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Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.

Fibromyalgia is a chronic condition characterised by widespread musculoskeletal pain. Although accumulating evidence suggests that exposure to stressful events increases the risk for this complex disorder, this is the first meta-analysis to compare the impact of a full range of lifetime stressors (e.g. physical trauma through to emotional neglect) on adult fibromyalgia. This review was performed in accordance with PRISMA guidelines. Random-effects models examined associations between different stressor exposures and fibromyalgia status with meta-regression investigating the effects of publication year and study quality on effect sizes. Nineteen studies were included in the meta-analysis. Significant associations with fibromyalgia status were observed for all six exposure types examined: odds ratios (OR) were highest for physical abuse (OR 3.23, 95% confidence interval 1.99-5.23) and total abuse (3.06, 1.71-5.46); intermediate for sexual abuse (2.65, 1.85-3.79) and smaller for medical trauma (1.80, 1.19-2.71), other lifetime stressors (1.70, 1.31-2.20), and emotional abuse (1.52, 1.27-1.81). Results were not significantly changed when childhood, as opposed to adult, exposures were used in studies that reported both. Meta-regression analyses demonstrated no effect of publication year or study quality on effect sizes. This study confirmed a significant association between stressor exposure and adult fibromyalgia with the strongest associations observed for physical abuse. Limitations related to current available literature were identified; we provide several suggestions for how these can be addressed in future studies. Stressors are likely to be one of many risk factors for fibromyalgia which we argue is best approached from a biopsychosocial perspective.

ObjectivesThe COVID-19 pandemic has led to increased use of digital clinical consultations (phone or video calls) within UK maternity services. This project aimed to review the evidence on digital clinical consultations in maternity systems to illuminate how, for whom and in what contexts, they can be used to support safe, personalised and equitable care.DesignA realist synthesis, drawing on diverse sources of evidence (2010–present) from OECD countries, alongside insights from knowledge user groups (representing healthcare providers and service users).MethodsThe review used three analytical processes (induction, abduction and retroduction) within three iterative stages (development of initial programme theories; evidence retrieval and synthesis; validation and refinement of the programme theories).ResultsNinety-three evidence sources were included in the final synthesis. Fifteen programme theories were developed showing that digital clinical consultations involve different mechanisms operating across five key contexts: the organisation, healthcare providers, the clinical relationship, the reason for consultation and women. The review suggests that digital clinical consultations can be effective and acceptable to stakeholders if there is access to appropriate infrastructure/digital resources and if implementation is able to ensure personalisation, informed choice, professional autonomy and relationship-focused connections. The review found relatively less evidence in relation to safety and equity.ConclusionsDue to the complexity of maternity systems, there can be ‘no one-size fits all’ approach to digital clinical consultations. Nonetheless, the review distills four ‘CORE’ implementation principles: C—creating the right environment, infrastructure and support for staff; O—optimising consultations to be responsive, flexible and personalised to different needs and preferences; R—recognising the importance of access and inclusion; and E—enabling quality and safety through relationship-focused connections. Service innovation and research are needed to operationalise, explore and evaluate these principles, particularly in relation to safety and equity.PROSPERO registration numberCRD42021288702.

Background Simulation via Instant Messaging- Birmingham Advance (SIMBA) delivers simulation-based learning (SBL) through WhatsApp® and Zoom® based on Kolb’s experiential learning theory. This study describes how Kolb’s theory was implemented in practice during SIMBA adrenal session. Methods SIMBA adrenal session was conducted for healthcare professionals and replicated Kolb’s 4-stage cycle: (a) concrete experience—online simulation of real-life clinical scenarios, (b) reflective observation—discussion and Q&A following simulation, (c) abstract conceptualisation—post-session MCQs, and (d) active experimentation—intentions to implement the acquired knowledge in future practice. Participants’ self-reported confidence levels for simulated and non-simulated cases pre- and post-SIMBA were analysed using Wilcoxon Signed-Rank test. Key takeaway and feedback were assessed quantitatively and qualitatively in a thematic analysis. Results Thirty-three participants were included in the analysis. A Wilcoxon signed-rank test showed that the SIMBA session elicited a statistically significant change in participants’ self-reported confidence in their approach to Cushing’s syndrome (Z = 3.873, p  = 0.0001) and adrenocortical carcinoma (Z = 3.970, p  < 0.0001). 93.9% ( n  = 31/33) and 84.8% ( n  = 28/33) strongly agreed/agreed the topics were applicable to their clinical practice and accommodated their personal learning style, respectively. 81.8% ( n  = 27/33) reported increase in knowledge on patient management, and 75.8% ( n  = 25/33) anticipated implementing learning points in their practice. Conclusions SIMBA effectively adopts Kolb’s theory to provide best possible experience to learners, highlighting the advantages of utilising social media platforms for SBL in medical education. The ability to conduct SIMBA sessions at modest cost internationally paves way to engage more healthcare professionals worldwide.

Copper is essential for healthy cellular functioning, but this heavy metal quickly becomes toxic when supply exceeds demand. Marine sediments receive widespread and increasing levels of copper contamination from antifouling paints owing to the 2008 global ban of organotin-based products. The toxicity of copper will increase in the coming years as seawater pH decreases and temperature increases. We used a factorial mesocosm experiment to investigate how increasing sediment copper concentrations and the presence of a cosmopolitan bioturbating amphipod, Corophium volutator, affected a range of ecosystem functions in a soft sediment microbial community. The effects of copper on benthic nutrient release, bacterial biomass, microbial community structure and the isotopic composition of individual microbial membrane [phospholipid] fatty acids (PLFAs) all differed in the presence of C. volutator. Our data consistently demonstrate that copper contamination of global waterways will have pervasive effects on the metabolic functioning of benthic communities that cannot be predicted from copper concentrations alone; impacts will depend upon the resident macrofauna and their capacity for bioturbation. This finding poses a major challenge for those attempting to manage the impacts of copper contamination on ecosystem services, e.g. carbon and nutrient cycling, across different habitats. Our work also highlights the paucity of information on the processes that result in isotopic fractionation in natural marine microbial communities. We conclude that the assimilative capacity of benthic microbes will become progressively impaired as copper concentrations increase. These effects will, to an extent, be mitigated by the presence of bioturbating animals and possibly other processes that increase the influx of oxygenated seawater into the sediments. Our findings support the move towards an ecosystem approach for environmental management.

IntroductionOne of the most commonly reported COVID-19-related changes to all maternity services has been an increase in the use of digital clinical consultations such as telephone or video calling; however, the ways in which they can be optimally used along maternity care pathways remain unclear. It is imperative that digital service innovations do not further exacerbate (and, ideally, should tackle) existing inequalities in service access and clinical outcomes. Using a realist approach, this project aims to synthesise the evidence around implementation of digital clinical consultations, seeking to illuminate how they can work to support safe, personalised and appropriate maternity care and to clarify when they might be most appropriately used, for whom, when, and in what contexts?Methods and analysisThe review will be conducted in four iterative phases, with embedded stakeholder involvement: (1) refining the review focus and generating initial programme theories, (2) exploring and developing the programme theories in light of evidence, (3) testing/refining the programme theories and (4) constructing actionable recommendations. The review will draw on four sources of evidence: (1) published literature (searching nine bibliographic databases), (2) unpublished (grey) literature, including research, audit, evaluation and policy documents (derived from Google Scholar, website searches and e-thesis databases), (3) expertise contributed by service user and health professional stakeholder groups (n=20–35) and (4) key informant interviews (n=12). Included papers will consist of any study design, in English and from 2010 onwards. The review will follow the Realist and Meta-narrative Evidence Synthesis Evolving Standards quality procedures and reporting guidance.Ethics and disseminationEthical approval has been obtained from the University of Nottingham, Faculty of Medicine and Health Sciences Ethics Committee (FMHS 426–1221). Informed consent will be obtained for all key informant interviews. Findings will be disseminated in a range of formats relevant to different audiences.PROSPERO registration numberCRD42021288702.

Background Within the United States, although there is strong motivation for incorporating family interviews into Fetal Infant Mortality Reviews (FIMR) and important potential for expanding it to other types of reviews, there is limited evidence that family interviews make a difference in review team outcomes. Objective This study aims to assess the impact of FIMR family interviews identifying health service gaps and generating actionable improvements. Design Mixed methods design with quantitative case‐control analysis and qualitative semi‐structured interviews. Quantitative data collection was secondary analysis of FIMR administrative records, comparing outcomes with and without family interviews using Generalized Estimating Equation (GEE) and descriptive analysis of annual FIMR team evaluation responses. Qualitative data collection included audio‐taping, transcribing and consensus coding of semi‐structured interviews. Setting and Participants The quantitative setting was Kalamazoo County, Michigan, FIMR reviews from 2015 to 2023, whereas the qualitative setting was virtual. Quantitative sample was the full population of completed FIMR case reviews (N = 158), and the 15 FIMR team case reviewers completing the 2023 annual evaluation. The qualitative sample was a purposive sample of 28 FIMR administrators across the United States. Main Outcome Measures Quantitative outcomes were review‐identified contributing stressors and subsequent recommendations generated in the case review process. Qualitative outcomes were thematic experiences of family interview implementation and impact within mortality review process. Results The 53 cases (34%) with family interviews were similar to the 105 (66%) non‐interview cases regarding multipleperinatal characteristics and were different regarding death type and manner. Controlling for these differences, GEE analysis found that family interviews were associated with increased identification of stressors, especially medical and socioeconomic, with a 2.6 increase in the number of stressors identified (aOR = 2.6, 95% CI: 1.5–4.7, p < 0.001). Family interviews were associated with a 40% increase in recommendations generated (aOR = 1.4, 95% CI: 1.0–2.0, p = 0.05), especially regarding patient‐provider communication. Two‐thirds of the FIMR team reported that family interviews were ‘Very Impactful’ in making meaningful system changes. Qualitatively, three primary themes emerged: Hurdles to Getting Interviews, Completing the Picture and Bringing the Human Connection. Conclusions This study drew upon multiple types of data, documenting the challenges obtaining interviews, while emphasizing their value identifying root causes, producing actionable healthcare service recommendations and motivating action. Patient or Public Contribution Locally, members of community advocate organizations representing birthing and parenting individuals and those representing people identifying as Black race contributed by actively refining the implementation of FIMR family interviews, including how interview information was utilized in FIMR case review meetings (study interventions). Mock FIMR case review meetings conducted as part of United Way public ‘bus tours’ and with undergraduate/graduate university students further refined recommendations coding and dissemination strategies. Leadership from public and private health service organizations shared the facilitators and barriers for applying FIMR recommendations to institutional policy and practice (shaping the development of recommendations coding as well as dissemination and interpretation of study findings). Nationally, a network of mortality review funders and administrators, in a 4‐year learning series convened by the National Center for Fatality Prevention and Review, provided input in centreing family interviews within different types of mortality review processes (influencing study objectives, qualitative interview structure and results interpretation). Additionally, US policy leaders in maternal child health and health equity provided historical and current context for FIMR family interview funding and enabling legislation (informing the interpretation of study results and specifically referenced within the manuscript).

Background Hyperkalaemia is an electrolyte abnormality associated with adverse clinical outcomes; however, few studies have investigated the relationship with patterns of hyperkalaemia over time. This study explored the impact of time spent in a hyperkalaemic state and variability of serum potassium (sK+) on major adverse cardiovascular events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD), resistant hypertension, heart failure and diabetes. Methods Cohorts comprised adult patients diagnosed with CKD stage 3+, resistant hypertension, heart failure or diabetes, and/or renin–angiotensin–aldosterone system inhibitor prescription, between 1 January 2003 and 30 June 2018, from the UK Clinical Practice Research Datalink. Associations between percentage of follow-up spent in a hyperkalaemic state (sK+ ≥5.0 mmol/L, ≥5.5 mmol/L, ≥6.0 mmol/L) or sK+ variability (standard deviation above or below median standard deviation) and all-cause mortality or MACE were investigated. Results For sK+ ≥5.0 mmol/L, time spent in a hyperkalaemic state was associated with reduced risk of all-cause mortality across all cohorts. For higher sK+ thresholds, this trend was attenuated or reversed; for time spent in a hyperkalaemic state at sK+ ≥6.0 mmol/L, an increased risk of mortality was seen in the overall cohort and for patients with diabetes, resistant hypertension or prescribed renin–angiotensin–aldosterone system inhibitors, with no consistent association seen for patients with CKD or heart failure. Risk of MACE in the overall cohort and in patients with CKD, diabetes or resistant hypertension increased with time spent in a hyperkalaemic state at all sK+ thresholds; however, no correlation was seen in patients with heart failure or those receiving dialysis. High sK+ variability was associated with a higher risk of MACE compared with low sK+ variability across most sK+ categories in the overall population and in all disease cohorts, except patients on dialysis; however, no association between sK+ variability and all-cause mortality was observed. Conclusions Patterns of hyperkalaemia, including time spent in hyperkalaemia and sK+ variability, are associated with adverse clinical outcomes. Regular monitoring of sK+ in high-risk populations in broader community, primary care and outpatient settings may enable guideline-recommended management of hyperkalaemia and help avoid adverse events.

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