Objectives: To (1) determine associations between maternal risk conditions and severe adverse outcomes that may benefit from risk-appropriate care and (2) assess whether associations between risk conditions and outcomes vary by level of maternal care (LoMC). Methods: We used the 2017-2019 National Inpatient Sample (NIS) to calculate associations between maternal risk conditions and severe adverse outcomes. Risk conditions included severe preeclampsia, placenta accreta spectrum (PAS) conditions, and cardiac conditions. Outcomes included disseminated intravascular coagulation (DIC) with blood products transfusion or shock, pulmonary edema or acute respiratory distress syndrome (ARDS), stroke, acute renal failure, and a composite cardiac outcome. Then we used 2019 delivery hospitalization data from five states linked to hospital LoMC. We calculated associations between risk conditions and outcomes overall and stratified by LoMC and assessed for effect modification by LoMC. Results: We found positive measures of association between risk conditions and outcomes. Among patients with severe preeclampsia or PAS, the magnitudes of the associations with DIC with blood products transfusion or shock, pulmonary edema or ARDS, and acute renal failure were lower in Level III/IV compared with <Level III facilities. Among patients with cardiac conditions, the magnitudes of the associations with these outcomes, along with stroke, were also lower in Level III/IV compared with <Level III facilities. The proportion of patients with risk conditions that delivered in <Level III facilities was 19.8-46.8%. Conclusions: Odds of severe adverse outcomes among women with selected risk conditions were lower for births occurring at higher-level facilities, supporting the benefit of risk-appropriate care.

In 2018, the Navi Mumbai Municipal Corporation implemented phase 1 of a public sector typhoid conjugate vaccine campaign in Navi Mumbai, India, targeting all children aged 9 months to 14 years within its administrative boundaries. To assess associations with receipt of vaccine in phase 1, we used generalized estimating equations to calculate estimates of vaccination by child-, household-, and community-level demographics (child education and age; household head education, income, and occupation; community informal settlement percent). Campaign vaccine receipt was most associated with children enrolled in school (odds ratio [OR] = 3.84, 95% CI: 2.18-6.77), the lowest household income tertile when divided into three equal parts (OR = 1.64, 95% CI: 1.43-1.84), and lower community-level socioeconomic status (OR = 1.06, 95% CI: 1.04-1.08 per 10% informal settlement proportion). The campaign was successful in reaching the most underserved populations of its target communities.

Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity. | Seasonal influenza (flu) viruses cause outbreaks every winter. People infected with influenza typically develop mild respiratory symptoms. But flu infections can cause serious illness in young children, older adults and people with chronic medical conditions. Infected or vaccinated individuals develop some immunity, but the viruses evolve quickly to evade these defenses in a process called antigenic drift. As the viruses change, they can re-infect previously immune people. Scientists update the flu vaccine yearly to keep up with this antigenic drift. The immune system fights flu infections by recognizing two proteins, known as antigens, on the virus’s surface, called hemagglutinin (HA) and neuraminidase (NA). However, mutations in the genes encoding these proteins can make them unrecognizable, letting the virus slip past the immune system. Scientists would like to know how these changes affect the size, severity and timing of annual influenza outbreaks. Perofsky et al. show that tracking genetic changes in HA and NA may help improve flu season predictions. The experiments compared the severity of 22 flu seasons caused by the A(H3N2) subtype in the United States with how much HA and NA had evolved since the previous year. The A(H3N2) subtype experiences the fastest rates of antigenic drift and causes more cases and deaths than other seasonal flu viruses. Genetic changes in HA and NA were a better predictor of A(H3N2) outbreak severity than the blood tests for protective antibodies that epidemiologists traditionally use to track flu evolution. However, the prevalence of another subtype of influenza A circulating in the population, called A(H1N1), was an even better predictor of how severe A(H3N2) outbreaks would be. Perofsky et al. are the first to show that genetic changes in NA contribute to the severity of flu seasons. Previous studies suggested a link between genetic changes in HA and flu season severity, and flu vaccines include the HA protein to help the body recognize new influenza strains. The results suggest that adding the NA protein to flu vaccines may improve their effectiveness. In the future, flu forecasters may want to analyze genetic changes in both NA and HA to make their outbreak predictions. Tracking how much of the A(H1N1) subtype is circulating may also be useful for predicting the severity of A(H3N2) outbreaks. | eng

Typbar-TCV®, a typhoid conjugate vaccine (TCV), was prequalified by the World Health Organization in 2017. We evaluated its effectiveness in a mass vaccination program targeting children 9 months to 14 years in Navi Mumbai, India, from September 2018 to July 2020. We compared laboratory-confirmed typhoid cases from six clinical sites with age-matched community controls. Of 38 cases, three (8.6%) received TCV through the campaign, compared with 53 (37%) of 140 controls. The adjusted odds ratio of typhoid fever among vaccinated children was 0.16 (95% CI: 0.05-0.55), equivalent to a vaccine effectiveness of 83.7% (95% CI: 45.0-95.3). Vaccine effectiveness of Typbar-TCV in this large public sector vaccine introduction was similar to prior randomized controlled trials, providing reassurance to policymakers that TCV effectiveness is robust in a large-scale implementation.

OBJECTIVE: To examine the relationship between stroke care infrastructure and stroke quality-of-care outcomes at 29 spoke hospitals participating in the <name concealed for blinding purposes> hub-and-spoke telestroke network. MATERIALS AND METHODS: Encounter-level data from <name concealed for blinding purposes> telestroke patient registry were filtered to include encounters during 2015-2022 for patients aged 18 and above with a clinical diagnosis of acute ischemic stroke, and who received intravenous tissue plasminogen activator. Unadjusted and adjusted generalized estimating equations assessed associations between time-related stroke quality-of-care metrics captured during the encounter and the existence of the two components of stroke care infrastructure-stroke coordinators and stroke center certifications-across all hospitals and within hospital subgroups defined by size and rurality. RESULTS: Telestroke encounters at spoke hospitals with stroke coordinators and stroke center certifications were associated with shorter door-to-needle (DTN) times (60.9 min for hospitals with both components and 57.3 min for hospitals with one, vs. 81.2 min for hospitals with neither component, p <.001). Similar patterns were observed for the percentage of encounters with DTN time of ≤60 min (63.8% and 68.9% vs. 32.0%, p <.001) and ≤45 min (34.0% and 38.4% vs. 8.42%, p <.001). Associations were similar for other metrics (e.g., door-to-registration time), and were stronger for smaller (vs. larger) hospitals and rural (vs. urban) hospitals. CONCLUSIONS: Stroke coordinators or stroke center certifications may be important for stroke quality of care, especially at spoke hospitals with limited resources or in rural areas.

BACKGROUND: Insecticide-treated nets (ITNs) contributed significantly to the decline in malaria since 2000. Their protective efficacy depends not only on access, use, and net integrity, but also location of people within the home environment and mosquito biting profiles. Anopheline mosquito biting and human location data were integrated to identify potential gaps in protection and better understand malaria transmission dynamics in Busia County, western Kenya. METHODS: Direct observation of human activities and human landing catches (HLC) were performed hourly between 1700 to 0700 h. Household members were recorded as home or away; and, if at home, as indoors/outdoors, awake/asleep, and under a net or not. Aggregated data was analysed by weighting hourly anopheline biting activity with human location. Standard indicators of human-vector interaction were calculated using a Microsoft Excel template. RESULTS: There was no significant difference between indoor and outdoor biting for Anopheles gambiae sensu lato (s.l.) (RR = 0.82; 95% CI 0.65-1.03); significantly fewer Anopheles funestus were captured outdoors than indoors (RR = 0.41; 95% CI 0.25-0.66). Biting peaked before dawn and extended into early morning hours when people began to awake and perform routine activities, between 0400-0700 h for An. gambiae and 0300-0700 h for An. funestus. The study population away from home peaked at 1700-1800 h (58%), gradually decreased and remained constant at 10% throughout the night, before rising again to 40% by 0600-0700 h. When accounting for resident location, nearly all bites within the peri-domestic space (defined as inside household structures and surrounding outdoor spaces) occurred indoors for unprotected people (98%). Using an ITN while sleeping was estimated to prevent 79% and 82% of bites for An. gambiae and An. funestus, respectively. For an ITN user, most remaining exposure to bites occurred indoors in the hours before bed and early morning. CONCLUSION: While use of an ITN was estimated to prevent most vector bites in this context, results suggest gaps in protection, particularly in the early hours of the morning when biting peaks and many people are awake and active. Assessment of additional human exposure points, including outside of the peri-domestic setting, are needed to guide supplementary interventions for transmission reduction.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

IMPORTANCE: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide. OBJECTIVE: To evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection. EXPOSURE: Respiratory syncytial virus. MAIN OUTCOMES AND MEASURES: Data were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity. RESULTS: The first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

Background: All pregnant women and those who may become pregnant are recommended by the Advisory Committee on Immunization Practices to receive the flu vaccine to prevent severe illness in the woman and infant. Despite the increased risk for complications in this population, flu vaccine uptake in pregnant women was 68.1% in the 2020-2021 flu season, with disparities by race and ethnicity. We sought to describe associations between provider recommendation with flu vaccine uptake by race and ethnicity in Tennessee women with a recent live birth. Materials and Methods: Weighted analysis used data from the 2016 to 2020 Tennessee Pregnancy Risk Assessment Monitoring System complex survey analysis procedures. Uptake was measured as receipt of flu vaccine in the 12 months before the most recent live birth, and positive recall of receiving provider advice to get the shot was the independent variable; for both we estimated 5-year averages stratified by race/ethnicity. Differences were assessed using chi-square tests. We modeled receipt of flu vaccine and estimated marginal predicted prevalence ratios (PRs); stratified models by race/ethnicity were constructed to estimate unadjusted and adjusted PRs. Results: The 5-year average for vaccine uptake before or during pregnancy was 56.7% but varied by race and ethnicity. Stratified bivariate analyses yielded different magnitudes of association by race/ethnicity between provider recommendation and flu vaccine receipt. After adjustment for payment source at delivery, marital status, age group, urbanicity, and maternal education, receiving a provider recommendation was strongly associated with flu vaccine uptake for all stratified models of pregnant women included in the study. The effect size was of a larger magnitude among non-Hispanic black women, a population with a lower vaccine uptake. Conclusions: Given the association between provider recommendation and vaccine uptake in all groups, attention should be focused on increasing rates of provider recommendation.

We performed whole-genome sequencing of 174 Salmonella Typhi and 54 Salmonella Paratyphi A isolates collected through prospective surveillance in the context of a phased typhoid conjugate vaccine introduction in Navi Mumbai, India. We investigate the temporal and geographical patterns of emergence and spread of antimicrobial resistance. We evaluated the relationship between the spatial distance between households and genetic clustering of isolates. Most isolates were non-susceptible to fluoroquinolones, with nearly 20% containing ≥3 quinolone resistance-determining region mutations. Two H58 isolates carried an IncX3 plasmid containing bla(SHV-12), associated with ceftriaxone resistance, suggesting that the ceftriaxone-resistant isolates from India independently evolved on multiple occasions. Among S. Typhi, we identified two main clades circulating (2.2 and 4.3.1 [H58]); 2.2 isolates were closely related following a single introduction around 2007, whereas H58 isolates had been introduced multiple times to the city. Increasing geographic distance between isolates was strongly associated with genetic clustering (odds ratio [OR] = 0.72 per km; 95% credible interval [CrI]: 0.66-0.79). This effect was seen for distances up to 5 km (OR = 0.65 per km; 95% CrI: 0.59-0.73) but not seen for distances beyond 5 km (OR = 1.02 per km; 95% CrI: 0.83-1.26). There was a non-significant reduction in odds of clustering for pairs of isolates in vaccination communities compared with non-vaccination communities or mixed pairs compared with non-vaccination communities. Our findings indicate that S. Typhi was repeatedly introduced into Navi Mumbai and then spread locally, with strong evidence of spatial genetic clustering. In addition to vaccination, local interventions to improve water and sanitation will be critical to interrupt transmission. IMPORTANCE Enteric fever remains a major public health concern in many low- and middle-income countries, as antimicrobial resistance (AMR) continues to emerge. Geographical patterns of typhoidal Salmonella spread, critical to monitoring AMR and planning interventions, are poorly understood. We performed whole-genome sequencing of S. Typhi and S. Paratyphi A isolates collected in Navi Mumbai, India before and after a typhoid conjugate vaccine introduction. From timed phylogenies, we found two dominant circulating lineages of S. Typhi in Navi Mumbai-lineage 2.2, which expanded following a single introduction a decade prior, and 4.3.1 (H58), which had been introduced repeatedly from other parts of India, frequently containing "triple mutations" conferring high-level ciprofloxacin resistance. Using Bayesian hierarchical statistical models, we found that spatial distance between cases was strongly associated with genetic clustering at a fine scale (<5 km). Together, these findings suggest that antimicrobial-resistant S. Typhi frequently flows between cities and then spreads highly locally, which may inform surveillance and prevention strategies.

Background: The WHO recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018 the Navi Mumbai Municipal Corporation (NMMC), implemented a TCV campaign. The campaign targeted all children aged 9-months through 14-years within NMMC boundaries (~320,000 children) over 2 vaccination phases. The phase 1 campaign occurred from July 14-August 25, 2018 (71% coverage, ~113,420 children). We evaluated the campaign's programmatic effectiveness in reducing typhoid cases at the community level. Method(s): We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai, offering blood cultures to children presenting with fever for at least 3 days. We employed a cluster-randomized test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched culture-confirmed typhoid cases with up to 3 culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression. Result(s): Between September 1, 2018-March 31, 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (campaign effectiveness, 56%, 95%CI: 25%-74%, p=0.002). Cases >= 5-years-old were 0.37 times as likely (95% CI: 0.19-0.70; p-value = 0.002) and cases during the first year of surveillance were 0.30 times as likely (95% CI: 0.14-0.64; p-value = 0.002) to live in vaccine campaign communities. Conclusion(s): Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever. 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.

Introduction Outside of pandemics, there is little information about occurrence of prolonged unplanned K-12 school closures (PUSC). We describe here the reasons, characteristics, and patterns of PUSC in the United States during 8 consecutive inter-pandemic academic years, 2011-2019. Methods From August 1, 2011 through June 30, 2019, daily systematic online searches were conducted to collect data on publicly announced unplanned school closures lasting >=1 school days in the United States. Closures were categorized as prolonged when schools were closed for >=5 unplanned days (approximating one full workweek), excluding weekends and scheduled days off per school calendars. Results During the eight academic years, a total of 22,112 PUSCs were identified, affecting over 800,000 teachers and 13 million students that resulted in 91.5 million student-days lost. A median of 62.9% of students in PUSC-affected schools were eligible for subsidized school meals. Most affected schools were in cities (35%) and suburban areas (33%). Natural disasters (47%), adverse weather conditions (35%), and budget/teacher strikes (15%) were the most frequently cited reasons for PUSC; illness accounted for 1%, and building/facility issues, environmental issues and violence together accounted for the remaining 2%. The highest number of PUSCs occurred in Health and Human Services Regions 2, 3, 4, and 6 encompassing areas that are frequently in the path of hurricanes and tropical storms. The majority of PUSCs in these regions were attributed to a handful of hurricanes during the fall season, including hurricanes Sandy, Irma, Harvey, Florence, and Matthew. Conclusions PUSCs occur annually in the United States due to a variety of causes and are associated with a substantive loss of student-days for in-school learning. Both these prior experiences with PUSCs and those during the current COVID-19 pandemic illustrate a need for creating sustainable solutions for high-quality distance learning and innovative supplemental feeding programs nationwide, especially in disaster-prone areas. 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.

Inadvertent ingestion of recreational waters contaminated with feces containing Cryptosporidium spp., an extremely chlorine-tolerant parasite, can result in gastrointestinal illness. In early 2023, a Massachusetts college notified the Massachusetts Department of Public Health (MDPH) that 19 of 50 (38%) members of the men’s and women’s swim teams had experienced diarrhea beginning 3 days after their return from a weeklong training trip to Puerto Rico. One ill swimmer reported receiving a positive ova and parasite test result for Cryptosporidium. On days 5 and 6 after return from Puerto Rico, symptomatic Massachusetts swimmers competed in two meets against New York and Rhode Island collegiate teams (meet 1 and meet 2, respectively), raising concern about the potential for secondary transmission.

BACKGROUND: Sporicidal products containing hydrogen peroxide (HP), peracetic acid (PAA), and acetic acid (AA) are used widely in multiple industries, including healthcare. Despite widespread use in healthcare, few studies have assessed associations between exposures to HP, PAA, and AA, and work-related symptoms in these settings. METHODS: In 2018, we performed a health and exposure assessment at a hospital where a sporicidal product consisting of HP, PAA, and AA, was used as the primary cleaner on hospital surfaces. We collected 56 personal and mobile air samples for HP, PAA, and AA on participants while they performed their regular cleaning duties; collected area samples for HP (n = 28), PAA (n = 28), and AA (n = 70) in multiple hospital locations where cleaning was performed; and administered a postshift survey to assess eye, skin, and upper and lower airway symptoms that occurred cross-shift or in the previous 4 weeks. RESULTS: Full-shift exposure levels for HP (range: <3-559 ppb), PAA (range: <0.2-8 ppb), and AA (range: <5-915 ppb) were all below US occupational exposure limits. We observed positive associations (p < 0.05) between shift, departmental average, and departmental 95th percentile exposures to HP, PAA, and AA vapors, and work-related acute (cross-shift) and chronic (previous 4 weeks) eye, upper airway, and lower airway symptoms after adjusting for age, gender, smoking status, use of other cleaning products containing sensitizers and irritants, allergic status, and stress. CONCLUSIONS: Our observations of work-related upper and lower airway symptoms among hospital workers exposed to vapors from a sporicidal product containing HP, PAA, and AA indicate a need for a combination of engineering, administrative, and PPE controls to reduce exposure. Additionally, alternative nonchemical disinfection technologies should be further investigated as a means to simultaneously reduce healthcare workers' exposure to disinfectants while also minimizing costly healthcare-acquired infections.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

BACKGROUND: People with a maternal substance use disorder (SUD) may experience a lack of access to necessary healthcare and more specifically, postpartum healthcare. It is not known whether increased insurance coverage introduced by Medicaid expansion has improved postpartum healthcare utilization among this population. METHODS: Oregon 2008-2016 birth certificates and Medicaid claims were used to examine whether continuous insurance enrollment and postpartum healthcare utilization increased post-Medicaid expansion in a population with and without SUD (n = 9,337). International Classification of Diseases codes were used to identify deliveries, SUD, and postpartum healthcare. Univariable and multivariable generalized linear regression with standard errors clustered by individual were used to estimate the association between Medicaid expansion and postpartum healthcare utilization, stratified by maternal SUD. RESULTS: Among the 10.3% with SUD, expansion was not associated with increased continuous enrollment or postpartum healthcare utilization. Among those without SUD, post-expansion deliveries were associated with increased continuous enrollment (+105.0 days; 95% CI=96.9-113.2), total (+4.4; 95% CI=2.9-6.0), postpartum (+0.3; 95% CI=0.2-0.4), inpatient (+0.9; 95% CI=0.7-1.1), outpatient (+2.3; 95% CI=1.4-3.3), office (+0.9; 95% CI=0.2-1.6), and emergency department (+0.3; 95% CI=0.1-0.5) visits. Among deliveries to postpartum people with SUD, 27.2% had opioid use disorder (OUD); expansion was associated with increased OUD medication use (12.0% vs 18.3%) and number of fills (6.7 vs 16.6). CONCLUSIONS: Medicaid expansion in Oregon was only associated with increased Medicaid-financed healthcare utilization for postpartum people without SUD, with the exception of those with OUD, demonstrating the need for assessing various strategies to improve postpartum healthcare utilization.

Navi Mumbai Municipal Corporation (NMMC), a local government in Mumbai, India, implemented the first public sector TCV campaign in 2018. This study estimated the delivery costs of this TCV campaign using a Microsoft Excel-based tool based on a micro-costing approach from the government (NMMC) perspective. The campaign's financial (direct expenditures) and economic costs (financial costs plus the monetized value of additional donated or existing items) incremental to the existing immunization program were collected. The data collection methods involved consultations with NMMC staff, reviews of financial and programmatic records of NMMC and the World Health Organization (WHO), and interviews with the health staff of sampled urban health posts (UHPs). Three UHPs were purposively sampled, representing the three dominant residence types in the catchment area: high-rise, slum, and mixed (high-rise and slum) areas. The high-rise area UHP had lower vaccination coverage (47%) compared with the mixed area (71%) and slum area UHPs (76%). The financial cost of vaccine and vaccination supplies (syringes, safety boxes) was $1.87 per dose, and the economic cost was $2.96 per dose in 2018 US dollars. Excluding the vaccine and vaccination supplies cost, the financial delivery cost across the 3 UHPs ranged from $0.37 to $0.53 per dose, and the economic delivery cost ranged from $1.37 to $3.98 per dose, with the highest delivery costs per dose in the high-rise areas. Across all 11 UHPs included in the campaign, the weighted average financial delivery cost was $0.38 per dose, and the economic delivery cost was $1.49 per dose. WHO has recommended the programmatic use of TCV in typhoid-endemic countries, and Gavi has included TCV in its vaccine portfolio. This first costing study of large-scale TCV introduction within a public sector immunization program provides empirical evidence for policymakers, stakeholders, and future vaccine campaign planning.

OBJECTIVE: Indoor mold after flooding poses health risks including rare but serious invasive mold infections. The purpose of this study was to evaluate use of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes for mold infection and mold exposure in Houston, Texas during the year before and the year after Hurricane Harvey. METHODS: This study used data from MarketScan, a large health insurance claims database. RESULTS: The incidence of invasive mold infections remained unchanged in the year after Hurricane Harvey; however, the incidence of diagnosis codes for mold exposure nearly doubled compared with the year before the hurricane (6.3 vs. 11.0 per 100,000 enrollees, rate ratio: 1.7, 95% confidence interval 1.0-3.1). CONCLUSIONS: Diagnosis codes alone may not be sufficiently sensitive to detect changes in invasive mold infection rates within this population and timeframe, demonstrating the need for more comprehensive studies.

BACKGROUND: The WHO recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018 the Navi Mumbai Municipal Corporation (NMMC), implemented a TCV campaign. The campaign targeted all children aged 9-months through 14-years within NMMC boundaries (∼320,000 children) over 2 vaccination phases. The phase 1 campaign occurred from July 14-August 25, 2018 (71% coverage, ∼113,420 children). We evaluated the phase 1 campaign's programmatic effectiveness in reducing typhoid cases at the community level. METHODS: We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai, offering blood cultures to children presenting with fever ≥ 3 days. We employed a cluster-randomized (by administrative boundary) test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched test-positive, culture-confirmed typhoid cases with up to 3 test-negative, culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression. RESULTS: Between September 1, 2018-March 31, 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (programmatic effectiveness, 56%, 95%CI: 25%-74%, p=0.002). Cases ≥ 5-years-old were 0.37 times as likely (95% CI: 0.19-0.70; p-value = 0.002) and cases during the first year of surveillance were 0.30 times as likely (95% CI: 0.14-0.64; p-value = 0.002) to live in vaccine campaign communities. CONCLUSIONS: Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.

BACKGROUND: Public health programs varied in ability to reach people with COVID-19 and their contacts to encourage separation from others. For both adult cases of COVID-19 and contacts, we estimated the impact of contact tracing activities on separation behaviors from January, 2020 until March, 2022. METHODS: We used a probability-based panel survey of a nationally representative sample to gather data for estimates and comparisons. RESULTS: An estimated 64,255,351 adults reported a positive SARS-CoV-2 test result; 79.6% isolated for >5 days, 60.2% isolated for >10 days, and 79.2% self-notified contacts. 24,057,139 (37.7%) completed a case investigation and 46.2% reported contacts to health officials. More adults who completed a case investigation isolated than adults who did not (>5 days, 82.6%; >10 days, 69.8% versus >5 days, 78.2% and >10 days 54.8%; p-values for both measures <0.05).84,946,636 adults were a contact to a COVID-19 case; 73.1% learned of their exposure directly from a case; 49.4% quarantined for >5 days, 18.7% quarantined for >14 days, and 13.5% completed a contact tracing call. More who completed a contact tracing call quarantined than those who did not (>5 days, 61.2%; >14 days, 25.2% versus >5 days, 48.5%; >14 days, 18.0%; p-values for both measures <0.05). CONCLUSIONS: Engagement in contact tracing positively correlated with isolation and quarantine. However, most adults with COVID-19 isolated and self-notified contacts regardless of whether the public health workforce was able to reach them. Identifying and reaching contacts was challenging, and limited the ability to promote quarantining, and testing.

OBJECTIVE: Evidence regarding effectiveness of interleukin-1 receptor antagonism in Multisystem Inflammatory Syndrome in Children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy. METHODS: We conducted a retrospective cohort study of MIS-C cases in a U.S. surveillance registry November 2020-December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids vs. anakinra plus IVIG and/or glucocorticoids (days 0-1), using inverse probability weighting to balance severity. Primary outcomes were vasopressor requirement (day 3) and impaired left ventricular ejection fraction (days 3-4). The secondary outcome was 50% reduction in C-reactive protein (day 3). RESULTS: Among 1516 MIS-C cases (44 sites), 193 (13%) received anakinra alone or with other immunomodulators as initial treatment (range 0-74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (N=121) vs. IVIG and glucocorticoids (N=389) was not associated with significant differences in vasopressor requirement (25.6% vs. 20.1%; RR 1.27, 95% CI [0.88-1.84]), ventricular dysfunction (33.7% vs. 25.7%; RR 1.31, 95% CI [0.98-1.75]), or C-reactive protein reduction. CONCLUSIONS: We identified substantial variation in initial anakinra use in a real-world population of children with MIS-C, but no average short-term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone.

BACKGROUND: Characterizing invasive mold infection (IMI) epidemiology in the context of large flooding events is important for public health planning and clinical decision making. METHODS: We assessed IMI incidence (per 10 000 healthcare encounters) 1 year before and after Hurricane Harvey at 4 hospitals in Houston, Texas. Potential IMI cases were assigned as proven or probable cases using established definitions, and surveillance cases using a novel definition. We used rate ratios to describe IMI incidence and multivariable logistic regression to examine patient characteristics associated with IMI case status. RESULTS: IMI incidence was significantly higher posthurricane (3.69 cases) than prehurricane (2.50 cases) (rate ratio, 1.48 [95% confidence interval, 1.10-2.00]), largely driven by surveillance IMI cases. Aspergillus was the most common species cultured (33.5% prehurricane and 39.9% posthurricane). About one-quarter (25.8%) of IMI patients lacked classical IMI risk factors such as hematologic malignancy and transplantations. Overall, 45.1% of IMI patients received intensive care, and in-hospital all-cause mortality was 24.2%. CONCLUSIONS: IMI incidence likely increased following Hurricane Harvey and outcomes for IMI patients were severe. Patient and clinician education on IMI prevention and identification is warranted, particularly as the frequency of extreme weather events increases due to climate change.

OBJECTIVE: Although the US infant mortality rate reached a record low in 2020, the sudden infant death syndrome (SIDS) rate increased from 2019. To understand if the increase was related to changing death certification practices or the coronavirus disease 2019 (COVID-19) pandemic, we examined sudden unexpected infant death (SUID) rates as a group, by cause, and by race and ethnicity. METHODS: We estimated SUID rates during 2015 to 2020 using US period-linked birth and death data. SUID included SIDS, unknown cause, and accidental suffocation and strangulation in bed. We examined changes in rates from 2019 to 2020 and assessed linear trends during prepandemic (2015-2019) using weighted least squares regression. We also assessed race and ethnicity trends and quantified COVID-19-related SUID. RESULTS: Although the SIDS rate increased significantly from 2019 to 2020 (P < .001), the overall SUID rate did not (P = .24). The increased SIDS rate followed a declining linear trend in SIDS during 2015 to 2019 (P < .001). Other SUID causes did not change significantly. Our race and ethnicity analysis showed SUID rates increased significantly for non-Hispanic Black infants from 2019 to 2020, widening the disparities between these two groups during 2017 to 2019. In 2020, <10 of the 3328 SUID had a COVID-19 code. CONCLUSIONS: Diagnositic shifting likely explained the increased SIDS rate in 2020. Why the SUID rate increased for non-Hispanic Black infants is unknown, but warrants continued monitoring. Interventions are needed to address persistent racial and ethnic disparities in SUID.

In 2007, voluntary medical male circumcision (VMMC) was endorsed by the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS after it was found to be associated with approximately a 60% reduction in the risk for female-to-male transmission of HIV (1). As a result of this endorsement, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), through partnerships with U.S. government agencies, including CDC, the U.S. Department of Defense, and the U.S. Agency for International Development, started supporting VMMCs performed in prioritized countries in southern and eastern Africa. During 2010-2016, CDC supported 5,880,372 VMMCs in 12 countries (2,3). During 2017-2021, CDC supported 8,497,297 VMMCs performed in 13 countries. In 2020, the number of VMMCs performed declined 31.8% compared with the number in 2019, primarily because of COVID-19-related disruptions to VMMC service delivery. PEPFAR 2017-2021 Monitoring, Evaluation, and Reporting data were used to provide an update and describe CDC's contribution to the scale-up of the VMMC program, which is important to meeting the 2025 Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 90% of males aged 15-59 years having access to VMMC services in prioritized countries to help end the AIDS epidemic by 2030 (4).

We used publicly available data to describe epidemiology, genomic surveillance, and public health and social measures from the first 3 COVID-19 pandemic waves in southern Africa during April 6, 2020-September 19, 2021. South Africa detected regional waves on average 7.2 weeks before other countries. Average testing volume 244 tests/million/day) increased across waves and was highest in upper-middle-income countries. Across the 3 waves, average reported regional incidence increased (17.4, 51.9, 123.3 cases/1 million population/day), as did positivity of diagnostic tests (8.8%, 12.2%, 14.5%); mortality (0.3, 1.5, 2.7 deaths/1 million populaiton/day); and case-fatality ratios (1.9%, 2.1%, 2.5%). Beta variant (B.1.351) drove the second wave and Delta (B.1.617.2) the third. Stringent implementation of safety measures declined across waves. As of September 19, 2021, completed vaccination coverage remained low (8.1% of total population). Our findings highlight opportunities for strengthening surveillance, health systems, and access to realistically available therapeutics, and scaling up risk-based vaccination.

From July-November 2020, mink (Neogale vison) on 12 Utah farms experienced an increase in mortality rates due to confirmed SARS-CoV-2 infection. We conducted epidemiologic investigations on six farms to identify the source of virus introduction, track cross-species transmission, and assess viral evolution. Interviews were conducted and specimens were collected from persons living or working on participating farms and from multiple animal species. Swabs and sera were tested by SARS-CoV-2 real-time reverse transcription polymerase chain reaction (rRT-PCR) and serological assays, respectively. Whole genome sequencing was attempted for specimens with cycle threshold values &lt;30. Evidence of SARS-CoV-2 infection was detected by rRT-PCR or serology in ≥1 person, farmed mink, dog, and/or feral cat on each farm. Sequence analysis showed high similarity between mink and human sequences on corresponding farms. On farms sampled at multiple time points, mink tested rRT-PCR positive up to 16 weeks post-onset of increased mortality. Workers likely introduced SARS-CoV-2 to mink, and mink transmitted SARS-CoV-2 to other animal species; mink-to-human transmission was not identified. Our findings provide critical evidence to support interventions to prevent and manage SARS-CoV-2 in people and animals on mink farms and emphasizes the importance of a One Health approach to address emerging zoonoses.

Spatial repellent (SR) products are envisioned to complement existing vector control methods through the continual release of volatile active ingredients (AI) providing: (i) protection against day-time and early-evening biting; (ii) protection in enclosed/semi-enclosed and peri-domestic spaces; (iii) various formulations to fit context-specific applications; and (iv) increased coverage over traditional control methods. SR product AIs also have demonstrated effect against insecticide-resistant vectors linked to malaria and Aedes-borne virus (ABV) transmission. Over the past two decades, key stakeholders, including World Health Organization (WHO) representatives, have met to discuss the role of SRs in reducing arthropod-borne diseases based on existing evidence. A key focus has been to establish a critical development path for SRs, including scientific, regulatory and social parameters that would constitute an outline for a SR target product profile, i.e. optimum product characteristics. The principal gap is the lack of epidemiological data demonstrating SR public health impact across a range of different ecological and epidemiological settings, to inform a WHO policy recommendation. Here we describe in brief trials that are designed to fulfill evidence needs for WHO assessment and initial projections of SR cost-effectiveness against malaria and dengue.

IMPORTANCE: In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complications. OBJECTIVE: To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021. DESIGN, SETTING, AND PARTICIPANTS: Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n=85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis. EXPOSURE: SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits). RESULTS: Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n=23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n=11), severe encephalopathy (n=5), acute fulminant cerebral edema (n=2), and Guillain-Barr syndrome (n=1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated. CONCLUSIONS AND RELEVANCE: SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.

Zoonotic transmission of SARS-CoV-2 from infected humans to other animals has been documented around the world, most notably in mink farming operations in Europe and the United States. Outbreaks of SARS-CoV-2 on Utah mink farms began in late July 2020 and resulted in high mink mortality. An investigation of these outbreaks revealed active and past SARS-CoV-2 infections in free-roaming and in feral cats living on or near several mink farms. Cats were captured using live traps, were sampled, fitted with GPS collars, and released on the farms. GPS tracking of these cats show they made frequent visits to mink sheds, moved freely around the affected farms, and visited surrounding residential properties and neighborhoods on multiple occasions, making them potential low risk vectors of additional SARS-CoV-2 spread in local communities.

Even with the COVID-19 pandemic, tuberculosis remains a leading cause of human death due to a single infectious agent. Until successfully treated, infected individuals may continue to transmit Mycobacterium tuberculosis bacilli to contacts. As with other respiratory pathogens, such as SARS-CoV-2, modeling the process of person-to-person transmission will inform efforts to develop vaccines and therapies that specifically impede disease transmission. The ferret (Mustela furo), a relatively inexpensive, small animal has been successfully employed to model transmissibility, pathogenicity, and tropism of influenza and other respiratory disease agents. Ferrets can become naturally infected with Mycobacterium bovis and are closely related to badgers, well known in Great Britain and elsewhere as a natural transmission vehicle for bovine tuberculosis. Herein, we report results of a study demonstrating that within 7 weeks of intratracheal infection with a high dose (>5 x 10(3) CFU) of M. tuberculosis bacilli, ferrets develop clinical signs and pathological features similar to acute disease reported in larger animals, and ferrets infected with very-high doses (>5 x 10(4) CFU) develop severe signs within two to four weeks, with loss of body weight as high as 30%. Natural transmission of this pathogen was also examined. Acutely-infected ferrets transmitted M. tuberculosis bacilli to co-housed naïve sentinels; most of the sentinels tested positive for M. tuberculosis in nasal washes, while several developed variable disease symptomologies similar to those reported for humans exposed to an active tuberculosis patient in a closed setting. Transmission was more efficient when the transmitting animal had a well-established acute infection. The findings support further assessment of this model system for tuberculosis transmission including the testing of prevention measures and vaccine efficacy.