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Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the "residual" exposure). These "local" causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method-the doubly-ranked method-has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects-that of low-density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest there should be extensive simulation and empirical methodological examination of performance of both methods for NLMR under different conditions before further use of these methods. In the interim, use of NLMR methods needs justification, and a number of sanity checks (such as analysis of negative and positive control outcomes, sensitivity analyses excluding removal of strata at the extremes of the distribution, examination of biological plausibility and triangulation of results) should be performed., (© 2024. The Author(s).)

Introduction: This study aims to assess the presence of overactive bladder syndrome (OAB), academic stress, and their impact on quality of life (QoL) of healthy university students., Methods: A cross-sectional study recruited university students from different academic streams, between January 2021 to December 2021. Demographics, overactive bladder-validated 8 questionnaire (OAB-V8), International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB) questionnaire, and Perception of Academic Stress (PAS) scale were collected. The correlation between the variables was assessed using the Social Sciences Statistical Package (SPSS) version 21., Results: Three hundred and 89 people met the inclusion criteria. There were 241 (62%) females, and 248 (63.8%) of the students were under the age of 22. Four academic streams were included: Engineering 96 (24.7%), Humanities 121 (31.1%), Medicine 85 (21.8%) and Nursing 87 (22.4%). OAB was found among 103 (26%) students. The mean OAB-V8 score was 5.8 ± 6.6. The mean PAS scale was 53.9 ± 9.4. The mean ICIQ-OAB score was 1.5 (0-9). Male gender 62 (60%), smoking 42 (40.8%), academic stream (Humanity 40 (38.8%)) and year (third and fourth-year students 34 (33%) and 33 (32%), respectively) have a statistically significant positive correlation with OAB ( p  < 0.001). Humanity stream (mean rank 169.2) and junior students (first and second years with mean rank of 174 and 177), respectively, had high level of academic stress and low PAS scale. There is a weak but statistically significant inverse correlation between OAB and the PAS scale ( r  = -0.211) ( p  < 0.001)., Conclusion: OAB is prevalent among healthy university students and is directly related to academic stress. Both OAB and academic stress have impact on quality of life. We hope this study will help to raise awareness of OAB among university students to early identify and treat such a condition, avoiding unnecessary bother among healthy university students., 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.

Aims: Plaque-type blue naevi are rare melanocytic tumours presenting as large, pigmented plaques at birth or during childhood. There is a risk for malignant transformation, but no larger comprehensive studies exist and the diagnosis is challenging, especially on limited biopsy material. The aim is to describe the clinicopathological features and behaviour of the disease more comprehensively., Methods and Results: We retrieved eight plaque-type blue naevi, presenting as large, pigmented plaques (median = 7 cm; range = 3-26) most frequently affecting the scalp (four) followed by the cheek, arm, abdominal wall and gluteal cleft (one each), with a slight female predilection. Median age at time of biopsy was 39.5 years (range = 15-90), but three tumours had been present at birth and one since childhood. Histopathologically, the tumours were poorly circumscribed and composed of cellular fascicles of uniform spindle cells in a background of variably prominent pigmented dendritic cells affecting dermis and subcutaneous tissues. The majority had mutations in GNAQ. One tumour showed malignant transformation, characterised by an expansile nodule of pleomorphic epithelioid melanocytes with rhabdoid morphology, high mitotic activity and areas of necrosis. This patient developed metastatic melanoma to lymph nodes. All patients are alive with a median follow-up of 60 months., Conclusion: Plaque-type blue naevi are diagnostically challenging tumours with risk for malignant transformation. Awareness and familiarity with the salient clinicopathological features are necessary for reliable diagnosis, and long-term clinical follow-up is required to monitor for malignant transformation., (© 2024 John Wiley & Sons Ltd.)

Background: People who have communication difficulties may benefit from using augmentative and alternative communication (AAC). Understanding and measuring outcomes from the use of AAC is an important part of evaluating the impact of devices and services. Outcome measurement needs to reflect the changing nature of the impact of using AAC on an individual's ability to participate in activities of daily life. There is a limited understanding of the concepts that should inform the evaluation of outcomes from AAC device provision, nor how people's expectations from AAC may change over time., Aims: To inform the development of a patient-reported outcome measure for AAC by understanding more about people's expectations from AAC and how these change over time., Methods & Procedures: A longitudinal qualitative research study was designed and carried out with seven participants over a period of 2 years. Participants were recruited from a regional specialist assessment service for AAC in the south-west of the UK. Four semi-structured interviews were carried out: (1) before assessment for AAC, (2) after assessment, (3) directly after provision of an AAC device and (4) between 6 and 12 months after provision. An original analytic method was used in this study that built on the principles of longitudinal interpretative phenomenology analysis, applied with a dialogic theoretical lens. This approach enabled the inclusion of a range of multimodal and embodied data collected to this study and allowed the research team to draw out salient themes across the cohort group while attending to the influence of time and context on experience., Outcomes & Results: The results confirm and extend the three core concepts that were used to guide analysis: changes; contexts; future possibilities. The contextual and temporal influences on outcomes attainable from AAC for this cohort were also identified and illustrated through cross-case comparison. Deeper, analytic, and conceptual engagement with theory, which was then applied to analysis of the data, provided methodological rigour in the study. The results enhance our understanding of people's hopes and expectations from AAC and how these change over time., Conclusions & Implications: This qualitative longitudinal research study provides new insights into the journeys of people who experience communication disability, and the shifting nature of their sense of identity as they engage with, and learn from using, AAC. The study is significant as it attends to the dynamic nature of experience and how contextual and experiential factors influence people's hopes and expectations from AAC. The paper presents an original application of longitudinal qualitative research methodology with people who use AAC which can be further applied and tested in the field of communication disability research., What This Paper Adds: What is already known on this subject We did not know the impact that time has on the concepts that have been identified to represent important outcomes from AAC. The existing concepts used to define outcomes from AAC were not adequately conceptualized to develop a patient-reported outcome measure. This study sought to extend our knowledge about outcomes from AAC. What this paper adds to the existing knowledge This study adds to the methodological toolkit available for qualitative inquiry in the field of communication disability research by presenting a longitudinal qualitative research methodology. It adds depth to our understanding of the concepts that underpin outcomes from AAC and highlights the dynamic nature of contexts and how this influences desired outcomes. What are the potential or actual clinical implications of this work? This longitudinal qualitative research study provides a broader perspective on the experience of getting AAC. It will enable clinicians to better navigate the contextual and transitionary factors that influence people's experience of acquiring AAC devices. The enhanced concepts described will also support clinical conversations that consider the wider facets of communication and what AAC can add to existing communicative tool kits beyond getting a message across., (© 2023 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Introduction and Hypothesis: The objective was to evaluate the prevalence of levator ani avulsion (LAA) among primiparous women with obstetric anal sphincter injury (OASI) and how this association could affect future pelvic floor dysfunction., Methods: Three electronic databases (MEDLINE/PubMed/EMBASE) were searched in December 2018 and again in October 2022. Nine full-text articles were included in the analysis. The exclusion criteria were language other than English, studies not based on primiparous women only, conference abstracts, and evaluation without ultrasound or MRI., Results: The overall prevalence of LAA was 24% (95% CI: 18-30%). Those with OASI, were at a higher risk of LAA, OR 3.49 (95% CI: 1.46 to 8.35). In women with LAA + OASI versus OASI alone, Three of Five studies showed worsened AI symptoms. Three of Five studies assessing urinary incontinence (UI) reported no significant difference in UI, whereas two reported increased UI. All studies that looked at pelvic organ prolapse reported a higher incidence of symptomatic prolapse and reduced pelvic floor muscle strength in women with LAA + OASI compared with those without LAA., Conclusion: Levator ani avulsion is prevalent following vaginal birth and is strongly associated with OASI. Incidence of AI does not increase in women with LAA and OASI, but they had greater symptom bother. OASI with LAA appears to increase the incidence of pelvic floor weakness and pelvic organ prolapse. There is no consensus agreement on the effect of LAA + OASI on UI., (© 2024. Crown.)

The 7th National Audit Project of the Royal College of Anaesthetists studied peri-operative cardiac arrest in the UK. We report the results of the vascular surgery cohort from the 12-month case registry, from 16 June 2021 to 15 June 2022. Anaesthesia for vascular surgery accounted for 2% of UK anaesthetic caseload and included 69 (8%) reported peri-operative cardiac arrests, giving an estimated incidence of 1 in 670 vascular anaesthetics (95%CI 1 in 520-830). The high-risk nature of the vascular population is reflected by the proportion of patients who were ASA physical status 4 (30, 43%) or 5 (19, 28%); the age of patients (80% aged > 65 y); and that most cardiac arrests (57, 83%) occurred during non-elective surgery. The most common vascular surgical procedures among patients who had a cardiac arrest were: aortic surgery (38, 55%); lower-limb revascularisation (13, 19%); and lower-limb amputation (8, 12%). Among patients having vascular surgery and who had a cardiac arrest, 28 (41%) presented with a ruptured abdominal aortic aneurysm. There were 48 (70%) patients who had died at the time of reporting to NAP7 and 11 (16%) were still in hospital, signifying poorer outcomes compared with the non-vascular surgical cohort. The most common cause of cardiac arrest was major haemorrhage (39, 57%), but multiple other causes reflected the critical illness of the patients and the complexity of surgery. This is the first analysis of the incidence, management and outcomes of peri-operative cardiac arrest during vascular anaesthesia in the UK., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD., Methods: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation., Results: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11., Conclusion: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Three commonly used approaches to the forearm in orthopedic surgery are Henry's, Thompson's, and the ulnar approach, each of which has the potential to cause injury to nerves around the wrist. Preserving these nerves is important to prevent complications such as neuroma formation and motor and sensory changes to the hand. We conducted a review of the literature to assess the nerves at risk and whether 'safe zones' exist to avoid these nerves. An independent reviewer conducted searches in Embase and MEDLINE of the literature from 2010 to 2020. A total of 68 papers were identified, with 18 articles being included in the review. Multiple nerves were identified as being at risk for each of the approaches described. In the anterior approach, the palmar cutaneous branch of the median nerve (PCBMN) is most at risk of injury. An incision immediately radial to the flexor carpi radialis (FCR) or directly over the FCR is most likely to avoid injury to both superficial branch of the radial nerve (SBRN) and PCBMN. With Thompson's approach, the safest zone for an incision is directly over or slightly radial to Lister's tubercle to avoid injury to SBRN and lateral cutaneous nerve of the forearm. For the ulnar approach, a safe zone was shown to be on the ulnar side of the wrist around the ulnar styloid (US) when the forearm was in supination or a neutral position to avoid injury to the dorsal branch of the ulna nerve (DBUN). Care must be taken around the US due to the density of nerves and the proximity of the last motor branch of the posterior interosseous nerve to the ulnar head. This review highlighted the proximity of nerves to the three most common surgical incisions used to access the forearm. In addition, anatomical variations may exist, and each of the nerves identified as being at risk has multiple branches. Both factors increase the potential of intraoperative damage if the anatomy is not properly understood. The surgeon must adhere carefully to the established approaches to the wrist and distal forearm to minimize damage to nerves and optimize surgical outcomes for the patient., (© 2023 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Background: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure., Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency., Design: A prospective multicentre observational cohort study (the 'SONAR' study)., Setting: Seventeen haemodialysis centres in the UK., Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created., Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings., Main Outcome Measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months., Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset ( n  = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data., Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit., Trial Registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment ; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

Peri-operative anaphylaxis is a rare but potentially catastrophic event which must be considered whenever unexpected and significant cardiovascular or respiratory compromise occurs during anaesthesia. The Resuscitation Council UK algorithm for peri-operative anaphylaxis highlights the importance of early intravenous adrenaline and fluid resuscitation and provides guidance on the treatment of refractory anaphylaxis and immediate follow-up. This algorithm is endorsed by the Royal College of Anaesthetists, Association of Anaesthetists, British Society of Allergy and Clinical Immunology and Clinical Immunology Professional Network of the British Society for Immunology. This document was produced by the Perioperative Allergy Network steering committee in collaboration with the Resuscitation Council UK., (© 2023 Association of Anaesthetists.)

Background: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively., Methods: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants., Results: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk., Conclusions: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play., Competing Interests: Competing interests: TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. He received conference support or speaker’s fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. LP served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fee by Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Sleep is fundamental to health. The aim of this study was to analyse and determine factors predicting sleep quality during and after national lockdowns due to severe acute respiratory syndrome coronavirus 2 (COVID-19) in the UK. A longitudinal online survey-based study (SleepQuest) involving UK adults was administered in Spring 2020, Winter 2020, and Winter 2022 including questionnaires probing sleep quality, depression, anxiety, beliefs about sleep, demographics, COVID-19 status, and exercise. The primary outcome was sleep quality (Pittsburgh Sleep Quality Index). A linear mixed-effects model evaluated factors associated with baseline and longitudinal sleep quality. Complete data were provided by 3306 participants in Spring 2020, 2196 participants in Winter 2020, and 1193 in Winter 2022. Participants were mostly female (73.8%), white (97.4%), and aged over 50 years (81.0%). On average, participants reported poor sleep quality in Spring 2020 (mean [SD] Pittsburgh Sleep Quality Index score = 6.59 [3.6]) and Winter 2020 (mean [SD] Pittsburgh Sleep Quality Index score = 6.44 [3.6]), with improved but still poor sleep quality in Winter 2022 (mean [SD] Pittsburgh Sleep Quality Index score = 6.17 [3.5]). Improved sleep quality was driven by better subjective sleep and reduced daytime dysfunction and sleep latency. Being female, older, having caring responsibilities, working nightshifts, and reporting higher levels of depression, anxiety, and unhelpful beliefs about sleep were associated with worse baseline PSQI scores. Better sleep quality was associated with more days exercising per week at baseline. Interventions focusing on improving mental health, exercise, and attitudes towards sleep, particularly in at-risk groups, may improve sleep-related outcomes in future pandemics., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Objectives: The COVID-19 pandemic required a change in resource priority from Neurosurgical care in order to treat medically unwell patients suffering from the complications of COVID-19 infections. We demonstrate the impact of COVID-19 on total bed days in 24 Neurosurgical centres in England offering adult Neurosurgery as well as the total spells (single inpatient episodes) for operative Neurosurgical patients between 2020 and 2022 when compared with 2019., Methods: We used Capse Healthcare Knowledge System software iCompare in order to show the change in total spells for patients undergoing a primary or secondary Neurosurgical procedure as defined using the National Neurosurgical Audit Programme (NNAP) OPCS-4 coding framework between 2019 and 2022., Results: The overall mortality rate of COVID-19 patients was 12.3% and the percentage of total bed days taken up by COVID-19 patients in hospitals at large was on average 7.7%. The total number of spells for all procedures over the 24 centres in 2022 was 39,019 compared with 45,742 in 2019. There was a cumulative deficit of 24,904 spells. The loss of spells was not equally distributed across regions and hospital Trusts. The average number of referral to treatment pathways completed within 18 weeks has declined from 76% to 57% over the study period and the referral to treatment clearance time has risen from 17 to 24 weeks., Conclusions: The mean elective cranial output in 2022 compared with 2019 is at 88% with spinal output lagging at 69%. If the rate of change year on year were to remain at current levels then we would reach pre-pandemic levels of output by 2026.

Introduction: Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved., Methods and Analysis: A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance., Ethics and Dissemination: Ethical approval for the consensus process will be obtained from the Queen's University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely., Registration: The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854)., Competing Interests: Competing interests: SM reports speaker honoraria from MSD, Roche, BD and Astra Zeneca; advisory boards for Lilly, Novartis, MSD, Roche and Astra Zeneca; conference travel and support from Roche, Lilly and MSD; and institutional research funding from Novartis. HI reports consulting fees from Daiichi Sankyo, Chugai, Astra Zeneca, Lilly, MSD, Pfizer and Gilead; honoraria from Daiichi Sankyo, Chugai, Astra Zeneca, Lilly, MSD, Pfizer, Taiho and Kyowa Kirin; and institutional research funding from Chugai, Daiichi Sankyo and Astra Zeneca. PD reports institutional research funding from Cepheid and Roche; consulting fees from Roche, and honoraria from Astra Zeneca and Oncoviews; and conference and travel support from Roche. H-BL reports research funding from Devicor Medical Product Inc. and is a co-founder and director of DCGen Co. Ltd. ALR reports consulting fees from Astra Zeneca and royalties from Myriad Genetics. GW reports consulting fees from Astra Zeneca, MSD, Novartis, Daiichi Sankyo and Roche; honoraria from Astra Zeneca, MSD, Novartis, Roche, Pfizer and Daiichi-Sankyo; and institutional research funding from Astra Zeneca/Medimmune, Roche/Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, MSD, Merck, Bayer, Janssen, Astellas Pharma, Libbs and Takeda. NZ reports consulting fees from Lilly, Eisai, Astra Zeneca, MSD, Novartis and Gilead; honoraria from Roche, Pfizer, Eisai, Amgen, Gilead, Novartis, Lilly and Astra Zeneca; and conference travel and support from Novartis, Astra Zeneca and Lilly. The remaining authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Existing research suggests that Acceptance and Commitment Therapy (ACT) training is beneficial for healthcare workers' professional practice and personal well-being. This review aimed to further understanding of healthcare workers' experiences of ACT training by synthesizing existing qualitative studies. Methods: A systematic literature review identified papers published up until April 2022 using the Embase, Ovid MEDLINE, and PsycINFO databases as well as relevant studies within the gray literature. Nine studies were included in the review, which were analyzed using Thematic Synthesis (Thomas & Harden, 2008). Results: Three analytical themes were identified through the thematic synthesis: I am both the patient and the professional; a powerful and empowering experience; and it is not always comfortable. Conclusion: This review has highlighted the importance of experiential learning. The training was a powerful experience for staff, but as such, it was not always comfortable. Recommendations for the future delivery of ACT training are made., (© Copyright 2024 Springer Publishing Company, LLC.)

Purpose: The aim of this study was to describe the 10-year findings from the UK National Ligament Registry (NLR)., Methods: A retrospective review was performed for prospectively collected data on the NLR between January 2013 and December 2022. All patients who underwent primary ACL reconstruction (ACLR) on the registry were included. Surgical characteristics were analysed, including surgeon grade and case volume, concomitant knee procedures, venous thromboembolic prophylaxis, graft characteristics, femoral and tibial tunnel drilling, and fixation methods. Clinical outcomes were collected preoperatively and at 6 months, 1 year, 2 years and 5 years following the index procedure., Results: During the study period, 17,492 unilateral ACLR procedures were recorded. Autograft was used in 98%, most commonly a combined semitendinosus and gracilis graft (77%) or patella tendon graft (31%). Allograft was used in only 1% of the patients. In 52% of cases, ACLR was associated with an additional procedure, with isolated medial meniscal surgery being the most common (21%). Femoral tunnel drilling was mostly performed through an anteromedial portal (73%) and tibial tunnel drilling using an outside-in technique (92%). The most common method of femoral graft fixation was with an Endobutton fixed loop suspensory device (77%), while interference screws predominated for tibial tunnel fixation (86%). Patients who underwent ACLR surgery showed significant improvement in their functional outcome scores at six months, 1 year, 2 years and 5 years postoperatively., Conclusion: Data from the NLR shows a detailed description of the current trends and evolution of ACLR in the United Kingdom over the last 10 years. Satisfactory functional outcomes were observed 5 years postoperatively. This study provides useful information on the prevalence of ACL-associated injuries and current surgical techniques with the aim of improving the quality of clinical care and patients' outcomes. Moreover, it provides surgeons with a benchmark against which to compare current practices and functional outcomes following ACLR across the United Kingdom., Level of Evidence: Level III., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background and Aims: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it., Methods: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis., Results: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m 2 , and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m 2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score., Conclusions: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance., Competing Interests: Declaration of competing interest HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer, SOBI and Kowa and research grants and donations from Akcea, Pfizer, MSD, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. ASW: Received grants from Akcea, Regeneron; Royalties from Elsevier and is a board member for familial hyperlipidaemia group, Europe. DD: Received honoraria for advisory boards from SOBI. NF: Received honoraria for presentations from SOBI. YT: Received speakers fee from Daiichi Sankyo and Amarin. PD: Received honoraria from SOBI, NOVARTIS, AMGEN and Daiichi Sankyo. PM: Participated on a Data Safety Monitoring Board and Advisory Board for Ionis, AKCEA, AMRYT, AMARIN, Ultragenix AG: received research grants from AMGEN, SANOFI, AMRYT, ULTRAGENYX, Consulting fee or honoraria from AMGEN, SANOFI, AMRYT, ULTRAGENYX, NOVARTIS, AKCEA, SERVIER. BB, SK, CD, AJ, FJ, MM, HD, PH, MM, AA, DO, PND: None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397., (© 2023. The Author(s).)

Background: Microplastics, produced through degradation of environmental plastic pollution, have been detected in human tissues including placenta and fetal meconium. Cell culture and animal studies have demonstrated potential reproductive toxicity of these particles; however, their association with adverse fertility or pregnancy outcomes in humans is not known., Objectives: To synthesise evidence for the presence of microplastics in human reproductive tissue and their associations with environmental exposures and reproductive outcomes., Search Strategy: MEDLINE, Embase, Emcare, CINAHL, ClinicalTrials.gov and ICTRP were searched from inception to 03/02/2023., Selection Criteria: Studies of human participants, assessing presence of microplastics in reproductive tissues, environmental exposures to microplastics, and fertility- or pregnancy-related outcomes., Data Collection and Analysis: Two independent reviewers selected studies and extracted data on study characteristics, microplastics detected, environmental exposures and reproductive outcomes. Narrative synthesis was performed due to methodological heterogeneity., Main Results: Of 1094 citations, seven studies were included, covering 96 participants. Microplastics composed of 16 different polymer types were detected in both placental and meconium samples. Two studies reported associations between lifestyle factors (daily water intake, use of scrub cleanser or toothpaste, bottled water and takeaway food) and placental microplastics. One study reported associations between meconium microplastics and reduced microbiota diversity. One reported placental microplastic levels correlated with reduced birthweights and 1-minute Apgar scores., Conclusions: There is a need for high-quality observational studies to assess the effects of microplastics on human reproductive health., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to report the demographic and mechanism of injury data in the UK National Ligament Registry (NLR) at 10 years and determine factors leading to poor compliance with completion of Patient-Reported Outcome Scores (PROMs)., Methods: A retrospective review was performed for prospectively collected data on the NLR between January 2013 and December 2022. All patients who underwent primary anterior cruciate ligament reconstruction (ACLR) were included. Patient demographics, mechanism of injury and patient compliance with completing PROMs were analysed. Patient characteristics were further analysed in relation to compliance with completing the different PROMs at the predefined time points. Patients were identified as nonresponders if they had not completed either 1- or 2-year postoperative Knee injury and Osteoarthritis Outcome Score (KOOS)., Results: A total of 17,492 patients were included in this study. The average age for patients undergoing ACLR between 2013 and 2022 was 29.4 (SD, 10.3). Seventy percent were men and 30% women. Football was the most common activity associated with an ACL injury. Patient compliance with recording PROMs was 55% preoperatively and 37%, 32% and 24% at 1-, 2- and 5-year postoperative follow-up, respectively. Nonresponders represented 54% of eligible patients. Multivariate analyses showed that sex, age, smoking, time interval between injury and surgery and low socioeconomic status were associated with low compliance with postoperative PROM completion (p < 0.001)., Conclusion: This study reports the demographic characteristics for patients on the NLR since 2013. Male sex, young age, increased waiting time between injury and surgery, smoking and lower socioeconomic class were predictors of low compliance with completion of postoperative PROMs on the UK NLR. Understanding the factors that affect patient compliance with PROMs improves our ability to provide targeted interventions and information to specific patient populations with the aim of enhancing inclusiveness and representation of population in the registry., Level of Evidence: Level III., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Western Europe boasts advanced health care systems, robust kidney care guidelines, and a well-established health care workforce. Despite this, significant disparities in kidney replacement therapy incidence, prevalence, and transplant access exist. This paper presents the third International Society of Nephrology Global Kidney Health Atlas's findings on kidney care availability, accessibility, affordability, and quality in 22 Western European countries, representing 99% of the region's population. The known chronic kidney disease (CKD) prevalence across Western Europe averages 10.6%, slightly above the global median. Cardiovascular diseases account for a substantial portion of CKD-related deaths. Kidney failure incidence varies. Government health expenditure differs; however, most countries offer government-funded acute kidney injury, dialysis, and kidney transplantation care. Hemodialysis and peritoneal dialysis are universally available, with variations in the number of dialysis centers. Kidney transplantation is available in all countries (except for 3 microstates), with variable transplant center prevalence. Conservative kidney management (CKM) is increasingly accessible. The region's kidney care workforce is substantial, exceeding global averages; however, workforce shortages are reported. Barriers to optimal kidney care include limited workforce capacity, lack of surveillance mechanisms, and suboptimal integration into national noncommunicable disease (NCD) strategies. Policy recognition of CKD as a health priority varies across countries. Although Western Europe exhibits strong kidney care infrastructure, opportunities for improvement exist, particularly in CKD prevention, surveillance, awareness, and policy implementation. Efforts to improve CKD care should include automated detection, educational support, and enhanced workflows. Based on these findings, health care professionals, stakeholders, and policymakers are called to act to enhance kidney care across the region., (© 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: A low protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD., Methods: The EQUAL study is a prospective, observational study, including patients ≥65 years, incident estimated glomerular filtration rate <20 ml/min/1.73m², in six European countries with follow-up up till six years. Nutritional status was assessed by 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (gram protein/kilogram/bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease by ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights., Results: Out of 1738 adults (631 prescribed LPD at any point during follow-up) there were 1319 with repeated SGA measurements of which 267 (20%) declined in SGA ≥ 2 points and 565 (32.5%) died. There was no difference in survival or decline in nutritional status for patients prescribed LPD ≤0.8 g/kg ideal bodyweight (Odds Ratio (OR) for mortality 1.15 (95% Confidence interval (CI) 0.86-1.55) and OR for decline in SGA 1.11 (95% CI 0.74-1.66) in the adjusted models. In patients prescribed LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and higher age >75 years, lower SGA, and higher comorbidity burden for both mortality and nutritional status decline., Conclusions: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The aim of this study was to provide an overview of age, sex and primary renal disease (PRD) distribution among first kidney transplant recipients across Europe., Method: The European Renal Association (ERA) Registry database was used to obtain data on patients aged 20 years or older receiving their first kidney transplant between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year., Results: In total, 99 543 adults received a first kidney transplant. Overall, 23% of the recipients were 65 years or older, 36% were female, and 21% had glomerulonephritis and 15% diabetes mellitus as PRD. Compared with deceased donor kidney transplant recipients, living donor kidney transplant recipients were less often 65 years or older (13% versus 26%), more often had glomerulonephritis (25% versus 20%) and less often diabetes mellitus (8% versus 17%) as PRD. We found large international differences, which were most prominent for age and PRD and less prominent for sex. Over time, the largest change in recipient characteristics was observed for the percentage of recipients aged 65 years or older, increasing from 18% in 2010 to 28% in 2019 for all countries combined with a similar trend in most countries., Conclusion: We observed large differences for age and PRD distribution between recipients of living and deceased donor kidneys and between European countries. Over time, the percentage of older first kidney transplant recipients increased., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background and Objective: The morbidity and mortality of infants born extremely preterm varies substantially across networks, within countries and throughout the globe. Most of the literature tends to focus on the management at birth and choices around active resuscitation of extremely preterm infants. Withdrawal and withholding of life sustaining treatment (WWLST) is an important and central process in the neonatal intensive care unit (NICU) and practices vary substantially. As such, our objective in this review was to explore whether end of life decisions also contribute to variations in the morbidity and mortality of periviable infants., Methods: This narrative literature review is based on studies from the last 15 years found using several searches of medical databases (OVID Medline, Scopus and Cochrane Systematic Reviews) performed between March 2021 and December 2023., Key Content and Findings: Just as outcomes in periviable infants vary, the rates of and processes behind WWLST differ in the periviable population. Variation increases as gestational age decreases. Parental involvement is crucial to share decision making but the circumstances and rates of parental involvement differ. Strict guidelines in end-of-life care may not be appropriate, however there is a need for more targeted guidance for periviable infants as a specific population. The current literature available relating to periviable infants or WWLST is minimal, with many datasets rapidly becoming outdated., Conclusions: Further research is needed to establish the role of WWLST in variation of periviable infants' outcomes. The unification of data, acquisition of more recent datasets and inclusion of variables relating to end-of-life decisions in data collection will aid in this process., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-468/coif). K.T. serves as an unpaid editorial board member of Translational Pediatrics from January 2023 to December 2024. The other authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Background: Problems in intrapartum electronic fetal monitoring with cardiotocography (CTG) remain a major area of preventable harm. Poor understanding of the range of influences on safety may have hindered improvement. Taking an interdisciplinary perspective, we sought to characterise the everyday practice of CTG monitoring and the work systems within which it takes place, with the goal of identifying potential sources of risk., Methods: Human factors/ergonomics (HF/E) experts and social scientists conducted 325 hours of observations and 23 interviews in three maternity units in the UK, focusing on how CTG tasks were undertaken, the influences on this work and the cultural and organisational features of work settings. HF/E analysis was based on the Systems Engineering Initiative for Patient Safety 2.0 model. Social science analysis was based on the constant comparative method., Results: CTG monitoring can be understood as a complex sociotechnical activity, with tasks, people, tools and technology, and organisational and external factors all combining to affect safety. Fetal heart rate patterns need to be recorded and interpreted correctly. Systems are also required for seeking the opinions of others, determining whether the situation warrants concern, escalating concerns and mobilising response. These processes may be inadequately designed or function suboptimally, and may be further complicated by staffing issues, equipment and ergonomics issues, and competing and frequently changing clinical guidelines. Practice may also be affected by variable standards and workflows, variations in clinical competence, teamwork and situation awareness, and the ability to communicate concerns freely., Conclusions: CTG monitoring is an inherently collective and sociotechnical practice. Improving it will require accounting for complex system interdependencies, rather than focusing solely on discrete factors such as individual technical proficiency in interpreting traces., Competing Interests: Competing interests: TD: research and innovation lead for PROMPT Maternity Foundation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are promising candidates for cell-based therapy for several immune-mediated inflammatory diseases (IMIDs) due to their multiplicity of immunomodulatory and reparative properties and favorable safety profile. However, although preclinical data were encouraging, the clinical benefit demonstrated in clinical trials of autologous MSC transplantation in a number of conditions has been less robust. This may be explained by the growing body of evidence pointing to abnormalities of the bone marrow microenvironment in IMIDs, including impaired MSC function. However, it is not currently known whether these abnormalities arise as a cause or consequence of disease, the role they play in disease initiation and/or progression, or whether they themselves are targets for disease modification. Here, we review current knowledge about the function of the BM microenvironment in IMIDs including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes, focusing on MSCs in particular. We predict that an improved understanding of disease-related changes in the bone marrow microenvironment including the role of MSCs in vivo, will yield new insights into pathophysiology and aid identification of new drug targets and optimization of cell-based therapy in IMIDs., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The international scale and spread of evidence-based perioperative medicine for older people undergoing surgery (POPS) services has not yet been fully realised. Implementation science provides a structured approach to understanding factors that act as barriers and facilitators to the implementation of POPS services. In this study, we aimed to identify factors that influence the implementation of POPS services in the UK., Methods: A qualitative case study at three UK health services was undertaken. The health services differed across contextual factors (population, workforce, size) and stages of POPS service implementation maturity. Semi-structured interviews with purposively sampled clinicians (perioperative medical, nursing, allied health, and pharmacy) and managers (n = 56) were conducted. Data were inductively coded, then thematically analysed using the Consolidated Framework for Implementation Research (CFIR)., Results: Fourteen factors across all five CFIR domains were relevant to the implementation of POPS services. Key shared facilitators included stakeholders understanding the rationale of the POPS service, with support from their networks, POPS champions, and POPS clinical leads. We found substantial variation and flexibility in the way that health services responded to these shared facilitators and this was relevant to the implementation of POPS services., Conclusions: Health services planning to implement a POPS service should use health service-specific strategies to respond flexibly to local factors that are acting as barriers or facilitators to implementation. To support implementation of a POPS service, we recommend health services prioritise understanding local networks, identifying POPS champions, and ensuring that stakeholders understand the rationale for the POPS service. Our study also provides a structure for future research to understand the factors associated with 'unsuccessful' implementation of a POPS service, which can inform ongoing efforts to implement evidence-based perioperative models of care for older people., (© 2024. The Author(s).)

Introduction: Pneumococcus remains a major cause of adult lower respiratory tract infections (LRTI). Few data exist on the relative contribution of serotypes included in pneumococcal vaccines to community-acquired pneumonia (CAP) and non-pneumonic (NP) LRTI. We measured the burden of all and vaccine-serotype pneumococcal respiratory infection following SARS-CoV-2 emergence to inform evidence-based vaccination policy., Methods: A prospective cohort study at two Bristol hospitals (UK) including all adults age ≥ 18-years hospitalised with acute lower respiratory tract disease (aLRTD) from Nov2021-Nov2022. LRTI patients were classified as: a) radiographically-confirmed CAP (CAP+/RAD+), b) clinically-diagnosed CAP without radiological confirmation (CAP+/RAD-), or c) NP-LRTI. Pneumococcus was identified by blood culture, BinaxNOW™and serotype-specific urine antigen detection assays (UAD)., Results: Of 12,083 aLRTD admissions, 10,026 had LRTI and 2,445 provided urine: 1,097 CAP + RAD+; 207 CAP + RAD-; and 1,141 NP-LRTI. Median age was 71.1y (IQR57.9-80.2) and Charlson comorbidity index = 4 (IQR2-5); 2.7 % of patients required intensive care, and 4.4 % died within 30-days of hospitalisation. Pneumococcus was detected in 280/2445 (11.5 %) participants. Among adults aged ≥ 65y and 18-64y, 12.9 % (198/1534) and 9.0 % (82/911), respectively, tested pneumococcus positive. We identified pneumococcus in 165/1097 (15.0 %) CAP + RAD+, 23/207 (11.1 %) CAP + RAD-, and 92/1141 (8.1 %) NP-LRTI cases. Of the 280 pneumococcal cases, 102 (36.4 %) were due to serotypes included in PCV13 + 6C, 115 (41.7 %) in PCV15 + 6C, 210 (75.0 %) in PCV20 + 6C/15C and 228 (81.4 %) in PPV23 + 15C. The most frequently identified serotypes were 8 (n = 78; 27.9 % of all pneumococcus), 7F (n = 25; 8.9 %), and 3 (n = 24; 8.6 %)., Discussion: Among adults hospitalised with respiratory infection, pneumococcus is an important pathogen across all subgroups, including CAP+/RAD- and NP-LRTI. Despite 20-years of PPV23 use in adults ≥ 65-years and herd protection due to 17-years of PCV use in infants, vaccine-serotype pneumococcal disease still causes a significant proportion of LRTI adult hospitalizations. Direct adult vaccination with high-valency PCVs may reduce pneumococcal disease burden., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CH is Principal Investigator of the AvonCAP study which is a collaborative study sponsored by the University of Bristol and funded by Pfizer. CH has previously received support from the NIHR in an Academic Clinical Fellowship. JO is a Co-Investigators on the AvonCAP Study. AF is a member of the Joint Committee on Vaccination and Immunization (JCVI) and, until December 2022 was chair of the World Health Organization European Technical Advisory Group of Experts on Immunization (ETAGE) committee. In addition to receiving research funding from Pfizer as Chief Investigator of this study, he leads another project investigating transmission of respiratory bacteria in families jointly funded by Pfizer and the Gates Foundation. ML, CT, JC, JS, MWP, EB, LJ and BG are employees of Pfizer Inc and may own stock. The other authors have no relevant conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We describe the use of direct superficial temporal artery puncture to access the left middle meningeal artery for embolization of a recurrent chronic subdural hematoma in a patient with a type A aortic dissection, involving the origin of the left common carotid artery which precluded conventional access from a radial or femoral approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The provision of healthcare itself contributes to the global health crisis of the climate emergency. As critical care is a carbon hotspot within hospital medicine, healthcare professionals must take collaborative action to mitigate the environmental impact of the sector., Aims: The purpose of the project was to engage the critical care multidisciplinary team with sustainability efforts, through involvement in a recycling Quality Improvement Project (QIP). The central QIP aimed to increase the recycling rates of single-use plastic enteral feed bottles in the intensive care unit (ICU) over a 31-day period., Study Design: A recycling 'challenge month' was launched, and staff opinion was surveyed before and after this intervention., Results: The QIP demonstrated an increase in feed bottle recycling by 53.2%, representing a carbon-saving effect of up to 6.02 kg CO2e for the intervention month. Following the central QIP, all survey respondents felt encouraged to consider their ICU's environmental impact., Conclusions: Simple successful QIPs can act as a springboard to engage the staff body with sustainability initiatives and ignite wider conversation and consideration of the climate emergency in daily practice., Relevance for Clinical Practice: Effective recycling constitutes only one element of responsible environmental stewardship, but authors discuss that it is an effective focus for QIPs. To maximize impact and success within critical care, nursing involvement in leading and participation is essential., (© 2024 British Association of Critical Care Nurses.)

Objectives: To explore prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIM) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study., Methods: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after 2 vaccine doses. We compared BIs characteristics and severity among IIMs, other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HC). Multivariable Cox regression models assessed the risk factors for BI, severe BI and hospitalisations among IIMs., Results: Among 9449 included response, BIs occurred in 1447 (15.3%) respondents, median age 44 years (IQR 21), 77.4% female, and 182 BIs (12.9%) occurred among 1406 IIMs. Multivariable Cox regression among IIMs showed age as a protective factor for BIs [Hazard Ratio (HR)=0.98, 95%CI = 0.97-0.99], hydroxychloroquine and sulfasalazine use were risk factors (HR = 1.81, 95%CI = 1.24-2.64, and HR = 3.79, 95%CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for severe BI (HR = 3.61, 95%CI = 1.09-11.8). Non-White ethnicity (HR = 2.61, 95%CI = 1.03-6.59) was a risk factor for hospitalisation. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIM = 6.0% vs AIRD = 1.8%, nrAID = 2.2%, and HC = 0.9%), intensive care unit admission (IIM = 2.2% vs AIRD = 0.6%, nrAID, and HC = 0%), advanced treatment with antiviral or monoclonal antibodies (IIM = 34.1% vs AIRD = 25.8%, nrAID = 14.6%, and HC = 12.8%), and had more hospitalisation (IIM = 7.7% vs AIRD = 4.6%, nrAID = 1.1%, and HC = 1.5%)., Conclusion: Patients with IIMs are susceptible to severe COVID-19 BI. Age and immunosuppressive treatments were related to the risk of BIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery., Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care., Design: This was a two-arm cluster randomised controlled trial., Setting: The trial was set in 30 NHS general practice sites in England., Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms., Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention., Main Outcome Measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms., Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm ( n = 17) and 553 in sites randomised to the control arm ( n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014)., Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.., Trial Registration: This trial is registered as ISRCTN11669964., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment ; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Objective: The p.E148Q variant in pyrin is present in different populations at a frequency of up to 29%, and has been associated with diseases, including vasculitis and FMF. The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, pathogenic mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines., Methods: We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC), which were analysed by flow cytometry to visualize inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome-dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors., Results: In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harboured the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1β and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation., Conclusion: The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Lung volume reduction surgery (LVRS) and endobronchial valve (EBV) placement can produce substantial benefits in appropriately selected people with emphysema. The UK Lung Volume Reduction (UKLVR) registry is a national multicentre observational study set up to support quality standards and assess outcomes from LVR procedures at specialist centres across the UK., Methods: Data were analysed for all patients undergoing an LVR procedure (LVRS/EBV) who were recruited into the study at participating centres between January 2017 and June 2022, including; disease severity and risk assessment, compliance with guidelines for selection, procedural complications and survival to February 2023., Results: Data on 541 patients from 14 participating centres were analysed. Baseline disease severity was similar in patients who had surgery n=244 (44.9%), or EBV placement n=219 (40.9%), for example, forced expiratory volume in 1 s (FEV 1) 32.1 (12.1)% vs 31.2 (11.6)%. 89% of cases had discussion at a multidisciplinary meeting recorded. Median (IQR) length of stay postprocedure for LVRS and EBVs was 12 (13) vs 4 (4) days(p=0.01). Increasing age, male gender and lower FEV 1 %predicted were associated with mortality risk, but survival did not differ between the two procedures, with 50 (10.8%) deaths during follow-up in the LVRS group vs 45 (9.7%) following EBVs (adjusted HR 1.10 (95% CI 0.72 to 1.67) p=0.661) CONCLUSION: Based on data entered in the UKLVR registry, LVRS and EBV procedures for emphysema are being performed in people with similar disease severity and long-term survival is similar in both groups., Competing Interests: Competing interests: SCB reports educational fees from PulmonX. CEB reports research grants from NIHR and Astra Zeneca and is a member on an advisory board for Roche. JWD declares he has received honoraria for participating in advisory boards and given lectures at meetings supported by GSK, Boerhinger Ingelheim, Chiesi, AstraZeneca, Fisher & Paykel, Aerogen; he has received sponsorship for attending international scientific meetings from Chiesi. TH reports speaker fees from Astra Zeneca. SVK reports consultancy work for PulmonX and is on the advisory board for Intuitive Surgical. PLS reports lecture fees from PulmonX., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: Standardisation of referral pathways and the transfer of patients with acute aortic syndromes (AAS) to regional centres are recommended by NHS England in the Acute Aortic Dissection Toolkit. The aim of the Transfer of Thoracic Aortic Vascular Emergencies to Regional Specialist INstitutes Group study was to establish an interdisciplinary consensus on the interhospital transfer of patients with AAS to specialist high-volume aortic centres., Methods: Consensus on the key aspects of interhospital transfer of patients with AAS was established using the Delphi method, in line with Conducting and Reporting of Delphi Studies guidelines. A national patient charity for aortic dissection was involved in the design of the Delphi study. Vascular and cardiothoracic surgeons, emergency physicians, interventional radiologists, cardiologists, intensivists and anaesthetists in the United Kingdom were invited to participate via their respective professional societies., Results: Three consecutive rounds of an electronic Delphi survey were completed by 212, 101 and 58 respondents, respectively. Using predefined consensus criteria, 60 out of 117 (51%) statements from the survey were included in the consensus statement. The study concluded that patients can be taken directly to a specialist aortic centre if they have typical symptoms of AAS on the background of known aortic disease or previous aortic intervention. Accepted patients should be transferred in a category 2 ambulance (response time <18 min), ideally accompanied by transfer-trained personnel or Adult Critical Care Transfer Services. A clear plan should be agreed in case of a cardiac arrest occurring during the transfer. Patients should reach the aortic centre within 4 hours of the initial referral from their local hospital., Conclusions: This consensus statement is the first set of national interdisciplinary recommendations on the interhospital transfer of patients with AAS. Its implementation is likely to contribute to safer and more standardised emergency referral pathways to regional high-volume specialist aortic units., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID., Methods: Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student's unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason's correlation coefficient was used to examine relationships between variables., Results: During cardiopulmonary exercise testing the V E /VCO 2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (-0.44 ± 0.23 l/min/ SpO 2 %, R 2  = 0.77 ± 0.20) compared to controls (-0.17 ± 0.13 l/min/SpO 2 %, R 2  = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the V E /VCO 2 slope (r = -0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity., Conclusions: The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients., (© 2024. The Author(s).)

Background: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity., Methods: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation., Results: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O 2PEAK . There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged., Conclusions: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM)., Registration: https://www.isrctn.com/ISRCTN65527208 (14/05/2018)., (© 2024. The Author(s).)

Background: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy., Methods: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy., Results: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group., Conclusions: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2024.)

It is unclear if cardiopulmonary resuscitation is an aerosol-generating procedure and whether this poses a risk of airborne disease transmission to healthcare workers and bystanders. Use of airborne transmission precautions during cardiopulmonary resuscitation may confer rescuer protection but risks patient harm due to delays in commencing treatment. To quantify the risk of respiratory aerosol generation during cardiopulmonary resuscitation in humans, we conducted an aerosol monitoring study during out-of-hospital cardiac arrests. Exhaled aerosol was recorded using an optical particle sizer spectrometer connected to the breathing system. Aerosol produced during resuscitation was compared with that produced by control participants under general anaesthesia ventilated with an equivalent respiratory pattern to cardiopulmonary resuscitation. A porcine cardiac arrest model was used to determine the independent contributions of ventilatory breaths, chest compressions and external cardiac defibrillation to aerosol generation. Time-series analysis of participants with cardiac arrest (n = 18) demonstrated a repeating waveform of respiratory aerosol that mapped to specific components of resuscitation. Very high peak aerosol concentrations were generated during ventilation of participants with cardiac arrest with median (IQR [range]) 17,926 (5546-59,209 [1523-242,648]) particles.l -1 , which were 24-fold greater than in control participants under general anaesthesia (744 (309-2106 [23-9099]) particles.l -1 , p < 0.001, n = 16). A substantial rise in aerosol also occurred with cardiac defibrillation and chest compressions. In a complimentary porcine model of cardiac arrest, aerosol recordings showed a strikingly similar profile to the human data. Time-averaged aerosol concentrations during ventilation were approximately 270-fold higher than before cardiac arrest (19,410 (2307-41,017 [104-136,025]) vs. 72 (41-136 [23-268]) particles.l -1 , p = 0.008). The porcine model also confirmed that both defibrillation and chest compressions generate high concentrations of aerosol independent of, but synergistic with, ventilation. In conclusion, multiple components of cardiopulmonary resuscitation generate high concentrations of respiratory aerosol. We recommend that airborne transmission precautions are warranted in the setting of high-risk pathogens, until the airway is secured with an airway device and breathing system with a filter., (© 2023 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Objective: Admissions to hospitals for people with anorexia nervosa (AN) often last over 2 months, during which significant time is often spent with other patients, but there is little qualitative research on the impact on recovery of the inter-patient relationships. Our aim was to conduct qualitative interviews with people with a history of inpatient treatment for AN, focusing on the impact of interactions and relationships between patients during hospital admission on recovery, including short-term and long-term effects., Method: We conducted nine semi-structured, one-to-one interviews, specifically exploring the helpful and unhelpful aspects of inter-patient relationships during inpatient treatment for AN. No type of relationship was either included or excluded. Participants were recruited as volunteers in response to an online advertisement; all who met the eligibility criteria were selected. Interviews were transcribed and analyzed using thematic analysis., Results: Thematic analysis identified five themes: (1) comparison and justification, (2) learnt unhelpful behaviors, (3) dealing with distress, (4) compassion, and (5) role-modeling. All participants expressed conflicting feelings about their relationships with other patients, but generally described developing more resilience to negative effects as they got closer to recovery. Positive effects, such as compassion, appeared to hold significance long term in participants' recovered lives., Discussion: The detailed exploration of themes in this study provides a deeper understanding of inter-patient relationships during inpatient treatment for AN. This could aid clinical decision-making when choosing appropriate treatment settings for individual patients as well as informing clinical practice in hospital., Public Significance: This study closely examines the effect on recovery of relationships with other patients during hospital treatment for AN, a severe eating disorder. Findings might help hospital staff to understand the feelings of those they look after and develop ways to protect patients from the negative effects of peer relationships and enhance the positive ones, to support recovery in hospital., (© 2023 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)