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Rabies is a fatal zoonotic disease that requires fast, accurate diagnosis to prevent disease in an exposed individual. The current gold standard for post-mortem diagnosis of human and animal rabies is the direct fluorescent antibody (DFA) test. While the DFA test has proven sensitive and reliable, it requires high quality antibody conjugates, a skilled technician, a fluorescence microscope and diagnostic specimen of sufficient quality. The LN34 pan-lyssavirus real-time RT-PCR assay represents a strong candidate for rabies post-mortem diagnostics due to its ability to detect RNA across the diverse Lyssavirus genus, its high sensitivity, its potential for use with deteriorated tissues, and its simple, easy to implement design. Here, we present data from a multi-site evaluation of the LN34 assay in 14 laboratories. A total of 2,978 samples (1,049 DFA positive) from Africa, the Americas, Asia, Europe, and the Middle East were tested. The LN34 assay exhibited low variability in repeatability and reproducibility studies and was capable of detecting viral RNA in fresh, frozen, archived, deteriorated and formalin-fixed brain tissue. The LN34 assay displayed high diagnostic specificity (99.68%) and sensitivity (99.90%) when compared to the DFA test, and no DFA positive samples were negative by the LN34 assay. The LN34 assay produced definitive findings for 80 samples that were inconclusive or untestable by DFA; 29 were positive. Five samples were inconclusive by the LN34 assay, and only one sample was inconclusive by both tests. Furthermore, use of the LN34 assay led to the identification of one false negative and 11 false positive DFA results. Together, these results demonstrate the reliability and robustness of the LN34 assay and support a role for the LN34 assay in improving rabies diagnostics and surveillance.

Borehole gravity sensing can be used in a number of applications to measure features around a well, including rock-type change mapping and determination of reservoir porosity. Quantum technology gravity sensors, based on atom interferometry, have the ability to offer increased survey speeds and reduced need for calibration. While surface sensors have been demonstrated in real world environments, significant improvements in robustness and reductions to radial size, weight, and power consumption are required for such devices to be deployed in boreholes. To realise the first step towards the deployment of cold atom-based sensors down boreholes, we demonstrate a borehole-deployable magneto-optical trap, the core package of many cold atom-based systems. The enclosure containing the magneto-optical trap itself had an outer radius of (60 ± 0.1) mm at its widest point and a length of (890 ± 5) mm. This system was used to generate atom clouds at 1 m intervals in a 14 cm wide, 50 m deep borehole, to simulate how in-borehole gravity surveys are performed. During the survey, the system generated, on average, clouds of (3.0 ± 0.1) × 105 87Rb atoms with the standard deviation in atom number across the survey observed to be as low as 8.9 × 104., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Vovrosh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Preterm birth (<37 weeks' gestation) is a risk factor for poor educational outcomes. A dose-response effect of earlier gestational age at birth on poor primary school attainment has been observed, but evidence for secondary school attainment is limited and focused predominantly on the very preterm (<32 weeks) population. We examined the association between gestational age at birth and academic attainment at the end of primary and secondary schooling in England. Data for children born in England from 2000-2001 were drawn from the population-based UK Millennium Cohort Study. Information about the child's birth, sociodemographic factors and health was collected from parents. Attainment on national tests at the end of primary (age 11) and secondary school (age 16) was derived from linked education records. Data on attainment in primary school was available for 6,950 pupils and that of secondary school was available for 7,131 pupils. Adjusted relative risks (aRRs) for these outcomes were estimated at each stage separately using modified Poisson regression. At the end of primary school, 17.7% of children had not achieved the expected level in both English and Mathematics and this proportion increased with increasing prematurity. Compared to full term (39-41 weeks) children, the strongest associations were among children born moderately (32-33 weeks; aRR = 2.13 (95% CI 1.44-3.13)) and very preterm (aRR = 2.06 (95% CI 1.46-2.92)). Children born late preterm (34-36 weeks) and early term (37-38 weeks) were also at higher risk with aRR = 1.18 (95% CI 0.94-1.49) and aRR = 1.21 (95% CI 1.05-1.38), respectively. At the end of secondary school, 45.2% had not passed at least five General Certificate of Secondary Education examinations including English and Mathematics. Following adjustment, only children born very preterm were at significantly higher risk (aRR = 1.26 (95% CI 1.03-1.54)). All children born before full term are at risk of poorer attainment during primary school compared with term-born children, but only children born very preterm remain at risk at the end of secondary schooling. Children born very preterm may require additional educational support throughout compulsory schooling., Competing Interests: The authors have declared that no competing interests exist.

Background: Breastfeeding duration is associated with improved cognitive development in children, but it is unclear whether this is a causal relationship or due to confounding. This study evaluates whether the observed association is explained by socioeconomic position (SEP) and maternal cognitive ability., Methods: Data from 7,855 singletons born in 2000-2002 and followed up to age 14 years within the UK Millennium Cohort Study were analysed. Mothers reported breastfeeding duration, and children's cognitive abilities were assessed at 5, 7, 11, and 14 years using validated measures. Standardised verbal (age 5 to 14) and spatial (age 5 to 11) cognitive scores were compared across breastfeeding duration groups using multivariable linear mixed-effects models (repeated outcome measures)., Results: At all ages, longer breastfeeding durations were associated with higher cognitive scores after accounting for the child's own characteristics. Adjustment for SEP approximately halved the effect sizes. Further adjustment for maternal cognitive scores removed the remaining associations at age 5, but not at ages 7, 11 and 14 (e.g.: verbal scores, age 14; breastfed ≥12 months vs never breastfed: 0.26 SD; 95%CI: 0.18, 0.34)., Conclusion: The associations between breastfeeding duration and cognitive scores persist after adjusting for SEP and maternal cognitive ability, however the effect was modest., Competing Interests: The authors have declared that no competing interests exist.

Background: Children born preterm (<37 completed weeks' gestation) have a higher risk of infection-related morbidity than those born at term. However, few large, population-based studies have investigated the risk of infection in childhood across the full spectrum of gestational age. The objectives of this study were to explore the association between gestational age at birth and infection-related hospital admissions up to the age of 10 years, how infection-related hospital admission rates change throughout childhood, and whether being born small for gestational age (SGA) modifies this relationship., Methods and Findings: Using a population-based, record-linkage cohort study design, birth registrations, birth notifications and hospital admissions were linked using a deterministic algorithm. The study population included all live, singleton births occurring in NHS hospitals in England from January 2005 to December 2006 (n = 1,018,136). The primary outcome was all infection-related inpatient hospital admissions from birth to 10 years of age, death or study end (March 2015). The secondary outcome was the type of infection-related hospital admission, grouped into broad categories. Generalised estimating equations were used to estimate adjusted rate ratios (aRRs) with 95% confidence intervals (CIs) for each gestational age category (<28, 28-29, 30-31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 42 weeks) and the models were repeated by age at admission (<1, 1-2, 3-4, 5-6, and 7-10 years). An interaction term was included in the model to test whether SGA status modified the relationship between gestational age and infection-related hospital admissions. Gestational age was strongly associated with rates of infection-related hospital admissions throughout childhood. Whilst the relationship attenuated over time, at 7-10 years of age those born before 40 weeks gestation were still significantly higher in comparison to those born at 40 weeks. Children born <28 weeks had an aRR of 6.53 (5.91-7.22) during infancy, declining to 3.16 (2.50-3.99) at ages 7-10 years, in comparison to those born at 40 weeks; whilst in children born at 38 weeks, the aRRs were 1·24 (1.21-1.27) and 1·18 (1.13-1.23), during infancy and aged 7-10 years, respectively. SGA status modified the effect of gestational age (interaction P<0.0001), with the highest rate among the children born at <28 weeks and SGA. Finally, study findings indicated that the associations with gestational age varied by subgroup of infection. Whilst upper respiratory tract infections were the most common type of infection experienced by children in this cohort, lower respiratory tract infections (LRTIs) (<28 weeks, aRR = 10.61(9.55-11.79)) and invasive bacterial infections (<28 weeks, aRR = 6.02 (4.56-7.95)) were the most strongly associated with gestational age at birth. Of LRTIs experienced, bronchiolitis (<28 weeks, aRR = 11.86 (10.20-13.80)), and pneumonia (<28 weeks, aRR = 9.49 (7.95-11.32)) were the most common causes., Conclusions: Gestational age at birth was strongly associated with rates of infection-related hospital admissions during childhood and even children born a few weeks early remained at higher risk at 7-10 years of age. There was variation between clinical subgroups in the strength of relationships with gestational age. Effective infection prevention strategies should include focus on reducing the number and severity of LRTIs during early childhood., Competing Interests: The authors have declared that no competing interests exist.

Background: Prelacteal feeding (PLF) is a recognised challenge to optimal breastfeeding but remains common in Indonesia. Meanwhile, PLF-related epidemiological research is limited, particularly in this setting. This study examines the prevalence and determinants of overall PLF as well as common PLF types (formula, other milk, and honey) in Indonesia., Methods: Data from 6127 mothers whose last child was ≤23-month-old were drawn from the 2017 Indonesia Demographic and Health Survey. Multivariable modified Poisson regression was used to measure the prevalence ratio (PR) for selected PLF risk factors. PLF was defined as anything to drink other than breast milk within three days after birth, before breastmilk flows. Additional analyses were performed on mothers who gave formula, other milk, and honey., Results: About 45% babies in Indonesia received PLF with formula being the most frequent (25%), followed by other milk (14%), plain water (5%), and honey (3%). Factors associated with higher prevalence of any PLF were higher wealth quintiles in rural area (PR 1.07; 95% CI 1.03-1.11 per increase in quintile), baby perceived to be small at birth (PR 1.23; 95% CI 1.12-1.35), caesarean deliveries at either public (PR 1.27; 95% CI 1.13-1.44) or private facilities (PR 1.15; 95% CI 1.01-1.31), and not having immediate skin-to-skin contact after birth (PR 1.32; 95% CI 1.23-1.42). PLF was less prevalent among mothers who gave birth to second/subsequent child (PR 0.82; 95% CI 0.76-0.88) and who had an antenatal card (PR 0.89; 95% CI 0.80-0.99). These patterns did not apply uniformly across all PLF types. For example, honey was more common among home births than deliveries at health facilities, but formula and other milk were more common among caesarean deliveries., Conclusions: Mapping risk factors for PLF, especially by types, could help to design more targeted interventions to reduce PLF and improve breastfeeding practices in Indonesia., Competing Interests: The authors have declared that no competing interests exist.

Background: Data from the UK Infant Feeding Surveys indicate that breastfeeding initiation increased between 1985 and 2010. During this period, societal changes in GB also influenced the sociodemographic characteristics of women in the childbearing population. As breastfeeding behaviour is highly socially patterned in GB, the increasing trend in breastfeeding initiation may have hidden inequalities in breastfeeding practices. This study examines the sociodemographic inequalities in breastfeeding initiation in GB between 1985 and 2010, exploring whether and how this may have been influenced by social and policy changes., Methods: Data drawn from the nationally representative 1985, 1990, 1995, 2000, 2005 and 2010 Infant Feeding Surveys were used to estimate changes in the proportion of mothers in selected sociodemographic groups over time. Logistic regression models estimated the independent associations between breastfeeding initiation in each survey year and maternal sociodemographic characteristics. Associations were adjusted for maternal sociodemographic, pregnancy-related and support factors. Evidence of a change in the association between breastfeeding initiation and each sociodemographic characteristic over time was assessed using a test for statistical heterogeneity., Results: The sociodemographic characteristics of mothers in GB changed substantially between 1985 and 2010. Mothers were increasingly more likely to be 30 or over; have higher education and socioeconomic status; and be single or cohabiting. An increasing proportion of mothers in GB identified as being of black or minority ethnic origin. Reported smoking in pregnancy declined. These same characteristics independently predicted higher odds of breastfeeding initiation; the associations between these characteristics and breastfeeding initiation did not vary significantly over time., Conclusions: Marked inequalities in breastfeeding initiation persisted over the study period, hidden among the increasing initiation rate at the population level. The increasing overall rate of initiation was most likely driven by the rising prevalence of those groups of mothers who were, and remain, characteristically most likely to breastfeed., Competing Interests: The authors have declared that no competing interests exist.

Objective: Fathers are increasingly involved in care of their babies and young children. We assessed the association of resident fathers' involvement with subsequent behaviour of their children, examining boys and girls separately., Methods: We used longitudinal data from the UK Millennium Cohort Study for children born in 2000-2001, divided into three separate analysis periods: ages 9 months to 3 years, 3 to 5 years, and 5 to 7 years. By exploratory factor analysis of self-reported attitudes and engagement in caring activities, we derived composite measures of various types of father involvement at 9 months, 3 and 5 years. Where possible we created equivalent measures of mother involvement. Child behaviour was assessed by the Strengths and Difficulties Questionnaire (SDQ), which was completed by the mother when the child was aged 3, 5 and 7 years. We estimated gender-specific odds ratios for behaviour problems per quintile of father involvement, using separate logistic regression models for boys and girls in each analysis period. We controlled for a wide range of potential confounders: characteristics of the child (temperament and development at 9 months, and illness and exact age at outcome), equivalent mother involvement where appropriate, and factors related to socioeconomic status, household change, and parental well-being, where statistically significant., Results: Paternal positive parenting beliefs at age 9 months and increased frequency of creative play at age 5 years were significantly associated with lower risk of subsequent behaviour problems (SDQ total difficulties) in both boys and girls (p<0.05), odds ratios ranging between 0.81 and 0.89 per quintile of involvement. No associations were observed for other composite measures of caring activity by the father at 9 months, 3 years or 5 years., Conclusion: Quality of parenting, rather than the division of routine care between parents, was associated with child behavioural outcomes., Competing Interests: The authors have declared that no competing interests exist.

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.

Background: Antimicrobial resistance (AMR) of infectious agents is a growing concern for public health organizations. Given the complexity of this issue and how widespread the problem has become, resources are often insufficient to address all concerns, thus prioritization of AMR pathogens is essential for the optimal allocation of risk management attention. Since the epidemiology of AMR pathogens differs between countries, country-specific assessments are important for the determination of national priorities., Objective: To develop a systematic and transparent approach to AMR risk prioritization in Canada., Methods: Relevant AMR pathogens in Canada were selected through a transparent multi-step consensus process (n=32). Each pathogen was assessed using ten criteria: incidence, mortality, case-fatality, communicability, treatability, clinical impact, public/political attention, ten-year projection of incidence, economic impact, and preventability. For each pathogen, each criterion was assigned a numerical score of 0, 1, or 2, and multiplied by criteria-specific weighting determined through researcher consensus of importance. The scores for each AMR pathogen were summed and ranked by total score, where a higher score indicated greater importance. A sensitivity analysis was conducted to determine the effects of changing the criteria-specific weights., Results: The AMR pathogen with the highest total weighted score was extended spectrum B-lactamase-producing (ESBL) Enterobacteriaceae (score=77). When grouped by percentile, ESBL Enterobacteriaceae, Clostridium difficile, carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus were in the 80-100th percentile., Conclusion: This assessment provides useful information for prioritising public health strategies regarding AMR resistance at the national level in Canada. As the AMR environment and challenges change over time and space, this systematic and transparent approach can be adapted for use by other stakeholders domestically and internationally. Given the complexity of influences, resource availability and multiple stakeholders, regular consideration of AMR activities in the public health realm is essential for appropriate and responsible prioritisation of risk management that optimises the health and security of the population.