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The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development.sup.1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure.sup.2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass., Author(s): B. Y. H. Lam [sup.1] [sup.2] , A. Williamson [sup.1] [sup.2] [sup.3] , S. Finer [sup.4] , F. R. Day [sup.3] , J. A. Tadross [sup.1] [sup.2] [sup.5] , [...]

Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol., (© 2024. The Author(s).)

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC)., Objectives: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6)., Methods: Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments., Results: At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%., Limitations: Nonrandomized study, nonsurvival primary end point., Conclusion: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC., Competing Interests: Conflicts of interest Dr Hughes reports consulting/advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, and Roche; and institutional research funding from Amgen. Dr Guminski reports personal fees and advisory board and travel support from Bristol-Myers Squibb and Sun Pharma; advisory board fees from Eisai, Merck KGaA, and Pfizer; travel support from Astellas; and clinical trial unit support from PPD Australia. Dr Bowyer reports advisory board roles for Eli Lilly Australia, Ipsen, Merck Sharp & Dohme, and Sanofi; virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and travel support from Merck Sharp & Dohme and AstraZeneca. Michael Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., and Sanofi; consulting fees from Feldan Therapeutics, Replimune, Stamford Pharma, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., and Replimune. Dr Schmults reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc.; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; and serving as a chair for the National Comprehensive Cancer Network. Dr Khushalani reports grants and advisory board fees from Bristol-Myers Squibb, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; advisory board fees from AstraZeneca (data safety monitoring committee), Castle Biosciences, Incyte (data safety monitoring committee), Instil Bio, Iovance, Jounce Therapeutics, Nektar, and Replimune; grants from Celgene, GlaxoSmithKline, HUYA, Modulation Therapeutics, and Replimune; honoraria from Genzyme, National Comprehensive Cancer Network (grant funding from general research support through Pfizer), and Nektar (study steering committee); common stock ownership of Amarin, Bellicum Pharmaceuticals, and Transenetrix; study steering committee membership for Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., and Replimune; and travel support from Regeneron Pharmaceuticals, Inc. Dr Chang reports consulting and advisory roles with Merck, and Regeneron Pharmaceuticals, Inc.; research funding from Galderma, Merck, Novartis, and Regeneron Pharmaceuticals, Inc., and consultancy for Castle Biosciences and Feldan. Dr Grob reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Philogen, Roche, and Sanofi; and an advisory role for Bristol-Myers Squibb. Dr Lewis reports employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. At the time of this study, Dr Lewis was affiliated with the University of Colorado Denver Cancer Center and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Day reports serving on an advisory board for Amgen, travel support from Merck; and clinical trial support (investigational medical product provision, no financial support) from AstraZeneca and Bristol-Myers Squibb. Dr Ladwa reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; consulting or advisory roles for AstraZeneca, and Roche; and travel, accommodation, and expenses from Merck Sharp & Dohme. Dr Stein reports ownership of stocks/shares in Icon Group. Dr Muñoz Couselo reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and clinical trial participation (principal investigator) for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. Dr Meier reports travel support, speaker’s fees, or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. Dr Hauschild reports institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. Dr Schadendorf reports honoraria from 4SC AG, Array BioPharma, Bristol-Myers Squibb, Immunocore, InflarxGmbH, Merck, Merck Sharp & Dohme, NeraCare GmbH, Novartis, Pierre Fabre, Pfizer, Philogen, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, Serono, Sun Pharma, Roche/Genentech, and Ultimovacs; advisory board and consulting fees from 4SC AG, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Nektar; speaker fees from Bristol-Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi; institutional research funding from Array BioPharma/Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and travel/accommodation expenses from Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. Dr Basset-Seguin reports serving as an invited speaker, advisory board member, and consultant for Galderma, Regeneron Pharmaceuticals, Inc., Sanofi, and Sun Pharma. Dr Modi reports consulting/advisory board participation for Merck, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and speaker bureau participation for Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme. Dr Dalac-Rat reports honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Sun Pharma. Dr Dunn reports advisory board participation for Merck and Regeneron Pharmaceuticals, Inc.; and research support from CUE-101, Regeneron Pharmaceuticals, Inc., Replimune Pharmaceuticals, and Seagen. Dr Flatz reports research funding from Hookipa Pharma; and advisory board fees from Bristol-Myers Squibb, Novartis, Philogen, and Sanofi. Dr Mortier reports personal fees and nonfinancial support from Bristol-Myers Squibb, and Merck Sharp & Dohme, Novartis, and Roche. Dr Guégan reports consulting fees from Bristol-Myers Squibb, Janssen, and Pierre Fabre; and technical support for congress attendance from Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Sanofi. Dr Heinzerling reports consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi; lecture fees from Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi; and travel grants from Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche. Dr Mehnert reports advisory board fees from Bristol-Myers Squibb, Eisai, Novartis, Pliant Therapeutics, Regeneron Pharmaceuticals, Inc., and Seagen; and consultancy fees from Merck. Dr Soria-Rivas reports speaker’s honoraria from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche Pharma, and Sanofi Aventis; and advisory board fees from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi Aventis. Dr Stratigos reports advisory board or steering committee roles for Janssen, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and research support from AbbVie, Bristol-Myers Squibb, Genesis Pharma, LEO Pharma, Novartis, and Pfizer. Dr Ulrich reports advisory board and speaker roles for Regeneron Pharmaceuticals, Inc., Roche, Sanofi, and Sun Pharma. Dr Wong reports grant funding to institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F-Star Therapeutics, Genentech, Gilead, Kura Oncology, Merck Sharp & Dohme, Pfizer, Regeneron Pharmaceuticals, Inc., and TopAlliance Biosciences, and consulting fees from Blueprint Medicines Corporation, Genzyme/Sanofi, and Regeneron Pharmaceuticals, Inc. Dr Beylot-Barry reports institutional research funding from Roche and speaker honoraria from Sun Pharma. Dr Bossi reports advisory board or conference honoraria for Merck, Merck Sharp & Dohme, Sanofi-Regeneron, and Sun Pharma. Dr Bugés Sánchez reports personal fees from Amgen, Merck, Novartis, and Sanofi. Dr Chandra reports honoraria from Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; consulting/advisory roles for Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; and institutional research funding from Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi. Dr Robert reports grants, personal fees, and advisory board roles for Amgen, Biothera, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. Dr Silk reports institutional research grant and funding from Biohaven Pharmaceuticals, Merck, Morphogenesis, Regeneron Pharmaceuticals, Inc., Replimune, and Shattuck Laboratories; advisory board fees from Natera, Merck and Regeneron Pharmaceuticals, Inc.; consulting fees from Leerink, and royalties from UpToDate, Inc. Ms Booth and Drs, Yoo, Seebach, Lowy, and Fury report employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. Dr Rischin reports institutional research grant and funding from ALX Oncology, Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and uncompensated scientific committee and advisory board roles for Eisai, Bicara, GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., and Sanofi. Drs Ansstas, Trabelsi, and Russell have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Accurately identifying and quantifying polar metabolites using untargeted metabolomics has proven challenging in comparison to mid to non-polar metabolites. Hydrophilic interaction chromatography and gas chromatography-mass spectrometry are predominantly used to target polar metabolites., Objectives: This study aims to demonstrate a simple one-step extraction combined with liquid chromatography-mass spectrometry (LC-MS) that reliably retains polar metabolites., Methods: The method involves a MilliQ + 10% trichloroacetic acid extraction from 6 healthy individuals serum, combined with porous graphitic carbon liquid chromatography-mass spectrometry (LC-MS). The coefficient of variation (CV) assessed retention reliability of polar metabolites with logP as low as - 9. QreSS (Quantification, Retention, and System Suitability) internal standards determined the method's consistency and recovery efficiency., Results: The method demonstrated reliable retention (CV < 0.30) of polar metabolites within a logP range of - 9.1 to 5.6. QreSS internal standards confirmed consistent performance (CV < 0.16) and effective recovery (70-130%) of polar to mid-polar metabolites. Quality control dilution series demonstrated that ~ 80% of annotated metabolites could be accurately quantified (Pearson's correlation coefficient > 0.80) within their concentration range. Repeatability was demonstrated through clustering of repeated extractions from a single sample., Conclusion: This LC-MS method is better suited to covering the polar segment of the metabolome than current methods, offering a reliable and efficient approach for accurate quantification of polar metabolites in untargeted metabolomics., (© 2024. The Author(s).)

Background: Moderately severe or major trauma (injury severity score (ISS) > 8) is common, often resulting in physical and psychological problems and leading to difficulties in returning to work. Vocational rehabilitation (VR) can improve return to work/education in some injuries (e.g. traumatic brain and spinal cord injury), but evidence is lacking for other moderately severe or major trauma., Methods: ROWTATE is an individually randomised controlled multicentre pragmatic trial of early VR and psychological support in trauma patients. It includes an internal pilot, economic evaluation, a process evaluation and an implementation study. Participants will be screened for eligibility and recruited within 12 weeks of admission to eight major trauma centres in England. A total of 722 participants with ISS > 8 will be randomised 1:1 to VR and psychological support (where needed, following psychological screening) plus usual care or to usual care alone. The ROWTATE VR intervention will be provided within 2 weeks of study recruitment by occupational therapists and where needed, by clinical psychologists. It will be individually tailored and provided for ≤ 12 months, dependent on participant need. Baseline assessment will collect data on demographics, injury details, work/education status, cognitive impairment, anxiety, depression, post-traumatic distress, disability, recovery expectations, financial stress and health-related quality of life. Participants will be followed up by postal/telephone/online questionnaires at 3, 6 and 12 months post-randomisation. The primary objective is to establish whether the ROWTATE VR intervention plus usual care is more effective than usual care alone for improving participants' self-reported return to work/education for at least 80% of pre-injury hours at 12 months post-randomisation. Secondary outcomes include other work outcomes (e.g. hours of work/education, time to return to work/education, sickness absence), depression, anxiety, post-traumatic distress, work self-efficacy, financial stress, purpose in life, health-related quality of life and healthcare/personal resource use. The process evaluation and implementation study will be described elsewhere., Discussion: This trial will provide robust evidence regarding a VR intervention for a major trauma population. Evidence of a clinically and cost-effective VR intervention will be important for commissioners and providers to enable adoption of VR services for this large and important group of patients within the NHS., Trial Registration: ISRCTN: 43115471. Registered 27/07/2021., (© 2024. The Author(s).)

Aims: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. The purpose of this study was to test the safety and efficacy of nivolumab given concurrently with hypofractionated chemoradiotherapy to patients with oligometastatic and obstructing esophageal tumors., Methods: Patients were enrolled in a planned single-arm, phase 2 clinical trial. Eligible participants had previously untreated oligometastatic (≤5 metastases on fludeoxyglucose-18 positron emission tomography scan outside the primary tumor radiotherapy field) esophageal or gastroesophageal carcinoma, dysphagia, and Eastern Cooperative Oncology Group performance status 0-1. Treatment was with 2 weeks of concurrent hypofractionated radiotherapy (30 Gy/10#) to the primary tumor, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m 2 , and q2weekly nivolumab 240 mg, followed by nivolumab 480 mg continuing q4weekly until disease progression or 24 months total. A single metastasis was treated with stereotactic radiotherapy (SBRT) (24 Gy/3#) in week 7., Results: Five patients were recruited before trial closure to new participants for logistical reasons. Existing participants continued treatment per protocol as a pilot study at one center. All five patients completed chemoradioimmunotherapy and SBRT. All patients derived an improvement in their dysphagia. Two patients completed 24 months of nivolumab without disease progression. Grade 3 adverse events (AEs) occurred in 3 patients, however, there were no grade 4 AEs, AEs due to SBRT, or AEs of special interest as defined by the protocol., Conclusion: Pilot results from five patients at one center found that treatment was well tolerated and effective for dysphagia relief. The efficacy of hypofractionated chemoradiotherapy with concurrent checkpoint inhibition should be tested in a multicentre study., (© 2024 The Authors. Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Background: UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS., Methods: Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a 'safety to exercise' check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences., Discussion: The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services., Trial Registration: ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022., (© 2024. The Author(s).)

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials., Study Design: Retrospective observational study; review of patient records in fifteen Australian institutions., Setting, Participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme., Main Outcome Measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival., Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths., Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Frailty is common in older age and is characterised by loss of biological reserves across multiple organ systems. These changes associated with frailty mean older people can be vulnerable to sudden, dramatic changes in health because of relatively small problems. Older people with frailty are at increased risk of adverse outcomes including disability, hospitalisation, and care home admission, with associated reduction in quality of life and increased NHS and social care costs. Personalised Care Planning offers an anticipatory, preventative approach to supporting older adults to live independently for longer, but it has not been robustly evaluated in a population of older adults with frailty., Methods: Following an initial feasibility study, this multi-centre, individually randomised controlled trial aims to establish whether personalised care planning for older people improves health-related quality of life. It will recruit 1337 participants from general practices across Yorkshire and Humber and Mid-Mersey in the North of England. Eligible patients will be aged 65 and over with an electronic frailty index score of 0.21 or above, living in their own homes, without severe cognitive impairment and not in receipt of end-of-life care. Following confirmation of eligibility, informed consent and baseline data collection, participants will be individually randomised to the PeRsOnaliSed care Planning for oldER people with frailty (PROSPER) intervention or usual care in a 2.6:1 allocation ratio. Participants will not be blinded to allocation, but data collection and analysis will be blinded. The intervention will be delivered over 12 weeks by a Personal Independence Co-ordinator worker based within a voluntary sector organisation, Age UK. The primary outcomes are health-related quality of life, measured using both the physical and mental components of the Short-Form 12 Item Health Questionnaire at 12 months after randomisation. Secondary outcomes comprise activities of daily living, self-management capabilities and loneliness, admission to care homes, hospitalisations, and health and social care resource use at 12 months post randomisation. Parallel cost-effectiveness and process evaluations will be conducted alongside the trial., Discussion: The PROSPER study will evaluate the effectiveness and cost-effectiveness of a personalised care planning approach for older people with frailty and inform the process of its implementation., Trial Registration: ISRCTN16123291 .  Registered on  28 August 2020., (© 2023. The Author(s).)

Single-cell RNA sequencing (scRNA-seq) of BAL cells has provided insights into coronavirus disease (COVID-19). However, reports have been limited by small patient cohorts. We performed a meta-analysis of BAL scRNA-seq data from healthy control subjects ( n  = 13) and patients with COVID-19 ( n  = 20), sourced from six independent studies (167,280 high-quality cells in total). Consistent with the source reports, increases in infiltrating leukocyte subtypes were noted, several with type I IFN signatures and unique gene expression signatures associated with transcellular chemokine signaling. Noting dramatic reductions of inferred NKX2-1 and NR4A1 activity in alveolar epithelial type II (AT-II) cells, we modeled pseudotemporal AT-II-to-AT-I progression. This revealed changes in inferred AT-II cell metabolic activity, increased transitional cells, and a previously undescribed AT-I state. This cell state was conspicuously marked by the induction of genes of the epidermal differentiation complex, including the cornified envelope protein SPRR3 (small proline-rich protein 3), upregulation of multiple KRT (keratin) genes, inferred mitochondrial dysfunction, and cell death signatures including apoptosis and ferroptosis. Immunohistochemistry of lungs from patients with COVID-19 confirmed upregulation and colocalization of KRT13 and SPRR3 in the distal airspaces. Forced overexpression of SPRR3 in human alveolar epithelial cells ex vivo did not activate caspase-3 or upregulate KRT13, suggesting that SPRR3 marks an AT-I cornification program in COVID-19 but is not sufficient for phenotypic changes.

Gut-microbiome-derived metabolites, such as 4-Ethylphenol [4EP], have been shown to modulate neurological health and function. Although the source of such metabolites is becoming better understood, knowledge gaps remain as to the mechanisms by which they enter host circulation, how they are transported in the body, how they are metabolised and excreted, and the way they exert their effects. High blood concentrations of host-modified 4EP, 4-ethylphenol sulfate [4EPS], are associated with an anxiety phenotype in autistic individuals. We have reviewed the existing literature and discuss mechanisms that are proposed to contribute influx from the gut microbiome, metabolism, and excretion of 4EP. We note that increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of 4EP and/or 4EPS across the gut epithelium and the Blood Brain Barrier [BBB]. Similarly, kidney dysfunction, another complication observed in autistic individuals, impacts clearance of 4EP and its derivatives from circulation. Evidence indicates that accumulation of 4EPS in the brain of mice affects connectivity between subregions, particularly those linked to anxiety. However, we found no data on the presence or quantity of 4EP and/or 4EPS in human brains, irrespective of neurological status, likely due to challenges sampling this organ. We argue that the penetrative ability of 4EP is dependent on its form at the BBB and its physicochemical similarity to endogenous metabolites with dedicated active transport mechanisms across the BBB. We conclude that future research should focus on physical (e.g., ingestion of sorbents) or metabolic mechanisms (e.g., conversion to 4EP-glucuronide) that are capable of being used as interventions to reduce the flux of 4EP from the gut into the body, increase the efflux of 4EP and/or 4EPS from the brain, or increase excretion from the kidneys as a means of addressing the neurological impacts of 4EP., Competing Interests: The authors declare 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 © 2023 Day, O’Sullivan and Pook.)

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk-based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll-out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co-development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Ocular cancers represent a rare pathology. The American Cancer Society estimates that 3,360 cases of ocular cancer occur annually in the United States. The major types of cancers of the eye include ocular melanoma (also known as uveal melanoma), ocular lymphoma, retinoblastoma, and squamous cell carcinoma. While uveal melanoma is one of the primary intraocular cancers with the highest occurrence in adults, retinoblastoma remains the most common primary intraocular cancer in children, and squamous cell carcinoma presents as the most common conjunctival cancer. The pathophysiology of these diseases involves specific cell signaling pathways. Oncogene mutations, tumor suppressor mutations, chromosome deletions/translocations and altered proteins are all described as causal events in developing ocular cancer. Without proper identification and treatment of these cancers, vision loss, cancer spread, and even death can occur. The current treatments for these cancers involve enucleation, radiation, excision, laser treatment, cryotherapy, immunotherapy, and chemotherapy. These treatments present a significant burden to the patient that includes a possible loss of vision and a myriad of side effects. Therefore, alternatives to traditional therapy are urgently needed. Intercepting the signaling pathways for these cancers with the use of naturally occurring phytochemicals could be a way to relieve both cancer burden and perhaps even prevent cancer occurrence. This research aims to present a comprehensive review of the signaling pathways involved in various ocular cancers, discuss current therapeutic options, and examine the potential of bioactive phytocompounds in the prevention and targeted treatment of ocular neoplasms. The current limitations, challenges, pitfalls, and future research directions are also discussed., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Patients with cancer who continue to smoke tobacco experience greater treatment-related complications, higher risk of secondary cancers, and greater mortality. Despite research to improve smoking cessation care within clinical oncology, implementation of proposed interventions within routine care remains challenging., Objective: To identify and recommend implementation strategies for smoking cessation interventions associated with improved screening, advice-giving, and referral for tobacco users recently diagnosed with cancer, as well as shifting smoking behaviors and attitudes in this patient population., Evidence Review: MEDLINE, CINAHL, Embase, and PsycINFO databases, as well as Google Scholar, were searched for articles published before September 7, 2020, using terms related to cancer, smoking cessation, and implementation science. Outcomes of interest were study characteristics, implementation strategies, and outcome measures (screening, advice, referral, abstinence rates, and attitudes). The Cochrane Risk of Bias Tool for randomized and nonrandomized studies was used to assess bias. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and Synthesis Without Meta-analysis (SWiM) guideline. Implementation strategies were categorized according to Expert Recommendations for Implementing Change (ERIC) study taxonomy. A systematic analysis was conducted focusing on studies with low or moderate risk of bias due to high heterogeneity in outcome measurement., Findings: In total, 6047 records were screened, yielding 43 articles (10 randomized clinical trials and 33 nonrandomized studies). Four strategies were associated with improved screening, advice-giving, and referral: (1) supporting clinicians, (2) training implementation stakeholders (including clinicians), (3) changing the infrastructure, and (4) developing stakeholder interrelationships., Conclusions and Relevance: In this systematic review, supporting clinicians by providing cessation care through a trained tobacco specialist was identified as important for achieving short-term abstinence and changing attitudes among patients with cancer. Combined with a theoretical framework and stakeholder involvement, these strategies provide the basis for successful implementation of cessation support; this systematic review serves as an illustration of the methodological application and synthesis of implementation studies and other medical conditions more generally.

Mangosteen (Garcinia mangostana L.), also known as the "queen of fruits", is a tropical fruit of the Clusiacea family. While native to Southeast Asian countries, such as Thailand, Indonesia, Malaysia, Myanmar, Sri Lanka, India, and the Philippines, the fruit has gained popularity in the United States due to its health-promoting attributes. In traditional medicine, mangosteen has been used to treat a variety of illnesses, ranging from dysentery to wound healing. Mangosteen has been shown to exhibit numerous biological and pharmacological activities, such as antioxidant, anti-inflammatory, antibacterial, antifungal, antimalarial, antidiabetic, and anticancer properties. Disease-preventative and therapeutic properties of mangosteen have been ascribed to secondary metabolites called xanthones, present in several parts of the tree, including the pericarp, fruit rind, peel, stem bark, root bark, and leaf. Of the 68 mangosteen xanthones identified so far, the most widely-studied are α-mangostin and γ-mangostin. Emerging studies have found that mangosteen constituents and phytochemicals exert encouraging antineoplastic effects against a myriad of human malignancies. While there are a growing number of individual research papers on the anticancer properties of mangosteen, a complete and critical evaluation of published experimental findings has not been accomplished. Accordingly, the objective of this work is to present an in-depth analysis of the cancer preventive and anticancer potential of mangosteen constituents, with a special emphasis on the associated cellular and molecular mechanisms. Moreover, the bioavailability, pharmacokinetics, and safety of mangosteen-derived agents together with current challenges and future research avenues are also discussed., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations., Methods: PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m 2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy., Discussion: This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response., Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 October 2019., (© 2022. The Author(s).)

Few rigorous studies provide a clear description of the methodological approach of developing an evidence-based implementation intervention, prior to implementation at scale. This study describes the development, mapping, rating, and review of the implementation strategies for the Care to Quit smoking cessation trial, prior to application in nine cancer services across Australia. Key stakeholders were engaged in the process from conception through to rating, reviewing and refinement of strategies and principles. An initial scoping review identified 21 barriers to provision of evidence-based smoking cessation care to patients with cancer, which were mapped to the Theoretical Domains Framework and Behaviour Change Wheel (BCW) to identify relevant intervention functions. The mapping identified 26 relevant behaviour change techniques, summarised into 11 implementation strategies. The implementation strategies were rated and reviewed against the BCW Affordability, Practicality, Effectiveness and cost-effectiveness, Acceptability, Side-effects/safety, and Equity criteria by key stakeholders during two interactive workshops to facilitate a focus on feasible interventions likely to resonate with clinical staff. The implementation strategies and associated intervention tools were then collated by form and function to provide a practical guide for implementing the intervention. This study illustrates the rigorous use of theories and frameworks to arrive at a practical intervention guide, with potential to inform future replication and scalability of evidence-based implementation across a range of health service settings., Supplementary Information: The online version contains supplementary material available at 10.1007/s10742-022-00288-6., Competing Interests: Conflict of interestSV has received honoraria from Astra Zeneca for participation in educational events. FD have served on an advisory board for Amgen, and received clinical trial support from Bristol Myers Squibb and AstraZeneca. All other authors declare that they have no competing interests., (© The Author(s) 2022.)

Background: Many patients with incurable esophageal cancer (ECa) present with dysphagia as their predominant symptom. Currently there is no consensus on how best to initially manage this scenario with multiple therapeutic options available. We aimed to assess the safety and efficacy of using hypofractionated radiotherapy given over a progressively shorter timeframe with concurrent carboplatin and paclitaxel in the management of patients with ECa and dysphagia., Methods: In this phase I trial we enrolled patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction with symptomatic dysphagia from local disease and not for curative treatment. Patients needed to be 18 years or older, have an ECOG performance status of 0-2 and be suitable to receive carboplatin and paclitaxel chemotherapy. Patients were placed in four progressively shorter radiation schedules culminating in 30 Gy in 10 fractions in a step wise manner, all with concurrent carboplatin AUC 2 and paclitaxel 50 mg/m 2 chemotherapy delivered weekly with the radiation therapy. The primary endpoint was the development of the dose limiting toxicities (DLTs) esophageal perforation or febrile neutropenia. Secondary endpoints were relief of dysphagia, time to improvement of dysphagia, dysphagia progression free survival and overall survival., Results: Eighteen patients were enrolled in the study between October 2014 and March 2019. There were no DLTs experienced during the trial. The most common grade 3 + acute toxicity experienced by patients were nausea and vomiting (both in 4/18 patients). The most common radiation specific acute toxicity experienced was esophagitis with 67% of patients experiencing grade 1-2 symptoms. All patients experienced improvement in dysphagia. The median time to dysphagia improvement was 3 weeks from the start of chemoradiotherapy (CTRT) (range 2-10 weeks). The median dysphagia free survival was 5.8 months with a median overall survival of 8.9 months., Conclusion: Hypofractionated palliative CTRT with 30 Gy/10# of radiation therapy with concurrent weekly carboplatin and paclitaxel chemotherapy is well tolerated and provides a good response in improvement of dysphagia. Further studies need to be undertaken which provide both symptomatic improvement in the primary tumor but also control of the metastatic burden in these patients., Clinical Trial Registration: This trial was prospectively registered with www.anzctr.org.au Identifier: ACTRN12614000821695., (© 2022. The Author(s).)

Background/purpose: Being diagnosed with a progressive type of multiple sclerosis (MS) has been associated with worse psychological outcomes compared to relapsing-remitting type. Previous studies of adjustment to MS have primarily focused on relapsing-remitting type MS. The present study aims to examine psychological adjustment for people newly diagnosed with progressive multiple sclerosis., Methods: This was a multicenter cross-sectional survey of 189 people newly diagnosed with progressive MS. A composite measure of psychological adjustment was created from questionnaires measuring psychological distress, positive affect, perceived-stress, life satisfaction and self-concept. Predictor variables included coping strategies, social support, relationship with partner, psychological vulnerability, MS-related beliefs, and responses to symptoms. Data were analysed using a regularised regression model to indicate which group of all variables are associated with adjustment., Results: People who were older ( b  = 0.17(0.07), p  = 0.02), in employment ( b  = 0.40 (0.17), p  = 0.01), and with lower illness severity ( b  = -0.24 (0.08), p  = 0.001) showed better adjustment. Based on a Lasso regression, the most important psychological and demographic variables associated with lower adjustment (out-of-sample cross-validation R 2  = 62.6%) were lower MS self-efficacy and higher avoidance, cognitive vulnerability, embarrassment avoidance, conflict, helplessness, and secondary progressive MS type., Conclusions and Implications: Helping newly diagnosed people to find ways to tolerate anxiety-causing situations by encouraging acceptance may help people adjust to progressive MS by lowering their avoidance. Further, building confidence in managing the illness and addressing relationship issues are key focus areas in psychological interventions for people with progressive multiple sclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Bogosian, Day, Norton, Silber, Sakel, Sharrack and Moss-Morris.)

Background: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood., Methods: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use., Results: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not., Conclusions: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Emotional disorders (such as anxiety and depression) are associated with considerable distress and impairment in day-to-day function for affected children and young people and for their families. Effective evidence-based interventions are available but require appropriate identification of difficulties to enable timely access to services. Standardised diagnostic assessment (SDA) tools may aid in the detection of emotional disorders, but there is limited evidence on the utility of SDA tools in routine care and equipoise among professionals about their clinical value., Methods and Analysis: A multicentre, two-arm, parallel group randomised controlled trial, with embedded qualitative and health economic components. Participants will be randomised in a 1:1 ratio to either the Development and Well-Being Assessment SDA tool as an adjunct to usual clinical care, or usual care only. A total of 1210 participants (children and young people referred to outpatient, specialist Child and Adolescent Mental Health Services with emotional difficulties and their parent/carers) will be recruited from at least 6 sites in England. The primary outcome is a clinician-made diagnosis about the presence of an emotional disorder within 12 months of randomisation. Secondary outcomes include referral acceptance, diagnosis and treatment of emotional disorders, symptoms of emotional difficulties and comorbid disorders and associated functional impairment., Ethics and Dissemination: The study received favourable opinion from the South Birmingham Research Ethics Committee (Ref. 19/WM/0133). Results of this trial will be reported to the funder and published in full in the Health Technology Assessment (HTA) Journal series and also submitted for publication in a peer reviewed journal., Trial Registration Number: ISRCTN15748675; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The levels of psychological distress and burnout among healthcare staff are high, with negative implications for patient care. A growing body of evidence indicates that workplace programmes based on Acceptance and Commitment Therapy (ACT) are effective for improving employees' general psychological health. However, there is a paucity of research examining the specific psychological and/or behavioural processes through which workplace ACT programmes transmit their beneficial effects. The aim of this randomised controlled trial was to investigate the outcomes and putative processes of change in a 4-session ACT training programme designed to reduce psychological distress among healthcare staff (n = 98). Ninety-eight employees of a healthcare organisation were randomly allocated to the ACT intervention or to a waiting list control group. Study measures were administered on four occasions (baseline, mid-intervention, post-intervention, and follow-up) over a three-month evaluation period. Results showed that the ACT intervention led to a significant decrease in symptoms of psychological distress and a less pronounced reduction in burnout. These effects were mediated primarily via an improvement in mindfulness skills and values-based behaviour and moderated by participants' initial levels of distress. At four-week post-intervention, 48% of participants who received the ACT intervention showed reliable improvements in psychological distress, with just under half of the aforementioned improvements (46.15%) meeting criteria for clinically significant change. The results advance ACT as an effective stress management intervention for healthcare staff. The findings should be confirmed in a large scale randomised controlled trial with longer follow-up and cost-effectiveness analyses., Competing Interests: The commercial affiliation [Fiona Day Consulting LTD, Leeds, UK] does not alter our adherence to PLOS ONE policies on sharing data and materials.

The axion has emerged in recent years as a leading particle candidate to provide the mysterious dark matter in the cosmos, as we review here for a general scientific audience. We describe first the historical roots of the axion in the Standard Model of particle physics and the problem of charge-parity invariance of the strong nuclear force. We then discuss how the axion emerges as a dark matter candidate and how it is produced in the early universe. The symmetry properties of the axion dictate the form of its interactions with ordinary matter. Astrophysical considerations restrict the particle mass and interaction strengths to a limited range, which facilitates the planning of experiments to detect the axion. A companion review discusses the exciting prospect that the axion could be detected in the near term in the laboratory.

Background: A large proportion of the healthcare workforce reports significant distress and burnout, which can lead to poor patient care. Several psychological interventions, such as Acceptance and Commitment Therapy (ACT), have been applied to improve general distress and work-related distress in healthcare professionals (HCPs). However, the overall efficacy of ACT in this context is unknown. This review and meta-analysis aimed to: 1) test the pooled efficacy of ACT trials for improving general distress and reducing work-related distress in HCPs; 2) evaluate the overall study quality and risk of bias; and 3) investigate potential moderators of intervention effectiveness., Method: Four databases (Ovid MEDLINE, EMBASE, PsycINFO, CINHAL) were searched, with 22 pre-post design and randomised controlled trial (RCTs) studies meeting the inclusion criteria. 10 RCTs studies were included in the meta-analysis., Results: Two random effects meta-analyses on general distress and work-related distress found that ACT outperformed pooled control conditions with a small effect size for general distress at post-intervention (g = 0.394, CIs [.040; .748]) and for work-related distress (g = 0.301, CIs [.122; .480]) at follow-up. However, ACT was more effective than controls. The number of treatment sessions was a moderator of intervention efficacy for general distress. ACT process measures (psychological flexibility) did not show significantly greater improvements in those who received the intervention., Limitations: The methodological quality of studies was poor and needs to be improved., Conclusions: Overall, ACT interventions are effective in improving general distress and work-related distress in HCPs. These findings have implications for policymakers, healthcare organisations and clinicians., (Copyright © 2021 Elsevier B.V. All rights reserved.)