Origin of Pinning Disorder in Magnetic-Field-Induced Wigner Solids.

At low Landau level filling factors (ν), Wigner solid phases of two-dimensional electron systems in GaAs are pinned by disorder and exhibit a pinning mode, whose frequency is a measure of the disorder that pins the Wigner solid. Despite numerous studies spanning the past three decades, the origin of the disorder that causes the pinning and determines the pinning mode frequency remains unknown. Here, we present a study of the pinning mode resonance in the low-ν Wigner solid phases of a series of ultralow-disorder GaAs quantum wells which are similar except for their varying well widths d. The pinning mode frequencies f_{p} decrease strongly as d increases, with the widest well exhibiting f_{p} as low as ≃35 MHz. The amount of reduction of f_{p} with increasing d can be explained remarkably well by tails of the wave function impinging into the alloy-disordered Al_{x}Ga_{1-x}As barriers that contain the electrons. However, it is imperative that the model for the confinement and wave function includes the Coulomb repulsion in the growth direction between the electrons as they occupy the quantum well.

The state of reporting context and implementation in peer-reviewed evaluations of water, sanitation, and hygiene interventions: A scoping review.

INTRODUCTION: To accurately assess evidence from environmental and public health field trials, context and implementation details of the intervention must be weighed with trial results; yet these details are under and inconsistently reported for water, sanitation, and hygiene (WASH), limiting the external validity of the evidence. METHODS: To quantify the level of reporting of context and implementation in WASH evaluations, we conducted a scoping review of the 40 most cited evaluations of WASH interventions published in the last 10 years (2012-2022). We applied criteria derived from a review of existing reporting guidance from other sectors including healthcare and implementation science. We subsequently reviewed main articles, supplements, protocols, and other associated resources to assess thoroughness of context and implementation reporting. RESULTS: Of the final 25 reporting items we searched for, four-intervention name, approach, location, and temporality-were reported by all studies. Five items-theory, implementer qualifications, dose intensity, targeting, and measured fidelity-were not reported in over a third of reviewed articles. Only two studies (5%) reported all items in our checklist. Only 74% of items were found in the main article, while the rest were found in separate papers (7%) or not at all (19%). DISCUSSION: Inconsistent reporting of WASH implementation illustrates a major challenge in the sector. It is difficult to know what interventions are actually being evaluated and how to compare evaluation results. This inconsistent and incomplete implementation reporting limits the ability of programmers and policy makers to apply the available evidence to their contexts. Standardized reporting guidelines would improve the application of the evidence for WASH field evaluations.

Success in vaccination programming through community health workers: a qualitative analysis of interviews and focus group discussions from Nepal, Senegal and Zambia.

OBJECTIVES: Community health workers are essential to front-line health outreach throughout low-income and middle-income countries, including programming for early childhood immunisation. Understanding how community health workers are engaged for successful early childhood vaccination among countries who showed success in immunisation coverage would support evidence-based policy guidance across contexts. DESIGN: We employed a multiple case study design using qualitative research methods. SETTING: We conducted research in Nepal, Senegal and Zambia. PARTICIPANTS: We conducted 207 interviews and 71 focus group discussions with 678 participants at the national, regional, district, health facility and community levels of the health systems of Nepal, Senegal and Zambia, from October 2019 to April 2021. We used thematic analysis to investigate contributing factors of community health worker programming that supported early childhood immunisation within each country and across contexts. RESULTS: Implementation of vaccination programming relied principally on the (1) organisation, (2) motivation and (3) trust of community health workers. Organisation was accomplished by expanding cadres of community health workers to carry out their roles and responsibilities related to vaccination. Motivation was supported by intrinsic and extrinsic incentives. Trust was expressed by communities due to community health worker respect and value placed on their work. CONCLUSION: Improvements in immunisation coverage was facilitated by community health worker organisation, motivation and trust. With the continued projection of health worker shortages, especially in low-income countries, community health workers bridged the equity gap in access to vaccination services by enabling wider reach to underserved populations. Although improvements in vaccination programming were seen in all three countries-including government commitment to addressing human resource deficits, training and remuneration; workload, inconsistency in compensation, training duration and scope, and supervision remain major challenges to immunisation programming. Health decision-makers should consider organisation, motivation and trust of community health workers to improve the implementation of immunisation programming.

Analysis of >15 000 Solid Organ Transplant Recipients Reveals Nonanal Genitourinary HPV-related Disease as Highest Risk Predictor for Anal Squamous Intraepithelial Lesions/Anal Cancer.

BACKGROUND: Solid organ transplantation is a risk predictor for virally-mediated anal squamous intraepithelial lesions and cancer (anal disease). Precancerous squamous intraepithelial lesions can be detected by screening, and treatment may prevent cancer progression. Screening recommendations are not well defined. We aim to define prevalence and describe risk predictors for anal disease in a large population of solid organ transplant recipients. METHODS: Retrospective single-center cohort analysis included solid organ transplant recipients cared for between 2001 and 2022 (N = 15 362). The cohort of recipients who developed anal disease was compared with those who did not. Greedy propensity score matching was performed for organ-specific recipients, and time-to-event analysis for the development of anal disease was performed in those with genitourinary human papilloma virus (HPV) disease versus those without. RESULTS: Prevalence of anal disease was 0.6% (cancer 0.2%). The average years from transplant to the diagnosis of anal disease was 11.67. Anal disease was more common in women (68.5% versus 31.5%, P < 0.001), patients who had other HPV-related genitourinary diseases (40.4% versus 0.6%, P < 0.001), who were of younger age at transplant (39.62 versus 46.58, P < 0.001), and had increased years from transplant (17.06 versus 12.57, P < 0.001). In multivariate analysis, the odds of anal disease increased by 4% each year posttransplant. History of genitourinary HPV disease (odds ratio 69.63) and female sex (odds ratio 1.96) were the most significant risk predictors for anal disease. CONCLUSIONS: The prevalence of anal cancer among solid organ transplant recipients was equal to the general population (0.2%). Due to the low prevalence of overall disease, these data suggest that anal screenings in transplant recipients should be targeted to higher-risk subsets: female recipients farther out from transplant and patients with genitourinary HPV-related diseases.

C-di-AMP accumulation disrupts glutathione metabolism and inhibits virulence program expression in Listeria monocytogenes.

C-di-AMP is an essential second messenger in many bacteria but its levels must be regulated. Unregulated c-di-AMP accumulation attenuates the virulence of many bacterial pathogens, including those that do not require c-di-AMP for growth. However, the mechanisms by which c-di-AMP regulates bacterial pathogenesis remain poorly understood. In Listeria monocytogenes , a mutant lacking both c-di-AMP phosphodiesterases, denoted as the ΔPDE mutant, accumulates a high c-di-AMP level and is significantly attenuated in the mouse model of systemic infection. All key L. monocytogenes virulence genes are transcriptionally upregulated by the master transcription factor PrfA, which is activated by reduced glutathione (GSH) during infection. Our transcriptomic analysis revealed that the ΔPDE mutant is significantly impaired for the expression of virulence genes within the PrfA core regulon. Subsequent quantitative gene expression analyses validated this phenotype both at the basal level and upon PrfA activation by GSH. A constitutively active PrfA * variant, PrfA G145S, which mimics the GSH-bound conformation, restores virulence gene expression in ΔPDE but only partially rescues virulence defect. Through GSH quantification and uptake assays, we found that the ΔPDE strain is significantly depleted for GSH, and that c-di-AMP inhibits GSH uptake. Constitutive expression of gshF (encoding a GSH synthetase) does not restore GSH levels in the ΔPDE strain, suggesting that c-di-AMP inhibits GSH synthesis activity or promotes GSH catabolism. Taken together, our data reveals GSH metabolism as another pathway that is regulated by c-di-AMP. C-di-AMP accumulation depletes cytoplasmic GSH levels within L. monocytogenes that leads to impaired virulence program expression. IMPORTANCE: C-di-AMP regulates both bacterial pathogenesis and interactions with the host. Although c-di-AMP is essential in many bacteria, its accumulation also attenuates the virulence of many bacterial pathogens. Therefore, disrupting c-di-AMP homeostasis is a promising antibacterial treatment strategy, and has inspired several studies that screened for chemical inhibitors of c-di-AMP phosphodiesterases. However, the mechanisms by which c-di-AMP accumulation diminishes bacterial pathogenesis are poorly understood. Such understanding will reveal the molecular function of c-di-AMP, and inform therapeutic development strategies. Here, we identify GSH metabolism as a pathway regulated by c-di-AMP that is pertinent to L. monocytogenes replication in the host. Given the role of GSH as a virulence signal, nutrient, and antioxidant, GSH depletion impairs virulence program expression and likely diminishes host adaptation.

Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.

iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.

Feasibility of a Novel Fluoroscopic Trainer for the Orthopaedic Trainee.

OBJECTIVE: We sought to create a novel method of teaching orthopedic trainees to efficiently obtain intraoperative radiographs using nonfluoroscopic digital cameras. Specifically, teaching them to make minor, uniplanar, adjustments while limiting the number of fluoroscopy images obtained during placement of a guidewire "start-point," for intramedullary nailing. DESIGN: Prospective cohort study including medical students from 2 academic centers. Two nonfluoroscopic digital cameras simulating orthogonal fluoroscopic images were utilized. A sponge was used to simulate soft tissue resistance while navigating a guidewire to the desired starting point. Three cannulated parallel cylinders in a triangular configuration are used to simulate our "start point." Students completed 4 phases; trial and error, teaching, testing and retention. SETTING: The protocol was completed at a single academic teaching hospital at the primary authors institution. PARTICIPANTS: We utilized medical students from 2 GME accredited medical schools to complete the protocol. Students were selected from orthopedic surgery interest groups at their respective institutions and participation was voluntary. RESULTS: Twenty-one medical students completed the protocol. The number of seconds to achieve each target along with the number of pictures to achieve each target were recorded and averaged. The paired t-test was used to compare the difference between phases. There is a statistically significant difference in the mean number of seconds to achieve each target between phase 1 (baseline) and phase 3 (testing) (p < 0.0001). This statistically significant difference was retained in phase 4 (retention) (p < 0.0001). CONCLUSIONS: We were able to demonstrate a statistically significant decrease in the number of images and time to obtain the correct "start point." This could theoretically decrease operative time and morbidity while teaching students in a low-stress training environment without exposure to radiation.

Quantifying Enteropathogen Contamination along Chicken Value Chains in Maputo, Mozambique: A Multidisciplinary and Mixed-Methods Approach to Identifying High Exposure Settings.

BACKGROUND: Small-scale poultry production is widespread and increasing in low- and middle-income countries (LMICs). Exposure to enteropathogens in poultry feces increases the hazard of human infection and related sequela, and the burden of disease due to enteric infection in children <5 y in particular is substantial. Yet, the containment and management of poultry-associated fecal waste in informal settings in LMICs is largely unregulated. OBJECTIVES: To improve the understanding of potential exposures to enteropathogens carried by chickens, we used mixed methods to map and quantify microbial hazards along production value chains among broiler, layer, and indigenous chickens in Maputo, Mozambique. METHODS: To map and describe the value chains, we conducted 77 interviews with key informants working in locations where chickens and related products are sold, raised, and butchered. To quantify microbial hazards, we collected chicken carcasses (n=75) and fecal samples (n=136) from chickens along the value chain and assayed them by qPCR for the chicken-associated bacterial enteropathogens C. jejuni/coli and Salmonella spp. RESULTS: We identified critical hazard points along the chicken value chains and identified management and food hygiene practices that contribute to potential exposures to chicken-sourced enteropathogens. We detected C. jejuni/coli in 84 (76%) of fecal samples and 52 (84%) of carcass rinses and Salmonella spp. in 13 (11%) of fecal samples and 16 (21%) of carcass rinses. Prevalence and level of contamination increased as chickens progressed along the value chain, from no contamination of broiler chicken feces at the start of the value chain to 100% contamination of carcasses with C. jejuni/coli at informal markets. Few hazard mitigation strategies were found in the informal sector. DISCUSSION: High prevalence and concentration of C. jejuni/coli and Salmonella spp. contamination along chicken value chains suggests a high potential for exposure to these enteropathogens associated with chicken production and marketing processes in the informal sector in our study setting. We identified critical control points, such as the carcass rinse step and storage of raw chicken meat, that could be intervened in to mitigate risk, but regulation and enforcement pose challenges. This mixed-methods approach can also provide a model to understand animal value chains, sanitary risks, and associated exposures in other settings. https://doi.org/10.1289/EHP11761.

Synthesising the evidence for effective hand hygiene in community settings: an integrated protocol for multiple related systematic reviews.

INTRODUCTION: Despite evidence for the efficacy and effectiveness of hand hygiene in reducing the transmission of infectious diseases, there are gaps in global normative guidance around hand hygiene in community settings. The goal of this review is to systematically retrieve and synthesise available evidence on hand hygiene in community settings across four areas: (1) effective hand hygiene; (2) minimum requirements; (3) behaviour change and (4) government measures. METHODS AND ANALYSIS: This protocol entails a two-phased approach to identify relevant studies for multiple related systematic reviews. Phase 1 involves a broad search to capture all studies on hand hygiene in community settings. Databases, trial registries, expert consultations and hand searches of reference lists will be used to ensure an exhaustive search. A comprehensive, electronic search strategy will be used to identify studies indexed in PubMed, Web of Science, EMBASE, CINAHL, Global Health, Cochrane Library, Global Index Medicus, Scopus, PAIS Index, WHO IRIS, UN Digital Library and World Bank eLibrary published in English from January 1980 to March 2023. The outcome of phase 1 will be a reduced sample of studies from which further screening, specific to research questions across the four key areas can be performed. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Quantitative and qualitative data will be extracted following best practices. We will assess all studies using the Mixed Method Appraisal Tool. All effect measures pertaining to review outcomes will be reported and a narrative synthesis of all studies will be presented including 'data-driven' descriptive themes and 'theory-driven' analytical themes as applicable. ETHICS AND DISSEMINATION: This systematic review is exempt from ethics approval because the work is carried out on published documents. The findings of the reviews will be disseminated in related peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42023429145.

Opportunities to Interrupt Transmission of Enteropathogens of Poultry Origin in Maputo, Mozambique: A Transmission Model Analysis.

BACKGROUND: The burden of diarrheal diseases remains high among children in low-income countries. Enteropathogens are challenging to control because they are transmitted via multiple pathways. Chickens are an important animal protein source, but live chickens and their products are often highly contaminated with enteropathogens. OBJECTIVES: We conducted this study to a) understand the contribution of multiple transmission pathways to the force of infection of Campylobacter spp. and nontyphoidal Salmonella spp., b) quantify the potential impact of reducing each pathway on human infection, and c) quantify hypothesized pathway reduction from the context of Maputo, Mozambique. METHODS: We developed transmission models for Campylobacter and Salmonella that captured person-to-person, water-to-person, food-to-person, soil-to-person, animal-to-person, and all-other-sources-to-person in an urban, low-income setting in Mozambique. We calibrated these models using prevalence data from Maputo, Mozambique and estimates of attributable fraction of transmission pathways for the region. We simulated the prevalence of human infection after reducing transmission through each pathway. RESULTS: Simulation results indicated that if foodborne transmission were reduced by 90%, the prevalence of Campylobacter and Salmonella infection would decline by [52.2%; 95% credible interval (CrI): 39.7, 63.8] and (46.9%; 95% CrI: 39, 55.4), respectively. Interruption of any other pathway did not have a substantial impact. Combined with survey and microbiology data, if contamination of broiler chicken meat at informal markets in Maputo could be reduced by 90%, the total infection of Campylobacter and Salmonella could be reduced by 21% (16-26%) and 12% (10-13%), respectively. DISCUSSION: Our transmission models showed that the foodborne transmission has to be reduced to control enteropathogen infections in our study site, and likely in other similar contexts, but mitigation of this transmission pathway has not received sufficient attention. Our model can serve as a tool to identify effective mitigation opportunities to control zoonotic enteropathogens. https://doi.org/10.1289/EHP12314.

Symptomatic and asymptomatic enteric protozoan parasitic infection and their association with subsequent growth parameters in under five children in South Asia and sub-Saharan Africa.

BACKGROUND: Entamoeba histolytica, Giardia, and Cryptosporidium are common intestinal protozoan parasites that contribute to a high burden of childhood morbidity and mortality. Our study quantified the association between intestinal protozoan parasites and child anthropometric outcomes among children under-5. METHODS: We analyzed data from 7,800 children enrolled in the Global Enteric Multicenter Study (GEMS) across seven study sites that were positive for intestinal protozoan parasites between December 2007 and March 2011. Parasites were assessed using stool immunoassays (ELISA). We applied multiple linear regression to test the association between any or concurrent parasite and child anthropometric outcomes: length/height-for-age (HAZ), weight-for-age (WAZ), and weight-for-length/height (WHZ) z-score after 60 days of enrollment. Models were stratified by diarrheal symptoms, driven by the study design, and adjusted for potential covariates. FINDINGS: During the follow-up at day 60 after enrollment, child anthropometric outcomes, among the asymptomatic children showed, negative associations between Giardia with HAZ [ß: -0.13; 95% CI: -0.17, -0.09; p<0.001] and WAZ [ß -0.07; 95% CI: -0.11, -0.04; p<0.001], but not WHZ [ß: -0.02; 95% CI:-0.06, 0.02; p = 0.36]; Cryptosporidium with WAZ [ß: -0.15; 95% CI: -0.22, -0.09; p<0.001] and WHZ [ß: -0.18; 95%CI: -0.25, -0.12; p<0.001], but not with HAZ [ß: -0.03; 95% CI: -0.09, 0.04; p = 0.40]. For symptomatic children, no associations were found between Giardia and anthropometry; negative associations were found between Cryptosporidium with HAZ [ß: -0.17; 95% CI: -0.23, -0.11; p<0.001], WAZ [ß: -0.25; 95% CI: -0.31, -0.19; p<0.001] and WHZ [ß: -0.23; 95% CI: -0.30, -0.17; p<0.001]. Among the asymptomatic 24-59 months children, Giardia had a negative association with HAZ [ß: -0.09; 95% CI: -0.15, -0.04; p = 0.001]. No significant associations were found between E. histolytica with child growth. CONCLUSIONS: While some studies have found that Giardia is not associated with (or protective against) acute diarrhea, our findings suggest that it is associated with growth shortfall. This observation underscores the need for preventive strategies targeting enteric protozoan parasites among young children, to reduce the burden of childhood malnutrition.

A TOPAS model for lens-based proton radiography.

Objective.Proton Radiography can be used in conjunction with proton therapy for patient positioning, real-time estimates of stopping power, and adaptive therapy in regions with motion. The modeling capability shown here can be used to evaluate lens-based radiography as an instantaneous proton-based radiographic technique. The utilization of user-friendly Monte Carlo program TOPAS enables collaborators and other users to easily conduct medical- and therapy- based simulations of the Los Alamos Neutron Science Center (LANSCE). The resulting transport model is an open-source Monte Carlo package for simulations of proton and heavy ion therapy treatments and concurrent particle imaging.Approach.The four-quadrupole, magnetic lens system of the 800-MeV proton beamline at LANSCE is modeled in TOPAS. Several imaging and contrast objects were modelled to assess transmission at energies from 230-930 MeV and different levels of particle collimation. At different proton energies, the strength of the magnetic field was scaled according toßγ,the inverse product of particle relativistic velocity and particle momentum.Main results.Materials with high atomic number, Z, (gold, gallium, bone-equivalent) generated more contrast than materials with low-Z (water, lung-equivalent, adipose-equivalent). A 5-mrad collimator was beneficial for tissue-to-contrast agent contrast, while a 10-mrad collimator was best to distinguish between different high-Z materials. Assessment with a step-wedge phantom showed water-equivalent path length did not scale directly according to predicted values but could be mapped more accurately with calibration. Poor image quality was observed at low energies (230 MeV), but improved as proton energy increased, with sub-mm resolution at 630 MeV.Significance.Proton radiography becomes viable for shallow bone structures at 330 MeV, and for deeper structures at 630 MeV. Visibility improves with use of high-Z contrast agents. This modality may be particularly viable at carbon therapy centers with accelerators capable of delivering high energy protons and could be performed with carbon therapy.

Critical success factors for high routine immunisation performance: a qualitative analysis of interviews and focus groups from Nepal, Senegal, and Zambia.

OBJECTIVES: Vaccination averts an estimated 2-3 million deaths annually. Although vaccine coverage improvements across Africa and South Asia have remained below global targets, several countries have outperformed their peers with significant increases in coverage. The objective of this study was to examine these countries' vaccination programmes and to identify and describe critical success factors that may have supported these improvements. DESIGN: Multiple case study design using qualitative research methods. SETTING: Three countries with high routine immunisation rates: Nepal, Senegal, and Zambia. PARTICIPANTS: We conducted 207 key informant interviews and 71 focus group discussions with a total of 678 participants. Participants were recruited from all levels, including government officials, health facility staff, frontline workers, community health workers, and parents. Participants were recruited from both urban and rural districts in Nepal, Senegal, and Zambia. RESULTS: Our data revealed that the critical success factors for vaccination programmes relied on the cultural, historical, and statutory context in which the interventions were delivered. In Nepal, Senegal, and Zambia, high immunisation coverage was driven by (1) strong governance structures and healthy policy environments; (2) adjacent successes in health system strengthening; (3) government-led community engagement initiatives, and (4) adaptation considering contextual factors at all levels of the health system. CONCLUSIONS: Throughout this project, our analysis returned to the importance of defining and understanding the context, governance, financing, and health systems within a country, rather than focusing on any one intervention. This paper augments findings from existing literature by highlighting how contextual factors impact implementation decisions that have led to improvements in childhood vaccine delivery. Findings from this research may help identify transferable lessons and support actionable recommendations to improve national immunisation coverage in other settings.

Factors associated with vaccine coverage improvements in Senegal between 2005 and 2019: a quantitative retrospective analysis.

OBJECTIVE: Senegal has demonstrated catalytic improvements in national coverage rates for early childhood vaccination, despite lower development assistance for childhood vaccines in Senegal compared with other low-income and lower-middle income countries. Understanding factors associated with historical changes in childhood vaccine coverage in Senegal, as well as heterogeneities across its 14 regions, can highlight effective practices that might be adapted to improve vaccine coverage elsewhere. DESIGN: Childhood vaccination coverage rates, demographic information and health system characteristics were identified from Senegal's Demographic and Health Surveys (DHS) and Senegal national reports for years 2005-2019. Multivariate logistic and linear regression analyses were performed to determine statistical associations of demographic and health system characteristics with respect to childhood vaccination coverage rates. SETTING: The 14 administrative regions of Senegal were chosen for analysis. PARTICIPANTS: DHS women's survey respondents with living children aged 12-23 months for survey years 2005-2019. OUTCOME MEASURES: Immunisation with the third dose of the diphtheria-tetanus-pertussis vaccine (DTP3), widely used as a proxy for estimating immunisation coverage levels and the retention of children in the vaccine programme. RESULTS: Factors associated with childhood vaccination coverage include urban residence (ß=0.61, p=0.0157), female literacy (ß=1.11, p=0.0007), skilled prenatal care (ß=1.80, p<0.0001) and self-reported ease of access to care when sick, considering travel distance to a healthcare facility (ß=-0.70, p=0.0009) and concerns over travelling alone (ß=-1.08, p<0.0001). Higher coverage with less variability over time was reported in urban areas near the capital and the coast (p=0.076), with increased coverage in recent years in more rural and landlocked areas. CONCLUSIONS: Childhood vaccination was more likely among children whose mothers had higher literacy, received skilled prenatal care and had perceived ease of access to care when sick. Overall, vaccination coverage is high in Senegal and disparities in coverage between regions have decreased significantly in recent years.

Listeria monocytogenes requires DHNA-dependent intracellular redox homeostasis facilitated by Ndh2 for survival and virulence.

Listeria monocytogenes is a remarkably well-adapted facultative intracellular pathogen that can thrive in a wide range of ecological niches. L. monocytogenes maximizes its ability to generate energy from diverse carbon sources using a respiro-fermentative metabolism that can function under both aerobic and anaerobic conditions. Cellular respiration maintains redox homeostasis by regenerating NAD+ while also generating a proton motive force. The end products of the menaquinone (MK) biosynthesis pathway are essential to drive both aerobic and anaerobic cellular respirations. We previously demonstrated that intermediates in the MK biosynthesis pathway, notably 1,4-dihydroxy-2-naphthoate (DHNA), are required for the survival and virulence of L. monocytogenes independent of their role in respiration. Furthermore, we found that restoration of NAD+/NADH ratio through expression of water-forming NADH oxidase could rescue phenotypes associated with DHNA deficiency. Here, we extend these findings to demonstrate that endogenous production or direct supplementation of DHNA restored both the cellular redox homeostasis and metabolic output of fermentation in L. monocytogenes. Furthermore, exogenous supplementation of DHNA rescues the in vitro growth and ex vivo virulence of L. monocytogenes DHNA-deficient mutants. Finally, we demonstrate that exogenous DHNA restores redox balance in L. monocytogenes specifically through the recently annotated NADH dehydrogenase Ndh2, independent of its role in the extracellular electron transport pathway. These data suggest that the production of DHNA may represent an additional layer of metabolic adaptability by L. monocytogenes to drive energy metabolism in the absence of respiration-favorable conditions.

Drivers of early childhood vaccination success in Nepal, Senegal, and Zambia: a multiple case study analysis using the Consolidated Framework for Implementation Research.

INTRODUCTION: The fundamental components of a vaccine delivery system are well-documented, but robust evidence is needed on how the related processes and implementation strategies - including the facilitators and barriers - contribute to improvements in childhood vaccination coverage. The purpose of this study was to identify critical facilitators and barriers to the implementation of common interventions across three countries that have dramatically increased coverage of early childhood vaccination over the past 20 years, and to qualify common or divergent themes in their success. METHODS: We conducted 278 key informant interviews and focus group discussions with public health leaders at the regional, district, and local levels and community members in Nepal, Senegal, and Zambia to identify intervention activities and the facilitators and barriers to implementation. We used thematic analysis grounded in the Consolidated Framework for Implementation Research (CFIR) constructs of inner and outer settings to identify immunization program key facilitators and barriers. RESULTS: We found that the common facilitators to program implementation across the countries were the CFIR inner setting constructs of (1) networks and communications, (2) goals and feedback, (3) relative priority, and (4) readiness for implementation and outer setting constructs of (5) cosmopolitanism and (6) external policies and mandates. The common barriers were incentives and rewards, available resources, access to knowledge and information, and patients' needs and resources. Critical to the success of these national immunization programs were prioritization and codification of health as a human right, clear chain of command and shared ownership of immunization, communication of program goals and feedback, offering of incentives at multiple levels, training of staff central to vaccination education, the provision of resources to support the program, key partnerships and guidance on implementation and adoption of vaccination policies. CONCLUSION: Adequate organizational commitment, resources, communication, training, and partnerships were the most critical facilitators for these countries to improve childhood vaccination.

Functional unknomics: Systematic screening of conserved genes of unknown function.

The human genome encodes approximately 20,000 proteins, many still uncharacterised. It has become clear that scientific research tends to focus on well-studied proteins, leading to a concern that poorly understood genes are unjustifiably neglected. To address this, we have developed a publicly available and customisable "Unknome database" that ranks proteins based on how little is known about them. We applied RNA interference (RNAi) in Drosophila to 260 unknown genes that are conserved between flies and humans. Knockdown of some genes resulted in loss of viability, and functional screening of the rest revealed hits for fertility, development, locomotion, protein quality control, and resilience to stress. CRISPR/Cas9 gene disruption validated a component of Notch signalling and 2 genes contributing to male fertility. Our work illustrates the importance of poorly understood genes, provides a resource to accelerate future research, and highlights a need to support database curation to ensure that misannotation does not erode our awareness of our own ignorance.

Critical interventions for demand generation in Zambia, Nepal, and Senegal with regards to the 5C psychological antecedents of vaccination.

Introduction: Childhood vaccination is an effective intervention for lowering the burden of infectious disease. Vaccine coverage has increased globally, but vaccine hesitancy and refusal threatens these gains. The 5C psychological antecedents of vaccination ("5C") provides a validated measure of "vaccine hesitancy or confidence" to assess individual thoughts and behaviors behind vaccination. We investigated population-level factors that contributed to high and sustained vaccination coverage in Zambia, Nepal, and Senegal, and alignment with the 5Cs. Methods: Data was collected in the larger Exemplars in Vaccine Delivery study, from focus group discussions (FDGs) and key informant interviews (KIIs) at the national, regional, district, health facility, and community levels of health systems in Zambia, Nepal, and Senegal. We assessed the demand environment, as relayed by participants, and identified interventions reported as successful for demand generation, then retroactively aligned the interventions with the 5C constructs. Results: Demand was positively correlated with high confidence and collective responsibility. Psychological constraints sometimes impacted demand. Physical constraints created barriers in some communities, particularly difficult to access (i.e., mountainous). Occasionally, physical constraints did not affect vaccination behavior - parents believed the benefits of vaccination worth pursuing. Factors negatively correlated with demand and intent, complacency and calculation, had limited impact. Critical interventions were: targeted and tailored health education activities (media partnerships, school outreach); community engagement; community ownership; and community involvement (community health workers, leaders, religious figures). Conclusion: We found similar interventions used to generate demand, with strategies aligned with the 5C constructs. Categorizing interventions by drivers of demand may help strategic planning and the division of resources; decision makers may choose to implement our suggested interventions. Assessing the 5Cs allows decision-makers to operationalize demand generation into concrete interventions and policies, and determine the individual impact of these constructs on the population and focus efforts on interventions tailored to a specific need.

Burden of disease attributable to unsafe drinking water, sanitation, and hygiene in domestic settings: a global analysis for selected adverse health outcomes.

BACKGROUND: Assessments of disease burden are important to inform national, regional, and global strategies and to guide investment. We aimed to estimate the drinking water, sanitation, and hygiene (WASH)-attributable burden of disease for diarrhoea, acute respiratory infections, undernutrition, and soil-transmitted helminthiasis, using the WASH service levels used to monitor the UN Sustainable Development Goals (SDGs) as counterfactual minimum risk-exposure levels. METHODS: We assessed the WASH-attributable disease burden of the four health outcomes overall and disaggregated by region, age, and sex for the year 2019. We calculated WASH-attributable fractions of diarrhoea and acute respiratory infections by country using modelled WASH exposures and exposure-response relationships from two updated meta-analyses. We used the WHO and UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene public database to estimate population exposure to different WASH service levels. WASH-attributable undernutrition was estimated by combining the population attributable fractions (PAF) of diarrhoea caused by unsafe WASH and the PAF of undernutrition caused by diarrhoea. Soil-transmitted helminthiasis was fully attributed to unsafe WASH. FINDINGS: We estimate that 1·4 (95% CI 1·3-1·5) million deaths and 74 (68-80) million disability-adjusted life-years (DALYs) could have been prevented by safe WASH in 2019 across the four designated outcomes, representing 2·5% of global deaths and 2·9% of global DALYs from all causes. The proportion of diarrhoea that is attributable to unsafe WASH is 0·69 (0·65-0·72), 0·14 (0·13-0·17) for acute respiratory infections, and 0·10 (0·09-0·10) for undernutrition, and we assume that the entire disease burden from soil-transmitted helminthiasis was attributable to unsafe WASH. INTERPRETATION: WASH-attributable burden of disease estimates based on the levels of service established under the SDG framework show that progress towards the internationally agreed goal of safely managed WASH services for all would yield major public-health returns. FUNDING: WHO and Foreign, Commonwealth & Development Office.

Quantifying Factors Associated with Personal Hygiene as Measured by the qPHAT Methodology: Andilaye Trial, Ethiopia.

Many water, sanitation, and hygiene (WASH) interventions target improvements in personal hygiene behaviors. Yet measuring personal hygiene behaviors is a challenge due to a lack of reliable, valid, objective, and simple-to-use approaches. The purpose of this study was to examine differences between two types of hygiene outcome measures and their ability to detect relationships between WASH-related behavioral factors and behaviors. We compared hygiene outcomes generated by the Quantitative Personal Hygiene Assessment Tool (qPHAT), which yields objective measures of cleanliness on an 11-point scale, and those generated by conventional, dichotomous indicators of cleanliness. We used cross-sectional data on hygiene outcomes related to facial and hand cleanliness collected during the Andilaye Trial, an impact evaluation of a community-based WASH intervention implemented in Amhara, Ethiopia. We fit multivariable models to examine associations between measures of children's facial and hand cleanliness, via both qPHAT and dichotomous indicators, and 1) household WASH conditions, 2) psychosocial factors, and 3) reported personal hygiene practices. The qPHAT-generated outcomes were able to detect relationships between intermediate behavioral factors and hygiene outcomes that dichotomous indicators were not, including associations with water insecurity and various psychosocial factors. qPHAT-generated outcomes were negatively associated with reported face washing practices, suggesting a bias in reported behaviors. Our study highlights the limitations of reported practices and dichotomous hygiene indicators and indicates that using more quantitative hygiene outcome measures, such as those generated by qPHAT, may reveal important intermediate factors that influence hygiene behavior and support improved monitoring and evaluation of interventions.