BACKGROUND: To optimize vaccination strategies, it is useful to detect breakthrough infections and assess vaccine effectiveness in programmatic use. Monitoring emerging SARS-CoV-2 variants and vaccine effectiveness against them is also essential to determine the most effective vaccine options. This study aims to monitor SARS-CoV-2 breakthrough infections, the emergence of new SARS-CoV-2 variants, and host immune response during the peri-infection period of COVID-19. The study will also assess the uptake of the COVID-19 vaccine booster doses, and associated barriers or motivations among healthcare workers (HCWs). METHODS: Leveraging an existing HCW cohort in Bangladesh, HCWs will be enrolled from purposively selected health facilities from four different administrative divisions across Bangladesh. We captured cohort data on HCW's demographic information, clinical information, COVID-19 illness, and exposure, and vaccination histories for COVID-19. However, no biological specimens were collected for testing during the first phase of the cohort. In the current study, we plan to follow enrolled HCWs biweekly for suspected COVID-19 illness and capture relevant data including illness outcomes. Respiratory swab samples from symptomatic and a subset of asymptomatic HCWs will be tested for SARS-CoV-2 by rRT-PCR and positive samples will undergo Sanger sequencing to identify the SARS-CoV-2 variants of concern (VOCs). We will also perform Whole Genome Sequencing on a subset of SARS-CoV-2 positive samples with low CT values (Ct ≤ 30) to identify emerging SARS-CoV-2 variants. To examine the antibody response, we will collect blood samples from the participants at 12-week intervals for one year. We will use the EUROIMMUN kit and will also perform in-house ELISA to assess host immune factors with Luminex platform. DISCUSSION: This proposed study will generate useful data on COVID-19 breakthrough infection and the durability of anti-SARS-CoV-2 antibodies among HCWs following vaccination. The findings on booster vaccination intention and uptake will inform government COVID-19 vaccination strategies. Information on circulating and emerging strains of SARS-CoV-2 and vaccine performance against those strains will help understand population-level risks of COVID-19 infection. The study will generate data on facilitators and barriers to COVID-19 booster uptake among HCWs which can inform health communication messaging to improve booster acceptance in this population.

Some studies report increased prevalence of autism spectrum disorder (ASD) and associated symptoms with prenatal cannabis exposure. We examined whether associations of maternal cannabis use from 3 months preconception through delivery ("peripregnancy") with behavior and development in the offspring varied with the presence of ASD symptoms. Children ages 30-68 months with ASD symptoms (i.e., met study criteria for ASD or had ASD symptoms on standardized assessments or community ASD diagnosis, N = 2734) and without ASD symptoms (other developmental delay/disorders or general population sample, N = 3454) were evaluated with the Child Behavior Checklist and Mullen Scales of Early Learning. We examined cannabis use during three time periods: peripregnancy, pregnancy, and only preconception. Peripregnancy cannabis exposure was reported for 6.0% of children with and 4.6% of children without ASD symptoms. Preconception-only cannabis use (versus no use) was associated with more aggressive behavior, emotional reactivity, and sleep problems in children with ASD symptoms, but not in children without ASD symptoms. Cannabis use during pregnancy was associated with increased attention and sleep problems in children with ASD symptoms; these associations did not differ significantly by ASD symptoms. Peripregnancy cannabis use was not associated with child developmental abilities regardless of ASD symptoms. In summary, associations of peripregnancy cannabis use with some behavioral outcomes differed in children with and without ASD symptoms. With rising cannabis use among pregnant women, future studies that examine a range of developmental risks associated with timing and patterns of cannabis use prior to conception as well as during pregnancy could inform clinical guidance.

The International Nuclear Workers Study (INWORKS) contributes knowledge on the dose-response association between predominantly low dose, low dose rate occupational exposures to penetrating forms of ionizing radiation and cause-specific mortality. By extending follow-up of 309,932 radiation workers from France (1968-2014), the United Kingdom (1955-2012), and the United States (1944-2016) we increased support for analyses of temporal variation in radiation-cancer mortality associations. Here, we examine whether age at exposure, time since exposure, or attained age separately modify associations between radiation and mortality from all solid cancers, solid cancers excluding lung cancer, lung cancer, and lymphohematopoietic cancers. Multivariable Poisson regression was used to fit general relative rate models that describe modification of the linear excess relative rate per unit organ absorbed dose. Given indication of greater risk per unit dose for solid cancer mortality among workers hired in more recent calendar years, sensitivity analyses considering the impact of year of hire on results were performed. Findings were reasonably compatible with those from previous pooled and country-specific analyses within INWORKS showing temporal patterns of effect measure modification that varied among cancers, with evidence of persistent radiation-associated excess cancer risk decades after exposure, although statistically significant temporal modification of the radiation effect was not observed. Analyses stratified by hire period (< 1958, 1958+) showed temporal patterns that varied; however, these analyses did not suggest that this was due to differences in distribution of these effect measure modifiers by hire year.

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

PURPOSE: To describe retention of an autism spectrum disorder (ASD) diagnosis from preschool to adolescence and the most common co-occurring diagnoses among children with ASD in preschool and adolescence. A second objective was to identify co-occurring diagnoses more likely to emerge between preschool and adolescence among children with ASD vs. another developmental or mental health diagnosis in preschool. METHODS: Children completed a case-control study when they were between 2 and 5 years of age. Caregivers reported their child's diagnoses of ASD and attention deficit hyperactivity disorder (ADHD), any developmental delay (DD), epilepsy/seizure disorder, obsessive-compulsive disorder, sensory integration disorder, and speech/language disorder when the child was preschool age and, separately, during adolescence. Any anxiety and depression/mood disorder, intellectual disability (ID), and learning disability (LD) were considered only in adolescence. RESULTS: 85.5% of preschool children retained their ASD diagnosis in adolescence. DD, sensory integration disorder, and speech-language disorder co-occurred in over 20% of preschool age children with ASD. These same conditions, along with anxiety disorders, ADHD, ID, and LD, co-occurred in over 20% of adolescents with ASD. Significantly more children with ASD vs. another developmental or mental health diagnosis in preschool gained diagnoses of ADHD, DD, sensory integration disorder, and speech-language disorder by adolescence. CONCLUSION: ASD is a highly stable diagnosis and co-occurring conditions are common. The prevalence of co-occurring diagnoses may depend on age, with some persisting from preschool to adolescence and others emerging over time. Health and education providers can use these findings to inform precision monitoring and treatment planning.

BACKGROUND: A major update to the International Nuclear Workers Study (INWORKS) was undertaken to strengthen understanding of associations between low-dose exposure to penetrating forms of ionising radiation and mortality. Here, we report on associations between radiation dose and mortality due to haematological malignancies. METHODS: We assembled a cohort of 309 932 radiation-monitored workers (269 487 [87%] males and 40 445 [13%] females) employed for at least 1 year by a nuclear facility in France (60 697 workers), the UK (147 872 workers), and the USA (101 363 workers). Workers were individually monitored for external radiation exposure and followed-up from Jan 1, 1944, to Dec 31, 2016, accruing 10·72 million person-years of follow-up. Radiation-mortality associations were quantified in terms of the excess relative rate (ERR) per Gy of radiation dose to red bone marrow for leukaemia excluding chronic lymphocytic leukaemia (CLL), as well as subtypes of leukaemia, myelodysplastic syndromes, non-Hodgkin and Hodgkin lymphomas, and multiple myeloma. Estimates of association were obtained using Poisson regression methods. FINDINGS: The association between cumulative dose to red bone marrow, lagged 2 years, and leukaemia (excluding CLL) mortality was well described by a linear model (ERR per Gy 2·68, 90% CI 1·13 to 4·55, n=771) and was not modified by neutron exposure, internal contamination monitoring status, or period of hire. Positive associations were also observed for chronic myeloid leukaemia (9·57, 4·00 to 17·91, n=122) and myelodysplastic syndromes alone (3·19, 0·35 to 7·33, n=163) or combined with acute myeloid leukaemia (1·55, 0·05 to 3·42, n=598). No significant association was observed for acute lymphoblastic leukaemia (4·25, -4·19 to 19·32, n=49) or CLL (0·20, -1·81 to 2·21, n=242). A positive association was observed between radiation dose and multiple myeloma (1·62, 0·06 to 3·64, n=527) whereas minimal evidence of association was observed between radiation dose and non-Hodgkin lymphoma (0·27, -0·61 to 1·39, n=1146) or Hodgkin lymphoma (0·60, -3·64 to 4·83, n=122) mortality. INTERPRETATION: This study reports a positive association between protracted low dose exposure to ionising radiation and mortality due to some haematological malignancies. Given the relatively low doses typically accrued by workers in this study (16 mGy average cumulative red bone marrow dose) the radiation attributable absolute risk of leukaemia mortality in this population is low (one excess death in 10 000 workers over a 35-year period). These results can inform radiation protection standards and will provide input for discussions on the radiation protection system. FUNDING: National Cancer Institute, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Institut de Radioprotection et de Sûreté Nucléaire, Orano, Electricité de France, UK Health Security Agency. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Radon is a known cause of lung cancer. Protective standards for radon exposure are derived largely from studies of working populations that are prone to healthy worker survivor bias. This bias can lead to under-protection of workers and is a key barrier to understanding health effects of many exposures. We apply inverse probability weighting to study a set of hypothetical exposure limits among 4,137 male, White and American Indian radon-exposed uranium miners in the Colorado Plateau followed from 1950 to 2005. We estimate cumulative risk of lung cancer through age 90 under hypothetical occupational limits. We estimate that earlier implementation of the current US Mining Safety and Health Administration annual standard of 4 working level months (implemented here as a monthly exposure limit) could have reduced lung cancer mortality from 16/100 workers to 6/100 workers (95% confidence intervals: 3/100, 8/100), in contrast with previous estimates of 10/100 workers. Our estimate is similar to that among contemporaneous occupational cohorts. Inverse probability weighting is a simple and computationally efficient way address healthy worker survivor bias in order to contrast health effects of exposure limits and estimate the number of excess health outcomes under exposure limits at work.

A major update to the International Nuclear Workers Study was undertaken that allows us to report updated estimates of associations between radiation and site-specific solid cancer mortality. A cohort of 309,932 nuclear workers employed in France, the United Kingdom, and United States were monitored for external radiation exposure and associations with cancer mortality were quantified as the excess relative rate (ERR) per gray (Gy) using a maximum likelihood and a Markov chain Monte Carlo method (to stabilize estimates via a hierarchical regression). The analysis included 28,089 deaths due to solid cancer, the most common being lung, prostate, and colon cancer. Using maximum likelihood, positive estimates of ERR per Gy were obtained for stomach, colon, rectum, pancreas, peritoneum, larynx, lung, pleura/mesothelioma, bone and connective tissue, skin, prostate, testis, bladder, kidney, thyroid, and residual cancers; negative estimates of ERR per Gy were found cancers of oral cavity and pharynx, esophagus, and ovary. A hierarchical model stabilized site-specific estimates of association, including for lung (ERR per Gy=0.65; 95% credible interval [CrI]: 0.24, 1.07), prostate (ERR per Gy=0.44; 95% CrI: -0.06, 0.91), and colon cancer (ERR per Gy=0.53; 95% CrI: -0.07, 1.11). The results contribute evidence regarding associations between low dose radiation and cancer.

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.

BACKGROUND: Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance. METHODS: Data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics. RESULTS: This dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014. DISCUSSION (CONCLUSION): The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

Zika virus (ZIKV) infection in pregnancy is associated with severe abnormalities of the brain and eye and other adverse outcomes. Zika en Embarazadas y Niños was a prospective cohort study conducted in multiple Colombian cities that enrolled pregnant women in their first trimester. Specimens collected from pregnant women (n = 1,519) during February 2017-September 2018 and their infants (n = 1,080) during June 2017-March 2019 were tested for prenatal ZIKV infection by nucleic acid amplification tests or IgM antibody testing. Zika virus infection in pregnancy was present in 3.2% of pregnant women (incidence rate [IR] per 1,000 person-months = 5.9, 95% CI: 4.3-7.8). Presumptive ZIKV infection was present in 0.8% of infants (IR = 1.6, 95% CI: 0.7-2.9). Five percent of infants with prenatal ZIKV exposure or infection presented with Zika-associated abnormalities; 4.7% were small for gestational age. Understanding the risk of ZIKV infection during pregnancy and associated adverse outcomes can help inform counseling efforts.

Background: An infant's presentation at delivery may be an early indicator of developmental differences. Non-vertex presentation (malpresentation) complicates delivery and often leads to caesarean section, which has been associated with neurodevelopmental delays, including autism spectrum disorder (ASD). However, malpresentation could be an early sign of an existing developmental problem that is also an upstream factor from caesarean delivery. Little research has been done to investigate the association between malpresentation and ASD. Objectives: We examine the association between malpresentation at delivery and ASD and whether this association differs by gestational age. Methods: We used data from the Study to Explore Early Development (SEED), a multi-site, case–control study of children with ASD compared to population controls. The foetal presentation was determined using medical records, birth records and maternal interviews. We defined malpresentation as a non-vertex presentation at delivery, then further categorised into breech and other malpresentation. We used multivariable logistic regression to estimate the adjusted odds ratio (aOR) for the association between malpresentation and ASD. Results: We included 4047 SEED participants, 1873 children with ASD and 2174 controls. At delivery, most infants presented vertex (n = 3760, 92.9%). Malpresentation was associated with higher odds of ASD (aOR 1.31, 95% confidence interval [CI] 1.02, 1.68) after adjustment for maternal age, poverty level, hypertensive disorder and smoking. The association was similar for breech and other types of malpresentation (aOR 1.28, 95% CI 0.97, 1.70 and aOR 1.40, 95% CI 0.87, 2.26, respectively) and did not differ markedly by gestational age. Conclusions: Malpresentation at delivery was modestly associated with ASD. Early monitoring of the neurodevelopment of children born with malpresentation could identify children with ASD sooner and enhance opportunities to provide support to optimise developmental outcomes. © 2024 John Wiley & Sons Ltd.

BACKGROUND: Autistic adults and those with other developmental disabilities (DD) have increased depressive symptoms and decreased activity engagement when compared to those with no DD. Few studies explore activities related to depressive symptoms in autistic people and those with other DD during adolescence. OBJECTIVE: The objectives of this analysis were to describe depressive symptoms and activity engagement among autistic adolescents and those with other DD and no DD and explore types of activities associated with depressive symptoms, stratified by study group. METHODS: Parents of adolescents completed a multi-site case-control study of autism and other DD when their child was 2-5 years of age and a follow-up survey when their child was 12-16 years of age. Questions asked about the adolescent's current diagnoses, depressive symptoms (i.e., diagnosis, medication use, or symptoms), and engagement in club, social, sport, vocational, volunteer, and other organized activities. RESULTS: Autistic adolescents (N = 238) and those with other DD (N = 222) were significantly more likely to have depressive symptoms than adolescents with no DD (N = 406), (31.9 %, 30.6 %, and 15.0 % respectively). Lower percentages of autistic adolescents participated in activities than peers with other DD, who had lower percentages than peers with no DD. Participation in sports was associated with lower likelihood of depressive symptoms in all groups. CONCLUSIONS: Autistic adolescents and those with other DD are at increased risk for depressive symptoms and reduced activity engagement. Participation in sports may be especially important for adolescent mental health regardless of disability status. Implications for public health education and intervention are discussed.

Sensory dysfunction is a common feature of autism spectrum disorder (ASD). The objectives of this analysis were to examine risk factors and clinical correlates of sensory dysfunction in preschool children with and without ASD. Children aged 2-5 years were enrolled in a multi-site case-control study. Data were collected in eight areas across the United States in three phases. Caregivers completed an interview with questions on assisted delivery, maternal alcohol use, maternal anxiety during pregnancy, pregnancy weight gain, neonatal jaundice, preterm birth, and child sensory diagnosis given by a healthcare provider. Caregivers also completed an interview and questionnaires on sensory symptoms and clinical correlates of sensory dysfunction in their child. There were 2059 children classified as ASD, 3139 as other developmental delay or disability (DD), and 3249 as population comparison (POP). Caregivers reported significantly more sensory diagnoses and sensory symptoms in children classified as ASD than DD or POP (23.7%, 8.6%, and 0.8%, respectively, for a sensory diagnosis and up to 78.7% [ASD] vs. 49.6% [DD] for sensory symptoms). Maternal anxiety during pregnancy and neonatal jaundice were significantly associated with a sensory diagnosis and certain sensory symptoms in children with ASD and DD. Children's anxiety, attention deficits/hyperactivity, and sleep problems were significantly albeit subtly correlated with both a sensory diagnosis and sensory symptoms in children with ASD and DD. These findings support sensory dysfunction as a distinguishing symptom of ASD in preschool children and identify risk factors and clinical correlates to inform screening and treatment efforts in those with atypical development.

BACKGROUND: Hospital-acquired infections (HAIs) and antimicrobial resistance (AMR) are major global health challenges. Drug-resistant infectious diseases continue to rise in developing countries, driven by shortfalls in infection control measures, antibiotic misuse, and scarcity of reliable diagnostics. These escalating global challenges have highlighted the importance of strengthening fundamental infection prevention and control (IPC) measures and implementing effective antimicrobial stewardship programs (ASP). This study aims to present a framework for enhancing IPC measures and ASP efforts to reduce the HAI and AMR burden in Bangladesh. METHODS: This implementation approach will employ a mixed-methods strategy, combining both quantitative and qualitative data from 12 tertiary hospitals in Bangladesh. A baseline assessment will be conducted using the Infection Prevention and Control Assessment Framework (IPCAF) developed by the WHO. We will record IPC practices through direct observations of hand hygiene, personal protective equipment (PPE) utilization, and hospital ward IPC infrastructure. Additionally, data on healthcare providers' knowledge, attitudes, and practices regarding IPC and antibiotic prescribing will be collected using both structured questionnaires and qualitative interviews. We will also assist the hospital leadership with establishing and/or strengthening IPC and ASP committees. Based on baseline assessments of each healthcare facility, tailored interventions and quality improvement projects will be designed and implemented. An end-line assessment will also be conducted after 12 months of intervention using the same assessment tools. The findings will be compared with the baseline to determine changes in IPC and antibiotic stewardship practices. DISCUSSION: Comprehensive assessments of healthcare facilities in low-resource settings are crucial for strengthening IPC measures and ASP activities,. This approach to assessing existing IPC and ASP activities will provide policy-relevant data for addressing current shortfalls. Moreover, this framework proposes identifying institutionally-tailored solutions, which will ensure that response activities are appropriately contextualized, aligned with stakeholder priorities, and offer sustainable solutions. CONCLUSION: Findings from this study can guide the design and implementation of feasible and sustainable interventions in resource-constrained healthcare settings to address gaps in existing IPC and ASP activities. Therefore, this protocol will be applicable across a broad range of settings to improve IPC and ASP and reduce the burden of hospital-acquired infections and AMR.

OBJECTIVE: To evaluate the effect of protracted low dose, low dose rate exposure to ionising radiation on the risk of cancer. DESIGN: Multinational cohort study. SETTING: Cohorts of workers in the nuclear industry in France, the UK, and the US included in a major update to the International Nuclear Workers Study (INWORKS). PARTICIPANTS: 309 932 workers with individual monitoring data for external exposure to ionising radiation and a total follow-up of 10.7 million person years. MAIN OUTCOME MEASURES: Estimates of excess relative rate per gray (Gy) of radiation dose for mortality from cancer. RESULTS: The study included 103 553 deaths, of which 28 089 were due to solid cancers. The estimated rate of mortality due to solid cancer increased with cumulative dose by 52% (90% confidence interval 27% to 77%) per Gy, lagged by 10 years. Restricting the analysis to the low cumulative dose range (0-100 mGy) approximately doubled the estimate of association (and increased the width of its confidence interval), as did restricting the analysis to workers hired in the more recent years of operations when estimates of occupational external penetrating radiation dose were recorded more accurately. Exclusion of deaths from lung cancer and pleural cancer had a modest effect on the estimated magnitude of association, providing indirect evidence that the association was not substantially confounded by smoking or occupational exposure to asbestos. CONCLUSIONS: This major update to INWORKS provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality based on some of the world's most informative cohorts of radiation workers. The summary estimate of excess relative rate solid cancer mortality per Gy is larger than estimates currently informing radiation protection, and some evidence suggests a steeper slope for the dose-response association in the low dose range than over the full dose range. These results can help to strengthen radiation protection, especially for low dose exposures that are of primary interest in contemporary medical, occupational, and environmental settings.

BACKGROUND: Hand hygiene (HH) is a fundamental element of patient safety. Adherence to HH among healthcare workers (HCW) varies greatly depending on a range of factors, including risk perceptions, institutional culture, auditing mechanisms, and availability of HH supplies. AIMS: This study aims to evaluate HH compliance and associated factors among healthcare workers in selected tertiary care hospitals in Bangladesh. METHODS: During September 2020 to May 2021, we conducted non-participatory observations at 10 tertiary-care hospitals using WHO '5-moments for hand hygiene tool' to record HH compliance among physicians, nurses, and cleaning staff. We also performed semi-structured interviews to determine the key barriers to complying with HH. RESULTS: We observed 14,668 hand hygiene opportunities. The overall HH compliance was 25.3%, the highest among nurses (28.5%), and the lowest among cleaning staff (9.9%). HCWs in public hospitals had significantly higher odds of complying with HH practices than those in private hospitals (AOR: 1.73, 95%CI: 1.55-1.93). The odds of performing HH after touching a patient were 3.36 times higher compared with before touching a patient (95% CI: 2.90-3.90). The reported key barriers to performing HH were insufficient supplies (57.9%), skin reactions (26.3%), workload (26.3%), and lack of facilities (22.7%). Overall, observed HH supplies were available in 81.7% of wards for physicians and 95.1% of wards for nurses, however, no designated HH facilities were found for the cleaning staff. CONCLUSIONS: HH compliance among HCWs fell significantly short of the standard for safe patient care. Inadequate HH supplies demonstrates a lack of prioritizing, promoting, and investing in infection prevention and control.

BACKGROUND: In order to reignite gains and accelerate progress toward improved malaria control and elimination, policy, strategy, and operational decisions should be derived from high-quality evidence. The U.S. President's Malaria Initiative (PMI) Insights project together with the Université Cheikh Anta Diop of Dakar, Senegal, conducted a broad stakeholder consultation process to identify pressing evidence gaps in malaria control and elimination across sub-Saharan Africa (SSA), and developed a priority list of country-driven malaria operational research (OR) and programme evaluation (PE) topics to address these gaps. METHODS: Five key stakeholder groups were engaged in the process: national malaria programmes (NMPs), research institutions in SSA, World Health Organization (WHO) representatives in SSA, international funding agencies, and global technical partners who support malaria programme implementation and research. Stakeholders were engaged through individual or small group interviews and an online survey, and asked about key operational challenges faced by NMPs, pressing evidence gaps in current strategy and implementation guidance, and priority OR and PE questions to address the challenges and gaps. RESULTS: Altogether, 47 interviews were conducted with 82 individuals, and through the online survey, input was provided by 46 global technical partners. A total of 33 emergent OR and PE topics were identified through the consultation process and were subsequently evaluated and prioritized by an external evaluation committee of experts from NMPs, research institutions, and the WHO. The resulting prioritized OR and PE topics predominantly focused on generating evidence needed to close gaps in intervention coverage, address persistent challenges faced by NMPs in the implementation of core strategic interventions, and inform the effective deployment of new tools. CONCLUSION: The prioritized research list is intended to serve as a key resource for informing OR and PE investments, thereby ensuring future investments focus on generating the evidence needed to strengthen national strategies and programme implementation and facilitating a more coordinated and impactful approach to malaria operational research.

Immune imprinting is a driver known to shape the anti-hemagglutinin (HA) antibody landscape of individuals born within the same birth cohort. With the HA and neuraminidase (NA) proteins evolving at different rates under immune selection pressures, anti-HA and anti-NA antibody responses since childhood influenza infections have not been evaluated in parallel at the individual level. This is partly due to the limited knowledge of changes in NA antigenicity, as seasonal influenza vaccines have focused on generating neutralising anti-HA antibodies against HA antigenic variants. Here we systematically characterised the NA antigenic variants of seasonal A(H1N1) viruses from 1977 to 1991 and completed the antigenic profile of N1 NAs from 1977 to 2015. We identified that NA proteins of A/USSR/90/77, A/Singapore/06/86, and A/Texas/36/91 were antigenically distinct and mapped N386K as a key determinant of the NA antigenic change from A/USSR/90/77 to A/Singapore/06/86. With comprehensive panels of HA and NA antigenic variants of A(H1N1) and A(H1N1)pdm09 viruses, we determined hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) antibodies from 130 subjects born between 1950-2015. Age-dependent imprinting was observed for both anti-HA and anti-NA antibodies, with the peak HI and NI titers predominantly detected from subjects at 4-12 years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations.IMPORTANCE Seasonal influenza vaccines have aimed to generate neutralizing anti-HA antibodies for protection since licensure. More recently, anti-NA antibodies have been established as an additional correlate of protection. While HA and NA antigenic changes occurred discordantly, the anti-HA and anti-NA antibody profiles have rarely been analysed in parallel at the individual level, due to the limited knowledge on NA antigenic changes. By characterizing NA antigenic changes of A(H1N1) viruses, we determined the anti-HA and anti-NA antibody landscape against antigenically distinct A(H1N1) and A(H1N1)pdm09 viruses using sera of 130 subjects born between 1950-2015. We observed age-dependent imprinting of both anti-HA and anti-NA antibodies against strains circulated during the first decade of life. 67.7% (88/130) and 90% (117/130) of participants developed cross-reactive antibodies to multiple HA and NA antigens at titers ≥1:40. With slower NA antigenic changes and cross-reactive anti-NA antibody responses, including NA protein in influenza vaccine preparation may enhance vaccine efficacy. (150 words)

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.Competing Interest StatementThe authors have declared no competing interest.

Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. We analyzed data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasite strains in Senegal to determine how historical changes in drug administration policy may have affected parasite evolution. We profiled several known drug resistance markers and their surrounding haplotypes using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole-genome sequence (WGS) based population genomics. We observed rapid changes in drug resistance markers associated with the withdrawal of chloroquine and introduction of sulfadoxine-pyrimethamine in 2003. We also observed a rapid increase in Pfcrt K76T and decline in Pfdhps A437G starting in 2014, which we hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC). Parasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

BACKGROUND: The risk of solid cancers from low-level protracted ionizing radiation is not well characterized. Nuclear workers provide valuable information on the effects of ionizing radiation in contemporary exposure scenarios relevant to workers and the public. METHODS: We evaluated the association between penetrating ionizing radiation exposure and solid cancer mortality among a pooled cohort of nuclear workers in the USA, with extended follow-up to examine cancers with long latencies. This analysis includes 101 363 workers from five nuclear facilities, with 12 069 solid cancer deaths between 1944 and 2016. The association between cumulative equivalent dose measured in sieverts (Sv) and solid cancer subtypes were modelled as the excess relative rate per Sv (ERR Sv-1) using Cox regression. RESULTS: For the association between ionizing radiation exposure and all solid cancer mortality we observed an elevated rate (ERR Sv-1=0.19; 95% CI: -0.10, 0.52), which was higher among a contemporary sub-cohort of workers first hired in 1960 or later (ERR Sv-1= 2.23; 95% CI: 1.13, 3.49). Similarly, we observed an elevated rate for lung cancer mortality (ERR Sv-1= 0.65; 95% CI: 0.09, 1.30) that was higher among contemporary hires (ERR Sv-1= 2.90; 95% CI: 1.00, 5.26). CONCLUSIONS: Although concerns remain about confounding, measurement error and precision, this analysis strengthens the evidence base indicating there are radiogenic risks for several solid cancer types.

OBJECTIVE: To compare mortality rates in World Trade Center (WTC)-exposed Fire Department of the City of New York (FDNY) firefighters with rates in similarly healthy, non-WTC-exposed/non-FDNY firefighters, and compare mortality in each firefighter cohort with the general population. METHODS: 10 786 male WTC-exposed FDNY firefighters and 8813 male non-WTC-exposed firefighters from other urban fire departments who were employed on 11 September 2001 were included in the analyses. Only WTC-exposed firefighters received health monitoring via the WTC Health Programme (WTCHP). Follow-up began 11 September 2001 and ended at the earlier of death date or 31 December 2016. Death data were obtained from the National Death Index and demographics from the fire departments. We estimated standardised mortality ratios (SMRs) in each firefighter cohort versus US males using demographic-specific US mortality rates. Poisson regression models estimated relative rates (RRs) of all-cause and cause-specific mortality in WTC-exposed versus non-WTC-exposed firefighters, controlling for age and race. RESULTS: Between 11 September 2001 and 31 December 2016, there were 261 deaths among WTC-exposed firefighters and 605 among non-WTC-exposed. Both cohorts had reduced all-cause mortality compared with US males (SMR (95% CI)=0.30 (0.26 to 0.34) and 0.60 (0.55 to 0.65) in WTC-exposed and non-WTC-exposed, respectively). WTC-exposed firefighters also had lower rates of all-cause mortality (RR=0.54, 95% CI=0.49 to 0.59) and cancer-specific, cardiovascular-specific and respiratory disease-specific mortality compared with non-WTC-exposed firefighters. CONCLUSION: Both firefighter cohorts had lower than expected all-cause mortality. Fifteen years post 11 September 2001, mortality was lower in WTC-exposed versus non-WTC-exposed firefighters. Lower mortality in the WTC-exposed suggests not just a healthy worker effect, but additional factors such as greater access to free health monitoring and treatment that they receive via the WTCHP.

Immune imprinting is a driver known to shape the anti-hemagglutinin (HA) antibody landscape of individuals born within the same birth cohort. With the HA and neuraminidase (NA) proteins evolving at different rates under immune selection pressures, anti-HA and anti-NA antibody responses since childhood influenza virus infections have not been evaluated in parallel at the individual level. This is partly due to the limited knowledge of changes in NA antigenicity, as seasonal influenza vaccines have focused on generating neutralizing anti-HA antibodies against HA antigenic variants. Here, we systematically characterized the NA antigenic variants of seasonal A(H1N1) viruses from 1977 to 1991 and completed the antigenic profile of N1 NAs from 1977 to 2015. We identified that NA proteins of A/USSR/90/77, A/Singapore/06/86, and A/Texas/36/91 were antigenically distinct and mapped N386K as a key determinant of the NA antigenic change from A/USSR/90/77 to A/Singapore/06/86. With comprehensive panels of HA and NA antigenic variants of A(H1N1) and A(H1N1)pdm09 viruses, we determined hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) antibodies from 130 subjects born between 1950 and 2015. Age-dependent imprinting was observed for both anti-HA and anti-NA antibodies, with the peak HI and NI titers predominantly detected from subjects at 4 to 12 years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations. IMPORTANCE Seasonal influenza vaccines have aimed to generate neutralizing anti-HA antibodies for protection since licensure. More recently, anti-NA antibodies have been established as an additional correlate of protection. While HA and NA antigenic changes occurred discordantly, the anti-HA and anti-NA antibody profiles have rarely been analyzed in parallel at the individual level, due to the limited knowledge on NA antigenic changes. By characterizing NA antigenic changes of A(H1N1) viruses, we determined the anti-HA and anti-NA antibody landscape against antigenically distinct A(H1N1) and A(H1N1)pdm09 viruses using sera of 130 subjects born between 1950 and 2015. We observed age-dependent imprinting of both anti-HA and anti-NA antibodies against strains circulated during the first decade of life. A total of 67.7% (88/130) and 90% (117/130) of participants developed cross-reactive antibodies to multiple HA and NA antigens at titers ≥1:40. With slower NA antigenic changes and cross-reactive anti-NA antibody responses, including NA protein in influenza vaccine preparation may enhance vaccine efficacy.

Objective: We performed a meta-analysis of epidemiological results for the association between occupational exposure as a firefighter and cancer as part of the broader evidence synthesis work of the IARC Monographs program. Methods: A systematic literature search was conducted to identify cohort studies of firefighters followed for cancer incidence and mortality. Studies were evaluated for the influence of key biases on results. Random-effects meta-analysis models were used to estimate the association between ever-employment and duration of employment as a firefighter and risk of 12 selected cancers. The impact of bias was explored in sensitivity analyses. Results: Among the 16 included cancer incidence studies, the estimated meta-rate ratio, 95% confidence interval (CI), and heterogeneity statistic (I2) for ever-employment as a career firefighter compared mostly to general populations were 1.58 (1.14–2.20, 8%) for mesothelioma, 1.16 (1.08–1.26, 0%) for bladder cancer, 1.21 (1.12–1.32, 81%) for prostate cancer, 1.37 (1.03–1.82, 56%) for testicular cancer, 1.19 (1.07–1.32, 37%) for colon cancer, 1.36 (1.15–1.62, 83%) for melanoma, 1.12 (1.01–1.25, 0%) for non-Hodgkin lymphoma, 1.28 (1.02–1.61, 40%) for thyroid cancer, and 1.09 (0.92–1.29, 55%) for kidney cancer. Ever-employment as a firefighter was not positively associated with lung, nervous system, or stomach cancer. Results for mesothelioma and bladder cancer exhibited low heterogeneity and were largely robust across sensitivity analyses. Conclusions: There is epidemiological evidence to support a causal relationship between occupational exposure as a firefighter and certain cancers. Challenges persist in the body of evidence related to the quality of exposure assessment, confounding, and medical surveillance bias. © 2023 Occupational Safety and Health Research Institute

Vaccines prevent 4-5 million deaths every year, but inequities in vaccine coverage persist among key disadvantaged subpopulations. Under-immunized subpopulations (e.g., migrants, slum residents) may be consistently missed with conventional methods for estimating immunization coverage and assessing vaccination barriers. Adaptive sampling, such as respondent-driven sampling, may offer useful strategies for identifying and collecting data from these subpopulations that are often "hidden" or hard-to-reach. However, use of these adaptive sampling approaches in the field of global immunization has not been systematically documented. We searched PubMed, Scopus, and Embase databases to identify eligible studies published through November 2020 that used an adaptive sampling method to collect immunization-related data. From the eligible studies, we extracted relevant data on their objectives, setting and target population, and sampling methods. We categorized sampling methods and assessed their frequencies. Twenty-three studies met the inclusion criteria out of the 3069 articles screened for eligibility. Peer-driven sampling was the most frequently used adaptive sampling method (57%), followed by geospatial sampling (30%), venue-based sampling (17%), ethnographic mapping (9%), and compact segment sampling (9%). Sixty-one percent of studies were conducted in upper-middle-income or high-income countries. Data on immunization uptake were collected in 65% of studies, and data on knowledge and attitudes about immunizations were collected in 57% of studies. We found limited use of adaptive sampling methods in measuring immunization coverage and understanding determinants of vaccination uptake. The current under-utilization of adaptive sampling approaches leaves much room for improvement in how immunization programs calibrate their strategies to reach "hidden" subpopulations.

INTRODUCTION: Infection prevention and control (IPC) in healthcare settings is imperative for the safety of patients as well as healthcare providers. To measure current IPC activities, resources, and gaps at the facility level, WHO has developed the Infection Prevention and Control Assessment Framework (IPCAF). This study aimed to assess the existing IPC level of selected tertiary care hospitals in Bangladesh during the COVID-19 pandemic using IPCAF to explore their strengths and deficits. METHODS: Between September and December 2020, we assessed 11 tertiary-care hospitals across Bangladesh. We collected the information from IPC focal person and/or hospital administrator from each hospital using the IPCAF assessment tool.. The score was calculated based on eight core components and was used to categorize the hospitals into four distinct IPC levels- Inadequate, Basic, Intermediate, and Advanced. Key performance metrics were summarized within and between hospitals. RESULTS: The overall median IPCAF score was 355.0 (IQR: 252.5-397.5) out of 800. The majority (73%) of hospitals scored as 'Basic' IPC level, while only 18% of hospitals were categorized as 'Intermediate'. Most hospitals had IPC guidelines as well as environments, materials and equipments. Although 64% of hospitals had IPC orientation and training program for new employees, only 30% of hospitals had regular IPC training program for the staff. None of the hospitals had an IPC surveillance system with standard surveillance case definitions to track HAIs. Around 90% of hospitals did not have an active IPC monitoring and audit system. Half of the hospitals had inadequate staffing considering the workload. Bed occupancy of one patient per bed in all units was found in 55% of hospitals. About 73% of hospitals had functional hand hygiene stations, but sufficient toilets were available in only 37% of hospitals. CONCLUSION: The majority of sampled tertiary care hospitals demonstrate inadequate IPC level to ensure the safety of healthcare workers, patients, and visitors. Quality improvement programs and feedback mechanisms should be implemented to strengthen all IPC core components, particularly IPC surveillance, monitoring, education, and training, to improve healthcare safety and resilience.

OBJECTIVE: Adults with diabetes are at risk for cardiovascular (CV) events, possibly due to increased arterial stiffness (AS) and cardiac autonomic neuropathy (CAN). We sought to determine whether 1) AS is associated with cardiac target organ damage in young adults with youth-onset diabetes, 2) whether CAN is associated with AS, as one possible etiology for increased AS in this cohort, and 3) whether these relationships differ by type of diabetes. RESEARCH DESIGN AND METHODS: Participants from the SEARCH for Diabetes in Youth Study (type 1 diabetes [T1D], n = 222; type 2 diabetes [T2D], n = 177; mean age 23 years) had clinical, echocardiographic, AS, and CAN assessed. Linear regression was performed to determine whether AS was associated with cardiac changes and CAN and whether relationships differed by diabetes type. RESULTS: AS was significantly associated with cardiac structure (left ventricular mass index, P < 0.0001), systolic function (ejection fraction, P = 0.03) and diastolic function (transmitral peak early [E]/atrial [A] wave velocities ratio, P = 0.008; early [e']/atrial [a'] waves, P = 0.02) after adjustments for CV risk factors. The association between AS and CAN was not significant when other important covariates were added. These relationships were mostly similar in both T1D and T2D. CONCLUSIONS: AS is associated with cardiac changes in young adults with diabetes. CAN-induced AS does not appear to be an etiology for cardiac abnormalities in this cohort.

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

The US National Institute of Standards and Technology (NIST) developed a Standard Reference Material (SRM) 3949 Folate Vitamers in Frozen Human Serum to replace SRM 1955 Homocysteine and Folate in Human Serum. The presence of increased endogenous levels of folic acid and 5-methyltetrahydrofolate (5mTHF) in SRM 3949, enhanced folate stability via addition of ascorbic acid, and inclusion of values for additional minor folates are improvements over SRM 1955 that should better serve the clinical folate measurement community. The new SRM contains folates at three levels. To produce SRM 3949, pilot sera were collected from 15 individual donors, 5 of whom were given a 400-g folic acid supplement 1h prior to blood draw to increase serum levels of 5mTHF and folic acid for the high-level material. To stabilize the folates, 0.5% (mass concentration) ascorbic acid was added as soon as possible after preparation of serum. These pilot sera were screened for five folates plus the pyrazino-s-triazine derivative of 4--hydroxy-5-methyltetrahydrofolate (MeFox) at the US Centers for Disease Control and Prevention (CDC) by isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS). Based on these results, a blending protocol was specified to obtain the three desired folate concentrations for SRM 3949. ID-LC-MS/MS analysis at the CDC and NIST was utilized to assign values for folic acid and 5mTHF, as well as several minor folates.