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We report a new measurement of the beam-spin asymmetry, Σ, for the γ→n→K+Σ− reaction using quasi-free neutrons in a liquid-deuterium target. The new dataset includes data at previously unmeasured photon energy and angular ranges, thereby providing new constraints on partial wave analyses used to extract properties of the excited nucleon states. The experimental data were obtained using the CEBAF Large Acceptance Spectrometer (CLAS), housed in Hall B of the Thomas Jefferson National Accelerator Facility (JLab). The CLAS detector measured reaction products from a liquid-deuterium target produced by an energy-tagged, linearly polarised photon beam with energies in the range 1.1 to 2.3 GeV. Predictions from an isobar model indicate strong sensitivity to N(1720)3/2+, Δ(1900)1/2−, and N(1895)1/2−, which corroborates results from a recent combined analysis of all KΣ channels. When our data are incorporated in the fits of partial-wave analyses, one observes significant changes in γ-n couplings of resonances which have small branching ratios to the πN channel.

Approximately 13% of the human genome at certain motifs have the potential to form noncanonical (non-B) DNA structures (e.g., G-quadruplexes, cruciforms, and Z-DNA), which regulate many cellular processes but also affect the activity of polymerases and helicases. Because sequencing technologies use these enzymes, they might possess increased errors at non-B structures. To evaluate this, we analyzed error rates, read depth, and base quality of Illumina, Pacific Biosciences (PacBio) HiFi, and Oxford Nanopore Technologies (ONT) sequencing at non-B motifs. All technologies showed altered sequencing success for most non-B motif types, although this could be owing to several factors, including structure formation, biased GC content, and the presence of homopolymers. Single-nucleotide mismatch errors had low biases in HiFi and ONT for all non-B motif types but were increased for G-quadruplexes and Z-DNA in all three technologies. Deletion errors were increased for all non-B types but Z-DNA in Illumina and HiFi, as well as only for G-quadruplexes in ONT. Insertion errors for non-B motifs were highly, moderately, and slightly elevated in Illumina, HiFi, and ONT, respectively. Additionally, we developed a probabilistic approach to determine the number of false positives at non-B motifs depending on sample size and variant frequency, and applied it to publicly available data sets (1000 Genomes, Simons Genome Diversity Project, and gnomAD). We conclude that elevated sequencing errors at non-B DNA motifs should be considered in low-read-depth studies (single-cell, ancient DNA, and pooled-sample population sequencing) and in scoring rare variants. Combining technologies should maximize sequencing accuracy in future studies of non-B DNA.

Introduction. Low-cost, accurate high-risk HPV tests are needed for cervical cancer screening in limited-resource settings. Objective. To compare the performance of the low-cost Hybribio-H13 test with the Hybrid Capture® 2 to detect cervical intraepithelial neoplasia grade 2 or 3 (CIN2 and CIN3). Materials and methods. Archived baseline samples tested by the Hybrid Capture® 2 from women of the ASCUS-COL trial, aged 20 to 69 years, with biopsy-colposcopy directed diagnosis of CIN2+ (n = 143), CIN3+ (n = 51), and < CIN2 (n = 632) were blindly tested by the Hybribio-H13 test. Results. The relative sensitivity of the Hybribio-H13 test versus the Hybrid Capture® 2 for detecting CIN2+ was 0.89 (90% CI = 0,80-0,98; NIT = 0,66), and for CIN3+ was 0,92 (90% CI = 0,85-0,98; NIT = 0,35). Relative specificity was 1.19 (90% CI = 1.05-1.33; NIT

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

PurposeDiphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).MethodsMolecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.ResultsDPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.ConclusionWe provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.

Introduction Water insecurity–the inability to access and benefit from affordable, reliable and safe water for basic needs–is a considerable global health threat. With the urgent need to target interventions to the most vulnerable, accurate and meaningful measurement is a priority. Households use diverse strategies to cope with water insecurity; however, these have not been systematically characterised nor measured. The Food Insecurity Coping Strategies Index has been insightful for targeting nutrition interventions to the most vulnerable. As a first step towards creating an analogous scale for water, this study characterises the largest empirical data set on water insecurity coping strategies and proposes guidance on measuring it using a novel toolkit.Methods Open-ended responses on water insecurity coping (n=2301) were collected across 11 sites in 10 low- and middle-income countries in the Household Water InSecurity Experiences (HWISE) Scale validation study. Responses were characterised and compared with behaviours identified in the literature to construct an instrument to systematically assess coping.Results We identified 19 distinct strategies that households used when experiencing water insecurity. These findings, paired with prior literature, were used to develop a Water Insecurity Coping Strategies Assessment Toolkit with guidance on its piloting to assess coping prevalence, frequency and severity.Conclusions The widespread occurrence of water insecurity coping strategies underscores the importance of understanding their prevalence and severity. The Water Insecurity Coping Strategies Assessment Toolkit offers a comprehensive approach to evaluate these strategies and inform the design and monitoring of interventions targeting those most vulnerable to water insecurity.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

BackgroundHandpumps are used by millions of people as their main source of water. Although handpumps represent only a basic form of water provision, there have been continuous efforts to improve the performance of these systems as they are likely to remain in use for many years to come. The introduction of a professional maintenance service in southern Kenya has shown an order of magnitude improvement in operational performance over community-based management, with 90% of handpump faults repaired within 3 days of being reported. One driver behind these efforts is the assumption that a more reliable water supply will lead to a reduction in water-related disease. However, it is not clear if operational improvements lead to health gains. Despite limited empirical evidence, some modeling studies suggest that even short periods of drinking contaminated water can lead to disproportionate negative health impacts. ObjectiveThe aim of this study was to assess whether the improvements in operational performance from the rapid professional maintenance of rural handpumps lead to improved household health outcomes. MethodsFrom a sample of households using handpumps as their primary water source in Kwale County, Kenya, we measured the 2-week prevalence of World Health Organization–defined diarrhea in children, reported by the adult respondent for each household. We compared the rates before and after a period during which the households’ handpumps were being professionally maintained. We then conducted a cross-sectional analysis, fitting logistic regression models with reported diarrhea as the dependent variable and speed of repair as the independent exposure of interest, adjusting for household socioeconomic characteristics; dwelling construction; and Water, Sanitation, and Hygiene (WASH)-related factors. We fitted an additional model to examine select interactions between covariates. ResultsReported diarrhea in children was lower in households whose pumps had been repaired within 24 hours (adjusted odds ratio 0.35, 95% CI 0.24-0.51). This effect was robust to the inclusion of multiple categories of covariates. No reduction was seen in households whose pump repairs took more than 24 hours. Analysis of interaction terms showed that certain interventions associated with improved WASH outcomes were only associated with reductions in diarrhea in conjunction with socioeconomic improvements. ConclusionsOnly pump repairs consistently made within 24 hours of failure led to a reduction in diarrhea in the children of families using handpumps. While the efficacy of reduction in diarrhea is substantial, the operational challenges of guaranteeing same-day repairs limits the effectiveness of even best-in-class pump maintenance. Maintenance regimes that cannot bring handpump downtimes close to zero will struggle to generate health benefits. Other factors that reduce diarrhea prevalence have limited effect in isolation, suggesting that WASH interventions will be more effective when undertaken as part of more holistic poverty-reduction efforts.

RESUMO Objetivo Determinar a consistência interna e confiabilidade do “Questionário de Impacto Emocional da Vertigem-CIEV” e validar o instrumento em relação ao Dizziness Handicap Inventory (DHI), em uma amostra de pacientes com distúrbio do equilíbrio corporal. Método Participaram 38 sujeitos, idades entre 23 e 85 anos, ambos os sexos, com queixas relacionadas à tontura, desequilíbrios e/ou quedas, atendidos em um ambulatório de Otoneurologia do Hospital Universitário. Foram excluídos sujeitos com queixas auditivas e/ou zumbido sem tontura associada, comorbidades psiquiátricas prévias e/ou comprometimento cognitivo que impedisse a compreensão dos questionários. Foi realizada anamnese, levantamento de prontuário para caracterização da amostra e aplicados os questionários de autopercepção, DHI e CIEV. O alfa de Cronbach verificou a consistência interna do CIEV e a confiabilidade e validade do CIEV em relação ao DHI foram calculadas pelo Índice de Correlação intraclasse (ICC) e teste de Correlação de Pearson, respectivamente. Resultados Houve correlação estatisticamente significante entre os escores obtidos, tanto à análise de confiabilidade quanto de validação (p

Class switch recombination (CSR) is a process by which B cells switch their immunoglobulin isotype and develop pathogen-eliminating antibodies. Here, the authors show that a protein kinase DYRK1A is required for protection from viral infection through the regulation of CSR and effective clonal expansion.

Objective: To analyze, by means of a systematic review and meta-analysis, the proportion of patients with Meniere’s disease who have altered caloric test and vHIT, as well as to determine the prevalence of altered caloric test and normal vHIT dissociation in the diagnosis of Meniere’s disease. Methods: The literature search had no restriction regarding the period of publication on the following indexed data platforms: PubMed, PubMed PMC, BVS-Bireme, Web of Science, Embase and Cochrane Library. Articles that evaluated patients with Meniere’s disease who underwent caloric test and vHIT were included. Two researchers independently conducted the analysis of the articles, promoting the selection and capture of data, following the recommendations of the PRISMA method, and complying with the criteria for articles inclusion and exclusion defined in the research protocol. In case of disagreement during the selection process, a third researcher was included for analysis. Results: From a total of 427 initial studies, the researchers selected 12 articles, published between 2014 and 2021, with a total of 708 patients evaluated, with a mean age of 52.72 years old. The prevalence of patients with Meniere’s disease with altered caloric reflex test was 64% (95% CI 57%‒71%), while the prevalence of altered vHIT was only 28% (95% CI 16%–40%). The prevalence of the altered caloric test + normal vHIT dissociation was 47% (95% CI 37%–57%). Conclusion: The video head impulse test and the caloric test are valuable tools for vestibular assessment. The dissociation of findings between these two tests in patients with Meniere’s disease was more prevalent in this meta-analysis and may be a result of the tonotopy of specialized hair cells in the ampullary crest. The prevalence of altered caloric test was 64% and anormal vHIT was 28%. The dissociation caloric asymmetry and normal vHIT was observed in 47% of the patients. Level of evidence: 1.

The measurement of household-level and individual-level water insecurity has accelerated over the past 5 years through innovation and dissemination of new survey-based experiential psychometric scales modelled after food insecurity scales. These measures offer needed insight into the relative frequency of various dimensions of water problems experienced by households or individuals. But they currently tell us nothing about the severity of these experiences, mitigating behaviours (ie, adaptation) or the effectiveness of water-related behaviours (ie, resilience). Given the magnitude of the global challenge to provide water security for all, we propose a low-cost, theoretically grounded modification to common water insecurity metrics in order to capture information about severity, adaptation and resilience. We also discuss ongoing challenges in cost-effective measurement related to multidimensionality, water affordability and perception of water quality for maximising the impact and sustainability of water supply interventions. The next generation of water insecurity metrics promises better monitoring and evaluation tools—particularly in the context of rapid global environmental change—once scale reliability across diverse contexts is better characterised.

Among women aged 27–45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27–45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27–45 years versus women and men aged 16–26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27–45 years. Efficacy of qHPV vaccine in men aged 27–45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27–45 years versus 16–26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27–45 years of age, and vaccine efficacy was inferred in men 27–45 years of age based on the serological results.

Summary: Blocking the interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with its angiotensin-converting enzyme 2 (ACE2) receptor was proved to be an effective therapeutic option. Various protein binders as well as monoclonal antibodies that effectively target the receptor-binding domain (RBD) of SARS-CoV-2 to prevent interaction with ACE2 were developed. The emergence of SARS-CoV-2 variants that accumulate alterations in the RBD can severely affect the efficacy of such immunotherapeutic agents, as is indeed the case with Omicron that resists many of the previously isolated monoclonal antibodies. Here, we evaluate an ACE2-based immunoadhesin that we have developed early in the pandemic against some of the recent variants of concern (VoCs), including the Delta and the Omicron variants. We show that our ACE2-immunoadhesin remains effective in neutralizing these variants, suggesting that immunoadhesin-based immunotherapy is less prone to escape by the virus and has a potential to remain effective against future VoCs.

Cervical cancer is the fourth most common cancer worldwide, with over 600,000 new cases annually and approximately 350,000 cancer-related deaths per year. The disease burden is disproportionately distributed, with cancer-related mortality ranging from 5.2 deaths per 100,000 individuals in highly-developed countries, to 12.4 deaths per 100,000 in less-developed countries. This article is a review of the current screening recommendations and potential future recommendations.

We estimate the effect of large dams on malaria incidence in India between 1975 and 1995. We combine instrumental variables approach with a panel model with unobserved common factors allowing us to fully capture the endogeneity of dam location and unobserved time-varying heterogeneity. Dams result in increased malaria incidence in districts where dams are located and in downstream areas. We find that the construction of a large dam increases a district’s annual malaria incidence by about 0.9 to 1.4 percent, and by about 1 to 1.5 percent in downstream districts. We also find that this malaria-increasing effect of dams persists over time. Our results imply that the construction of dams in malaria-sensitive areas should be coupled with direct interventions, such as the wide deployment of insecticide-treated nets or the roll-out of future vaccines. Furthermore, we examine the contribution of agricultural development to this malaria-increasing effect of dams. We find that dam construction benefits agriculture in the vicinity of dams, as well as in downstream areas. These positive effects are driven by increased irrigation and cultivation in the vicinity of dams, while they are driven by changes in cropping patterns in downstream areas, where the cultivation of high-yielding variety crops increases. Finally, a back-of-the-envelope calculation suggests that the agricultural production gains from dam construction dominate the economic losses resulting from increased malaria.

Introduction Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16INK4a as a predictor for CIN2 regression is lacking.Methods and analysis We will conduct a historical cohort study including 500 women aged 23–40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000–2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome.Ethics and dissemination The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings.Trial registration number NCT05049252.

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Visible light communications emerges as a promising wireless communication technology that has been found suitable for numerous indoor and outdoor applications. In this article, a new in-vehicle VLC system is designed, implemented, and experimentally evaluated. The purpose of this new system is to provide car passengers with optical wireless communications. The proposed system consists of a VLC emitter integrated into the vehicle’s ambient lighting system and a mobile VLC receiver. Unlike any previous works, this article proposes a VLC emitter in which the light from a 3 W LED is distributed on a 2 square meter surface using 500 optical fibers whose main purpose is a decorative one. The proposed prototype has been implemented on a car and evaluated in relevant working conditions. The experimental evaluation of the proposed system has demonstrated the viability of the proposed concept and showed a data rate of 250 kb/s while providing a BER lower than 10−7. As far as we know, the proposed concept is totally new in the VLC literature, opening a new area of utilization for VLC technology: using VLC with optical fiber distributed light.

Background: Women living in disadvantaged neighborhoods present with increased prevalence rates of triple-negative breast cancer (TNBC). This study takes a spatiotemporal epidemiological approach to understand the impact of socioenvironmental contextual factors on TNBC prevalence rates. Methods: We analyzed 935 TNBC cases from a major cancer center registry, between 2005 and 2017, to explore spatial and space-time clusters of TNBC prevalence rates at the census tract and neighborhood scales. Spatial regression analysis was performed to examine relationships between nine socioenvironmental factors and TNBC prevalence rates at both ecological scales. Results: We observed spatial clustering of high TNBC prevalence rates along a north-south corridor of Miami-Dade County along Interstate 95, a region containing several majority non-Hispanic Black neighborhoods. Among the ecologic measures, the percent of a region designated as a brownfield was associated with TNBC prevalence rates at the tract-level (β = 4.27; SE = 1.08; P < 0.001) and neighborhood-level (β = 8.61; SE = 2.20; P < 0.001). Conclusions: Our spatiotemporal analysis identified robust patterns of hot spots of TNBC prevalence rates in a corridor of several disadvantaged neighborhoods in the northern half of the county. These patterns of TNBC align with the literature regarding at-risk groups and neighborhood-level effects on TNBC; however, remain to be validated in a population-based sample. [ABSTRACT FROM AUTHOR]

Pediatric pedestrian injuries (PPI) are a major public health concern. This study utilized geospatial analysis to characterize the risk and injury severity of PPI. A retrospective chart review of PPI patients (age < 18) from a level 1 trauma center was performed (2013–2020). A geographic information system geocoded injury location to home and other public landmarks. Incidents were aggregated to zip codes and the Local Indicators of Spatial Association statistic tested for spatial clustering of injury rates per 10,000 children. Predictors for increased injury severity were assessed by logistic regression. PPI encompassed 6% (n = 188) of pediatric traumas. Most patients were black (54%), male (58%), >13 years (56%), and with Medicaid insurance (68%). Nine zip codes comprised a statistically significant cluster of PPI. Nearly half (40%) occurred within a quarter mile of home; 7% occurred at home. Most (65%) PPI occurred within 1 mile of a school, and 45% occurred within a quarter mile of a park. Nearly all (99%) PPI occurred within a quarter mile of a major intersection and/or roadway. Using admission to ICU as a marker for injury severity, farther distance from home (OR 1.060, 95% CI 1.001–1.121, p = 0.045) and age <13 years (3.662, 95% CI 1.854–7.231, p < 0.001) were independent predictors of injury severity. There are significant sociodemographic disparities in PPI. Most injuries occur near patients' homes and other public landmarks. Multidisciplinary injury prevention collaboration can help inform policymakers, direct local safety programs, and provide a model for PPI prevention at the national level. Level IV. [Display omitted] [ABSTRACT FROM AUTHOR]