Objectives: In the United States, firearm injuries disproportionately occur in low-income communities and among racial and ethnic minority populations. Recognizing these patterns across social conditions is vital for effective public health interventions. Using timely and localized data, we examined the association between social vulnerability and firearm injuries in King County, Washington. Methods: For this ecological, cross-sectional study, we used health reporting areas (HRAs) (n = 61), a subcounty geography of King County. We obtained HRA-level counts of firearm injuries by using responses from King County emergency medical services (EMS) from 2019 through 2023. We measured HRA-level social vulnerability by using the Social Vulnerability Index (SVI) from the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry, categorized into tertiles (low, moderate, and high SVI). We used bivariate choropleth mapping to illustrate spatial associations between SVI and rates of firearm injuries per 10 000 residents. We used Bayesian spatial negative binomial regression to quantify the strength of these associations. Results: Bivariate choropleth mapping showed a correlation between SVI and rates of firearm injuries. In spatial models, HRAs categorized as high SVI had a 3 times higher rate of firearm injuries than HRAs categorized as low SVI (incidence rate ratio = 3.01; 95% credible interval, 2.02-4.47). Rates of firearm injuries were also higher in HRAs categorized as moderate versus low SVI (incidence rate ratio = 1.72; 95% credible interval, 1.23-2.40). Conclusion: In King County, areas with high social vulnerability had high rates of EMS responses to firearm injuries. SVI can help identify geographic areas for intervention and provide a framework for identifying upstream factors that might contribute to spatial disparities in firearm injuries. © 2024, Association of Schools and Programs of Public Health.

BACKGROUND: Spatial repellent products are used for prevention of insect bites, and a body of evidence exists on spatial repellent entomological efficacy. A new option for vector control, spatial repellent products are designed to release active ingredient into the air for disruption of human-vector contact thereby reducing human exposure to mosquito-borne pathogens. Clinical trials have shown spatial repellent epidemiological efficacy against Aedes-borne viruses but inconclusive outcomes against malaria. We aimed to show and quantify the protective efficacy of spatial repellents in reducing malaria infection incidence in Busia County, Kenya. METHODS: A prospective, cluster-randomised, controlled trial in Busia County, western Kenya was done to quantify the efficacy of a transfluthrin-based spatial repellent against human malaria infection following mass distribution of insecticide treated nets. Investigators, staff, and study participants were masked to cluster allocation. Infection incidence was measured by microscopy in children aged 6 months to younger than 10 years during a 4-month baseline (March-July 2021) and 24-month follow-up period with intervention (October, 2021-October, 2023). From 58 clusters (29 intervention, 29 placebo), a total of 1526 and 1546 participants from two consecutive, 12-month cohorts were assessed for first-time malaria infection (primary endpoint) by survival analysis at interim and end-of-trial timepoints, respectively. This trial is registered with ClinicalTrials.gov, NCT04766879 and is complete. FINDINGS: The outcome of the primary endpoint indicated that spatial repellents significantly reduced the hazard rate of first-time malaria infection by 33·4% (95% CI 11·1-50·1; p=0·0058) and the hazard rate of overall new malaria infections by 32·1% (15·9-45·2; p=0·0004). No reported adverse events and serious adverse events were deemed to be associated with the spatial repellent. INTERPRETATION: Our trial provides the first evidence of a demonstrative spatial repellent protective efficacy in reducing risk of malaria infection in an African setting characterised by high malaria transmission, pyrethroid resistant malaria vectors, and high coverage of insecticide treated nets. Results support spatial repellent products as a beneficial component of malaria prevention. FUNDING: This study was funded by Unitaid to the University of Notre Dame.

The global spread of the highly pathogenic avian influenza (HPAI) A(H5N1) virus poses a serious pandemic threat, necessitating the swift development of effective vaccines. The success of messenger RNA (mRNA) vaccine technology in the COVID-19 pandemic, marked by its rapid development and scalability, demonstrates its potential for addressing other infectious threats, such as HPAI A(H5N1). We therefore evaluated mRNA vaccine candidates targeting panzootic influenza A(H5) clade 2.3.4.4b viruses, which have been shown to infect a range of mammalian species, including most recently being detected in dairy cattle. Ferrets were immunized with mRNA vaccines encoding either hemagglutinin alone or hemagglutinin and neuraminidase, derived from a 2.3.4.4b prototype vaccine virus recommended by the World Health Organization. Kinetics of the immune responses, as well as protection against a lethal challenge dose of A(H5N1) virus, were assessed. Two doses of mRNA vaccination elicited robust neutralizing antibody titers against a 2022 avian isolate and a 2024 human isolate. Further, mRNA vaccination conferred protection from lethal challenge, whereas all unvaccinated ferrets succumbed to infection. It also reduced viral titers in the upper and lower respiratory tracts of infected ferrets. These results underscore the effectiveness of mRNA vaccines against HPAI A(H5N1), showcasing their potential as a vaccine platform for future influenza pandemics.

BACKGROUND: Egg-based inactivated quadrivalent seasonal influenza vaccine (eIIV4), cell culture-based inactivated quadrivalent seasonal influenza vaccine (ccIIV4), and recombinant haemagglutinin (HA)-based quadrivalent seasonal influenza vaccine (RIV4) have been licensed for use in the USA. In this study, we used antigen-specific serum proteomics analysis to assess how the molecular composition and qualities of the serological antibody repertoires differ after seasonal influenza immunisation by each of the three vaccines and how different vaccination platforms affect the HA binding affinity and breadth of the serum antibodies that comprise the polyclonal response. METHODS: In this comparative, prospective, observational cohort study, we included female US health-care personnel (mean age 47·6 years [SD 8]) who received a single dose of RIV4, eIIV4, or ccIIV4 during the 2018-19 influenza season at Baylor Scott & White Health (Temple, TX, USA). Eligible individuals were selected based on comparable day 28 serum microneutralisation titres and similar vaccination history. Laboratory investigators were blinded to assignment until testing was completed. The preplanned exploratory endpoints were assessed by deconvoluting the serological repertoire specific to A/Singapore/INFIMH-16-0019/2016 (H3N2) HA before (day 0) and after (day 28) immunisation using bottom-up liquid chromatography-mass spectrometry proteomics (referred to as Ig-Seq) and natively paired variable heavy chain-variable light chain high-throughput B-cell receptor sequencing (referred to as BCR-Seq). Features of the antigen-specific serological repertoire at day 0 and day 28 for the three vaccine groups were compared. Antibodies identified with high confidence in sera were recombinantly expressed and characterised in depth to determine the binding affinity and breadth to time-ordered H3 HA proteins. FINDINGS: During September and October of the 2018-19 influenza season, 15 individuals were recruited and assigned to receive RIV4 (n=5), eIIV4 (n=5), or ccIIV4 (n=5). For all three cohorts, the serum antibody repertoire was dominated by back-boosted antibody lineages (median 98% [95% CI 88-99]) that were present in the serum before vaccination. Although vaccine platform-dependent differences were not evident in the repertoire diversity, somatic hypermutation, or heavy chain complementarity determining region 3 biochemical features, antibodies boosted by RIV4 showed substantially higher binding affinity to the vaccine H3/HA (median half-maximal effective concentration [EC50] to A/Singapore/INFIMH-16-0019/2016 HA: 0·037 μg/mL [95% CI 0·012-0·12] for RIV4; 4·43 μg/mL [0·030-100·0] for eIIV4; and 18·50 μg/mL [0·99-100·0] μg/mL for ccIIV4) and also the HAs from contemporary H3N2 strains than did those elicited by eIIV4 or ccIIV4 (median EC50 to A/Texas/50/2012 HA: 0·037 μg/mL [0·017-0·32] for RIV4; 1·10 μg/mL [0·045-100] for eIIV4; and 12·6 μg/mL [1·8-100] for ccIIV4). Comparison of B-cell receptor sequencing repertoires on day 7 showed that eIIV4 increased the median frequency of canonical egg glycan-targeting B cells (0·20% [95% CI 0·067-0·37] for eIIV4; 0·058% [0·050-0·11] for RIV4; and 0·035% [0-0·062] for ccIIV4), whereas RIV4 vaccination decreased the median frequency of B-cell receptors displaying stereotypical features associated with membrane proximal anchor-targeting antibodies (0·062% [95% CI 0-0·084] for RIV4; 0·12% [0·066-0·16] for eIIV4; and 0·18% [0·016-0·20] for ccIIV4). In exploratory analysis, we characterised the structure of a highly abundant monoclonal antibody that binds to both group 1 and 2 HAs and recognises the HA trimer interface, despite its sequence resembling the stereotypical sequence motif found in membrane-proximal anchor binding antibodies. INTERPRETATION: Although all three licensed seasonal influenza vaccines elicit serological antibody repertoires with indistinguishable features shaped by heavy imprinting, the RIV4 vaccine selectively boosts higher affinity monoclonal antibodies to contemporary strains and elicits greater serum binding potency and breadth, possibly as a consequence of the multivalent structural features of the HA immunogen in this vaccine formulation. Collectively, our findings show advantages of RIV4 vaccines and more generally highlight the benefits of multivalent HA immunogens in promoting higher affinity serum antibody responses. FUNDING: Centers for Disease Control and Prevention, National Institutes of Health, and Bill & Melinda Gates Foundation.

PURPOSE: Renal ultrasounds are performed in patients with myelomeningocele to screen for markers of kidney health, including hydronephrosis. We evaluated the diagnostic accuracy of hydronephrosis to screen for low kidney function defined by estimated glomerular filtration rate (eGFR). MATERIALS AND METHODS: We performed a retrospective cross-sectional study using data from 2 cohorts of children and youth with myelomeningocele. The first cohort is the Urological Management to Preserve Initial Renal Function Protocol for Young Children With Spina Bifida (UMPIRE; 2016-2022) and the second from the National Spina Bifida Patient Registry (NSBPR; 2009-2021). We identified patients aged 1 to 18 years with available eGFR data within 6 months of an ultrasound. We excluded NSBPR patients younger than 6 years to address potential duplication across cohorts. The primary outcome was eGFR < 90 mL/min/1.73 m(2), calculated using the bedside Schwartz formula. Hydronephrosis was dichotomized into any/none. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of any hydronephrosis using eGFR as the reference standard. RESULTS: In UMPIRE, 221 patients were included with median age 2.4 years (IQR, 1.9-3.8) and 24% having eGFR < 90. Any hydronephrosis vs none conferred a sensitivity/specificity/PPV/NPV of 25%/75%/24%/77%, respectively. In NSBPR, 2269 patients were included with median age 13 years (IQR, 9.6-16.3) and 17% having eGFR < 90. Any hydronephrosis vs none conferred a sensitivity/specificity/PPV/NPV of 24%/87%/26%/85%, respectively. CONCLUSIONS: In 2 cohorts of children and youth with myelomeningocele, hydronephrosis conferred a sensitivity of ∼25% for a creatinine-based eGFR < 90 mL/min/1.73 m(2). This low sensitivity suggests that hydronephrosis alone is a poor screening marker of kidney health.

BACKGROUND: Trachoma programs use the indicator trachomatous inflammation--follicular (TF) to monitor indication for and response to treatment for trachoma at the district level. Alternative indicators, including serologic markers, are increasingly being evaluated for trachoma surveillance. We evaluated seroprevalence of IgG antibodies to the Pgp3 antigen in two districts in Maradi, Niger thought to have low TF prevalence. METHODS: Data were collected as part of the baseline assessment of the Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) trial in September 2021. A random sample of 80 communities was selected from Mayahi and Guidan Roumdji districts, both of which had TF prevalence <20% at their most recent trachoma impact survey in 2018. A random sample of 50 children per community was sampled. We collected field grades, conjunctival swabs for processing PCR for ocular Chlamydia trachomatis, and dried blood spots for serologic assessment. RESULTS: Of 3,994 children sampled in 80 communities, 49% were female and median age was 4 years. Overall TF prevalence was 4.6% (95% CI 3.5 to 5.8%) and trachomatous inflammation-intense (TI) prevalence was 0.6% (95% 0.3 to 0.9%). The prevalence of ocular chlamydia was 0.03% (95% CI 0.08%). Seroprevalence for Pgp3 antibodies was 6.3% (95% CI 5.5 to 7.1%) in 1-9-year-olds and 3.7% (95% CI 2.9 to 4.4%) in 1-5-year-olds. TF and Pgp3 seroprevalence were better correlated in 1-5-year-olds (correlation coefficient 0.29) compared to 1-9-year-olds (correlation coefficient 0.09). CONCLUSIONS: In this low trachoma prevalence setting in Niger, seroprevalence of antibodies to Pgp3 were consistent with little ongoing transmission of C. trachomatis.

Endurance exercise training (ExT) induces metabolic, structural, and functional adaptations via lipidomic modifications, yet the systematic elucidation of lipidome alterations in response to ExT remains incomplete. As a part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we leveraged non-targeted and targeted lipidomics for the systematic discovery of lipid alterations in the brown adipose tissue, heart, hippocampus, kidney, liver, lung, skeletal muscle gastrocnemius, subcutaneous white adipose tissue, and plasma in response to 1, 2, 4 or 8 weeks of ExT in 6-month-old male and female Fischer-344 rats. This study demonstrates that these tissues, each with distinct lipidomic features, underwent dynamic, sexually dimorphic lipid remodeling. Exercise trained animals showed reduced whole-body adiposity and improved cardiorespiratory fitness, along with enhanced utilization of lipid stores and dynamic triacylglycerol remodeling compared to sedentary controls in all tissues except hippocampus. They also showed modifications in phospholipids, lysophospholipids, oxylipins, and ceramides in several tissues. Coordinated changes across tissues reflect systemic tissue communication, with liver-plasma-heart connection potentially playing a key role in systemic lipid metabolism during ExT. These data will improve our understanding of lipid-associated biological processes underlying the health-promoting benefits of ExT.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentrations in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17 274 participants, there were 101 cases with new HIV-1 diagnosis (.77 per 100 person-years; 95% confidence interval [CI]: .63-.94). In 78 cases with resistance data, 18 (23%) had M184I or V, 1 (1.3%) had K65R, and 3 (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/wk, respectively, and the corresponding incidence was 3.9 (95% CI: 2.9-5.3), .24 (.060-.95), .27 (.12-.60), and .054 (.008-.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

As the world is approaching the eradication of wild poliovirus serotype 1, the last of the three wild types, the question of how to maintain a polio-free world becomes imminent. To mitigate the risk of sporadic vaccine-associated paralytic polio (VAPP) caused by oral polio vaccines (OPVs) that are routinely used in global immunization programs, the Polio Antivirals Initiative (PAI) was established in 2006. The primary goal of the PAI is to facilitate the discovery and development of antiviral drugs to stop the excretion of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) in B cell-deficient individuals. This review summarizes the major progress that has been made in the development of safe and effective poliovirus antivirals and highlights the candidates that have shown promising results in vitro, in vivo, and in clinical trials.

BACKGROUND: Implications of relabeling grade group (GG) 1 prostate cancer as non-cancer will depend on the recommended active surveillance (AS) strategy. Whether relabeling should prompt de-intensifying, PSA-based active monitoring approaches is unclear. We investigated outcomes of biopsy-based AS strategies vs PSA-based active monitoring for GG1 diagnoses under different patient adherence rates. METHODS: We analyzed longitudinal PSA levels and time to GG ≥ 2 reclassification among 850 patients diagnosed with GG1 disease from the Canary Prostate Active Surveillance Study (2008-2013). We then simulated 20,000 patients over 12 years, comparing GG ≥ 2 detection under biennial biopsy against three PSA-based strategies:(1) PSA: biopsy for PSA change ≥20%/year, (2) PSA+MRI: MRI for PSA change ≥20%/year and biopsy for PI-RADS ≥3, and (3) Predicted risk: biopsy for predicted upgrading risk ≥10%. RESULTS: Under biennial biopsies and 20% dropout to active treatment, 17% of patients had a > 2-year delay in GG ≥ 2 detection. The PSA strategy reduced biopsies by 39% but delayed detection in 32% of patients. The PSA+MRI strategy cut biopsies by 52%, with a 34% delay. The predicted risk strategy reduced biopsies by 31%, with only an 8% delay. These findings are robust to biopsy sensitivity and confirmatory biopsy. CONCLUSIONS: PSA-based active monitoring could substantially reduce biopsy frequency; however, a precision strategy based on an individual upgrading risk is most likely to minimize delays in disease progression detection. This strategy may be preferred if AS is deintensified under relabeling, provided patient adherence remains unaffected.

BACKGROUND: In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against prostate cancer screening using the prostate-specific antigen (PSA) test for all age groups. In 2018 the USPSTF's recommendation shifted from a "D" (not recommended) to a "C" (selectively offering PSA-based screening based on professional judgment and patient preferences) in men ages 55-69. Limited reliable county-level prostate cancer screening data is available for cancer surveillance purposes. METHODS: Utilizing data from the National Health Interview Survey (NHIS) and Behavioral Risk Factor Surveillance System (BRFSS) collected in 2012-2019, state- and county-level small area models were developed for estimating PSA testing. Model diagnosis, internal validation, and external validation examining associations of PSA testing and prostate cancer incidence were conducted. RESULTS: Model-based estimates of PSA testing rate were produced for all U.S. states and 3,142 counties for two data periods: 2012-2016 and 2018-2019. Geographic variations across counties were demonstrated through maps. Moderate positive correlations between PSA-based screening and prostate cancer incidence were observed, for example, the state-level weighted Pearson's correlation coefficients were 0.5025 (p-value=0.0002) and 0.3691 (p-value=0.0077) for 2012-2016 and 2018-2019, respectively. CONCLUSIONS: These modeled estimates showed improved precision and adjusted for the differences between BRFSS and NHIS. The approach of combining NHIS and BRFSS utilized strengths of the larger sample size of BRFSS and generally higher response rates and better household coverage from the NHIS. IMPACT: The resulting small area estimates offer a valuable resource for the cancer surveillance community, aiding in targeted interventions, decision-making, and further research endeavors.

BACKGROUND: A peri-urban outbreak of Rift Valley fever virus (RVFV) among dairy cattle from May through August 2018 in northern Tanzania was detected through testing samples from prospective livestock abortion surveillance. We sought to identify concurrent human infections, their phylogeny, and epidemiologic characteristics in a cohort of febrile patients enrolled from 2016-2019 at hospitals serving the epizootic area. METHODS: From September 2016 through May 2019, we conducted a prospective cohort study that enrolled febrile patients hospitalized at two hospitals in Moshi, Tanzania. Archived serum, plasma, or whole blood samples were retrospectively tested for RVFV by PCR. Human samples positive for RVFV were sequenced and compared to RVFV sequences obtained from cattle through a prospective livestock abortion study. Phylogenetic analysis was performed on complete RVFV genomes. RESULTS: Among 656 human participants, we detected RVFV RNA in four (0.6%), including one death with hepatic necrosis and other end-organ damage at autopsy. Humans infected with RVFV were enrolled from June through August 2018, and all resided in or near urban areas. Phylogenetic analysis of human and cattle RVFV sequences demonstrated that most clustered to lineage B, a lineage previously described in East Africa. A lineage E strain clustering with lineages in Angola was also identified in cattle. CONCLUSION: We provide evidence that an apparently small RVFV outbreak among dairy cattle in northern Tanzania was associated with concurrent severe and fatal infections among humans. Our findings highlight the unidentified scale and diversity of inter-epizootic RVFV transmission, including near and within an urban area.

Since April 2024, sporadic infections with highly pathogenic avian influenza (HPAI) A(H5) viruses have been detected among dairy farm workers in the United States. To date, infections have mostly been detected through worker monitoring, and have been mild despite the possibility of more severe illness. During June-August 2024, CDC collaborated with the Michigan Department of Health and Human Services and the Colorado Department of Public Health and Environment to implement cross-sectional serologic surveys to ascertain the prevalence of recent infection with HPAI A(H5) virus among dairy workers. In both states, a convenience sample of persons who work in dairies was interviewed, and blood specimens were collected. Among 115 persons, eight (7%; 95% CI = 3.6%-13.1%) had serologic evidence of recent infection with A(H5) virus; all reported milking cows or cleaning the milking parlor. Among persons with serologic evidence of infection, four recalled being ill around the time cows were ill; symptoms began before or within a few days of A(H5) virus detections among cows. This finding supports the need to identify and implement strategies to prevent transmission among dairy cattle to reduce worker exposures and for education and outreach to dairy workers concerning prevention, symptoms, and where to seek medical care if the workers develop symptoms. Timely identification of infected herds can support rapid initiation of monitoring, testing, and treatment for human illness, including mild illness, among exposed dairy workers.

The World Trade Center (WTC) Health Program is a limited federal health care program that provides medical monitoring and treatment for WTC-related health conditions to responders and survivors impacted by the terrorist attacks on September 11, 2001.This study described the characteristics of the Program survivor members (who lived, worked, went to school, daycare or adult daycare or present in the New York City Disaster Area of 9/11/2001) to stimulate innovative ideas for improving healthcare services, generate new research interest, and serve as a reference for future research on this population. Administrative and medical claims data collected from the Program start date (07/01/2011) through 2022 were used. As of 12/31/2022, there were 37,384 enrolled survivors: 5.0% were aged ≤21 years on 9/11/2001, 45.9% females, and 31.2% non-Hispanic Whites. A total of 24,148 (64.6%) were certified for at least one WTC-related condition, including neoplasms (36.0%), aerodigestive disorders (35.6%) and mental health conditions (18.6%); 22.9% were certified for more than one category. Certification rates of some WTC-related conditions differed by sex, age and race/ethnicity. WTC survivor population is diverse in sex, age and race/ethnicity, with a high proportion certified for certain WTC-related health conditions, providing great opportunities for research in various areas.

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

We report the complete genome sequences of nine double recombinant vaccine-derived novel oral poliovirus type 2 genomes from acute flaccid paralysis (AFP) cases (n = 3), AFP case contacts (n = 4), and environmental surveillance sampling (n = 2) in Nigeria.

IMPORTANCE: Although influenza vaccination has been found to be safe in pregnancy, few studies have assessed repeated influenza vaccination over successive pregnancies, including 2 vaccinations in a year, in terms of adverse perinatal outcomes. OBJECTIVE: To examine the association of seasonal influenza vaccination across successive pregnancies with adverse perinatal outcomes and whether the association varies by interpregnancy interval (IPI) and vaccine type (quadrivalent or trivalent). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included individuals with at least 2 successive singleton live-birth pregnancies between January 1, 2004, and December 31, 2018. Data were collected from the Vaccine Safety Datalink, a collaboration between the Centers for Disease Control and Prevention and integrated health care organizations. Data analysis was performed between January 8, 2021, and July 17, 2024. EXPOSURES: Influenza vaccination was identified using vaccine administration codes. The vaccinated cohort consisted of people who received influenza vaccines during the influenza season (August 1 through April 30) in 2 successive pregnancies. The comparator cohort consisted of people identified as unvaccinated during both pregnancies. MAIN OUTCOMES AND MEASURES: Main outcomes were risk of preeclampsia or eclampsia, placental abruption, fever, preterm birth, preterm premature rupture of membranes, chorioamnionitis, and small for gestational age among individuals with and without vaccination in both pregnancies. Adjusted relative risks (RRs) from Poisson regression were used to assess the magnitude of associations. The associations with adverse outcomes by IPI and vaccine type were evaluated. RESULTS: Of 82 055 people with 2 singleton pregnancies between 2004 and 2018, 44 879 (54.7%) had influenza vaccination in successive pregnancies. Mean (SD) age at the start of the second pregnancy was 32.2 (4.6) years for vaccinated individuals and 31.2 (5.0) years for unvaccinated individuals. Compared with individuals not vaccinated in both pregnancies, vaccination in successive pregnancies was not associated with increased risk of preeclampsia or eclampsia (adjusted RR, 1.10; 95% CI, 0.99-1.21), placental abruption (adjusted RR, 1.01; 95% CI, 0.84-1.21), fever (adjusted RR, 0.87; 95% CI, 0.47-1.59), preterm birth (adjusted RR, 0.83; 95% CI, 0.78-0.89), preterm premature rupture of membranes (RR, 1.00; 95% CI, 0.94-1.06), chorioamnionitis (adjusted RR, 1.03; 95% CI, 0.90-1.18), or small for gestational age birth (adjusted RR, 0.99; 95% CI, 0.93-1.05). IPI and vaccine type did not modify the observed associations. CONCLUSIONS AND RELEVANCE: In this large cohort study of successive pregnancies, influenza vaccination was not associated with increased risk of adverse perinatal outcomes, irrespective of IPI and vaccine type. Findings support recommendations to vaccinate pregnant people or those who might be pregnant during the influenza season.

BACKGROUND: Existing surveillance systems monitor nonfatal and fatal opioid overdoses but do not monitor severe nonfatal overdoses that require intensive medical interventions. METHODS: The Centers for Disease Control and Prevention's Drug Overdose Surveillance and Epidemiology system was used to query emergency department data from local syndromic systems and the National Syndromic Surveillance Program from January 2019 to August 2022. Opioid overdoses were classified as not severe or severe using a definition from the patient's chief complaint terms and discharge diagnosis codes. The percentage of opioid overdoses treated in emergency departments classified as severe was described by patient demographics, US Census region, and month. RESULTS: Among 503 156 opioid overdoses in 29 states and Washington, DC, from January 2019 to August 2022, 17.4% were classified as severe. Common key terms found among severe opioid overdoses were hypoxia (34.8%), unresponsive (32.9%), and naloxone/Narcan (20.9%). The largest severity percentage was in the South Census region (19.6%). The trends of severe opioid overdoses remained stable during the study period. DISCUSSION: Based on the severe opioid overdose definition, there was minimal change in the severity of opioid overdoses during the study period. This definition can help monitor trends of severe opioid overdoses, guiding public health action such as focusing on naloxone and fentanyl test strip distribution to areas of need.

BACKGROUND: Antiviral post-exposure prophylaxis with neuraminidase inhibitors can reduce the incidence of influenza and the risk of symptomatic influenza, but the efficacy of the other classes of antiviral remains unclear. To support an update of WHO influenza guidelines, this systematic review and network meta-analysis evaluated antiviral drugs for post-exposure prophylaxis of influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023 that evaluated the efficacy and safety of antivirals compared with another antiviral or placebo or standard care for prevention of influenza. Pairs of reviewers independently screened studies, extracted data, and assessed the risk of bias. We performed network meta-analyses with frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The outcomes of interest were symptomatic or asymptomatic infection, admission to hospital, all-cause mortality, adverse events related to antivirals, and serious adverse events. This study is registered with PROSPERO, CRD42023466450. FINDINGS: Of 11 845 records identified by our search, 33 trials of six antivirals (zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine) that enrolled 19 096 individuals (mean age 6·75-81·15 years) were included in this systematic review and network meta-analysis. Most of the studies were rated as having a low risk of bias. Zanamivir, oseltamivir, laninamivir, and baloxavir probably achieve important reductions in symptomatic influenza in individuals at high risk of severe disease (zanamivir: risk ratio 0·35, 95% CI 0·25-0·50; oseltamivir: 0·40, 0·26-0·62; laninamivir: 0·43, 0·30-0·63; baloxavir: 0·43, 0·23-0·79; moderate certainty) when given promptly (eg, within 48 h) after exposure to seasonal influenza. These antivirals probably do not achieve important reductions in symptomatic influenza in individuals at low risk of severe disease when given promptly after exposure to seasonal influenza (moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir might achieve important reductions in symptomatic zoonotic influenza in individuals exposed to novel influenza A viruses associated with severe disease in infected humans when given promptly after exposure (low certainty). Oseltamivir, laninamivir, baloxavir, and amantadine probably decrease the risk of all influenza (symptomatic and asymptomatic infection; moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir probably have little or no effect on prevention of asymptomatic influenza virus infection or all-cause mortality (high or moderate certainty). Oseltamivir probably has little or no effect on admission to hospital (moderate certainty). All six antivirals do not significantly increase the incidence of drug-related adverse events or serious adverse events, although the certainty of evidence varies. INTERPRETATION: Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir probably decreases the risk of symptomatic seasonal influenza in individuals at high risk for severe disease after exposure to seasonal influenza viruses. Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir might reduce the risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease in infected humans. FUNDING: World Health Organization.

BACKGROUND: The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023, that enrolled hospitalised patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. Pairs of coauthors independently extracted data on study characteristics, patient characteristics, antiviral characteristics, and outcomes, with discrepancies resolved by discussion or by a third coauthor. Key outcomes of interest were time to alleviation of symptoms, duration of hospitalisation, admission to intensive care unit, progression to invasive mechanical ventilation, duration of mechanical ventilation, mortality, hospital discharge destination, emergence of antiviral resistance, adverse events, adverse events related to treatments, and serious adverse events. We conducted frequentist network meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This study is registered with PROSPERO, CRD42023456650. FINDINGS: Of 11 878 records identified by our search, eight trials with 1424 participants (mean age 36-60 years for trials that reported mean or median age; 43-78% male patients) were included in this systematic review, of which six were included in the network meta-analysis. The effects of oseltamivir, peramivir, or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza were of very low certainty. Compared with placebo or standard care, we found low certainty evidence that duration of hospitalisation for seasonal influenza was reduced with oseltamivir (mean difference -1·63 days, 95% CI -2·81 to -0·45) and peramivir (-1·73 days, -3·33 to -0·13). Compared with standard care, there was little or no difference in time to alleviation of symptoms with oseltamivir (0·34 days, -0·86 to 1·54; low certainty evidence) or peramivir (-0·05 days, -0·69 to 0·59; low certainty evidence). There were no differences in adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir (very low certainty evidence). Uncertainty remains about the effects of antivirals on other outcomes for patients with severe influenza. Due to the small number of eligible trials, we could not test for publication bias. INTERPRETATION: In hospitalised patients with severe influenza, oseltamivir and peramivir might reduce duration of hospitalisation compared with standard care or placebo, although the certainty of evidence is low. The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials. FUNDING: World Health Organization.

Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear-distinct philosophical traditions suggest different views of wisdom's cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets' wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions-Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets-as perceived by participants-score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

PROBLEM/CONDITION: In 2021, approximately 75,000 persons died of violence-related injuries in the United States. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) on violent deaths that occurred in 48 states, the District of Columbia, and Puerto Rico in 2021. Results are reported by sex, age group, race and ethnicity, method of injury, type of location where the injury occurred, circumstances of injury, and other selected characteristics. This report introduces additional incident and circumstance variables, which now include child victim-specific circumstance information. This report also incorporates new U.S. Census Bureau race and ethnicity categories, which now account for more than one race and Native Hawaiian or other Pacific Islander categories and include updated denominators to calculate rates for these populations. PERIOD COVERED: 2021. DESCRIPTION OF SYSTEM: NVDRS collects data regarding violent deaths from death certificates, coroner and medical examiner records, and law enforcement reports. This report includes data collected for violent deaths that occurred in 2021. Data were collected from 48 states (all states with exception of Florida and Hawaii), the District of Columbia, and Puerto Rico. Forty-six states had statewide data, two additional states had data from counties representing a subset of their population (31 California counties, representing 64% of its population, and 13 Texas counties, representing 63% of its population), and the District of Columbia and Puerto Rico had jurisdiction-wide data. NVDRS collates information for each violent death and links deaths that are related (e.g., multiple homicides, homicide followed by suicide, or multiple suicides) into a single incident. RESULTS: For 2021, NVDRS collected information on 68,866 fatal incidents involving 70,688 deaths that occurred in 48 states (46 states collecting statewide data, 31 California counties, and 13 Texas counties), and the District of Columbia. The deaths captured in NVDRS accounted for 86.5% of all homicides, legal intervention deaths, suicides, unintentional firearm injury deaths, and deaths of undetermined intent in the United States in 2021. In addition, information was collected for 816 fatal incidents involving 880 deaths in Puerto Rico. Data for Puerto Rico were analyzed separately. Of the 70,688 deaths, the majority (58.2%) were suicides, followed by homicides (31.5%), deaths of undetermined intent that might be due to violence (8.2%), legal intervention deaths (1.3%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force acting in the line of duty, excluding legal executions), and unintentional firearm injury deaths (<1.0%). The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision, and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.Demographic patterns and circumstances varied by manner of death. The suicide rate was higher for males than for females. Across all age groups, the suicide rate was highest among adults aged ≥85 years. In addition, non-Hispanic American Indian or Alaska Native (AI/AN) persons had the highest suicide rates among all racial and ethnic groups. Among both males and females, the most common method of injury for suicide was a firearm. Among all suicide victims, when circumstances were known (84.4%), suicide was most often preceded by a mental health, intimate partner, or physical health problem or by a recent or impending crisis during the previous or upcoming 2 weeks. The homicide rate was higher for males than for females. Among all homicide victims, the homicide rate was highest among persons aged 20-24 years compared with other age groups. Non-Hispanic Black or African American (Black) males experienced the highest homicide rate of any racial or ethnic group. Among all homicide victims, the most common method of injury was a firearm. When the relationship between a homicide victim and a suspect was known, the suspect was most frequently an acquaintance or friend for male victims and a current or former intimate partner for female victims. Homicide most often was precipitated by an argument or conflict, occurred in conjunction with another crime, or, for female victims, was related to intimate partner violence. Nearly all victims of legal intervention deaths were male, and the legal intervention death rate was highest among men aged 30-34 years. The legal intervention death rate was highest among AI/AN males, followed by Black males. A firearm was used in the majority of legal intervention deaths. When circumstances were known, the most frequent circumstances reported for legal intervention deaths were as follows: the victim used a weapon in the incident and the victim had a substance use problem (other than alcohol use). Other causes of death included unintentional firearm injury deaths and deaths of undetermined intent. Unintentional firearm injury deaths were most frequently experienced by males, non-Hispanic White (White) persons, and persons aged 15-24 years. These deaths most frequently occurred while the shooter was playing with a firearm and were precipitated by a person unintentionally pulling the trigger. The rate of deaths of undetermined intent was highest among males, particularly among AI/AN and Black males, and among adults aged 30-54 years. Poisoning was the most common method of injury in deaths of undetermined intent, and opioids were detected in nearly 80% of decedents tested for those substances. INTERPRETATION: This report provides a detailed summary of data from NVDRS on violent deaths that occurred in 2021. The suicide rate was highest among AI/AN and White males, whereas the homicide rate was highest among Black males. Intimate partner violence precipitated a large proportion of homicides for females. Mental health problems, intimate partner problems, interpersonal conflicts, and acute life stressors were primary precipitating circumstances for multiple types of deaths examined. PUBLIC HEALTH ACTION: Violence is preventable, and data can guide public health action. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in developing, implementing, and evaluating programs, policies, and practices to reduce and prevent violent deaths. NVDRS data can be used to enhance prevention efforts into actionable strategies. States or jurisdictions have used their Violent Death Reporting System (VDRS) data to guide suicide prevention efforts and highlight where additional focus is needed. For example, North Carolina VDRS program data have played a significant role in expanding activities related to firearm safety and injury prevention. The program served as a primary data source for partners, which led to the creation of the Office of Violence Prevention in the state, focusing on combatting firearm-related deaths. In Maine, the VDRS provided data on law enforcement officer suicides that were used to help support a bill mandating mental health resiliency and awareness training in the state's law enforcement training academy, along with plans for similar training addressing mental health, substance use, and alcohol problems among corrections officers. In addition, states and jurisdictions have also used their VDRS data to examine factors related to homicide in their state or jurisdiction. For example, Georgia VDRS collaborated with the City of Atlanta Mayor's Office of Violence Reduction to develop two public dashboards that not only offer comprehensive data on violent deaths but also present data on the geographic distribution of populations disproportionately affected by violence to help inform violence prevention interventions.

COVID-19, caused by the SARS-CoV-2 virus, is a highly pathogenic emerging infectious disease. Healthcare personnel (HCP) are presumably at higher risk of acquiring emerging infections because of occupational exposure. The prevalence of COVID-19 in HCP is unknown, particularly in low- to middle-income countries like El Salvador. The goal of this study was to determine the seroprevalence of anti-SARS-CoV-2 antibodies among HCP in El Salvador just prior to vaccine rollout in March 2021. We evaluated 2176 participants from a nationally representative sample of national healthcare institutions. We found 40.4% (n = 880) of the study participants were seropositive for anti-spike protein antibodies. Significant factors associated with infection included younger age; living within the central, more populated zone of the country; living in a larger household (≥7 members); household members with COVID-19 or compatible symptoms; and those who worked in auxiliary services (i.e., housekeeping and food services). These findings provide insight into opportunities to mitigate SARS-CoV-2 risk and other emerging respiratory pathogens in HCP in El Salvador.

IMPORTANCE: People with HIV (PWH) may be at increased risk for severe outcomes with COVID-19 illness compared with people without HIV. Little is known about COVID-19 vaccination coverage and factors associated with primary series completion among PWH. OBJECTIVES: To evaluate COVID-19 vaccination coverage among PWH and examine sociodemographic, clinical, and community-level factors associated with completion of the primary series and an additional primary dose. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used electronic health record data to assess COVID-19 vaccination information from December 14, 2020, through April 30, 2022, from 8 health care organizations of the Vaccine Safety Datalink project in the US. Participants were adults diagnosed with HIV on or before December 14, 2020, enrolled in a participating site. MAIN OUTCOMES AND MEASURES: The percentage of PWH with at least 1 dose of COVID-19 vaccine and PWH who completed the COVID-19 vaccine primary series by December 31, 2021, and an additional primary dose by April 30, 2022. Rate ratios (RR) and 95% CIs were estimated using Poisson regression models for factors associated with completing the COVID-19 vaccine primary series and receiving an additional primary dose. RESULTS: Among 22 058 adult PWH (mean [SD] age, 52.1 [13.3] years; 88.8% male), 90.5% completed the primary series by December 31, 2021. Among 18 374 eligible PWH who completed the primary series by August 12, 2021, 15 982 (87.0%) received an additional primary dose, and 4318 (23.5%) received a booster dose by April 30, 2022. Receipt of influenza vaccines in the last 2 years was associated with completion of the primary series (RR, 1.17; 95% CI, 1.15-1.20) and an additional primary dose (RR, 1.61; 95% CI, 1.54-1.69). PWH with uncontrolled viremia (HIV viral load ≥200 copies/mL) (eg, RR, 0.90 [95% CI, 0.85-0.95] for viral load 200-10 000 copies/mL vs undetected or <200 copies/mL for completing the primary series) and Medicaid insurance (eg, RR, 0.89 [95% CI, 0.87-0.90] for completing the primary series) were less likely to be fully vaccinated. By contrast, greater outpatient utilization (eg, RR, 1.07 [95% CI, 1.05-1.09] for ≥7 vs 0 visits for primary series completion) and residence in counties with higher COVID-19 vaccine coverage (eg, RR, 1.06 [95% CI, 1.03-1.08] for fourth vs first quartiles for primary series completion) were associated with primary series and additional dose completion (RRs ranging from 1.01 to 1.21). CONCLUSIONS AND RELEVANCE: Findings from this cohort study suggest that, while COVID-19 vaccination coverage was high among PWH, outreach efforts should focus on those who did not complete vaccine series and those who have uncontrolled viremia.

COVID-19 vaccinations protect against severe illness and death, but associations with post-COVID conditions (PCC) are less clear. We aimed to evaluate the association between prior COVID-19 vaccination and new-onset PCC among individuals with SARS-CoV-2 infection across eight large healthcare systems in the United States. This retrospective matched cohort study used electronic health records (EHR) from patients with SARS-CoV-2 positive tests during March 2021-February 2022. Vaccinated and unvaccinated COVID-19 cases were matched on location, test date, severity of acute infection, age, and sex. Vaccination status was ascertained using EHR and integrated data on externally administered vaccines. Adjusted relative risks (RRs) were obtained from Poisson regression. PCC was defined as a new diagnosis in one of 13 PCC categories 30 days to 6 months following a positive SARS-CoV-2 test. The study included 161,531 vaccinated COVID-19 cases and 161,531 matched unvaccinated cases. Compared to unvaccinated cases, vaccinated cases had a similar or lower risk of all PCC categories except mental health disorders (RR: 1.06, 95% CI: 1.02-1.10). Vaccination was associated with ≥10% lower risk of sensory (RR: 0.90, 0.86-0.95), circulatory (RR: 0.88, 0.83-0.94), blood and hematologic (RR: 0.79, 0.71-0.89), skin and subcutaneous (RR: 0.69, 0.66-0.72), and non-specific COVID-19 related disorders (RR: 0.53, 0.51-0.56). In general, associations were stronger at younger ages but mostly persisted regardless of SARS-CoV-2 variant period, receipt of ≥3 vs. 1-2 vaccine doses, or time since vaccination. Pre-infection vaccination was associated with reduced risk of several PCC outcomes and hence may decrease the long-term consequences of COVID-19.

BACKGROUND: Even moderate differences in rotavirus vaccine effectiveness against nonvaccine genotypes may exert selective pressures on circulating rotaviruses. Whether this vaccine effect or natural temporal fluctuations underlie observed changes in genotype distributions is unclear. METHODS: We systematically reviewed studies reporting rotavirus genotypes from children <5 years of age globally between 2005 and 2023. We compared rotavirus genotypes between vaccine-introducing and nonintroducing settings globally and by World Health Organization (WHO) region, calendar time, and time since vaccine introduction. RESULTS: Crude pooling of genotype data from 361 studies indicated higher G2P[4], a nonvaccine genotype, prevalence in vaccine-introducing settings, both globally and by WHO region. This difference did not emerge when examining genotypes over time in the Americas, the only region with robust longitudinal data. Relative to nonintroducing settings, G2P[4] detections were more likely in settings with recent introduction (eg, 1-2 years postintroduction adjusted odds ratio [aOR], 4.39; 95% confidence interval [CI], 2.87-6.72) but were similarly likely in settings with more time elapsed since introduction, (eg, 7 or more years aOR, 1.62; 95% CI, .49-5.37). CONCLUSIONS: When accounting for both regional and temporal trends, there was no substantial evidence of long-term vaccine-related selective pressures on circulating genotypes. Increased prevalence of G2P[4] may be transient after rotavirus vaccine introduction.

We estimated the prevalence of respiratory symptoms, chronic obstructive pulmonary disease (COPD) risk level, and receipt of a breathing test among adults without reported COPD in 26 states and the District of Columbia by using 2017-2018 Behavioral Risk Factor Surveillance System data. Among adults without reported COPD, the 3 respiratory symptoms indicating COPD (chronic cough, phlegm or mucus production, shortness of breath) were common (each >10%). About 15.0% were at higher COPD risk (based on the number of symptoms, age, and smoking status); 41.4% of adults at higher risk reported receipt of a breathing test. Patient-provider recognition and communication of risk symptoms, appropriate screening, and follow-up are important for early diagnosis and treatment.

During the COVID-19 pandemic, forecasting COVID-19 trends to support planning and response was a priority for scientists and decision makers alike. In the United States, COVID-19 forecasting was coordinated by a large group of universities, companies, and government entities led by the Centers for Disease Control and Prevention and the US COVID-19 Forecast Hub (https://covid19forecasthub.org). We evaluated approximately 9.7 million forecasts of weekly state-level COVID-19 cases for predictions 1-4 weeks into the future submitted by 24 teams from August 2020 to December 2021. We assessed coverage of central prediction intervals and weighted interval scores (WIS), adjusting for missing forecasts relative to a baseline forecast, and used a Gaussian generalized estimating equation (GEE) model to evaluate differences in skill across epidemic phases that were defined by the effective reproduction number. Overall, we found high variation in skill across individual models, with ensemble-based forecasts outperforming other approaches. Forecast skill relative to the baseline was generally higher for larger jurisdictions (e.g., states compared to counties). Over time, forecasts generally performed worst in periods of rapid changes in reported cases (either in increasing or decreasing epidemic phases) with 95% prediction interval coverage dropping below 50% during the growth phases of the winter 2020, Delta, and Omicron waves. Ideally, case forecasts could serve as a leading indicator of changes in transmission dynamics. However, while most COVID-19 case forecasts outperformed a naïve baseline model, even the most accurate case forecasts were unreliable in key phases. Further research could improve forecasts of leading indicators, like COVID-19 cases, by leveraging additional real-time data, addressing performance across phases, improving the characterization of forecast confidence, and ensuring that forecasts were coherent across spatial scales. In the meantime, it is critical for forecast users to appreciate current limitations and use a broad set of indicators to inform pandemic-related decision making.

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Pf parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ Vaccine dose. Machine learning identified spliceosome, proteosome, and resting dendritic cell signatures as pre-vaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline CSP-specific IgG predicted non-protection. Pre-vaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T-cell responses post-vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naïve mice while diminishing the CD8+ T-cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggest that PfSPZ Vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.