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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.

Critical reflection and self-awareness are two of the most crucial components in developing equity-centered leaders (Dugan and Humbles, 2018; Madsen, 2020; Patti, Madrazo, Senge, and Stern, 2015). Leading for equity requires the leader to face both personal bias and professional challenges (Boske, 2014). Many leaders are willing to engage in the work of leading for equity but lack clarity about where to start and how to proceed, often seeking out external tools. Using narrative inquiry, this study collected leaders' stories to understand the participants' perspective of self, the understanding of their own journey, and the connections to their leadership work.

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.

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.

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 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.

Abstract Background In this study we compare results obtained when applying the monozygotic twin difference cross‐lagged panel model (MZD‐CLPM) and a random intercept cross‐lagged panel model (RI‐CLPM) to the same data. Each of these models is designed to strengthen researchers' ability to draw causal inference from cross‐lagged associations. We explore differences and similarities in how each model does this, and in the results each model produces. Specifically, we examine associations between maladaptive parenting and child emotional and behavioural problems in identical twins aged 9, 12 and 16. Method Child reports of 5698 identical twins from the Twins Early Development Study (TEDS) were analysed. We ran a regular CLPM to anchor our findings within the current literature, then applied the MZD‐CLPM and the RI‐CLPM. Results The RI‐CLPM and MZD‐CLPM each enable researchers to evaluate the direction of effects between correlated variables, after accounting for unmeasured sources of potential confounding. Our interpretation of these models therefore focusses primarily on the magnitude and significance of cross‐lagged associations. In both the MZD‐CLPM and the RI‐CLPM behavioural problems at age 9 resulted in higher levels of maladaptive parenting at age 12. Other effects were not consistently significant across the two models, although the majority of estimates pointed in the same direction. Conclusion In light of the triangulated methods, differences in the results obtained using the MZD‐CLPM and the RI‐CLPM underline the importance of careful consideration of what sources of unmeasured confounding different models control for and that nuance is required when interpreting findings using such models. We provide an overview of what the CLPM, RI‐CLPM and MZD‐CLPM can and cannot control for in this respect and the conclusions that can be drawn from each model.

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.

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 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.

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 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.