Rwanda achieved unprecedented malaria control gains from 2000 to 2010, but cases increased 20-fold between 2011 and 2017. Vector control challenges and environmental changes were noted as potential explanations, but no studies have investigated causes of the resurgence or identified which vector species drove transmission. We conducted a retrospective study in four sites in eastern Rwanda that conducted monthly entomological surveillance and outpatient malaria care. We compared sporozoite rates, human blood index (HBI), and relative abundance of the primary vectors, Anopheles gambiae and Anopheles arabiensis, from 2017 to 2020. We then modeled the effects of vector control interventions, insecticide resistance, and temperature changes on species composition and reported malaria incidence. Sporozoite rates were 28 times higher and HBI was four times higher in An. gambiae compared with An. arabiensis. Insecticide-treated bed nets, first distributed nationally in 2010, were associated with decreased An. gambiae relative abundance. However, increased pyrethroid resistance was associated with increased An. gambiae relative abundance and malaria incidence. Epidemic malaria peaks corresponded to periods of model-predicted An. gambiae re-emergence, and increased regional air temperatures during the period were further associated with increased malaria incidence. Indoor residual spraying (IRS), implemented with non-pyrethroid insecticides later in the period, was associated with 86% reductions in An. gambiae relative abundance and 75% reductions in malaria incidence. These findings suggest that increased pyrethroid resistance and the re-emergence of An. gambiae were closely linked to the malaria resurgence in eastern Rwanda. Non-pyrethroid IRS or other control measures that effectively target An. gambiae may help prevent future resurgences.

This study aims to understand availability of school-based infectious disease surveillance data (e.g., COVID-19 cases, student absences) based on experiences during the COVID-19 pandemic using a national sample of public K-12 schools (n = 1,602). Based on surveys administered to school administrators throughout the 2021-2022 school year, we found high levels of missingness data for school-level COVID-19 cases, quarantines, and student absenteeism, increasing missingness over time, and variations in missingness by school characteristics (e.g., school size) and protocols (e.g., having a school-based system to report at-home COVID-19 tests). For the same sample of schools, using data requests to health departments, we found similarly high levels of missingness of school-level COVID-19 case data and varying approaches in data collection. Developing nationally standardized case definitions-and systems to surveil or collect and monitor school-based infectious disease outcomes early in a public health emergency-may be helpful in producing actionable data.

Aedes mosquito-borne viruses (ABVs) place a substantial strain on public health resources in the Americas. Vector control of Aedes mosquitoes is an important public health strategy to decrease or prevent spread of ABVs. The ongoing Targeted Indoor Residual Spraying (TIRS) trial is an NIH-sponsored clinical trial to study the efficacy of a novel, proactive vector control technique to prevent dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) infections in the endemic city of Merida, Yucatan, Mexico. The primary outcome of the trial is laboratory-confirmed ABV infections in neighborhood clusters. Despite the difficulties caused by the COVID-19 pandemic, by early 2021 the TIRS trial completed enrollment of 4,792 children aged 2-15 years in 50 neighborhood clusters which were allocated to control or intervention arms via a covariate-constrained randomization algorithm. Here, we describe the makeup and ABV seroprevalence of participants and mosquito population characteristics in both arms before TIRS administration. Baseline surveys showed similar distribution of age, sex, and socio-economic factors between the arms. Serum samples from 1,399 children were tested by commercially available ELISAs for presence of anti-ABV antibodies. We found that 45.1% of children were seropositive for one or more flaviviruses and 24.0% were seropositive for CHIKV. Of the flavivirus-positive participants, most were positive for ZIKV-neutralizing antibodies by focus reduction neutralization testing which indicated a higher proportion of participants with previous ZIKV than DENV infections within the cohort. Both study arms had statistically similar seroprevalence for all viruses tested, similar socio-demographic compositions, similar levels of Ae. aegypti infestation, and similar observed mosquito susceptibility to insecticides. These findings describe a population with a high rate of previous exposure to ZIKV and lower titers of neutralizing antibodies against DENV serotypes, suggesting susceptibility to future outbreaks of flaviviruses is possible, but proactive vector control may mitigate these risks.

OBJECTIVES: We assessed the differences between the first version of the Centers for Disease Control and Prevention (CDC) opioid surveillance definition for suspected nonfatal opioid overdoses (hereinafter, CDC definition) and the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT) surveillance definition to determine whether the North Carolina definition should include additional International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and/or chief complaint keywords. METHODS: Two independent reviewers retrospectively reviewed data on North Carolina emergency department (ED) visits generated by components of the CDC definition not included in the NC DETECT definition from January 1 through July 31, 2018. Clinical reviewers identified false positives as any ED visit in which available evidence supported an alternative explanation for patient presentation deemed more likely than an opioid overdose. After individual assessment, reviewers reconciled disagreements. RESULTS: We identified 2296 ED visits under the CDC definition that were not identified under the NC DETECT definition during the study period. False-positive rates ranged from 2.6% to 41.4% for codes and keywords uniquely identifying ≥10 ED visits. Based on uniquely identifying ≥10 ED visits and a false-positive rate ≤10.0%, 4 of 16 ICD-10-CM codes evaluated were identified for NC DETECT definition inclusion. Only 2 of 25 keywords evaluated, "OD" and "overdose," met inclusion criteria to be considered a meaningful addition to the NC DETECT definition. PRACTICE IMPLICATIONS: Quantitative and qualitative trends in coding and keyword use identified in this analysis may prove helpful for future evaluations of surveillance definitions.

BACKGROUND: Viruses are the leading etiology of acute respiratory infections (ARI) in children. However, there is limited knowledge on drivers of severe acute respiratory infection (SARI) cases involving viruses. We aimed to identify factors associated with severity and prolonged hospitalization of viral SARI among children < 5 years in Burkina Faso. METHODS: Data were collected from four SARI sentinel surveillance sites during October 2016 through April 2019. A SARI case was a child < 5 years with an acute respiratory infection with history of fever or measured fever ≥ 38 °C and cough with onset within the last ten days, requiring hospitalization. Very severe ARI cases required intensive care or had at least one danger sign. Oropharyngeal/nasopharyngeal specimens were collected and analyzed by multiplex real-time reverse-transcription polymerase chain reaction (rRT-PCR) using FTD-33 Kit. For this analysis, we included only SARI cases with rRT-PCR positive test results for at least one respiratory virus. We used simple and multilevel logistic regression models to assess factors associated with very severe viral ARI and viral SARI with prolonged hospitalization. RESULTS: Overall, 1159 viral SARI cases were included in the analysis after excluding exclusively bacterial SARI cases (n = 273)very severe viral ARI cases were common among children living in urban areas (AdjOR = 1.3; 95% CI: 1.1-1.6), those < 3 months old (AdjOR = 1.5; 95% CI: 1.1-2.3), and those coinfected with Klebsiella pneumoniae (AdjOR = 1.9; 95% CI: 1.2-2.2). Malnutrition (AdjOR = 2.2; 95% CI: 1.1-4.2), hospitalization during the rainy season (AdjOR = 1.71; 95% CI: 1.2-2.5), and infection with human CoronavirusOC43 (AdjOR = 3; 95% CI: 1.2-8) were significantly associated with prolonged length of hospital stay (> 7 days). CONCLUSION: Younger age, malnutrition, codetection of Klebsiella pneumoniae, and illness during the rainy season were associated with very severe cases and prolonged hospitalization of SARI involving viruses in children under five years. These findings emphasize the need for preventive actions targeting these factors in young children.

PURPOSE: The COVID-19 pandemic disrupted pediatric health care in the United States, and this disruption layered on existing barriers to health care. We sought to characterize disparities in unmet pediatric health care needs during this period. METHODS: We analyzed data from Wave 1 (October through November 2020) and Wave 2 (March through May 2021) of the COVID Experiences Survey, a national longitudinal survey delivered online or via telephone to parents of children aged 5 through 12 years using a probability-based sample representative of the US household population. We examined 3 indicators of unmet pediatric health care needs as outcomes: forgone care and forgone well-child visits during fall 2020 through spring 2021, and no well-child visit in the past year as of spring 2021. Multivariate models examined relationships of child-, parent-, household-, and county-level characteristics with these indicators, adjusting for child's age, sex, and race/ethnicity. RESULTS: On the basis of parent report, 16.3% of children aged 5 through 12 years had forgone care, 10.9% had forgone well-child visits, and 30.1% had no well-child visit in the past year. Adjusted analyses identified disparities in indicators of pediatric health care access by characteristics at the level of the child (eg, race/ethnicity, existing health conditions, mode of school instruction), parent (eg, childcare challenges), household (eg, income), and county (eg, urban-rural classification, availability of primary care physicians). Both child and parent experiences of racism were also associated with specific indicators of unmet health care needs. CONCLUSIONS: Our findings highlight the need for continued research examining unmet health care needs and for continued efforts to optimize the clinical experience to be culturally inclusive.

Mental and behavioral health conditions among school-aged children, including substance use disorders and overall emotional well-being, are a public health concern in the United States. Timely data on seasonal patterns in child and adolescent conditions can guide optimal timing of prevention and intervention strategies. CDC examined emergency department (ED) visit data from the National Syndromic Surveillance Program for 25 distinct conditions during January 2018-June 2023 among U.S. children and adolescents aged 5-17 years, stratified by age group. Each year, during 2018-2023, among persons aged 10-14 and 15-17 years, the number and proportion of weekly ED visits for eight conditions increased in the fall school semester and remained elevated throughout the spring semester; ED visits were up to twice as high during school semesters compared with the summer period. Among children aged 5-9 years, the number and proportion of visits increased for five mental and behavioral health conditions. Seasonal increases in ED visits for some conditions among school-aged children warrant enhanced awareness about mental distress symptoms and the challenges and stressors in the school environment. Systemic changes that prioritize protective factors (e.g., physical activity; nutrition; sleep; social, community, or faith-based support; and inclusive school and community environments) and incorporate preparedness for increases in conditions during back-to-school planning might improve child and adolescent mental health.

Four Chlamydia psittaci isolates were recovered from clinical specimens from ill workers during a multistate outbreak at two chicken processing plants. Whole genome sequencing analyses revealed high similarity to C. psittaci genotype D. The isolates differed from each other by only two single nucleotide polymorphisms, indicating a common source.

Capture-recapture methods are widely applied in estimating the number (N) of prevalent or cumulatively incident cases in disease surveillance. Here, we focus the bulk of our attention on the common case in which there are two data streams. We propose a sensitivity and uncertainty analysis framework grounded in multinomial distribution-based maximum likelihood, hinging on a key dependence parameter that is typically non-identifiable but is epidemiologically interpretable. Focusing on the epidemiologically meaningful parameter unlocks appealing data visualizations for sensitivity analysis and provides an intuitively accessible framework for uncertainty analysis designed to leverage the practicing epidemiologist's understanding of the implementation of the surveillance streams as the basis for assumptions driving estimation of N. By illustrating the proposed sensitivity analysis using publicly available HIV surveillance data, we emphasize both the need to admit the lack of information in the observed data and the appeal of incorporating expert opinion about the key dependence parameter. The proposed uncertainty analysis is an empirical Bayes-like approach designed to more realistically acknowledge variability in the estimated N associated with uncertainty in an expert's opinion about the non-identifiable parameter, together with the statistical uncertainty. We demonstrate how such an approach can also facilitate an appealing general interval estimation procedure to accompany capture-recapture methods. Simulation studies illustrate the reliable performance of the proposed approach for quantifying uncertainties in estimating N in various contexts. Finally, we demonstrate how the recommended paradigm has the potential to be directly extended for application to data from more than two surveillance streams. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Crimean-Congo Hemorrhagic Fever (CCHF) is a viral disease that can infect humans via contact with tick vectors or livestock reservoirs and can cause moderate to severe disease. The first human case of CCHF in Uganda was identified in 2013. To determine the geographic distribution of the CCHF virus (CCHFV), serosampling among herds of livestock was conducted in 28 Uganda districts in 2017. A geostatistical model of CCHF seroprevalence among livestock was developed to incorporate environmental and anthropogenic variables associated with elevated CCHF seroprevalence to predict CCHF seroprevalence on a map of Uganda and estimate the probability that CCHF seroprevalence exceeded 30% at each prediction location. Environmental and anthropogenic variables were also analyzed in separate models to determine the spatially varying drivers of prediction and determine which covariate class resulted in best prediction certainty. Covariates used in the full model included distance to the nearest croplands, average annual change in night-time light index, percent sand soil content, land surface temperature, and enhanced vegetation index. Elevated CCHF seroprevalence occurred in patches throughout the country, being highest in northern Uganda. Environmental covariates drove predicted seroprevalence in the full model more than anthropogenic covariates. Combination of environmental and anthropogenic variables resulted in the best prediction certainty. An understanding of the spatial distribution of CCHF across Uganda and the variables that drove predictions can be used to prioritize specific locations and activities to reduce the risk of future CCHF transmission. © 2023 The Authors

As of March 7, 2023, a total of 30,235 confirmed and probable monkeypox (mpox) cases were reported in the United States,(†) predominantly among cisgender men(§) who reported recent sexual contact with another man (1). Although most mpox cases during the current outbreak have been self-limited, cases of severe illness and death have been reported (2-4). During May 10, 2022-March 7, 2023, 38 deaths among persons with probable or confirmed mpox(¶) (1.3 per 1,000 mpox cases) were reported to CDC and classified as mpox-associated (i.e., mpox was listed as a contributing or causal factor). Among the 38 mpox-associated deaths, 94.7% occurred in cisgender men (median age = 34 years); 86.8% occurred in non-Hispanic Black or African American (Black) persons. The median interval from symptom onset to death was 68 days (IQR = 50-86 days). Among 33 decedents with available information, 93.9% were immunocompromised because of HIV. Public health actions to prevent mpox deaths include integrated testing, diagnosis, and early treatment for mpox and HIV, and ensuring equitable access to both mpox and HIV prevention and treatment, such as antiretroviral therapy (ART) (5).

Capture-recapture methods are widely applied in estimating the number (N) of prevalent or cumulatively incident cases in disease surveillance. Here, we focus the bulk of our attention on the common case in which there are two data streams. We propose a sensitivity and uncertainty analysis framework grounded in multinomial distribution-based maximum likelihood, hinging on a key dependence parameter that is typically non-identifiable but is epidemiologically interpretable. Focusing on the epidemiologically meaningful parameter unlocks appealing data visualizations for sensitivity analysis and provides an intuitively accessible framework for uncertainty analysis designed to leverage the practicing epidemiologist's understanding of the implementation of the surveillance streams as the basis for assumptions driving estimation of N. By illustrating the proposed sensitivity analysis using publicly available HIV surveillance data, we emphasize both the need to admit the lack of information in the observed data and the appeal of incorporating expert opinion about the key dependence parameter. The proposed uncertainty analysis is a simulation-based approach designed to more realistically acknowledge variability in the estimated N associated with uncertainty in an expert's opinion about the non-identifiable parameter, together with the statistical uncertainty. We demonstrate how such an approach can also facilitate an appealing general interval estimation procedure to accompany capture-recapture methods. Simulation studies illustrate the reliable performance of the proposed approach for quantifying uncertainties in estimating N in various contexts. Finally, we demonstrate how the recommended paradigm has the potential to be directly extended for application to data from more than two surveillance streams.

Uganda reported cases of Rift Valley fever virus (RVFV) for the first time in almost 50 years in 2016, following an outbreak of Rift Valley fever (RVF) that caused four human infections, two of which resulted in death. Subsequent outbreak investigation serosurveys found high seroprevalence of IgG antibodies without evidence of acute infection or IgM antibodies, suggesting the possibility of undetected RVFV circulation prior to the outbreak. After the 2016 outbreak investigation, a serosurvey was conducted in 2017 among domesticated livestock herds across Uganda. Sampling data were incorporated into a geostatistical model to estimate RVF seroprevalence among cattle, sheep, and goats. Variables resulting in the best fit to RVF seroprevalence sampling data included annual variability in monthly precipitation and enhanced vegetation index, topographic wetness index, log human population density percent increase, and livestock species. Individual species RVF seroprevalence prediction maps were created for cattle, sheep, and goats, and a composite livestock prediction was created based on the estimated density of each species across the country. Seroprevalence was greater in cattle compared with sheep and goats. Predicted seroprevalence was greatest in the central and northwestern quadrant of the country, surrounding Lake Victoria, and along the Southern Cattle Corridor. We identified areas that experienced conditions conducive to potential increased RVFV circulation in 2021 in central Uganda. An improved understanding of the determinants of RVFV circulation and locations with high probability of elevated RVF seroprevalence can guide prioritization of disease surveillance and risk mitigation efforts.

BACKGROUND: Detection of malaria parasitaemia in samples that are negative by rapid diagnostic tests (RDTs) requires resource-intensive molecular tools. While pooled testing using a two-step strategy provides a cost-saving alternative to the gold standard of individual sample testing, statistical adjustments are needed to improve accuracy of prevalence estimates for a single step pooled testing strategy. METHODS: A random sample of 4670 malaria RDT negative dried blood spot samples were selected from a mass testing and treatment trial in Asembo, Gem, and Karemo, western Kenya. Samples were tested for malaria individually and in pools of five, 934 pools, by one-step quantitative polymerase chain reaction (qPCR). Maximum likelihood approaches were used to estimate subpatent parasitaemia (RDT-negative, qPCR-positive) prevalence by pooling, assuming poolwise sensitivity and specificity was either 100% (strategy A) or imperfect (strategy B). To improve and illustrate the practicality of this estimation approach, a validation study was constructed from pools allocated at random into main (734 pools) and validation (200 pools) subsets. Prevalence was estimated using strategies A and B and an inverse-variance weighted estimator and estimates were weighted to account for differential sampling rates by area. RESULTS: The prevalence of subpatent parasitaemia was 14.5% (95% CI 13.6-15.3%) by individual qPCR, 9.5% (95% CI (8.5-10.5%) by strategy A, and 13.9% (95% CI 12.6-15.2%) by strategy B. In the validation study, the prevalence by individual qPCR was 13.5% (95% CI 12.4-14.7%) in the main subset, 8.9% (95% CI 7.9-9.9%) by strategy A, 11.4% (95% CI 9.9-12.9%) by strategy B, and 12.8% (95% CI 11.2-14.3%) using inverse-variance weighted estimator from poolwise validation. Pooling, including a 20% validation subset, reduced costs by 52% compared to individual testing. CONCLUSIONS: Compared to individual testing, a one-step pooled testing strategy with an internal validation subset can provide accurate prevalence estimates of PCR-positivity among RDT-negatives at a lower cost.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

BACKGROUND: Rotavirus vaccine performance appears worse in countries with high rotavirus genotype diversity. Evidence suggests diminished vaccine efficacy (VE) against G2P[4], which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive. METHODS: We pooled individual-level data from ten Phase II and III clinical trials of rotavirus vaccine containing G1 and P[8] antigens (RV1) conducted between 2000 and 2012. We estimated VE against both any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for non-specific VE against any RVGE, genotype-specific VE, and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with RV1 antigens. We adjusted models for concomitant oral poliovirus and RV1 vaccination and the country's designated child mortality stratum. RESULTS: Analysis included 87,644 infants from 22 countries in the Americas, Europe, Africa, and Asia. For VE against severe RVGE, non-specific VE was 91% (95% confidence interval (CI): 87-94%). Genotype-specific VE ranged from 96% (95% CI: 89-98%) against G1P[8] to 71% (43-85%) against G2P[4]. RV1-typic VE was 92% (95% CI: 84-96%) against partially heterotypic genotypes but 83% (67-91%) against fully heterotypic genotypes. For VE against any-severity RVGE, non-specific VE was 82% (95% CI: 75-87%). Genotype-specific VE ranged from 94% (95% CI: 86-97%) against G1P[8] to 63% (41-77%) against G2P[4]. RV1-typic VE was 83% (95% CI: 72-90%) against partially heterotypic genotypes but 63% (40-77%) against fully heterotypic genotypes. CONCLUSIONS: RV1 VE is comparatively diminished against fully heterotypic genotypes including G2P[4].

BACKGROUND: Associations between birth defects and fevers attributed to colds, influenza, and urinary tract infections (UTIs) have been observed in previous studies. Our aim was to study associations between birth defects and fevers attributed to other causes. METHODS: We analyzed data from 34,862 participants in the National Birth Defects Prevention Study, a multistate case-control study of major structural birth defects. Using multivariable logistic regression, we assessed the association between maternal report of fever during early pregnancy due to causes other than colds, influenza, or UTI and 36 categories of birth defects. RESULTS: Maternal reports of fever due to other causes were associated with significantly elevated odds ratios ranging from 1.93 to 10.60 for 8 of 36 birth defects, primarily involving the spine, limbs, and heart (spina bifida, intestinal atresia, intercalary limb deficiency, transverse limb deficiency, congenital heart defect with heterotaxy, tetralogy of Fallot, pulmonary atresia and atrial septal defect, not otherwise specified). CONCLUSION: Our data suggests fever itself or other physiologic changes associated with many infections are associated with some birth defects. Women who are pregnant or planning to become pregnant may want to consider speaking with their healthcare provider about the best ways to avoid infections that may cause fever and for guidance on how to treat fevers during pregnancy.

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the U.S. appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight U.S. surveillance sites on 8-59-month olds with acute gastroenteritis symptoms. Children's stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention (CDC). We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with CDC confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year-vaccination interaction, and the second including annual percent of rotavirus positive tests plus a percent positive-vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year-vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive-vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.

BACKGROUND: Lower respiratory tract infections are a leading cause of death in young children, but few studies have collected the specimens needed to define the role of specific causes. The Child Health and Mortality Prevention Surveillance (CHAMPS) platform aims to investigate causes of death in children aged <5 years in high-mortality rate settings, using postmortem minimally invasive tissue sampling and other advanced diagnostic techniques. We examined findings for deaths identified in CHAMPS sites in 7 countries in sub-Saharan Africa and south Asia to evaluate the role of respiratory syncytial virus (RSV). METHODS: We included deaths that occurred between December 2016 and December 2019. Panels determined causes of deaths by reviewing all available data including pathological results from minimally invasive tissue sampling, polymerase chain reaction screening for multiple infectious pathogens in lung tissue, nasopharyngeal swab, blood, and cerebrospinal fluid samples, clinical information from medical records, and verbal autopsies. RESULTS: We evaluated 1213 deaths, including 695 in neonates (aged <28 days), 283 in infants (28 days to <12 months), and 235 in children (12-59 months). RSV was detected in postmortem specimens in 67 of 1213 deaths (5.5%); in 24 deaths (2.0% of total), RSV was determined to be a cause of death, and it contributed to 5 other deaths. Younger infants (28 days to <6 months of age) accounted for half of all deaths attributed to RSV; 6.5% of all deaths in younger infants were attributed to RSV. RSV was the underlying and only cause in 4 deaths; the remainder (n = 20) had a median of 2 (range, 1-5) other conditions in the causal chain. Birth defects (n = 8) and infections with other pathogens (n = 17) were common comorbid conditions. CONCLUSIONS: RSV is an important cause of child deaths, particularly in young infants. These findings add to the substantial body of literature calling for better treatment and prevention options for RSV in high-mortality rate settings.

Skin cancer is the most common, yet oftentimes preventable, cancer type in the United States. Exposure to ultraviolet (UV) radiation from sunlight is the most prominent environmental risk factor for skin cancer. Besides environmental exposure, demographic characteristics such as race, age, and socioeconomic (SES) status may make some groups more vulnerable. Based on county-level UV data and demographic risk factors, two vulnerability indices for skin cancer were generated using an additive percentile rank approach. With these indices, univariate local Moran's I spatial autocorrelation identified significant clusters, or hotspots, of neighboring counties with high overall vulnerability indices. Clusters were identified separately for skin cancer incidence and mortality. Counties with high vulnerabilities were spatially distributed across the United States in a pattern that generally increased to the South and West. Clusters of counties with high skin cancer incidence vulnerability were mostly observed in Utah and Colorado, even with highly conservative levels of significance. Meanwhile, clusters for skin cancer mortality vulnerability were observed in southern Alabama and west Florida as well as across north Alabama, north Georgia and up through the Tennessee-North Carolina area. These highly vulnerable counties where environmental and demographic risk factors significantly overlap could be prioritized for preventive interventions, emphasizing local need based on unique underlying spatial patterns of risk for each skin cancer outcome.

BACKGROUND: Maternal pregestational diabetes and obesity are risk factors for birth defects. Diabetes and obesity often occur together; it is unclear whether their co-occurrence compounds birth defect risk. METHODS: We analyzed 1997-2011 data on 29,671 cases and 10,963 controls from the National Birth Defects Prevention Study, a multisite case-control study. Mothers self-reported height, pregestational weight, and diabetes (pregestational and gestational; analyzed separately). We created four exposure groups: no obesity or diabetes (referent), obesity only, diabetes only, and both obesity and diabetes. We estimated odds ratios (ORs) using logistic regression and the relative excess risk due to interaction (RERI). RESULTS: Among mothers with pregestational obesity without diabetes, modest associations (OR range: 1.1-1.5) were observed for neural tube defects, small intestinal atresia, anorectal atresia, renal agenesis/hypoplasia, omphalocele, and several congenital heart defects. Pregestational diabetes, regardless of obesity, was strongly associated with most birth defects (OR range: 2.0-75.9). Gestational diabetes and obesity had a stronger association than for obesity alone and the RERI (in parentheses) suggested additive interaction for hydrocephaly (1.2; 95% confidence interval [CI]: -0.1, 2.5), tetralogy of Fallot (0.9; 95% CI: -0.01, 1.8), atrioventricular septal defect (1.1; 95% CI: -0.1, 2.3), hypoplastic left heart syndrome (1.1; 95% CI: -0.2, 2.4), and atrial septal defect secundum or not otherwise specified (1.0; 95% CI: 0.3, 1.6; only statistically significant RERI). CONCLUSIONS: Our results do not support a synergistic relationship between obesity and diabetes for most birth defects examined. However, there are opportunities for prevention by reducing obesity and improving glycemic control among women with pregestational diabetes before conception.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), evolved rapidly in the United States. This report describes the demographic, clinical, and epidemiologic characteristics of 544 U.S. persons under investigation (PUI) for COVID-19 with complete SARS-CoV-2 testing in the beginning stages of the pandemic from January 17 through February 29, 2020. METHODS: In this surveillance cohort, the U.S. Centers for Disease Control and Prevention (CDC) provided consultation to public health and healthcare professionals to identify PUI for SARS-CoV-2 testing by quantitative real-time reverse-transcription PCR. Demographic, clinical, and epidemiologic characteristics of PUI were reported by public health and healthcare professionals during consultation with on-call CDC clinicians and subsequent submission of a CDC PUI Report Form. Characteristics of laboratory-negative and laboratory-positive persons were summarized as proportions for the period of January 17-February 29, and characteristics of all PUI were compared before and after February 12 using prevalence ratios. RESULTS: A total of 36 PUI tested positive for SARS-CoV-2 and were classified as confirmed cases. Confirmed cases and PUI testing negative for SARS-CoV-2 had similar demographic, clinical, and epidemiologic characteristics. Consistent with changes in PUI evaluation criteria, 88% (13/15) of confirmed cases detected before February 12, 2020, reported travel from China. After February 12, 57% (12/21) of confirmed cases reported no known travel- or contact-related exposures. CONCLUSIONS: These findings can inform preparedness for future pandemics, including capacity for rapid expansion of novel diagnostic tests to accommodate broad surveillance strategies to assess community transmission, including potential contributions from asymptomatic and presymptomatic infections.

BACKGROUND: Reliable diagnostics are a key to identifying influenza infections. OBJECTIVES: Our objectives were to describe the detection of influenza among severe acute respiratory infection (SARI) cases, to compare test results from the Fast Track Diagnostics (FTD) Kit for influenza detection to the Centers for Disease Control (CDC) human influenza virus detection and characterization panel, and to assess seasonality of influenza in Burkina Faso. METHODS: Nasopharyngeal and oropharyngeal specimens from SARI cases (hospitalized patients with fever, cough, and onset in the previous 10 days) were tested using the FTD-33 Kit and the CDC rRT-PCR influenza assays. We assessed sensitivity and specificity of the FTD-33 Kit for detecting influenza A, influenza B, and the influenza A(H1N1)pdm09 strain using the CDC human influenza rRT-PCR panel as the gold standard. RESULTS: From December 2016 to February 2019, 1706 SARI cases were identified, 1511 specimens were tested, and 211 were positive for influenza A (14.0%) and 100 for influenza B (6.6%) by either assay. Higher influenza circulation occurred between November and April with varying peaks of influenza A and influenza B. Sensitivity of the FTD-33 assay was 91.9% for influenza A, 95.7% for influenza B, and 93.8% for A(H1N1)pdm09 subtype. Specificity was over 99% for all three tests. CONCLUSIONS: Our study indicates that Burkina Faso has one peak of influenza each year which is similar to the Northern Hemisphere and differs from other countries in West Africa. We found high concordance of influenza results between the two assays indicating FTD-33 can be used to reliably detect influenza among SARI cases.

BACKGROUND: To better understand the relation between sleep problems and CKD, we examined temporal trends in the prevalence of self-reported sleep problems in adults in the United States and their associations with CKD and all-cause mortality. METHODS: Using data from 27,365 adult participants in five biannual National Health and Examination Surveys (2005-2006 through 2013-2014), we studied five self-reported sleep problems-trouble sleeping, sleep disorder, nocturia (urinating ≥2 times/night), inadequate sleep (<7 hours/night), and excessive sleep (>9 hours/night)-plus a composite index. We conducted three types of analysis: temporal trends in the prevalence of each sleep measure by CKD status, using model-based standardization; cross-sectional analysis of associations between four CKD measures and each sleep measure, using logistic regression; and survival analysis of the association between each sleep measure and mortality, using Cox regression. RESULTS: The prevalence of trouble sleeping and sleep disorder increased over the five surveys by 4% and 3%, respectively, whereas the other sleep problems remained relatively stable. All sleep problems, except inadequate sleep, were more common during the study period among adults with CKD than without CKD (40% versus 21% for nocturia; 5% versus 2% for excessive sleep; 30% versus 25% for trouble sleeping; 12% versus 8% for sleep disorder). Both eGFR <30 ml/min per 1.73 m(2) and albuminuria were positively associated with nocturia and excessive sleep. Excessive sleep and nocturia were also associated with higher mortality (adjusted hazard ratio for >9 versus 7-9 hours/night=1.7; 95% CI, 1.3 to 2.1; and for nocturia=1.2; 95% CI, 1.1 to 1.4). CONCLUSIONS: The high prevalence of sleep problems among persons with CKD and their associations with mortality suggest their potential importance to clinical practice. Future work could examine the health effects of identifying and treating sleep problems in patients with CKD.

BACKGROUND: Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces. METHODS/DESIGN: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2-15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A "fried egg" design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the "yolk," the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1-2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons. DISCUSSION: The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343521 . Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1). PRIMARY SPONSOR: National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).

Respiratory diphtheria, characterized by a firmly adherent pseudomembrane, is caused by toxin-producing strains of Corynebacterium diphtheriae, with similar illness produced occasionally by toxigenic Corynebacterium ulcerans or, rarely, Corynebacterium pseudotuberculosis While diphtheria laboratory confirmation requires culture methods to determine toxigenicity, real-time PCR (RT-PCR) provides a faster method to detect the toxin gene (tox). Nontoxigenic tox-bearing (NTTB) Corynebacterium isolates have been described, but impact of these isolates on the accuracy of molecular diagnostics is not well characterized. Here, we describe a new triplex RT-PCR assay to detect tox and distinguish C. diphtheriae from the closely related species C. ulcerans and C. pseudotuberculosis Analytical sensitivity and specificity of the assay were assessed in comparison to culture using 690 previously characterized microbial isolates. The new triplex assay characterized Corynebacterium isolates accurately, with 100% analytical sensitivity for all targets. Analytical specificity with isolates was 94.1%, 100%, and 99.5% for tox, Diph_rpoB, and CUP_rpoB targets, respectively. Twenty-nine NTTB Corynebacterium isolates, representing 5.9% of 494 nontoxigenic isolates tested, were detected by RT-PCR. Whole-genome sequencing of NTTB isolates revealed varied mutations putatively underlying their lack of toxin production, as well as eight isolates with no mutation in tox or the promoter region. This new Corynebacterium RT-PCR method provides a rapid tool to screen isolates and identify probable diphtheria cases directly from specimens. However, the sporadic occurrence of NTTB isolates reinforces the viewpoint that diphtheria culture diagnostics continue to provide the most accurate case confirmation.

Since February 12, 2020, approximately 6.5 million cases of SARS-CoV-2 infection, the cause of coronavirus disease 2019 (COVID-19), and 190,000 SARS-CoV-2-associated deaths have been reported in the United States (1,2). Symptoms associated with SARS-CoV-2 infection are milder in children compared with adults (3). Persons aged <21 years constitute 26% of the U.S. population (4), and this report describes characteristics of U.S. persons in that population who died in association with SARS-CoV-2 infection, as reported by public health jurisdictions. Among 121 SARS-CoV-2-associated deaths reported to CDC among persons aged <21 years in the United States during February 12-July 31, 2020, 63% occurred in males, 10% of decedents were aged <1 year, 20% were aged 1-9 years, 70% were aged 10-20 years, 45% were Hispanic persons, 29% were non-Hispanic Black (Black) persons, and 4% were non-Hispanic American Indian or Alaska Native (AI/AN) persons. Among these 121 decedents, 91 (75%) had an underlying medical condition,* 79 (65%) died after admission to a hospital, and 39 (32%) died at home or in the emergency department (ED).(†) These data show that nearly three quarters of SARS-CoV-2-associated deaths among infants, children, adolescents, and young adults have occurred in persons aged 10-20 years, with a disproportionate percentage among young adults aged 18-20 years and among Hispanics, Blacks, AI/ANs, and persons with underlying medical conditions. Careful monitoring of SARS-CoV-2 infections, deaths, and other severe outcomes among persons aged <21 years remains particularly important as schools reopen in the United States. Ongoing evaluation of effectiveness of prevention and control strategies will also be important to inform public health guidance for schools and parents and other caregivers.

Norovirus is the leading cause of acute gastroenteritis outbreaks in the United States. We estimated the basic (R(0)) and effective (R(e)) reproduction numbers for 7,094 norovirus outbreaks reported to the National Outbreak Reporting System (NORS) during 2009-2017 and used regression models to assess whether transmission varied by outbreak setting. The median R(0) was 2.75 (interquartile range [IQR] 2.38-3.65), and median R(e) was 1.29 (IQR 1.12-1.74). Long-term care and assisted living facilities had an R(0) of 3.35 (95% CI 3.26-3.45), but R(0) did not differ substantially for outbreaks in other settings, except for outbreaks in schools, colleges, and universities, which had an R(0) of 2.92 (95% CI 2.82-3.03). Seasonally, R(0) was lowest (3.11 [95% CI 2.97-3.25]) in summer and peaked in fall and winter. Overall, we saw little variability in transmission across different outbreaks settings in the United States.

Among 146 nasopharyngeal (NP) and oropharyngeal (OP) swab pairs collected </=7 days since illness onset, CDC real-time RT-PCR SARS-CoV-2 assay diagnostic results were 95.2% concordant. However, NP swab Ct values were lower (indicating more virus) in 66.7% of concordant-positive pairs, suggesting NP swabs may more accurately detect amount of SARS-CoV-2.

Among 146 nasopharyngeal (NP) and oropharyngeal (OP) swab pairs collected </=7 days since illness onset, CDC real-time RT-PCR SARS-CoV-2 assay diagnostic results were 95.2% concordant. However, NP swab Ct values were lower (indicating more virus) in 66.7% of concordant-positive pairs, suggesting NP swabs may more accurately detect amount of SARS-CoV-2.