BACKGROUND: Pneumococcal conjugate vaccines (PCVs) introduced in childhood national immunization programs lowered vaccine-type invasive pneumococcal disease (IPD), but replacement with non-vaccine-types persisted throughout the PCV10/13 follow-up period. We assessed PCV10/13 impact on pneumococcal meningitis incidence globally. METHODS: The number of cases with serotyped pneumococci detected in cerebrospinal fluid and population denominators were obtained from surveillance sites globally. Site-specific meningitis incidence rate ratios (IRRs) comparing pre-PCV incidence to each year post-PCV10/13 were estimated by age (<5, 5-17 and ≥18 years) using Bayesian multi-level mixed effects Poisson regression, accounting for pre-PCV trends. All-site weighted average IRRs were estimated using linear mixed-effects regression stratified by age, product (PCV10 or PCV13) and prior PCV7 impact (none, moderate, or substantial). Changes in pneumococcal meningitis incidence were estimated overall and for product-specific vaccine-types and non-PCV13-types. RESULTS: Analyses included 10,168 cases <5 y from PCV13 sites and 2849 from PCV10 sites, 3711 and 1549 for 5-17 y and 29,187 and 5653 for ≥18 y from 42 surveillance sites (30 PCV13, 12 PCV10, 2 PCV10/13) in 30 countries, primarily high-income (84%). Six years after PCV10/PCV13 introduction, pneumococcal meningitis declined 48-74% across products and PCV7 impact strata for children <5 y, 35-62% for 5-17 y and 0-36% for ≥18 y. Impact against PCV10-types at PCV10 sites, and PCV13-types at PCV13 sites was high for all age groups (<5 y: 96-100%; 5-17 y: 77-85%; ≥18 y: 73-85%). After switching from PCV7 to PCV10/13, increases in non-PCV13-types were generally low to none for all age groups. CONCLUSION: Pneumococcal meningitis declined in all age groups following PCV10/PCV13 introduction. Plateaus in non-PCV13-type meningitis suggest less replacement than for all IPD. Data from meningitis belt and high-burden settings were limited.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) that are ten-valent (PCV10) and 13-valent (PCV13) became available in 2010. We evaluated their global impact on invasive pneumococcal disease (IPD) incidence in all ages. METHODS: Serotype-specific IPD cases and population denominators were obtained directly from surveillance sites using PCV10 or PCV13 in their national immunisation programmes and with a primary series uptake of at least 50%. Annual incidence rate ratios (IRRs) were estimated comparing the incidence before any PCV with each year post-PCV10 or post-PCV13 introduction using Bayesian multi-level, mixed-effects Poisson regressions, by site and age group. All site-weighted average IRRs were estimated using linear mixed-effects regression, stratified by product and previous seven-valent PCV (PCV7) effect (none, moderate, or substantial). FINDINGS: Analyses included 32 PCV13 sites (488 758 cases) and 15 PCV10 sites (46 386 cases) in 30 countries, primarily high income (39 sites), using booster dose schedules (41 sites). By 6 years after PCV10 or PCV13 introduction, IPD due to PCV10-type serotypes and PCV10-related serotype 6A declined substantially for both products (age <5 years: 83-99% decline; ≥65 years: 54-96% decline). PCV7-related serotype 19A increases before PCV10 or PCV13 introduction were reversed at PCV13 sites (age <5 years: 61-79% decline relative to before any PCV; age ≥65 years: 7-26% decline) but increased at PCV10 sites (age <5 years: 1·6-2·3-fold; age ≥65 years: 3·6-4·9-fold). Serotype 3 IRRs had no consistent trends for either product or age group. Non-PCV13-type IPD increased similarly for both products (age <5 years: 2·3-3·3-fold; age ≥65 years: 1·7-2·3-fold). Despite different serotype 19A trends, all-serotype IPD declined similarly between products among children younger than 5 years (58-74%); among adults aged 65 years or older, declines were greater at PCV13 (25-29%) than PCV10 (4-14%) sites, but other differences between sites precluded attribution to product. INTERPRETATION: Long-term use of PCV10 or PCV13 reduced IPD substantially in young children and more moderately in older ages. Non-vaccine-type serotypes increased approximately two-fold to three-fold by 6 years after introduction of PCV10 or PCV13. Continuing serotype 19A increases at PCV10 sites and declines at PCV13 sites suggest that PCV13 use would further reduce IPD at PCV10 sites. FUNDING: Bill & Melinda Gates Foundation as part of the WHO Pneumococcal Vaccines Technical Coordination Project.

OBJECTIVES: Vitamin D deficiency is highly prevalent worldwide; however, few large population-based studies have examined occupational risk factors. We examined associations between shift work, work schedule, hours worked, outdoor work, occupation and serum 25-hydroxyvitamin D (25(OH)D) levels in the US working population. METHODS: This cross-sectional study included 8601 workers from the 2005-2010 National Health and Nutrition Examination Survey (NHANES) cycles. NHANES occupational data were supplemented with measures of outdoor work from the Occupational Information Network. Serum 25(OH)D concentration in nanomoles per litre (nmol/L) was categorised as sufficient (≥75), insufficient (50-<75), moderately deficient (30-<50) and severely deficient (<30). Age-adjusted weighted multinomial and binary logistic regression were used to examine associations between work-related factors and vitamin D status with sex-race/ethnicity stratification. RESULTS: Shift workers had higher odds of severe vitamin D deficiency compared with day workers (OR: 1.64, 95% CI 1.22 to 2.19). Compared with those in white-collar occupations, those in natural resources were less likely to be deficient (OR: 0.31, 95% CI 0.19 to 0.52), while those in production were more likely to be deficient (OR: 2.25, 95% CI 1.48 to 3.43). Women working ≥40 hours/week compared with <40 hours/week were more likely to be moderately deficient (OR: 1.30, 95% CI 1.06 to 1.59). Black women working in sales were more likely to be deficient than those in management (OR: 1.53, 95% CI 1.03 to 2.27). Mexican American men working nights had the highest odds of deficiency (OR: 2.64, 95% CI 1.38 to 5.06). CONCLUSIONS: Work-related factors were associated with vitamin D status and there were race/ethnicity and sex differences. Targeted vitamin D screening and supplementation interventions may reduce these disparities.

BACKGROUND: Low levels of COVID-19 vaccination coverage in many countries prompted the use of rapid assessments to characterize barriers to vaccination and identify corrective measures. The World Health Organization recommended the use of intra-action reviews (IARs) to identify best practices, gaps, and lessons learned to make real-time improvements to the COVID-19 vaccination response. OBJECTIVE: The Democratic Republic of the Congo (DRC) implemented a national IAR in July 2021 that was poorly attended by the provincial health level, where vaccination activities are planned and implemented. To bridge this gap, we proposed sub-national IARs focused on COVID-19 vaccine program implementation at the provincial level. METHODS: Using the WHO methodology, we organized a four-day provincial IAR workshop and invited national, provincial and health zone Ministry of Health (MoH) representatives and private and non-governmental organizations involved in the provincial COVID-19 vaccination response. Participants were divided into six groups based on their expertise, affiliation, and role within the health system to assess and identify lessons learned, challenges and the solutions within each of the six technical areas: (1) coordination, planning and monitoring; (2) service delivery; (3) risk communication and community engagement; (4) adverse effects following immunization (AEFI); (5) logistics; (6) and data management, monitoring and evaluation. RESULTS: The first provincial COVID-19 IAR was conducted in Goma, North Kivu, from January 19-22, 2022. A total of 56 participants came from provincial and health zone offices, and non-governmental organizations. Through work group discussions, they identified best practices, challenges, and lessons learned, and made recommendations to improve implementation of vaccination activities and reach coverage targets. Activities were proposed to operationalize recommendations and address challenges to improve the provincial response. CONCLUSION: This provincial IAR was a useful tool for reviewing progress and areas of improvement, while evaluating aspects of the COVID-19 vaccine rollout. It provided a means to share information with vaccination partners on areas of intervention, tailored to the local context.

To better identify emerging or reemerging pathogens in patients with difficult-to-diagnose infections, it is important to improve access to advanced molecular testing methods. This is particularly relevant for cases where conventional microbiologic testing has been unable to detect the pathogen and the patient's specimens test negative. To assess the availability and utility of such testing for human clinical specimens, a literature review of published biomedical literature was conducted. From a corpus of more than 4,000 articles, a set of 34 reports was reviewed in detail for data on where the testing was being performed, types of clinical specimens tested, pathogen agnostic techniques and methods used, and results in terms of potential pathogens identified. This review assessed the frequency of advanced molecular testing, such as metagenomic next generation sequencing that has been applied to clinical specimens for supporting clinicians in caring for difficult-to-diagnose patients. Specimen types tested were from cerebrospinal fluid, respiratory secretions, and other body tissues and fluids. Publications included case reports and series, and there were several that involved clinical trials, surveillance studies, research programs, or outbreak situations. Testing identified both known human pathogens (sometimes in new sites) and previously unknown human pathogens. During this review, there were no apparent coordinated efforts identified to develop regional or national reports on emerging or reemerging pathogens. Therefore, development of a coordinated sentinel surveillance system that applies advanced molecular methods to clinical specimens which are negative by conventional microbiological diagnostic testing would provide a foundation for systematic characterization of emerging and underdiagnosed pathogens and contribute to national biodefense strategy goals.

The surveillance and identification of emerging, reemerging, and unknown infectious disease pathogens is essential to national public health preparedness and relies on fluidity, coordination, and interconnectivity between public and private pathogen surveillance systems and networks. Developing a national sentinel surveillance network with existing resources and infrastructure could increase efficiency, accelerate the identification of emerging public health threats, and support coordinated intervention strategies that reduce morbidity and mortality. However, implementing and sustaining programs to detect emerging and reemerging pathogens in humans using advanced molecular methods, such as metagenomic sequencing, requires making large investments in testing equipment and developing networks of clinicians, laboratory scientists, and bioinformaticians. In this study, we sought to gain an understanding of how federal government agencies currently support such pathogen agnostic testing of human specimens in the United States. We conducted a landscape analysis of federal agency websites for publicly accessible information on the availability and type of pathogen agnostic testing and details on flow of clinical specimens and data. The website analysis was supplemented by an expert review of results with representatives from the federal agencies. Operating divisions within the US Department of Health and Human Services and the US Department of Veterans Affairs have developed and sustained extensive clinical and research networks to obtain patient specimens and perform metagenomic sequencing. Metagenomic facilities supported by US agencies were not equally geographically distributed across the United States. Although many entities have work dedicated to metagenomics and/or support emerging infectious disease surveillance specimen collection, there was minimal formal collaboration across agencies.

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

Hypervirulent Klebsiella pneumoniae (hvKp) is a concerning pathogen that can cause life-threatening infections in otherwise healthy individuals. Importantly, although strains of hvKp have been acquiring antimicrobial resistance, the effect on virulence is unclear. Therefore, it is of critical importance to determine whether a given antimicrobial resistant K. pneumoniae isolate is hypervirulent. This report determined which combination of genotypic and phenotypic markers could most accurately identify hvKp strains with acquired resistance. Both logistic regression and a machine-learning prediction model demonstrated that biomarker count alone was the strongest predictor. The presence of all five of the biomarkers iucA, iroB, peg-344, rmpA, and rmpA2 was most accurate (94%); the presence of ≥4 of these biomarkers was most sensitive (100%). Accurately identifying hvKp is vital for surveillance and research, and the availability of biomarker data could alert the clinician that hvKp is a consideration, which, in turn, would assist in optimizing patient care.

OBJECTIVES: Flight attendants perform physically demanding work such as lifting baggage, pushing service carts and spending the workday on their feet. We examined if more frequent exposure to occupational physical demands could explain why previous studies have found that flight attendants have a higher reported prevalence of menstrual cycle irregularities than other workers. METHODS: We conducted a cross-sectional analysis of 694 flight attendants and 120 teachers aged 18-44 years from three US cities. Eligible participants were married, had not had a hysterectomy or tubal ligation, were not using hormonal contraception and were not recently pregnant. Participants reported menstrual cycle characteristics (cramps, pain, irregular cycles, flow, bleed length, cycle length) and occupational physical demands (standing, lifting, pushing/pulling, bending/twisting, overall effort). We used modified Poisson regression to examine associations between occupation (flight attendant, teacher) and menstrual irregularities; among flight attendants, we further examined associations between occupational physical demands and menstrual irregularities. RESULTS: All occupational physical demands were more commonly reported by flight attendants than teachers. Flight attendants reported more frequent menstrual cramps than teachers, and most occupational physical demands were associated with more frequent or painful menstrual cramps. Lifting heavy loads was also associated with irregular cycles. CONCLUSIONS: Occupational physical demands were associated with more frequent and worse menstrual pain among flight attendants. The physical demands experienced by these workers may contribute to the high burden of menstrual irregularities reported by flight attendants compared with other occupational groups, such as teachers.

OBJECTIVE: A decline in musculoskeletal health during pregnancy is an under-appreciated adverse outcome of pregnancy that can have immediate and long-term health consequences. High physical job demands are known risk factors for non-traumatic musculoskeletal disorders in the general working population. Evidence from meta-analyses suggest occupational lifting and prolonged standing during pregnancy may increase risk of adverse pregnancy outcomes. This systematic review examined associations between occupational lifting or postural load in pregnancy and associated musculoskeletal disorders and related sequalae. DATA SOURCES: Five electronic databases (Medline, Embase, CINAHL, NIOSHTIC-2 and Ergonomic Abstracts) were searched from 1990 to July 2022 for studies in any language. A Web of Science snowball search was performed in December 2022. Reference lists were manually reviewed. ELIGIBILITY CRITERIA: Eligible studies reported associations between occupational lifting or postural load and musculoskeletal health or sequelae (e.g., employment outcomes) among pregnant and postpartum workers. METHODS: Data were extracted using a customized form to document study and sample characteristics, and details of exposures, outcomes, covariates, and analyses. Investigators independently assessed study quality for seven risk of bias domains and overall utility, with discrepant ratings resolved through discussion. A narrative synthesis was conducted due to heterogeneity. RESULTS: Sixteen studies (11 cohort studies, 2 nested case-control studies, and 3 cross-sectional studies) from 8 countries were included (N=142,320 pregnant and N=1,744 postpartum workers). Limited but consistent evidence with variable quality ratings, ranging from critical concern to high, suggests that pregnant workers exposed to heavy lifting (usually defined as ≥22 lbs or ≥10 kg) may be at increased risk of functionally limiting pelvic girdle pain and antenatal leave. Moreover, reports of dose-response relationships suggest graded risk levels according to lifting frequency, ranging from 21% to 45% for pelvic girdle pain and 58% to 202% for antenatal leave. Limited but consistent evidence also suggests that postural load increases the risk of employment cessation. CONCLUSION: Limited but consistent evidence suggests that pregnant workers exposed to heavy lifting and postural load are at increased risk of pelvic girdle pain and employment cessation. Job accommodations to reduce exposure levels may promote safe sustainable employment for pregnant workers.

OBJECTIVES: Work schedule demands contribute to circadian disruption and may influence health via an inflammatory response. We examined the impact of shiftwork and long work hours on inflammation in a national US sample. METHODS: Participants included 12 487 employed black and white men and women aged ≥45 years enrolled in the REasons for Geographic and Racial Differences in Stroke Study who completed an occupational questionnaire (2011-2013) and clinical examination (2013-2016). Cross-sectional associations between shiftwork and work hours with log-transformed high-sensitivity C reactive protein (CRP) and white blood cell (WBC) count were examined by multiple linear regression analysis, overall and by race-sex subgroups. RESULTS: Overall, rotating shift workers had higher log-CRP concentration compared with day workers (β=0.09, 95% CI:0.02 to 0.16) and findings for WBC were null. Black women had the highest geometric mean CRP (2.82 mg/L), while white men had the highest WBC (6.35×10(9)/L). White men who worked afternoons had higher log-CRP compared with those who worked days (β=0.20, 95% CI: 0.08 to 0.33). Black men engaged in shiftwork <10 years working ≥55 hours/week had higher log-CRP and log-WBC compared with those working days <55 hours/week (β=0.33, 95% CI: 0.02 to 0.64 and β=0.10, 95% CI: 0.003 to 0.19). Among shift workers, non-retired white women working forward and backward shift rotations had higher log-CRP compared with those working forward only (β=0.49, 95% CI: 0.02 to 0.96). CONCLUSIONS: Shift workers had higher inflammatory markers compared with day workers and race-sex disparities should be examined further. These findings highlight a potential biological pathway linking work schedule demands and chronic disease.

Background HIV testing and counseling is a key component of HIV prevention and the entry point into the treatment cascade, which improves for individual clinical outcomes and reduces onward HIV transmission. Current guidelines recommend at least annual testing for key populations. More frequent testing could provide health benefits, but these additional services increase the program the cost-effectiveness is not well-evaluated. Methods We used a compartmental mathematical model to simulate the health and economic impact of HIV testing one to four times per year for men who have sex with men, people who inject drugs, and female sex workers in Viet Nam. Model outcomes included costs, HIV infections, HIV-related deaths, and disability-adjusted life years (DALYs) associated with each scenario. We used an opportunity cost-based cost-effectiveness threshold of US $2,255 per DALY averted, discounted costs and health benefits at 3% annually, and used a time horizon from 2021 to 2030 to calculate incremental cost-effectiveness ratios (ICERs). Results Compared to the baseline scenario, more frequent HIV testing was estimated to incrementally avert 10.2%, 5.2%, 3.0%, and 1.6% discounted infections for one-, two-, three-, and four-tests per year, respectively. ICERs associated with each scenario ranged from $464, $1,190, $1,762, and $2,727 per DALY averted for one-, two-, three-, and four-tests per year, respectively. Conclusions Increased HIV testing frequency for key populations was projected to avert HIV incidence, mortality, and disability in Viet Nam and was cost-effective. Settings with a similar context should consider strategies on how to optimize retesting among key populations. 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 4.0 International license.

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. | HIGHLIGHTS: TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.

BACKGROUND: Retirement represents a crucial transitional period for many adults with possible consequences for cognitive aging. We examined trajectories of cognitive change before and after retirement in Black and White adults. METHODS: Longitudinal examination of up to 10 years (mean = 7.1 ± 2.2 years) using data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study-a national, longitudinal study of Black and White adults ≥45 years of age. Data were from 2226 members of the REGARDS study who retired around the time when an occupational ancillary survey was administered. Cognitive function was an average of z-scores for tests of verbal fluency, memory, and global function. RESULTS: Cognitive functioning was stable before retirement (Estimate = 0.05, p = 0.322), followed by a significant decline after retirement (Estimate = -0.15, p < 0.001). The decline was particularly pronounced in White (Estimate = -0.19, p < 0.001) compared with Black (Estimate = -0.07, p = 0.077) participants, twice as large in men (Estimate = -0.20, p < 0.001) compared with women (Estimate = -0.11, p < 0.001), highest among White men (Estimate = -0.22, p < 0.001) and lowest in Black women (Estimate = -0.04, p = 0.457). Greater post-retirement cognitive decline was also observed among participants who attended college (Estimate = -0.14, p = 0.016). While greater work complexity (Estimate = 0.92, p < 0.05) and higher income (Estimate = 1.03, p < 0.05) were related to better cognitive function at retirement, neither was significantly related to cognitive change after retirement. CONCLUSION: Cognitive functioning may decline at an accelerated rate immediately post-retirement, more so in White adults and men than Black adults and women. Lifelong structural inequalities including occupational segregation and other social determinants of cognitive health may obscure the role of retirement in cognitive aging.

Haul truck fatal accidents and injuries continue to be a significant concern for the mining industry. However, the availability of high-quality training materials continues to be limited. Near-miss incident accounts, if packaged well, could help fill this gap, because for every fatality, there are hundreds of reportable accidents and thousands of undocumented near misses. Researchers from the National Institute for Occupational Safety and Health (NIOSH) collected detailed accounts of 21 near-miss incidents in virtual interviews with mineworkers at surface mining operations across the country. From these interviews, researchers created four simulation videos using the Unity game engine. The simulation videos bring these events to life through first-person retelling and various visual perspectives of actual events. Each video exemplifies a critical safety message and a common haul truck hazard. This paper describes the process of taking narratives and turning them into impactful visual stories using graphic simulation. NIOSH plans to co-release these simulation videos with the Mine Safety and Health Administration (MSHA) to the mining industry to raise awareness and ultimately help reduce haul truck-related accidents and fatalities in mining.

AIMS: Elevated triglycerides (TG) are associated with development and progression of kidney disease, and TG distributions across lipoprotein subclasses predict kidney dysfunction in adults with type 1 diabetes (T1D). Little is known regarding these relationships in youth. METHODS: In this single center study conducted from October 2018-2019, lipid constituents from lipoprotein subclasses were quantified by targeted nuclear magnetic resonance spectroscopy. Glomerular filtration rate (GFR), renal plasma flow (RPF), afferent arteriolar resistance (R(A)), efferent arteriolar resistance (R(E)), intraglomerular pressure (P(GLO)), urine albumin-to-creatinine ratio (UACR), and chitinase-3-like protein 1 (YKL-40), a marker of kidney tubule injury, were assessed. Cross-sectional relationships were assessed by correlation and multivariable linear regression (adjusted for age, sex, HbA1c) models. RESULTS: Fifty youth with T1D (age 16 ± 3 years, 50 % female, HbA1c 8.7 ± 1.3 %, T1D duration 5.7 ± 2.6 years) were included. Very-low-density lipoprotein (VLDL)-TG concentrations correlated and associated with intraglomerular hemodynamic function markers including GFR, P(GLO), UACR, as did small low-density lipoprotein (LDL)-TG and small high-density lipoprotein (HDL)-TG. YKL-40 correlated with all lipoprotein subclasses. CONCLUSION: TG within lipoprotein subclasses, particularly VLDL, associated with P(GLO,) GFR, albuminuria, and YKL-40. Lipid perturbations may serve as novel targets to mitigate early kidney disease.

At a workshop on 22-24 March 2022, leaders of 33 advanced vaccinology courses were invited to meet with partners to further the aims of the International Collaboration on Advanced Vaccinology Training (ICAVT) initiated in 2018 to assist courses in addressing challenges in priority areas and facilitate interactions and exchange of information. This included: an update to the landscape analysis of advanced vaccinology courses conducted in 2018, sharing experiences and good practices in the implementation of virtual training, reviewing the training needs of target audiences, informing courses of the principles, challenges, and added value of accreditation, discussing course evaluations and measurement of course impact, reviewing principles and support needed for quality cascade training, reviewing COVID-19 impact on training and identifying remaining related training needs, and identifying solutions to facilitate refresher courses and ways to facilitate networking of courses' alumni (particularly for virtual courses). The aims were to identify needs and impediments and implement necessary actions to facilitate sharing of information and resources between courses, to identify need for further developments of the e-Portal of the Collaboration (icavt.org) established to facilitate communication between the different courses and assist future course participants identify the most suitable course for them, and to discuss the formalization of the Collaboration. During the workshop, participants looked at several reports of surveys completed by courses and courses' alumni or partners. The COVID-19 pandemic impacted the delivery of some vaccinology courses leading to postponement, delivery online or hybrid training events. Lack of sustainable funding remained a major constraint for advanced vaccinology training and needs to be addressed. The Collaboration was consolidated with responsibilities and benefits for the members better defined. There was strong support for the Collaboration to continue with the organization of educational sessions at future workshops. The meeting re-enforced the view that there was much enthusiasm and commitment for the Global Collaboration and its core values.

The 2014-2016 Ebola outbreak in Guinea revealed systematic weaknesses in the existing disease surveillance system, which contributed to delayed detection, underreporting of cases, widespread transmission in Guinea and cross-border transmission to neighboring Sierra Leone and Liberia, leading to the largest Ebola epidemic ever recorded. Efforts to understand the epidemic's scale and distribution were hindered by problems with data completeness, accuracy, and reliability. In 2017, recognizing the importance and usefulness of surveillance data in making evidence-based decisions for the control of epidemic-prone diseases, the Guinean Ministry of Health (MoH) included surveillance strengthening as a priority activity in their post-Ebola transition plan and requested the support of partners to attain its objectives. The U.S. Centers for Disease Control and Prevention (US CDC) and four of its implementing partners-International Medical Corps, the International Organization for Migration, RTI International, and the World Health Organization-worked in collaboration with the Government of Guinea to strengthen the country's surveillance capacity, in alignment with the Global Health Security Agenda and International Health Regulations 2005 objectives for surveillance and reporting. This paper describes the main surveillance activities supported by US CDC and its partners between 2015 and 2019 and provides information on the strategies used and the impact of activities. It also discusses lessons learned for building sustainable capacity and infrastructure for disease surveillance and reporting in similar resource-limited settings.

OBJECTIVES: Key populations, including sex workers, men who have sex with men, and people who inject drugs, have a high risk of HIV and sexually transmitted infections. We assessed the health and economic impacts of different HIV and syphilis testing strategies among three key populations in Viet Nam using a dual HIV/syphilis rapid diagnostic test (RDT). SETTING: We used the spectrum AIDS impact model to simulate the HIV epidemic in Viet Nam and evaluated five testing scenarios among key populations. We used a 15-year time horizon and a provider perspective for costs. PARTICIPANTS: We simulate the entire population of Viet Nam in the model. INTERVENTIONS: We modelled five testing scenarios among key populations: (1) annual testing with an HIV RDT, (2) annual testing with a dual RDT, (3) biannual testing using dual RDT and HIV RDT, (4) biannual testing using HIV RDT and (5) biannual testing using dual RDT. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is incremental cost-effectiveness ratios. Secondary outcomes include HIV and syphilis cases. RESULTS: Annual testing using a dual HIV/syphilis RDT was cost-effective (US$10 per disability-adjusted life year (DALY)) and averted 3206 HIV cases and treated 27727 syphilis cases compared with baseline over 15 years. Biannual testing using one dual test and one HIV RDT (US$1166 per DALY), or two dual tests (US$5672 per DALY) both averted an additional 875 HIV cases, although only the former scenario was cost-effective. Annual or biannual HIV testing using HIV RDTs and separate syphilis tests were more costly and less effective than using one or two dual RDTs. CONCLUSIONS: Annual HIV and syphilis testing using dual RDT among key populations is cost-effective in Vietnam and similar settings to reach global reduction goals for HIV and syphilis.

BACKGROUND: The 2014-2016 Ebola virus disease outbreak in West Africa revealed weaknesses in the health systems of the three most heavily affected countries, including a shortage of public health professionals at the local level trained in surveillance and outbreak investigation. In response, the Frontline Field Epidemiology Training Program (FETP) was created by CDC in 2015 as a 3-month, accelerated training program in field epidemiology that specifically targets the district level. In Guinea, the first two FETP-Frontline cohorts were held from January to May, and from June to September 2017. Here, we report the results of a cross-sectional evaluation of these first two cohorts of FETP-Frontline in Guinea. METHODS: The evaluation was conducted in April 2018 and consisted of interviews with graduates, their supervisors, and directors of nearby health facilities, as well as direct observation of data reports and surveillance tools at health facilities. Interviews and site visits were conducted using standardized questionnaires and checklists. Qualitative data were coded under common themes and analyzed using descriptive statistics. RESULTS: The evaluation revealed a significant perception of improvement in all assessed skills by the graduates, as well as high levels of self-reported involvement in key activities related to data collection, analysis, and reporting. Supervisors highlighted improvements to systematic and quality case and summary reporting as key benefits of the FETP-Frontline program. At the health facility level, staff reported the training had resulted in improvements to information sharing and case notifications. Reported barriers included lack of transportation, available support personnel, and other resources. Graduates and supervisors both emphasized the importance of continued and additional training to solidify and retain skills. CONCLUSIONS: The evaluation demonstrated a strongly positive perceived benefit of the FETP-Frontline training on the professional activities of graduates as well as the overall surveillance system. However, efforts are needed to ensure greater gender equity and to recruit more junior trainee candidates for future cohorts. Moreover, although improvements to the surveillance system were observed concurrent with the completion of the two cohorts, the evaluation was not designed to directly measure impact on surveillance or response functions. Combined with the rapid implementation of FETP-Frontline around the world, this suggests an opportunity to develop standardized evaluation toolkits, which could incorporate metrics that would directly assess the impact of equitable field epidemiology workforce development on countries' abilities to prevent, detect, and respond to public health threats.

OBJECTIVE: We examined changes in the excretion of various amino acids and in glycolysis and ketogenesis-related metabolites, during and after diabetic ketoacidosis (DKA) diagnosis, in youth with known or new onset type 1 diabetes (T1D). METHODS: Urine samples were collected from 40 youth with DKA (52% boys, mean age 114years, venous pH7.20.1, blood glucose 451163mg/dL) at 3 time points: 0-8h and 12-24h after starting an insulin infusion, and 3months after hospital discharge. Mixed-effects models evaluated the changes in amino acids and other metabolites in the urine. RESULTS: Concentrations of urine histidine, threonine, tryptophan, and leucine per creatinine were highest at 0-8h (148.823.5, 59.512.3, 15.41.4, and 24.52.4% of urine creatinine, respectively), and significantly decreased over 3months (p=0.028, p=0.027, p=0.019, and p<0.0001, respectively). Urine histidine, threonine, tryptophan, and leucine per urine creatinine decreased by 10.619.2, 0.70.9, 1.30.9, and 0.50.3-fold, respectively, between 0 and 8h and 3months. CONCLUSIONS: In our study, DKA was associated with profound aminoaciduria, suggestive of proximal tubular dysfunction analogous to Fanconi syndrome.

IMPORTANCE: Although prescribers face numerous patient-centered challenges during transitions of care (TOC) at hospital discharge, prolonged duration of antimicrobial therapy for common infections remains problematic, and resources are needed for antimicrobial stewardship throughout this period. OBJECTIVE: To evaluate a pharmacist-driven intervention designed to improve selection and duration of oral antimicrobial therapy prescribed at hospital discharge for common infections. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study used a nonrandomized stepped-wedge design with 3 study phases from September 1, 2018, to August 31, 2019. Seventeen distinct medicine, surgery, and specialty units from a health system in Southeast Michigan participated, including 1 academic tertiary hospital and 4 community hospitals. Hospitalized adults who had urinary, respiratory, skin and/or soft tissue, and intra-abdominal infections and were prescribed antimicrobials at discharge were included in the analysis. Data were analyzed from February 18, 2020, to February 28, 2022. INTERVENTIONS: Clinical pharmacists engaged in a new standard of care for antimicrobial stewardship practices during TOC by identifying patients to be discharged with a prescription for oral antimicrobials and collaborating with primary teams to prescribe optimal therapy. Academic and community hospitals used both antimicrobial stewardship and clinical pharmacists in a multidisciplinary rounding model to discuss, document, and facilitate order entry of the antimicrobial prescription at discharge. MAIN OUTCOMES AND MEASURES: The primary end point was frequency of optimized antimicrobial prescription at discharge. Health system guidelines developed from national guidelines and best practices for short-course therapies were used to evaluate optimal therapy. RESULTS: A total of 800 patients prescribed oral antimicrobials at hospital discharge were included in the analysis (441 women [55.1%]; mean [SD] age, 66.8 [17.3] years): 400 in the preintervention period and 400 in the postintervention period. The most common diagnoses were pneumonia (264 [33.0%]), upper respiratory tract infection and/or acute exacerbation of chronic obstructive pulmonary disease (214 [26.8%]), and urinary tract infection (203 [25.4%]). Patients in the postintervention group were more likely to have an optimal antimicrobial prescription (time-adjusted generalized estimating equation odds ratio, 5.63 [95% CI, 3.69-8.60]). The absolute increase in optimal prescribing in the postintervention group was consistent in both academic (37.4% [95% CI, 27.5%-46.7%]) and community (43.2% [95% CI, 32.4%-52.8%]) TOC models. There were no differences in clinical resolution or mortality. Fewer severe antimicrobial-related adverse effects (time-adjusted generalized estimating equation odds ratio, 0.40 [95% CI, 0.18-0.88]) were identified in the postintervention (13 [3.2%]) compared with the preintervention (36 [9.0%]) groups. CONCLUSIONS AND RELEVANCE: The findings of this quality improvement study suggest that targeted antimicrobial stewardship interventions during TOC were associated with increased optimal, guideline-concordant antimicrobial prescriptions at discharge.

A robust epidemic-prone disease surveillance system is a critical component of public health infrastructure and supports compliance with the International Health Regulations (IHR). One digital health platform that has been implemented in numerous low- and middle-income countries is the District Health Information System Version 2 (DHIS2). In 2015, in the wake of the Ebola epidemic, the Ministry of Health in Guinea established a strategic plan to strengthen its surveillance system, including adoption of DHIS2 as a health information system that could also capture surveillance data. In 2017, the DHIS2 platform for disease surveillance was piloted in two regions, with the aim of ensuring the timely availability of quality surveillance data for better prevention, detection, and response to epidemic-prone diseases. The success of the pilot prompted the national roll-out of DHIS2 for weekly aggregate disease surveillance starting in January 2018. In 2019, the country started to also use the DHIS2 Tracker to capture individual cases of epidemic-prone diseases. As of February 2020, for aggregate data, the national average timeliness of reporting was 72.2%, and average completeness 98.5%; however, the proportion of individual case reports filed was overall low and varied widely between diseases. While substantial progress has been made in implementation of DHIS2 in Guinea for use in surveillance of epidemic-prone diseases, much remains to be done to ensure long-term sustainability of the system. This paper describes the implementation and outcomes of DHIS2 as a digital health platform for disease surveillance in Guinea between 2015 and early 2020, highlighting lessons learned and recommendations related to the processes of planning and adoption, pilot testing in two regions, and scale up to national level.

Majority African-American neighborhoods on the edges of North Carolina municipalities are less likely than white peri-urban neighborhoods to be served by a community system regulated under the Safe Drinking Water Act. These households rely on unregulated private wells, which are at much higher risk of contamination than neighboring community water supplies. Yet, risk awareness of consuming well water is low, and no prior research has tested risk communication interventions for these communities. We present a randomized-controlled trial of an oversized postcard to promote water testing among this audience. The postcard design followed the mental models approach to risk communication. To our knowledge, this is the first U.S. randomized-controlled trial of a mailed communication to promote water testing in any audience and one of few trials of the mental models approach. We evaluated the postcard's effects on self-reported water testing with and without a free water test offer (vs. no-intervention control) via a survey mailed one month after the interventions. The combined communication and free test doubled the odds of self-reported water testing, compared to the control group (p = 0.046). It increased the odds of testing by 65%, compared to the free test alone. Recall of receiving a postcard about water testing increased the odds of self-reported testing twelve-fold (p < 0.001). Although these results suggest that targeted risk information delivered by mail can promote water testing when paired with a free test, the mechanism remains unclear. Additional research on beliefs influencing perceptions about well water may yield interventions that are even more effective.

Streptococcus pneumoniae serotype 1 (ST1) was an important cause of invasive pneumococ-cal disease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) con-taining ST1 antigen. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERE‐ NADE) project gathered ST1 IPD surveillance data from sites globally and aimed to estimate PCV10/13 impact on ST1 IPD incidence. We estimated ST1 IPD incidence rate ratios (IRRs) compar-ing the pre‐PCV10/13 period to each post‐PCV10/13 year by site using a Bayesian multi‐level, mixed-effects Poisson regression and all‐site IRRs using a linear mixed‐effects regression (N = 45 sites). Following PCV10/13 introduction, the incidence rate (IR) of ST1 IPD declined among all ages. After six years of PCV10/13 use, the all‐site IRR was 0.05 (95% credibility interval 0.04–0.06) for all ages, 0.05 (0.04–0.05) for <5 years of age, 0.08 (0.06–0.09) for 5–17 years, 0.06 (0.05–0.08) for 18–49 years, 0.06 (0.05–0.07) for 50–64 years, and 0.05 (0.04–0.06) for ≥65 years. PCV10/13 use in infant immunization programs was followed by a 95% reduction in ST1 IPD in all ages after approximately 6 years. Limited data availability from the highest ST1 disease burden countries using a 3+0 schedule constrains generalizability and data from these settings are needed.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.

Concerns about the quality and use of immunization and vaccine-preventable disease (VPD) surveillance data have been highlighted on the global agenda for over two decades. In August 2017, the Strategic Advisory Group of Experts (SAGE) established a Working Group (WG) onthe Quality and Use of Global Immunization and Surveillance Data to review the current status and evidence to make recommendations, which were presented to SAGE in October 2019. The WG synthesized evidence from landscape analyses, literature reviews, country case-studies, a data triangulation analysis, as well as surveys of experts. Data quality (DQ) was defined as data that are accurate, precise, relevant, complete, and timely enough for the intended purpose (fit-for-purpose), and data use as the degree to which data are actually used for defined purposes, e.g., immunization programme management, performance monitoring, decision-making. The WG outlined roles and responsibilities for immunization and surveillance DQ and use by programme level. The WG found that while DQ is dependent on quality data collection at health facilities, many interventions have targeted national and subnational levels, or have focused on new technologies, rather than the people and enabling environments required for functional information systems. The WG concluded that sustainable improvements in immunization and surveillance DQ and use will require efforts across the health system - governance, people, tools, and processes, including use of data for continuous quality improvement (CQI) - and that the approaches need to be context-specific, country-owned and driven from the frontline up. At the country level, major efforts are needed to: (1) embed monitoring DQ and use alongside monitoring of immunization and surveillance performance, (2) increase workforce capacity and capability for DQ and use, starting at the facility level, (3) improve the accuracy of immunization programme targets (denominators), (4) enhance use of existing data for tailored programme action (e.g., immunization programme planning, management and policy-change), (5) adopt a data-driven CQI approach as part of health system strengthening, (6) strengthen governance around piloting and implementation of new information and communication technology tools, and (7) improve data sharing and knowledge management across areas and organizations for improved transparency and efficiency. Global and regional partners are requested to support countries in adopting relevant recommendations for their setting and to continue strengthening the reporting and monitoring of immunization and VPD surveillance data through processes periodic needs assessment and revision processes. This summary of the WG's findings and recommendations can support "data-guided" implementation of the new Immunization Agenda 2030.

OBJECTIVES: Short and long sleep duration are associated with poor health outcomes and are most prevalent among racial/ethnic minorities. Few studies have investigated the intersection of other sociodemographic characteristics with race/ethnicity on sleep duration prevalence. DESIGN: Longitudinal retrospective analysis of continental U.S. cohort, the REasons for Geographic And Racial Differences in Stroke (REGARDS) PARTICIPANTS: Black (n = 7,547) and white (n = 12,341) adults, 56% women, >/=45 years MEASUREMENTS: At baseline (2003-07), participants reported age, sex, race, education, income, marital status, U.S. region, and employment status. The weighted average of reported sleep duration on weekdays and weekends, assessed at follow-up (2008-10), was categorized as <6, 6.0-6.99, 7.0-7.99 [reference], 8.0-8.99, and >/=9 h. Multinomial logistic regression models examined the independent and multivariable associations of sociodemographic factors with sleep duration. Interactions terms between race with education, income, region, and sex were examined. RESULTS: Average sleep duration was 7.0 h (SD=1.3). Prevalence of short (<6 h) and long (>/=9 h) sleep duration was 11.4% (n = 2,260) and 7.0% (n = 1,395), respectively. In the multivariable model, interactions terms race*income, race*sex, and race*region were significant (P < .05). Relative to white adults, black adults, were most likely to have short sleep duration. The magnitude of that likelihood increased across greater levels of household income, but with greatest odds among black adults living outside of the Southeast and Appalachian United States, particularly for men (>/=$75k; black men OR = 5.47, 95%CI: 3.94,7.54; black women OR = 4.28, 95%CI: 3.08, 5.96). CONCLUSIONS: Race in the context of socioeconomic, sex, and regional factors should be examined as key modifiers of sleep duration.

The Global Vaccine Action Plan 2011-2020 (GVAP) was developed to realize the ambitions of the Decade of Vaccines - that all individuals and communities enjoy lives free from vaccine-preventable diseases. It included a comprehensive monitoring and evaluation/accountability framework to assess progress towards global targets with recommendations for corrective actions. While many of the GVAP targets are very unlikely to be met by the end of 2020, substantial progress has nevertheless been made, establishing a strong foundation for a successor global immunization strategy, the Immunization Agenda 2030 (IA2030). The Strategic Advisory Group of Experts on immunization has made a series of recommendations to ensure that the lessons learned from GVAP inform the development and implementation of IA2030.