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The chemical compound 1,2-dichloroethane (DCE), or ethylene dichloride, is an industrial very short-lived substance (VSLS) whose major use is as a feedstock in the production chain of polyvinyl chloride (PVC). Like other chlorinated VSLSs, transport of DCE (and/or its atmospheric oxidation products) to the stratosphere could contribute to ozone depletion there. However, despite annual production volumes greatly exceeding those of more prominent VSLSs (e.g. dichloromethane), global DCE observations are sparse; thus, the magnitude and distribution of DCE emissions and trends in its atmospheric abundance are poorly known. In this study, we performed an exploratory analysis of the global DCE budget between 2002 and 2020. Combining bottom-up data on annual production and assumptions around fugitive losses during production and feedstock use, we assessed the DCE source strength required to reproduce atmospheric DCE observations. We show that the TOMCAT/SLIMCAT 3-D chemical transport model (CTM) reproduces DCE measurements from various aircraft missions well, including HIPPO (2009–2011), ATom (2016–2018), and KORUS-AQ (2016), along with surface measurements from Southeast Asia, when assuming a regionally varying production emission factor in the range of 0.5 %–1.5 %. Our findings imply substantial fugitive losses of DCE and/or substantial emissive applications (e.g. solvent use) that are poorly reported. We estimate that DCE's global source increased by ∼ 45 % between 2002 (349 ± 61 Gg yr−1) and 2020 (505 ± 90 Gg yr−1), with its contribution to stratospheric chlorine increasing from 8.2 (± 1.5) to ∼ 12.9 (± 2.4) ppt Cl (where ppt denotes parts per trillion) over this period. DCE's relatively short overall tropospheric lifetime (∼ 83 d) limits, although does not preclude, its transport to the stratosphere, and we show that its impact on ozone is small at present. Annually averaged, DCE is estimated to have decreased ozone in the lower stratosphere by up to several parts per billion (< 1 %) in 2020, although a larger effect in the springtime Southern Hemisphere polar lower stratosphere is apparent (decreases of up to ∼ 1.3 %). Given strong potential for growth in DCE production tied to demand for PVC, ongoing measurements would be of benefit to monitor potential future increases in its atmospheric abundance and its contribution to ozone depletion.

Abstract Background The COVID-19 pandemic accelerated the adoption of remote care, or telemedicine, in many clinical areas including maternity care. One component of remote care, the use of self-monitoring of blood pressure in pregnancy, could form a key component in post-pandemic care pathways. The BUMP trials evaluated a self-monitoring of blood pressure intervention in addition to usual care, testing whether it improved detection or control of hypertension for pregnant people at risk of hypertension or with hypertension during pregnancy. This paper reports the qualitative evaluation which aimed to understand how the intervention worked, the perspectives of participants in the trials, and, crucially, those who declined to participate. Methods The BUMP trials were conducted between November 2018 and May 2020. Thirty-nine in-depth qualitative interviews were carried out with a diverse sample of pregnant women invited to participate in the BUMP trials across five maternity units in England. Results Self-monitoring of blood pressure in the BUMP trials was reassuring, acceptable, and convenient and sometimes alerted women to raised BP. While empowering, taking a series of self-monitored readings also introduced uncertainty and new responsibility. Some declined to participate due to a range of concerns. In the intervention arm, the performance of the BUMP intervention may have been impacted by women’s selective or delayed reporting of raised readings and repeated testing in pursuit of normal BP readings. In the usual care arm, more women were already self-monitoring their blood pressure than expected. Conclusions The BUMP trials did not find that among pregnant individuals at higher risk of preeclampsia, blood pressure self-monitoring with telemonitoring led to significantly earlier clinic-based detection of hypertension nor improved management of blood pressure. The findings from this study help us understand the role that self-monitoring of blood pressure can play in maternity care pathways. As maternity services consider the balance between face-to-face and remote consultations in the aftermath of the COVID-19 pandemic, these findings contribute to the evidence base needed to identify optimal, effective, and equitable approaches to self-monitoring of blood pressure.

Abstract Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Abstract Background Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models. Results Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals’ preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place. Conclusions The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases.

Climate models, derived from process understanding, are essential tools in the study of climate change and its wide-ranging impacts. Hindcast and future simulations provide comprehensive spatiotemporal estimates of climatology that are frequently employed within the environmental sciences community, although the output can be afflicted with bias that impedes direct interpretation. Post-processing bias correction approaches utilise observational data to address this challenge, although they are typically criticised for not being physically justified and not considering uncertainty in the correction. This paper proposes a novel Bayesian bias correction framework that robustly propagates uncertainty and models underlying spatial covariance patterns. Shared latent Gaussian processes are assumed between the in situ observations and climate model output, with the aim of partially preserving the covariance structure from the climate model after bias correction, which is based on well-established physical laws. Results demonstrate added value in modelling shared generating processes under several simulated scenarios, with the most value added for the case of sparse in situ observations and smooth underlying bias. Additionally, the propagation of uncertainty to a simulated final bias-corrected time series is illustrated, which is of key importance to a range of stakeholders, such as climate scientists engaged in impact studies, decision-makers trying to understand the likelihood of particular scenarios and individuals involved in climate change adaption strategies where accurate risk assessment is required for optimal resource allocation. This paper focuses on one-dimensional simulated examples for clarity, although the code implementation is developed to also work on multi-dimensional input data, encouraging follow-on real-world application studies that will further validate performance and remaining limitations. The Bayesian framework supports uncertainty propagation under model adaptations required for specific applications, providing a flexible approach that increases the scope of data assimilation tasks more generally.

Background Hypertensive pregnancies are associated with an increased risk of cardiovascular and neurological diseases in the offspring during later life. However, less is known about the potential impact on multi‐organ phenotypes in offspring before disease symptoms occur. The objective of this systematic review was to determine the associations of fetal exposure to maternal hypertensive pregnancy with multi‐organ phenotypes across developmental stages. Methods and Results Ovid MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), WoS, Scopus, CINAHL, and ClinicalTrials.gov were systematically searched until February 2024. Records were independently screened by 2 authors. Studies reporting on the structure or function of the heart, blood vessels, brain, liver, and kidneys in offspring of hypertensive pregnancies compared with a normotensive control population were included. Risk of bias was assessed using the Newcastle‐Ottawa Scale. Extracted data were presented using harvest plots. Seventy‐three studies including 7091 offspring of hypertensive pregnancies and 42 164 controls were identified that met the inclusion criteria. Thirty‐two studies were investigations in fetuses, 24 in neonates and infants, 12 in children, 2 in adolescents, and 3 in adults. Offspring of hypertensive pregnancies had structural and functional changes in the heart compared with controls in some studies across developmental stages. Offspring of hypertensive pregnancies also had smaller occipital and parietal vessels, higher aortic intima‐media thickness, and lower retinal arteriolar‐to‐venular ratio. Some conflicting evidence existed for other phenotypical alterations. Conclusions There is still inconsistent evidence of multi‐organ structural and functional differences in offspring of hypertensive pregnancies. The evidence base could therefore be further strengthened through well‐designed and conducted prospective studies. Registration Information www.crd.york.ac.uk. Unique Identifier: CRD42023387550.

Ataxia Telangiectasia (AT) is a rare disorder caused by mutations in the ATM gene and results in progressive neurodegeneration for reasons that remain poorly understood. In addition to its central role in nuclear DNA repair, ATM operates outside the nucleus to regulate metabolism, redox homeostasis and mitochondrial function. However, a systematic investigation into how and when loss of ATM affects these parameters in relevant human neuronal models of AT was lacking. We therefore used cortical neurons and brain organoids from AT-patient iPSC and gene corrected isogenic controls to reveal levels of mitochondrial dysfunction, oxidative stress, and senescence that vary with developmental maturity. Transcriptome analyses identified disruptions in regulatory networks related to mitochondrial function and maintenance, including alterations in the PARP/SIRT signalling axis and dysregulation of key mitophagy and mitochondrial fission-fusion processes. We further show that antioxidants reduce ROS and restore neurite branching in AT neuronal cultures, and ameliorate impaired neuronal activity in AT brain organoids. We conclude that progressive mitochondrial dysfunction and aberrant ROS production are important contributors to neurodegeneration in AT and are strongly linked to ATM's role in mitochondrial homeostasis regulation.

Hypertension during pregnancy affects up to 10% of pregnancies and is associated with significant cardiovascular morbidity and mortality. In the short-term it can result in pre-eclampsia, haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, or even hypertension associated acute heart failure, all of which may necessitate pre-term delivery to prevent maternal or neonatal death. In the long term, a history of gestational hypertension and pre-eclampsia significantly increases the risk of future cardiovascular disease including chronic hypertension, coronary artery disease, heart failure and stroke. This review explores our current level of knowledge of the phenotypes of heart failure, paying particular attention to those specific to women, and the role of pregnancy and non-pregnancy related risk factors in the development of this condition. We discuss why women with hypertensive pregnancy may be disproportionately affected by heart failure with preserved ejection fraction (HFpEF) and whether a unique phenotype of heart failure unique to hypertensive pregnancy exists. Finally, we explore how future cardiovascular risk may be predicted based on cardiac remodelling during or after pregnancy and suggest potential areas of further research in the field.

Supraglacial lakes form on the Greenland ice sheet in the melt season (May to October) when meltwater collects in surface depressions on the ice. Supraglacial lakes can act as a control on ice dynamics since, given a large enough volume of water and a favourable stress regime, hydrofracture of the lake can occur, which enables water transfer from the ice surface to the bedrock, where it can lubricate the base. The depth (and thus volume) of these lakes is typically estimated by applying a radiative transfer equation (RTE) to optical satellite imagery. This method can be used at scale across entire ice sheets but is poorly validated due to a paucity of in situ depth data. Here we intercompare supraglacial lake depth detection by means of ArcticDEM digital elevation models, ICESat-2 photon refraction, and the RTE applied to Sentinel-2 images across five lakes in southwest Greenland. We found good agreement between the ArcticDEM and ICESat-2 approaches (Pearson's r=0.98) but found that the RTE overestimates lake depth by up to 153 % using the green band (543–578 nm) and underestimates lake depth by up to 63 % using the red band (650–680 nm). Parametric uncertainty in the RTE estimates is substantial and is dominated by uncertainty in estimates of reflectance at the lakebed, which are derived empirically. Uncertainty in lake depth estimates translates into a poor understanding of total lake volume, which could mean that hydrofracture likelihood is poorly constrained, in turn affecting ice velocity predictions. Further laboratory studies to constrain spectral radiance loss in the water column and investigation of the potential effects of cryoconite on lakebed reflectance could improve the RTE in its current format. However, we also suggest that future work should explore multi-sensor approaches to deriving lake depth from optical satellite imagery, which may improve depth estimates and will certainly result in better-constrained uncertainties.

Subglacial lakes form beneath ice sheets and ice caps if water is available and if bedrock and surface topography are able to retain the water. On a regional scale, the lakes modulate the timing and rate of freshwater flow through the subglacial system to the ocean by acting as reservoirs. More than 100 hydrologically active subglacial lakes that drain and recharge periodically have been documented under the Antarctic Ice Sheet, while only approximately 20 active lakes have been identified in Greenland. Active lakes may be identified by local changes in ice topography caused by the drainage or recharge of the lake beneath the ice. The small size of the Greenlandic subglacial lakes puts additional demands on mapping capabilities to resolve the evolving surface topography in sufficient detail to record their temporal behaviour. Here, we explore the potential for using CryoSat-2 swath-processed data, together with TanDEM-X digital elevation models, to improve the monitoring capabilities of active subglacial lakes in Greenland. We focus on four subglacial lakes previously described in the literature and combine the data with ArcticDEMs to obtain improved measurements of the evolution of these four lakes. We find that with careful tuning of the swath processor and filtering of the output data, the inclusion of these data, together with the TanDEM-X data, provides important information on lake activity, documenting, for example, that the ice surface collapse basin on Flade Isblink Ice Cap was 50 % (30 m) deeper than previously recorded. We also present evidence of a new, active subglacial lake in southwestern Greenland, which is located close to an already known lake. Both lakes probably drained within 1 month in the summer of 2012, which suggests either that they are hydrologically connected or that the drainages were independently triggered by extensive surface melt. If the hydrological connection is confirmed, this would to our knowledge be the first indication of hydrologically connected subglacial lakes in Greenland.

Abstract Background People with severe COVID anxiety have poor mental health and impaired functioning, but the course of severe COVID anxiety is unknown and the quality of evidence on the acceptability and impact of psychological interventions is low. Methods A quantitative cohort study with a nested feasibility trial. Potential participants aged 18 and over, living in the UK with severe COVID anxiety, were recruited online and from primary care services. We examined levels of COVID anxiety in the six months after recruitment, and factors that influenced this, using linear regression. Those scoring above 20 on the short Health Anxiety Inventory were invited to participate in a feasibility trial of remotely delivered Cognitive Behavioural Therapy for Health Anxiety (CBT-HA). Exclusion criteria were recent COVID-19, current self-isolation, or current receipt of psychological treatment. Key outcomes for the feasibility trial were the level of uptake of CBT-HA and the rate of follow-up. Results 204 (70.2%) of 285 people who took part in the cohort study completed the six month follow-up, for whom levels of COVID anxiety fell from 12.4 at baseline to 6.8 at six months (difference = -5.5, 95% CI = -6.0 to -4.9). Reductions in COVID anxiety were lower among older people, those living with a vulnerable person, those with lower baseline COVID anxiety, and those with higher levels of generalised anxiety and health anxiety at baseline. 36 (90%) of 40 participants enrolled in the nested feasibility trial were followed up at six months. 17 (80.9%) of 21 people in the active arm of the trial received four or more sessions of CBT-HA. We found improved mental health and social functioning among those in the active, but not the control arm of the trial (Mean difference in total score on the Work and Social Adjustment Scale between baseline and follow up, was 9.7 (95% CI = 5.8–13.6) among those in the active, and 1.0 (95% C.I. = -4.6 to 6.6) among those in the control arm of the trial. Conclusions While the mental health of people with severe COVID anxiety appears to improve over time, many continue to experience high levels of anxiety and poor social functioning. Health anxiety is highly prevalent among people with severe COVID anxiety and may provide a target for psychological treatment. Trial registration Retrospectively registered at ISRCTN14973494 on 09/09/2021.

Introduction Evidence-based psychological treatments for people with personality disorder usually involve attending group-based sessions over many months. Low-intensity psychological interventions of less than 6 months duration have been developed, but their clinical effectiveness and cost-effectiveness are unclear.Methods and analysis This is a multicentre, randomised, parallel-group, researcher-masked, superiority trial. Study participants will be aged 18 and over, have probable personality disorder and be treated by mental health staff in seven centres in England. We will exclude people who are: unwilling or unable to provide written informed consent, have a coexisting organic or psychotic mental disorder, or are already receiving psychological treatment for personality disorder or on a waiting list for such treatment. In the intervention group, participants will be offered up to 10 individual sessions of Structured Psychological Support. In the control group, participants will be offered treatment as usual plus a single session of personalised crisis planning. The primary outcome is social functioning measured over 12 months using total score on the Work and Social Adjustment Scale (WSAS). Secondary outcomes include mental health, suicidal behaviour, health-related quality of life, patient-rated global improvement and satisfaction, and resource use and costs. The primary analysis will compare WSAS scores across the 12-month period using a general linear mixed model adjusting for baseline scores, allocation group and study centre on an intention-to-treat basis. In a parallel process evaluation, we will analyse qualitative data from interviews with study participants, clinical staff and researchers to examine mechanisms of impact and contextual factors.Ethics and dissemination The study complies with the Helsinki Declaration II and is approved by the London—Bromley Research Ethics Committee (IRAS ID 315951). Study findings will be published in an open access peer-reviewed journal; and disseminated at national and international conferences.Trial registration number ISRCTN13918289.

IntroductionIn October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS.MethodsA survey (n = 159) and semi-structured interviews (n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future.ResultsOverall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions.ConclusionHealthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals.

Abstract Background Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom. Methods We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases. Results Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three—a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%). Conclusions Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions.

Abstract Ultrasound contrast agents (UCAs) have a well-established role in clinical cardiology. Contrast echocardiography has evolved into a routine technique through the establishment of contrast protocols, an excellent safety profile, and clinical guidelines which highlight the incremental prognostic utility of contrast enhanced echocardiography. This document aims to provide practical guidance on the safe and effective use of contrast; reviews the role of individual staff groups; and training requirements to facilitate its routine use in the echocardiography laboratory.

The Greenland Ice Sheet (GrIS) is losing mass as the climate warms through both increased meltwater runoff and ice discharge at marine-terminating sectors. At the ice sheet surface, meltwater runoff forms a dynamic supraglacial hydrological system which includes stream and river networks and large supraglacial lakes (SGLs). Streams and rivers can route water into crevasses or into supraglacial lakes with crevasses underneath, both of which can then hydrofracture to the ice sheet base, providing a mechanism for the surface meltwater to access the bed. Understanding where, when, and how much meltwater is transferred to the bed is important because variability in meltwater supply to the bed can increase ice flow speeds, potentially impacting the hypsometry of the ice sheet in grounded sectors, and iceberg discharge to the ocean. Here we present a new, physically based, supraglacial hydrology model for the GrIS that is able to simulate (a) surface meltwater routing and SGL filling; (b) rapid meltwater drainage to the ice sheet bed via the hydrofracture of surface crevasses both in and outside of SGLs; (c) slow SGL drainage via overflow in supraglacial meltwater channels; and, by offline coupling with a second model, (d) the freezing and unfreezing of SGLs from autumn to spring. We call the model the Supraglacial Hydrology Evolution and Drainage (or SHED) model. We apply the model to three study regions in southwest Greenland between 2015 and 2019 (inclusive) and evaluate its performance with respect to observed supraglacial lake extents and proglacial discharge measurements. We show that the model reproduces 80 % of observed lake locations and provides good agreement with observations in terms of the temporal evolution of lake extent. Modelled moulin density values are in keeping with those previously published, and seasonal and inter-annual variability in proglacial discharge agrees well with that which is observed, though the observations lag the model by a few days since they include transit time through the subglacial system, while the model does not. Our simulations suggest that lake drainage behaviours may be more complex than traditional models suggest, with lakes in our model draining through a combination of both overflow and hydrofracture and with some lakes draining only partially and then refreezing. This suggests that, in order to simulate the evolution of Greenland's surface hydrological system with fidelity, a model that includes all of these processes needs to be used. In future work, we will couple our model to a subglacial model and an ice flow model and thus use our estimates of where, when, and how much meltwater gets to the bed to understand the consequences for ice flow.