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Background: Within the current medical workforce, diversity is limited among surgical specialties. However, diversity allows physicians to provide culturally competent care. This paper discusses the trends in racial, ethnic, and gender representation within different surgical subspecialties with an emphasis on neurosurgery over a 20-year time frame., Methods: A retrospective review of data collected by the Accreditation Council for Graduate Medical Education over the past twenty years, as reported in Journal of the American Medical Association, was conducted. Residents from 5 surgical specialties were evaluated based on gender, race, and ethnic identifications from 2002 to 2022. One-way analysis of variance was performed to compare the levels and retention rates of racial, ethnic, and gender diversity within these specialties., Results: Analysis of resident demographics of the 5 surgical specialties reveals an overall trend of increasing diversity over the study period. Over the past 20 years, neurosurgery had an overall increase in Asian (+5.1%), Hispanic (+3.0%), and female (+11.4%) residents, with a decrease in White residents by 2.1% and Black residents by 1.1%. Among the surgical specialties analyzed, otolaryngology had the greatest overall increase in minority residents. Notably, there has been an overall increase in female residents across all 5 surgical specialties, with the highest in otolaryngology (+20.3%) which was significantly more than neurosurgery (P < 0.001)., Conclusions: This chronological analysis spanning 20 years demonstrates that neurosurgery, like other specialties, has seen a growth in several racial and ethnic categories. Relative differences are notable in neurosurgery, including Black, Asian, Hispanic, and White ethnic categories, with growth in females, but at a significantly lesser pace than seen in otolaryngology and plastic surgery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chemotherapy-induced nausea and vomiting (CINV) is a common toxicity that may impair the quality of life of patients with various malignancies ranging from early to end stages. In light of frequent changes to the guidelines for optimal management of CINV, we undertook this narrative review to compare the most recent guidelines published by ASCO (2020), NCCN (2023), MASCC/ESMO (2023), and CCO (2019). The processes undertaken by each organization to evaluate existing literature were also described. Although ASCO, NCCN, MASCC/ESMO, and CCO guidelines for the treatment and prevention of CINV share many fundamental similarities, the literature surrounding low and minimal emetic risk regimens is lacking. Current data regarding adherence to these guidelines is poor and warrants further investigation to improve care., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Health-related quality of life (HRQoL) measures are predictors of adverse health outcomes in older adults. Studies have demonstrated cross-sectional associations between HRQoL measures and blood-based biochemical markers. Acylcarnitines (ACs) are a class of metabolites generated in the mitochondria and are predictive of multiple geriatric syndromes. Changes in ACs reflect alterations in central carbon metabolic pathways. However, the prospective relationship between plasma ACs and declining HRQoL has not been examined. This study aimed to investigate both cross-sectional and longitudinal associations of baseline ACs with baseline and declining EuroQol-5 Dimension/EuroQol Visual Analogue Scale (EQ-5D/EQ-VAS) in community-dwelling older adults., Methods: One hundred and twenty community-dwelling older adults with EQ-5D/EQ-VAS measurements at baseline and follow-up were included. We quantified ACs at baseline using targeted plasma metabolomics profiling. Multivariate regressions were performed to examine cross-sectional and longitudinal associations between the measures., Results: Cross-sectionally, ACs showed no significant associations with either EQ-5D index or EQ-VAS scores. Longitudinally, multiple baseline short-chain ACs were significantly and inversely associated with declining EQ-5D index score, explaining up to 8.5% of variance in the decline., Conclusions: Within a cohort of community-dwelling older adults who had high HRQoL at baseline, we showed that higher levels of short-chain ACs are longitudinally associated with declining HRQoL. These findings reveal a novel association between central carbon metabolic pathways and declining HRQoL. Notably, dysregulation in mitochondrial central carbon metabolism could be detected prior to clinically important decline in HRQoL, providing the first evidence of objective biomarkers as novel predictors to monitor HRQoL in nonpharmacological interventions and epidemiology., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Consolidated Standards of Reporting Trials extension for Artificial Intelligence interventions (CONSORT-AI) was published in September 2020. Since its publication, several randomised controlled trials (RCTs) of AI interventions have been published but their completeness and transparency of reporting is unknown. This systematic review assesses the completeness of reporting of AI RCTs following publication of CONSORT-AI and provides a comprehensive summary of RCTs published in recent years. 65 RCTs were identified, mostly conducted in China (37%) and USA (18%). Median concordance with CONSORT-AI reporting was 90% (IQR 77-94%), although only 10 RCTs explicitly reported its use. Several items were consistently under-reported, including algorithm version, accessibility of the AI intervention or code, and references to a study protocol. Only 3 of 52 included journals explicitly endorsed or mandated CONSORT-AI. Despite a generally high concordance amongst recent AI RCTs, some AI-specific considerations remain systematically poorly reported. Further encouragement of CONSORT-AI adoption by journals and funders may enable more complete adoption of the full CONSORT-AI guidelines., (© 2024. The Author(s).)

Competing Interests: Conflicts of interest P.L. has received grants from the Lady Davis Institute for Medical Research, from the Jewish General Hospital Foundation and from the Jewish General Hospital Department of Medicine for this work. R.M. is the executive director of the Canadian Skin Patient Alliance, and receives funding from governments, individuals and corporations, including pharmaceutical companies. A full list of sponsors can be viewed here: https://www.canadianskin.ca/about-us/sponsors. A.P. is an inventor on two patents covering the use of peptidic transforming growth factor-β antagonists as antifibrotic agents.

Background: Developing strategies to prevent breast cancer-related arm lymphoedema (BCRAL) is a critical unmet need because there are no effective interventions to eradicate it once it reaches a chronic state. Certain strategies such as prospective surveillance programs and prophylactic lymphatic reconstruction have been reported to be effective in clinical trials. However, a large variation exists in practice based on clinician preference, organizational standards, and local resources., Methods: A two-round international Delphi consensus process was performed from February 27, 2023 to May 25, 2023 to compile opinions of 55 experts involved in the care and research of breast cancer and lymphoedema on such interventions., Findings: Axillary lymph node dissection, use of post-operative radiotherapy, relative within-arm volume increase one month after surgery, greater number of lymph nodes dissected, and high body mass index were recommended as the most important risk factors to guide selection of patients for interventions to prevent BCRAL. The panel recommended that prospective surveillance programs should be implemented to screen for and reduce risks of BCRAL where feasible and resources allow. Prophylactic compression sleeves, axillary reverse mapping and prophylactic lymphatic reconstruction should be offered for patients who are at risk for developing BCRAL as options where expertise is available and resources allow. Recommendations on axillary management in clinical T1-2, node negative breast cancer patients with 1-2 positive sentinel lymph nodes were also provided by the expert panel. Routine axillary lymph node dissection should not be offered in these patients who receive breast conservation therapy. Axillary radiation instead of axillary lymph node dissection should be considered in the same group of patients undergoing mastectomy., Interpretation: An individualised approach based on patients' preferences, risk factors for BCRAL, availability of treatment options and expertise of the healthcare team is paramount to ensure patients at risk receive preventive interventions for BCRAL, regardless of where they are receiving care., Funding: This study was not supported by any funding. RJC received investigator grant support from the Australian National Health and Medical Research Council (APP1194051)., Competing Interests: Elizabeth Dylke received support to attend Australasian Lymphology Association Symposium 2022 and 2023, and is the President and Director of Australasian Lymphology Association and Secretary of the Council of the Deans of Physiotherapy Australia and New Zealand; Yuichiro Kikawa received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or education events from Eisai, Lilly, Chugai, Pfizer, Daiichi Sankyo and Novartis; Michael Lock received consulting fees from Bayer and Tersera, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or education events from Knight Therapeutics, Abbvie and Eisai, and have stock options from Myovant; Icro Meattini received honoraria for lectures from Eli Lily, AstraZeneca, SeaGen, Gilead, Daiichi, Sankyo, Pfizer and Novartis; Tammy Mondry received consulting fees from Teladoc Health, and payment for honoraria from Klose Training; Abram Recht received grants or contracts from the Joint Centre for Radiation Therapy Foundation paid to his institution, received consulting fees from eviCore healthcare and EXACT Sciences Corporation, and has stock ownership of Imagine Scientific, Inc.; Jolien Robijns received grants or contracts from Kom op Tegen Kanker and Limburgs Kankerfonds paid to Hasselt University. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd.)

Background: There is a well-documented risk of secondary cutaneous malignancies following allogeneic hematopoietic stem cell transplant (HSCT), but data on risk in pediatric populations are limited. The objective of this study is to perform a systematic review of reported features and outcomes of skin cancers in pediatric allogeneic HSCT recipients., Methods: MEDLINE, EMBASE, CINAHL, Cochrane, and Web of Science were systematically searched (Prospero CRD42022342139). Studies reporting cutaneous cancer outcomes were included if the age at transplant was ≤19 years. Titles, abstracts, and full-text articles were screened in duplicate., Results: Out of 824 citations that were screened, 12 articles were selected for analysis. The final sample included 67 pediatric HSCT recipients, comprising 65 allogeneic transplant recipients and 2 cases of HSCT with an unknown donor type. The median age at transplant and skin cancer diagnosis were 7.4 and 13 years, respectively. Out of the 67 pediatric HSCT recipients, some patients developed more than one lesion, resulting in 71 lesions. The most common skin cancer type was cutaneous squamous cell carcinoma (32 lesions), followed by basal cell carcinoma (25 lesions). The median latency period between HSCT and skin cancer diagnosis ranged from 0 to 29 years. Identified risk factors for skin cancers included younger age at the time of transplant, exposure to total body irradiation, prolonged post-transplant immunosuppression, graft versus host disease, and sunburn., Conclusion: Skin cancers are reported in pediatric allogeneic HSCT recipients, and the risk appears to be increased. More data are needed to better characterize this risk., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Despite the critical importance of clinical trials to provide evidence about the effects of intervention for children and youth, a paucity of published high-quality pediatric clinical trials persists. Sub-optimal reporting of key trial elements necessary to critically appraise and synthesize findings is prevalent. To harmonize and provide guidance for reporting in pediatric controlled clinical trial protocols and reports, reporting guideline extensions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines specific to pediatrics are being developed: SPIRIT-Children (SPIRIT-C) and CONSORT-Children (CONSORT-C)., Methods: The development of SPIRIT-C/CONSORT-C will be informed by the Enhancing the Quality and Transparency of Health Research Quality (EQUATOR) method for reporting guideline development in the following stages: (1) generation of a preliminary list of candidate items, informed by (a) items developed during initial development efforts and child relevant items from recent published SPIRIT and CONSORT extensions; (b) two systematic reviews and environmental scan of the literature; (c) workshops with young people; (2) an international Delphi study, where a wide range of panelists will vote on the inclusion or exclusion of candidate items on a nine-point Likert scale; (3) a consensus meeting to discuss items that have not reached consensus in the Delphi study and to "lock" the checklist items; (4) pilot testing of items and definitions to ensure that they are understandable, useful, and applicable; and (5) a final project meeting to discuss each item in the context of pilot test results. Key partners, including young people (ages 12-24 years) and family caregivers (e.g., parents) with lived experiences with pediatric clinical trials, and individuals with expertise and involvement in pediatric trials will be involved throughout the project. SPIRIT-C/CONSORT-C will be disseminated through publications, academic conferences, and endorsement by pediatric journals and relevant research networks and organizations., Discussion: SPIRIT/CONSORT-C may serve as resources to facilitate comprehensive reporting needed to understand pediatric clinical trial protocols and reports, which may improve transparency within pediatric clinical trials and reduce research waste., Trial Registration: The development of these reporting guidelines is registered with the EQUATOR Network: SPIRIT-Children ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials-protocols/#35 ) and CONSORT-Children ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#CHILD )., (© 2024. The Author(s).)

Competing Interests: Conflicts of interest I.S. has received honoraria from Sanofi-Genzyme. R.M. is the executive director of the Canadian Skin Patient Alliance, which receives funding from governments, individuals and corporations, including pharmaceutical companies. A full list of sponsors can be viewed here: https://www.canadianskin.ca/about-us/sponsors. A.P. is an inventor on two patents covering the use of peptidic transforming growth factor-β antagonists as antifibrotic agents.

Competing Interests: Conflicts of interest R.M. is the executive director of the Canadian Skin Patient Alliance receiving funding from governments, individuals and corporations, including ­pharmaceutical ­companies. A full list of sponsors can be viewed here https://www.canadianskin.ca/about-us/sponsors. C.N. has received honoraria for advisory boards and talks by Merck, EMD Sorono, Novartis and Sanofi. A.B. is a coinventor on a patent covering the use of neddylation activating enzyme inhibitors as enhancers of RNA viruses. A.P. is an inventor on two patents covering the use of peptidic transforming growth factor-β antagonists as antifibrotic agents.

Introduction: Bones are frequent sites of metastatic disease, observed in 30-75% of advanced cancer patients. Quality of life (QoL) is an important endpoint in studies evaluating the treatments of bone metastases (BM), and many patient-reported outcome tools are available. The primary objective of this systematic review was to compile a list of QoL issues relevant to BM and its interventions. The secondary objective was to identify common tools used to assess QoL in patients with BM, and the QoL issues they fail to address., Methods: A search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and 27 January 2023 with the keywords "bone metastases", "quality of life", and "patient reported outcomes". Specific QoL issues in original research studies and the QoL tools used were extracted., Results: The review identified the QoL issues most prevalent to BM in the literature. Physical and functional issues observed in patients included pain, interference with ambulation and daily activities, and fatigue. Psychological symptoms, such as helplessness, depression, and anxiety were also common. These issues interfered with patients' relationships and social activities. Items not mentioned in existing QoL tools were related to newer treatments of BM, such as pain flare, flu-like symptoms, and jaw pain due to osteonecrosis., Conclusions: This systematic review highlights that QoL issues for patients with BM have expanded over time due to advances in BM-directed treatments. If they are relevant, additional treatment-related QoL issues identified need to be validated prospectively by patients and added to current assessment tools., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal., Objective: To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials., Design: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist., Findings: This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported., Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.

Importance: Trial protocols outline a trial's objectives as well as the methods (design, conduct, and analysis) that will be used to meet those objectives, and transparent reporting of trial protocols ensures objectives are clear and facilitates appraisal regarding the suitability of study methods. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, no extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement, which provides guidance on reporting of trial protocols, for factorial trials is available., Objective: To develop a consensus-based extension to the SPIRIT 2013 Statement for factorial trials., Evidence Review: The SPIRIT extension for factorial trials was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework. First, a list of reporting recommendations was generated using a scoping review of methodological articles identified using a MEDLINE search (inception to May 2019), which was supplemented with relevant articles from the personal collections of the authors. Second, a 3-round Delphi survey (January to June 2022, completed by 104 panelists from 14 countries) was conducted to assess the importance of items and identify additional recommendations. Third, a hybrid consensus meeting was held, attended by 15 panelists to finalize selection and wording of the checklist., Findings: This SPIRIT extension for factorial trials modified 9 of the 33 items in the SPIRIT 2013 checklist. Key reporting recommendations were that the rationale for using a factorial design should be provided, including whether an interaction is hypothesized; the treatment groups that will form the main comparisons should be identified; and statistical methods for each main comparison should be provided, including how interactions will be assessed., Conclusions and Relevance: In this consensus statement, 9 factorial-specific items were provided that should be addressed in all protocols of factorial trials to increase the trial's utility and transparency.

Introduction: Malignant spinal cord compression (MSCC) is an oncological emergency that may result in a devastating combination of malignancy and disability. Existing quality of life (QoL) questionnaires commonly used in MSCC literature (EORTC QLQ-C30, BM-22, Brief Pain Inventory, and Spine Oncology Study Group Outcomes) may not capture all the commonly reported symptoms and lack specificity to MSCC. The primary objective of this systematic review is to determine unmet patient needs and underreported QoL issues and compile a comprehensive list of QoL issues. The secondary objective of this review is to compile all existing QoL tools and questionnaires and determine whether any QoL issues are not addressed in the existing tools currently used in the literature., Methods: A literature search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and February 6, 2023, to compile all QoL issues and existing questionnaires used to assess QoL in patients with MSCC. All study designs were included given that they discussed QoL issues specific to patients with MSCC., Results: The results of this systematic review identified the most frequently discussed QoL issues in the literature studying MSCC. This included direct symptoms of MSCC such as back pain, paralysis, limb weakness/numbness, and urinary/bowel incontinence. Indirect symptoms coming from radiotherapy treatment such as dysphagia, painful swallowing, mouth pain, dry mouth, diarrhea, fatigue, and nausea/vomiting were also noted. Other symptoms resulting from corticosteroid treatment included difficulty sleeping, blurring of vision, weight gain, and mood disturbance. Patients also experienced psychosocial issues such as anxiety, depression, emotional distress, low self-esteem, concerns about dependence on others, concerns about getting home, and fear about their prognosis and future., Conclusion: This review highlights the QoL issues specific to patients with MSCC and QoL tools capturing these issues. Relevance of QoL issues identified in this systematic review must be prospectively validated by patients and healthcare professionals with experience in treating MSCC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: This study aimed to compare SBRT and cEBRT for treating spinal metastases through a systematic review and meta-analysis of randomized controlled trials (RCTs)., Methods: PubMed, EMBASE and Cochrane Library were searched up to 6 May 2023 for RCTs comparing SBRT and cEBRT for spinal metastases. Overall and complete pain response, local progression, overall survival, quality of life and adverse events were extracted. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) for dichotomous outcomes, and hazard ratios (HRs) for time-to-event outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I 2 statistic., Results: Three RCTs were identified involving 642 patients. No differences were seen in overall pain response comparing SBRT and cEBRT (RR at 3 months: 1.12, 95% CI, 0.74-1.70, p = 0.59; RR at 6 months: 1.29, 95% CI, 0.97-1.72, p = 0.08). Only two of three studies presented complete pain response data. SBRT demonstrated a statistically significant improvement in complete pain response compared to cEBRT (RR at 3 months: 2.52; 95% CI, 1.58-4.01; P < 0.0001; RR at 6 months: 2.48; 95% CI, 1.23-4.99; P = 0.01). There were no significant differences in local progression and overall survival. Adverse events were similar, except for any grade radiation dermatitis, which was significantly lower in SBRT arm (RR 0.17, 95% CI 0.03-0.96, P = 0.04)., Conclusion: SBRT is a safe treatment option for spine metastases. It may provide better complete pain response compared to cEBRT. Additional trials are needed to determine the potential benefits of SBRT in specific patient subsets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Apicomplexan parasites use Ca 2+ -regulated exocytosis to secrete essential virulence factors from specialized organelles called micronemes. Ca 2+ -dependent protein kinases (CDPKs) are required for microneme exocytosis; however, the molecular events that regulate trafficking and fusion of micronemes with the plasma membrane remain unresolved. Here, we combine sub-minute resolution phosphoproteomics and bio-orthogonal labeling of kinase substrates in Toxoplasma gondii to identify 163 proteins phosphorylated in a CDPK1-dependent manner. In addition to known regulators of secretion, we identify uncharacterized targets with predicted functions across signaling, gene expression, trafficking, metabolism, and ion homeostasis. One of the CDPK1 targets is a putative HOOK activating adaptor. In other eukaryotes, HOOK homologs form the FHF complex with FTS and FHIP to activate dynein-mediated trafficking of endosomes along microtubules. We show the FHF complex is partially conserved in T. gondii , consisting of HOOK, an FTS homolog, and two parasite-specific proteins (TGGT1&#95;306920 and TGGT1&#95;316650). CDPK1 kinase activity and HOOK are required for the rapid apical trafficking of micronemes as parasites initiate motility. Moreover, parasites lacking HOOK or FTS display impaired microneme protein secretion, leading to a block in the invasion of host cells. Taken together, our work provides a comprehensive catalog of CDPK1 targets and reveals how vesicular trafficking has been tuned to support a parasitic lifestyle., Competing Interests: AC, MB, EY, NH, SC, EA, AH, ES, MT No competing interests declared, SL Reviewing editor, eLife, (© 2023, Chan et al.)

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

Background and Objective: Leptomeningeal disease (LMD) is associated with poor survival and health-related quality of life (HRQoL). There is an urgent need for clinical research in this area to improve the outcomes. The purpose of this study is to summarize the areas of active clinical research in LMD, identify the knowledge gap, and suggest future research directions., Methods: A narrative review of clinical trials in LMD was conducted based on a search in clinicatrials.gov using the search term "leptomeningeal" under "condition or disease". Clinical trials in patients with LMD arising from solid malignancy that were labelled as "not yet recruiting", "recruiting", "enrolling by invitation" or "active, not recruiting" were included. Studies which were deemed to have significant impact on future research direction in LMD were selected for discussion., Key Content and Findings: A total of 38 clinical trials were included. Of these 38 trials, 19 are discussed in this review, with focus on their research questions and impact on future research directions. Most of the studies that were not selected for discussion focused on biomarker-driven interventions. Four key areas of research were identified, namely the (I) diagnosis, response assessment or molecular profiling of LMD (n=2); (II) advances in radiotherapy (n=3); (III) intrathecal treatment (n=13); (IV) novel drug carrier for systemic treatment (n=1). The research questions in the 19 discussed clinical trials included the tumour microenvironment of LMD, the role of novel molecular techniques in LMD, combination of radiotherapy with drugs, and cell-based immunotherapy. Among these 19 studies, 11 were phase 1 trials, 3 were phase 2 or phase 1/2 trials, 2 were phase 3 or phase 2/3 trials and the study phase was not reported in the remaining 3 studies. The existing knowledge gaps are discussed, including the lack of primary site-specific prognostic tools, cost-effectiveness studies, dedicated HRQoL assessment tools for LMD and sequencing of treatment., Conclusions: The current clinical trials in LMD offer the promise to improve the diagnosis and treatment outcomes of patients with LMD. More research is needed to overcome the potential hurdles in the current treatment and bridge the knowledge gaps as identified in this review, to improve patients' quantity and quality of survival.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the MRC-NIHR Methodology Research Programme for the submitted work. JdB has served on advisory boards and received fees from companies including Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Daiichi, Genentech/Roche, GlaxoSmithKline (GSK), Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp and Dohme, Pfizer, and Sanofi Aventis; is an employee of the ICR, which has received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex (the ICR has a commercial interest in abiraterone and poly (ADP-ribose) polymerase (PARP) inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); was named as an inventor, with no financial interest for patent 8 822 438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been chief investigator/principal investigator of many industry sponsored clinical trials; and is an NIHR senior investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. AM is employed by GSK. TRJE has received honorariums for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen and honorariums for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Eisai, Nucana, Otsuka, MSD, Roche, Medivir, Seagen, and United Medical; has received support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, GSK, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immunocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, UCB, Sapience, Seagen, Avacta, and Codiak; has received funding from Cancer Research UK, Chief Scientist’s Office Scotland, and the MRC; and is also the editor-in-chief of the British Journal of Cancer and has an honorary clinical contract with the NHS Greater Glasgow and Clyde Health Board. RP is an employee and a stockholder in F Hoffmann la Roche, and a family member is also an employee and a stockholder of F Hoffmann la Roche. KSH declares grant funding (payable to the employing institution) received by the Medical Research Future Fund (grant 2007425), National Health and Medical Research Council of Australia (grants 2016420 and 2015705), and Heart Foundation of Australia (grant 106607). SH and A-WC are members of the SPIRIT-CONSORT executive group and leading the current update of the SPIRIT 2013 and CONSORT 2010 reporting guidelines, funded by the UK MRC NIHR Better Methods, Better Research (MR/W020483/1). MU acted as consultant for eXYSTAT, Saryga, PTC Therapeutics International, ImCheck Therapeutics. MC is director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, director of the Centre for Patient Reported Outcomes Research, and is an NIHR senior investigator. MJC receives funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR, Applied Research Collaboration West Midlands, UK SPINE, Research England, European Regional Development Fund DEMAND Hub at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and the NIHR Birmingham-Oxford Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics; funding from Health Data Research UK, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, Gilead Sciences, European Commission, European Federation of Pharmaceutical Industries and Associations, and the Brain Tumour Charity; personal fees from Aparito, CIS Oncology, Takeda Pharmaceuticals, Merck, Daiichi Sankyo, Glaukos, GSK, the Patient-Centered Outcomes Research Institute, Genentech, and Vertex Pharmaceuticals outside the submitted work; and lecture fees from the University of Maastricht, Maastricht, Netherlands; in addition, a family member owns shares in GSK. DPR is the volunteer vice president of the Canadian Arthritis Patient Alliance, a patient led and run organisation that derives most of its funding from independent grants from pharmaceutical companies. OB is an employee of Bayer AG. JM is an employee of Cytel (Australia). LS declares grant funding from AstraZeneca, Bayer, Pfizer, Merck, Roche, REPARE, Treadwell, and Janssen; has provided expert testimony for CADTH Health Canada; and also declares ownership of AstraZeneca stock/options. LM received speaker fees from Bayer; co-organiser, chair, and speaker fees at two educational preceptorships (online webinars); advisory board/consultancy honorariums from Tesaro, BMS, and Illumina; and is a member of external data monitoring committees for early phase clinical trials run between Eisai and Merck. RL is an employee and stockholder of Bristol Myers Squibb. JB declares consultancy fees from Mirati, Insmed, Oxford Biotherapeutics, Biosapien, EMD Serono, Ipsen, Merck Sharp and Dohme, Perus, BMS, and Bexion; grant funding from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Transcenta Therapeutics, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, Parthenon, and Hibercell; JB also sits on data safety monitoring committees for Astra Zeneca, Novocure, and Boehringer-Ingelheim. All other authors declare no conflicts of interest.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work. JdB has served on advisory boards and received fees from companies including Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Daiichi, Genentech/Roche, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp and Dohme, Pfizer, and Sanofi Aventis; is an employee of the Institute of Cancer Research (ICR), which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme (MSD), Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex (the ICR has a commercial interest in abiraterone and poly (ADP-ribose) polymerase (PARP) inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income)); was named as an inventor, with no financial interest, for patent 8 822 438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been the chief investigator/principal investigator of many industry sponsored clinical trials; and is a National Institute for Health Research (NIHR) senior investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. AM is employed by GSK. TRJE has received honorariums for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen; honorariums for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Eisai, Nucana, Otsuka, Medivir, MSD, Roche, Seagen, and United Medical; support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, Glaxo Smith Kline, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immnuocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, Union Chimique Belge, Sapience, Seagen, Avacta, and Codiak; and funding from Cancer Research UK, Chief Scientist’s Office Scotland, and Medical Research Council UK; is the editor-in-chief of the British Journal of Cancer and has an honorary clinical contract with the NHS Greater Glasgow and Clyde Health Board. RP is an employee and a stockholder in F Hoffmann la Roche, and a family member is also an employee and a stockholder of F Hoffmann la Roche. KSH declares grant funding (payable to the employing institution) received by the Medical Research Future Fund (grant 2007425), National Health and Medical Research Council of Australia (grants 2016420 and 2015705), and Heart Foundation of Australia (grant 106607). SH and A-WC are members of the SPIRIT-CONSORT executive group and are leading the current update of the SPIRIT 2013 and CONSORT 2010 reporting guidelines, funded by the UK Medical Research Council NIHR Better Methods, Better Research (MR/W020483/1). MU acted as consultant for eXYSTAT, Saryga, PTC Therapeutics International, and ImCheck Therapeutics. MC is director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, director of the Centre for Patient Reported Outcomes Research, and is a NIHR senior investigator. MJC has received funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR, Applied Research Collaboration West Midlands, UK SPINE, Research England, European Regional Development Fund DEMAND Hub at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and NIHR Birmingham-Oxford Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics; funding from Health Data Research UK, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, Gilead Sciences, European Commission, European Federation of Pharmaceutical Industries and Associations, and the Brain Tumour Charity; and personal fees from Aparito, CIS Oncology, Takeda Pharmaceuticals, Merck, Daiichi Sankyo, Glaukos, GSK, the Patient-Centered Outcomes Research Institute, Genentech, and Vertex Pharmaceuticals outside the submitted work; has received lecture fees from the University of Maastricht, Maastricht, Netherlands; a family member owns shares in GSK. DPR is the volunteer vice president of the Canadian Arthritis Patient Alliance, a patient led and run organisation that derives most funding from independent grants from pharmaceutical companies. OB is an employee of Bayer AG. JM is an employee of Cytel (Australia). LS declares grant funding from AstraZeneca, Bayer, Pfizer, Merck, Roche, REPARE, Treadwell, and Janssen; has provided expert testimony for CADTH Health Canada; and declares AstraZeneca stock/options ownership. LM received honorariums for speaker fees from Bayer and as co-organiser, chair, and speaker at two educational preceptorships (online webinars); and advisory board/consultancy honorariums from Tesaro, BMS, and Illumina; is also a member of external data monitoring committees for early phase clinical trials run between Eisai and Merck. RL is an employee and stockholder of Bristol Myers Squibb. JB declares consultancy fees from Mirati, Insmed, Oxford BioTherapeutics, Biosapien, EMD Serono, Ipsen, Merck Sharp and Dohme, Perus, BMS, and Bexion; declares grant funding from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Transcenta Therapeutics, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, Parthenon, and Hibercell; and sits on data safety monitoring committees for Astra Zeneca, Novocure, and Boehringer-Ingelheim. All other authors declare no conflict of interest.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials., Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials., Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators., Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence., Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded., Competing Interests: Sylwia Bujkiewicz is a member of the NICE Decision Support Unit (DSU) and NICE Guidelines Technical Support Unit (TSU), has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA and RTI Health Solutions, received payments for educational events from NICE and Roche and has received research funding from European Federation of Pharmaceutical Industries & Associations (EEPIA) and Johnson & Johnson. Mario Ouwens works for and has shares in AstraZeneca. Joseph Ross is an Associate Editor at BMJ and co-founder (unpaid) of medRxiv; research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Nancy Butcher has received consulting fees from Nobias Therapeutics, Inc. Alain Amstutz and Yousef Rezaei are Associate Editors at BMC Trials. Robin Christensen is a founding member of the OMERACT Technical Advisory Group which might be perceived as a possible conflict of interest. Ray Harris has shares in Johnson and Johnson. John Powers has been a consultant for Adaptive Phage, Arrevus, Atheln, Bavaria Nordic, Cellularity, Eicos, Evofem, Eyecheck, Gilead, GSK, Mustang, OPKO, Otsuka, Resolve, Romark, SpineBioPPharma, UTIlity, Vir. Achilles Thoma received royalties from Springer Publishing for his book “Evidence Based Surgery: A Guide to Understanding and Interpreting the Surgical Literature”, 2019., (© 2023 The Author(s).)

Background: Falls in older adults are the result of a complex web of interacting causes, that further results in other physical, emotional, and psychological sequelae. A conceptual framework that represents the reciprocal dynamics of these causal factors can enable clinicians, researchers, and policymakers to clarify goals in falls intervention in older adults., Methods: A Group Model Building (GMB) exercise was conducted with researchers and clinicians from academic units and public healthcare institutes in Singapore. The aim of the exercise was to produce a shared visual representation of the causal structure for falls and engage in discussions on how current and future falls intervention programmes can address falls in the older adults, especially in the Asian context. It was conducted in four steps: 1) Outlining and prioritising desirable patient outcomes, 2) Conceptual model building, 3) Identifying key intervention elements of effective falls intervention programmes, 4) Mapping of interventions to outcomes. This causal loop diagram (CLD) was then used to generate insights into the current understanding of falls causal relationships, current efforts in falls intervention in Singapore, and used to identify gaps in falls research that could be further advanced in future intervention studies., Results: Four patient outcomes were identified by the group as key in falls intervention: 1) Falls, 2) Injurious falls, 3) Fear of falling, and 4) Restricted mobility and life space. A CLD of the reciprocal relationships between risk factors and these outcomes are represented in four sub-models: 1) Fear of falling, 2) Injuries associated with falls, 3) Caregiver overprotectiveness, 4) Post-traumatic stress disorder and psychological resilience. Through this GMB exercise, the group gained the following insights: (1) Psychological sequelae of falls is an important falls intervention outcome. (2) The effects of family overprotectiveness, psychological resilience, and PTSD in exacerbating the consequences of falls are not well understood. (3) There is a need to develop multi-component falls interventions to address the multitude of falls and falls related sequelae., Conclusion: This work illustrates the potential of GMB to promote shared understanding of complex healthcare problems and to provide a roadmap for the development of more effective preventive actions., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Aims: Major genomic drivers of hepatocellular carcinoma (HCC) are nowadays well recognized, although models to establish their roles in human HCC initiation remain scarce. Here, we used human liver organoids in experimental systems to mimic the early stages of human liver carcinogenesis from the genetic lesions of TP53 loss and L3 loop R249S mutation. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) of HCC cell lines shed important functional insights into the initiation of HCC consequential to the loss of tumor-suppressive function from TP53 deficiency and gain-of-function activities from mutant p53., Approach and Results: Human liver organoids were generated from surgical nontumor liver tissues. CRISPR knockout of TP53 in liver organoids consistently demonstrated tumor-like morphological changes, increased in stemness and unrestricted in vitro propagation. To recapitulate TP53 status in human HCC, we overexpressed mutant R249S in TP53 knockout organoids. A spontaneous increase in tumorigenic potentials and bona fide HCC histology in xenotransplantations were observed. ChIP-seq analysis of HCC cell lines underscored gain-of-function properties from L3 loop p53 mutants in chromatin remodeling and overcoming extrinsic stress. More importantly, direct transcriptional activation of PSMF1 by mutant R249S could increase organoid resistance to endoplasmic reticulum stress, which was readily abrogated by PSMF1 knockdown in rescue experiments. In a patient cohort of primary HCC tumors and genome-edited liver organoids, quantitative polymerase chain reaction corroborated ChIP-seq findings and verified preferential genes modulated by L3 mutants, especially those enriched by R249S., Conclusions: We showed differential tumorigenic effects from TP53 loss and L3 mutations, which together confer normal hepatocytes with early clonal advantages and prosurvival functions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: This systematic review and meta-analysis evaluates the efficacy of Mepitel Film in preventing acute radiation dermatitis (RD) in patients with head and neck cancer (HNC) across randomized controlled trials (RCTs)., Methods: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials were searched on 5 March 2023 to identify relevant RCTs. RD assessment tools and outcomes were compared across studies. Pooled effect sizes and 95% confidence intervals (CI) were estimated based on random-effects analysis using RevMan 5.4., Results: Three RCTs conducted between 2018 and 2020 were included. Mepitel Film decreased RD severity when compared to Sorbolene or Biafine but not when compared to mometasone. A per-protocol analysis of two of the trials revealed that, overall, Mepitel Film significantly reduced the incidence of grade 2-3 RD (odds ratio (OR), 0.24; 95% CI, 0.09-0.65; p = 0.005) and moist desquamation (OR, 0.21; 95% CI, 0.10-0.46; p < 0.0001) and decreased average patient, researcher, and combined components of the Radiation-Induced Skin Reaction Assessment Scale (the standardized mean difference (SMD) for patient ratings, - 2.56; 95% CI, - 3.15 to - 1.96, p < 0.00001; SMD for researcher ratings, - 3.47; 95% CI, - 6.63 to - 0.31, p = 0.03; SMD for combined scores, - 3.68; 95% CI, - 6.43 to - 0.92, p = 0.009). Noted issues with Mepitel Film included itchiness and poor adherence., Conclusion: While there were discrepancies across studies, Mepitel Film demonstrated a decrease in the incidence of grade 2-3 RD and moist desquamation. These findings emphasize the need for further examining Mepitel Film's efficacy across diverse patient groups and the importance of standardizing RD severity assessment methodologies and control arms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This systematic review and meta-analysis aimed to evaluate the efficacy of Mepitel film in preventing or treating acute radiation dermatitis (RD) in patients with breast cancer in randomized controlled trials (RCTs)., Methods: Embase, APA PsychInfo, Journals@Ovid Full Text, Ovid MEDLINE, PubMed, and Cochrane Trials were searched until December 12, 2022, to identify RCTs on the use of Mepitel film for preventing or treating acute RD from breast cancer radiotherapy. Per-protocol analysis was used to compare outcomes, calculate pooled effect sizes, odds ratio (OR), and 95% confidence intervals (CI), and to create forest plots using random effects analysis in RevMan 5.4., Results: Three RCTs were included in this review. Mepitel film significantly reduced the incidence of grade 3 RD (OR 0.15 95% CI 0.06, 0.37, p<0.0001) and grade 2 or 3 RD (OR 0.16 95% CI 0.04, 0.65, p=0.01) as scored on either the CTCAE or the RTOG scale. Additionally, Mepitel film significantly reduced RISRAS mean scores assessed by patients and combined researcher and patient (standardized mean difference (SMD) -7.59, 95% CI -14.42, -0.76, p=0.03; SMD -15.36, 95% CI -30.01, -0.71 p=0.04) but not the researcher component of the assessment tool (SMD -17.55, 95% CI -36.94, 1.84, p=0.08)., Conclusion: Mepitel film reduced the incidence of acute RD and improved patient-reported outcomes with minimal side effects, the main one being itchiness. Future research should assess the feasibility of Mepitel film with respect to specific patient-reported outcomes such as health-related quality of life issues associated with its use., (© 2023. Crown.)

Purpose: To evaluate the overall efficacy of StrataXRT, a topical gel dressing, in preventing acute radiation dermatitis (RD) in breast cancer patients undergoing radiotherapy (RT)., Methods: A systematic search was conducted on April 25, 2023 in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Randomized controlled trials (RCTs) assessing the effectiveness of StrataXRT in preventing acute RD in breast cancer patients undergoing adjuvant RT to the breast or chest wall with or without regional nodes were included. Pooled incidence odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model, with analysis and forest plots generated in RevMan v5.4., Results: The analysis included three RCTs with a total of 189 patients assessed using per-protocol analysis. Two RCTs compared StrataXRT to standard of care, while the third compared it with Mepitel film and was reported separately. In the former RCTs, the odds ratio (OR) for developing acute grade 3 RD favored StrataXRT at 0.05 (95% CI, 0.01-0.22; P < 0.0001). The OR for developing acute grades 2-3 RD was 0.32 (95% CI, 0.03-3.18; P = 0.33). The RCT comparing StrataXRT with Mepitel film showed insignificant ORs for grade 3 and grades 2-3 RD. One RCT reported significantly lower erythema index (P = 0.008) and melanin index (P = 0.015) in StrataXRT patients. The use of StrataXRT did not raise additional safety concerns., Conclusion: StrataXRT may help prevent severe acute RD in breast cancer RT patients. Further high quality, large-scale studies are needed to confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood., Objective: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival., Design: Retrospective cohort study., Setting: Academic Medical Center (Massachusetts General Hospital, Boston)., Participants: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging., Measurements: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV)., Results: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001)., Conclusions and Relevance: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hassan 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.)

Background: To investigate the relationship between disease-related parameters and joint space width (JSW) on high-resolution peripheral quantitative computed tomography (HR-pQCT) in psoriatic arthritis (PsA) patients., Methods: PsA patients who underwent HR-pQCT examination of the second to fourth metacarpophalangeal joint (MCPJ 2-4) were recruited in this cross-sectional study. The joint space metrics included joint space volume (JSV), mean, minimum, and maximum JSW, JSW asymmetry, and distribution. Correlation analysis and multivariable linear regression models were used to determine the association between disease-related variables and JSW., Results: Sixty-seven patients [37 (55.2%) males; median (IQR) age: 57.0 (53.0, 63.0); median disease duration: 21 (16, 28) years] were included in this analysis. Multivariable linear regression analysis demonstrated that males had larger JSV (MCPJ 2-4), mean (MCPJ 4), and maximum JSW (MCPJ 3). Longer disease duration (MCPJ 2-3) and higher ESR values (MCPJ 3) were negatively associated with mean and maximum JSW, while higher damage joint count was negatively associated with mean and minimum JSW (MCPJ 2). Use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) was negatively associated with minimum JSW (MCPJ 3) while use of biologic DMARDs (bDMARDs) was positively associated with minimum JSW (MCPJ 2)., Conclusion: Higher inflammatory burden as reflected by longer disease duration, higher ESR levels, and damage joint count was negatively associated with mean, maximum, and minimum JSW, while suppression of inflammation using bDMARDs seems to limit the decline in JSW., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial., Objective: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers., Methods: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis., Results: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses., Limitations: Residual confounding due to the observational design., Conclusions: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ., Competing Interests: Conflicts of interest Dr Azoulay received speaker fees from Janssen, Pfizer, and Roche for work unrelated to this study. Dr Platt received consulting fees from Biogen, Boehringer Ingelheim, Merck, Nant Pharma, and Pfizer for work unrelated to this study. Dr Abibula conducted this research during his employment as Staff Scientist at the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital prior to his employment at Complete HEOR Solutions. Authors St-Jean and Dahl; and Drs Quail, Brophy, Chan, Bresee, Carney, Eltonsy, and Tamim have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB., Design: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models., Results: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1 + T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1 + T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1 + T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1 + T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models., Conclusion: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items., Study Design and Setting: Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items., Results: After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1-6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7-9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11-14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15-16); and informing trial participants about using surrogate end points (item 17)., Conclusion: The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials-SURROGATE and Consolidated Standards of Reporting Trials-SURROGATE extensions., Competing Interests: Declaration of competing interest Sylwia Bujkiewicz is a member of the NICE Decision Support Unit and NICE Guidelines Technical Support Unit. She has served as a paid consultant, providing methodological advice, to NICE, Roche, IQVIA, and RTI Health Solutions, received payments for educational events from Roche, and has received research funding from European Federation of Pharmaceutical Industries and Associations and Johnson & Johnson. Mario Ouwens works for and has shares in AstraZeneca. Joseph Ross is an Associate Editor at BMJ and co-founder (unpaid) of medRxiv; research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (U01FD005938); from the Agency for Healthcare Research and Quality (R01HS022882); from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Nancy Butcher has received consulting fees from Nobias Therapeutics, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Falls among older adults are a significant health problem globally. Studies of multicomponent fall prevention programs in randomized controlled trials demonstrate effectiveness in reducing falls; however, the translation of research into the community remains challenging. Although there is an increasing interest to understand the factors contributing to implementation barriers, the dynamic relationships between factors are less well examined. Furthermore, evidence on implementation barriers from Asia is lacking as most of these studies originate from the West. As such, this study aims to engage stakeholders in uncovering the factors that facilitate or inhibit implementing community-based fall prevention programs in Singapore, with a focus on the interrelationship between those factors., Research Design and Methods: Health care professionals familiar with fall prevention programs were invited to discuss the enablers and challenges to the implementation. This effort was facilitated using a systems modeling methodology of Group Model Building (GMB) to share ideas and create a common conceptual model of the challenges. The GMB employs various engagement techniques to draw on the experiences and perceptions of all stakeholders involved., Results: This process led to the development of a Causal Loop Diagram (CLD), a qualitative conceptual model of the dynamic relationships between the barriers and facilitators of implementing fall prevention programs. Results from the CLD show that implementation is influenced by two main drivers: health care provider factors that influenced referrals, and patient factors that influenced referral acceptance and long-term adherence. Key leverage points for potential interventions were identified as well., Discussion and Implications: The overall recommendation emphasized closer coordination and collaboration across providers to ensure sustainable and effective community-based fall prevention programs. This has to be supported by a national effort, involving a multidisciplinary stakeholder advisory group. These findings generated would be promising to guide future approaches to fall prevention., Competing Interests: The authors have no conflict of interest to declare. Preliminary findings were presented at the 18th Biennial European Conference of the Society for Medical Decision Making (May 21–23, 2023)., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE)., Methods: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback., Results: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar., Conclusions: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility., Trial Registration: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ )., (© 2023. The Author(s).)

Malignant superior vena cava syndrome (SVCS) is no longer considered a medical emergency in most cases because it rarely leads to life-threatening complications. However, it results in disturbing symptoms that can significantly affect patients' quality of life. Treating this condition effectively while minimising treatment-related morbidity is of increasing importance as cancer patients are living longer from advances in oncological treatments. This clinical practice review discusses the implications of these advances on the decision to consider stenting as the initial treatment for SVCS. Stenting is increasingly popular as it provides quick symptomatic relief with low rates of complications. Systemic treatments have evolved in the past two decades with the development of immunotherapy and targeted therapies that have different response patterns compared to conventional chemotherapy. Furthermore, major changes have also been seen in radiotherapy techniques that allow treatments to better conform to targets while sparing normal tissues. These advances have changed practice patterns for stent placement in SVCS patients in both the localised and metastatic settings. Prospective studies using standardised patient-reported outcome tools are needed to determine the optimal treatment sequence for SVCS patients, as current recommendations are mainly based on retrospective single-arm studies. An individualized approach with multidisciplinary input is therefore important to optimize patient outcomes before more robust evidence is available.

Competing Interests: The authors declare no conflicts of interest.

Introduction: Due to an aging population, the rising prevalence and incidence of hip fractures and the associated health and economic burden present a challenge to healthcare systems worldwide. Studies have shown that a complex interplay of physiological, psychological, and social factors often affects the recovery trajectories of older adults with hip fractures, often complicating the recovery process., Methods: This research aims to actively engage stakeholders (including doctors, physiotherapists, hip fracture patients, and caregivers) using the systems modeling methodology of Group Model Building (GMB) to elicit the factors that promote or inhibit hip fracture recovery, incorporating a feedback perspective to inform system-wide interventions. Hip fracture stakeholder engagement was facilitated through the Group Model Building approach in a two-half-day workshop of 25 stakeholders. This approach combined different techniques to develop a comprehensive qualitative whole-system view model of the factors that promote or inhibit hip fracture recovery., Results: A conceptual, qualitative model of the dynamics of hip fracture recovery was developed that draws on stakeholders' personal experiences through a moderated interaction. Stakeholders identified four domains (i.e., expectation formation, rehabilitation, affordability/availability, and resilience building) that play a significant role in the hip fracture recovery journey.., Discussion: The insight that recovery of loss of function due to hip fracture is attributed to (a) the recognition of a gap between pre-fracture physical function and current physical function; and (b) the marshaling of psychological resilience to respond promptly to a physical functional loss via uptake of rehabilitation services is supported by findings and has several policy implications., 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., (© 2023 Ansah, Chia, Koh, Lai, Koh, Goh, Yeo, Howe, Seow, Mamun, Balasubramanian, Varman, Yeo, Elamin, Chan and Matchar.)

Importance: Numerous studies have shown that adherence to reporting guidelines is suboptimal., Objective: To evaluate whether asking peer reviewers to check if specific reporting guideline items were adequately reported would improve adherence to reporting guidelines in published articles., Design, Setting, and Participants: Two parallel-group, superiority randomized trials were performed using manuscripts submitted to 7 biomedical journals (5 from the BMJ Publishing Group and 2 from the Public Library of Science) as the unit of randomization, with peer reviewers allocated to the intervention or control group., Interventions: The first trial (CONSORT-PR) focused on manuscripts that presented randomized clinical trial (RCT) results and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline, and the second trial (SPIRIT-PR) focused on manuscripts that presented RCT protocols and reported following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. The CONSORT-PR trial included manuscripts that described RCT primary results (submitted July 2019 to July 2021). The SPIRIT-PR trial included manuscripts that contained RCT protocols (submitted June 2020 to May 2021). Manuscripts in both trials were randomized (1:1) to the intervention or control group; the control group received usual journal practice. In the intervention group of both trials, peer reviewers received an email from the journal that asked them to check whether the 10 most important and poorly reported CONSORT (for CONSORT-PR) or SPIRIT (for SPIRIT-PR) items were adequately reported in the manuscript. Peer reviewers and authors were not informed of the purpose of the study, and outcome assessors were blinded., Main Outcomes and Measures: The difference in the mean proportion of adequately reported 10 CONSORT or SPIRIT items between the intervention and control groups in published articles., Results: In the CONSORT-PR trial, 510 manuscripts were randomized. Of those, 243 were published (122 in the intervention group and 121 in the control group). A mean proportion of 69.3% (95% CI, 66.0%-72.7%) of the 10 CONSORT items were adequately reported in the intervention group and 66.6% (95% CI, 62.5%-70.7%) in the control group (mean difference, 2.7%; 95% CI, -2.6% to 8.0%). In the SPIRIT-PR trial, of the 244 randomized manuscripts, 178 were published (90 in the intervention group and 88 in the control group). A mean proportion of 46.1% (95% CI, 41.8%-50.4%) of the 10 SPIRIT items were adequately reported in the intervention group and 45.6% (95% CI, 41.7% to 49.4%) in the control group (mean difference, 0.5%; 95% CI, -5.2% to 6.3%)., Conclusions and Relevance: These 2 randomized trials found that it was not useful to implement the tested intervention to increase reporting completeness in published articles. Other interventions should be assessed and considered in the future., Trial Registration: ClinicalTrials.gov Identifiers: NCT05820971 (CONSORT-PR) and NCT05820984 (SPIRIT-PR).

Successful infection strategies must balance pathogen amplification and persistence. In the obligate intracellular parasite Toxoplasma gondii this is accomplished through differentiation into dedicated cyst-forming chronic stages that avoid clearance by the host immune system. The transcription factor BFD1 is both necessary and sufficient for stage conversion; however, its regulation is not understood. In this study we examine five factors that are transcriptionally activated by BFD1. One of these is a cytosolic RNA-binding protein of the CCCH-type zinc-finger family, which we name bradyzoite formation deficient 2 (BFD2). Parasites lacking BFD2 fail to induce BFD1 and are consequently unable to fully differentiate in culture or in mice. BFD2 interacts with the BFD1 transcript under stress, and deletion of BFD2 reduces BFD1 protein levels but not messenger RNA abundance. The reciprocal effects on BFD2 transcription and BFD1 translation outline a positive feedback loop that enforces the chronic-stage gene-expression programme. Thus, our findings help explain how parasites both initiate and commit to chronic differentiation. This work provides new mechanistic insight into the regulation of T. gondii persistence, and can be exploited in the design of strategies to prevent and treat these key reservoirs of human infection., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Photoprotection is a critical health prevention strategy to reduce the deleterious effects of ultraviolet radiation (UVR) and visible light (VL). Methods of photoprotection are reviewed in this paper, with an emphasis on sunscreen. The most appropriate sunscreen formulation for personal use depends on several factors. Active sunscreen ingredients vary in their protective effect over the UVR and VL spectrum. There are dermatologic diseases that cause photosensitivity or that are aggravated by a particular action spectrum. In these situations, sunscreen suggestions can address the specific concern. Sunscreen does not represent a single entity. Appropriate personalized sunscreen selection is critical to improve compliance and clinical outcomes. Health care providers can facilitate informed product selection with awareness of evolving sunscreen formulations and counseling patients on appropriate use. This review aims to summarize different forms of photoprotection, discuss absorption of sunscreen ingredients, possible adverse effects, and disease-specific preferences for chemical, physical or oral agents that may decrease UVR and VL harmful effects., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Historically, quality-of-care monitoring was performed separately for transcatheter and surgical aortic valve replacement (TAVR, SAVR). Using consensus indicators, we provide a global report on the quality of care for treatment of aortic stenosis across the highest-volume treatments: transfemoral (TF) TAVR, isolated SAVR, and SAVR combined with coronary artery bypass graft., Methods: Retrospective observational cohort study of consecutive patients in a regional system of care. Primary endpoint was 30-day and 1-year mortality (2015-2019). Secondary endpoints included rate of new pacemaker, rate of readmission, and length of stay (2012-2019). Following multivariable logistic regressions, we developed mortality case-mix adjustment models to report risk estimates., Results: The proportion of patients receiving TAVR grew from 32% to 53% (2015-2019). Those receiving TF TAVR were significantly older, with higher rates of comorbidities. Observed 30-day and 1-year all-cause mortality after TF TAVR decreased from 3.1% to 0.6% ( P  = 0.03), and 13.6% to 6.6% ( P  = 0.09), respectively; surgical mortality rates for isolated SAVR and SAVR combined with coronary artery bypass graft were low and did not change significantly over time, ranging from 0.3% to 1.4% and from 0.9% to 3.4%, respectively at 30 days, and from 0.9% to 3.4% and from 4.7% to 6.7 at 1 year. In the TF TAVR cohort, the observed vs expected ratio for 30-day and 1-year mortality decreased significantly from 1.9 (95% confidence interval [CI] 0.9, 3.5) to 0.3 (95% CI 0.1, 0.8), and from 1.3 (95% CI 0.9, 1.7) to 0.7 (95% CI 0.5, 0.99), respectively; no change occurred in risk-adjusted surgical mortality., Conclusions: Consensus quality indicators provide unique insights on the quality of care for patients receiving treatment for aortic stenosis., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.)

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.