall, we found that the evidence base did not contain any major gaps. Nevertheless, additional smaller-scale research studies would be valuable in providing a more complete picture of rotavirus vaccine performance and benefit. Documentation of India's experience with rotavirus vaccines may provide lessons learned for other countries in the Asia region, where rotavirus disease burden remains high, yet vaccine adoption has been slow, as well as for countries worldwide that may be considering implementation of the Indian-made rotavirus vaccines.

BACKGROUND: Enteric infections are hypothesized to be associated with intussusception in children. A small increase in intussusception following rotavirus vaccination has been seen in some settings. We conducted post-marketing surveillance for intussusception following rotavirus vaccine, Rotavac introduction in India and evaluated association of intussusception with enteric pathogens. METHODS: In a case-control study nested within a large sentinel hospital-based surveillance program in India, stool samples from 272 children aged less than 2 years admitted for intussusception and 272 age-, gender- and location-matched controls were evaluated with Taqman array card based molecular assays to detect enteric viruses, bacterial enteropathogens and parasites. Matched case-control analysis with conditional logistic regression evaluated association of enteropathogens with intussusception. Population attributable fractions (PAF) were calculated for enteropathogens significantly associated with intussusception. RESULTS: The most prevalent enteropathogens in cases and controls were enteroaggregative Escherichia coli, adenovirus 40/41, adenovirus C serotypes and enteroviruses. Children with intussusception were more likely to harbor adenovirus C serotypes (adjusted odds-ratio (aOR) = 1.74; 95% confidence interval (CI) 1.06-2.87) and enteroviruses (aOR = 1.77; 95% CI 1.05-2.97) than controls. Rotavirus was not associated with increased intussusception risk. Adenovirus C (PAF = 16.9%; 95% CI 4.7% - 27.6%) and enteroviruses (PAF = 14.7%; 95% CI 4.2% - 24.1%) had the highest population attributable fraction for intussusception. CONCLUSION: Adenovirus C serotypes and enteroviruses were significantly associated with intussusception in Indian children. Rotavirus was not associated with risk of intussusception.

Case investigation and contact tracing (CICT) are public health measures that aim to break the chain of pathogen transmission. Changes in viral characteristics of COVID-19 variants have likely affected the effectiveness of CICT programs. We estimated and compared the cases averted in Vermont when the original COVID-19 strain circulated (Nov. 25, 2020-Jan. 19, 2021) with two periods when the Delta strain dominated (Aug. 1-Sept. 25, 2021, and Sept. 26-Nov. 20, 2021). When the original strain circulated, we estimated that CICT prevented 7180 cases (55% reduction in disease burden), compared to 1437 (15% reduction) and 9970 cases (40% reduction) when the Delta strain circulated. Despite the Delta variant being more infectious and having a shorter latency period, CICT remained an effective tool to slow spread of COVID-19; while these viral characteristics did diminish CICT effectiveness, non-viral characteristics had a much greater impact on CICT effectiveness.

BACKGROUND: Facing a surge of COVID-19 cases in late August 2021, the U.S. state of Illinois re-enacted its COVID-19 mask mandate for the general public and issued a requirement for workers in certain professions to be vaccinated against COVID-19 or undergo weekly testing. The mask mandate required any individual, regardless of their vaccination status, to wear a well-fitting mask in an indoor setting. METHODS: We used Illinois Department of Public Health's COVID-19 confirmed case and vaccination data and investigated scenarios where masking and vaccination would have been reduced to mimic what would have happened had the mask mandate or vaccine requirement not been put in place. The study examined a range of potential reductions in masking and vaccination mimicking potential scenarios had the mask mandate or vaccine requirement not been enacted. We estimated COVID-19 cases and hospitalizations averted by changes in masking and vaccination during the period covering October 20 to December 20, 2021. RESULTS: We find that the announcement and implementation of a mask mandate are likely to correlate with a strong protective effect at reducing COVID-19 burden and the announcement of a vaccinate-or-test requirement among frontline professionals is likely to correlate with a more modest protective effect at reducing COVID-19 burden. In our most conservative scenario, we estimated that from the period of October 20 to December 20, 2021, the mask mandate likely prevented approximately 58,000 cases and 1,175 hospitalizations, while the vaccinate-or-test requirement may have prevented at most approximately 24,000 cases and 475 hospitalizations. CONCLUSION: Our results indicate that mask mandates and vaccine-or-test requirements are vital in mitigating the burden of COVID-19 during surges of the virus.

Malnourished children are at higher risk of mortality and morbidity following diarrheal illness and certain enteropathogens have been associated with malnutrition in children. Very few studies have comprehensively looked at the etiology of diarrhea in malnourished children and most have used conventional diagnostic methods with suboptimal sensitivity. We used a highly sensitive molecular approach against a broad range of pathogens causing diarrhea and examined their association with malnutrition. In addition, we looked at the pathogen diversity of pediatric diarrhea, three years after the nationwide rotavirus vaccine introduction to understand the evolving landscape of pathogens, which is crucial for planning strategies to further reduce the diarrhea burden. Clinical details and diarrheal stool samples were collected from hospitalized children aged < 5 years from three sentinel sites in India for a period of one year. The samples were tested by qPCR for 16 established causes of diarrhea using TaqMan Array Cards. A total of 772 children were enrolled, from whom 482 (62.4%) stool specimens were tested. No specific pathogen was associated with diarrhea among children with acute or chronic malnutrition compared to those with better nutritional status. Overall, adenovirus was the leading pathogen (attributable fraction (AF) 16.9%; 95% CI 14.1 to 19.2) followed by rotavirus (AF 12.6%; 95% CI 11.8 to 13.1) and Shigella (AF 10.9%; 95% CI 8.4 to 16.4). The majority of diarrhea requiring hospitalization in children aged < 2 years could be attributed to viruses, while Shigella was the most common pathogen among children aged > 2 years. These data on the prevalence and epidemiology of enteropathogens identified potential pathogens for public health interventions.

OBJECTIVE: To assess recovery in childhood and adolescent vaccine ordering since initial declines in 2020 due to COVID-19 pandemic-related disruptions. METHODS: Using vaccine ordering data provided by Merck & Co., Inc., Rahway, NJ, USA, the number of measles-containing vaccine doses ordered each month in the U.S. during January 1, 2020-May 31, 2022 were compared to doses ordered during the corresponding month in 2018 and human papillomavirus (HPV) vaccine doses ordered during January 1, 2020-December 31, 2022 were compared to corresponding month in 2019. Differences stratified by public vs. private funding source and state and urbanicity of the county where the provider is located were examined. RESULTS: The cumulative deficit for measles-containing vaccines was 1,314,179 doses (-5.7%) as of May 2022 and 3,911,020 doses (-13.6%) for HPV vaccine as of December 2022. Deficits in publicly funded doses and HPV doses ordered in rural counties were greater than deficits in privately funded doses and HPV doses ordered in urban counties. CONCLUSIONS: Findings show that monthly measles-containing and HPV vaccine ordering has recovered; however, deficits remain. Greater deficits in publicly funded vaccine doses and HPV ordering in rural counties suggest varying level of recovery. To reduce gaps in deficits, health care providers are strongly encouraged to use every visit to recommend needed vaccines.

After the introduction of the rotavirus vaccine into the Universal Immunization Program in India in 2016, relatively few studies have assessed the prevalence and epidemiological patterns of acute gastroenteritis (AGE) among hospitalized children ≤5 years of age. We used a uniform protocol to recruit children with AGE as well as standardized testing and typing protocols. Stool specimens from children with AGE younger than 5 years of age admitted to six hospitals in three cities in India were collected from January 2017 through December 2019. Norovirus was detected by real-time reverse transcription-polymerase chain reaction (RT-qPCR) followed by typing positive specimens by conventional RT-PCR and Sanger sequencing. Norovirus was detected in 322 (14.8%) of 2182 specimens with the highest rate in 2018 (17.6%, 146/829), followed by 2019 (14.4%, 122/849) and 2017 (10.7%, 54/504). Rotavirus vaccine status was known for 91.6% of the children of which 70.4% were vaccinated and 29.6% not. Norovirus positivity in rotavirus-vaccinated children was 16.3% and 12% in unvaccinated children. GII.4 Sydney[P16] (39.3%), GII.4 Sydney[P31] (18.7%), GII.2[P16] (10%), GI.3[P13] (6.8%), GII.3[P16] (5.9%), and GII.13[P16] (5%) accounted for 85.8% (188/219) of the typed strains. Our data highlight the importance of norovirus in Indian children hospitalized with AGE.

We read with interest the article by Kang et al. [1], “Hemoglobin distributions and prevalence of anemia in a multiethnic United States pregnant population,” as well as the accompanying Editorial by Merz and Achebe [2], “Iron deficiency in pregnancy: a health inequity [2].” Both Kang et al. [1] and Merz and Achebe [2] incorrectly stated that the Centers for Disease Control and Prevention (CDC) recommend use of lower race-adjusted thresholds to define anemia for Black individuals. The CDC does not recommend separate diagnostic thresholds to define anemia for Black individuals or any other race/ethnic group. Here, we clarify misinterpretations in recent American Journal of Clinical Nutrition publications regarding the CDC anemia threshold recommendations. | | The 1998 “Recommendations to prevent and control iron deficiency in the United States” [3], the most recent CDC publication providing guidance on thresholds to define anemia in individuals, did not recommend race-specific cutoff values for anemia. The 1998 recommendations included criteria for anemia threshold adjustments based on age, sex, pregnancy status, gestational age, altitude, and smoking status [3]. To guide the development of these 1998 CDC recommendations, the CDC requested that the Institute of Medicine (IOM) convene an expert committee to develop recommendations for preventing, detecting, and treating iron deficiency anemia among children and women of reproductive age in United States. The IOM report published in 1993 [4] is independent and not an official institutional CDC/federal recommendations publication. The 1998 CDC recommendations considered inputs from the IOM report [4], conclusions of a CDC expert panel convened in April 1994, and from other multidisciplinary subject matter experts [3].

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]). | Salmonella Typhi (Typhi) is a type of bacteria that causes typhoid fever. More than 110,000 people die from this disease each year, predominantly in areas of sub-Saharan Africa and South Asia with limited access to safe water and sanitation. Clinicians use antibiotics to treat typhoid fever, but scientists worry that the spread of antimicrobial-resistant Typhi could render the drugs ineffective, leading to increased typhoid fever mortality. The World Health Organization has prequalified two vaccines that are highly effective in preventing typhoid fever and may also help limit the emergence and spread of resistant Typhi. In low resource settings, public health officials must make difficult trade-off decisions about which new vaccines to introduce into already crowded immunization schedules. Understanding the local burden of antimicrobial-resistant Typhi and how it is spreading could help inform their actions. The Global Typhoid Genomics Consortium analyzed 13,000 Typhi genomes from 110 countries to provide a global overview of genetic diversity and antimicrobial-resistant patterns. The analysis showed great genetic diversity of the different strains between countries and regions. For example, the H58 Typhi variant, which is often drug-resistant, has spread rapidly through Asia and Eastern and Southern Africa, but is less common in other regions. However, distinct strains of other drug-resistant Typhi have emerged in other parts of the world. Resistance to the antibiotic ciprofloxacin was widespread and accounted for over 85% of cases in South Africa. Around 70% of Typhi from Pakistan were extensively drug-resistant in 2020, but these hard-to-treat variants have not yet become established elsewhere. Variants that are resistant to both ciprofloxacin and ceftriaxone have been identified, and azithromycin resistance has also appeared in several different variants across South Asia. The Consortium’s analyses provide valuable insights into the global distribution and transmission patterns of drug-resistant Typhi. Limited genetic data were available fromseveral regions, but data from travel-associated cases helped fill some regional gaps. These findings may help serve as a starting point for collective sharing and analyses of genetic data to inform local public health action. Funders need to provide ongoing supportto help fill global surveillance data gaps. | eng

ABSTRACTDespite the human immunodeficiency virus (HIV) pandemic continuing worldwide for 40 years, no vaccine to combat the disease has been licensed for use in at risk populations. Here, we describe a novel recombinant vesicular stomatitis virus (rVSV) vector vaccine expressing modified HIV envelope glycoproteins and Ebola virus glycoprotein. Three heterologous immunizations successfully prevented infection by a different clade SHIV in 60% of nonhuman primates (NHPs). No trend was observed between resistance and antibody interactions. Resistance to infection was associated with high proportions of central memory T cell CD69 and CD154 marker upregulation, increased IL-2 production, and a reduced IFN-γ response, offering insight into correlates of protection.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are associated with less favorable blood lipid profiles in epidemiological studies. However, little is known about the potential role of PFAS in longitudinal changes in lipids among midlife women even though women become more susceptible to metabolic alterations during the menopausal transition. OBJECTIVES: To examine associations of serum PFAS concentrations with longitudinal trajectories of blood total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in midlife women undergoing menopausal transition. METHODS: The sample included 1,130 women from the Study of Women's Health Across the Nation 45-56 y of age at baseline (1999-2000). We measured serum PFAS concentrations including linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), linear and branched perfluorooctanesulfonic acid (n-PFOS and Sm-PFOS, respectively), and perfluorohexanesulfonic acid (PFHxS) at baseline. We used k-means clustering to identify subgroups with different patterns of PFAS mixture. Blood lipids were measured annually or biannually through 2016 with an average follow-up of 14.8 y. We identified longitudinal trajectories of each lipid using latent class growth models. We used multinomial log-linear models adjusted for covariates to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of lipid trajectory classes by PFAS and their mixtures. RESULTS: Three distinct trajectories (low, middle, high) of total, LDL, and HDL cholesterol and two distinct trajectories (low and high) of triglycerides were identified. n-PFOS, Sm-PFOS, and PFHxS were positively associated with total and LDL cholesterol trajectories. n-PFOS was inversely associated with triglycerides trajectories. PFAS mixtures (high vs. low) showed positive associations with total and LDL cholesterol trajectories (high vs. low), showing ORs (95% CIs) of 1.69 (95% CI: 1.36, 2.12) and 1.79 (95% CI: 1.44, 2.22), respectively. DISCUSSION: Concentrations of serum PFAS were positively associated with trajectories of total and LDL cholesterol, providing a line of evidence supporting adverse effects of PFAS on lipid homeostasis. https://doi.org/10.1289/EHP12351.

With concerns about the efficacy of repeat annual influenza vaccination, it is important to better understand the impact of priming vaccine immunity and develop an effective vaccination strategy. Here, we determined the impact of heterologous prime-boost vaccination on inducing broader protective immunity compared to repeat vaccination with the same antigen. The primed mice that were intramuscularly boosted with a heterologous inactivated influenza A virus (H1N1, H3N2, H5N1, H7N9, H9N2) vaccine showed increased strain-specific hemagglutination inhibition titers against prime and boost vaccine strains. Heterologous prime-boost vaccination of mice with inactivated viruses was more effective in inducing high levels of IgG antibodies specific for groups 1 and 2 hemagglutinin stalk domains, as well as cross-protection, compared to homologous vaccination. Both humoral and T cell immunity were found to play a critical role in conferring cross-protection by heterologous prime-boost vaccination. These results support a strategy to enhance cross-protective efficacy by heterologous prime-boost influenza vaccination.

Introduction Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10, a secreted serine protease) as a flow-sensitive gene in arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown.Methods and Results Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated KLK10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced inflammation and permeability dysfunction in human artery ECs (HAECs). Further, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of KLK10-expressing plasmids inhibited atherosclerosis in ApoE-/- mice. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10’s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques.Conclusion KLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.Competing Interest StatementThe authors have declared no competing interest.

Variation in susceptibility is a known contributor to bias in studies estimating immune protection acquired from vaccination or natural infection. However, difficulty measuring this heterogeneity hinders assessment of its influence on estimates. Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis in low- and middle-income countries (LMICs). We sought to understand differences in susceptibility among children enrolled in two birth-cohort studies of rotavirus in LMICs, and to explore the implications for estimation of immune protection. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 unvaccinated children experienced 1418 rotavirus infections and 371 episodes of rotavirus gastroenteritis (RVGE) over 17,636 child-months. We developed a model characterizing susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings, and tested whether modelgenerated susceptibility measurements were associated with demographic and anthropometric factors. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of diarrhea due to other causes. Simulations suggest that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in transmission intensity and susceptibility of children. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that bias owing to differences in rotavirus transmission intensity and population susceptibility may hinder comparison of estimated immune protection against RVGE.Author summary Differences in susceptibility can help explain why some individuals, and not others, acquire infection and exhibit symptoms when exposed to infectious disease agents. However, it is difficult to distinguish between differences in susceptibility versus exposure in epidemiological studies. We developed a modeling approach to distinguish transmission intensity and susceptibility in data from cohort studies of rotavirus infection among children in Mexico City, Mexico, and Vellore, India, and evaluated how these factors may have contributed to differences in estimates of naturally-acquired immune protection between the studies. We found that more children were at “high risk” of acquiring rotavirus infection, and of experiencing gastroenteritis when infected, in Vellore versus Mexico City. The probability of belonging to this high-risk stratum was associated with recognized risk factors such as lower socioeconomic status, lower birth weight, and risk of diarrhea due to other causes. We also found the risk for rotavirus infections to cause symptoms declined with age, and was independent of acquired immunity. Together, these findings can account for estimates of lower protective efficacy of acquired immunity against rotavirus gastroenteritis in high-incidence settings, which mirrors estimates of reduced effectiveness of live oral rotavirus vaccines in low- and middle-income countries.

Salmonella enterica serovar (Salmonella Typhi) is the causative bacterial agent of typhoid fever. Environmental surveillance of wastewater and wastewater-impacted surface waters has proven effective in monitoring various pathogens and has recently been applied to Salmonella Typhi. This study evaluated eight sample collection and concentration methods with 12 variations currently being developed and used for Salmonella Typhi surveillance globally to better understand the performance of each method based on its ability to detect Salmonella Typhi and its feasibility. Salmonella Typhi strains Ty21a and Ty2 were seeded to influent wastewater at known concentrations to evaluate the following methods: grab sampling using electropositive filters, centrifugation, direct enrichment, or membrane filtration and trap sampling using Moore swabs. Concentrated samples underwent nucleic acid extraction and were detected and/or quantified via quantitative polymerase chain reaction (qPCR). Results suggest that all methods tested can be successful at concentrating Salmonella Typhi for subsequent detection by qPCR, although each method has its own strengths and weaknesses, including the Salmonella Typhi concentration it is best suited for, with a range of positive detections observed as low as 0.1-0.001 colony-forming units (CFU) Ty21a/mL and 0.01 CFU Ty2/mL. These factors should be considered when identifying a method for environmental surveillance and will greatly depend on the use case planned.

Salmonella enterica serovar (Salmonella Typhi) is the causative bacterial agent of Typhoid fever. Environmental surveillance of wastewater and wastewater-impacted surface waters has proven effective in monitoring various pathogens, and has recently been applied to Salmonella Typhi. This study evaluated eight sample collection and concentration methods with twelve variations currently being developed and used for Salmonella Typhi surveillance globally to better understand the performance of each method based on their ability to detect Salmonella Typhi and feasibility. Salmonella Typhi strains, Ty21a and Ty2, were seeded to influent wastewater at known concentrations to evaluate the following methods: grab sampling using electropositive filters, centrifugation, direct enrichment, or membrane filtration and trap sampling using Moore swabs. Concentrated samples underwent nucleic acid extraction and were detected and/or quantified via qPCR. Results suggest that all methods tested can be successful at concentrating Salmonella Typhi for subsequent detection by qPCR, although each method has its own strengths and weaknesses including the Salmonella Typhi concentrations they are best suited for with a range of positive detections observed as low as 0.1-0.001 CFU Ty21a/mL and 0.01 CFU Ty2/mL. These factors should be considered when identifying a method for environmental surveillance and will greatly depend on the use case planned. 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.

Laboratory tests were conducted to characterize the composition of emissions from sanding Corian(®), a solid-surface composite material mainly composed of alumina trihydrate (ATH) and acrylic polymer. Three sandpaper materials (ceramic, silicon carbide, and aluminum oxide) were tested to distinguish the contribution of aluminum-containing dust in the emission from Corian(®) and sandpaper itself. The result can help identify the main cause of the pulmonary fibrosis from exposure to aluminum-containing dust while sanding Corian(®). Airborne dust samples were measured using direct-reading instruments and collected using a Micro-Orifice Uniform Deposit Impactor (MOUDI) for estimating the normalized dust generation rate. The size-classified dust samples from MOUDI were analyzed for elemental aluminum content. Additionally, air samples were analyzed for characterizing methyl methacrylate (MMA). The results from the direct-reading instruments reveal that the size distribution of particulate from sanding Corian(®) differs from that of sawing Corian(®), showing that the size distribution of dust is affected by the fabrication process. The normalized respirable dust generation rate indicates that more respirable dust was generated during sanding Corian(®) board. However, the use of aluminum oxide sandpaper does not result in a higher aluminum content in the respirable dust from sanding Corian(®), suggesting that the aluminum content of the respirable dust is primarily originated from Corian(®) itself. The generation rates of MMA from sanding did not vary much among all types of sandpapers, and they were much lower than that of sawing, likely due to the higher temperature in the sawing process.

Improving ventilation has been one of several COVID-19 prevention strategies implemented by kindergarten through grade 12 (K-12) schools to stay open for safe in-person learning. Because transmission of SARS-CoV-2 occurs through inhalation of infectious viral particles, it is important to reduce the concentration of and exposure time to infectious aerosols (1-3). CDC examined reported ventilation improvement strategies among U.S. K-12 public school districts using telephone survey data collected during August-December 2022. Maintaining continuous airflow through school buildings during active hours was the most frequently reported strategy by school districts (50.7%); 33.9% of school districts reported replacement or upgrade of heating, ventilation, and air conditioning (HVAC) systems; 28.0% reported installation or use of in-room air cleaners with high-efficiency particulate air (HEPA) filters; and 8.2% reported installation of ultraviolet (UV) germicidal irradiation (UVGI) devices, which use UV light to kill airborne pathogens, including bacteria and viruses. School districts in National Center for Education Statistics (NCES) city locales, the West U.S. Census Bureau region, and those designated by U.S. Census Bureau Small Area Income Poverty Estimates (SAIPE) as high-poverty districts reported the highest percentages of HVAC system upgrades and HEPA-filtered in-room air cleaner use, although 28%-60% of all responses were unknown or missing. Federal funding remains available to school districts to support ventilation improvements. Public health departments can encourage K-12 school officials to use available funding to improve ventilation and help reduce transmission of respiratory diseases in K-12 settings.

OBJECTIVE: Clinical practice guidelines are often created through collaboration among organizations. Use of inconsistent terminology may cause poor communication and delays. This study aimed to develop a glossary of terms related to collaboration in guideline development. STUDY DESIGN AND SETTING: A literature review of collaborative guidelines was performed to develop an initial list of terms related to guideline collaboration. The list of terms was presented to the members of the Guideline International Network Guidelines Collaboration Working Group, who provided presumptive definitions for each term and proposed additional terms to be included. The revised list was subsequently reviewed by an international, multidisciplinary panel of expert stakeholders. Recommendations received during this pre-Delphi review were implemented to augment an initial draft glossary. The glossary was then critically evaluated and refined through two rounds of Delphi surveys and a virtual consensus meeting with all panel members as Delphi participants. RESULTS: Forty-nine experts participated in the pre-Delphi survey and 44 participated in the two-round Delphi process. Consensus was reached for 37 terms and definitions. CONCLUSION: Uptake and utilization of this guideline collaboration glossary by key organizations and stakeholder groups may facilitate collaboration among guideline-producing organizations by improving communication, minimizing conflicts, and increasing guideline development efficiency.

Broadly neutralizing antibodies against SARS-CoV-2 variants are sought to curb COVID-19 infections. Here we produced and characterized a set of mouse monoclonal antibodies (mAbs) specific for the ancestral SARS-CoV-2 receptor binding domain (RBD). Two of them, 17A7 and 17B10, were highly potent in microneutralization assay with 50% inhibitory concentration (IC(50) ) ≤ 135 ng/ml against infectious SARS-CoV-2 variants, including G614, Alpha, Beta, Gamma, Delta, Epsilon, Zeta, Kappa, Lambda, B.1.1.298, B.1.222, B.1.5 and R.1. Both mAbs (especially 17A7) also exhibited strong in vivo efficacy in protecting K18-hACE2 transgenic mice from the lethal infection with G614, Alpha, Beta, Gamma and Delta viruses. Structural analysis indicated that 17A7 and 17B10 target the tip of the receptor binding motif (RBM) in the RBD-up conformation. A third RBD-reactive mAb (3A6) although escaped by Beta and Gamma, was highly effective in cross-neutralizing Delta and Omicron BA.1 variants in vitro and in vivo. In competition experiments, antibodies targeting epitopes similar to these 3 mAbs were rarely enriched in human COVID-19 convalescent sera or post-vaccination sera. These results are helpful to inform new antibody/vaccine design and these mAbs can be useful tools for characterizing SARS-CoV-2 variants and elicited antibody responses. This article is protected by copyright. All rights reserved.

The aim of the study was to assess barriers to Vaccines for Children (VFC) provider practices participating in the COVID-19 Vaccination Program and intentions to offer COVID-19 vaccination to children aged <5 years. We invited a random sample of 15 000 VFC provider practices in the United States to complete an online survey during February 28 to March 11, 2022. Of 2809 practices that completed the survey, 2246 (80.0%) were enrolled in the COVID-19 Vaccination Program. Concerns around staff resources, vaccine and supply storage space, and vaccine wastage from multidose vials were the most frequently reported program-enrollment barriers. Among enrolled practices that have decided whether to offer COVID-19 vaccination to the children aged <5 years, 1641 (88.8% of 1848) reported likely offering it to current patients, and 1165 reported likely offering it to children who are not current patients. Addressing participation barriers and encouraging active promotion may increase COVID-19 vaccination coverage of children.

BACKGROUND: Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs). METHODS: Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum. FINDINGS: 20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76-0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76-0·88]). INTERPRETATION: The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges-Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns. FUNDING: NASA, National Institutes of Health-The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation.

INTRODUCTION: Diarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions. METHODS: We established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale. RESULTS: During 2017-2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516). CONCLUSIONS: Despite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality.

Electrochemical fluorination manufacture of perfluorooctane sulfonic acid (PFOS), one of the most studied per- and polyfluoroalkyl substances, produces mixtures of linear and branched isomers, but little is known about human exposure to linear or branched PFOS isomers. We examined determinants affecting isomer-specific patterns of PFOS in serum in two adult populations in the United States, the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). After adjusting for demographic variables, fish consumption (in both populations), a glomerular filtration rate above 90 mL/min/1.73 m(2) (observed in NHANES; not tested in SWAN-MPS), premenopausal status (only observed in SWAN-MPS), and less consumption of processed food (observed in SWAN-MPS; not tested in NHANES) were associated with a higher proportion of linear PFOS. Non-Hispanic Black and Asian participants were likely to have a higher proportion of linear PFOS than non-Hispanic White participants in both populations. Our findings suggest that isomer-specific patterns of PFOS serum concentrations in humans vary depending on population characteristics that affect PFOS exposure and excretion. Consideration of specific PFOS isomers in future human biomonitoring and epidemiologic studies can provide useful insight to better understand PFOS exposure.

Here we interrogate the factors responsible for SARS-CoV-2 breakthrough infections in a K18-hACE2 transgenic mouse model. We show that Delta and the closely related Kappa variant cause viral pneumonia and severe lung lesions in K18-hACE2 mice. Human COVID-19 mRNA post-vaccination sera after the 2(nd) dose are significantly less efficient in neutralizing Delta/Kappa than early 614G virus in vitro and in vivo. By 5 months post-vaccination, ≥50% of donors lack detectable neutralizing antibodies against Delta and Kappa and all mice receiving 5-month post-vaccination sera die after the lethal challenges. Although a 3(rd) vaccine dose can boost antibody neutralization against Delta in vitro and in vivo, the mean log neutralization titers against the latest Omicron subvariants are 1/3-1/2 of those against the original 614D virus. Our results suggest that enhanced virulence, greater immune evasion and waning of vaccine-elicited protection account for SARS-CoV-2 variants caused breakthrough infections.

Adjuvants can increase the magnitude and durability of the immune response generated by the vaccine antigen. Aluminum salts (Alum) remain the main adjuvant licensed for human use. A few new adjuvants have been licensed for use in human vaccines since the 1990s. QS-21, a mixture of saponin compounds, was included in the AS01-adjuvanted Shingrix vaccine. Here, we investigated the adjuvant effects of VSA-1, a newly developed semisynthetic analog of QS-21, on promoting protection in mice after vaccination with the inactivated split virus vaccine. The adjuvant effects of VSA-1 on improving vaccine efficacy after prime immunization were evident as shown by significantly higher levels of hemagglutination-inhibiting antibody titers and enhanced homologous protection compared to those by QS-21 and Alum adjuvants. The adjuvant effects of VSA-1 on enhancing heterosubtypic protection after two doses of adjuvanted vaccination were comparable to those of QS-21. T cell immunity played an important role in conferring cross-protection by VSA-1-adjuvanted vaccination. Overall, the findings in this study suggest that VSA-1 exhibits desirable adjuvant properties and a unique pattern of innate and adaptive immune responses, contributing to improved homologous and heterosubtypic protection by inactivated split influenza vaccination in mice.

What is already known about this topic A COVID-19 vaccine booster dose provides enhanced protection against SARS-CoV-2 infection, COVID-19-associated emergency department visits, hospitalization, and death. What is added by this report Among 214 million eligible persons aged 5 years, approximately one half received a booster dose. Among 55 million eligible persons aged 50 years, approximately one third received a second booster dose. Booster and second booster dose coverage rates were lower among the youngest age groups; males; non-Hispanic Black or African American, Hispanic or Latino, and multiracial persons; residents of rural counties; and Janssen (Johnson & Johnson) primary series recipients. What are the implications for public health practice Focused interventions to improve vaccine equity and effectiveness of outreach to populations with low booster and second booster dose coverage should be developed and implemented. 2022 Department of Health and Human Services. All rights reserved.