MEF2 is an in vivo immune-metabolic switch.

Infections disturb metabolic homeostasis in many contexts, but the underlying connections are not completely understood. To address this, we use paired genetic and computational screens in Drosophila to identify transcriptional regulators of immunity and pathology and their associated target genes and physiologies. We show that Mef2 is required in the fat body for anabolic function and the immune response. Using genetic and biochemical approaches, we find that MEF2 is phosphorylated at a conserved site in healthy flies and promotes expression of lipogenic and glycogenic enzymes. Upon infection, this phosphorylation is lost, and the activity of MEF2 changes--MEF2 now associates with the TATA binding protein to bind a distinct TATA box sequence and promote antimicrobial peptide expression. The loss of phosphorylated MEF2 contributes to loss of anabolic enzyme expression in Gram-negative bacterial infection. MEF2 is thus a critical transcriptional switch in the adult fat body between metabolism and immunity.

Estimating the Potential Public Health Value of BCG Revaccination.

An upcoming trial may provide further evidence that adolescent/adult-targeted BCG revaccination prevents sustained Mycobacterium tuberculosis infection, but its public health value depends on its impact on overall tuberculosis morbidity and mortality, which will remain unknown. Using previously calibrated models for India and South Africa, we simulated BCG revaccination assuming 45% prevention-of-infection efficacy, and we evaluated scenarios varying additional prevention-of-disease efficacy between +50% (reducing risk) and -50% (increasing risk). Given the assumed prevention-of-infection efficacy and range in prevention-of-disease efficacy, BCG revaccination may have a positive health impact and be cost-effective. This may be useful when considering future evaluations and implementation of adolescent/adult BCG revaccination.

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion F Protein Vaccine when Co-administered with Adjuvanted Seasonal Quadrivalent Influenza Vaccine in Older Adults: A Phase 3 Randomized Trial.

BACKGROUND: We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds. METHODS: This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed. RESULTS: Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups. CONCLUSIONS: Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine. CLINICAL TRIALS REGISTRATION: NCT05568797.

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Racial disparities in low-risk cesarean birth rates across hospitals.

BACKGROUND: We compared low-risk cesarean birth rates for Black and White women across hospitals serving increasing proportions of Black women and identified hospitals where Black women had low-risk cesarean rates less than or equal to White women. METHODS: In this cross-sectional analysis of secondary data from four states, we categorized hospitals by their proportion of Black women giving birth from "low" to "high". We analyzed the odds of low-risk cesarean for Black and White women across hospital categories. RESULTS: Our sample comprised 493 hospitals and the 65,524 Black and 251,426 White women at low risk for cesarean who birthed in them. The mean low-risk cesarean rate was significantly higher for Black, compared with White, women in the low (20.1% vs. 15.9%) and medium (18.1% vs. 16.9%) hospital categories. In regression models, no hospital structural characteristics were significantly associated with the odds of a Black woman having a low-risk cesarean. For White women, birthing in a hospital serving the highest proportion of Black women was associated with a 21% (95% CI: 1.01-1.44) increase in the odds of having a low-risk cesarean. DISCUSSION: Black women had higher odds of a low-risk cesarean than White women and were more likely to access care in hospitals with higher low-risk cesarean rates. The existence of hospitals where low-risk cesarean rates for Black women were less than or equal to those of White women was notable, given a predominant focus on hospitals where Black women have poorer outcomes. Efforts to decrease the low-risk cesarean rate should focus on (1) improving intrapartum care for Black women and (2) identifying differentiating organizational factors in hospitals where cesarean birth rates are optimally low and equivalent among racial groups as a basis for system-level policy efforts to improve equity and reduce cesarean birth rates.

Are Racial Disparities in Cesarean Due to Differences in Labor Induction Management?

OBJECTIVE: While there are known racial disparities in cesarean delivery (CD) rates, the exact etiologies for these disparities are multifaceted. We aimed to determine if differences in induction of labor (IOL) management contribute to these disparities. STUDY DESIGN: This retrospective cohort study evaluated all nulliparous patients with an unfavorable cervix and intact membranes who underwent IOL of a term, singleton gestation at a single institution from October 1, 2018, to September 30, 2020. IOL management was at clinician discretion. Patients were classified as Black, Indigenous, and People of Color (BIPOC) or White based on self-report. Overall rates of CD were compared for BIPOC versus White race. Chart review then evaluated various IOL management strategies as possible contributors to differences in CD by race. RESULTS: Of 1,261 eligible patients, 915 (72.6%) identified as BIPOC and 346 (27.4%) as White. BIPOC patients were more likely to be younger (26 years interquartile range (IQR): [22-30] vs. 32 years IQR: [30-35], p < 0.001) and publicly insured (59.1 vs. 9.9%, p < 0.001). Indication for IOL and modified Bishop score also differed by race (p < 0.001; p = 0.006). There was 40% increased risk of CD for BIPOC patients, even when controlling for confounders (30.7 vs. 21.7%, p = 0.001; adjusted relative risk (aRR) = 1.41, 95% confidence interval (CI): [1.06-1.86]). Despite this difference in CD, there were no identifiable differences in IOL management prior to decision for CD by race. Specifically, there were no differences in choice of cervical ripening agent, cervical dilation at or time to amniotomy, use and maximum dose of oxytocin, or dilation at CD. However, BIPOC patients were more likely to undergo CD for fetal indications and failed IOL. CONCLUSION: BIPOC nulliparas are 40% more likely to undergo CD during IOL than White patients within our institution. These data suggest that the disparity is not explained by differences in IOL management prior to cesarean, indicating that biases outside of induction management may be important to target to reduce CD disparities. KEY POINTS: · The etiologies for racial disparities in cesarean are likely multifaceted.. · In this work, there were no differences by race in measures of labor induction management.. · Biases outside of induction management during labor may be targeted to reduce CD disparities..

Associations Between Hospital Nursing Resources and Breastfeeding Outcomes: A Narrative Review.

PURPOSE: To summarize how nursing resources and missed nursing care are associated with hospital breastfeeding outcomes, including human milk provision. BACKGROUND: Nurses are the primary providers of breastfeeding support in the hospital. Nursing resources, eg, staffing and the work environment, enable nurses to carry out their work successfully. If resources are constrained, nurses may miss providing breastfeeding support. There is a gap in the literature about the relationships among nursing resources, missed nursing care, and breastfeeding outcomes. METHODS: The Cumulative Index to Nursing and Allied Health Literature and PubMed were searched with keywords such as: "nurse staffing," "nurse work environment," "missed nursing care," "breastfeeding," "human milk," and "lactation." We included peer-reviewed studies of US samples in English published between 2014 and 2022. RESULTS: Of 312 references, 8 met inclusion criteria: 5 quantitative and 3 qualitative. Better nurse staffing and breastfeeding support were associated with improved breastfeeding outcomes in the qualitative and quantitative literature. Missed care partially mediated the relationship between staffing and exclusive breast milk feeding rates. Better nurse work environments were associated with increased breastfeeding support and provision of human milk. CONCLUSIONS: Empirical evidence supports an association between the nurse work environment, nurse staffing, breastfeeding support, and outcomes. Implications for practice and research: Poor staffing may be associated with decreased breastfeeding support and outcomes. Hospital administrators and nurse managers may consider improving nurse staffing and the work environment to improve breastfeeding outcomes. Future research should simultaneously examine staffing and the work environment and address breastfeeding outcome disparities.

Effects of Nurse Staffing on Missed Breastfeeding Support in Maternity Units With Different Nurse Work Environments.

PURPOSE: To examine the effect of nurse staffing in varying work environments on missed breastfeeding teaching and support in inpatient maternity units in the United States. BACKGROUND: Breast milk is the optimal food for newborns. Teaching and supporting women in breastfeeding are primarily a nurse's responsibility. Better maternity nurse staffing (fewer patients per nurse) is associated with less missed breastfeeding teaching and support and increased rates of breastfeeding. We examined the extent to which the nursing work environment, staffing, and nurse education were associated with missed breastfeeding care and how the work environment and staffing interacted to impact missed breastfeeding care. METHODS: In this cross-sectional study using the 2015 National Database of Nursing Quality Indicator survey, maternity nurses in hospitals in 48 states and the District of Columbia responded about their workplace and breastfeeding care. Clustered logistic regression models with interactions were used to estimate the effects of the nursing work environment and staffing on missed breastfeeding care. RESULTS: There were 19 486 registered nurses in 444 hospitals. Nearly 3 in 10 (28.2%) nurses reported missing breastfeeding care. In adjusted models, an additional patient per nurse was associated with a 39% increased odds of missed breastfeeding care. Furthermore, 1 standard deviation decrease in the work environment was associated with a 65% increased odds of missed breastfeeding care. In an interaction model, staffing only had a significant impact on missed breastfeeding care in poor work environments. CONCLUSIONS: We found that the work environment is more fundamental than staffing for ensuring that not only breastfeeding care is not missed but also breastfeeding care is sensitive to nurse staffing. Improvements to the work environment support the provision of breastfeeding care. IMPLICATIONS FOR RESEARCH AND PRACTICE: Both nurse staffing and the work environment are important for improving breastfeeding rates, but the work environment is foundational.

Emergency Nurses' Well-Being in Magnet Hospitals and Recommendations for Improvements in Work Environments: A Multicenter Cross-Sectional Observational Study.

INTRODUCTION: This study aimed to determine the well-being outcomes and quality of work environment among emergency nurses compared with inpatient nurses working in Magnet hospitals and identify recommendations in emergency department work environments that hold promise for enhancing emergency nurses' well-being. METHODS: This is a cross-sectional analysis of multicenter survey data collected in 2021 from 11,743 nurses practicing in 60 United States Magnet hospitals. Nurses report on burnout, job dissatisfaction, intent to leave, work environment, and recommendations to improve well-being. RESULTS: Emergency nurses are significantly more likely to report high burnout (P = .04), job dissatisfaction (P < .001), and intent to leave (P < .001) than inpatient nurses working in the same Magnet hospitals. Emergency nurses are significantly more likely to report insufficient staffing (P = .001), an unfavorable work environment (P < .001), and lack confidence that management will act to resolve problems in patient care (P < .001) but did report significantly better working relationships with physicians (P < .001) than their inpatient counterparts. The 2 greatest recommendations to improve well-being included improving nurse staffing (91.4%) and the ability to take uninterrupted breaks (86.7%); the lowest-ranked recommendations were employing more advanced practice providers (25.9%) and appointing a wellness champion (21.2%). DISCUSSION: High burnout and other adverse nurse outcomes are common among emergency nurses in Magnet hospitals. Modifiable features of ED work environments including inadequate nurse staffing, inability of nurses to take uninterrupted breaks, and lack of responsiveness of management to persistent problems in patient care warrant high priority attention by Magnet hospital leaders.

The Y46D Mutation Destabilizes Dense Packing of the Second Greek Key Pair of Human γC-Crystallin Causing Congenital Nuclear Cataracts.

The γ-crystallins are highly expressed structural lens proteins comprising four Greek key motifs arranged in two domains. Their globular structure and short-range spatial ordering are essential for lens transparency. Aromatic residues play a vital role in stabilizing Greek key folds by forming Greek key or non-Greek key pairs or tyrosine corners. We investigated the effects of the cataractogenic Y46D mutation in the second Greek key pair (Y46-Y51) of human γC-crystallin on its stability and aggregation. Wild-type and Y46D mutant human γC-crystallin were overexpressed in E. coli BL-21(DE3) PLysS cells, purified using ion-exchange and size-exclusion chromatography, and analyzed by fluorescence spectroscopy and circular dichroism spectroscopy. The Y46D mutation does not affect the γC-crystallin backbone conformation under benign conditions but alters the tryptophan microenvironment, exposing hydrophobic residues to the surface. The Y46D mutant undergoes a three-state transition under thermal stress with midpoints of 54.6 and 67.7 °C while the wild type shows a two-state transition with a midpoint of 77.6 °C. The Y46D mutant also shows a three-state transition under GuHCl stress with Cm values of 0.9 and 2.1 M while the wild type shows a two-state transition with a Cm of 2.4 M GuHCl. Mutant but not wild-type γC-crystallin forms light scattering particles upon heating at 65 °C. Overall, the Y46D CRYGS mutation leaves the protein fold intact under benign conditions but destabilizes the molecule by altering the tryptophan microenvironment and exposing hydrophobic residues to its surface, thus increasing its susceptibility to thermal and chemical stress with resultant self-aggregation, light scattering, and cataract.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

The potential impact of novel tuberculosis vaccine introduction on economic growth in low- and middle-income countries: A modeling study.

BACKGROUND: Most individuals developing tuberculosis (TB) are working age adults living in low- and middle-income countries (LMICs). The resulting disability and death impact economic productivity and burden health systems. New TB vaccine products may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on gross domestic product (GDP) growth in 105 LMICs. METHODS AND FINDINGS: We adapted an existing macroeconomic model to simulate country-level GDP trends between 2020 and 2080, comparing scenarios for introduction of hypothetical infant and adolescent/adult vaccines to a no-new-vaccine counterfactual. We parameterized each scenario using estimates of TB-related mortality, morbidity, and healthcare spending from linked epidemiological and costing models. We assumed vaccines would be introduced between 2028 and 2047 and estimated incremental changes in GDP within each country from introduction to 2080, in 2020 US dollars. We tested the robustness of results to alternative analytic specifications. Both vaccine scenarios produced greater cumulative GDP in the modeled countries over the study period, equivalent to $1.6 (95% uncertainty interval: $0.8, 3.0) trillion for the adolescent/adult vaccine and $0.2 ($0.1, 0.4) trillion for the infant vaccine. These GDP gains were substantially lagged relative to the time of vaccine introduction, particularly for the infant vaccine. GDP gains resulting from vaccine introduction were concentrated in countries with higher current TB incidence and earlier vaccine introduction. Results were sensitive to secular trends in GDP growth but relatively robust to other analytic assumptions. Uncertain projections of GDP could alter these projections and affect the conclusions drawn by this analysis. CONCLUSIONS: Under a range of assumptions, introducing novel TB vaccines would increase economic growth in LMICs.

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.

BACKGROUND: Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies. METHODS AND FINDINGS: We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. CONCLUSIONS: TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

New tuberculosis vaccines in India: modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01E and BCG-revaccination.

BACKGROUND: India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. METHODS: We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. RESULTS: M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. CONCLUSIONS: M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.

Health TAPESTRY Ontario: A Multi-Site Randomized Controlled Trial Testing Implementation and Reproducibility.

PURPOSE: Health Teams Advancing Patient Experience: Strengthening Quality (Health TAPESTRY) is a complex primary care program aimed at assisting older adults to stay healthier for longer. This study evaluated the feasibility of implementation across multiple sites, and the reproducibility of the effects found in the previous randomized controlled trial. METHODS: This was a pragmatic, unblinded, 6-month parallel group randomized controlled trial. Participants were randomized (intervention or control) using a computer-generated system. Eligible patients, aged 70 years and older, were rostered to 1 of 6 participating interprofessional primary care practices (urban and rural). In total, 599 (301 intervention, 298 control) patients were recruited from March 2018 through August 2019. Intervention participants received a home visit from volunteers to collect information on physical and mental health, and social context. An interprofessional care team created and implemented a plan of care. The primary outcomes were physical activity and number of hospitalizations. RESULTS: Based on the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework, Health TAPESTRY had widespread reach and adoption. In the intention-to-treat analysis (257 intervention, 255 control), there were no statistically significant between-group differences for hospitalizations (incidence rate ratio = 0.79; 95% CI, 0.48-1.30; P = .35) or total physical activity (mean difference = -0.26; 95% CI, -1.18 to 0.67; P = .58). There were 37 non-study related serious adverse events (19 intervention, 18 control). CONCLUSIONS: We found Health TAPESTRY was successfully implemented for patients in diverse primary care practices; however, implementation did not reproduce the effect on hospitalizations and physical activity found in the initial randomized controlled trial.

PFAS Electroanalysis in Low-Oxygen River Water Using Electrogenerated Dioxygen.

Per- and polyfluoroalkyl substances (PFAS), nicknamed "forever chemicals" due to the strength of their carbon-fluorine bonds, are a class of potent micropollutants that cause deleterious health effects in mammals. The current state-of-the-art detection method requires the collection and transport of water samples to a centralized facility where chromatography and mass spectrometry are performed for the separation, identification, and quantification of PFAS. However, for efficient remediation efforts to be properly informed, a more rapid in-field testing method is required. We previously demonstrated the development and use of dioxygen as the mediator molecule. The use of dioxygen is predicated on the assumption that there will be consistent ambient dioxygen levels in natural waters. This is not always the case in hypoxic groundwater and at high altitudes. To overcome this challenge and further advance the strategies that will enable in-field electroanalysis of PFAS, we demonstrate, as a proof of concept, that dioxygen can be generated in solution through the hydrolysis of water. The electrogenerated dioxygen can then be used as a mediator molecule for the indirect detection of PFOS via molecularly imprinted polymer (MIP)-based electroanalysis. We demonstrate that calibration curves can be constructed with high precision and sensitivity (LOD < 1 ppt or 1 ng/L). Our results provide a foundation for enabling in-field hypoxic PFAS electroanalysis.

Understanding collaborative implementation between community and academic partners in a complex intervention: a qualitative descriptive study.

BACKGROUND: Community-academic partnerships (CAPs) can improve the relevance, sustainability, and uptake of new innovations within the community. However, little is known about what topics CAPs focus on and how their discussions and decisions impact implementation at ground level. The objectives of this study were to better understand the activities and learnings from implementation of a complex health intervention by a CAP at the planner/decision-maker level, and how that compared to experiences implementing the program at local sites. METHODS: The intervention, Health TAPESTRY, was implemented by a nine-partner CAP including academic, charitable organizations, and primary care practices. Meeting minutes were analyzed using qualitative description, latent content analysis, and a member check with key implementors. An open-answer survey about the best and worst elements of the program was completed by clients and health care providers and analyzed using thematic analysis. RESULTS: In total, 128 meeting minutes were analyzed, 278 providers and clients completed the survey, and six people participated in the member check. Prominent topics of discussion categories from the meeting minutes were: primary care sites, volunteer coordination, volunteer experience, internal and external connections, and sustainability and scalability. Clients liked that they learned new things and gained awareness of community programs, but did not like the volunteer visit length. Clinicians liked the regular interprofessional team meetings but found the program time-consuming. CONCLUSIONS: An important learning was about who had "voice" at the planner/decision-maker level: many of the topics discussed in meeting minutes were not identified as issues or lasting impacts by clients or providers; this may be due to differing roles and needs, but may also identify a gap. Overall, we identified three phases that could serve as a guide for other CAPs: Phase (1) recruitment, financial support, and data ownership; Phase (2) considerations for modifications and adaptations; Phase (3) active input and reflection.

Detecting Methamphetamine in Aerosols by Electroanalysis in a Soap Bubble Wall.

We present a facile method to detect methamphetamine in aerosols by trapping aerosols in a soap bubble wall for electroanalysis. A microwire was placed through a soap bubble wall as a sensing electrode along with a 1 mm diameter platinum wire as the counter/reference electrode. The resulting electrochemical cell and electrode geometry are unique and allow for reproducible electrochemistry between bubble walls. We first provide a thorough investigation of the cell and electrode geometry and an electrochemical characterization of ferrocene methanol in a soap bubble wall composed of 0.1 M KCl and 0.1% Triton X-100 (v/v). To visualize the boundary where the bubble wets the microwire (the effective electrode area) with tens of nanometer resolution, we electrodeposited platinum on carbon microwire. Scanning electron microscopy and energy dispersive X-ray spectroscopy revealed the bubble contact (i.e., cylindrical electrode height) is 157 ± 30 µm. Correlated digital microscopy suggests that the wetting reaches r ∼ 125 µm along the bubble wall laterally from the microwire. Beyond the wetting region, the bubble thickness is 18 ± 1 µm, as indicated by ultraviolet-visible spectroscopy experiments probing dissolved bis(bipyridine)ruthenium(II) chloride. We illustrate that the voltammetric character in this system is highly dependent on the bubble wetting parameters, which are tuned by changing the microwire material. We then applied this system to the collection and electrochemical detection of methamphetamine in liquid aerosols, where the bubble wall acts as a low volume collector.

The implementation and validation of the NoMAD during a complex primary care intervention.

BACKGROUND: Normalization process theory (NPT) has been widely used to better understand how new interventions are implemented and embedded. The NoMAD (Normalization Measurement Development questionnaire) is a 23-item NPT instrument based on NPT. As the NoMAD is a relatively new instrument, the objectives of this paper are: to describe the experience of implementing the NoMAD, to describe it being used as a feedback mechanism to gain insight into the normalization process of a complex health intervention, and to further explore the psychometric properties of the instrument. METHODS: Health TAPESTRY was implemented in six Family Health Teams (total of seven sites) across Ontario. Healthcare team members at each site were invited to complete the NoMAD, and three general questions about normalization, six times over a 12-month period. Each site was then provided a visual traffic light summary (TLS) reflecting the implementation of the Health TAPESTRY. The internal consistency of each sub-scale and validity of the NoMAD were assessed. Learnings from the implementation of the NoMAD and subsequent feedback mechanism (TLS) are reported descriptively. RESULTS: In total, 56 diverse health care team members from six implementation sites completed the NoMAD. Each used it at least once during the 12-month study period. The implementation of the NoMAD and TLS was time consuming to do with multiple collection (and feedback) points. Most (60%) internal consistency values of the four subscales (pooled across site) across each collection point were satisfactory. All correlations were positive, and most (86%) were statistically significant among NoMAD subscales. All but one correlation between the NoMAD subscales and the general questions were positive, and most (72%) were significant. Generally, scores on the subscales were higher at 12-month than baseline, albeit did not follow a linear pattern of change across implementation. Generally, scores were higher for experienced sites compared to first-time implementors. CONCLUSION: Our experience would suggest fewer collection points; three timepoints spaced out by several months are adequate, if repeated administration of the NoMAD is used for feedback loops. We provide additional evidence of the psychometric properties of the NoMAD. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT03397836 .