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In degraded urban habitats, nature-based solutions aim to enhance ecosystem functioning and service provision. Bivalves are increasingly reintroduced to urban environments to enhance water quality through biofiltration, yet their long-term sustainability remains uncertain. Following the restoration of the disused South Docks in Liverpool in the 1980s, natural colonization of mussels rapidly improved dock-basin water quality and supported diverse taxa, including other filter feeders. While the initial colonization phase has been well documented, there has been limited published research since the mid-1990s, despite ongoing routine water quality monitoring. Here, we assessed the long-term persistence of mussel populations, their associated biodiversity, and physico-chemical parameters of the water in Queens and Albert Docks by comparing historical (1980s to 1990s) and contemporary data from follow-up surveys (2012,2022). Following an initial period of poor water quality (high contamination and turbidity, low oxygen), the natural colonization of mussels from Albert Dock in 1988 extended throughout the South Docks. By the mid-1990s, the environment of the South Docks and its mussel populations had stabilized. The dock walls were dominated by mussels which provided important complex secondary substrate for invertebrates and macroalgae. Surveys conducted in 2012 and 2022 confirmed the continued dominance of mussels and estimates of mussel biofiltration rates confirm that mussels are continuing to contribute to maintaining water quality. A decline in salinity was observed in both docks in 2022, with evidence of recovery. While these ecosystems appear relatively stable, careful management of the hydrological regime is crucial to ensuring the persistence of mussels and resilient ecosystem service provision through biofiltration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epidemiological studies on health effects of air pollution usually estimate exposure at the residential address. However, ignoring daily mobility patterns may lead to biased exposure estimates, as documented in previous exposure studies. To improve the reliable integration of exposure related to mobility patterns into epidemiological studies, we conducted a systematic review of studies across all continents that measured air pollution concentrations in various modes of transport using portable sensors. To compare personal exposure across different transport modes, specifically active versus motorized modes, we estimated pairwise exposure ratios using a Bayesian random-effects meta-analysis. Overall, we included measurements of six air pollutants (black carbon (BC), carbon monoxide (CO), nitrogen dioxide (NO 2 ), particulate matter (PM 10 , PM 2.5 ) and ultrafine particles (UFP)) for seven modes of transport (i.e., walking, cycling, bus, car, motorcycle, overground, underground) from 52 published studies. Compared to active modes, users of motorized modes were consistently the most exposed to gaseous pollutants (CO and NO 2 ). Cycling and walking were the most exposed to UFP compared to other modes. Active vs passive mode contrasts were mostly inconsistent for other particle metrics. Compared to active modes, bus users were consistently more exposed to PM 10 and PM 2.5 , while car users, on average, were less exposed than pedestrians. Rail modes experienced both some lower exposures (compared to cyclists for PM 10 and pedestrians for UFP) and higher exposures (compared to cyclist for PM 2.5 and BC). Ratios calculated for motorcycles should be considered carefully due to the small number of studies, mostly conducted in Asia. Computing exposure ratios overcomes the heterogeneity in pollutant levels that may exist between continents and countries. However, formulating ratios on a global scale remains challenging owing to the disparities in available data between countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Hip fractures are common and cause a huge socioeconomic burden to patients, their carers, and healthcare services worldwide. Our aim was to examine how much hip fracture numbers would be expected to rise over coming decades, simply as a consequence of the ageing of the population., Methods: We used data from the National Hip Fracture Database on the volume of hip fractures occurring in England, Wales and Northern Ireland in the year 2019 (n = 67,210). We projected future numbers of hip fractures by applying this number, assuming stable rates, to population growth forecast data provided by the Office for National Statistics up to the year 2060., Results: By 2060, the number of hip fractures occurring in England, Wales and Northern Ireland are projected to increase by 107 % (n = 139,105). In males, there was an estimated increase of 130 % compared with 97 % in females. There was an estimated increase across all age ranges, however the oldest age groups demonstrated the largest relative increases. The estimated increase for those aged 90 years or over was as high as 348 % and 198 % for males and females, respectively., Conclusion: As a consequence of future ageing of the population, the demand on the health service posed by people with hip fracture is projected to more than double by the year 2060. Policymakers should be striving to mitigate against the huge public health impact of these projections by maximising fracture prevention strategies as far as possible and by improving the quality of hip fracture care., Competing Interests: Declaration of competing interest MW undertakes teaching on basic sciences for Orthopaedic trainees preparing for the FRCS. His institution receives market rate payment for this teaching from Heraeus. He undertakes teaching on total hip replacement for Orthopaedic Consultants and trainees. His institution receives market rate payment for this teaching from DePuy. He is PI on a commercially funded grant (CeramTec) investigating the outcome of ceramic bearings in total hip replacement. He is PI of the National Joint Registry lot 2 contract (statistical analysis) team. GM has received personal fees for undertaking medicolegal work for Leigh Day. AJu has received consultancy fees from Freshfields Bruckhaus Deringer and has held advisory board positions (which involved receipt of fees) from Anthera Pharmaceuticals, INC. TM, DC, SH, AJo have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A novel single-use, analyser-free, molecular point-of-care test for SARS-CoV-2 (Veros COVID-19 test, Sherlock Biosciences) could reduce time to results and improve patient care and flow in the emergency department (ED), but its performance in this setting is unknown., Methods: Adults aged ≥18 years presenting to Southampton General Hospital (UK) with suspected COVID-19 were tested with the Veros COVID-19 test in addition to standard of care near-patient PCR. Measures of diagnostic accuracy were calculated for the Veros COVID-19 test stratified by Ct value. Discrepant results underwent viral culture., Findings: Between Jan 16 and May 2, 2023, 400 patients were enrolled with a median (IQR) age of 60 (34-77) and 141 (35·3%) were SARS-CoV-2 positive by PCR. The Veros test gave valid results on the first test in 384 (96·0%), and sensitivity and specificity were 127/141 (90·1%, 95%CI 83·9-94·5) and 258/259 (99·6%, 95%CI 97·9-100) overall. For those with high or moderate viral load (Ct ≤30), sensitivity was 125/129 (96·9%, 95%CI 92·3-99·2). One (7·1%) of 14 PCR positive/Veros test negative samples was culture positive. Median (IQR) time from sample collection to result was 19 (18-20) mins with the Veros test versus 73 (59-92) mins with PCR (p < 0·0001)., Interpretation: The Veros COVID-19 test generated results in near real-time, around 1 h sooner than rapid, near-patient, analyser-based PCR, and accuracy was excellent for samples with moderate and high viral loads. The Veros test represents a step-change in molecular diagnostics for infection and could significantly reduce time to results and improve patient management in EDs and other settings., Competing Interests: Declaration of Competing Interest The author Professor Tristan W Clark is an Associate Editor for Journal of Infection and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TWC has received speaker fees, honoraria, travel reimbursement, and equipment and consumables at discount or free of charge for the purposes independent of research, outside of this submitted study, from BioFire diagnostics, BioMerieux and QIAGEN. He has received consultancy fees from Cepheid, Synairgen research, Roche, Janssen, Biofire diagnostic and BioMerieux. He has received honoraria for participation in advisory boards from Cepheid, Roche, Janssen, Shionogi, GSK, Seqirus and Sanofi. He is a member of an independent data monitoring committee for a trial sponsored by Roche. He has acted as the UK chief investigator for a study sponsored by Janssen. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Mindfulness-based interventions can improve psychological health; yet the mechanisms of change are underexplored. This pre-registered remote RCT evaluated a freely accessible digital mindfulness programme aiming to improve well-being, mental health and sleep quality. Health behaviour cognitions were explored as possible mediators., Methods: Participants from 91 countries (N = 1247, M age  = 27.03 [9.04]) were randomized to 30 days of mindfulness practice or attention-matched control condition. Measures of well-being, depression, anxiety, stress, sleep quality, barriers self-efficacy, self-regulation and behavioural predictors (e.g., attitudes and behavioural intentions) were taken at baseline, 1-month (post-intervention) and 2-months (follow-up). Linear regression examined intervention effects between and within groups. Longitudinal mediation analyses explored indirect effects through health behaviour cognitions., Results: Three hundred participants completed post-intervention measures. Those receiving mindfulness training reported significantly better well-being (M difference  = 2.34, 95%CIs .45-4.24, p = .016), lower depression (M difference  = -1.47, 95%CIs -2.38 to -.56, p = .002) and anxiety symptoms (M difference  = -.77, 95%CIs -1.51 to -.02, p = .045) than controls. Improvements in well-being and depression were maintained at follow-up. Intervention effects on primary outcomes were mediated by attitudes towards health maintenance and behavioural intentions. Mediating effects of attitudes remained when controlling for prior scores in models of depression and well-being., Conclusions: Digital, self-administered mindfulness practice for 30 days meaningfully improved psychological health, at least partially due to improved attitudes towards health behaviours and stronger behavioural intentions. This trial found that digital mindfulness is a promising and scalable well-being tool for the general population, and highlighted its role in supporting health behaviours., (© 2024 The Author(s). British Journal of Health Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Prospective cohort studies of kidney equity are limited by a focus on advanced rather than early disease and selective recruitment. Whole population studies frequently rely on area-level measures of deprivation as opposed to individual measures of social disadvantage. Here, we linked kidney health and individual census records in the North of Scotland (Grampian area), 2011-2021 (GLOMMS-CORE) and identified incident kidney presentations at thresholds of estimated glomerular filtration rate (eGFR) under 60 (mild/early), under 45 (moderate), under 30 ml/min/1.73m 2 (advanced), and acute kidney disease (AKD). Household and neighborhood socioeconomic measures, living circumstances, and long-term mortality were compared. Case-mix adjusted multivariable logistic regression (living circumstances), and Cox models (mortality) incorporating an interaction between the household and the neighborhood were used. Among census respondents, there were 48546, 29081, 16116, 28097 incident presentations of each respective eGFR cohort and AKD. Classifications of socioeconomic position by household and neighborhood were related but complex, and frequently did not match. Compared to households of professionals, people with early kidney disease in unskilled or unemployed households had increased mortality (adjusted hazard ratios: 95% confidence intervals) of (1.26: 1.19-1.32) and (1.77: 1.60-1.96), respectively with adjustment for neighborhood indices making little difference. Those within either a deprived household or deprived neighborhood experienced greater mortality, but those within both had the poorest outcomes. Unskilled and unemployed households frequently reported being limited by illness, adverse mental health, living alone, basic accommodation, lack of car ownership, language difficulties, and visual and hearing impairments. Thus, impacts of deprivation on kidney health are spread throughout society-complex, serious, and not confined to those living in deprived neighborhoods., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative morbidity in patients undergoing curative colorectal cancer surgery is high. Prehabilitation has been suggested to reduce postoperative morbidity, however its effectiveness is still lacking., Objective: The aim of this study was to investigate the effectiveness of prehabilitation in reducing postoperative morbidity and length of hospital stay in patients undergoing colorectal cancer surgery., Methods: A comprehensive electronic search was conducted in the CINAHL, Cochrane Library, Medline, PsychINFO, AMED, and Embase databases from inception to April 2023. Randomised controlled trials testing the effectiveness of prehabilitation, including exercise, nutrition, and/or psychological interventions, compared with usual care in patients undergoing colorectal cancer surgery were included. Two independent review authors extracted relevant information and assessed the risk of bias. Random-effect meta-analyses were used to pool outcomes, and the quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines., Results: A total of 23 trials were identified (N = 2475 patients), including multimodal (3 trials), exercise (3 trials), nutrition (16 trials), and psychological (1 trial) prehabilitation. There was moderate-quality evidence that preoperative nutrition significantly reduced postoperative infectious complications (relative risk 0.65, 95% confidence interval [CI] 0.45-0.94) and low-quality evidence on reducing the length of hospital stay (mean difference 0.87, 95% CI 0.17-1.58) compared with control. A single trial demonstrated an effect of multimodal prehabilitation on postoperative complication., Conclusion: Nutrition prehabilitation was effective in reducing infectious complications and length of hospital stay. Whether other multimodal, exercise, and psychological prehabilitation modalities improve postoperative outcomes after colorectal cancer surgery is uncertain as the current quality of evidence is low., Protocol Registration: Open Science Framework ( https://doi.org/10.17605/OSF.IO/VW72N )., (© 2024. The Author(s).)

Feeling loved by one's parents is critical for children's health and well-being. How can such feelings be fostered? A vital feature of loving interactions is reciprocal self-disclosure, where individuals disclose intimate information about themselves. In a proof-of-concept experiment, we examined whether encouraging reciprocal self-disclosure in parent-child dyads would make children feel more loved during the conversation. Participants were 218 children (ages 8-13, 50% girls, 94% Dutch) and one of their parents (ages 28-56, 62% women, 90% Dutch). Parent-child dyads received a list of 14 questions and took turns asking them each other for 9 min. Dyads were assigned randomly to engage in self-disclosure (questions invoking escalated intimacy) or small talk (questions invoking minimal intimacy). Before and after, children reported how loved they felt by their parent during the conversation. Self-disclosure made children feel more loved during the conversation than did small talk. Compared to small talk, self-disclosure did not instigate conversations that were lengthier or more positive; rather, it instigated conversations that were more emotionally charged (reflecting anger, anxiety, and sadness), social (discussing family and friends), reflective (creating insight), and meaningful (addressing deeply personal topics, including the passing of loved ones). The dyad's gender composition did not significantly moderate these effects. Our research suggests that reciprocal self-disclosure can make children feel more loved in the moment, uncovers linguistic signatures of reciprocal self-disclosure, and offers developmental scientists a tool to examine causal effects of reciprocal self-disclosure in parent-child dyads. Future work should examine long-term effects in everyday parent-child interactions. RESEARCH HIGHLIGHTS: How can parents make children feel more loved by them in the moment? We theorize that these feelings can be cultivated through reciprocal self-disclosure. In a proof-of-concept experiment, we examined effects of reciprocal self-disclosure versus small talk in 218 parent-child dyads, with children aged 8-13. Self-disclosure (vs. small talk) made children feel more loved during the conversation. Linguistically, self-disclosure instigated conversations that were more emotionally charged, social, reflective, and meaningful. This research provides an experimental method to study self-disclosure in parent-child dyads and suggests that self-disclosure can make children feel more loved in the moment., (© 2024 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

This paper presents statistical shape models of the four fingers of the hand, with an emphasis on anatomic analysis of the proximal and distal interphalangeal joints. A multi-body statistical shape modelling pipeline was implemented on an exemplar training dataset of computed tomography (CT) scans of 10 right hands (5F:5M, 27-37 years, free from disease or injury) imaged at 0.3 mm resolution, segmented, meshed and aligned. Model generated included pose neutralisation to remove joint angle variation during imaging. Repositioning was successful; no joint flexion variation was observed in the resulting model. The first principal component (PC) of morphological variation represented phalanx size in all fingers. Subsequent PCs showed variation in position along the palmar-dorsal axis, and bone breadth: length ratio. Finally, the models were interrogated to provide gross measures of bone lengths and joint spaces. These models have been published for open use to support wider community efforts in hand biomechanical analysis, providing bony anatomy descriptions whilst preserving the security of the underlying imaging data and privacy of the participants. The model describes a small, homogeneous population, and assumptions cannot be made about how it represents individuals outside the training dataset. However, it supplements anthropometric datasets with additional shape information, and may be useful for investigating factors such as joint morphology and design of hand-interfacing devices and products. The model has been shared as an open-source repository ( https://github.com/abel-research/OpenHands ), and we encourage the community to use and contribute to it., (© 2024. The Author(s).)

Objectives: Early interventions improve outcomes for people at high risk of psychosis and are likely to be cost saving. This group tends to seek help for emotional problems - depression and anxiety - via primary care services, where early detection methods are poor. We sought to determine prevalence rates of high risk for psychosis in UK primary care mental health services and clinical outcomes following routinely delivered psychological therapies., Methods: We used a brief screen designed for settings with low base rates and significant time constraints to determine prevalence of high risk for psychosis in UK 'Talking Therapies' services. We examined socio-demographic characteristics, presenting problems and recovery trajectories for this group, compared with people not at risk of psychosis., Results: A 2-item screen selected for specificity yielded a prevalence rate of 3% in primary care mental health services. People at elevated risk of psychosis were younger and more likely to report at least one long-term physical condition. This group presented with higher levels of depression, anxiety and trauma symptoms at assessment and were less likely to have recovered at the end of treatment, compared to people not at risk., Conclusions: Very brief screening tools can be implemented in busy health care settings. The 3% of referrals to UK primary care psychological therapies services at elevated risk of psychosis typically present with more severe symptoms and greater levels of comorbidity and may require augmented interventions to recover fully., (© 2024 The Author(s). British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes., Competing Interests: Declaration of competing interest MS received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, Otsuka. IB received consulting fees from Gedeon Richter and Janssen/Janssen-Cilag; speaker's honoraria from Gedeon Richter, Hikma Pharmaceuticals, Janssen/Janssen-Cilag, KRKA, Lundbeck and Medichem Pharmaceuticals Inc. by Unilab; received research grant from Gedeon Richter; royalties from Oxford University Press. JT has participated in research projects funded by grants from Janssen-Cilag to his employing institution; he has been a consultant to HLS Therapeutics, Janssen, Orion, Teva, and WebMed Global and received lecture fees from Janssen, Lundbeck and Otsuka. PG received during the last 5 years fees for presentations at congresses or participation in scientific boards from Biogen, Janssen, Lundbeck, Merk, Otsuka, Richter and Viatris. R.E.N. has, within the past 3 years, been an investigator for Compass Pharmaceuticals, Janssen-Cilag, Sage and Boehringer-Ingelheim for clinical trials; has received speaking fees from Lundbeck, Teva Pharmaceuticals, Janssen-Cilag and Otsuka Pharmaceuticals; and has acted as advisor to Lundbeck and Janssen-Cilag. JF is supported by a UK Research and Innovation Future Leaders Fellowship (MR/T021780/1) and has received honoraria / consultancy fees from Atheneum, Informa, Gillian Kenny Associates, Bayer, Big Health, Hedonia, Strive Coaching, Wood For Trees, Nutritional Medicine Institute, Angelini, ParachuteBH, Richmond Foundation and Nirakara, independent of this work. RIGH has received fees for lecturing from EASD, Eli Lilly, Encore, Liberum, Novo Nordisk, ROVI and funding for conference attendance from Novo Nordisk and Eli Lilly. HT has participated in research projects funded by grants from Janssen-Cilag to her employing institution; and she has received lecture fees from Gedeon Richter, Janssen, Lundbeck and Otsuka. MF received honoraria for his speaker activity from the American Society of Clinical Psychopharmacology (ASCP) and served as a consultant for Angelini, Otsuka, Lundbeck, Sanofi-Aventis, and Boehringer Ingelheim. BS is on the Editorial Board of Ageing Research Reviews, Mental Health and Physical Activity, The Journal of Evidence Based Medicine, and The Brazilian Journal of Psychiatry. Brendon has received honorarium from a co-edited book on exercise and mental illness (Elsevier), and unrelated advisory work from ASICS, in addition to honorarium and stock options at FitXR LTD. HL reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. Henrik Larsson is editor-in-chief of JCPP Advances. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, Viatris and Xenon Pharmaceuticals. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. PL reports institutional grants from AstraZeneca, Biogen, Jansen, MSD and Novartis. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Beckley-Psytech, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Luye Pharma, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris, outside the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes., Design: Superiority, double-blind randomised controlled trial., Setting: A total of 20 UK fetal medicine units., Population: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22 +0 and 29 +6  weeks of gestation., Methods: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation., Main Outcome Measures: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85., Results: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm)., Conclusions: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Biomaterial-based approaches for bone regeneration seek to explore alternative strategies to repair non-healing fractures and critical-sized bone defects. Fracture non-union occurs due to a number of factors resulting in the formation of bone defects. Rigorous evaluation of the biomaterials in relevant models and assessment of their potential to translate towards clinical use is vital. Large animal experimentation can be used to model fracture non-union while scaling-up materials for clinical use. Growth factors modulate cell phenotype, behaviour and initiate signalling pathways leading to changes in matrix deposition and tissue formation. Bone morphogenetic protein-2 (BMP-2) is a potent osteogenic growth factor, with a rapid clearance time in vivo necessitating clinical use at a high dose, with potential deleterious side-effects. The current studies have examined the potential for Laponite® nanoclay coated poly(caprolactone) trimethacrylate (PCL-TMA900) scaffolds to bind BMP-2 for enhanced osteoinduction in a large animal critical-sized bone defect. An ovine femoral condyle defect model confirmed PCL-TMA900 scaffolds coated with Laponite®/BMP-2 produced significant bone formation compared to the uncoated PCL-TMA 900 scaffold in vivo, assessed by micro-computed tomography (μCT) and histology. This indicated the ability of Laponite® to deliver the bioactive BMP-2 on the PCL-TMA900 scaffold. Bone formed around the Laponite®/BMP-2 coated PCL-TMA900 scaffold, with no erroneous bone formation observed away from the scaffold material confirming localisation of BMP-2 delivery. The current studies demonstrate the ability of a nanoclay to localise and deliver bioactive BMP-2 within a tailored octet-truss scaffold for efficacious bone defect repair in a large animal model with significant implications for translation to the clinic., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Richard Oreffo reports financial support was provided by Biotechnology and Biological Sciences Research Council. Prof Molly Stevens reports financial support was provided by UK Regenerative Medicine Platform, and she invested in, consults for (or is on the scientific advisory boards or boards of directors) and conducts sponsored research funded by companies related to the biomaterials field. R.O.C. Oreffo and J.I. Dawson are co-founders and shareholders in a university spin out company with a license to IP indirectly related to the current manuscript. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex., Methods: Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI)., Results: In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17])., Conclusion: In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide., Competing Interests: Declaration of competing interest John D. Ryan received consultancy fees from Falk, Gilead, Pfizer and a speaker honorarium from Takeda. Luca Valenti reports consulting fees from Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept pharmaceuticals, Diatech Pharmacogenetics, IONIS, Viatris; honoraria from MSD, Gilead, AlfaSigma, AbbVie, Resalis, grants from Gilead. Alice Pik-Shan Kong has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi and Zuellig Pharma. Gregory Y. H. Lip serves as consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-PI of the AFFIRMO project on multimorbidity in AF (grant agreement No 899871), TARGET project on digital twins for personalised management of atrial fibrillation and stroke (grant agreement No 101136244) and ARISTOTELES project on artificial intelligence for management of chronic long term conditions (grant agreement No 101080189), which are all funded by the EU's Horizon Europe Research & Innovation programme. Anoop Misra has received honorarium from Abbott, Roche, Jannsen, Boehringer Ingelheim, Lupin, Cipla, US Vitamins, and Novo Nordisk. Christopher D. Byrne has received grant support from Echosens. Wah-Kheong Chan is a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. Christos S. Mantzoros reports grants through his institution from Merck, Massachusetts Life Sciences Center and Boehringer Ingelheim, has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Olympus, Genfit, Lumos, Novo Nordisk, Amgen, Biodexa, Laekna, Corcept, Intercept, 89 Bio, Madrigal, Aligos, Esperion and Regeneron, travel support and fees from UptoDate, TMIOA, Elsevier, and the Cardio Metabolic Health Conference. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. No other disclosures were reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Associations between different sarcopenia definitions and the risk of injurious falls were investigated in 75-80-year-old women in the Swedish SUPERB cohort. Only sarcopenia according to the Sarcopenia Definitions and Outcomes Consortium (SDOC) definition was associated with incident injurious falls with and without fractures in older women., Purpose: To investigate the association between three commonly used sarcopenia definitions and the risk of injurious falls in a population of older Swedish women., Methods: A total of 2,883 75-80-year-old women with complete data on relevant sarcopenia definitions from the Swedish SUPERB cohort were studied. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC: low handgrip strength and gait speed), revised European Working Group on Sarcopenia in Older People (EWGSOP2: low appendicular lean mass index (ALMI, dual-energy X-ray absorptiometry (DXA)-derived), appendicular lean mass (kg)/height (m 2 ), hand grip strength (kg), or low chair stand time (s)), and Asian Working Group for Sarcopenia (AWGS: low ALMI and hand grip strength (kg) or low gait speed (m/s)). Questionnaires captured the occurrence of falls in the past 12 months. Incident injurious falls were identified using national registers. Cox regression (hazard ratios (HR) and 95% confidence intervals (CI)) analyses were performed without adjustment and after adjustment for age, body mass index, previous falls, and the Charlson comorbidity index., Results: During a median (IQR) follow-up time of 7.06 (6.2-7.9) years, there were 491 injurious falls without fracture and 962 injurious falls when also including falls resulting in a fracture. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased risk of injurious falls. Individuals with sarcopenia defined by SDOC had a higher risk of injurious falls with and without fracture (HR 2.11; 95% CI, 1.63-2.73 and HR, 2.16; 95% CI, 1.55-3.02, respectively)., Conclusion: Sarcopenia definitions confined to muscle function and strength such as SDOC, rather than including DXA-determined ALMI (EWGSOP2 and AWGS), are associated with incident injurious falls with and without fractures in older women., (© 2024. The Author(s).)

Aim: To determine patients', nurses' and researchers' opinions on the appropriateness and completeness of the proposed conceptualization of nurses' support of hospitalised patients' self-management., Design: A modified Delphi study., Methods: We conducted a two-round Delphi survey. The panel group consisted of patients, nurses and researchers. The conceptualization of nurses' support of hospitalised patients' self-management presented in the first Delphi round was based on previous research, including a scoping review of the literature. Data was analysed between both rounds and after the second round. Results are reported in accordance with the guidance on Conducting and Reporting Delphi Studies (CREDES)., Results: In the first round all activities of the proposed conceptualization were considered appropriate to support the patients' self-management. Panel members' comments led to the textual adjustment of 19 activities, the development of 15 new activities, and three general questions related to self-management support during hospitalisation. In the second round the modified and the newly added activities were also deemed appropriate. The clarification statements raised in the first Delphi round were accepted, although questions remained about the wording of the activities and about what is and what is not self-management support., Conclusion: After textual adjustments and the addition of some activities, the proposed conceptualization of nurses' support in patients' self-management while hospitalised have been considered appropriate and complete. Nevertheless, questions about the scope of this concept still remains. The results provide a starting point for further discussion and the development of self-management programs aimed at the hospitalised patient., Implication for the Profession And/or Patient Care: The results can be considered as a starting point for practice to discuss the concept of nurses' support for hospitalised patients' self-management and develop, implement and research self-management programs specific for their patient population., Reporting Method: Results are reported in accordance with the guidance on Conducting and Reporting Delphi Studies (CREDES)., Patient or Public Contribution: Patients were involved as expert panellist in this Delphi study. Impact statement What problem did the study address? Self-management support during hospitalisation is understudied, which undermines the development of evidence-based interventions. What were the main findings? A panel, consisting of patients, nurses and researchers, agreed on the appropriateness of a conceptualization of nurses' support of inpatients' self-management, and identified some points for discussion, mainly related to the boundaries of the concept self-management. Where and on whom will the research have an impact? This study is crucial for generating conceptual understanding of how nurses support patients' self-management during hospitalisation. This is necessary for policy, clinical practice, education, and research on this topic., (© 2024 John Wiley & Sons Ltd.)

Background: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel., Methods: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS)., Results: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes., Conclusion: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future., Competing Interests: Declaration of competing interest T Powles has received travel expenses and research funding from Roche, Pfizer, MSD, AstraZeneca, Ipsen, BMS, Merck, Exelixis, Novartis, Seattle Genetics, Merck Serono, Astellas, Johnson and Johnson and Eisai, and has received honoraria from Roche, Pfizer, MSD, AstraZeneca, Ipsen, BMS, Merck, Exelixis, Incyte, Novartis, Seattle Genetics, Merck Serono, Astellas, Johnson and Johnson and Eisai. B Szabados has received travel expenses and research funding from Roche, Genentech, Merck Sharp and Dohme, Pfizer and Bristol Myers Squibb, and has received honoraria from Merck, Roche, Pfizer, Ellipses and Ipsen. F Jackson-Spence has received travel expenses from EUSA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies., Design: Cross-sectional survey., Setting: International., Population: Clinicians involved in the management of MCDA twin pregnancies with sFGR., Methods: A structured, self-administered survey., Main Outcome Measures: Clinical practices and attitudes to diagnostic criteria and management strategies., Results: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide., Conclusions: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose of Review: With ageing populations and rising prevalence of key risk factors, the prevalence of many long-term conditions including chronic kidney disease (CKD) is increasing globally. Health-related quality of life (HRQoL) is important to people living with CKD but not all HRQoL determinants are modifiable. This review summarizes recently identified potentially modifiable factors affecting HRQoL for people with CKD and recent trials incorporating HRQoL as an outcome., Recent Findings: Considering a broad definition of 'potentially modifiable', many factors have been associated with HRQoL in recent observational studies. These include mental health conditions, symptoms, medications, health behaviours, weight-related issues, poor social support, lower education, limited literacy and directly CKD- related factors such as anaemia. Some potentially modifiable factors have been tested in CKD trials, though often with HRQoL as a secondary outcome, so may be underpowered for HRQoL. Interventions with evidence of effect on HRQoL include physical activity, education, some nutritional interventions and medications targeting CKD-related anaemia., Summary: Clinicians should consider the range of potentially modifiable factors influencing HRQoL as part of a holistic approach to CKD care. High-quality, adequately-powered trials, with HRQoL as a primary outcome, with interventions focusing on the other potentially modifiable factors identified are needed., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Many studies highlight poor health-related quality of life (HRQoL) in children treated for brain tumours and their parents. However, little is known about the extent to which their informational, healthcare and communication needs regarding HRQoL are met during medical outpatient consultations., Aim: To explore the experiences of families regarding communication with physicians about HRQoL issues during consultations after treatment for childhood brain tumours., Methods: Interviews were conducted with 18 families of children and adolescents aged 8-17 years after completion of brain tumour treatment. Participants had completed treatment within the last 5 years and were receiving regular outpatient follow-up care. Thematic analysis was undertaken using the Framework Method., Results: Five main themes were identified: (i) unmet emotional and mental health needs; (ii) double protection; (iii) unmet information needs; (iv) communication barriers within consultations; and (v) finding a new normal., Conclusion: There was a need to improve communication between clinicians and these families, improve information provision, and overcome barriers to conversing with children within these outpatient consultations. Children and their parents should be supported to voice their current needs and concerns regarding their HRQoL. These findings will inform further development of the UK version of the 'KLIK' patient- and parent-reported outcome (PROM) portal., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Hypoxia-inducible factors (HIFs) play a pivotal role as master regulators of tumor survival and growth, controlling a wide array of cellular processes in response to hypoxic stress. Clinical data correlates upregulated HIF-1 and HIF-2 levels with an aggressive tumor phenotype and poor patient outcome. Despite extensive validation as a target in cancer, pharmaceutical targeting of HIFs, particularly the interaction between α and βsubunits that forms the active transcription factor, has proved challenging. Nonetheless, many indirect inhibitors of HIFs have been identified, targeting diverse parts of this pathway. Significant strides have also been made in the development of direct inhibitors of HIF-2, exemplified by the FDA approval of Belzutifan for the treatment of metastatic clear cell renal carcinoma. While efforts to target HIF-1 using various therapeutic modalities have shown promise, no clinical candidates have yet emerged. This review aims to provide insights into the intricate and extensive role played by HIFs in cancer, and the ongoing efforts to develop therapeutic agents against this target.

Bone tissue engineering aims to harness materials to develop functional bone tissue to heal 'critical-sized' bone defects. This study examined a robust, coated poly(caprolactone) trimethacrylate (PCL-TMA) 3D-printable scaffold designed to augment bone formation. Following optimisation of the coatings, three bioactive coatings were examined, i) elastin-like polypeptide (ELP), ii) poly(ethyl acrylate) (PEA), fibronectin (FN) and bone morphogenetic protein-2 (BMP-2) applied sequentially (PEA/FN/BMP-2) and iii) both ELP and PEA/FN/BMP-2 coatings applied concurrently. The scaffold material was robust and showed biodegradability. The coatings demonstrated a significant (p < 0.05) osteogenic response in vitro in alkaline phosphatase gene upregulation and alkaline phosphatase production. The PCL-TMA scaffold and coatings supported angiogenesis and displayed excellent biocompatibility following evaluation on the chorioallantoic membrane assay. No significant (p < 0.05) heterotopic bone formed on the scaffolds within a murine subcutaneous implantation model, compared to the positive control of BMP-2 loaded collagen sponge following examination by micro-computed tomography or histology. The current studies demonstrate a range of innovative coated scaffold constructs with in vitro efficacy and clearly illustrate the importance of an appropriate in vivo environment to validate in vitro functionality prior to scale up and preclinical application., (© 2024. The Author(s).)

Evolutionary innovations have played an important role in shaping the diversity of life on Earth. However, how these innovations arise and their downstream effects on patterns of morphological diversification remain poorly understood. Here, we examine the impact of evolutionary innovation on trait diversification in tetraodontiform fishes (pufferfishes, boxfishes, ocean sunfishes, and allies). This order provides an ideal model system for studying morphological diversification owing to their range of habitats and divergent morphologies, including the fusion of the teeth into a beak in several families. Using three-dimensional geometric morphometric data for 176 extant and fossil species, we examine the effect of skull integration and novel habitat association on the evolution of innovation. Strong integration may be a requirement for rapid trait evolution and facilitating the evolution of innovative structures, like the tetraodontiform beak. Our results show that the beak arose in the presence of highly conserved patterns of integration across the skull, suggesting that integration did not limit the range of available phenotypes to tetraodontiforms. Furthermore, we find that beaks have allowed tetraodontiforms to diversify into novel ecological niches, irrespective of habitat. Our results suggest that general rules pertaining to evolutionary innovation may be more nuanced than previously thought., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Although the LiCoO 2 (LCO) cathode material has been widely used in commercial lithium ion batteries (LIB) and shows high stability, LIB's improvements have several challenges that still need to be overcome. In this paper, we have studied the in-operando structural properties of LCO within battery cells using Bragg Coherent X-ray Diffraction Imaging to identify ways to optimise the LCO batteries' cycling. We have successfully reconstructed the X-ray scattering phase variation (a fingerprint of atomic displacement) within a  ≈ (1.6 × 1.4 × 1.3) μm 3 LCO nanocrystal across a charge/discharge cycle. Reconstructions indicate strained domains forming, expanding, and fragmenting near the surface of the nanocrystal during charging, with a determined maximum relative lattice displacements of 0.467 Å. While discharging, all domains replicate in reverse the effects observed from the charging states, but with a lower maximum relative lattice displacements of 0.226 Å. These findings show the inefficiency-increasing domain dynamics within LCO lattices during cycling., (© 2024. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is an etiologically complex disease characterized by acute exacerbations and stable phases. We aimed to identify biological functions modulated in specific COPD conditions, using whole blood samples collected in the AERIS clinical study (NCT01360398). Considered conditions were exacerbation onset, severity of airway obstruction, and presence of respiratory pathogens in sputum samples. With an integrative multi-network gene community detection (MNGCD) approach, we analyzed expression profiles to identify communities of correlated genes. The approach combined different layers of gene interactions for each explored condition/subset of samples: gene expression similarity, protein-protein interactions, transcription factors, and microRNAs validated regulons. Heme metabolism, interferon-alpha, and interferon-gamma pathways were modulated in patients at both exacerbation and stable-state visits, but with the involvement of distinct sets of genes. An important gene community was enriched with G2M checkpoint, E2F targets, and mitotic spindle pathways during exacerbation. Targets of TAL1 regulator and hsa-let-7b - 5p microRNA were modulated with increasing severity of airway obstruction. Bacterial infections with Moraxella catarrhalis and, particularly, Haemophilus influenzae triggered a specific cellular and inflammatory response in acute exacerbations, indicating an active reaction of the host to infections. In conclusion, COPD is a complex multifactorial disease that requires in-depth investigations of its causes and features during its evolution and whole blood transcriptome profiling can contribute to capturing some relevant regulatory mechanisms associated with this disease. In this work, we explored multi-network modeling that integrated diverse layers of regulatory gene networks and enhanced our comprehension of the biological functions implicated in the COPD pathogenesis., (© 2024. GSK.)

Introduction Exploring the barriers and facilitators that people with epilepsy face in accessing care and adhering to medications could enable a better understanding of how India's epilepsy treatment gap could be addressed. Furthermore, there is a paucity of research on the topic, and we could not find any studies exploring these barriers from the perspective of healthcare workers. Aim The study aimed to explore the barriers and facilitators to accessing care and adhering to medications faced by people with epilepsy in India. Methodology Purposive sampling was used to recruit healthcare workers at a private hospital and a non-governmental organization in Pune, India. A total of 13 participants were interviewed, with all of these interviews being audio-recorded. Findings were transcribed and then analyzed by thematic analysis. Findings Several barriers to accessing care were identified, with misconceptions surrounding epilepsy being the most frequently mentioned barrier. Facilitators to accessing care mentioned by participants included higher symptom severity and a higher level of education. Several barriers to medication adherence were discussed, with misconceptions and finances being key themes in participants' responses. Finally, four key themes arose from exploring facilitators to adherence, namely the low cost of medicines, counselling, a good doctor-patient relationship, and a higher education level. Discussion The barriers and facilitators in this study were similar to the barriers and facilitators identified in similar studies. However, some key differences were seen too. For example, this study found financial difficulties to be a key barrier to adherence, but a similar study in South India did not find financial difficulties to be a barrier. Several recommendations can be made based on the findings of this study on how to address India's epilepsy treatment gap. Conclusion People with epilepsy in India face several barriers and facilitators to accessing care and adhering to medications. India's epilepsy treatment gap is a complex and multifactorial issue and will therefore be challenging to address., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Leeds Institute of Health Sciences Research Ethics Sub-Committee (FMHREC-18-2.1) issued approval N/A. Ethical approval was obtained on May 9, 2019, by the Leeds Institute of Health Sciences Research Ethics Sub-Committee (FMHREC-18-2.1). The approval included the consent form, information sheet, and draft question guide. Participants received an information sheet detailing the research and were given 24 hours before deciding whether to consent to the study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tomlins et al.)

Objectives: Self-medication with antibiotics is common practice in many low- and middle-income countries (LMIC). This review synthesizes the qualitative evidence on influences on perceptions and practices in relation to self-medication by the public with antibiotics in LMIC., Methods: A systematic search was conducted of relevant medical, international and social science databases. Searching, screening, data extraction and quality appraisal followed standard methods. A meta-ethnographic approach was used for synthesis, starting with translation of studies and using a line-of-argument approach to develop the final themes., Results: The search identified 78 eligible studies. Antibiotics were understood as a powerful, potentially dangerous but effective medicine for treating infections. This perception was strongly influenced by the common experience of being prescribed antibiotics for infections, both individually and collectively. This contributed to an understanding of antibiotics as a rational treatment for infection symptoms that was sanctioned by medical authorities. Accessing antibiotics from medical professionals was often difficult logistically and financially. In contrast, antibiotics were readily available over the counter from local outlets. People viewed treating infection symptoms with antibiotics as rational practice, although they were concerned about the risks to the individual and only took them when they believed they were needed., Conclusions: A new model to explain self-medication with antibiotics is presented. This uses the socio-ecological model to integrate influences that operate at individual, community and wider socioeconomic levels, drawing on theories of medical authority and the medicalization and commercialization of health. Interventions to reduce overuse of antibiotics in LMIC need to address both clinical practice and community self-medication practices together., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Upper-ocean fronts are an important component of the global climate system, regulating both the oceanic energy cycle and material transports. In the common paradigm, upper-ocean fronts are generated by frontogenesis at the mesoscale (20-300 km), driven predominantly by confluent horizontal flows initiated by a background straining field. However, the mechanisms by which this frontogenesis extends down to and influences the submesoscale (0.2-20 km), which dominates vertical transports in the ocean, are still understudied. Here, we provide direct observational evidence that submesoscale frontogenesis, defined as the rate at which submesoscale buoyancy gradients intensify, is closely linked to convergent flows. Analysis of year-long measurements by a mooring array in the North Atlantic indicates that both the upper-ocean frontogenetic rate and the horizontal convergence exhibit strong seasonality and scale dependence, with larger magnitudes in winter and at smaller horizontal scales (down to at least 2 km). The frontogenetic rate is found to correlate more strongly with horizontal convergence as the scale decreases, suggesting that convergent flows are the main driver of submesoscale frontogenesis. Crucially, a rapid forward cascade of kinetic energy and enhanced vertical velocities preferentially occur during periods of submesoscale frontogenesis. Our findings highlight a mechanism underpinning the key role of submesoscale fronts in the oceanic kinetic energy cascade and as a focus of vertical transports, and call for a parameterization of such effects in climate-scale ocean models., (© 2024. The Author(s).)

Background: Mindfulness-based interventions can successfully improve wellbeing in young adults. Mindful colouring is an applied mindfulness practice and improves short-term wellbeing. Less evidence is available about the effectiveness of regular, self-guided colouring. We investigated a self-guided two-week colouring intervention for university student wellbeing., Methods: One-hundred and forty university students completed a minimum of 10-min self-guided colouring, six times over two weeks. Participants were assessed at baseline and two-week follow-up using self-report measures of wellbeing, relating to quality of life, perceived stress, anxiety, depression, and mindfulness., Results: Colouring significantly improved all measures of mental health, wellbeing and mindfulness in students who completed at least six sessions of self-guided colouring., Conclusion: Colouring is an accessible activity that can improve student wellbeing when carried out regularly over two weeks. Future research should investigate the impact of longer-term colouring practice on wellbeing, and the effect of this intervention in the general adult population.

Sacrificing a target to save a group violates deontological ethics against harm but upholds utilitarian ethics to maximize outcomes. Although theorists examine many factors that influence dilemma decisions, we examined justice concerns: We manipulated the moral character of sacrificial targets, then measured participants' dilemma responses and just world beliefs. Across four studies ( N =1116), participants considering guilty versus innocent targets scored lower on harm-rejection (deontological) responding, but not outcome-maximizing (utilitarian) responding assessed via process dissociation. Just world beliefs (both personal and general) predicted lower utilitarian and somewhat lower deontological responding, but these effects disappeared when accounting for shared variance with psychopathy. Results suggest that dilemma decisions partly reflect the moral status of sacrificial targets and concerns about the fairness implications of sacrificing innocent targets to save innocent groups., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Both microplastics and phytoplankton are found together in the ocean as suspended microparticles. There is a need for deployable technologies that can identify, size, and count these particles at high throughput to monitor plankton community structure and microplastic pollution levels. In situ analysis is particularly desirable as it avoids the problems associated with sample storage, processing, and degradation. Current technologies for phytoplankton and microplastic analysis are limited in their capability by specificity, throughput, or lack of deployability. Little attention has been paid to the smallest size fraction of microplastics and phytoplankton below 10 μm in diameter, which are in high abundance. Impedance cytometry is a technique that uses microfluidic chips with integrated microelectrodes to measure the electrical impedance of individual particles. Here, we present an impedance cytometer that can discriminate and count microplastics sampled directly from a mixture of phytoplankton in a seawater-like medium in the 1.5-10 μm size range. A simple machine learning algorithm was used to classify microplastic particles based on dual-frequency impedance measurements of particle size (at 1 MHz) and cell internal electrical composition (at 500 MHz). The technique shows promise for marine deployment, as the chip is sensitive, rugged, and mass producible.

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Richard Holt reports a relationship with Boehringer Ingelheim Ltd that includes: speaking and lecture fees. Richard Holt reports a relationship with European Association for the Study of Diabetes that includes: speaking and lecture fees and travel reimbursement. Richard Holt reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees and travel reimbursement. Richard Holt reports a relationship with ENCORE HEALTHCARE that includes: speaking and lecture fees. Richard Holt reports a relationship with Liberum that includes: speaking and lecture fees. Richard Holt reports a relationship with Novo Nordisk that includes: speaking and lecture fees and travel reimbursement. Richard Holt reports a relationship with Rovi Pharmaceutical Laboratories that includes: speaking and lecture fees. RIGH is the chair of the EASD Committee for Clinical Affairs If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Suicide is a significant leading cause of death among young people, particularly those struggling with mental disorders. The present study utilised data from 230 young people (aged 16-18 years) undergoing a transitional care process from Child and Adolescent Mental Health Services to Adult Mental Health Services within the MILESTONE European project (2014-2019), a longitudinal cluster randomised controlled trial. The objectives of this study were to monitor temporal patterns of general health and social functioning over two years, to detect sex differences, and to identify factors associated with Suicidal Thoughts and Behaviours (STB) at the first and last time points. The results demonstrate a decrease in STB over the two-year follow-up period among all participants. Females exhibited a higher prevalence of STB across all time points, whereas males only exhibited STB at the nine-month follow-up. The most influential factors associated with STB were previous suicide attempts and mood disorders at baseline, and mood disorders and relational problems at the end of follow-up. These findings emphasise the importance of monitoring STB and informing young people undergoing a transitional care period about its key risk factors. Moreover, sex differences in STB suggest the need for different preventive strategies for males and females., (© 2024. The Author(s).)

Background: Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally., Methods: VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance., Discussion: There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test., Trial Registration: ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020., (© 2024. The Author(s).)

The effects of air pollution on health outcomes are well-established. However, little is known about perceptions of air pollution and how it may influence exercise behaviours. The aim of this study was to understand the perceived importance of air pollution during planned exercise, and where relevant, explore how those perceptions may differ between those living in different locations. A questionnaire was disseminated to several running and cycling clubs in the United Kingdom, covering population characteristics to determine urban, rural or coastal residents and exercisers, self-reported asthma, perceptions of air quality during active travel, planned exercise and attitudes towards learning more about the topic. Anonymised responses were gained from 381 adult participants (≥18 years and 60% female), 119 of whom answered questions related to active travel. More than half (54%) of all respondents think about the air quality they are exposed to during exercise and how it may affect their health. More urban than rural respondents (59% vs. 47% and p = 0.03) think about air quality and the impact it may have on their health when exercising. There were insufficient coastal respondents for direct comparison. Most survey respondents (57%) state that they would take the most severe course of action regarding exercise behaviour by avoiding it altogether during periods of heavy road traffic. Individuals with self-reported asthma (n = 60), irrespective of place of residence, are the most likely to be conscious of the potential effects of air pollution on their health and exercise performance compared to counterparts without self-reported asthma., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Purpose: This work developed a novel preclinical test of total knee replacements (TKRs) in order to explain TKR instability linked to patient dissatisfaction. It was hypothesized that stability tests on the isolated moving prostheses would provide novel comparative data on the stability and kinematics among TKR designs., Methods: Three TKR designs, DePuy Synthes Attune MS, Stryker Triathlon and Zimmer Biomet Persona MC, were assessed using a robotic arm while flexing-extending 0-140°. Tests imposed 710 N body weight combined with three tibial loads: no anterior-posterior (AP) force, 90 N anterior or 90 N posterior force. Other load effects were minimized and the kinematics was recorded. Each implant was tested six times to investigate the repeatability of the method. Data were analysed using statistical parametric mapping with one-way analysis of variance (ANOVA). If significance was found (p < 0.05), post hoc t tests with Bonferroni correction were used to contrast groups., Results: Significant differences were found throughout flexion-extension. Femoral rollback, AP stability, coupled internal-external rotation and AP position (roll-back) were all influenced by implant design. AP stability of the TKRs reduced with flexion reaching Attune 15 mm, Persona 13 mm and Triathlon 21 mm at 140° flexion. Tractive rolling significantly affected kinematics in the less congruent Triathlon design, with 6 mm different paths between flexion and extension motion (p < 0.05 across 5-100°). Paradoxical anterior femoral sliding in early flexion (0-40°) occurred in Persona and Triathlon designs., Conclusions: The novel testing technique provides, for the first time, comparative data on the inherent stability and kinematics of the TKR implants themselves across the arc of flexion-extension, independent of variables including soft tissue behaviour and surgical technique. The data show how much each prosthesis can contribute to the stability and motion of the implanted knee. Similar data from a wider range of designs will enable more informed decisions regarding implant design choice, aiming to reduce the prevalence of TKR instability in patients., Level of Evidence: Controlled laboratory study., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Reducing inequalities in preconception health and care is critical to improving the health and life chances of current and future generations. A hybrid workshop was held at the 2023 UK Preconception Early and Mid-Career Researchers (EMCR) Network conference to co-develop recommendations on ways to address inequalities in preconception health and care. The workshop engaged multi-disciplinary professionals across diverse career stages and people with lived experience (total n = 69). Interactive discussions explored barriers to achieving optimal preconception health, driving influences of inequalities and recommendations. The Socio-Ecological Model framed the identified themes, with recommendations structured at interpersonal (e.g. community engagement), institutional (e.g. integration of preconception care within existing services) and environmental/societal levels (e.g. education in schools). The co-developed recommendations provide a framework for addressing inequalities in preconception health, emphasising the importance of a whole-systems approach. Further research and evidence-based interventions are now needed to advance the advocacy and implementation of our recommendations.

Background: In the UK, about 14% of community-dwelling adults aged 65 and over are estimated to be at risk of malnutrition. Screening older adults in primary care and treating those identified as 'at risk' may help reduce malnutrition risk and associated healthcare use, and improve quality of life. The aim of this study is to explore how primary care practitioners (PCPs) and older adults perceive, use and respond to an intervention to support those identified as 'at risk'., Methods: We developed and optimised an intervention (screen and treat protocol, online tools and printed materials) to support primary care practitioners to identify malnutrition risk among older adults, and intervene where necessary. We recruited older adults (described as 'patients' here) taking part in a feasibility study, and carried out semi-structured interviews to assess PCPs' and patients' engagement with the intervention, and identify any contextual issues that supported or undermined their engagement., Results: Four themes were developed, encompassing patients' and PCPs' perceptions of undernutrition, study measures and appointments, constraints on PCPs' enthusiasm to make a difference, and patients' expectations of nutritional appointments. Key findings included patients commonly not accepting advice for undernutrition/malnutrition but welcoming support for their nutritional needs; checklists potentially distracting patients from recalling discussions about their nutritional needs; a tension between PCPs' desire to recruit less-well patients and logistical difficulties in doing so; and patients compromising their nutritional needs to suit others., Conclusions: Diverse factors influence whether an intervention succeeds in primary care. PCPs learn about an intervention/study in different ways, vary in how they understand and accept its aims, and desire to make a difference to their patients. Patients bring perceptions and expectations about the study's aims, coloured by their habits and preferences, prior experience of research and healthcare, and pressure from social expectations. Each aspect must be considered when developing a successful primary care intervention that is viewed as relevant and meaningful, and presented using language that aligns with participants' values and goals. Our findings suggest that references to 'malnutrition risk' should be avoided in any patient-facing materials/interactions as participants do not accept or identify with this label., (© 2024. The Author(s).)

Five experiments (N = 2,204) examined responses to a realistic moral dilemma: a military pilot must decide whether to bomb a dangerous enemy target, also killing a bystander. Few people endorsed bombing when the bystander was an innocent civilian; however, when the bystander's identity was unknown, over twice as many people endorsed the bombing. Follow-up studies tested boundary conditions and found the effect to extend beyond modern-day conflicts in the Middle East, showing a similar pattern of judgment for a fictional war. Bombing endorsement was predicted by attitudes towards total war, the theory that there should be no distinction between military and civilian targets in wartime conflict. Bombing endorsement was lower for UK compared to US participants due to differences in total war attitudes. This work has implications for conflicts where unidentified bystanders are common by revealing a potentially deadly bias: people often assume unidentified bystanders are guilty unless proven innocent., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Danielson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Exercise prehabilitation may improve the tolerance and effectiveness of anticancer treatments such as chemotherapy. This systematic review assesses the impact of exercise on chemotherapy outcomes and identifies research priorities. Nineteen studies (1418 patients) were reviewed, including 11 randomised controlled trials and eight observational studies. Exercise led to improvements in body composition, fitness, strength and quality of life (QoL) across studies. Exercise can be safely and effectively delivered during chemotherapy. Limited standardisation and small sample sizes highlight the need for larger, better-designed studies to optimise this low-cost intervention., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Objectives: This systematic review aimed to examine the impact of videoconferencing peer support groups on individuals living with dementia and their caregivers., Method: A narrative synthesis of articles identified via searches of five databases (MEDLINE, PsycINFO, EMBASE, CINAHL, and Web of Science). The search was carried out in January 2024. The review included qualitative, quantitative, and mixed methods research reporting the experiences of dementia patients and/or their caregivers participating in online support groups that took place through video call., Results: 16 studies met the inclusion criteria for the review. In all studies, participants indicated that taking part in a virtual support group was beneficial, as they valued being able to connect with others in a similar situation, receive advice, and learn coping strategies. Videoconferencing support groups were seen as convenient to attend, even though participants sometimes experienced technical difficulties (e.g. internet connectivity issues). The provision of IT training and support helped participants access this type of support effectively., Conclusion: Videoconferencing support groups can be beneficial for caregivers of people living with dementia, especially when groups meet frequently and provide some manner of IT support. More research is needed to understand the potential benefits of videoconferencing for people with dementia.

Background: Most people living with dementia live in their own home supported by family carers. One of the most challenging problems they face is managing toilet-use and continence. Carers have repeatedly asked for better advice from healthcare professionals. The purpose of this systematic review was to inform the development of an intervention to support healthcare professionals to provide existing continence management advice to the carers of people living at home with dementia. It aimed to identify and synthesise lessons from the development and evaluation of interventions, involving primary or community healthcare professionals, to support the provision of management advice aimed at supporting people living at home with dementia and their carers with activities of daily living. Due to a lack of relevant continence or toilet-use interventions, this included, but was not limited to, toileting or continence care., Methods: Literature (February 2009-November 2022) was searched using five databases: MEDLINE (Ovid); PsycINFO (Ovid); EMBASE (Ovid); Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO); and Cochrane Central Register of Controlled Trials (CENTRAL). Empirical studies using a variety of methodologies were included and thus the quality of papers appraised using the Mixed-Methods Appraisal Tool. No studies were excluded based on quality. A narrative synthesis was undertaken., Results: Twelve articles reporting on 10 interventions were included. Most comprised the provision of online resources only, although some combined these with online or face-to-face contact with healthcare professionals. A variety of methodologies was utilised including randomised controlled trials. The quality of included studies was variable. Six main themes were identified: mode of delivery; targeted and tailored resources; content, design and navigation; credibility; user involvement in the development and evaluation of information resources; and role of professionals and organisations., Conclusions: Despite the urgent need to better support people living at home with dementia and their carers, this review highlights the paucity of studies reporting on interventions delivered within primary and community healthcare contexts to provide management advice aimed at supporting this population with activities of daily living. This review has identified important considerations that will potentially aid the development, delivery and evaluation of such interventions., Systematic Review Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42022372456., (© 2024. The Author(s).)

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is used to quantify the blood-brain barrier (BBB) permeability-surface area product. Serial measurements can indicate changes in BBB health, of interest to the study of normal physiology, neurological disease, and the effect of therapeutics. We performed a scan-rescan study to inform both sample size calculation for future studies and an appropriate reference change value for patient care. The final dataset included 28 healthy individuals (mean age 53.0 years, 82% female) scanned twice with mean interval 9.9 weeks. DCE-MRI was performed at 3T using a 3D gradient echo sequence with whole brain coverage, T1 mapping using variable flip angles, and a 16-min dynamic sequence with a 3.2-s time resolution. Segmentation of white and grey matter (WM/GM) was performed using a 3D magnetization-prepared gradient echo image. The influx constant K i was calculated using the Patlak method. The primary outcome was the within-subject coefficient of variation (CV) of K i in both WM and GM. K i values followed biological expectations in relation to known GM/WM differences in cerebral blood volume (CBV) and consequently vascular surface area. Subject-derived arterial input functions showed marked within-subject variability which were significantly reduced by using a venous input function (CV of area under the curve 46 vs. 12%, p < 0.001). Use of the venous input function significantly improved the CV of K i in both WM (30 vs. 59%, p < 0.001) and GM (21 vs. 53%, p < 0.001). Further improvement was obtained using motion correction, scaling the venous input function by the artery, and using the median rather than the mean of individual voxel data. The final method gave CV of 27% and 17% in WM and GM, respectively. No further improvement was obtained by replacing the subject-derived input function by one standard population input function. CV of K i was shown to be highly sensitive to dynamic sequence duration, with shorter measurement periods giving marked deterioration especially in WM. In conclusion, measurement variability of 3D brain DCE-MRI is sensitive to analysis method and a large precision improvement is obtained using a venous input function., Competing Interests: The authors declare no potential conflicts of interest relevant to this work., (© 2024 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Objectives: Intolerance of uncertainty, the tendency to interpret and react negatively to uncertainty, is a transdiagnostic risk factor for anxiety, depression and eating-related disorders. Given the high comorbidity between anxiety, depression and schizophrenia-spectrum diagnoses (SSDs), there is potential for intolerance of uncertainty to play a role in modulating psychosis symptoms. To address this gap in our understanding, we conducted the first prospectively registered systematic review on intolerance of uncertainty and psychotic symptoms in both people with SSDs and in the general population., Methods: Four databases were searched (PsycINFO, Medline, Web of Science and PubMed), which identified ten studies with a total of 1503 participants that measured intolerance of uncertainty and psychosis symptoms., Results: Key findings suggest the following: (1) Intolerance of uncertainty was associated with total negative psychotic symptoms with small-medium effect sizes; (2) intolerance of uncertainty was higher in individuals with an 'at-risk' mental state for psychosis compared to controls; (3) higher intolerance of uncertainty was associated with more individual psychotic symptoms related to delusions and paranoia within clinical and nonclinical samples; and (4) there was mixed evidence for a relationship between intolerance of uncertainty and auditory hallucinations and intolerance of uncertainty and total positive symptoms in clinical samples., Conclusions: Overall, these findings highlight that intolerance of uncertainty may be an important transdiagnostic dimension and potential treatment target for psychotic symptoms such as delusions and paranoia in people with SSDs., (© 2024 The Author(s). British Journal of Clinical Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

Miller has recently argued that fetuses have the same inherent value as non-disabled adults. However, we do not need to postulate some property possessed equally by all humans, including fetuses, in order to explain the equality of non-disabled adults. It would suffice if there were some property possessed by all non-disabled adults, but not by fetuses., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To delineate the characteristics of the work undertaken by general practitioners (GPs) and staff in implementing and utilising video consultation within their situated clinical contexts., Methods: The data material comprises 33 semi-structured interviews with GPs and staff and 132 hours of ethnographic fieldwork across seven clinics in Denmark. The data collection period spanned from June 2021 to August 2022. Reflexive thematic analysis was employed to analyse the data, drawing inspiration from the concept of invisible work as proposed by Susan Leigh Star and Anselm Strauss., Results: Four types of invisible work were identified through the analysis: (1) the work of introducing video consultations, (2) the work of stabilising video consultation use, (3) the work of coordinating users and systems, (4) the work of repair as a response to breakdowns., Conclusions: The video consultation changes the organisational structure and leads to a reconfiguration of professional roles and existing work practices. Moreover, implementing and using video consultations demands articulation, inclusion and affective work by GPs and staff, and this work includes allocating time to coordinate tasks, do workarounds and repair breakdowns., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Pangenome graphs can represent all variation between multiple reference genomes, but current approaches to build them exclude complex sequences or are based upon a single reference. In response, we developed the PanGenome Graph Builder, a pipeline for constructing pangenome graphs without bias or exclusion. The PanGenome Graph Builder uses all-to-all alignments to build a variation graph in which we can identify variation, measure conservation, detect recombination events and infer phylogenetic relationships., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aim: The diabetes annual review is an important part of clinical care. Non-attendance is increasingly common and associated with poor health outcomes. At-home self-collection of blood tests, urine samples and anthropometric data through a postal box may facilitate engagement. We aimed to explore the views of people living with diabetes on the use of a postal box as an alternative to usual care for self-collecting blood samples, urine samples and anthropometric data and to understand whether the availability of a postal box would facilitate the uptake of the diabetes annual review., Methods: We conducted semi-structured interviews and focus groups with adults who have type 1 or type 2 diabetes. Purposive sampling was used to obtain a high representation of infrequent attendees of annual review appointments within the study population. Transcripts were collated and analysed thematically., Results: Twenty participants took part including eight infrequent attendees. All infrequent attendees and most regular attendees responded positively to a postal box, with convenience being the most prominent value described. Concerns raised related to capability of self-collection and the accuracy of results. Participants were asked for suggestions to improve the postal box. The most common themes related to communication; needing clearer information about each test in the postal box; feedback of results; and utilising the box to communicate priorities for discussion at future consultations., Conclusion: Postal boxes for annual reviews were well-received by those living with diabetes. Designed well, they have the potential to overcome more than just the physical barriers to annual review attendance., (© 2024 Diabetes UK.)