A call to implement preclinical study registration in animal ethics review.

Protocol registration is required in clinical trials. Registration of animal studies could improve research transparency and reduce redundancy, yet uptake has been minimal. Integrating study registration into institutional approval of animal use protocols is a promising approach to increase uptake.

Identifying barriers and enablers to rigorous conduct and reporting of preclinical laboratory studies.

Use of rigorous study design methods and transparent reporting in publications are 2 key strategies proposed to improve the reproducibility of preclinical research. Despite promotion of these practices by funders and journals, assessments suggest uptake is low in preclinical research. Thirty preclinical scientists were interviewed to better understand barriers and enablers to rigorous design and reporting. The interview guide was informed by the Theoretical Domains Framework, which is a framework used to understand determinants of current and desired behavior. Four global themes were identified; 2 reflecting enablers and 2 reflecting barriers. We found that basic scientists are highly motivated to apply the methods of rigorous design and reporting and perceive a number of benefits to their adoption (e.g., improved quality and reliability). However, there was varied awareness of the guidelines and in implementation of these practices. Researchers also noted that these guidelines can result in disadvantages, such as increased sample sizes, expenses, time, and can require several personnel to operationalize. Most researchers expressed additional resources such as personnel and education/training would better enable the application of some methods. Using existing guidance (Behaviour Change Wheel (BCW); Expert Recommendations for Implementing Change (ERIC) project implementation strategies), we mapped and coded our interview findings to identify potential interventions, policies, and implementation strategies to improve routine use of the guidelines by preclinical scientists. These findings will help inform specific strategies that may guide the development of programs and resources to improve experimental design and transparent reporting in preclinical research.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide administration (the most common ALI model) that reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers. We used a random-effects inverse variance meta-analysis, expressing data as standardized mean difference (SMD) with 95% confidence intervals (CIs). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified six studies involving 132 animals across 11 independent experiments. A total of 41 outcomes were extracted, with the direction of effect suggesting greater severity in males than females in 26/41 outcomes (63%). One study reported on lung histology and found that male mice exhibited greater injury than females (SMD: 1.61, 95% CI: 0.53-2.69). Meta-analysis demonstrated significantly elevated albumin levels (SMD: 2.17, 95% CI: 0.63-3.70) and total cell counts (SMD: 0.80, 95% CI: 0.27-1.33) in bronchoalveolar lavage fluid from male mice compared with female mice. Most studies had an "unclear risk of bias." Our findings suggest sex-related differences in ALI severity. However, these conclusions are drawn from a small number of animals and studies. Further research is required to address the fundamental issue of biological sex differences in LPS-induced ALI.

Epidemiology and reporting characteristics of preclinical systematic reviews.

In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common-along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE's] risk of bias tool). We performed a cross-sectional study of a sample of recent preclinical systematic reviews (2015-2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating diverse topics have been conducted; however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.

BACKGROUND: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. METHODS: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. RESULTS: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12-$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. CONCLUSION: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. PATIENT OR PUBLIC CONTRIBUTIONS: The patient partner coauthor informed protocol development, identified data items, and interpreted findings.

Perioperative quality indicators specific to the practice of anesthesia in noncardiac surgery: an umbrella review.

PURPOSE: Improvement in delivery of perioperative care depends on the ability to measure outcomes that can direct meaningful changes in practice. We sought to identify and provide an overview of perioperative quality indicators specific to the practice of anesthesia in noncardiac surgery. SOURCE: We conducted an umbrella review (a systematic review of systematic reviews) according to Joanna Briggs Institute methodology. We included systematic reviews examining perioperative indicators in patients ≥ 18 yr of age undergoing noncardiac surgery. Our primary outcome was any quality indicator specific to anesthesia. Indicators were classified by the Donabedian system and perioperative phase of care. The quality of systematic reviews was assessed using AMSTAR 2 criteria. Level of evidence of quality indicators was stratified by the Oxford Centre for Evidence-Based Medicine Classification. PRINCIPAL FINDINGS: Our search returned 1,475 studies. After removing duplicates and screening of abstracts and full texts, 23 systematic reviews encompassing 3,164 primary studies met our inclusion criteria. There were 330 unique quality indicators. Process indicators were most common (n = 169), followed by outcome (n = 114) and structure indicators (n = 47). Few identified indicators were supported by high-level evidence (45/330, 14%). Level 1 evidence supported indicators of antibiotic prophylaxis (1a), venous thromboembolism prophylaxis (1a), postoperative nausea/vomiting prophylaxis (1b), maintenance of normothermia (1a), and goal-directed fluid therapy (1b). CONCLUSION: This umbrella review highlights the scarcity of perioperative quality indicators that are supported by high quality evidence. Future development of quality indicators and recommendations for outcome measurement should focus on metrics that are supported by level 1 evidence. Potential targets for evidence-based quality-improvement programs in anesthesia are identified herein. STUDY REGISTRATION: PROSPERO (CRD42020164691); first registered 28 April 2020.

RéSUMé: OBJECTIF: L'amélioration de la prestation des soins périopératoires dépend de la capacité de mesurer les résultats qui peuvent orienter des changements significatifs dans la pratique. Nous avons cherché à identifier et à fournir une vue d'ensemble des indicateurs périopératoires de qualité spécifiques à la pratique de l'anesthésie en chirurgie non cardiaque. SOURCES: Nous avons mené une revue d'ensemble (une revue systématique des revues systématiques) selon la méthodologie de l'Institut Joanna Briggs. Nous avons inclus des revues systématiques examinant les indicateurs périopératoires chez les patient·es âgé·es de 18 ans ou plus bénéficiant d'une chirurgie non cardiaque. Notre critère d'évaluation principal était tout indicateur de qualité spécifique à l'anesthésie. Les indicateurs ont été classés en fonction du système de Donabedian et de la phase périopératoire des soins. La qualité des revues systématiques a été évaluée à l'aide des critères AMSTAR 2. Le niveau de donnée probante des indicateurs de qualité a été stratifié selon l'Oxford Centre for Evidence-Based Medicine Classification. CONSTATATIONS PRINCIPALES: Notre recherche a permis de trouver 1475 études. Après avoir éliminé les doublons et examiné les résumés et les textes intégraux, 23 revues systématiques englobant 3164 études primaires ont répondu à nos critères d'inclusion. Il y avait 330 indicateurs de qualité uniques. Les indicateurs de processus étaient les plus courants (n = 169), suivi des indicateurs de résultats (n = 114) et des indicateurs de structure (n = 47). Peu d'indicateurs identifiés étaient étayés par des données probantes de haut niveau (45/330, 14 %). Les données probantes de niveau 1 ont confirmé les indicateurs de l'antibioprophylaxie (1a), de la prophylaxie pour la thromboembolie veineuse (1a), de la prophylaxie postopératoire pour les nausées/vomissements (1b), du maintien de la normothermie (1a) et de la fluidothérapie ciblée (1b). CONCLUSION: Cet examen d'ensemble met en évidence la rareté des indicateurs périopératoires de qualité qui sont étayés par des données probantes de haute qualité. L'élaboration future d'indicateurs de qualité et de recommandations pour la mesure des résultats devrait être axée sur des paramètres étayés par des données probantes de niveau 1. Les cibles potentielles des programmes d'amélioration de la qualité de l'anesthésie fondés sur des données probantes sont identifiées dans le présent manuscrit. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42020164691); premier enregistrement le 28 avril 2020.

Measuring the Predictive Accuracy of Preoperative Clinical Frailty Instruments Applied to Electronic Health Data in Older Patients Having Emergency General Surgery: A Retrospective Cohort Study.

OBJECTIVE: To compare predictive accuracy of frailty instruments operationalizable in electronic data for prognosticating outcomes among older adults undergoing emergency general surgery (EGS). BACKGROUND: Older patients undergoing EGS are at higher risk of perioperative morbidity and mortality. Preoperative frailty is a common and strong perioperative risk factor in this population. Despite this, existing barriers preclude routine preoperative frailty assessment. METHODS: We conducted a retrospective cohort study of adults above 65 undergoing EGS from 2012 to 2018 using Institute for Clinical Evaluative Sciences (ICES) provincial healthcare data in Ontario, Canada. We compared 4 frailty instruments: Frailty Index (FI), Hospital Frailty Risk Score (HFRS), Risk Analysis Index-Administrative (RAI), ACG Frailty-defining diagnoses indicator (ACG). We compared predictive accuracy beyond baseline risk models (age, sex, American Society of Anesthesiologists' score, procedural risk). Predictive performance was measured using discrimination, calibration, explained variance, net reclassification index and Brier score (binary outcomes); using explained variance, root mean squared error and mean absolute prediction error (continuous outcomes). Primary outcome was 30-day mortality. Secondary outcomes were 365-day mortality, nonhome discharge, days alive at home, length of stay, and 30-day and 365-day health systems cost. RESULTS: A total of 121,095 EGS patients met inclusion criteria. Of these, 11,422 (9.4%) experienced death 30 days postoperatively. Addition of FI, HFRS, and RAI to the baseline model led to improved discrimination, net reclassification index, and R2 ; RAI demonstrated the largest improvements. CONCLUSIONS: Adding 4 frailty instruments to typically assessed preoperative risk factors demonstrated strong predictive performance in accurately prognosticating perioperative outcomes. These findings can be considered in developing automated risk stratification systems among older EGS patients.

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

BACKGROUND AIMS: Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. METHODS: A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. RESULTS: Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42-0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. CONCLUSIONS: MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.

An International Society for Cell and Gene Therapy Mesenchymal Stromal Cells (MSC) Committee perspectives on International Standards Organization/Technical Committee 276 Biobanking Standards for bone marrow-MSCs and umbilical cord tissue-derived MSCs for research purposes.

The rapidly growing field of mesenchymal stromal cell (MSC) basic and translational research requires standardization of terminology and functional characterization. The International Standards Organization's (ISO) Technical Committee (TC) on Biotechnology, working with extensive input from the International Society for Cells and Gene Therapy (ISCT), has recently published ISO standardization documents that are focused on biobanking of MSCs from two tissue sources, Wharton's Jelly, MSC(WJ) and Bone Marrow, MSC(M)), for research and development purposes and development. This manuscript explains the path towards the consensus on the following two documents: the Technical Standard ISO/TS 22859 for MSC(WJ) and the full ISO Standard 24651 for MSC(M) biobanking. The ISO standardization documents are aligned with ISCT's MSC committee position and recommendations on nomenclature because there was active input and incorporation of ISCT MSC committee recommendations in the development of these standards. The ISO standardization documents contain both requirements and recommendations for functional characterization of MSC(WJ) and MSC(M) using a matrix of assays. Importantly, the ISO standardization documents have a carefully defined scope and are meant for research use of culture expanded MSC(WJ) and MSC(M). The ISO standardization documents can be updated in a revision process and will be systematically reviewed after 3-5 years as scientific insights grow. They represent international consensus on MSC identity, definition, and characterization; are rigorous in detailing multivariate characterization of MSCs and represent an evolving-but-important first step in standardization of MSC biobanking and characterization for research use and development.

A systematic review of perioperative clinical practice guidelines for care of older adults living with frailty.

BACKGROUND: Perioperative frailty is prevalent and requires complex management, which could be guided by clinical practice guidelines (CPGs). The objective of this systematic review was to identify and synthesise CPGs that provide perioperative recommendations specific to older adults living with frailty. METHODS: After protocol registration, we performed a systematic review of CPGs. MEDLINE, Embase, CINAHL, and 14 grey literature databases were searched (January 1, 2000 until December 22, 2021). We included all CPGs that contained at least one frailty-specific recommendation related to any phase of the perioperative period. We compiled all relevant recommendations, extracted underlying strength of evidence, and categorised them by perioperative phase of care. Within each phase, recommendations were synthesised inductively into themes. Quality of CPGs was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. RESULTS: From 4707 citations, 13 guidelines were included; 8/13 were focused on the perioperative care of older surgical patients in general. Among 110 recommendations extracted, 37 themes were generated, with the majority pertaining to preoperative care. Four themes were supported by strong evidence: performing preoperative frailty assessments, using multidimensional frailty instruments, reducing urinary catheter use, and following multidisciplinary care and communication throughout the perioperative period. Per AGREE II, most guidelines (8/13; 62%) were recommended for use with modifications. CONCLUSIONS: Despite increasing numbers of patients living with frailty, few guidelines exist that address frailty-specific perioperative care. Given the lack of strong evidence-based recommendations, particularly outside the preoperative period, high-quality primary research is required to underpin future guidelines and better inform the care of older surgical patients with frailty. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42022320149.

Association of preoperative anaesthesia consultation prior to elective noncardiac surgery with patient and health system outcomes: a population-based study.

BACKGROUND: Surgical volumes and use of preoperative anaesthesia consultations are increasing. However, contemporary data estimating the association between preoperative anaesthesia consultation and patient (days alive and at home [DAH30], mortality) and system (costs, length of stay, and readmissions) outcomes are not available. METHODS: We conducted a population-based comparative effectiveness study using linked health administrative data among patients aged ≥40 yr who underwent intermediate-risk to high-risk elective, inpatient, noncardiac surgery in Ontario, Canada (2009-17). Our primary outcome was DAH30. Secondary outcomes included DAH90, 30-day and 1-yr mortality, 30-day health system costs, length of index admission, and 30-day readmissions. Propensity score overlap weights were used to adjust for confounders. Prespecified effect modifier analyses focused on high-risk subgroups. RESULTS: Among 364 149 patients, 274 365 (75.3%) received a preoperative anaesthesia consultation. No adjusted association was found (22.5 days vs 22.5 days; adjusted ratio of means 1.00, 95% CI 1.00-1.00) between consultation and DAH30 in the full population. We identified significant effect modification (significantly more DAH30) among patients with ischaemic heart disease, ASA physical status ≥4, frailty index score ≥0.21, and who underwent vascular surgery. Secondary outcomes were associated with preoperative consultation, including greater DAH90, decreased length of stay, lower 30-day and 1-yr mortality, and reduced 30-day costs. CONCLUSIONS: Preoperative anaesthesia consultation was not associated with greater DAH30 across the overall study population. However, important potential benefits were observed among high-risk subgroups. Research is needed to identify optimal patient populations and consultation processes.

Barriers and facilitators to participation in exercise prehabilitation before cancer surgery for older adults with frailty: a qualitative study.

BACKGROUND: Older adults with frailty are at an increased risk of adverse outcomes after surgery. Exercise before surgery (exercise prehabilitation) may reduce adverse events and improve recovery after surgery. However, adherence with exercise therapy is often low, especially in older populations. The purpose of this study was to qualitatively assess the barriers and facilitators to participating in exercise prehabilitation from the perspective of older people with frailty participating in the intervention arm of a randomized trial. METHODS: This was a research ethics approved, nested descriptive qualitative study within a randomized controlled trial of home-based exercise prehabilitation vs. standard care with older patients (≥ 60 years) having elective cancer surgery, and who were living with frailty (Clinical Frailty Scale ≥ 4). The intervention was a home-based prehabilitation program for at least 3 weeks before surgery that involved aerobic activity, strength and stretching, and nutritional advice. After completing the prehabilitation program, participants were asked to partake in a semi-structured interview informed by the Theoretical Domains Framework (TDF). Qualitative analysis was guided by the TDF. RESULTS: Fifteen qualitative interviews were completed. Facilitators included: 1) the program being manageable and suitable to older adults with frailty, 2) adequate resources to support engagement, 3) support from others, 4) a sense of control, intrinsic value, noticing progress and improving health outcomes and 5) the program was enjoyable and facilitated by previous experience. Barriers included: 1) pre-existing conditions, fatigue and baseline fitness, 2) weather, and 3) guilt and frustration when unable to exercise. A need for individualization and variety was offered as a suggestion by participants and was therefore described as both a barrier and facilitator. CONCLUSIONS: Home-based exercise prehabilitation is feasible and acceptable to older people with frailty preparing for cancer surgery. Participants identified that a home-based program was manageable, easy to follow with helpful resources, included valuable support from the research team, and they reported self-perceived health benefits and a sense of control over their health. Future studies and implementation should consider increased personalization based on health and fitness, psychosocial support and modifications to aerobic exercises in response to adverse weather conditions.

Mesenchymal stem/stromal cell-based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS: All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, -0.69; 95% CI, -1.15 to -0.22; P = .004; I2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION: Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.

Understanding potential barriers and enablers to a perioperative early phase cell therapy trial.

BACKGROUND AIMS: Early-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation. METHODS: To optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers. RESULTS: Forty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions). CONCLUSIONS: Prospectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial.

Derivation and external validation of a 30-day mortality risk prediction model for older patients having emergency general surgery.

BACKGROUND: Older people (≥65 yr) are at increased risk of morbidity and mortality after emergency general surgery. Risk prediction models are needed to guide decision making in this high-risk population. Existing models have substantial limitations and lack external validation, potentially limiting their applicability in clinical use. We aimed to derive and validate, both internally and externally, a multivariable model to predict 30-day mortality risk in older patients undergoing emergency general surgery. METHODS: After protocol publication, we used the National Surgical Quality Improvement Program (NSQIP) database (2012-6; estimated to contain 90% data from the USA and 10% from Canada) to derive and internally validate a model to predict 30-day mortality for older people having emergency general surgery using logistic regression with elastic net regularisation. Internal validation was done with 10-fold cross-validation. External validation was done using a temporally separate health administrative database exclusively from Ontario, Canada. RESULTS: Overall, 6012 (12.0%) of the 50 221 patients died within 30 days. The model demonstrated strong discrimination (area under the curve [AUC]=0.871) and calibration across the spectrum of observed and predicted risks. Ten-fold internal cross-validation demonstrated minimal optimism (AUC=0.851, optimism 0.019 [standard deviation=0.06]) with excellent calibration. External validation demonstrated lower discrimination (AUC=0.700) and degraded calibration. CONCLUSION: A multivariable mortality risk prediction model was strongly discriminative and well calibrated internally. However, poor external validation suggests the model may not be generalisable to non-NSQIP data and hospitals. The findings highlight the importance of external validation before clinical application of risk models.

Comparing the predictive accuracy of frailty instruments applied to preoperative electronic health data for adults undergoing noncardiac surgery.

BACKGROUND: Preoperative frailty is associated with increased risk of postoperative mortality and complications. Routine preoperative frailty assessment is underperformed. Automation of preoperative frailty assessment using electronic health data could improve adherence to guideline-based care if an accurate instrument is identified. METHODS: We conducted a retrospective cohort study of adults >65 yr undergoing elective noncardiac surgery between 2012 and 2018. Four frailty instruments were compared: Frailty Index, Hospital Frailty Risk Score, Risk Analysis Index-Administrative, and Adjusted Clinical Groups frailty-defining diagnoses indicator. We compared the predictive performance of each instrument added to a baseline model (age, sex, ASA physical status, and procedural risk) using discrimination, calibration, explained variance, net reclassification, and Brier score (binary outcomes); and explained variance, root mean squared error, and mean absolute prediction error (continuous outcomes). Primary outcome was 30-day mortality. Secondary outcomes included 365-day mortality, length of stay, non-home discharge, days alive at home, and 365-day costs. RESULTS: For this study, 171 576 patients met the inclusion criteria; 1370 (0.8%) died within 30 days. Compared with the baseline model predicting 30-day mortality (area under the curve [AUC] 0.85; R2 0.08), the addition of Hospital Frailty Risk Score led to the greatest improvement in discrimination (AUC 0.87), explained variance (R2 0.09), and net reclassification (Net Reclassification Index 0.65). Brier and calibration scores were comparable. CONCLUSIONS: All four frailty instruments significantly improved discrimination and risk reclassification when added to typically assessed preoperative risk factors. Accurate identification of the presence or absence of preoperative frailty using electronic frailty instruments may improve perioperative risk stratification. Future research should evaluate the impact of automated frailty assessment in guiding surgical planning and patient-centred optimisation amongst older surgical patients.

Association between frailty and patient outcomes after cancer surgery: a population-based cohort study.

BACKGROUND: Frailty is associated with poor postoperative outcomes, but existing data do not describe frailty's interaction with tumour characteristics at the time of cancer surgery. Our objective was to estimate the association between frailty and long-term survival, and to explore any interaction with tumour stage and grade. METHODS: This was a population-based cohort study conducted using linked provincial health administrative data in Ontario, Canada (2009-20). Using a cancer registry, we identified adults having elective cancer surgery. Frailty was measured using a validated index (range 0-1; higher score=greater frailty). Associations between frailty and long-term postoperative survival (primary outcome) were estimated using proportional hazards regression. Secondary outcomes were length of stay, discharge destination, days alive at home, and healthcare costs. RESULTS: We identified and included 52 012 patients. Mean frailty score was 0.13 (standard deviation 0.07). During follow-up, 19 378 (37.3%) patients died. After adjustment for risk factors, each 10% increase in frailty was associated with a 1.60-fold relative decrease in survival (95% confidence interval: 1.56-1.64). The frailty-survival association was strongest for patients with lower stage and grade cancers. Increased frailty was associated with longer hospital stays (3 days), fewer days alive and at home (42 days yr-1), more frequent discharge to a nursing facility (2.38-fold), and increased healthcare costs ($6048). CONCLUSIONS: Patient frailty is associated with decreased long-term survival after cancer surgery. The association is stronger for early-stage and -grade cancers, which would otherwise have a better survival prognosis.

Home-based prehabilitation with exercise to improve postoperative recovery for older adults with frailty having cancer surgery: the PREHAB randomised clinical trial.

BACKGROUND: Frailty is a state of vulnerability as a result of decreased reserves. Prehabilitation may increase reserve and improve postoperative outcomes. Our objective was to determine if home-based prehabilitation improves postoperative functional recovery in older adults with frailty having cancer surgery. METHODS: This double blind randomised trial enrolled people ≥60 yr having elective cancer surgery and ≥3 weeks from enrolment to surgery as eligible. Participation in a remotely supported, home-based exercise prehabilitation program plus nutritional guidance was compared with standard care plus written advice on age-appropriate activity and nutrition. The primary outcome was 6-min walk test (6MWT) distance at the first postoperative clinic visit. Secondary outcomes included physical performance, quality of life, disability, length of stay, non-home discharge, and 30-day readmission. RESULTS: Of 543 patients assessed, 254 were eligible and 204 (80%) were randomised (102 per arm); 182 (94 intervention and 88 control) had surgery and were analysed. Mean age was 74 yr and 57% were female. Mean duration of participation was 5 weeks, mean adherence was 61% (range 0%-100%). We found no significant difference in 6MWT at follow-up (+14 m, 95% confidence interval -26-55 m, P=0.486), or for secondary outcomes. Analyses using a prespecified adherence definition of ≥80% supported improvements in 6MWT distance, complication count, and disability. CONCLUSIONS: A home-based prehabilitation program did not significantly improve postoperative recovery or other outcomes in older adults with frailty having cancer surgery. Program adherence may be a key mediator of prehabilitation efficacy. CLINICAL TRIAL REGISTRATION: NCT02934230.