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Abstract Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent and selective covalent inhibitors of the peptidyl arginine deiminase, PADI4 or PAD4, that react exclusively at the active site cysteine. We envisage this approach will enable covalent peptide inhibitor discovery for a range of related enzymes and expansion to alternative warheads in the future.

Peptidyl arginine deiminase 6 (PADI6 or PAD6) is vital for early embryonic development in mice and humans, yet its function remains elusive. PADI6 is less conserved than other PADIs and it is currently unknown whether it has a catalytic function. Here we show that human PADI6 dimerises like hPADIs 2–4, however, does not bind Ca2+ and is inactive in in vitro assays against standard PADI substrates. By determining the crystal structure of hPADI6, we show that hPADI6 is structured in the absence of Ca2+ where hPADI2 and hPADI4 are not, and the Ca-binding sites are not conserved. Moreover, we show that whilst the key catalytic aspartic acid and histidine residues are structurally conserved, the cysteine is displaced far from the active site centre and the hPADI6 active site pocket appears closed through a unique evolved mechanism in hPADI6, not present in the other PADIs. Taken together, these findings provide insight into how the function of hPADI6 may differ from the other PADIs based on its structure and provides a resource for characterising the damaging effect of clinically significant PADI6 variants.

Abstract Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses and cellular reprogramming, although the full extent of its physiological roles is unexplored. Despite detailed molecular knowledge of PADI4 activation in vitro, we lack understanding of its regulation within cells, largely due to a lack of appropriate systems and tools. Here, we develop and apply a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screen >1012 cyclic peptides for high-affinity, conformation-selective binders. We report PADI4_3, a cell-active inhibitor specific for the active conformation of PADI4; PADI4_7, an inert binder, which we functionalise for the isolation and study of cellular PADI4; and PADI4_11, a cell-active PADI4 activator. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes cellular PADI4 activation. This work contributes to our understanding of PADI4 regulation and provides a toolkit for the study and modulation of PADI4 across (patho)physiological contexts.

Abstract Background The double-blind, 2 × 2 factorial design, placebo-controlled ASCEND randomized trial compared the effects of 100 mg aspirin daily and, separately, 1 g omega-3 fatty acids (FAs) daily on the primary prevention of cardiovascular disease in 15,480 UK adults with diabetes. We report the effects of these randomized treatment allocations on scores derived from the National Eye Institute’s Visual Function Questionnaire-25 (NEI-VFQ-25) in a subset of participants involved in the ASCEND-Eye sub-study. Methods Ordinal data from the NEI-VFQ-25 were analyzed using proportional odds regression methods. A common odds ratio with a 95% confidence interval was used to interpret the average effect size of randomization to each study treatment on composite and subdomain scores from the questionnaire. Results Neither randomization to aspirin nor omega-3 FAs for 7.5 years significantly affected composite or subdomain scores from the NEI-VFQ-25. Conclusion Applying the NEI-VFQ-25 in ASCEND-Eye represents one of the largest surveys of vision-targeted health-related quality of life in people with diabetes. Further observational analyses of these data are planned, to identify the clinical and demographic characteristics associated with lower composite and subdomain scores in a diabetic population. Trial registration Eudract No. 2004–000991-15; Multicentre Research Ethics Committee Ref No. 03/8/087 (29th December 2003); ClinicalTrials.gov No. NCT00135226 (24th August 2005); ISRCTN No. ISRCTN60635500 (1st September 2005).

Introduction Prostate cancer (PCa) is the most common cancer in men. Recurrence may occur in up to half of patients initially treated with curative intent for high-risk localised/locally advanced PCa. Pelvic nodal recurrence is common in this setting, but no clear standard of care exists for these patients, with potential therapeutic approaches including stereotactic body radiotherapy (SBRT) to the involved node(s) alone, extended nodal irradiation (ENI) to treat sites of potential micrometastatic spread in addition to involved node(s) and androgen deprivation therapy with or without additional systemic anticancer therapies. Based on observational studies, ENI is associated with promising metastasis-free survival (MFS) compared with SBRT and appears to result in low rates of severe late toxicity.Methods and analysis Pelvis Or Involved Node Treatment: Eradicating Recurrence in Prostate Cancer is a UK multicentre, open-label, phase III randomised controlled trial, which will deliver much needed, high-quality evidence of the impact on metastatic progression from ENI compared with SBRT in patients with PCa pelvic nodal recurrence. The trial will also evaluate the long-term toxicity of 5-fraction ENI compared with a standard 20-fraction schedule. The trail will randomise 480 participants in a ratio of 2:1:1 to SBRT, 5-fraction ENI or 20-fraction ENI from 35 to 40 UK radiotherapy sites over 4 years. Coprimary endpoints are MFS at 3 years and participant-reported late bowel toxicity at 3 years. Secondary endpoints include overall survival, biochemical progression-free survival, failure-free survival, patterns of failure, participant-reported/clinician-reported toxicity and health-related quality of life. Collection of blood and tissue samples will enable future evaluation of biomarkers of disease and toxicity and support stratification of salvage therapeutic approaches.Ethics and dissemination Ethical approval was obtained from NHS Health Research Authority, East of England – Cambridgeshire and Hertfordshire Research Ethics Committee (24/EE/0099). Trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines.Trial registration number ISRCTN11089334, registered on 23 September 2024.

Abstract Background The National Institute of Health and Social Care Research (NIHR) Health Informatics Collaborative (HIC) for Hearing Health has been established in the UK to curate routinely collected hearing health data to address research questions. This study defines priority research areas, outlines its aims, governance structure and demonstrates how hearing health data have been integrated into a common data model using pure tone audiometry (PTA) as a case study. Methods After identifying key research aims in hearing health, the governance structure for the NIHR HIC for Hearing Health is described. The Observational Medical Outcomes Partnership (OMOP) was chosen as our common data model to provide a case study example. Results The NIHR HIC Hearing Health theme have developed a data architecture outlying the flow of data from all of the various siloed electronic patient record systems to allow the effective linkage of data from electronic patient record systems to research systems. Using PTAs as an example, OMOPification of hearing health data successfully collated a rich breadth of datapoints across multiple centres. Conclusion This study identified priority research areas where routinely collected hearing health data could be useful. It demonstrates integration and standardisation of such data into a common data model from multiple centres. By describing the process of data sharing across the HIC, we hope to invite more centres to contribute and utilise data to address research questions in hearing health. This national initiative has the power to transform UK hearing research and hearing care using routinely collected clinical data.

Abstract CRISPR-Cas9 technology has facilitated development of strategies that can potentially provide more humane and effective methods to control invasive vertebrate species, such as mice. One promising strategy is X chromosome shredding which aims to bias offspring towards males, resulting in a gradual and unsustainable decline of females. This method has been explored in insects with encouraging results. Here, we investigated this strategy in Mus musculus by targeting repeat DNA sequences on the X chromosome with the aim of inducing sufficient DNA damage to specifically eliminate X chromosome-bearing sperm during gametogenesis. We tested three different guide RNAs (gRNAs) targeting different repeats on the X chromosome, together with three male germline-specific promoters for inducing Cas9 expression at different stages of spermatogenesis. A modest bias towards mature Y-bearing sperm was detected in some transgenic males, although this did not translate into significant male-biasing of offspring. Instead, cleavage of the X chromosome during meiosis typically resulted in a spermatogenic block, manifest as small testes volume, empty tubules, low sperm concentration, and sub/infertility. Our study highlights the importance of controlling the timing of CRISPR-Cas9 activity during mammalian spermatogenesis and the sensitivity of spermatocytes to X chromosome disruption.

Abstract The post-landfall decay of tropical cyclones (TC) is often closely linked to the magnitude of damage to the environment, properties, and the loss of human lives. Despite growing interest in how climate change affects TC decay, data uncertainties still prevent a consensus on changes in TC decay rates and related precipitation. Here, after strict data-quality control, we show that the rate of decay of TCs after making landfall in China has significantly slowed down by 45% from 1967 to 2018. We find that, except the warmer sea surface temperature, the eastward shift of TC landfall locations also contributes to the slowdown of TC decay over China. That is TCs making landfall in eastern mainland China (EC) decay slower than that in southern mainland China (SC), and the eastward shift of TCs landfall locations causes more TCs landfalling in EC with slower decay rate. TCs making landfall in EC last longer at sea, carry more moisture upon landfall, and have more favorable dynamic and thermodynamic conditions sustaining them after landfall. Observational evidence shows that the decay of TC-induced precipitation amount and intensity within 48 h of landfall is positively related to the decay rate of landfalling TCs. The significant increase in TC-induced precipitation over the long term, due to the slower decay of landfalling TCs, increases flood risks in China’s coastal areas. Our results highlight evidence of a slowdown in TC decay rates at the regional scale. These findings provide scientific support for the need for better flood management and adaptation strategies in coastal areas under the threat of greater TC-induced precipitation.

BackgroundMany parents with a mental illness report a desire for both recognition of their parental role and support for themselves and their children. However, parents are often fearful of negative judgements from professionals about their ability to be a parent, which inhibits raising concerns about their children with clinical teams. Consequently, an essential first step to supporting families is for professionals to proactively identify which patients are parents, although evidence indicates this is not consistently part of services. Professionals could play a pivotal role in guiding parents about how to talk to their children about their mental illness; this in turn can facilitate family functioning and enable children to access evidence-based interventions. This approach is crucial for mitigating the well-documented intergenerational risk of poorer outcomes and mental illness in children of affected parents. This study aimed to explore adult mental healthcare professionals’ beliefs and experiences of talking with patients about: i) their role as parents ii) communication with their children about mental illness.MethodsSemi-structured qualitative interviews were conducted with 19 adult mental healthcare professionals with 4-30 years’ experience of working with adult patients under the care of NHS adult mental healthcare services in England. Audio recordings were transcribed verbatim and analysed using an inductive coding approach following the principles of thematic analysis.ResultAll participants recognised their responsibility to identify patients’ children through routine safeguarding protocols, but supporting patients around telling their children the diagnosis was less common. Many participants expressed concerns that raising the topic of children with patients could conflict with other parts of their professional role or would not be welcomed. Obstacles to these conversations were identified, across individual, environmental and organisational factors. Potential facilitators included specific staff training and resources for clinical teams and families around how to tell children about mental illness.ConclusionAdult mental healthcare professionals would benefit from enhanced training on the importance and methods of guiding parents to communicate with their children about mental illness. This should include routine identification of which patients are parents and recognition of the impact of an adult’s mental illness on the wider family system.

Engineered transfer RNA is an emerging therapeutic modality, particularly suited to treatment of diseases caused by genetic disorders based on premature termination codons, frameshifts, or missense mutations. It is also extensively used in reprogramming of in vitro translation systems to generate non-canonical amino acid-containing proteins and peptides, such as in mRNA display. Due to its length, chemical synthesis of tRNA is challenging and production of engineered tRNA at scale is currently limited to in vitro transcription from a DNA template. Previously, the highest reported in vitro transcription yield was 2.5 g/L, significantly below the industry standard for mRNA production of 7–10 g/L. To improve this process, we implemented monitoring of nucleoside triphosphate consumption and tRNA production during in vitro transcription, using at-line high-performance liquid chromatography, with a monolithic solid phase. This allowed for optimization of nucleoside triphosphate concentration, reduction of the in vitro transcription time to 90% step yield was then developed. These improvements in the production and purification of tRNA represent an important step in facilitating production of tRNA for research purposes, and provide a method for purification of therapeutic tRNAs that is scalable and compatible with Good Manufacturing Practice requirements for clinical production.

Abstract Anthropogenic climate change (ACC) strengthens the global terrestrial water cycle (TWC) through increases in annual total precipitation (PRCPTOT) over global land. While the increase in the average global terrestrial PRCPTOT has been attributed to ACC, it is unclear whether this is equally true in dry and wet regions, given the difference in PRCPTOT changes between the two climatic regions. Here, we show the increase in PRCPTOT in dry regions is twice as fast as in wet regions of the globe during 1961–2018 in both observations and simulations. This faster increase is projected to grow with future warming, with an intensified human-induced TWC in the driest regions of the globe. We show this phenomenon can be explained by the faster warming and precipitation response rates as well as the stronger moisture transport in dry regions under ACC. Quantitative detection and attribution results show that the global increase in PRCPTOT can no longer be attributed to ACC if dry regions are excluded. From 1961–2018, the observed PRCPTOT increased by 5.63%~7.39% (2.44%~2.80%) over dry (wet) regions, and as much as 89% (as little as 5%) can be attributed to ACC. The faster ACC-induced TWC in dry regions is likely to have both beneficial and detrimental effects on dry regions of the globe, simultaneously alleviating water scarcity while increasing the risk of major flooding.

Summary: Midbrain dopaminergic neurons (DANs) are subject to extensive metabotropic regulation, but the repertoire of G protein-coupled receptors (GPCRs) present in these neurons has not been mapped. Here, we isolate DANs from Dat-eGFP mice to generate a GPCR atlas by unbiased qPCR array expression analysis of 377 GPCRs. Combined with data mining of scRNA-seq databases, we identify multiple receptors in DAN subpopulations with 38 of these receptors representing the majority of transcripts. We identify 41 receptors expressed in midbrain DANs but not in non-DAN midbrain cells, including the free fatty acid receptor 4 (FFAR4). Functional expression of FFAR4 is validated by ex vivo Ca2+ imaging, and in vivo experiments support that FFAR4 negatively regulates food and water intake and bodyweight. In addition to providing a critical framework for understanding metabotropic DAN regulation, our data suggest fatty acid sensing by FFAR4 as a mechanism linking high-energy intake to the dopamine-reward pathway.

BackgroundThe period before, during, and after pregnancy presents an opportunity to reduce diabetes-related risks, which in Australia disproportionately impact Aboriginal and Torres Strait Islander women. Collaboration with Aboriginal and Torres Strait Islander women/communities is essential to ensure acceptability and sustainability of lifestyle modifications. Using a novel co-design approach, we aimed to identify shared priorities and potential lifestyle strategies. We also reflected on learnings from this approach.MethodsWe conducted 11 workshops and 8 interviews at two sites in Australia’s Northern Territory (Central Australia and Top End), using experience-based co-design (EBCD) and incorporating principles of First Nations participatory research. Workshops/interviews explored participant’ experiences and understanding of diabetes in pregnancy, contextual issues, and potential lifestyle strategies. Participants included three groups: 1) Aboriginal and Torres Strait Islander women of reproductive age (defined as aged 16-45 years); 2) Aboriginal and Torres Strait Islander community members; and 3) health/community services professionals. The study methodology sought to amplify the voices of Aboriginal women.FindingsParticipants included 23 women between ages 16-45 years (9 with known lived experience of diabetes in pregnancy), 5 community members and 23 health professionals. Key findings related to identified priority issues, strategies to address priorities, and reflections on use of EBCD methodology. Priorities were largely consistent across study regions: access to healthy foods and physical activity; connection to traditional practices and culture; communication regarding diabetes and related risks; and the difficulty for women of prioritising their health among competing priorities. Strategies included implementation of a holistic women’s program in Central Australia, while Top End participants expressed the desire to improve nutrition, peer support and community awareness of diabetes. EBCD provided a useful structure to explore participants’ experiences and collectively determine priorities, while allowing for modifications to ensure co-design methods were contextually appropriate. Challenges included the resource-intensive nature of stakeholder engagement, and collaborating effectively with services and communities when researchers were “outsiders”.ConclusionsA hybrid methodology using EBCD and First Nations participatory research principles enabled collaboration between Aboriginal women, communities and health services to identify shared priorities and solutions to reduce diabetes-related health risks. Genuine co-design processes support self-determination and enhance acceptability and sustainability of health strategies.

Abstract Ocean-onto-land droughts (OTLDs)—i.e., droughts originating over the oceans and migrating onto land—are a recently identified phenomenon with severe natural and human impacts. However, the influence of anthropogenic emissions on past and future changes in OTLDs and their underlying mechanisms remain unclear. Here, using precipitation-minus-evaporation deficits to identify global OTLDs, we find OTLDs have intensified due to anthropogenic climate change during the past 60 years. Under a future high-emissions scenario, the OTLDs would become more frequent (+39.68%), persistent (+54.25%), widespread (+448.92%), and severe (+612.78%) globally. Intensified OTLDs are associated with reduced moisture transport driven by subtropical anticyclones in the northern hemisphere and complex circulation patterns in the southern hemisphere. The reduction in moisture transport during OTLDs is mainly caused by the atmospheric thermodynamic responses to human-induced global warming. Our results underscore the importance of improving understanding of this type of drought and adopting climate mitigation measures.

Abstract Background The economic impact of managing long COVID in primary care is unknown. We estimated the costs of primary care consultations associated with long COVID and explored the relationship between risk factors and costs. Methods Data were obtained on non-hospitalised adults from the Clinical Practice Research Datalink Aurum primary care database. We used propensity score matching with an incremental cost method to estimate additional primary care consultation costs associated with long COVID (12 weeks after COVID-19) at an individual and UK national level. We applied multivariable regression models to estimate the association between risk factors and consultations costs beyond 12 weeks from acute COVID-19. Results Based on an analysis of 472,173 patients with COVID-19 and 472,173 unexposed individuals, the annual incremental cost of primary care consultations associated with long COVID was £2.44 per patient and £23,382,452 at the national level. Among patients with COVID-19, a long COVID diagnosis and reporting of longer-term symptoms were associated with a 43% and 44% increase in primary care consultation costs respectively, compared to patients without long COVID symptoms. Older age, female sex, obesity, being from a white ethnic group, comorbidities and prior consultation frequency were all associated with increased primary care consultation costs. Conclusions The costs of primary care consultations associated with long COVID in non-hospitalised adults are substantial. Costs are significantly higher among those diagnosed with long COVID, those with long COVID symptoms, older adults, females, and those with obesity and comorbidities.

Abstract Global warming increases the atmospheric water‐holding capacity, consequently altering the frequency, and intensity of extreme hydrological events. River floods characterized by large peak flow or prolonged duration can amplify the risk of social disruption and affect ecosystem stability. However, previous studies have mostly focused on univariate flood magnitude characteristics, such as flood peak or volume, and there is still limited understanding of how these joint flood characteristics (i.e., magnitude and duration) might co‐evolve under different warming levels. Here, we develop a systematical bivariate framework to project future flood risk in 11,528 catchments across the globe. By constructing the joint distribution of flood peak and duration with copulas, we examine global flood risk with a bivariate framework under varying levels of global warming (i.e., within a range of 1.5–3.0°C above pre‐industrial levels). The flood projections are produced by driving five calibrated lumped hydrological models (HMs) using the simulations with bias adjustment of five global climate models (GCMs) under three shared socioeconomic pathways (SSP126, SSP370, and SSP585). On average, global warming from 1.5 to 3.0°C tends to amplify flood peak and lengthen flood duration across almost all continents, but changes are not unidirectional and vary regionally around the globe. The joint return period (JRP) of the historical (1985–2014) 50‐year flood event is projected to decrease to a median with 36 years under a medium emission pathway at the 1.5°C warming level. Finally, we evaluate the drivers of these JRP changes in the future climate and quantify the uncertainty arising from the different GCMs, SSPs, and HMs. Our findings highlight the importance of limiting greenhouse gas emission to slow down global warming and developing climate adaptation strategies to address future flood hazards.

Objectives Leadership knowledge and skills are known to be developed by health professionals during global health experiences overseas. However, volunteers struggle to recognise and use these new skills on return to their workplace. A series of bespoke leadership workshops were designed, delivered and evaluated by leadership experts to help enhance the transferability of leadership skills back to the UK National Health Service.Design A mixed-methods participatory action research methodology was employed to explore the impact of the workshops. This approach lends itself to a complex, situated project involving multiple partners. Quantitative and qualitative descriptive data were collected via online survey (n=29 participants) and focus groups (n=18 focus groups) and thematically analysed.Setting The authors delivered the tailored leadership workshops online to globally engaged National Health Service (NHS) healthcare professionals based in England who had all worked overseas within the past 5 years.Participants 29 participants attended: 11 medical doctors; 6 nurses/midwives; 10 allied health professionals; 1 NHS manager and 1 student nurse (who was also working as a healthcare assistant).Results Participants were able to network both during the large group discussions and while in smaller breakout groups. Data highlighted the substantial benefits obtained from this networking, with 91% of participants reporting it enriched their learning experience, particularly within a multi-disciplinary context, and by having the time and space for facilitated reflection on leadership. Furthermore, 78% agreed that they learned new skills for influencing change beyond their position and 76% reported they could maximise the impact of this change for themselves and their employer. Participants also reported the development of systems and ethical leadership knowledge that they felt they could transfer to their NHS roles.Conclusions This study extends explorations of global health experiences by moving beyond the skills gained while working in low-income and middle-income countries. The innovative online leadership workshops gave agency to individuals to recognise and use the skills gained from global health placements on return to the NHS.

Summary: Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3–4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor β partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.

Abstract Increasing atmospheric moisture content is expected to intensify precipitation extremes under climate warming. However, extreme precipitation sensitivity (EPS) to temperature is complicated by the presence of reduced or hook-shaped scaling, and the underlying physical mechanisms remain unclear. Here, by using atmospheric reanalysis and climate model projections, we propose a physical decomposition of EPS into thermodynamic and dynamic components (i.e., the effects of atmospheric moisture and vertical ascent velocity) at a global scale in both historical and future climates. Unlike previous expectations, we find that thermodynamics do not always contribute to precipitation intensification, with the lapse rate effect and the pressure component partly offsetting positive EPS. Large anomalies in future EPS projections (with lower and upper quartiles of −1.9%/°C and 8.0%/°C) are caused by changes in updraft strength (i.e., the dynamic component), with a contrast of positive anomalies over oceans and negative anomalies over land areas. These findings reveal counteracting effects of atmospheric thermodynamics and dynamics on EPS, and underscore the importance of understanding precipitation extremes by decomposing thermodynamic effects into more detailed terms.

Abstract Background Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. Methods We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons’ preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants’ preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. Discussion This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. Trial registration ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Abstract Photoaffinity labelling is a promising method for studying protein-ligand interactions. However, obtaining a specific, efficient crosslinker can require significant optimisation. We report a modified mRNA display strategy, photocrosslinking-RaPID (XL-RaPID), and exploit its ability to accelerate the discovery of cyclic peptides that photocrosslink to a target of interest. As a proof of concept, we generated a benzophenone-containing library and applied XL-RaPID screening against a model target, the second bromodomain of BRD3. This crosslinking screening gave two optimal candidates that selectively labelled the target protein in cell lysate. Overall, this work introduces direct photocrosslinking screening as a versatile technique for identifying covalent peptide ligands from mRNA display libraries incorporating reactive warheads.

Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders. Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies. Results: Autosomal recessive (AR) modeling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These “knockout” regions included 37 genes, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of NPHP1, followed by OTOA, both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed “knockout” patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families. Conclusion: A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy.

Abstract Subseasonal rainfall forecast skill is critical to support preparedness for hydrometeorological extremes. We assess how a process‐informed evaluation, which subsamples forecasting model members based on their ability to represent potential predictors of rainfall, can improve monthly rainfall forecasts within Central America in the following month, using Costa Rica and Guatemala as test cases. We generate a constrained ensemble mean by subsampling 130 members from five dynamic forecasting models in the C3S multimodel ensemble based on their representation of both (a) zonal wind direction and (b) Pacific and Atlantic sea surface temperatures (SSTs), at the time of initialization. Our results show in multiple months and locations increased mean squared error skill by 0.4 and improved detection rates of rainfall extremes. This method is transferrable to other regions driven by slowly‐changing processes. Process‐informed subsampling is successful because it identifies members that fail to represent the entire rainfall distribution when wind/SST error increases.

Abstract Greening of Northern China and the Tibetan Plateau (NCTP) has been observed by increases in the remotely sensed leaf area index (LAI), driven primarily by CO2 fertilization effects, anthropogenic warming, and the implementation of ecological restoration programs. Continued growth of LAI throughout the 21st century is also projected by the Coupled Model Intercomparison Project Phase 6 (CMIP6) scenarios. However, the question of whether local water resources can sustain ongoing grassland greening has not been adequately investigated. Here we assessed the sustainability of water resources under grassland greening across NCTP under various climate scenarios using water yield (WY, defined as precipitation minus actual evapotranspiration) as the key metric. Unexpectedly, we observe the coexistence of increases in LAI and WY in most of NCTP. In a warming climate with increasing precipitation and CO2, we find that grasses maintain high water use efficiency to sustain their growth, contributing to continued local water resource availability. Thus, livestock production may also continue to increase under the simultaneous growth of LAI and WY in the future.

Abstract High air temperatures and low atmospheric humidity can result in severe disasters such as flash droughts in regions characterized by high humidity (monsoon regions). However, it remains unclear whether responses of hot extremes to warming temperature are amplified on dry days as well as the response of dry extremes on hot days. Here, taking eastern monsoon China (EMC) as a typical monsoon region, we find a faster increase in air temperature on drier summer days, and a faster decrease in atmospheric humidity on hotter days, indicating “hotter days get drier” and “drier days get hotter” (i.e., coupling hotter and drier extremes), especially in southern EMC. The southern EMC is also a hotspot where the coupling hot‐dry extremes has become significantly stronger during the past six decades. The stronger hot‐dry coupling in southern EMC is associated with anomalies in large‐scale circulations, such as reduced total cloud cover, abnormal anticyclones in the upper atmosphere, intense descending motion, and strong moisture divergence over this region. Land‐atmosphere feedback enhance the hot‐dry coupling in southern EMC by increasing land surface dryness (seen as a decrease in the evaporation fraction). The decreasing evaporation fraction is associated with drying surface soil moisture, controlled by decreases in pre‐summer 1‐m soil moisture and summer‐mean precipitation. Given hot extremes are projected to increase and atmospheric humidity is predicted to decrease in the future, it is very likely that increasing hot‐dry days and associated disasters will be witnessed in monsoon regions, which should be mitigated against by adopting adaptive measures.

Abstract Even with extensive transfusion support, trauma-induced bleeding often leads to death. Early intervention may improve outcomes, yet which blood products, factor concentrates, or other drugs constitute optimal treatment is unclear. Patients with acute traumatic coagulopathy (ATC), arising from trauma and haemorrhagic shock, have the worst prognosis. Here, multiple interventions were compared in a mouse model of ATC. After the trauma of tissue excision, anaesthetized mice were bled to 35 mm Hg mean arterial pressure, maintained under shock for 60 min, and resuscitated with fluids equal in volume to the shed blood. Resuscitated mice were subjected to liver laceration to test haemostasis and blood loss was quantified. Saline-treated mice lost two- to three-fold more blood than sham-treated animals and were coagulopathic by prothrombin time elevation post- versus pre-procedure. Murine fresh-frozen plasma (mFFP), anti-activated protein C aptamer HS02-52G, or prothrombin complex concentrates eliminated the bleeding diathesis and coagulopathy; fibrinogen, plasminogen activator inhibitor-1, or tranexamic acid ameliorated bleeding or coagulopathy, but not both. HS02-52G and mFFP also eliminated the changes in plasma aPC and tissue plasminogen activator levels observed in saline-treated mice, as judged via microtiter plate biomarker assays. Procoagulant interventions, especially inhibiting aPC, could be beneficial in human ATC.

Abstract Background Given that common mental disorders are one of the leading causes of disease burden worldwide, it is likely that many children are growing up with a parent or other adult within their family who has anxiety or depression. Parents with a mental illness may not consider it appropriate to discuss their illness with their child, and consequently an absence of communication may lead to stigmatization, shame, misunderstanding their parents’ symptoms, and even blaming themselves. There is a scarcity of research exploring the experiences and perceptions of healthcare professionals about communication with children of parents with mental illness in low-resource and African contexts. Methods A qualitative study using semi-structured interviews with healthcare professionals (n = 15) was conducted within the Bushbuckridge sub-district of Mpumalanga Province, South Africa. Data were analysed using Thematic Analysis. Results Four themes were identified relating to the obstacles around communication with children. These included: (1) finding an appropriate language to describe mental illness, as well as the prevailing cultural explanations of mental illness (2) the stigma associated with mental illness (3) the perceived role of children in society and (4) mental health services and staff skills. Two themes that addressed facilitators of communication about parental mental illness were identified: (1) the potential to increase mental health awareness amongst the broader community through social media, the internet, and general psychoeducation (2) healthcare professionals’ concerns for the wellbeing and future mental health of patients’ children, as well as their hopes for increased mental health awareness amongst future generations. Conclusions This study provides insight into healthcare professionals’ attitudes and perceptions about talking to patients and families within their community about mental illness. The results provide recommendations about possible ways to promote sharing information about a parent’s mental illness with children at an individual and community level. Future research should focus on the collaborative creation of culturally sensitive psychoeducational resources and evidence-based guidelines. This must be supported by systemic and organisational change in order for professionals to successfully facilitate conversations with patients who are parents, and their children.

Abstract Background/objective Sexually transmitted infections (STIs) not only have an impact on the health sector but also the private resources of those affected, their families and other sectors of society (i.e. labour, education). This study aimed to i) review and identify economic evaluations of interventions relating to STIs, which aimed to include a societal perspective; ii) analyse the intersectoral costs (i.e. costs broader than healthcare) included; iii) categorise these costs by sector; and iv) assess the impact of intersectoral costs on the overall study results. Methods Seven databases were searched: MEDLINE (PubMed), EMBASE (Ovid), Web of Science, CINAHL, PsycINFO, EconLit and NHS EED. Key search terms included terms for economic evaluation, STIs and specific infections. This review considered trial- and model-based economic evaluations conducted in an OECD member country. Studies were included that assessed intersectoral costs. Intersectoral costs were extracted and categorised by sector using Drummond’s cost classification scheme (i.e. patient/family, productivity, costs in other sectors). A narrative synthesis was performed. Results Twenty-nine studies qualified for data extraction and narrative synthesis. Twenty-eight studies applied a societal perspective of which 8 additionally adopted a healthcare or payer perspective, or both. One study used a modified payer perspective. The following sectors were identified: patient/family, informal care, paid labour (productivity), non-paid opportunity costs, education, and consumption. Patient/family costs were captured in 11 studies and included patient time, travel expenses, out-of-pocket costs and premature burial costs. Informal caregiver support (non-family) and unpaid help by family/friends was captured in three studies. Paid labour losses were assessed in all but three studies. Three studies also captured the costs and inability to perform non-paid work. Educational costs and future non-health consumption costs were each captured in one study. The inclusion of intersectoral costs resulted in more favourable cost estimates. Conclusions This systematic review suggests that economic evaluations of interventions relating to STIs that adopt a societal perspective tend to be limited in scope. There is an urgent need for economic evaluations to be more comprehensive in order to allow policy/decision-makers to make better-informed decisions.

Abstract In July 2021, Typhoon In‐Fa produced record‐breaking extreme precipitation events (hereafter referred to as the 2021 EPEs) in central and eastern China, and caused serious socioeconomic losses and casualties. However, it is still unknown whether the 2021 EPEs can be attributed to anthropogenic climate change (ACC) and how the occurrence probabilities of precipitation events of a similar magnitude might evolve in the future. The 2021 EPEs in central (eastern) China occurred in the context of no linear trend (a significantly increasing trend at a rate of 4.44%/decade) in the region‐averaged Rx5day (summer maximum 5‐day accumulated precipitation) percentage precipitation anomaly (PPA), indicating that global warming might have no impact on the 2021 EPE in central China but might have impacted the 2021 EPE in eastern China by increasing the long‐term trend of EPEs. Using the scaled generalized extreme value distribution, we detected a slightly negative (significantly positive) association of the Rx5day PPA time series in central (eastern) China with the global mean temperature anomaly, suggesting that global warming might have no (a detectable) contribution to the changes in occurrence probability of precipitation extremes like the 2021 EPEs in central (eastern) China. Historical attributions (1961–2020) showed that the likelihood of the 2021 EPE in central/eastern China decreased/increased by approximately +47% (−23% to +89%)/+55% (−45% to +201%) due to ACC. By the end of the 21st century, the likelihood of precipitation extremes similar to the 2021 EPE in central/eastern China under SSP585 is 14 (9–19)/15 (9–20) times higher than under historical climate conditions.

Abstract Objective To update the systematic review which informed the National Institute for Health and Care Excellence guideline “Inducing Labour” (NG207), including additional data and analyses, and comparison with a recent individual patient data analysis of 41‐ versus 42‐week induction. Search Strategy Multiple database search (including Cochrane Central Register of Controlled Trials, MEDLINE, and Embase) from inception to 10th September 2021 for randomised controlled trials (RCTs) comparing different induction timing in uncomplicated singleton pregnancies. Data Collection and Analysis One reviewer screened, extracted, analysed, and assessed the quality/certainty of the evidence (using ROB1 and GRADE), with second reviewer verification. Main Results Five week‐to‐week comparisons, and one overall comparison (induction vs. delayed induction, 20 RCTs, n = 15 725 pregnant women) for assessment of predefined subgroups. Most data were for 41 versus 42 weeks and 39 versus 41 weeks: 10 times as many participants as the other week‐to‐week comparisons. There was evidence of an effect at 41 versus 42 weeks (five RCTs, n = 5819) in favour of 41‐week induction: fewer perinatal deaths and neonatal intensive care unit admissions (low‐to‐moderate certainty of the evidence); there was no evidence of an effect in either direction for the remaining outcomes (very‐low to moderate certainty). There was no evidence of an effect for outcomes reported for: 40 versus 42 weeks (three RCTs, n = 668, very‐low to low certainty); 39 versus 42 weeks (three RCTs, n = 1103, very‐low to moderate certainty); 39 versus 41 weeks (four RCTs, n = 7101, very‐low to low certainty); and 41/42 versus 43/44 weeks (four RCTs, n = 954, very‐low to low certainty). Conclusion The evidence supports offering induction at 41 + 0 weeks compared to 42 + 0 weeks to reduce adverse perinatal and obstetric outcomes.

Abstract Background Perinatal healthcare professionals (PHCPs) provide essential support to all parents in the perinatal period, including young parents aged 16–24, who are at an increased risk of morbidity and mortality. Little is known about the impact of COVID-19 restrictions on the provision of perinatal services, and on perinatal healthcare professionals, caring for young parents in the UK. Methods A UK based qualitative study using semi-structured interviews with perinatal healthcare professionals (n = 17). Data were analysed using thematic analysis. Results Two themes were identified describing perinatal healthcare professionals’ perceptions of providing care to young parents during the pandemic. Perinatal healthcare professionals perceived that young parents’ needs were amplified by the pandemic and that pandemic-related changes to the service, such as the use of telemedicine to replace face-to-face interactions, did not manage to successfully mitigate the increased feelings of anxiety and isolation experienced by young parents. Concerns were raised by perinatal healthcare professionals that these changes reduced young parent’s access to vital support for themselves and their child and may contribute to exacerbating pre-existing inequalities. Conclusions This study provides insight into the impact of the COVID-19 pandemic on the provision of perinatal care to young parents. Perinatal mental health professionals felt these negative impacts could be overcome by using a blended approach of technology and face-to-face interactions allowing regular contact with young parents and facilitating the exchange of vital information, while maintaining access to opportunities for social interactions with other parents. Findings from this study could be used to future-proof services against further COVID-19 restrictions.

Plastic pollution in rivers is of increased global concern. Rivers act both as pathways for land-based plastic waste into the ocean, and as plastic reservoirs for long-term retention. Reliable observations are key to designing, optimizing and evaluating strategies to prevent and reduce plastic pollution. Several measurement methods have been developed to quantify macroplastic (>0.5 cm) storage and transport in rivers, including visual counting from bridges, net sampling, and images-based techniques. Method harmonization is crucial to make sure data collected using different techniques remains consistent. In turn, this would allow for comparative analysis of plastic pollution within and between rivers. In this paper, we present a harmonization approach to estimate floating plastic item and mass transport from data collected using different methods. The approach allows estimating the same values based on different measurement methods and data collection protocols. We applied our approach to the Mekong-Tonlé Sap-Bassac river system around the city of Phnom Penh, Cambodia. We estimated the floating plastic item and mass transport in the wet and dry season by combining data from net sampling and visual counting. During the wet season, plastic transport in the Mekong increased with a factor of up to 170 (item transport) and 294 (mass transport) compared to the dry season. The river plastic mass balance around Phnom Penh changed considerably, which was mainly due to the flow reversal of Tonlé Sap river between the wet and dry season. Downstream of Phnom Penh, the total plastic transport was consistently higher than upstream, although less in the wet season (1.5–1.7 times) compared to the dry season (3.8–5.9 times), emphasizing the city’s role as entry point of plastic pollution into the Mekong. The largest sources of uncertainty are assumed to be caused by key differences between methods, including the size ranges, extrapolation from observation point to full river width, and the contribution of submerged plastic to the total transport. Future work should focus on including data from other methods than net sampling and visual counting, and reducing the uncertainties related to combining data from different methods. Our results show that river plastic transport dynamics are highly variable over time and space, especially around confluences, bifurcations and urban areas. With our paper we aim to contribute to further harmonization of river plastic monitoring.

BackgroundReducing the rates of sexually transmitted infections (STIs) among young people is a public health priority. The best way to avoid STIs from penetrative sex is to use a condom, but young people report inconsistent use. A missed opportunity to intervene to increase condom use is when young people access self-sampling kits for STIs through the internet. The potential of this opportunity is enhanced by the increasing numbers of young people being tested through this route every year in England. Hence, in a cocreation by young people, stakeholders, and researchers, Wrapped was developed––a fully automated, multicomponent, and interactive digital behavior change intervention developed for users of STI self-sampling websites, who are aged 16-24 years. ObjectiveThis paper is a protocol for a feasibility randomized controlled trial (fRCT). The fRCT seeks to establish whether it is feasible to run a randomized controlled trial to test the effectiveness and cost-effectiveness of Wrapped. Wrapped aims to reduce the incidence of STIs through increasing correct and consistent use of condoms among users of STI self-sampling websites, who are aged 16-24 years. MethodsA 2-arm parallel-group randomized fRCT of Wrapped plus usual care, compared to usual care only (basic information on STIs and condom use), with a nested qualitative study. A minimum of 230 participants (aged 16-24 years) are recruited from an existing chlamydia self-sampling website. Participants are randomized into 1 of 2 parallel groups (1:1 allocation). Primary outcomes are the percentage of users recruited to the fRCT and the percentage of randomized participants who return a chlamydia self-sampling kit at month 12. Additionally, besides chlamydia positivity based on biological samples, surveys at baseline, month 3, month 6, and month 12, are used to assess condom use attitude, behavioral capability, self-efficacy, and intention, along with details of any partnered sexual activity and condom use, and health economic data. Nested qualitative interviews with trial participants are used to gain insight into the factors affecting recruitment and attrition. ResultsRecruitment to the fRCT began in March 2021 and was completed in October 2021. Data collection was completed in December 2022. ConclusionsThis feasibility study will provide data to inform the design of a future-definitive trial. This work is timely given a rapid rise in the use of internet testing for STIs and the sustained high levels of STIs among young people. Trial RegistrationISRCTN Registry ISRCTN17478654; http://www.isrctn.com/ISRCTN17478654 International Registered Report Identifier (IRRID)DERR1-10.2196/43645

Summary Hydrogen is a clean alternative to fossil fuels. It has applications for electricity generation and transportation and is used for the manufacturing of ammonia and steel. However, today, H2 is almost exclusively produced from coal and natural gas. As such, methods to produce H2 that do not use fossil fuels need to be developed and adopted. The biological manufacturing of H2 may be one promising solution as this process is clean and renewable. Hydrogen is produced biologically via enzymes called hydrogenases. There are three classes of hydrogenases namely [FeFe], [NiFe] and [Fe] hydrogenases. The [FeFe] hydrogenase HydA1 from the model unicellular algae Chlamydomonas reinhardtii has been studied extensively and belongs to the A1 subclass of [FeFe] hydrogenases that have the highest turnover frequencies amongst hydrogenases (21,000 ± 12,000 H2 s−1 for CaHydA from Clostridium acetobutyliticum). Yet to date, limitations in C. reinhardtii H2 production pathways have hampered commercial scale implementation, in part due to O2 sensitivity of hydrogenases and competing metabolic pathways, resulting in low H2 production efficiency. Here, we describe key processes in the biogenesis of HydA1 and H2 production pathways in C. reinhardtii. We also summarize recent advancements of algal H2 production using synthetic biology and describe valuable tools such as high‐throughput screening (HTS) assays to accelerate the process of engineering algae for commercial biological H2 production.

Reduction of uncertainty in climate projections is a key issue for climate change adaptation. Here the authors show that an applying an emergent constraint effectively reduces projection uncertainty across Asia, and reveals less warming and a slower increase in water availability than previously estimated.

Abstract Platelets mediate arterial thrombosis, a leading cause of myocardial infarction and stroke. During injury, platelets adhere and spread over exposed subendothelial matrix substrates of the damaged blood vessel wall. The mechanisms which govern platelet activation and their interaction with a range of substrates are therefore regularly investigated using platelet spreading assays. These assays often use differential interference contrast (DIC) microscopy to assess platelet morphology and analysis performed using manual annotation. Here, a convolutional neural network (CNN) allowed fully automated analysis of platelet spreading assays captured by DIC microscopy. The CNN was trained using 120 generalised training images. Increasing the number of training images increases the mean average precision of the CNN. The CNN performance was compared to six manual annotators. Significant variation was observed between annotators, highlighting bias when manual analysis is performed. The CNN effectively analysed platelet morphology when platelets spread over a range of substrates (CRP-XL, vWF and fibrinogen), in the presence and absence of inhibitors (dasatinib, ibrutinib and PRT-060318) and agonist (thrombin), with results consistent in quantifying spread platelet area which is comparable to published literature. The application of a CNN enables, for the first time, automated analysis of platelet spreading assays captured by DIC microscopy.

Abstract Young parents (aged 16–24 years) in the perinatal period are at an increased risk of poor mental health especially during the COVID-19 pandemic, due to multiple risk factors including social and economic instability. COVID-19 related restrictions had profound implications for the delivery of perinatal care services and other support structures for young parents. Investigating young parents’ experiences during the pandemic, including their perceived challenges and needs, is important to inform good practice and provide appropriate support for young parents. Qualitative interviews were conducted with young parents (n = 21) during the COVID-19 pandemic in the United Kingdom from February – May 2021. Data were analysed using thematic analysis. Three key themes were identified to describe parents’ experiences during the COVID-19 pandemic. Parents reported specific COVID-19 related anxieties and stressors, including worries around contracting the virus and increased feelings of distress due to uncertainty created by the implications of the pandemic. Parents described feeling alone both at home and during antenatal appointments and highlighted the absence of social support as a major area of concern. Parents also felt their perinatal care had been disrupted by the pandemic and experienced difficulties accessing care online or over the phone. This study highlights the potential impact of the COVID-19 pandemic on young parents, including their mental wellbeing and the perinatal support they were able to access. Insights from this study can inform the support and services offered to families going forward. Specifically, the findings emphasise the importance of (a) supporting both parents during perinatal appointments, (b) providing parents with mental health support early on and (c) finding ways to facilitate communication pathways between professionals and parents.

Abstract Recent decadal changes in tropical cyclone (TC) frequency since the mid‐1990s have been widely reported; however, it is unclear whether there have also been any changes in TC translation distance. Here, we show that long‐term decrease in global TC translation distance during 1975–2020 is caused by an abrupt change point around the year 1997. This change point marks a switch between an increasing translation distance during 1975–1997 and decreasing translation distance during 1998–2020. The shift in TC translation distance is attributed to changes in the distance between the location of TC genesis and land, and the percentage of landfalling TCs to all TCs, which is driven by the Pacific Decadal Oscillation (PDO) and Atlantic Multidecadal Oscillation (AMO) phase switch in the mid‐1990s. In the last 20 years, the cool, La Niña‐like sea surface temperatures (SST) during the PDO negative phase and the warm SST pattern during the AMO positive phase have enhanced the genesis potential index and the potential intensity in offshore areas, resulting in greater TC genesis landward. Phase shifts of PDO and AMO modulate environmental conditions, regulating TC genesis location and landfall frequency, and their combined effects on the translation distance of Pacific TCs. The warm SST anomalies during the AMO positive phase enhance these circulation patterns in two possible ways: via the Indian Ocean and the subtropical eastern Pacific relaying effects at a multidecadal timescale. Our findings suggest that the PDO and AMO act as key pacemakers for decadal changes in global TC translation distance.

Abstract The urgent need to scale up testing capacity during the COVID-19 pandemic has prompted the rapid development of point-of-care diagnostic tools such as lateral flow immunoassays (LFIA) for large-scale community-based rapid testing. However, studies of how the general public perform when using LFIA tests in different environmental settings are scarce. This user experience (UX) study of 264 participants in Northern Ireland aimed to gather a better understanding of how self-administered LFIA tests were performed by the general public at home. The UX performance was assessed via analysis of a post-test questionnaire including 30 polar questions and 11 7-point Likert scale questions, which covers the multidimensional aspects of UX in terms of ease of use, effectiveness, efficiency, accuracy and satisfaction. Results show that 96.6% of participants completed the test with an overall average UX score of 95.27% [95% confidence interval (CI) 92.71–97.83%], which suggests a good degree of user experience and effectiveness. Efficiency was assessed based on the use of physical resources and human support received, together with the mental effort of self-administering the test measured via NASA Task Load Index (TLX). The results for six TLX subscales show that the participants scored the test highest for mental demand and lowest for physical demand, but the average TLX score suggests that the general public have a relatively low level of mental workload when using LFIA self-testing at home. Five printed LFIA testing results (i.e. the ‘simulated’ results) were used as the ground truth to assess the participant’s performance in interpreting the test results. The overall agreement (accuracy) was 80.63% [95% CI 75.21–86.05%] with a Kappa score 0.67 [95% CI 0.58–0.75] indicating substantial agreement. The users scored lower in confidence when interpreting test results that were weak positive cases (due to the relatively low signal intensity in the test-line) compared to strong positive cases. The end-users also found that the kit was easier to use than they expected (p < 0.001) and 231 of 264 (87.5%) reported that the test kit would meet their requirements if they needed an antibody testing kit. The overall findings provide an insight into the opportunities for improving the design of self-administered SARS-CoV-2 antibody testing kits for the general public and to inform protocols for future UX studies of LFIA rapid test kits.

Abstract Background Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well‐recognised problem but other allergic conditions are less well documented in CF. Objective To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. Methods A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. Results The cohort included 37 children with median age of 9 years (interquartile range: 6‐12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross‐sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

Objectives This study aimed to explore how published communication frameworks could be amended to ensure applicability and cultural appropriateness for professionals to support family-centred conversations by investigating’ healthcare professionals’ (1) experiences of providing support to families when a caregiver or a dependent child (

Objectives Sexual health is a complex public health challenge and can generate wide-ranging health, social and economic impacts both within and beyond the health sector (ie, intersectoral costs and benefits). Methods are needed to capture these intersectoral impacts in economic studies to optimally inform policy/decision-making. The objectives of this study were (1) to explore the different intersectoral costs and benefits associated with sexual health issues and interventions, (2) to categorise these into sectors and (3) to develop a preliminary framework to better understand these impacts and to guide future research and policy.Design A qualitative study based on in-depth semi-structured online interviews.Setting OECD (Organisation for Economic Co-operation and Development) member countries.Participants Professionals with expertise in the field of sexual health including clinicians, medical practitioners, sexologists, researchers, professionals working for international governmental or non-governmental health (policy) organisations and professionals involved in implementation and/or evaluation of sexual health interventions/programmes.Methods Sampling of participants was undertaken purposively. We conducted in-depth semi-structured online interviews to allow for a systemic coverage of key topics and for new ideas to emerge. We applied a Framework approach for thematic data analysis.Results 28 experts were interviewed. Six themes emerged from the interviews: (1) Interconnections to other areas of health (ie, reproductive health, mental health), (2) Relationships and family, (3) Productivity and labour, (4) Education, (5) Criminal justice/sexual violence, (6) Housing, addiction and other sectors. The findings confirm that sexual health is complex and can generate wide-ranging impacts on other areas of health and other non-health sectors of society.Conclusion These different sectors need to be considered when evaluating interventions and making policy decisions. The preliminary framework can help guide future research and policy/decision-making. Future research could explore additional sectors not covered in this study and expand the preliminary framework.

Introduction The past decade has seen a rapid increase in the volume and proportion of testing for sexually transmitted infections that are accessed via online postal self-sampling services in the UK. ASSIST (Assessing the impact of online postal self-sampling for sexually transmitted infections on health inequalities, access to care and clinical outcomes in the UK) aims to assess the impact of these services on health inequalities, access to care, and clinical and economic outcomes, and to identify the factors that influence the implementation and sustainability of these services.Methods and analysis ASSIST is a mixed-methods, realist evaluated, national study with an in-depth focus of three case study areas (Birmingham, London and Sheffield). An impact evaluation, economic evaluation and implementation evaluation will be conducted. Findings from these evaluations will be analysed together to develop programme theories that explain the outcomes. Data collection includes quantitative data (using national, clinic based and online datasets); qualitative interviews with service users, healthcare professionals and key stakeholders; contextual observations and documentary analysis. STATA 17 and NVivo will be used to conduct the quantitative and qualitative analysis, respectively.Ethics and dissemination This study has been approved by South Central – Berkshire Research Ethics Committee (ref: 21/SC/0223). All quantitative data accessed and collected will be anonymous. Participants involved with qualitative interviews will be asked for informed consent, and data collected will be anonymised.Our dissemination strategy has been developed to access and engage key audiences in a timely manner and findings will be disseminated via the study website, social media, in peer-reviewed scientific journals, at research conferences, local meetings and seminars and at a concluding dissemination and networking event for stakeholders.

The collection of dried blood spots (DBS) facilitates newborn screening for a variety of rare, but very serious conditions in healthcare systems around the world. Sub-punches of varying sizes (1.5–6 mm) can be taken from DBS specimens to use as inputs for a range of biochemical assays. Advances in DNA sequencing workflows allow whole-genome sequencing (WGS) libraries to be generated directly from inputs such as peripheral blood, saliva, and DBS. We compared WGS metrics obtained from libraries generated directly from DBS to those generated from DNA extracted from peripheral blood, the standard input for this type of assay. We explored the flexibility of DBS as an input for WGS by altering the punch number and size as inputs to the assay. We showed that WGS libraries can be successfully generated from a variety of DBS inputs, including a single 3 mm or 6 mm diameter punch, with equivalent data quality observed across a number of key metrics of importance in the detection of gene variants. We observed no difference in the performance of DBS and peripheral-blood-extracted DNA in the detection of likely pathogenic gene variants in samples taken from individuals with cystic fibrosis or phenylketonuria. WGS can be performed directly from DBS and is a powerful method for the rapid discovery of clinically relevant, disease-causing gene variants.

Abstract Background Sexually transmitted infections (STIs) and HIV can generate costs both within and outside the health sector (i.e. intersectoral costs). This systematic review aims (i) to explore the intersectoral costs associated with STIs and HIV considered in cost-of-illness (COI) studies, (ii) to categorise and analyse these costs according to cost sectors, and (iii) to illustrate the impact of intersectoral costs on the total cost burden. Methods Medline (PubMed), EMBASE (Ovid), Web of Science, CINAHL, PsycINFO, EconLit and NHS EED were searched between 2009 and 2019. Key search terms included terms for cost-of-illness, cost analysis and all terms for STIs including specific infections. Studies were included that assessed intersectoral costs. A standardised data extraction form was adopted. A cost component table was established based on pre-defined sector-specific classification schemes. Cost results for intersectoral costs were recorded. The quality of studies was assessed using a modified version of the CHEC-list. Results 75 COI studies were considered for title/abstract screening. Only six studies were available in full-text and eligible for data extraction and narrative synthesis. Intersectoral costs were captured in the following sectors: Patient & family, Informal care and Productivity (Paid Labour). Patient & family costs were addressed in four studies, including patient out-of-pocket payments/co-payments and travel costs. Informal care costs including unpaid (home) care support by family/friends and other caregiver costs were considered in three studies. All six studies estimated productivity costs for paid labour including costs in terms of absenteeism, disability, cease-to-work, presenteeism and premature death. Intersectoral costs largely contributed to the total economic cost burden of STIs and HIV. The quality assessment revealed methodological differences. Conclusions It is evident that intersectoral costs associated with STIs and HIV are substantial. If relevant intersectoral costs are not included in cost analyses the total cost burden of STIs and HIV to society is severely underestimated. Therefore, intersectoral costs need to be addressed in order to ensure the total economic burden of STIs and HIV on society is assessed, and communicated to policy/decision-makers.

BackgroundSchistosomiasis is a neglected tropical disease (NTD) that affects over 230 million people in low and middle-income countries (LMICs) and can lead to long-term debilitating health effects. It is associated with impoverishment and has been prioritised by the World Health Organization for prevention, control and elimination. This systematic review aimed to identify and evaluate existing economic evaluations of interventions to tackle schistosomiasis.MethodologyA comprehensive search strategy of four databases and additional hand-searching was employed on the 17th July 2020. The articles were screened and sorted using a two-stage classification system. Full economic evaluations published in English between 1st January 1998 and 17th July 2020 were included, and methodological quality was appraised using the international decision support initiative (iDSI), Phillips and Evers checklists.ResultsEighteen economic evaluations were identified, nine trial-based and nine model-based, with the majority focused on preventative chemotherapy. Schistosomiasis interventions were collectively found to be cost-effective, but the quantity and quality of studies were limited. The outcome measures and time-horizons utilised varied substantially making comparison difficult. The majority of papers failed to address equity and affordability.ConclusionSeveral methodological issues were highlighted which might have implications for optimal decision-making. Future research is needed to ensure the standardisation of methods, in order to ensure that scarce healthcare resources are focused on the most cost-effective programmes to tackle schistosomiasis and other NTDs.

Abstract Lateral flow immunoassays are low cost, rapid and highly efficacious point-of-care devices, which have been used for SARS-CoV-2 antibody testing by professionals. However, there is a lack of understanding about how self-administered tests are used by the general public for mass testing in different environmental settings. The purpose of this study was to assess the user experience (UX) (including usability) of a self-testing kit to identify COVID-19 antibodies used by a representative sample of the public in their cars, which included 1544 participants in Northern Ireland. The results based on 5-point Likert ratings from a post-test questionnaire achieved an average UX score of 96.03% [95% confidence interval (CI) 95.05–97.01%], suggesting a good degree of user experience. The results of the Wilcoxon rank sum tests suggest that UX scores were independent of the user’s age and education level although the confidence in this conclusion could be strengthened by including more participants aged younger than 18 and those with only primary or secondary education. The agreement between the test result as interpreted by the participant and the researcher was 95.85% [95% CI 94.85–96.85%], Kappa score 0.75 [95% CI 0.69–0.81] (indicating substantial agreement). Text analysis via the latent Dirichlet allocation model for the free text responses in the survey suggest that the user experience could be improved for blood-sample collection, by modifying the method of sample transfer to the test device and giving clearer instructions on how to interpret the test results. The overall findings provide an insight into the opportunities for improving the design of SARS-CoV-2 antibody testing kits to be used by the general public and therefore inform protocols for future user experience studies of point-of-care tests.

Abstract Background Associations between kidney disease and periodontal disease are not well documented among Aboriginal people of Australia. The purpose of this investigation was to report and compare demographic, oral health, anthropometric and systemic health status of Aboriginal Australians with kidney disease and to compare against relevant Aboriginal Australians and Australian population estimates. This provides much needed evidence to inform dental health service provision policies for Aboriginal Australians with kidney disease. Methods Sample frequencies and means were assessed in adults represented in six datasets including: (1) 102 Aboriginal Australians with kidney disease residing in Central Australia who participated in a detailed oral health assessment; (2) 312 Aboriginal participants of the Northern Territory’s PerioCardio study; (3) weighted estimates from 4775 participants from Australia’s National Survey of Adult Oral Health (NSAOH); (4) Australian 2016 Census (all Australians); (5) National Health Survey 2017–2018 (all Australians) and; (6) Australian Health Survey: Biomedical Results for Chronic Diseases, 2011–2012 (all Australians). Oral health status was described by periodontal disease and experience of dental caries (tooth decay). Statistically significant differences were determined via non-overlapping 95% confidence intervals. Results Aboriginal Australians with kidney disease were significantly older, less likely to have a tertiary qualification or be employed compared with both PerioCardio study counterparts and NSAOH participants. Severe periodontitis was found in 54.3% of Aboriginal Australians with kidney disease, almost 20 times the 2.8% reported in NSAOH. A higher proportion of Aboriginal Australians with kidney disease had teeth with untreated caries and fewer dental restorations when compared to NSAOH participants. The extent of periodontal attachment loss and periodontal pocketing among Aboriginal Australians with kidney disease (51.0%, 21.4% respectively) was several magnitudes greater than PerioCardio study (22.0%, 12.3% respectively) and NSAOH (5.4%, 1.3% respectively) estimates. Conclusions Aboriginal Australians with kidney disease exhibited more indicators of poorer oral health than both the general Australian population and a general Aboriginal population from Australia’s Northern Territory. It is imperative that management of oral health among Aboriginal Australians with kidney disease be included as part of their ongoing medical care.