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Background: The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and health care efficiencies., Patients and Methods: CheckMate 67T (NCT04810078) was a phase III, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20 000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). The primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis [time-averaged serum concentration over the first 28 days (C avgd28 ), and minimum steady-state serum concentration (C minss ); noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios (GMR) ≥0.8]. Objective response rate (ORR) was a key secondary endpoint powered for noninferiority [noninferiority threshold: lower boundary of 95% CI of relative risk of ORR (subcutaneous versus intravenous nivolumab) ≥0.60]., Results: Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of C avgd28 and C minss was 2.098 (90% CI 2.001-2.200) and 1.774 (90% CI 1.633-1.927), respectively. After 8 months of minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI 19.0%-30.0%) versus 18.2% with intravenous nivolumab [95% CI 13.6%-23.6%; relative risk: 1.33 (95% CI 0.94-1.87)]. Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar., Conclusions: Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Medicinal plants are valued for their contributions to human health. However, the growing demand for medicinal plants and the concerns regarding their quality and sustainability have prompted the reassessment of conventional production practices. Controlled-environment cropping systems, such as vertical farms, offer a transformative approach to production of medicinal plants. By enabling precise control over environmental factors, such as light, carbon dioxide, temperature, humidity, nutrients, and airflow, controlled environments can improve the consistency, concentration, and yield of bioactive phytochemicals in medicinal plants. This review explores the potential of controlled-environment systems for enhancing production of medicinal plants. First, we describe how controlled environments can overcome the limitations of conventional production in improving the quality of medicinal plants. Next, we propose strategies based on plant physiology to manipulate environmental conditions for enhancing the levels of bioactive compounds in plants. These strategies include improving photosynthetic carbon assimilation, light spectrum signalling, purposeful stress elicitation, and chronoculture. We describe the underlying mechanisms and practical applications of these strategies. Finally, we highlight the major knowledge gaps and challenges that limit the application of controlled environments, and discuss future research directions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Orofacial clefting (OFC) is a frequent congenital anomaly and can occur either in the context of underlying syndromes or in isolation (nonsyndromic). The two common OFC phenotypes are cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). In this study, we searched for penetrant CL/P genes, by evaluating de novo copy number variants (CNV) from an exome sequencing dataset of 50 nonsyndromic patient-parent trios. We detected a heterozygous 86 kb de novo deletion affecting exons 4-11 of ZFHX4, a gene previously associated with OFC. Genetic and phenotypic data from our in-house and the AGORA cohort (710 and 229 individuals with nonsyndromic CL/P) together with literature and database reviews demonstrate that ZFHX4 variants can lead to both nonsyndromic and syndromic forms not only of CL/P but also CPO. Expression analysis in published single-cell RNA-sequencing data (mouse embryo, zebrafish larva) at relevant time-points support an important role of Zfhx4/zfhx4 in craniofacial development. To characterize the role of zfhx4 in zebrafish craniofacial development, we knocked out/down the zebrafish orthologue. Cartilage staining of the zfhx4 CRISPR F0 knockout and morpholino knockdown at 4 days post-fertilization showed an underdeveloped and abnormally shaped ethmoid plate and cartilaginous jaw (resembling micrognathia). While there is evidence for the dominant inheritance of ZFHX4 variants in OFC, we here present a patient with a possible recessive inheritance. In conclusion, ZFHX4 has a highly heterogeneous phenotypic spectrum and variable mode of inheritance. Our data highlight that ZFHX4 should be considered in genetic testing in patients with nonsyndromic clefting., Competing Interests: Competing interests: For the sake of completeness, we declare that D.D. provides compensated consulting services outside of academia as an independent consultant. Furthermore, K.U.L. is a co-founder of LAMPseq Diagnostics GmbH. Although past and current clients might include biotech, life science, and pharma companies, the services are not related to the presented work and all authors are unaware of any possible competing interests. Ethical approval: Written informed consent was obtained from all participants, or the respective parents/legal guardians, prior to inclusion. The study was approved by the ethics committee of the Medical Faculty of the University of Bonn (ethics approval number 295/14, last dated June 20th, 2022). Animal husbandry and experimental setups were in accordance with European Legislation for the Protection of Animals used for Scientific Purposes (Directive 2010/62/EU). National law exempts all zebrafish experiments conducted at larval stages up to 5 dpf, before larvae begin to feed, from ethical approval., (© 2024. The Author(s).)

Background and Purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre-specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT-2) was assessed., Methods: RIGHT-2 was a pre-hospital-initiated multicentre randomized sham-controlled blinded-endpoint trial that randomized patients with presumed ultra-acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2)., Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre-morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70-3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09-13.59)., Conclusions: Pre-hospital ultra-acute transdermal GTN did not improve overall functional outcome in patients with investigator-diagnosed TIA compared with sham treatment., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer., Methods: In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed., Results: A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group., Conclusions: Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 8HW ClinicalTrials.gov number, NCT04008030.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Rare movement disorders often have a genetic etiology. New technological advances have increased the odds of achieving genetic diagnoses: next-generation sequencing (NGS) (whole-exome sequencing-WES; whole-genome sequencing-WGS) and long-read sequencing (LRS). In 2017, we launched a WES program for patients with rare movement disorders of suspected genetic etiology. We aim to describe the accumulated experience of a modern movement disorder genetic clinic, highlighting how different available genetic tests might be prioritized according to the clinical phenotype and pattern of inheritance. Methods: Participants were studied through WES analysis. Descriptive statistics, including the mean, standard deviation, counts, and percentages, were used to summarize demographic and clinical characteristics in all subjects and with each type of result [pathogenic or likely pathogenic, variants of uncertain significance (VUS), negative]. Results: We studied 88 patients (93.2% Caucasian, 5.72% African American, and 1.08% Hispanic or Latino). After excluding six family members from four index participants, the diagnostic yield of WES reached 27% (22/82 probands). The age at onset was significantly lower in patients with pathogenic/likely pathogenic variants. The most common clinical phenotypes were ataxia and parkinsonism. Dystonia, ataxia, leukoencephalopathy, and parkinsonism were associated with most genetic diagnoses. Conclusions: We propose a comprehensive protocol with decision tree testing for WGS and LRS, a return of results, and a re-analysis of inconclusive genetic data to increase the diagnostic yield of patients with rare neurogenetic disorders.

Background: Glofitamab monotherapy induces durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma after two or more previous therapies, but has not previously been assessed as a second-line therapy. We investigated the efficacy and safety of glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) versus rituximab (R)-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma., Methods: The phase 3, randomised, open-label STARGLO trial was done at 62 centres in 13 countries in Asia and Australia, Europe, and North America. We recruited transplant-ineligible patients (aged ≥18 years) with histologically confirmed relapsed or refractory diffuse large B-cell lymphoma after one or more previous therapies. Patients were randomly assigned in permuted blocks (block size of six) via an interactive voice or web response system (2:1; stratified by 1 vs ≥2 previous lines of therapy and relapsed vs refractory status) to Glofit-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus glofitamab step-up dosing to 30 mg; for a total of eight cycles, plus four additional cycles of glofitamab monotherapy) or R-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus rituximab 375 mg/m 2 ; for a total of eight cycles). The trial independent review committee, which evaluated all response-based endpoints, was masked to treatment assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat in all randomly assigned patients. We present results from both the primary analysis (cutoff: March 29, 2023) and updated analysis after all patients had completed study therapy (cutoff: Feb 16, 2024). Safety analyses included all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT04408638, and is ongoing (closed to recruitment)., Findings: From Feb 23, 2021, to March 14, 2023, 274 patients were enrolled and randomly assigned to receive Glofit-GemOx (n=183) or R-GemOx (n=91). 158 (58%) patients were male and 116 (42%) were female; median age was 68 years (IQR 58-74). At the primary analysis after a median follow-up of 11·3 months (95% CI 9·6-12·7), overall survival was significantly improved with Glofit-GemOx versus R-GemOx (median not estimable [NE; 95% CI 13·8 months-NE] vs 9·0 months [7·3-14·4]; hazard ratio [HR] 0·59 [95% CI 0·40-0·89]; p=0·011). At the updated analysis after a median follow-up of 20·7 months (19·9-23·3), a consistent improvement in overall survival was observed with Glofit-GemOx versus R-GemOx (median 25·5 months [18·3-NE] vs 12·9 months [7·9-18·5]; HR 0·62 [0·43-0·88]). In the safety sets, 180 (100%) patients in the Glofit-GemOx group and 84 (96%) of 88 patients in the R-GemOx group had at least one adverse event during the study period. Cytokine release syndrome occurred in 76 (44%) of 172 glofitamab-exposed patients and was predominantly low grade. Deaths related to glofitamab or rituximab occurred in five (3%) patients in the Glofit-GemOx group and in one (1%) patient in the R-GemOx group., Interpretation: Glofit-GemOx had a significant overall survival benefit compared with R-GemOx, supporting its use in transplant-ineligible patients with relapsed or refractory diffuse large B-cell lymphoma after one or more previous lines of therapy., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests JSA has received grants or contracts from BMS, Cellectis, Merck, Mustang Bio, Regeneron, and Seagen; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Celgene, Cellectar, Caribou Biosciences, Century Therapeutics, Celgene, Epizyme, Foresight Diagnostics, Genentech, Gilead, Interius, Lilly, F Hoffmann-La Roche, Seagen, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS, Incyte, Janssen, MorphoSys, Novartis, and Regeneron. MKu has received grants or contracts and consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche; a grant from BeiGene; and consulting fees from AbbVie. MH has received grants from Janssen and F Hoffmann-La Roche; consulting fees from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, Gilead, and Pfizer; and participated on a data safety monitoring board or advisory board for Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead. CPF has received grants or contracts from BeiGene, F Hoffmann-La Roche, Genmab, and AbbVie; consulting fees from AbbVie, AstraZeneca, Atarabio, BMS, Genmab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, SOBI, and Takeda; and participated on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI. DHY has received grants or contracts from AbbVie, BeiGene, Boryung, Celltrion, Kyowa Kirin, Janssen, Samyang, and Sanofi; consulting fees from Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Antengene, BMS, Boryung, GSK, Kyowa Kirin, Novartis, F Hoffmann-La Roche, Takeda, and Janssen; and participated on a data safety monitoring board or advisory board for Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio. HA has received grants or contracts from Morphosys, Genentech, Novartis, BMS, Epizyme, and Pfizer; consulting fees from Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Genentech; and participated on a data safety monitoring board or advisory board for Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie. WT has received grants or contracts and support for attending meetings or travel from F Hoffmann-La Roche; consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Takeda, AbbVie, Sobi, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Takeda, Gilead, and AbbVie; and is grateful for and acknowledges funding and support from the University College London Hospitals NHS Foundation Trust Biomedical Research Centre. CH has received grants or contracts from Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen-Cilag, AbbVie, and Gilead; and support for attending meetings or travel from Janssen-Cilag, AbbVie, and F Hoffmann-La Roche. JMZ has received consulting fees from and participated on a data safety monitoring board or advisory board for Pierre Fabre, Takeda, BMS, Gilead, Novartis, Pfizer, Amgen, F Hoffmann-La Roche, AstraZeneca, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, and AbbVie; and support for attending meetings or travel from F Hoffmann-La Roche and AbbVie. CYC has received grants or contracts from BMS, F Hoffmann-La Roche, AbbVie, MSD, and Lilly; consulting fees from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS. HG has received consulting fees from F Hoffmann-La Roche, BMS, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead, F Hoffmann-La Roche, BMS, AbbVie, and Takeda. SS is an employee of and has received grants or contracts from Genentech; and has stock or stock options with F Hoffmann-La Roche. VO-N is an employee of Genentech and has provided all support for the present manuscript for Genentech and F Hoffmann-La Roche. RT is an employee of Genentech and has provided all support for the present manuscript for, has received support for attending meetings or travel from, and has stock or stock options with Genentech and F Hoffmann-La Roche. JR is an employee of and has received grants or contracts from F Hoffmann-La Roche, and has stock or stock options with F Hoffmann-La Roche. MD is an employee of, has provided all support for the present manuscript for, and has stock or stock options with F Hoffmann-La Roche. MKa is an employee of F Hoffmann-La Roche, and has received grants or contracts from Roche Diagnostics International and F Hoffmann-La Roche. EM is an employee of, has received grants or contracts from, has received support for attending meetings or travel from, and has stock or stock options with F Hoffmann-La Roche. HH is an employee of F Hoffmann-La Roche. LL is an employee of, has received grants or contracts from, has received royalties or licences from, has patents planned, issued or pending with, and has stock or stock options with F Hoffmann-La Roche. GPG has received grants or contracts from BeiGene and Merck; consulting fees from Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche, and Prelude Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and F Hoffmann-La Roche; and participated on a data safety monitoring board or advisory board for Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche and Prelude Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: A chronic subdural haematoma (cSDH) is an encapsulated collection of fluid and blood degradation products in the subdural space. It is increasingly common, affecting older people and those living with frailty. Currently, no guidance exists to define optimal care from onset of symptoms through to recovery. This paper presents the first consensus-built recommendations for best practice in the care of cSDH, co-designed to support each stage of the patient pathway., Methods: Guideline development was led by a multidisciplinary Steering Committee with representation from diverse clinical groups, professional associations, patients, and carers. Literature searching to identify relevant evidence was guided by core clinical questions formulated through facilitated discussion with specially convened working groups. A modified Delphi exercise was undertaken to build consensus on draft statements for inclusion in the guideline using survey methodology and an in-person meeting. The proposed guideline was subsequently endorsed by the Society for British Neurological Surgeons, Neuroanaesthesia and Critical Care Society, Association of Anaesthetists, British Association of Neuroscience Nurses, British Geriatric Society, and Centre for Perioperative Care., Results: We identified that high quality evidence was generally lacking in the literature, although randomised controlled trial (RCT) data were available to inform specific recommendations on aspects of surgical technique and use of corticosteroids. The final guideline represents the outcome of synthesising available evidence, consensus-built expert opinion and patient involvement. The guideline comprises 67 recommendations across eight major themes, covering: presentation and diagnosis, neurosurgical triage and shared decision-making, non-operative management, perioperative management (including anticoagulation), timing of surgery, intraoperative and postoperative care, rehabilitation and recovery., Conclusions: We present the first multidisciplinary guideline for the care of patients with cSDH. The recommendations reflect a paradigm shift in the care of cSDH, recognising and formalising the need for multidisciplinary and collaborative clinical management, communication and decision-making delivered effectively across secondary and tertiary care.

Social prescribing has become a global phenomenon. A Delphi study was recently conducted with 48 social prescribing experts from 26 countries to establish global agreement on the definition of social prescribing. We reflect on the use and utility of the outputs of this work, and where we go from here., (© 2024. The Author(s).)

Background: Large-scale improvement programmes are a frequent response to quality and safety problems in health systems globally, but have mixed impact. The extent to which they meet criteria for programme quality, particularly in relation to transparency of reporting and evaluation, is unclear., Aim: To identify large-scale improvement programmes focused on intrapartum care implemented in English National Health Service maternity services in the period 2010-2023, and to conduct a structured quality assessment., Methods: We drew on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidance to inform the design and reporting of our study. We identified relevant programmes using multiple search strategies of grey literature, research databases and other sources. Programmes that met a prespecified definition of improvement programme, that focused on intrapartum care and that had a retrievable evaluation report were subject to structured assessment using selected features of programme quality., Results: We identified 1434 records via databases and other sources. 14 major initiatives in English maternity services could not be quality assessed due to lack of a retrievable evaluation report. Quality assessment of the 15 improvement programmes meeting our criteria for assessment found highly variable quality and reporting. Programme specification was variable and mostly low quality. Only eight reported the evidence base for their interventions. Description of implementation support was poor and none reported customisation for challenged services. None reported reduction of inequalities as an explicit goal. Only seven made use of explicit patient and public involvement practices, and only six explicitly used published theories/models/frameworks to guide implementation. Programmes varied in their reporting of the planning, scope and design of evaluation, with weak designs evident., Conclusions: Poor transparency of reporting and weak or absent evaluation undermine large-scale improvement programmes by limiting learning and accountability. This review indicates important targets for improving quality in large-scale programmes., Competing Interests: Competing interests: TJD: Research and Innovation lead for PROMPT Maternity Foundation and has a part-time appointment at NHS Resolution where he leads on a Safety Action within the Maternity Incentive Scheme., (© 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.)

Aspergillus fumigatus is a globally distributed mold and a major cause of opportunistic infections in humans. Because most infections are from environmental exposure, it is critical to understand environmental populations of A. fumigatus . Soil is a major ecological niche for A. fumigatus . Here, we analyzed 748 soil isolates from 21 locations in six provinces and one territory in Canada. All isolates were genotyped using nine microsatellite markers. Due to small sample size and/or close proximities for some local samples, these isolates were grouped into 16 local geographic and ecological populations. Our results indicated high allelic and genotypic diversities within most local and provincial populations. Interestingly, low but statistically significant genetic differentiations were found among geographic populations within Canada, with relatively similar proportions of strains and genotypes belonging to two large genetic clusters. In Hamilton, Ontario, and Vancouver, BC, where two and three ecological populations were analyzed, respectively, we found limited genetic difference among them. Most local and provincial populations showed evidence of both clonality and recombination, with no population showing random recombination. Of the 748 soil isolates analyzed here, two were resistant to triazole antifungals. We discuss the implications of our results to the evolution and epidemiology of A. fumigatus ., Competing Interests: The authors declare there are no competing interests.

Background: Dominant conceptualisations of access to health care are limited, framed in terms of speed and supply. The Candidacy Framework offers a more comprehensive approach, identifying diverse influences on how access is accomplished., Aim: To characterise how the Candidacy Framework can explain access to general practice - an increasingly fraught area of public debate and policy., Design and Setting: Qualitative review guided by the principles of critical interpretive synthesis., Method: We conducted a literature review using an author-led approach, involving iterative analytically guided searches. Articles were eligible for inclusion if they related to the context of general practice, without geographical or time limitations. Key themes relating to access to general practice were extracted and synthesised using the Candidacy Framework., Results: A total of 229 articles were included in the final synthesis. The seven features identified in the original Candidacy Framework are highly salient to general practice. Using the lens of candidacy demonstrates that access to general practice is subject to multiple influences that are highly dynamic, contingent, and subject to constant negotiation. These influences are socioeconomically and institutionally patterned, creating risks to access for some groups. This analysis enables understanding of the barriers to access that may exist, even though general practice in the UK is free at the point of care, but also demonstrates that a Candidacy Framework specific to this setting is needed., Conclusion: The Candidacy Framework has considerable value as a way of understanding access to general practice, offering new insights for policy and practice. The original framework would benefit from further customisation for the distinctive setting of general practice., (© The Authors.)

S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive inborn error of metabolism affecting methylation by disrupting the methionine cycle. Its clinical spectrum spans from severe perinatal encephalomyopathy and liver failure to asymptomatic course in patients with isolated hypermethioninemia. We present two new cases of S-adenosylhomocysteine hydrolase deficiency from Pakistani origin clinically asymptomatic at presentation. Both siblings showed mild chronic liver failure and elevation of creatine kinase. The older patient presented at 6 years of age with isolated verbal processing difficulty and mild diffuse leukodystrophy, reversible 12 months after introduction of methionine dietary restriction. The patient showed subtle atrophy in the muscle MRI at the age of 7 years. S-adenosylhomocysteine hydrolase deficiency was confirmed with homozygous missense variant c.146G>A (p.Arg49His) in the AHCY gene, a genotype previously reported in Pakistani patients with mild presentation. Dietary methionine restriction decreased plasma methionine but not plasma S-adenosylhomocysteine and S-adenosylmethionine. This work expands the mild spectrum of S-adenosylhomocysteine hydrolase deficiency with no noticeable clinical symptoms in children, highlighting a specific hotspot variant from South Asia. This mild form of the disease is likely underdiagnosed and raises the question of therapeutic management to prevent long-term complications documented in the literature, such as hepatocellular carcinoma and myopathy in early adulthood., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Introduction: Despite increasing incidence of impacted fetal head at cesarean birth and associated injury, it is unclear which techniques are most effective for prevention and management. A high quality evidence review in accordance with international reporting standards is currently lacking. To address this gap, we aimed to identify, assess, and synthesize studies comparing techniques to prevent or manage impacted fetal head at cesarean birth prior to or at full cervical dilatation., Material and Methods: We searched MEDLINE, Emcare, Embase and Cochrane databases up to 1 January 2023 (PROSPERO: CRD420212750016). Included were randomized controlled trials (any size) and non-randomized comparative studies (n ≥ 30 in each arm) comparing techniques or adjunctive measures to prevent or manage impacted fetal head at cesarean birth. Following screening and data extraction, we assessed risk of bias for individual studies using RoB2 and ROBINS-I, and certainty of evidence using GRADE. We synthesized data using meta-analysis where appropriate, including sensitivity analyses excluding data published in potential predatory journals or at risk of retraction., Results: We identified 24 eligible studies (11 randomized and 13 non-randomized) including 3558 women, that compared vaginal disimpaction, reverse breech extraction, the Patwardhan method and/or the Fetal Pillow®. GRADE certainty of evidence was low or very low for all 96 outcomes across seven reported comparisons. Pooled analysis mostly showed no or equivocal differences in outcomes across comparisons of techniques. Although some maternal outcomes suggested differences between techniques (eg risk ratio of 3.41 [95% CI: 2.50-4.66] for uterine incision extension with vaginal disimpaction vs. reverse breech extraction), these were based on unreliable pooled estimates given very low GRADE certainty and, in some cases, additional risk of bias introduced by data published in potential predatory journals or at risk of retraction., Conclusions: The current weaknesses in the evidence base mean that no firm recommendations can be made about the superiority of any one impacted fetal head technique over another, indicating that high quality training is needed across the range of techniques. Future studies to improve the evidence base are urgently required, using a standard definition of impacted fetal head, agreed maternal and neonatal outcome sets for impacted fetal head, and internationally recommended reporting standards., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objectives: The impact of incident investigations in improving patient safety may be linked to the quality of risk controls recommended in investigation reports. We aimed to identify the range and apparent strength of risk controls generated from investigations into serious incidents, map them against contributory factors identified in investigation reports, and characterize the nature of the risk controls proposed., Methods: We undertook a content analysis of 126 action plans of serious incident investigation reports from a multisite and multispeciality UK hospital over a 3-year period to identify the risk controls proposed. We coded each risk control against the contributory factor it aimed to address. Using a hierarchy of risk controls model, we assessed the strength of proposed risk controls. We used thematic analysis to characterize the nature of proposed risk controls., Results: A substantial proportion (15%) of factors identified in investigation reports as contributing to serious incidents were not addressed by identifiable risk controls. Of the 822 proposed risk controls in action plans, most (74%) were assessed as weak, typically focusing on individualized interventions-even when the problems were organizational or systemic in character. The following 6 broad approaches to risk controls could be identified: improving individual or team performance; defining, standardizing, or reinforcing expected practice; improving the working environment; improving communication; process improvements; and disciplinary actions., Conclusions: The identified shortfalls in the quality of risk controls following serious incident investigations-including a 15% mismatch between contributory factors and aligned risk controls and 74% of proposed risk controls centering on weaker interventions-represent significant gaps in translating incident investigations into meaningful systemic improvements. Advancing the quality of risk controls after serious incident investigations will require involvement of human factors specialists in their design, a theory-of-change approach, evaluation, and curation and sharing of learning, all supported by a common framework., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Ocean acidification (OA) caused by increased atmospheric carbon dioxide is affecting marine systems globally and is more extreme in coastal waters. A wealth of research to determine how species will be affected by OA, now and in the future, is emerging. Most studies are discrete and generally do not include the full life cycle of animals. Studies that include the potential for adaptation responses of animals from areas with different environmental conditions and the most vulnerable life stages are needed. Therefore, we conducted experiments with the widely distributed blue mussel, Mytilus edulis, from populations regularly exposed to different OA conditions. Mussels experienced experimental conditions prior to spawning, through embryonic and larval development, both highly vulnerable stages. Survivorship to metamorphosis of larvae from all populations was negatively affected by extreme OA conditions (pH 7.3, Ωar, 0.39, pCO2 2479.74), but, surprisingly, responses to mid OA (pH 7.6, Ωar 0.77, pCO21167.13) and low OA (pH 7.9, Ωar 1.53, pCO2 514.50) varied among populations. Two populations were robust and showed no effect of OA on survivorship in this range. One population displayed the expected negative effect on survivorship with increased OA. Unexpectedly, survivorship in the fourth population was highest under mid OA conditions. There were also significant differences in development time among populations that were unaffected by OA. These results suggest that adaptation to OA may already be present in some populations and emphasizes the importance of testing animals from different populations to see the potential for adaptation to OA., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Adverse childhood events (ACEs) contribute to the development of mood and anxiety disorders and substance dependence. However, the extent to which these effects are direct or indirect and whether genetic risk moderates them is unclear. We examined associations among ACEs, mood/anxiety disorders and substance dependence in 12,668 individuals (44.9% female, 42.5% African American/Black, 42.1% European American/white). Using latent variables for each phenotype, we modelled direct and indirect associations of ACEs with substance dependence, mediated by mood/anxiety disorders (the forward or 'self-medication' model) and of ACEs with mood/anxiety disorders, mediated by substance dependence (the reverse or 'substance-induced' model). In a subsample, we tested polygenic scores for the substance dependence and mood/anxiety disorder factors as moderators in the mediation models. Although there were significant indirect paths in both directions, mediation by mood/anxiety disorders (the forward model) was greater than that by substance dependence (the reverse model). Greater genetic risk for substance use disorders was associated with a weaker direct association between ACEs and substance dependence in both ancestry groups (reflecting gene × environment interactions) and a weaker indirect association in European-ancestry individuals (reflecting moderated mediation). We found greater evidence that substance dependence reflects self-medication of mood/anxiety disorders than that mood/anxiety disorders are substance induced. Among individuals at higher genetic risk for substance dependence, ACEs were less associated with that outcome. Following exposure to ACEs, multiple pathways appear to underlie the associations between mood/anxiety disorders and substance dependence. Specification of these pathways could inform individually targeted prevention and treatment approaches., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Wheat germ (WG), a by-product of flour milling, is rich in bioactive substances that may help improve health complications associated with increased adiposity. This study investigated the effects of WG on gut health, metabolic, and inflammatory markers in adults classified as overweight. We hypothesized that WG, because of its many bioactive components, would improve gut health and metabolic, and inflammatory markers in overweight adults. Forty adults (18-45 years old) and with a body mass index between 25 and 30 kg/m 2 participated in this single-blinded randomized controlled pilot study. Participants consumed the study supplements containing 30 g of either cornmeal (control, CL) or WG daily for 4 weeks. Primary outcome variables were gut health markers including gut microbiota, gut integrity markers, and fecal short-chain fatty acids, whereas secondary outcome variables included metabolic and inflammatory parameters assessed at baseline and at the end of supplementation. Thirty-nine participants (n = 19 and 20 for CL and WG group, respectively) completed the study. The genus Faecalibacterium was significantly higher in the WG group compared to CL post-supplementation but no significant changes in other gut health markers, short-chain fatty acids, inflammatory markers, and lipid profiles were observed. Compared with baseline, WG improved markers of glucose homeostasis including insulin (P = .02), homeostatic model assessment of insulin resistance (P = .03), glycated hemoglobin (P = .07), and the pro-inflammatory adipokine, resistin (P = .04). However, these parameters after intervention were not different with control. Our findings suggest that WG supplementation have modest effects on gut health but may provide an economical option for individuals to improve glycemic control., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A basic mathematical model for IL-2-based cancer immunotherapy is proposed and studied. Our analysis shows that the outcome of therapy is mainly determined by three parameters, the relative death rate of CD4 + T cells, the relative death rate of CD8 + T cells, and the dose of IL-2 treatment. Minimal equilibrium tumor size can be reached with a large dose of IL-2 in the case that CD4 + T cells die out. However, in cases where CD4 + and CD8 + T cells persist, the final tumor size is independent of the IL-2 dose and is given by the relative death rate of CD4 + T cells. Two groups of in silico clinical trials show some short-term behaviors of IL-2 treatment. IL-2 administration can slow the proliferation of CD4 + T cells, while high doses for a short period of time over several days transiently increase the population of CD8 + T cells during treatment before it recedes to its equilibrium. IL-2 administration for a short period of time over many days suppresses the tumor population for a longer time before approaching its steady-state levels. This implies that intermittent administration of IL-2 may be a good strategy for controlling tumor size., Competing Interests: Declaration of competing interest On behalf of all coauthors, I state that: There is non-financial interest in this research., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prior research has showed the importance of providing integrated support services to prevent and reduce youth not in education, employment, or training (NEET) related challenges. There is limited evidence on NEET youth's perspectives and preferences for employment, education, and training services. The objective of this study was to identify employment, education and training service preferences of NEET youth. We acknowledge the deficit-based lens associated with the term NEET and use 'upcoming youth' to refer to this population group., Methods: Canadian youth (14-29 years) who reported Upcoming status or at-risk of Upcoming status were recruited to the study. We used a discrete choice experiment (DCE) survey, which included ten attributes with three levels each indicating service characteristics. Sawtooth software was used to design and administer the DCE. Participants also provided demographic information and completed the Global Appraisal of Individual Needs-Short Screener. We analyzed the data using hierarchical Bayesian methods to determine service attribute importance and latent class analyses to identify groups of participants with similar service preferences., Results: A total of n=503 youth participated in the study. 51% of participants were 24-29 years of age; 18.7% identified as having Upcoming status; 41.1% were from rural areas; and 36.0% of youth stated that they met basic needs with a little left. Participants strongly preferred services that promoted life skills, mentorship, basic income, and securing a work or educational placement. Three latent classes were identified and included: (i) job and educational services (38.9%), or services that include career counseling and securing a work or educational placement; (ii) mental health and wellness services (34.9%), or services that offer support for mental health and wellness in the workplace and free mental health and substance use services; and (iii) holistic skills building services (26.1%), or services that endorsed skills for school and job success, and life skills., Conclusions: This study identified employment, education, and training service preferences among Upcoming youth. The findings indicate a need to create a service model that supports holistic skills building, mental health and wellness, and long-term school and job opportunities., (© 2024. The Author(s).)

Background: System problems, known as operational failures, can greatly affect the work of GPs, with negative consequences for patient and professional experience, efficiency, and effectiveness. Many operational failures are tractable to improvement, but which ones should be prioritised is less clear., Aim: To build consensus among GPs and patients on the operational failures that should be prioritised to improve NHS general practice., Design and Setting: Two modified Delphi exercises were conducted online among NHS GPs and patients in several regions across England., Method: Between February and October 2021, two modified Delphi exercises were conducted online: one with NHS GPs, and a subsequent exercise with patients. Over two rounds, GPs rated the importance of a list of operational failures ( n = 45) that had been compiled using existing evidence. The resulting shortlist was presented to patients for rating over two rounds. Data were analysed using median scores and interquartile ranges. Consensus was defined as 80% of responses falling within one value below and above the median., Results: Sixty-two GPs responded to the first Delphi exercise, and 53.2% ( n = 33) were retained through to round two. This exercise yielded consensus on 14 failures as a priority for improvement, which were presented to patients. Thirty-seven patients responded to the first patient Delphi exercise, and 89.2% ( n = 33) were retained through to round two. Patients identified 13 failures as priorities. The highest scoring failures included inaccuracies in patients' medical notes, missing test results, and difficulties referring patients to other providers because of problems with referral forms., Conclusion: This study identified the highest-priority operational failures in general practice according to GPs and patients, and indicates where improvement efforts relating to operational failures in general practice should be focused., (© The Authors.)

Background: High-quality antenatal care is important for ensuring optimal birth outcomes and reducing risks of maternal and fetal mortality and morbidity. The COVID-19 pandemic disrupted the usual provision of antenatal care, with much care shifting to remote forms of provision. We aimed to characterise what quality would look like for remote antenatal care from the perspectives of those who use, provide and organise it., Methods: This UK-wide study involved interviews and an online survey inviting free-text responses with: those who were or had been pregnant since March 2020; maternity professionals and managers of maternity services and system-level stakeholders. Recruitment used network-based approaches, professional and community networks and purposively selected hospitals. Analysis of interview transcripts was based on the constant comparative method. Free-text survey responses were analysed using a coding framework developed by researchers., Findings: Participants included 106 pregnant women and 105 healthcare professionals and managers/stakeholders. Analysis enabled generation of a framework of the domains of quality that appear to be most relevant to stakeholders in remote antenatal care: efficiency and timeliness; effectiveness; safety; accessibility; equity and inclusion; person-centredness and choice and continuity. Participants reported that remote care was not straightforwardly positive or negative across these domains. Care that was more transactional in nature was identified as more suitable for remote modalities, but remote care was also seen as having potential to undermine important aspects of trusting relationships and continuity, to amplify or create new forms of structural inequality and to create possible risks to safety., Conclusions: This study offers a provisional framework that can help in structuring thinking, policy and practice. By outlining the range of domains relevant to remote antenatal care, this framework is likely to be of value in guiding policy, practice and research., Competing Interests: Competing interests: TD is Vice President of the Royal College of Obstetricians and Gynaecologists. RJM has previously received BP monitors from Omron Healthcare for research purposes and is working with them on a telemonitoring system., (© 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.)

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow-on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations. These dietary management recommendations can support dietitians, nutritionists, and physicians in initiation and monitoring of lysine reduction therapies for PDE-ALDH7A1 patients and families., Competing Interests: Annemiek M. J. van Wegberg has received a research grant from Nutricia, travel support from Nutricia and Vitaflo and participated in nutritional product research evaluation studies for Vitaflo International Ltd UK. Marjorie Dixon has received honoraria, travel support from Danone Nutricia and Vitaflo International Ltd and participated in nutritional product research evaluation studies for Vitaflo International Ltd and Nutricia, UK. Clara D. M. van Karnebeek was the principal investigator in nutritional product research evaluation studies for Vitaflo International Ltd. Chloe Millington participated in nutritional product research evaluation studies for Vitaflo International Ltd. Sommer Gaughan received an honorarium from Nutricia North America for PDE case write up. The other authors (Laurie Bernstein, Curtis R. Coughlin II, Morgan Drumm) declare no conflict of interest., (© 2024 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D 2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects., Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit., Methods: We used data from two dose-response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D 2 receptor occupancy to extrapolate our recommendations., Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation., Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JRO is acknowledged for his contribution to the Maudsley Deprescribing Guidelines but has not received any direct payment for this. AJ is funded through a PhD scholarship from the Bradford District Care NHS Foundation Trust in partnership with the University of Bradford. MD is Assistant Registrar of the College of Mental Health Pharmacy, who has corporate partnerships with Rovi, Accord UK Ltd and Janssen Cilag Ltd. CL is currently acting as a Sub-Investigator for a trial being run by Boehringer Ingelheim through his role at Southern Health NHS Foundation Trust, but he does not receive any direct funding or payment for this. SLM and AGC have no financial or business conflicts of interests to declare in relation to the content of this paper.

Breast cancer (BC) is one of the most common cancers in the United States. Advances in detection and treatment have resulted in an increased survival rate, meaning an increasing population experiencing declines in muscle mass and strength. Creatine supplementation has consistently demonstrated improvements in strength and muscle performance in older adults, though these findings have not been extended to cancer populations., Purpose: The purpose of this study was to investigate the effects of short-term creatine supplementation on muscular performance in BC survivors., Methods: Using a double-blind, placebo-controlled, randomized design, 19 female BC survivors (mean ± SD age = 57.63 ± 10.77 years) were assigned to creatine (SUPP) ( n = 9) or dextrose placebo (PLA) ( n = 10) groups. The participants completed two familiarization sessions, then two test sessions, each separated by 7 days, where the participants supplemented with 5 g of SUPP or PLA 4 times/day between sessions. The testing sessions included sit-to-stand power, isometric/isokinetic peak torque, and upper/lower body strength via 10 repetition maximum (10RM) tests. The interaction between supplement (SUPP vs. PLA) and time (Pre vs. Post) was examined using a group × time ANOVA and effect sizes., Results: No significant effects were observed for sit-to-stand power ( p = 0.471; η p 2 = 0.031), peak torque at 60°/second ( p = 0.533; η p 2 = 0.023), peak torque at 120°/second ( p = 0.944; η p 2 < 0.001), isometric peak torque ( p = 0.905; η p 2 < 0.001), 10RM chest press ( p = 0.407; η p 2 = 0.041), and 10RM leg extension ( p = 0.932; η p 2 < 0.001). However, a large effect size for time occurred for the 10RM chest press (η p 2 = 0.531) and leg extension (η p 2 = 0.422)., Conclusion: Seven days of creatine supplementation does not influence muscular performance among BC survivors.

Competing Interests: Competing interests: We have read and understood BMJ policy on competing interests and declare: MD-W is currently undertaking evaluative work for the Care Quality Commission. She is an unpaid director and founder of THIS Labs. CS gave oral evidence to the House of Lords Science and Technology Committee Inquiry into Clinical Academics and the NHS. She is employed by the University of Cambridge, is an honorary consultant at Cambridge University Hospitals NHS Foundation Trust, and is director of studies in clinical medicine at Selwyn College, Cambridge. MM is an employee of The BMJ and has acted in various advisory roles for the health service including for the Welsh government. KP has no interests to declare.

Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes' assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration. Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14 days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts. Results : Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3 years (range 24-80 years), and 67.4% ( N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration. Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure., Competing Interests: The study sponsor was involved in the design of the study, interpretation of the data, and preparation, review, and approval of the manuscript. JC, MM, NS, and AS are employed by Evidera, which provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. As Evidera employees, they work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. BB and MD are employees of Bristol-Myers Squibb. JR reported receiving personal fees as a speaker and/or in an advisory role from Pierre Fabre, Amgen, Sanofi, Takeda, Astra Zeneca, Bristol-Myers Squibb; research funding from Takeda. SL received research funding (to Institution) from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol-Myers Squibb; personal honoraria as invited speaker from Roche, Eli Lilly, Bristol-Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, Merck Sharp & Dohme. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Skalicky, Bennett, Raimbourg, Lonardi, Correll, Lugowska, Dixon, Sargalo and Martin.)

Clinical tools for use in practice-such as medicine reconciliation charts, diagnosis support tools and track-and-trigger charts-are endemic in healthcare, but relatively little attention is given to how to optimise their design. User-centred design approaches and co-design principles offer potential for improving usability and acceptability of clinical tools, but limited practical guidance is currently available. We propose a framework (FRamework for co-dESign of Clinical practice tOols or 'FRESCO') offering practical guidance based on user-centred methods and co-design principles, organised in five steps: (1) establish a multidisciplinary advisory group; (2) develop initial drafts of the prototype; (3) conduct think-aloud usability evaluations; (4) test in clinical simulations; (5) generate a final prototype informed by workshops. We applied the framework in a case study to support co-design of a prototype track-and-trigger chart for detecting and responding to possible fetal deterioration during labour. This started with establishing an advisory group of 22 members with varied expertise. Two initial draft prototypes were developed-one based on a version produced by national bodies, and the other with similar content but designed using human factors principles. Think-aloud usability evaluations of these prototypes were conducted with 15 professionals, and the findings used to inform co-design of an improved draft prototype. This was tested with 52 maternity professionals from five maternity units through clinical simulations. Analysis of these simulations and six workshops were used to co-design the final prototype to the point of readiness for large-scale testing. By codifying existing methods and principles into a single framework, FRESCO supported mobilisation of the expertise and ingenuity of diverse stakeholders to co-design a prototype track-and-trigger chart in an area of pressing service need. Subject to further evaluation, the framework has potential for application beyond the area of clinical practice in which it was applied., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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.)

Objective: To identify the social-structural determinants of health risk factors associated with maternal morbidity and mortality in the United States during the prenatal and postpartum periods., Data Sources: We searched MEDLINE, CINAHL, and Social Sciences Citation Index through November 2022 for eligible studies that examined exposures related to social and structural determinants of health and at least one health or health care-related outcome for pregnant and birthing people., Methods of Study Selection: After screening 8,378 unique references, 118 studies met inclusion criteria., Tabulation, Integration, and Results: We grouped studies by social and structural determinants of health domains and maternal outcomes. We used alluvial graphs to summarize results and provide additional descriptions of direction of association between potential risk exposures and outcomes. Studies broadly covered risk factors including identity and discrimination, socioeconomic, violence, trauma, psychological stress, structural or institutional, rural or urban, environment, comorbidities, hospital, and health care use. However, these risk factors represent only a subset of potential social and structural determinants of interest. We found an unexpectedly large volume of research on violence and trauma relative to other potential exposures of interest. Outcome domains included maternal mortality, severe maternal morbidity, hypertensive disorders, gestational diabetes, cardiac and metabolic disorders, weathering depression, other mental health or substance use disorders, and cost per health care use outcomes. Patterns between risk factors and outcomes were highly mixed. Depression and other mental health outcomes represented a large proportion of medical outcomes. Risk of bias was high, and rarely did studies report the excess risk attributable to a specific exposure., Conclusion: Limited depth and quality of available research within each risk factor hindered our ability to understand underlying pathways, including risk factor interdependence. Although recently published literature showed a definite trend toward improved rigor, future research should emphasize techniques that improve the ability to estimate causal effects. In the longer term, the field could advance through data sets designed to fully ascertain data required to robustly examine racism and other social and structural determinants of health, their intersections, and feedback loops with other biological and medical risk factors., Systematic Review Registration: PROSPERO, CRD42022300617., Competing Interests: Financial Disclosure Huda Bashir receives funding from African American Babies Coalition. The other authors did not report any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2)., Methods: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined 'brain frailty' markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI., Results: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging 'brain frailty' was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke., Conclusions: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials., Competing Interests: Competing interests: JPA is supported by an NIHR Health and Care Research Scholarship. PMB is Stroke Association Professor of Stroke Medicine and an NIHR Senior Investigator. TR is a NIHR Senior Investigator. GM is the Stroke Association Edith Murphy Foundation Senior Clinical Lecturer (SA L-SMP 18\1000). JW is supported by the UK Dementia Research Institute which receives its funding from DRI, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The remaining authors report no declarations of interest., (© 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 Safety Case is a regulatory technique that requires organisations to demonstrate to regulators that they have systematically identified hazards in their systems and reduced risks to being as low as reasonably practicable. It is used in several high-risk sectors, but only in a very limited way in healthcare. We examined the first documented attempt to apply the Safety Case methodology to clinical pathways., Methods: Data are drawn from a mixed-methods evaluation of the Safer Clinical Systems programme. The development of a Safety Case for a defined clinical pathway was a centrepiece of the programme. We base our analysis on 143 interviews covering all aspects of the programme and on analysis of 13 Safety Cases produced by clinical teams., Results: The principles behind a proactive, systematic approach to identifying and controlling risk that could be curated in a single document were broadly welcomed by participants, but was not straightforward to deliver. Compiling Safety Cases helped teams to identify safety hazards in clinical pathways, some of which had been previously occluded. However, the work of compiling Safety Cases was demanding of scarce skill and resource. Not all problems identified through proactive methods were tractable to the efforts of front-line staff. Some persistent hazards, originating from institutional and organisational vulnerabilities, appeared also to be out of the scope of control of even the board level of organisations. A particular dilemma for organisational senior leadership was whether to prioritise fixing the risks proactively identified in Safety Cases over other pressing issues, including those that had already resulted in harm., Conclusions: The Safety Case approach was recognised by those involved in the Safer Clinical Systems programme as having potential value. However, it is also fraught with challenge, highlighting the limitations of efforts to transfer safety management practices to healthcare from other sectors., 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: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear., Methods: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI., Discussion: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis., Trial Registration: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41., (© 2024. The Author(s).)

Background: Ambulance services are increasingly research active and the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is the largest United Kingdom (UK) ambulance-based randomized controlled trial in stroke. We explore the complexities and challenges encountered during RIGHT-2., Methods: Five hundred and sixteen of 1487 paramedics from eight UK ambulance services serving 54 comprehensive or primary stroke care centers screened and consented 1149 patients presenting within 4 h of FAST-positive stroke and with systolic blood pressure >120 mmHg; participants were randomized to treatment with transdermal glyceryl trinitrate versus sham patch in the ambulance., Key Findings: Working with multiple ambulance services demanded flexibility in the trial protocol to overcome variation in operating procedures to ensure deliverability. Many paramedics are novice researchers, and research concepts and practices are emerging including consent strategies in emergency stroke care. Regional variation in hospital participation and hours/days of operation presented paramedics with additional considerations prior to patient recruitment. The working hours of hospital research staff often do not reflect the 24/7 nature of ambulance work, which challenged deliverability until trial processes became fully embedded. Management of investigational medicinal product between ambulance stations, in-transit when on ambulance vehicles and on handover at hospital, necessitated an in-depth review to maintain accountability., Conclusion: RIGHT-2 demonstrated that although there are significant practical challenges to conducting multicenter ambulance-based research in a time-dependent environment, careful planning and management facilitated delivery. Lessons learned here will help inform the design and conduct of future ambulance-based trials.

Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C., Competing Interests: The authors have no conflict of interest to declare., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Objectives: Despite their widespread use, the evidence base for the effectiveness of quality improvement collaboratives remains mixed. Lack of clarity about 'what good looks like' in collaboratives remains a persistent problem. We aimed to identify the distinctive features of a state-wide collaboratives programme that has demonstrated sustained improvements in quality of care in a range of clinical specialties over a long period., Design: Qualitative case study involving interviews with purposively sampled participants, observations and analysis of documents., Setting: The Michigan Collaborative Quality Initiatives programme., Participants: 38 participants, including clinicians and managers from 10 collaboratives, and staff from the University of Michigan and Blue Cross Blue Shield of Michigan., Results: We identified five features that characterised success in the collaboratives programme: learning from positive deviance; high-quality coordination; high-quality measurement and comparative performance feedback; careful use of motivational levers; and mobilising professional leadership and building community. Rigorous measurement, securing professional leadership and engagement, cultivating a collaborative culture, creating accountability for quality, and relieving participating sites of unnecessary burdens associated with programme participation were all important to high performance., Conclusions: Our findings offer valuable learning for optimising collaboration-based approaches to improvement in healthcare, with implications for the design, structure and resourcing of quality improvement collaboratives. These findings are likely to be useful to clinicians, managers, policy-makers and health system leaders engaged in multiorganisational approaches to improving quality and safety., Competing Interests: Competing interests: The Michigan Quality Collaboratives are supported by Blue Cross and Blue Shield of Michigan. MJE receives salary support from Blue Cross and Blue Shield of Michigan as well as the NIH and the Michigan DHHS. DAC, GLK and MJE’s institution (University of Michigan) receives a partial salary paid for by the Blue Cross Blue Shield of Michigan Value Partnerships for the Michigan Surgical Quality Collaborative. GLK, DAC and MJE are employed by the Michigan Surgical Quality Collaborative. MJE and JBD were interviewed as participants in the study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Treatment for stroke is time-dependent, and ambulance services play a vital role in the early recognition, assessment and transportation of stroke patients. Innovations which begin in ambulance services to expedite delivery of treatments for stroke are developing. However, research delivery in ambulance services is novel, developing and not fully understood., Aims: To synthesise literature encompassing ambulance service-based randomised controlled interventions for acute stroke with consideration to the characteristics of the type of intervention, consent modality, time intervals and issues unique to research delivery in ambulance services. Online searches of MEDLINE, EMBASE, Web of Science, CENTRAL and WHO IRCTP databases and hand searches identified 15 eligible studies from 538. Articles were heterogeneous in nature and meta-analysis was partially available as 13 studies reported key time intervals, but terminology varied. Randomised interventions were evident across all points of contact with ambulance services: identification of stroke during the call for help, higher dispatch priority assigned to stroke, on-scene assessment and clinical interventions, direct referral to comprehensive stroke centres and definitive care delivery at scene. Consent methods ranged between informed patient, waiver and proxy modalities with country-specific variation. Challenges unique to the prehospital setting comprise the geographical distribution of ambulance resources, low recruitment rates, prolonged recruitment phases, management of investigational medicinal product and incomplete datasets., Conclusion: Research opportunities exist across all points of contact between stroke patients and ambulance services, but randomisation and consent remain novel. Early collaboration and engagement between trialists and ambulance services will alleviate some of the complexities reported., Registration Number: PROSPERO 2018CRD42018075803., (© 2023. The Author(s).)

The future quantum internet will leverage existing communication infrastructures, including deployed optical fibre networks, to enable novel applications that outperform current information technology. In this scenario, we perform a feasibility study of quantum communications over an industrial 224 km submarine optical fibre link deployed between Southport in the United Kingdom (UK) and Portrane in the Republic of Ireland (IE). With a characterisation of phase drift, polarisation stability and the arrival time of entangled photons, we demonstrate the suitability of the link to enable international UK-IE quantum communications for the first time.

Background: Recent studies have suggested that the COVID-19 pandemic has increased existing health challenges experienced by transgender (trans) and non-binary people. Additionally, COVID-19 has also negatively impacted youth mental health. However, the impact of the COVID-19 pandemic with respect to the intersection of youth and trans and non-binary populations is currently not well established. The present longitudinal qualitative study aimed to examine the evolving challenges experienced by trans and non-binary youth during the COVID-19 pandemic., Methods: Gender-diverse youth, defined as participants who did not identify as cisgender in April 2020, were invited to participate from among the participant pool of a COVID-19 cohort study in Canada. Qualitative interviews were conducted in August 2020, January 2021, and August 2021, during the first year and a half of the COVID-19 pandemic. Qualitative themes were identified based on reflexive thematic analysis and plot-line narrative inquiry., Results: Ten participants aged 18 to 28 were included in the present analysis, yielding 29 transcripts. We identified themes of (1) losses of connection to gender-diverse communities, (2) changes in gender identity, affirmation, and self-reflection, (3) a dual burden of trans and non-binary specific health and service access challenges as well as COVID-19 pandemic related health challenges, and (4) virtually rebuilding gender-diverse communities during the COVID-19 pandemic., Conclusions: Gender-diverse youth may experience unique challenges during the COVID-19 pandemic. The losses with gender-diverse communities may further isolate queer people from access to healthcare, housing, and employment. Public health policy targeted at gender-diverse youth may consider addressing "upstream" disparities in healthcare and housing in order to support the rebuilding of queer and gender-diverse communities by gender-diverse people., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Everest et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)-based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform - investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.

Objective: To investigate the hypothesis that risk factors in addition to an abnormal fetal heart rate pattern (aFHRp) are independently associated with adverse neonatal outcomes of labour., Design: Observational prospective cohort study., Setting: 17 UK maternity units., Sample: 585 291 pregnancies between 1988 and 2000 inclusive., Methods: Adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were estimated from multivariable logistic regression., Main Outcome Measures: Adverse neonatal outcome at term (5-minute Apgar score <7, and a composite measure comprising 5-minute Apgar score <7, resuscitation by intubation and/or perinatal death)., Results: Analysis was based on 302 137 vaginal births at 37-42 weeks inclusive. We found a higher odds of Apgar score at 5 minutes <7 with suspected fetal growth restriction (OR 1.34, 95% CI 1.16-1.53), induction of labour (OR 1.41, 95% CI 1.25-1.58), nulliparity (OR 1.48, 95% CI 1.34-1.63), booking body mass index ≥30 (OR 1.18, 95% CI 1.02-1.37), maternal age <25 (OR 1.23, 95% CI 1.10-1.39), black ethnicity (OR 1.21, 95% CI 1.03-1.43), early-term birth at 37-38 weeks (OR 1.13, 95% CI 1.02-1.25), late-term birth at 41-42 weeks (OR 1.14, 95% CI 1.01-1.28), use of oxytocin (OR 1.27, 95% CI 1.14-1.41), maternal pyrexia (OR 1.87, 95% CI 1.46-2.40), aFHRp and presence of meconium (aFHRp without meconium: OR 2.40, 95% CI 2.15-2.69; meconium without aFHRp: OR 2.20, 195% CI.94-2.49; both aFHRp and meconium: OR 4.26, 95% CI 3.74-4.87). The results were similar when the composite adverse outcome was considered., Conclusions: A range of risk factors, including suspicion of fetal growth restriction, maternal pyrexia and presence of meconium, are implicated in poor birth outcomes in addition to aFHRp. Interpretation of the fetal heart rate pattern alone is insufficient as a basis for decisions about escalation and intervention., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Adverse childhood events (ACEs) contribute to the development of mood and anxiety disorders and substance dependence. However, the extent to which these effects are direct or indirect and whether genetic risk moderates them is unclear., Methods: We examined associations among ACEs, mood/anxiety disorders, and substance dependence in 12,668 individuals (44.9% female, 42.5% African American/Black, 42.1% European American/White). We generated latent variables for each phenotype and modeled direct and indirect effects of ACEs on substance dependence, mediated by mood/anxiety disorders (forward or "self-medication" model) and of ACEs on mood/anxiety disorders, mediated by substance dependence (reverse or "substance-induced" model). In a sub-sample, we also generated polygenic scores for substance dependence and mood/anxiety disorder factors, which we tested as moderators in the mediation models., Results: Although there were significant indirect effects in both directions, mediation by mood/anxiety disorders (forward model) was greater than by substance dependence (reverse model). Greater genetic risk for substance dependence was associated with a weaker direct effect of ACEs on substance dependence in both the African- and European-ancestry groups (i.e., gene-environment interaction) and a weaker indirect effect in European-ancestry individuals (i.e., moderated mediation)., Conclusion: We found greater evidence that substance dependence results from self-medication of mood/anxiety disorders than that mood/anxiety disorders are substance induced. Among individuals at higher genetic risk for substance dependence who are more likely to develop a dependence diagnosis, ACEs exert less of an effect in promoting that outcome. Following exposure to ACEs, multiple pathways lead to mood/anxiety disorders and substance dependence. Specification of these pathways could inform individually targeted prevention and treatment approaches.

Background: Adverse childhood events (ACEs) contribute to the development of mood and anxiety disorders and substance dependence. However, the extent to which these effects are direct or indirect and whether genetic risk moderates them is unclear., Methods: We examined associations among ACEs, mood/anxiety disorders, and substance dependence in 12,668 individuals (44.9% female, 42.5% African American/Black, 42.1% European American/White). We generated latent variables for each phenotype and modeled direct and indirect effects of ACEs on substance dependence, mediated by mood/anxiety disorders (forward or "self-medication" model) and of ACEs on mood/anxiety disorders, mediated by substance dependence (reverse or "substance-induced" model). In a sub-sample, we also generated polygenic scores for substance dependence and mood/anxiety disorder factors, which we tested as moderators in the mediation models., Results: Although there were significant indirect effects in both directions, mediation by mood/anxiety disorders (forward model) was greater than by substance dependence (reverse model). Greater genetic risk for substance dependence was associated with a weaker direct effect of ACEs on substance dependence in both the African- and European-ancestry groups (i.e., gene-environment interaction) and a weaker indirect effect in European-ancestry individuals (i.e., moderated mediation)., Conclusion: We found greater evidence that substance dependence results from self-medication of mood/anxiety disorders than that mood/anxiety disorders are substance induced. Among individuals at higher genetic risk for substance dependence who are more likely to develop a dependence diagnosis, ACEs exert less of an effect in promoting that outcome. Following exposure to ACEs, multiple pathways lead to mood/anxiety disorders and substance dependence. Specification of these pathways could inform individually targeted prevention and treatment approaches.