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Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.

Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available.

Frogs produce two distinct yet highly coordinated ventilatory behaviors, buccal and lung. Lung ventilation occurs in short episodes, interspersed with periods of buccal ventilation. Recent data suggests that two brainstem oscillators are involved in generating these behaviors, one primarily responsible for buccal ventilation, the other for lung. Here we use a modeling approach to demonstrate that the episodic pattern of lung ventilation might be an emergent property of the coupling between the oscillators, and may not require a perturbing input from another, as yet unidentified but previously postulated, neuronal oscillator. © 2004 Elsevier B.V. All rights reserved.

The 12C+12C fusion reaction at deep subbarrier energies is important for understanding the carbon burning process in massive star and explosive binary systems. However, its reaction rates are very difficult to measure directly or evaluate by simple extrapolation due to the extremely small cross sections and complex resonance structures near the Gamow window. In this work, we use one of its exit channels, i.e. 23Na+p to populate the excited states of the compound nucleus 24Mg via the conventional thick-target inverse kinematics method. By applying γ-charged particle coincidence, we have obtained excitation functions for the proton and α emission channels, respectively, and derived the resonance parameters through a simultaneous multi-channel R-matrix analysis. It is clear that a series of discrete resonances exist in the most relevant excitation energy region of 24Mg. The astrophysical S-factor of the 12C+12C fusion reaction is evaluated by adopting a systematic reduced width for the entrance channel. In particular, branching ratios of the dominant four decay channels are estimated across the entire Gamow window of the 12C+12C fusion reactions. Significant fluctuations are shown that may have strong impacts on the final outcome of the carbon burning process.

Abstract Mechanical stress during muscle contraction is a constant threat to proteome integrity. However, there is a lack of experimental systems to identify critical proteostasis regulators under mechanical stress conditions. Here, we present the transgenic Caenorhabditis elegans model OptIMMuS (Optogenetic Induction of Mechanical Muscle Stress) to study changes in the proteostasis network associated with mechanical forces. Repeated blue light exposure of a muscle-expressed Chlamydomonas rheinhardii channelrhodopsin-2 variant results in sustained muscle contraction and mechanical stress. Using OptIMMuS, combined with proximity labeling and mass spectrometry, we identify regulators that cooperate with the myosin-directed chaperone UNC-45 in muscle proteostasis. One of these is the TRIM E3 ligase NHL-1, which interacts with UNC-45 and muscle myosin in genetic epistasis and co-immunoprecipitation experiments. We provide evidence that the ubiquitylation activity of NHL-1 regulates myosin levels and functionality under mechanical stress. In the future, OptIMMuS will help to identify muscle-specific proteostasis regulators of therapeutic relevance.

Abstract Background Thailand is approaching local elimination of malaria in the eastern provinces. It has successfully reduced the number of cases over the past decade, but there are persistent transmission hot spots in and around forests. This study aimed to use data from the malaria surveillance system to describe the spatiotemporal trends of malaria in Northeast Thailand and fine-scale patterns in locally transmitted cases between 2011 and 2021. Methods Case data was stratified based on likely location of infection and parasite species. Annual Parasite Index per 1000 population (API) was calculated for different categories. Time series decomposition was performed to identify trends and seasonal patterns. Statistically significant clusters of high (hot spots) and low (cold spots) API were identified using the Getis-Ord Gi* statistic. The stability of those hot spots and the absolute change in the proportion of API density from baseline were compared by case type. Results The total number of confirmed cases experienced a non-linear decline by 96.6%, from 1061 in 2011 to 36 in 2021. There has been a decline in both Plasmodium vivax and Plasmodium falciparum case numbers, with only four confirmed P. falciparum cases over the last two years—a 98.89% drop from 180 in 2011. API was generally higher in Si Sa Ket province, which had peaks every 2–3 years. There was a large outbreak in Ubon Ratchathani in 2014–2016 which had a high proportion of P. falciparum reported. The proportion of cases classified increased over the study period, and the proportion of cases classed as indigenous to the village of residence increased from 0.2% to 33.3%. There were stable hot spots of indigenous and imported cases in the south of Si Sa Ket and southeast of Ubon Ratchathani. Plasmodium vivax hot spots were observed into recent years, while those of P. falciparum decreased to zero in Ubon in 2020 and emerged in the eastern part in 2021, the same year that P. falciparum hot spots in Si Sa Ket reached zero. Conclusions There has been a large, non-linear decline in the number of malaria cases reported and an increasing proportion of cases are classed as indigenous to the patient’s village of residence. Stable hot spots of ongoing transmission in the forested border areas were identified, with transmission likely persisting because of remote location and high-risk forest-going behaviours. Future efforts should include cross-border collaboration and continued targeting of high-risk behaviours to reduce the risk of imported cases seeding local transmission.

Abstract The growing number of portable consumer-grade electroencephalography (EEG) wearables offers potential to track brain activity and neurological disease in real-world environments. However, accompanying open software tools to standardize custom recordings and help guide independent operation by users is lacking. To address this gap, we developed HEROIC, an open-source software that allows participants to remotely collect advanced EEG data without the aid of an expert technician. The aim of HEROIC is to provide an open software platform that can be coupled with consumer grade wearables to record EEG data during customized neurocognitive tasks outside of traditional research environments. This article contains a description of HEROIC’s implementation, how it can be used by researchers and a proof-of-concept demonstration highlighting the potential for HEROIC to be used as a scalable and low-cost EEG data collection tool. Specifically, we used HEROIC to guide healthy participants through standardized neurocognitive tasks and captured complex brain data including event-related potentials (ERPs) and powerband changes in participants’ homes. Our results demonstrate HEROIC’s capability to generate data precisely synchronized to presented stimuli, using a low-cost, remote protocol without reliance on an expert operator to administer sessions. Together, our software and its capabilities provide the first democratized and scalable platform for large-scale remote and longitudinal analysis of brain health and disease.

Abstract Background Thailand aimed to eliminate malaria by 2024, and as such is planning for future prevention of re-establishment in malaria free provinces. Understanding the receptivity of local areas to malaria allows the appropriate targeting of interventions. Current approaches to assessing receptivity involve collecting entomological data. Forest coverage is known to be associated with malaria risk, as an environment conducive to both vector breeding and high-risk human behaviours. Methods Geolocated, anonymized, individual-level surveillance data from 2011 to 2021 from the Thai Division of Vector-Borne Disease (DVBD) was used to calculate incidence and estimated Rc at village level. Forest cover was calculated using raster maps of tree crown cover density and year of forest loss from the publicly available Hansen dataset. Incidence and forest cover were compared graphically and using Spearman’s rho. The current foci classification system was applied to data from the last 5 years (2017–2021) and forest cover for 2021 compared between the classifications. A simple risk score was developed to identify villages with high receptivity. Results There was a non-linear decrease in annual cases by 96.6% (1061 to 36) across the two provinces from 2011 to 2021. Indigenous Annual Parasite Index (API) and approximated Rc were higher in villages in highly forested subdistricts, and with higher forest cover within 5 km. Forest cover was also higher in malaria foci which consistently reported malaria cases each year than those which did not. An Rc > 1 was only reported in villages in subdistricts with > 25% forest cover. When applying a simple risk score using forest cover and recent case history, the classifications were comparable to those of the risk stratification system currently used by the DVBD. Conclusions There was a positive association between forest coverage around a village and indigenous malaria cases. Most local transmission was observed in the heavily forested subdistricts on the international borders with Laos and Cambodia, which are where the most receptive villages are located. These areas are at greater risk of importation of malaria due to population mobility and forest-going activities. Combining forest cover and recent case surveillance data with measures of vulnerability may be useful for prediction of malaria recurrence risk.

Purpose – The study aims to investigate how personal values (PVS) influence research self-efficacy (RSE) among academics in public universities in Tanzania. Design/methodology/approach – A cross-sectional design was utilized by the study to gather data once through structured questionnaires administered to 247 academic staff from four public universities in Tanzania. Findings – Generally, the results show that PVS positively and significantly influence RSE in universities. Specifically, OPC has β value of 0.284 and p

This paper examines the moderating effect of social capital in the relationship between compensation and time performance of force account projects. Data were collected from 192 force account projects in selected local government authorities in Tanzania, where contractors participated in filling out structured questionnaires. The study employed partial least squares structural equation modelling to examine the hypothesized relationships. The findings indicate that compensation has a positive and significant effect on-time performance of force account projects. On the other hand, social capital negatively moderates the relationship between compensation and time performance, such that at high levels of social capital, the effect of compensation on time performance diminishes compared to lower levels. Therefore, the study offers intriguing insights into the negative effect of social capital on the relationship between compensation and time performance in the context of force account projects. This study makes a distinct contribution to the academic field by examining the moderating effect of social capital on the relationship between laborers’ compensation and time performance within the context of force account projects, a relatively neglected area in existing literature. While effective compensation practices are crucial for enhancing performance, the presence of social capital as a moderator impedes the positive effects of compensation in these projects. Future studies could further explore the complex dynamics between compensation, social capital, and time performance across different contexts and industries.

While previous studies have shown mixed results regarding the impact of human resource (HR) recruitment on construction project outcomes, they are limited in explaining the mechanisms through which HR recruitment influences construction project performance. The current study examines the influence of HR recruitment on the cost performance of force account construction projects, while also investigating the mediating effect of quality performance. The hypothesized model was established and empirically tested using partial least squares structural equation modeling. Data were collected from 192 force account construction projects through structured questionnaires administered to local contractors in surveyed local government authorities in Tanzania. The results reveal a positive and significant influence of HR recruitment on project cost performance. Furthermore, quality performance mediates the link between HR recruitment and cost performance. The study contributes to the limited literature on HR recruitment and construction project performance by highlighting the need for construction companies to customize their recruitment practices to align with their unique situations and needs. The findings provide practical implications to construction practitioners to enhance HR practices towards improving quality performance, which, in turn, strengthens the cost performance of force account construction projects. Additionally, the study can help policymakers develop guidelines on HR recruitment practices to ensure higher quality and cost performance in force account construction projects.

Twelve percent of the foot ganglion cysts occur on the toes, and they are often symptomatic and recurrent. When conservative treatment failed, surgical excision is recommended, which is classically an open resection of the ganglion cyst. However, communicating lesions between ganglion cysts and the interphalangeal joint or tendon sheath make it difficult to prevent a recurrence. Techniques of arthroscopic or endoscopic toe ganglionectomy have been reported, which is either arthroscopic/endoscopic internal drainage to the adjacent joint or tendon sheath or endoscopic resection of the ganglion cyst. Difficulty in identifying the communicating valvular lesion and high incidence of multiloculated lesions make endoscopic internal drainage not always feasible for toe ganglion. The purpose of this Technical Note is to describe the details of endoscopic resection of horseshoe ganglion of the great toe. This minimal invasive approach may help to reduce the risk of recurrence.

Introduction Acute febrile illness (AFI), traditionally attributed to malaria, is a common reason for seeking primary healthcare in rural South and Southeast Asia. However, malaria transmission has declined while health workers are often poorly equipped to manage non-malarial AFIs. This results in indiscriminate antibiotic prescribing and care escalation, which promotes antibiotic resistance and may increase healthcare costs. To address this problem, an electronic clinical decision support algorithm (eCDSA) called ‘Electronic clinical Decision support for Acute fever Management (EDAM)’ has been developed for primary health workers which integrates clinical, epidemiological and vital sign data with simple point-of-care tests to produce a diagnosis and management plan.Methods and analysis This is a pragmatic cluster-randomised trial aiming to assess the effect of EDAM and related training on antibiotic prescribing rates in rural Cambodian primary health centres (PHCs) as the primary outcome, along with a range of secondary outcomes including safety. Patients with AFI are eligible for recruitment if they are aged ≥1 year. A cluster is defined as a PHC and PHCs will be randomised to control (standard of care) and intervention (EDAM and associated training) arms, with 15 PHCs per arm. Patients will be followed up after 7 days to ascertain the safety profile of EDAM. Each PHC will recruit 152 patients (total 4560), based on a baseline antibiotic prescription rate of 25% and expected reduction to 17.5% with EDAM.Ethics and dissemination Results will be published in international peer-reviewed journals to inform the design of future versions of EDAM and of future trials of similar eCDSAs and other digital health interventions targeted towards rural populations. This study was approved by the Oxford University Tropical Research Ethics Committee (550-23) and the Cambodian National Ethics Committee for Health Research (395-NECHR).Trial registration number International Standard Randomized Controlled Trial Number Registry (ISRCTN15157105).

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Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary Babies that are very small in the womb are at greater risk of a poor outcome to the pregnancy such as stillbirth and learning difficulties in surviving children. Usually, a baby grows small because the placenta, which feeds the baby, is poorly formed. The study wanted to know whether using a medication, which improves the blood supply to the placenta, will give the baby more nutrition and allow better growth. This would allow doctors to keep the baby inside the womb for longer. The study used a medication called sildenafil to improve the blood supply. To be sure if it worked, the study wanted to compare this drug against an identical looking blank tablet (placebo) so women and their healthcare professionals would not know what medication was being given. Women with very small babies and who were pregnant between 22 weeks and 0 days to 29 weeks and 6 days were asked to take part in the study. Treatment was three times a day and continued until delivery or 31 weeks and 6 days. A total of 135 women agreed to take part in the study. Seventy were given sildenafil and 65 were given placebo. A computer decided which medication would be given to which women with a 50 : 50 chance of each. Women were kept in the study until discharge of their baby from hospital. Surviving babies were seen with their mothers at 2 years of age to test for brain injury and problems with thinking, speech and language, or movement (neurodevelopment). The study showed no benefit of sildenafil when compared to placebo in helping the baby grow or in preventing early delivery. In surviving babies there was no benefit for neurodevelopment 2 years after treatment with sildenafil. The findings of our study mean that sildenafil should not be used for the treatment of small babies. Scientific summary Background Severe early-onset intrauterine growth restriction (IUGR) is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is currently no treatment for IUGR with timely delivery being the only management option available. The researchers know from human placentas from IUGR pregnancies that there is often a failure to remodel the maternal spiral arteries within the uterus and myometrium. This inadequate remodelling leads to the persistence of a vasoactive responsiveness within these vessels. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide (NO), encouraging vasodilation of vasoactive vessels. Previous studies in animal models and human ex vivo samples have shown recovery of placental function and improvement in fetal growth. Small numbers of clinical trials have also shown an increase in fetal growth or vascular flow (Doppler studies) from maternal use of sildenafil. The STRIDER trial aims to address whether maternal treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Objectives The STRIDER United Kingdom (UK) study was designed to answer the following objectives in two phases; phase 1 – recruitment to a randomised controlled trial of sildenafil versus placebo for the treatment of early-onset intrauterine fetal growth restriction, and phase 2 – follow-up at 2 years of age to assess cardiovascular and neurodevelopmental outcomes effect the surviving infants. The primary objective of the phase 1 study was to determine whether sildenafil, compared to placebo therapy, delays the need to deliver a severely growth-restricted fetus by a minimum of 1 week. The secondary objectives were as follows: To investigate impact on fetal growth and fetal well‐being by comparing differential effect on vascular resistance in the uterine arteries, umbilical, fetal middle cerebral artery and fetal ductus venosus and differences in birthweight centiles in infants treated in utero with sildenafil and placebo. To examine, through collaboration with an international consortium, the hypothesis that sildenafil therapy compared to placebo therapy increases the rate of infant survival free of major neurodisability. To report frequency of adverse and serious adverse events (SAEs) associated with sildenafil use. To investigate the impact on maternal cardiovascular parameters by measurements of maternal heart rate and peripheral blood pressure (BP) before and after administration of study medication. To elucidate the precise mechanism and location of action of sildenafil in pregnancy by investigating the effects of sildenafil therapy on omental (representative of the wider maternal systemic vasculature), myometrial (uterine vasculature) and chorionic plate artery (placental vasculature) reactivity. The objective of the phase 2 follow-up study was to examine neurodevelopmental and cardiovascular outcomes at 2 years of age in children born to mothers who received sildenafil compared with placebo during pregnancy. It was hypothesised that: STRIDER UK children whose mothers received sildenafil will have improved neurodevelopmental outcomes at age 2–3 years (corrected) compared with controls exposed to placebo. There will be no difference in BP at 2–3 years (corrected) between STRIDER UK children whose mothers received sildenafil compared with controls exposed to placebo. Methods The STRIDER study was a Phase III clinical trial to quantify the effects of administration of sildenafil on pregnancy outcome in severe early‐onset IUGR. The study was designed as a randomised double-blind, placebo-controlled trial with sildenafil or placebo prescribed orally at a dose of 25 mg three times per day. All participants recruited had a singleton pregnancy between 22+0 weeks’ gestation and 29+6 weeks’ gestation with a diagnosis of IUGR and had agreed to expectant management. For the purpose of the study, IUGR was defined as a fetus with an estimated fetal weight or abdominal circumference below the 10th centile using local charts and absent or reversed end-diastolic flow in the umbilical artery on Doppler velocimetry. All participants were recruited from one of the 19 STRIDER research sites located in the UK. All sites were leading obstetric units within the UK with a high level of fetal medicine and neonatal services provided. Gestational age was confirmed by first trimester ultrasound and in each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities. Following diagnosis and informed consent, a full history, measurements of maternal cardiovascular parameters (BP and pulse rate), fetal biometry and Doppler velocimetry were taken. Maternal venepuncture for angiogenic biomarkers was also performed. All participants had further BP and pulse rate measurements and blood sampling 2 hours after receiving the first dose of the study drug. Subsequently, participants were followed up within 3–4 days and at weekly intervals thereafter, or earlier if clinically indicated. The remainder of clinical care was at the discretion of the local fetal medicine experts and included regular ultrasound assessment of growth and Doppler blood flow and antenatal cardiotocography. Study medication was over encapsulated (Sharp Clinical Services, Crickhowell, UK) to ensure that participants, clinicians and pharmacists were masked to the study drug. Medication was dispensed in 10-day supplies with a new supply being provided weekly to ensure there was no period where medication was missed. Treatment ended at 31+6 weeks’ gestation or delivery, whichever came first. All participants were advised of the potential side effects. Data on pregnancy outcome were collected prospectively from clinical maternity notes and entered onto a secure electronic case report form (eCRF) platform at research sites. Data quality and protocol compliance were monitored regularly by central and on-site monitoring methods. All surviving infants of mothers recruited to the STRIDER study were eligible and invited for follow-up. A study invitation pack was sent to all parents/carers of surviving children. This included an invitation letter, participant information sheet and informed consent form. Participants who did not contact the research team within 2 weeks were contacted by a member of the research team. Assessments took place in a clinical research setting or in the child’s home. Informed written consent was obtained before the assessment began. All assessments were performed by a single senior research psychologist with expertise in developmental assessment techniques. This researcher was blinded to treatment allocation. Assessments included the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BSID-III); Hempel’s Neurological Examination for Toddler Age to identify major neurological impairment (cerebral palsy; CP) and subtle deviations from typical neurological and neuromotor function. In addition, a cardiovascular assessment was undertaken, which included brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) augmentation index (AIx). Where potential participants cancelled or failed to attend follow-up appointments on more than three occasions, they were invited to participate remotely. All such participants received a Follow-up questionnaire pack, which included participant information sheet, consent form and all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire-3 (in place of the BSID-III, neurodevelopmental assessment). The health status classification system – preschool version (HSCS-PS) is a parental (or clinician) proxy measurement of the health status of a child. The overall health status is described as a 10-element vector consisting of one level for each domain. In this study, to facilitate comparisons between groups, a total ‘disability score’ for the overall health state of a child was calculated as the sum of the level codes for the original domains. Therefore, the range of the disability score varied from 10 (no disability on any domain) to 41 (maximum disability on all 10 domains). The child behaviour checklist (CBCL) 1.5–5 was used to assess emotional and behavioural difficulties. Raw scores are normalised into T-scores [mean: 50, standard deviation (SD): 10]. Higher T-scores represent more problematic behaviour. T-scores below 60 are in the normal range, T-scores of 60–63 (84th to 90th percentile) are in the borderline range, and T-scores above 63 (above 90th percentile) are in the clinical range. The T-scores are dichotomised into typical (scores in the normal range) and atypical (scores in the borderline and clinical range). The behaviour rating inventory of executive function – preschool version (BRIEF-P) is a parent questionnaire for early assessment of executive function to assess severity of executive dysfunction in day-to-day situations. Age-based T-scores are computed for each subscale and index, and a score of 65 or higher is considered a clinically significant problem. Results The study recruited 135 participants between 21 November 2014 and 6 July 2016. A number of 75 participants were recruited before 26+0 weeks’ gestation and 60 between 26+0 and 29+6 weeks’ gestation. A total of 70 participants were randomly assigned to receive sildenafil and 65 to placebo. None of the participants withdrew their consent nor were lost to follow-up prior to delivery, therefore, additional ‘per-protocol’ analysis was not performed. Differences at baseline were not clinically important between the sildenafil group and the placebo group. The median gestation at randomisation was 24.4 weeks [interquartile range (IQR) 24.0–27.5]. Two babies were postnatally diagnosed with Down syndrome (one sildenafil and one placebo) and two had confirmed cytomegalovirus infection (one sildenafil and one placebo); all four babies were included in the intention to treat (ITT) analysis. There was no beneficial effect on maternal cardiovascular function from treatment with sildenafil. The follow-up phase was delayed due to the impact of the COVID-19 pandemic on research staff’s availability and access to patients. Out of the 75 babies who were discharged alive from the neonatal unit, 61 babies (81.3%) were included in the follow-up phase. Of those not followed up, 1 baby died (placebo), 3 declined follow-up and 10 were uncontactable. By the nature of follow-up participants were not randomised by treatment leaving 32 mothers who had received sildenafil and 29 had received placebo. There was no difference in the sex, birthweight, gestation at delivery (median 29.2 weeks vs. 29.9 weeks), mode of delivery, or oxygen usage. The physical characteristics of the population available for follow-up showed no difference in height or weight. Head circumference was slightly larger in those treated with sildenafil (49.25, 46.43–50.26) versus placebo (47.18, 44.71–48.95). There was no difference between systolic and diastolic BP between those children treated with sildenafil or placebo. Median values were appropriate for children aged 2 years. The Bayley assessment showed no significant differences in cognitive, language (including receptive and expressive language), or motor (including fine and gross motor) subscales between children of sildenafil-and placebo-treated mothers. Total scores were somewhat lower than expected across all three domains compared with standard population norms (i.e. 100, SD = 15); however, the difference was neither clinically nor statistically significant. There was no difference between the sildenafil and placebo groups for the presence of CP reported by parents. Functional assessment with the BRIEF-P demonstrated no difference in adjusted T-scores between sildenafil and placebo for any of the assessed domains. Likewise, the median total CBCL scores and adjusted T-scores also showed no difference between babies whose mothers were treated with sildenafil versus placebo for any of the assessed domains. The HSCS scores are shown as a total score by domain and as individual components. There was no difference between infants who had received sildenafil to those who had received placebo for any of the domains assessed. It was not possible to record the HEMPEL assessments and as such neurology could not be assessed. Unfortunately, no children were able to tolerate the NICOM (Non-invasive Cardiac Output Monitor)cardiovascular test, leaving BP as the sole assessment of infant cardiovascular status. Conclusions The results of the STRIDER study demonstrated that sildenafil did not result in prolongation of pregnancy, improvements in fetal growth, or perinatal outcome when administered to pregnant women with a severely-growth restricted fetus. These results have subsequently been confirmed in a number of other studies. Our study demonstrated a lack of benefit on any neurodevelopmental, emotional or behavioural assessment from treatment with sildenafil. This study represents the first study to report to the impact of antenatal treatment of women with severe early-onset FGR on their infants’ well-being at 2 years of age. Along with the findings of no benefit on prolongation of pregnancy or perinatal outcome this study it confirms the ineffectiveness of this treatment to improve outcomes in babies with severe early-onset FGR. Further to this lack of benefit there were concerns raised during the Dutch STRIDER trial of increased perinatal mortality in the sildenafil group. Further assessment deemed this excess mortality to be predominantly due to persistent pulmonary hypertension of the neonates (PPHN), which has been proposed to be a pathophysiological mechanism of ‘rebound’ vasoconstriction after cessation of sildenafil. Both the UK and the New Zealand/Australia STRIDER Trials reviewed their data using the same criteria for PPHN as the Dutch STRIDER trial and did not find an increased mortality. The international STRIDER studies are committed to combine the study data in a prospective individual participant data (IPD) meta-analysis to look for any possible long-term effect of sildenafil, particularly on neurodevelopmental and cardiovascular outcome. On current evidence, the researchers do not believe that there is likely to be any beneficial effect on fetal growth, perinatal outcomes or neurodevelopment in this patient group and would advise that further use of sildenafil in this population should be stopped. Prior to any further studies using PDE5 inhibitors to treat FGR being performed, pharmacokinetic and pharmacodynamic experiments specific to pregnancy should be performed to establish an efficacious therapeutic dose. Therefore, the STRIDER study showed no beneficial effect for any perinatal outcome for mother or baby from treatment with 25 mg sildenafil TDS for severe early-onset FGR. The follow-up study confirmed that there was no beneficial effect from maternal treatment with sildenafil on behavioural assessment performed at 2 years of age in the surviving infants. There was also no effect on infant BP from treatment with sildenafil. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

Background While biologic therapy, typically with infliximab or Roferon, was used for Behçet syndrome after first-line immunosuppressants, no high-quality randomised trials or predictive biomarkers were available. Objective To undertake a randomised controlled clinical trial of infliximab versus Roferon in Behçet syndrome and identify potential biomarkers for response. Design Pragmatic, standard of care, single-masked, randomised, two-arm, parallel head-to-head trial, with exploratory study on potential role of interferon lambda 3 and interferon lambda 4 single nucleotide polymorphisms and urinary metabolomics biomarkers. Setting Three national UK Behçet syndrome centres and allied clinics. Participants Patients with active Behçet syndrome, fulfilling International Study Group 1990 criteria, with inadequate response to or intolerance of first-line treatment. Intervention Randomisation to infliximab (5 mg/kg intravenous infusion) or Roferon (subcutaneous injection), utilising the UK Behçet syndrome drug pathway protocol. Outcomes Primary outcome: modified Behçet’s disease activity index at 12 weeks of therapy. Secondary outcomes: (1) modified Behçet’s disease activity index score at 24 weeks and (2) significant improvement at 12 and 24 weeks from baseline in vitreous haze and best corrected visual acuity change, oral ulcer severity score, number of genital ulcers, arthritis pain, adverse events, reduction in dose of glucocorticoid, quality-of-life scores and Physician’s Global Assessment of disease activity. Sample size Utilising a Bayesian analysis of covariance model (80% credible interval), initial sample size was 45/arm (Bayesian power 90%). With an anticipated 10% dropout rate, 100 patients were to be recruited. Following recommendations to reduce the overall length of the trial, this was revised down to 80 patients (36 in each arm, allowing for 10% dropout): 80% equi-tailed credibility interval, Bayesian power 88%. In total, 79 patients were eventually recruited for the study. Methods Patients with refractory active Behçet syndrome underwent stratified block randomisation, based on randomly permuted blocks with random block sizes of two and four, allocating treatment to either infliximab or Roferon. Follow up with symptom-directed examination at weeks 12 and 24 according to standard of care. Analysis of the primary end point was undertaken using a Bayesian analysis of covariance approach. Informative priors for the anticipated treatment effect were derived from a cohort of six international experts prior to the start of the study. Results In this first prospective head-to-head randomised controlled clinical trial of two biologic drugs in Behçet syndrome, both infliximab and Roferon were equally effective [mean difference (80% credibility interval) = 0.13 (–0.19 to 0.46)], with a trend for minor benefit in favour of infliximab in terms of tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in the interferon lambda 3 (interleukin 28B) gene locus in the Roferon-treated arm. However, with the relatively small sample size, statistical significance of the association was lost when correcting for multiple tests. Metabolomic analysis identified potential markers of a metabolic response to treatment with infliximab. Limitations Single-masked design. Slow recruitment with fewer patients recruited in total, limiting the strength of analysis for secondary outcomes and mechanistic studies. Conclusion We report clinical efficacy in both infliximab and Roferon in refractory active Behçet syndrome, together with the potential for a novel metabolomic biomarker identifying response to infliximab. Future work Further work will characterise the appropriate metabolite(s) from existing samples to inform future prospective trials to study this in more detail clinically. The efficacy of Roferon in Behçet syndrome may support future manufacture of this drug. Trial registration This trial is registered as EudraCT Number: 2014-005390-36; ISRCTN49793874. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/46) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 17. See the NIHR Funding and Awards website for further award information. Plain language summary Behçet syndrome, a very rare disease in the UK, causes major illness. Yet without high-quality, randomised, controlled trials, choosing treatment is somewhat hit and miss. We set up a randomised controlled clinical trial to study the two most widely used biologic drugs in Behçet syndrome, infliximab and Roferon, head-to-head and searched for potential blood and urinary markers for response. Patients with active Behçet syndrome, in the United Kingdom national Behçet syndrome centres and allied clinics, who had not responded to or could not tolerate first-line treatment were randomised to either infliximab infusions or Roferon injections. The primary outcome was modified Behçet’s disease activity index at 12 weeks of therapy. Secondary outcomes included modified Behçet’s disease activity index at 24 weeks and significant improvements in individual organs, quality of life and Physician’s Global Assessments of activity at 12 and 24 weeks. Initial assessment suggested 100 patients were required for a statistically meaningful outcome but was revised down to 80 following recommendations to shorten the trial. In this first prospective head-to-head randomised controlled clinical trial of two biologics in Behçet syndrome, both drugs worked equally well. There was a non-significant trend for minor benefits of infliximab in terms of tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in the interferon lambda 3 (interleukin 28B) gene locus in the Roferon arm, but statistical significance was lost with the relatively small sample size. Metabolomics analysis identified potential markers of a metabolic response to infliximab. The limitations of the study included the single-masked design: patients (but not clinicians) were aware of their treatment, and fewer patients were studied than planned. This limited the strength of analysis for secondary outcomes and mechanistic studies. We now plan to characterise the metabolite(s) from existing samples to design future trials to study if there can be effective targeting of treatment in Behçet syndrome. Scientific summary Background Behçet syndrome (BS), a multisystem inflammatory vasculitis, is infrequent in the UK, but it has the potential to cause significant morbidity and mortality. The evidence base supporting biologic treatment, which is used for active disease after failure of standard immunosuppression or when prognosis is poor, is largely based on uncontrolled studies. At the time of the trial, the UK National guideline for therapy of Behçet’s indicated that either the tumour necrosis factor alpha inhibitor infliximab or the interferon alpha drug Roferon could be employed as treatment for patients following failure of first-line treatment with standard immunomodulators. The Bio Behçet’s trial was conceived to exploit the opportunity of the three UK National Centres of Excellence for Behçet’s and associated satellite centres to undertake the first randomised clinical trial to compare infliximab and Roferon as treatment for BS, together with an exploratory analysis of potential genomic and metabolomic biomarkers of therapeutic response. Methods The Bio Behçet’s trial is a pragmatic, standard of care, single-masked, randomised, two-arm, parallel trial comparing the efficacies of infliximab and Roferon employed after failure of first-line therapy in BS. Patients with BS, diagnosed according to the International Study Group 1990 criteria, with active disease who had failed to respond to, or were intolerant of, first-line treatment of BS with topical steroids or small-molecule immunosuppressants were randomised to treatment with either infliximab (Remicade) 5 mg/kg intravenous infusions or Roferon subcutaneous injection (in variable dose), utilising the treatment protocol for each of these drugs in normal clinical care as detailed in the BS drugs pathway for England. The trial utilised a Bayesian design utilising priors informed by a small survey of international experts in BS. Utilising a Bayesian analysis of covariance model, with an 80% credible interval, a sample size of 45 patients per arm was deemed appropriate and gave a Bayesian power of 90%. Allowing for an anticipated 10% dropout rate, 100 patients were planned to be recruited but reduced to 80 following recommendations to reduce the overall length of the trial. Allowing for a 10% dropout rate, estimates of study power based on 72 evaluable patients (36 on each arm) and an 80% credible interval a Bayesian power of 88% was obtained. Between June 2016 and February 2020, 161 patients were screened, and 79 patients were randomised. The intention-to-treat analysis was restricted to 37 subjects allocated to infliximab and 37 to Roferon. Based on previous work with hepatitis C infection and response to interferon therapy and given the role of the innate immune system in the pathogenesis of BS, we examined interferon lambda 3 (IFNL3) and interferon lambda 4 (IFNL4) single nucleotide polymorphisms (SNPs) as biomarkers of response to treatment with alpha interferon and/or infliximab in BS. We also examined the potential for urine metabolomics to act as biomarkers for drug response. The primary outcome was a modified version of the Behçet’s disease activity index (mBDAI) after 3 months of therapy. Secondary outcomes comprised mBDAI score after 6 months of therapy and significant improvement in organ systems after 3 and 6 months (week 12 and week 24 visits) assessed by: reduction in vitreous haze using the SUN consensus group grading scale and best corrected visual acuity change [using the logarithm of the minimal angle of resolution (LogMAR) chart at 4 m] from baseline; change in oral ulcer severity score; change in number of genital ulcers; arthritis pain (10 cm Likert scale); adverse events (AEs) in each group; reduction in dose of prednisolone (or equivalent glucocorticoid) at 3 months (week 12 visit); reduction in dose of prednisolone (or equivalent glucocorticoid) at 6 months (week 24 visit); quality-of-life (QoL) scores at 3 and 6 months (week 12 and week 24 visits) and Physician’s Global Assessment of disease activity at 3 and 6 months (week 12 and week 24 visits). Results Baseline characteristics of the two treatment arms did not differ significantly by sex, ethnic profile, baseline disease characteristics and steroid use. For the primary outcome measure, change in mBDAI between baseline and 3 months (and as a secondary outcome between baseline and 6 months) did not differ significantly between the two treatments [mean difference (80% CrI) = 0.13 (–0.19 to 0.46)]. A significantly higher proportion of patients randomised to Roferon swapped away from their randomised treatment compared to those randomised to infliximab treatment (Roferon 11 of 37, infliximab 3 of 37; p = 0.0104). The clinician’s overall perception of disease activity indicated a reduction in disease activity for most patients between baseline and 3 months and between baseline and 6 months, with a median reduction of −2.0 (infliximab) and −1.0 (Roferon) at 3 months and −3.0 (infliximab) and −2.0 (alpha interferon) at 6 months. There was a small but significant difference in favour of infliximab compared to Roferon at both 3 and 6 months (p

Abstract Genome organization is thought to underlie cell type specific gene expression, yet how it is regulated in progenitors to produce cellular diversity is unknown. In Drosophila, a developmentally-timed genome reorganization in neural progenitors terminates competence to produce early-born neurons. These events require downregulation of Distal antenna (Dan), part of the conserved pipsqueak DNA-binding superfamily. Here we find that Dan forms liquid-like condensates with high protein mobility, and whose size and subnuclear distribution are balanced with its DNA-binding. Further, we identify a LARKS domain, a structural motif associated with condensate-forming proteins. Deleting just 13 amino acids from LARKS abrogates Dan’s ability to retain the early-born neural fate gene, hunchback, in the neuroblast nuclear interior and maintain competence in vivo. Conversely, domain-swapping with LARKS from known phase-separating proteins rescues Dan’s effects on competence. Together, we provide in vivo evidence for condensate formation and the regulation of progenitor nuclear architecture underlying neuronal diversification.

Hydrogenated amorphous silicon (a-Si:H) devices on flexible substrates are currently being studied for application in dosimetry and beam flux measurements. The necessity of in vivo dosimetry requires thin devices with maximal transparency and flexibility. For this reason, a thin (7 to 2.49 × 1010 p/(cm2 s).

Ultrasound imaging is widely valued for its safety, non-invasiveness, and real-time capabilities but is often limited by operator variability, affecting image quality and reproducibility. Robot-assisted ultrasound may provide a solution by delivering more consistent, precise, and faster scans, potentially reducing human error and healthcare costs. Effective force control is crucial in robotic ultrasound scanning to ensure consistent image quality and patient safety. However, existing robotic ultrasound systems rely heavily on expensive commercial force sensors or the integrated sensors of commercial robotic arms, limiting their accessibility. To address these challenges, we developed a cost-effective, lightweight, 3D-printed force sensor and a hybrid position–force control strategy tailored for robotic ultrasound scanning. The system integrates patient-to-robot registration, automated scanning path planning, and multi-sensor data fusion, allowing the robot to autonomously locate the patient, target the region of interest, and maintain optimal contact force during scanning. Validation was conducted using an ultrasound-compatible abdominal aortic aneurysm (AAA) phantom created from patient CT data and healthy volunteer testing. For the volunteer testing, during a 1-min scan, 65% of the forces were within the good image range. Both volunteers reported no discomfort or pain during the whole procedure. These results demonstrate the potential of the system to provide safe, precise, and autonomous robotic ultrasound imaging in real-world conditions.

Background Scrub typhus is a neglected life-threatening vector-borne disease mainly caused by the bacterium Orientia tsutsugamushi, which is occasionally transmitted to humans during feeding of larval mites. It has been estimated that more than 1 billion persons are potentially threatened and 1 million clinical cases occur annually across the world; however, it is unclear how this estimate was computed (and what the original source was) and much remains unknown regarding its global burden and risk factors. This systematic review aims to provide a comprehensive overview of the spatial-temporal distribution of scrub typhus, associated burden and risk factors at global, national and subnational resolutions, and to review the burden estimation models used at those different scales. Methods A systematic search for literature on scrub typhus occurrence, risk factors and modelling methods will be conducted. PubMed and five other databases will be searched for published literature, and Google Scholar and nine other databases will be used to search for grey literatures. All titles/abstracts of the searched records will be separately assessed by two reviewers, who will then screen the full-text of potential records to decide eligibility. A pre-formatted spreadsheet will be used by one reviewer to extract data from qualifying research, with a second reviewer checking the results. Data will be tabulated, synthesized descriptively, and summarized narratively for each review question. Where appropriate, meta-analyses will be conducted. The risk of bias will be assessed, and potential publication bias will be detected. Discussion This review will provide a comprehensive understanding of the current occurrence, spatial-temporal distribution, and burden of scrub typhus, identify associated risk factors from global to subnational resolutions, consolidate the best practice modeling framework(s) to estimate the burden of scrub typhus at various geographic/temporal resolutions, and decompose the relative contributions of various risk factors at scale. PROSPERO Registration CRD42022315209

Introduction: Androgen Deprivation Therapy (ADT) for prostate cancer (PC) has substantial negative impacts on the musculoskeletal system and body composition. Many studies have focused on the effects of ADT on areal bone mineral density (aBMD), but aBMD does not capture key determinants of bone strength and fracture risk, for example volumetric bone density (vBMD), geometry, cortical thickness and porosity, trabecular parameters and rate of remodelling. More specialist imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) have become available to evaluate these parameters. Although it has previously been demonstrated that bone microarchitectural deterioration occurs in men undergoing ADT, the aim of the ANTELOPE study was to examine longitudinal changes in bone microstructure alongside a range of musculoskeletal parameters and frailty, comparing men with PC receiving ADT alone or ADT plus chemotherapy for metastatic disease, with a healthy age-matched population. Methods: We used HR-pQCT to investigate effects of 12 months of ADT on vBMD and microstructural parameters, complemented by assessment of changes in aBMD, serum bone turnover markers, sex hormones, body composition, grip strength, physical and muscle function, frailty and fracture risk. We studied three groups: Group A − men with localised/locally advanced PC due to commence ADT; Group B − men with newly diagnosed hormone-sensitive, metastatic PC, starting ADT alongside docetaxel chemotherapy and steroids; Group C − healthy, age-matched men. The primary endpoint was change in vBMD (Group A vs Group C) at the distal radius. Results: Ninety-nine participants underwent baseline study assessments (Group A: n = 38, Group B: n = 30 and Group C: n = 31). Seventy-five participants completed all study assessments (Group A (29), Group B (18), Group C (28). At baseline, there were no significant differences between Groups A and C in any of the BMD or bone microstructure outcomes of interest. After 12 months of ADT treatment, there was a significantly greater decrease in vBMD (p

Abstract Malnutrition has remained a global public health issue, particularly in low- and middle-income countries (LMICs). Researchers have committed to studying malnutrition (especially in children under the age of five) to address the nine malnutrition targets, set by the WHO to be achieved by 2025. This study seeks to evaluate the prevalence, the individual and contextual predictors of malnutrition among children aged 6–59 months across Nigeria and its states. Two separates, independently collected, nationally representative cross-sectional surveys, the National Human Development Report (NHDR 2018) and the 2018 Nigeria Demographic and Health Survey (2018 NDHS) were linked for this study. Spatial map was used to describe the prevalence of malnutrition, a 3-level multivariate multilevel logistic regression models were fitted where children/individuals (at level 1) were nested in communities/clusters (at level 2) and nested in states (at level 3). A weighted sample of 7,770 children 6–59 months were considered in this study. The results showed that an estimated 43.6% of children aged 6–59 months are poorly nourished in Nigeria. The proportions of poorly nourished children were generally highest in the Northern Nigeria. Child’s gender, age, birth size, preceding birth order, anaemia status, maternal education, work status, body weight, household wealth status, number of bedrooms were among individual/household predictors of malnutrition. On the community level, being from community with high wealth index, distance to nearest health facilities is no big problem. Regional variations and gender inequality index were the state level predictors of malnutrition among children in Nigeria. This study has shown that two-third of children aged 6–59 months in Nigeria were poorly nourished, an indication of a growing concern of double burden of malnutrition in Nigeria.

The hand-held power sander is a frequently used tool in woodworking, and it is a significant source of risk in terms of dust, vibration, and, notably, noise. The purpose of a hand-held power sander manufacturer’s noise emission statement is to provide information that is useful for assessing the risks associated with noise exposure and should assist users in selecting a hand-held power sander with reduced noise emissions. The stated levels of emitted noise obtained in accordance with a harmonized test procedure may not, in all circumstances, give a reliable indication of the actual risk of noise exposure during the typical use of a hand-held power sander. The aim of this work was to investigate the difference between the values declared by the manufacturers of hand-held power sanders and the measured noise values during actual use. The measurements of the equivalent sound pressure levels were carried out using an integrating–averaging sound level meter (B&K, model 2245) during the sanding of beech and spruce wood with different types of hand-held electric sanders (belt, random orbital, and orbital) with abrasives of coarse, medium, or fine grit. Upon comparing the measured and declared noise values, differences ranging from −6.3 dB to 19 dB(A) were identified for distinct sander types. The results of this study show that the use of declared noise emission values during risk assessments underestimates the magnitude of operator noise exposure.

Abstract Future searches for new physics beyond the Standard Model are without doubt in need of a diverse approach and experiments with complementary sensitivities to different types of classes of models. One of the directions that should be explored is feebly interacting particles (FIPs) with masses below the electroweak scale. The interest in FIPs has significantly increased in the last ten years. Searches for FIPs at colliders have intrinsic limitations in the region they may probe, significantly restricting exploration of the mass range $$m_{\text {FIP}} < 5{-}10$$ m FIP < 5 - 10 GeV/c $$^2$$ 2 . Beam dump-like experiments, characterized by the possibility of extremely high luminosity at relatively high energies and the effective coverage of the production and decay acceptance, are the perfect option to generically explore the “coupling frontier” of the light FIPs. Several proposals for beam-dump detectors are currently being considered by CERN for implementation at the SPS ECN3 beam facility. In this paper, we analyse in depth how the characteristic geometric parameters of a beam dump experiment influence the signal yield. We apply an inclusive approach by considering the phenomenology of different types of FIPs. From the various production modes and kinematics, we demonstrate that the optimal layout that maximises the production and decay acceptance consists of a detector located on the beam-axis, at the shortest possible distance from the target defined by the systems required to suppress the beam-induced backgrounds.

Purpose – The major purpose of this paper is to examine the influence of openness to change on research publication in higher education institutions (HEI) in Tanzania. Design/methodology/approach – With a sample of 247 academics, a cross-sectional survey design was used and questionnaires were the primary data collection tool. The collected data were tested using mean and standard deviations, and the causal–effect relationship between the independent and dependent variables was tested using simple linear regression. Findings – The findings of this study revealed that openness to change positively and significantly influence research publication in higher education (β = 0.598 and p

Abstract Background Near-real time surveillance of excess mortality has been an essential tool during the COVID-19 pandemic. It remains critical for monitoring mortality as the pandemic wanes, to detect fluctuations in the death rate associated both with the longer-term impact of the pandemic (e.g. infection, containment measures and reduced service provision by the health and other systems) and the responses that followed (e.g. curtailment of containment measures, vaccination and the response of health and other systems to backlogs). Following the relaxing of social distancing regimes and reduction in the availability of testing, across many countries, it becomes critical to measure the impact of COVID-19 infection. However, prolonged periods of mortality in excess of the expected across entire populations has raised doubts over the validity of using unadjusted historic estimates of mortality to calculate the expected numbers of deaths that form the baseline for computing numbers of excess deaths because many individuals died earlier than they would otherwise have done: i.e. their mortality was displaced earlier in time to occur during the pandemic rather than when historic rates predicted. This is also often termed “harvesting” in the literature. Methods We present a novel Cox-regression-based methodology using time-dependent covariates to estimate the profile of the increased risk of death across time in individuals who contracted COVID-19 among a population of hip fracture patients in England (N = 98,365). We use these hazards to simulate a distribution of survival times, in the presence of a COVID-19 positive test, and then calculate survival times based on hazard rates without a positive test and use the difference between the medians of these distributions to estimate the number of days a death has been displaced. This methodology is applied at the individual level, rather than the population level to provide a better understanding of the impact of a positive COVID-19 test on the mortality of groups with different vulnerabilities conferred by sociodemographic and health characteristics. Finally, we apply the mortality displacement estimates to adjust estimates of excess mortality using a “ball and urn” model. Results Among the exemplar population we present an end-to-end application of our methodology to estimate the extent of mortality displacement. A greater proportion of older, male and frailer individuals were subject to significant displacement while the magnitude of displacement was higher in younger females and in individuals with lower frailty: groups who, in the absence of COVID-19, should have had a substantial life expectancy. Conclusion Our results indicate that calculating the expected number of deaths following the first wave of the pandemic in England based solely on historical trends results in an overestimate, and excess mortality will therefore be underestimated. Our findings, using this exemplar dataset are conditional on having experienced a hip fracture, which is not generalisable to the general population. Fractures that impede mobility in the weeks that follow the accident/surgery considerably shorten life expectancy and are in themselves markers of significant frailty. It is therefore important to apply these novel methods to the general population, among whom we anticipate strong patterns in mortality displacement – both in its length and prevalence – by age, sex, frailty and types of comorbidities. This counterfactual method may also be used to investigate a wider range of disruptive population health events. This has important implications for public health monitoring and the interpretation of public health data in England and globally.

Summary: Background: Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe the incidence and differences in demographic and clinical characteristics in recorded long COVID in primary care records in England. Methods: With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. Using OpenSAFELY, we calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and adjusted (for age, sex, 9 NHS regions of England, and the dominant variant circulating) rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings: We identified a total of 55,465 people recorded to have long COVID over the study period, which included 20,025 diagnoses codes and 35,440 codes for further assessment. The incidence of new long COVID records increased steadily over 2021, and declined over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5–179) and 100.5 in men (99.5–102). The majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 or more weeks before the long COVID record. Interpretation: In this descriptive study, EHR recorded long COVID was very low between 2020 and 2023, and incident records of long COVID declined over 2022. Using EHR diagnostic or referral codes unfortunately has major limitations in identifying and ascertaining true cases and timing of long COVID. Funding: This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073).

Trade of wild-caught animals is illegal for many taxa and in many countries. Common regulatory procedures involve documentation and marking techniques. However, these procedures are subject to fraud and thus should be complemented by routine genetic testing in order to authenticate the captive-bred origin of animals intended for trade. A suitable class of genetic markers are SNPSTRs that combine a short tandem repeat (STR) and single nucleotide polymorphisms (SNPs) within one amplicon. This combined marker type can be used for genetic identification and for parentage analyses and in addition, provides insight into haplotype history. As a proof of principle, this study establishes a set of 20 SNPSTR markers for Athene noctua, one of the most trafficked owls in CITES Appendix II. These markers can be coamplified in a single multiplex reaction. Based on population data, the percentage of observed and expected heterozygosities of the markers ranged from 0.400 to 1.000 and 0.545 to 0.850, respectively. A combined probability of identity of 5.3 * 10−23 was achieved with the whole set, and combined parentage exclusion probabilities reached over 99.99%, even if the genotype of one parent was missing. A direct comparison of an owl family and an unrelated owl demonstrated the applicability of the SNPSTR set in parentage testing. The established SNPSTR set thus proved to be highly useful for identifying individuals and analysing parentage to determine wild or captive origin. We propose to implement SNPSTR-based routine certification in wildlife trade as a way to reveal animal laundering and misdeclaration of wild-caught animals.

Summary: Background: Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. We aimed to evaluate and estimate the differences in health impacts of long COVID across sociodemographic categories and quantify this in Quality-Adjusted Life-Years (QALYs), widely used measures across health systems. Methods: With the approval of NHS England, we utilised OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Findings: The total OpenPROMPT cohort consisted of 7575 individuals who consented to data collection, with which we used data from 6070 participants who completed a baseline research questionnaire where 24.6% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a higher likelihood or odds of reporting loss in quality-of-life (Odds Ratio (OR): 4.7, 95% CI: 3.72–5.93) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 17.7, 95% CI: 10.37–30.33) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Interpretation: We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease. Funding: This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073).

Rapid diagnostic tests (RDTs) are critical for preparedness and response against an outbreak or pandemic and have been highlighted in the 100 Days Mission, a global initiative that aims to prepare the world for the next epidemic/pandemic by driving the development of diagnostics, vaccines and therapeutics within 100 days of recognition of a novel Disease X threat.RDTs play a pivotal role in early case identification, surveillance and case management, and are critical for initiating deployment of vaccine and monoclonal antibodies. Currently available RDTs, however, have limited clinical sensitivity and specificity and inadequate validation. The development, validation and implementation of RDTs require adequate and sustained financing from both public and private sources. While the World Health Assembly recently passed a resolution on diagnostic capacity strengthening that urges individual Member States to commit resources towards this, the resolution is not binding and implementation will likely be impeded by limited financial resources and other competing priorities, particularly in low-income countries. Meanwhile, the diagnostic industry has not sufficiently invested in RDT development for high priority pathogens.Currently, vaccine development projects are getting the largest funding support among medical countermeasures. Yet vaccines are insufficient tools in isolation, and pandemic preparedness will be incomplete without parallel investment in diagnostics and therapeutics.The Pandemic Fund, a global financing mechanism recently established for strengthening pandemic prevention, preparedness and response, may be a future avenue for supporting diagnostic development.In this paper, we discuss why RDTs are critical for preparedness and response. We also discuss RDT investment challenges and reflect on the way forward.

Abstract Background Malaria causes significant morbidity and mortality in tropical and sub-tropical regions, particularly in humanitarian emergencies including refugee camps in malaria endemic areas. An epidemiological investigation was conducted on malaria disease distribution and risk factors in the world’s largest refugee settlement, the Rohingya refugee camps on the south-eastern border area of Bangladesh, within 2017–2020. Methods From February 2017 to March 2020, 30,460 febrile patients were tested for malaria using light microscopy and rapid diagnostic tests. Most were self-presenting symptomatic patients and a minority were from door-to-door malaria screening. Diagnostic tests were done by trained medical technologists upon the advice of the concerned physicians in the camps. Test positivity rate (%) and annual parasite incidence were calculated and compared using chi-squared (χ 2) test or odds ratios. Results The overall average annual test positivity rate (TPR) was 0.05%. TPR was highest in people who had travelled to the forest in the previous 2 months, at 13.60%. Cases were clustered among male adults aged 15–60 years. There were no cases among children under five years or pregnant women and no deaths from malaria. Conclusion This study found very few malaria cases among Rohingya refugees with the majority of cases being imported from hilly forested areas, which were thus assumed to act as the reservoir for transmission.

Abstract Neurological diseases are on the rise worldwide, leading to increased healthcare costs and diminished quality of life in patients. In recent years, Big Data has started to transform the fields of Neuroscience and Neurology. Scientists and clinicians are collaborating in global alliances, combining diverse datasets on a massive scale, and solving complex computational problems that demand the utilization of increasingly powerful computational resources. This Big Data revolution is opening new avenues for developing innovative treatments for neurological diseases. Our paper surveys Big Data’s impact on neurological patient care, as exemplified through work done in a comprehensive selection of areas, including Connectomics, Alzheimer’s Disease, Stroke, Depression, Parkinson’s Disease, Pain, and Addiction (e.g., Opioid Use Disorder). We present an overview of research and the methodologies utilizing Big Data in each area, as well as their current limitations and technical challenges. Despite the potential benefits, the full potential of Big Data in these fields currently remains unrealized. We close with recommendations for future research aimed at optimizing the use of Big Data in Neuroscience and Neurology for improved patient outcomes.

Cardiac ablation (CA) is an interventional electrophysiological procedure used to disrupt arrhythmic substrates in the myocardium by inducing localized scarring. Current CA training relies on the master–apprentice model. In different fields of medicine including CA, virtual and physical simulators have proven to enhance, and even outperform, conventional training modalities while providing a risk-free learning environment. Despite the benefits, high costs and operational difficulties limit the widespread use of interventional simulators. Our previous research introduced a low-cost CA simulator using a 3D-printed biatrial cardiac model, successfully recording ten ablation lesions on the phantom myocardium. In this work, we present and evaluate an enhanced version: compared to the previous version, the cardiac phantom’s electrical behavior and ablation settings were optimized to produce consistent lesions, while 3D-printed components improved the haptic and radiographic properties of the simulator. Seven cardiologists compared the experimental simulator’s performance to the leading commercial system from Heartroid in a 24-question survey on a 5-point Likert scale. The four following areas of fidelity were considered: catheter entry, anatomical correctness, radiographic appearance, and mapping and ablation. The experimental simulator significantly outperformed the commercial system (p < 0.01), particularly in radiographic appearance (p < 0.01). The results show the potential for the experimental simulator in routine CA training.

This paper presents a comprehensive study of hydrogenated amorphous silicon (a-Si)-based detectors, utilizing electrical characterization, Raman spectroscopy, photoemission, and inverse photoemission techniques. The unique properties of a-Si have sparked interest in its application for radiation detection in both physics and medicine. Although amorphous silicon (a-Si) is inherently a highly defective material, hydrogenation significantly reduces defect density, enabling its use in radiation detector devices. Spectroscopic measurements provide insights into the intricate relationship between the structure and electronic properties of a-Si, enhancing our understanding of how specific configurations, such as the choice of substrate, can markedly influence detector performance. In this study, we compare the performance of a-Si detectors deposited on two different substrates: crystalline silicon (c-Si) and flexible Kapton. Our findings suggest that detectors deposited on Kapton exhibit reduced sensitivity, despite having comparable noise and leakage current levels to those on crystalline silicon. We hypothesize that this discrepancy may be attributed to the substrate material, differences in film morphology, and/or the alignment of energy levels. Further measurements are planned to substantiate these hypotheses.