Frailty and decisional regret after elective noncardiac surgery: a multicentre prospective cohort study.

BACKGROUND: Frailty is associated with morbidity and mortality after surgery. The association of frailty with decisional regret is poorly defined. Our objective was to estimate the association of preoperative frailty with decisional regret status in the year after surgery. METHODS: We conducted a secondary analysis of a prospective, multicentre cohort study of patients aged ≥65 years who underwent elective noncardiac surgery. Decisional regret about having undergone surgery was ascertained at 30, 90, and 365 (primary time point) days after surgery using a 3-point ordinal scale. Bayesian ordinal logistic regression was used to estimate the association of frailty with decisional regret, adjusted for surgery type, age, sex, and mental health conditions. Subgroup and sensitivity analyses were conducted. RESULTS: We identified 669 patients; 293 (43.8%) lived with frailty. At 365 days after surgery, the unadjusted odds ratio (OR) associating frailty with greater decisional regret was 2.21 (95% credible interval [CrI] 0.98-5.09; P(OR>1)=0.97), which was attenuated after confounder adjustment (adjusted OR 1.68, 95% CrI 0.84-3.36; P(OR>1)=0.93). Similar results were estimated at 30 and 90 days. Additional adjustment for baseline comorbidities and disability score substantially altered the OR at 365 days (0.89, 95% CrI 0.37-2.12; P(OR>1)=0.39). There was a high probability that surgery type was an effect modifier (non-orthopaedic: OR 1.90, 95% CrI 1.00-3.59; P(OR>1)=0.98); orthopaedic: OR 0.87, 95% CrI 0.41-1.91; P(OR>1)=0.36). CONCLUSIONS: Among older surgical patients, there appears to be a complex association with frailty and decisional regret, with substantial heterogeneity based on assumed causal pathways and surgery type. Future studies are required to untangle the complex interplay between these factors.

Home-based exercise prehabilitation to improve disease-free survival and return to intended oncologic treatment after cancer surgery in older adults with frailty: a secondary analysis of a randomized trial.

BACKGROUND: Improving survivorship for patients with cancer and frailty is a priority. We aimed to estimate whether exercise prehabilitation improves disease-free survival and return to intended oncologic treatment for older adults with frailty undergoing cancer surgery. METHODS: We conducted a secondary analysis of the oncologic outcomes of a randomized trial of patients ≥ 60 yr of age with frailty undergoing elective cancer surgery. Participants were randomized either to a supported, home-based exercise program plus nutritional guidance or to usual care. Outcomes for this analysis were one-year disease-free survival and return to intended oncologic treatment. We estimated complier average causal effects to account for intervention adherence. RESULTS: We randomized 204 participants (102 per arm); 182 were included in our modified intention-to-treat population and, of these participants, 171/182 (94%) had complete one-year follow up. In the prehabilitation group, 18/94 (11%) died or experienced cancer recurrence, compared with 19/88 (11%) in the control group (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.66 to 2.34; P = 0.49). Return to intended oncologic treatment occurred in 24/94 (29%) patients the prehabilitation group vs 20/88 (23%) in the usual care group (HR, 1.53; 95% CI, 0.84 to 2.77; P = 0.16). Complier average causal effects directionally diverged for disease-free survival (HR, 0.91; 95% CI, 0.20 to 4.08; P = 0.90) and increased the point estimate for return to treatment (HR, 2.04; 95% CI, 0.52 to 7.97; P = 0.30), but in both cases the CIs included 1. CONCLUSIONS: Randomization to home-based exercise prehabilitation did not lead to significantly better disease-free survival or earlier return to intended oncologic treatment in older adults with frailty undergoing cancer surgery. Our results could inform future trials powered for more plausible effect sizes, especially for the return to intended oncologic treatment outcome. STUDY REGISTRATION: ClinicalTrials.gov ( NCT02934230 ); first submitted 22 August 2016.

RéSUMé: CONTEXTE: L'amélioration de la survie des personnes atteintes de cancer et de fragilité est une priorité. Nous avons cherché à estimer si la préadaptation physique améliore la survie sans maladie et le retour au traitement oncologique prévu pour les personnes âgées fragiles bénéficiant d'une chirurgie du cancer. MéTHODE: Nous avons effectué une analyse secondaire des issues oncologiques d'une étude randomisée de patient·es âgé·es de 60 ans ou plus atteint·es de fragilité bénéficiant d'une chirurgie carcinologique non urgente. Nous avons randomisé les personnes participantes à un programme d'exercice à domicile accompagné de conseils nutritionnels ou à recevoir les soins habituels. Les critères d'évaluation de cette analyse étaient la survie sans maladie à un an et le retour au traitement oncologique prévu. Nous avons estimé les effets moyens causaux d'observance pour tenir compte de l'adhérence à l'intervention. RéSULTATS: Nous avons randomisé 204 participant·es (102 par bras); 182 personnes ont été incluses dans notre population modifiée en intention de traiter et, parmi ces participant·es, 171/182 (94%) ont fait l'objet d'un suivi complet à un an. Dans le groupe préadaptation, 18/94 (11%) personnes sont décédées ou ont connu une récidive du cancer, contre 19/88 (11 %) dans le groupe témoin (rapport de risque [HR], 1,25; intervalle de confiance [IC] à 95%, 0.66 à 2.34; P = 0.49). Le retour au traitement oncologique prévu a eu lieu chez 24 patient·es sur 94 (29 %) dans le groupe préadaptation vs 20/88 (23 %) dans le groupe de soins habituels (RR, 1.53; IC 95%, 0.84 à 2.77; P = 0.16). Les effets moyens causaux d'observance ont divergé directionnellement pour la survie sans maladie (RR, 0.91; IC 95%, 0.20 à 4.08; P = 0.90) et augmenté l'estimation ponctuelle du retour au traitement (RR, 2.04; IC 95%, 0.52 à 7.97; P = 0.30), mais dans les deux cas, les IC comprenaient 1. CONCLUSION: La randomisation pour la préadaptation physique à domicile n'a pas entraîné d'amélioration significative de la survie sans maladie ou de retour plus précoce au traitement oncologique prévu chez les personnes âgées fragiles bénéficiant d'une chirurgie du cancer. Nos résultats pourraient éclairer de futures études alimentées par des tailles d'effet plus plausibles, en particulier pour le critère de retour prévu au traitement oncologique. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT02934230 ); première soumission le 22 août 2016.

Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis.

BACKGROUND: Dexmedetomidine is increasingly used for surgical patients requiring general anaesthesia. However, its effectiveness on patient-centred outcomes remains uncertain. Our main objective was to evaluate the patient-centred effectiveness of intraoperative dexmedetomidine for adult patients requiring surgery under general anaesthesia. METHODS: We conducted a systematic search of MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to October 2023. Randomised controlled trials (RCTs) comparing intraoperative use of dexmedetomidine with placebo, opioid, or usual care in adult patients requiring surgery under general anaesthesia were included. Study selection, data extraction, and risk of bias assessment were performed by two reviewers independently. We synthesised data using a random-effects Bayesian regression framework to derive effect estimates and the probability of a clinically important effect. For continuous outcomes, we pooled instruments with similar constructs using standardised mean differences (SMDs) and converted SMDs and credible intervals (CrIs) to their original scale when appropriate. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our primary outcome was quality of recovery after surgery. To guide interpretation on the original scale, the Quality of Recovery-15 (QoR-15) instrument was used (range 0-150 points, minimally important difference [MID] of 6 points). RESULTS: We identified 49,069 citations, from which 44 RCTs involving 5904 participants were eligible. Intraoperative dexmedetomidine administration was associated with improvement in postoperative QoR-15 (mean difference 9, 95% CrI 4-14, n=21 RCTs, moderate certainty of evidence). We found 99% probability of any benefit and 88% probability of achieving the MID. There was a reduction in chronic pain incidence (odds ratio [OR] 0.42, 95% CrI 0.19-0.79, n=7 RCTs, low certainty of evidence). There was also increased risk of clinically significant hypotension (OR 1.98, 95% CrI 0.84-3.92, posterior probability of harm 94%, n=8 RCTs) and clinically significant bradycardia (OR 1.74, 95% CrI 0.93-3.34, posterior probability of harm 95%, n=10 RCTs), with very low certainty of evidence for both. There was limited evidence to inform other secondary patient-centred outcomes. CONCLUSIONS: Compared with placebo or standard of care, intraoperative dexmedetomidine likely results in meaningful improvement in the quality of recovery and chronic pain after surgery. However, it might increase clinically important bradycardia and hypotension. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023439896).

Perioperative Transfusion Practices in Adults Having Noncardiac Surgery.

Surgical patients are often transfused to manage bleeding and anemia. Best practices for red blood cell (RBC) transfusion administration in patient having noncardiac surgery remains controversial and a robust evaluation and description of perioperative transfusion practices is lacking. We characterized perioperative hemoglobin concentrations and transfusion practices from the prospective VISION cohort which included 39,222 patients aged ≥45 years who had inpatient noncardiac surgery. Variations in transfusion practices were analyzed using hierarchical mixed models, and associations with mortality and complications were evaluated using a nested frailty survival model. Within the cohort, 16.1% (n = 6296) were given perioperative RBC transfusions, with the fraction declining from 20% to 13% over the 6-year study period. The proportion of patients transfused varied by surgery type from 6.4% for low-risk operations (i.e., minor surgery) to 31.5% for orthopedic surgeries. Variations were largely associated with patient hemoglobin concentrations, but also with center (range: 3.7%-27.3%) and country (0.4%-25.3%). Even after adjusting for baseline hemoglobin, comorbidities and type of surgery, both center and country were significant sources of variation in transfusion practices. Among transfused participants, 60.4% (n = 3728/6170) had at least 1 hemoglobin concentration ≤80g/L and 86.0% (n = 5305/6170) had at least 1 hemoglobin concentration ≤90g/L, suggesting that relatively restrictive transfusion strategies were used in most. The proportion of patients receiving at least 1 RBC transfusion declined from 20% to 13% over 6 years. However, there was considerable unexplained variation in transfusion practices.

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.

Effectiveness of dexmedetomidine during surgery under general anaesthesia on patient-centred outcomes: a systematic review and Bayesian meta-analysis protocol.

INTRODUCTION: Dexmedetomidine is a promising pharmaceutical strategy to minimise opioid use during surgery. Despite its growing use, it is uncertain whether dexmedetomidine can improve patient-centred outcomes such as quality of recovery and pain. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis following the recommendations of the Cochrane Handbook for Systematic Reviews. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL approximately in October 2023. We will include randomised controlled trials evaluating the impact of systemic intraoperative dexmedetomidine on patient-centred outcomes. Patient-centred outcome definition will be based on the consensus definition established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC). Our primary outcome will be the quality of recovery after surgery. Our secondary outcomes will be patient well-being, function, health-related quality of life, life impact, multidimensional assessment of postoperative acute pain, chronic pain, persistent postoperative opioid use, opioid-related adverse events, hospital length of stay and adverse events. Two reviewers will independently screen and identify trials and extract data. We will evaluate the risk of bias of trials using the Cochrane Risk of Bias Tool (RoB 2.0). We will synthesise data using a random effects Bayesian model framework, estimating the probability of achieving a benefit and its clinical significance. We will assess statistical heterogeneity with the tau-squared and explore sources of heterogeneity with meta-regression. We have involved patient partners, clinicians, methodologists, and key partner organisations in the development of this protocol, and we plan to continue this collaboration throughout all phases of this systematic review. ETHICS AND DISSEMINATION: Our systematic review does not require research ethics approval. It will help inform current clinical practice guidelines and guide development of future randomised controlled trials. The results will be disseminated in open-access peer-reviewed journals, presented at conferences and shared among collaborators and networks. PROSPERO REGISTRATION NUMBER: CRD42023439896.

Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

BACKGROUND: In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. OBJECTIVE: To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. METHODS: A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. RESULTS: Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. CONCLUSIONS: These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

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.

Intraoperative Blood Management Strategies for Patients Undergoing Noncardiac Surgery: The Ottawa Intraoperative Transfusion Consensus.

Importance: There is marked variability in red blood cell (RBC) transfusion during the intraoperative period. The development and implementation of existing clinical practice guidelines have been ineffective in reducing this variability. Objective: To develop an internationally endorsed consensus statement about intraoperative transfusion in major noncardiac surgery. Evidence Review: A Delphi consensus survey technique with an anonymous 3-round iterative rating and feedback process was used. An expert panel of surgeons, anesthesiologists, and transfusion medicine specialists was recruited internationally. Statements were informed by extensive preparatory work, including a systematic reviews of intraoperative RBC guidelines and clinical trials, an interview study with patients to explore their perspectives about intraoperative transfusion, and interviews with physicians to understand the various behaviors that influence intraoperative transfusion decision-making. Thirty-eight statements were developed addressing (1) decision-making (interprofessional communication, clinical factors, procedural considerations, and audits), (2) restrictive transfusion strategies, (3) patient-centred considerations, and (4) research considerations (equipoise, outcomes, and protocol suspension). Panelists were asked to score statements on a 7-point Likert scale. Consensus was established with at least 75% agreement. Findings: The 34-member expert panel (14 of 33 women [42%]) included 16 anesthesiologists, 11 surgeons, and 7 transfusion specialists; panelists had a median of 16 years' experience (range, 2-50 years), mainly in Canada (52% [17 of 33]), the US (27% [9 of 33]), and Europe (15% [5 of 33]). The panel recommended routine preoperative and intraoperative discussion between surgeons and anesthesiologists about intraoperative RBC transfusion as well as postoperative review of intraoperative transfusion events. Point-of-care hemoglobin testing devices were recommended for transfusion guidance, alongside an algorithmic transfusion protocol with a restrictive hemoglobin trigger; however, more research is needed to evaluate the use of restrictive triggers in the operating room. Expert consensus recommended a detailed preoperative consent discussion with patients of the risks and benefits of both anemia and RBC transfusion and routine disclosure of intraoperative transfusion. Postoperative morbidity and mortality were recommended as the most relevant outcomes associated with intraoperative RBC transfusion, and transfusion triggers of 70 and 90 g/L were considered acceptable hemoglobin triggers to evaluate restrictive and liberal transfusion strategies, respectively, in clinical trials. Conclusions and Relevance: This consensus statement offers internationally endorsed expert guidance across several key domains on intraoperative RBC transfusion practice for noncardiac surgical procedures for which patients are at medium or high risk of bleeding. Future work should emphasize knowledge translation strategies to integrate these recommendations into routine clinical practice and transfusion research activities.

Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

Purpose: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Results: Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). Conclusions: AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. Translational Relevance: This systematic review will help to inform and guide future clinical trials.

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.

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.

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

INTRODUCTION: For close to a century opioid administration has been a standard of care to complement anaesthesia during surgery. Considering the worldwide opioid epidemic, this practice is now being challenged and there is a growing use of systemic pharmacological opioid minimising strategies. Our aim is to conduct a scoping review that will examine clinical trials that have evaluated the impact of intraoperative opioid minimisation strategies on patient-centred outcomes and identify promising strategies. METHODS AND ANALYSIS: Our scoping review will follow the framework developed by Arksey and O'Malley. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL from their inception approximately in March 2023. We will include randomised controlled trials, assessing the impact of systemic intraoperative pharmacologic opioid minimisation strategies on patient-centred outcomes. We define an opioid minimisation strategy as any non-opioid drug with antinociceptive properties administered during the intraoperative period. Patient-centred outcomes will be defined and classified based on the consensus definitions established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC group) and informed by knowledge users and patient partners. We will use a coproduction approach involving interested parties. Our multidisciplinary team includes knowledge users, patient partners, methodologists and knowledge user organisations. Knowledge users will provide input on methods, outcomes, clinical significance of findings, implementation and feasibility. Patient partners will participate in assessing the relevance of our design, methods and outcomes and help to facilitate evidence translation. We will provide a thorough description of available clinical trials, compare their reported patient-centred outcome measures with established recommendations and identify promising strategies. ETHICS AND DISSEMINATION: Ethics approval is not required for the review. Our scoping review will inform future research including clinical trials and systematic reviews through identification of important intraoperative interventions. Results will be disseminated through a peer-reviewed publication, presentation at conferences and through our network of knowledge user collaborators. REGISTRATION: Open Science Foundation (currently embargoed).

Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.

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.

High-Sensitivity Cardiac Troponin I Thresholds to Identify Myocardial Injury After Noncardiac Surgery: A Cohort Study.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is common and associated with short- and long-term major cardiovascular events. Diagnostic criteria for MINS using Abbott high-sensitivity cardiac troponin I (hs-cTnI) are unknown. METHODS: We performed a prospective cohort study of adults who had in-patient noncardiac surgery and measured hs-cTnI (Abbott Laboratories) on postoperative serum samples collected up to postoperative day 3. The objective was to determine prognostically important hs-cTnI thresholds associated with major cardiac events and death at 30 days after noncardiac surgery. Using Cox proportional iterative analyses, we determined peak postoperative hs-cTnI thresholds associated with the occurrence of the 30-day composite of major cardiac events (ie, nonfatal myocardial infarction after 3 postoperative days, cardiac arrest, and congestive heart failure) and death. RESULTS: Of 3953 included patients, 66 (1.7%) experienced the primary outcome at 30 days. Peak hs-cTnI values and associated incidence of major cardiac events and death were as follows: < 60 ng/L: 1.0% (95% CI 0.7-1.3); 60 to < 700 ng/L: 8.6% (5.6-13.0); and ≥ 700 ng/L: 27.3% (16.4-41.9). Compared with peak hs-cTnI < 60 ng/L, adjusted hazard ratios were 7.54 (95% CI% 4.27-13.32) for hs-cTnI values of 60 to < 700 ng/L and 26.87 (13.27-54.41) for values ≥ 700 ng/L. CONCLUSIONS: Hs-cTnI elevation within the first 3 days after noncardiac surgery independently predicts major cardiac events and death at 30 days. A postoperative hs-cTnI ≥ 60 ng/L was associated with a > 7-fold increase in the risk of subsequent major cardiac events and mortality at 30 days.

Identifying effect modifiers of CAR-T cell therapeutic efficacy: a systematic review and individual patient data meta-analysis protocol.

BACKGROUND: Chimeric antigen receptor T cell therapy (CAR-T) represents a promising and exciting new therapy for hematologic malignancies, where prognosis for relapsed/refractory patients remains poor. Encouraging results from clinical trials have often been tempered by heterogeneity in response to treatment among patients, as well as safety concerns including cytokine release syndrome. The identification of specific patient or treatment-specific factors underlying this heterogeneity may provide the key to the long-term sustainability of this complex and expensive therapy. An individual patient data meta-analysis (IPMDA) may provide potential explanations for the high degree of heterogeneity. Therefore, our objective is to perform a systematic review and IPDMA of CAR-T cell therapy in patients with hematologic malignancies to explore potential effect modifiers of CAR-T cell therapy. METHODS AND ANALYSIS: We will search MEDLINE, Embase, and the Cochrane Central Register of Controlled Clinical Trials. Studies will be screened in duplicate at the abstract level, then at the full-text level by two independent reviewers. We will include any prospective clinical trial of CAR-T cell therapy in patients with hematologic malignancies. Our primary outcome is complete response, while secondary outcomes of interest include overall response, progression-free survival, overall survival, and safety. IPD will be collected from each included trial and, in the case of missing data, corresponding authors/study sponsors will be contacted. Standard aggregate meta-analyses will be performed, followed by the IPD meta-analysis using a one-stage approach. A modified Institute of Health Economics tool will be used to evaluate the risk of bias of included studies. ETHICS AND DISSEMINATION: Identifying characteristics that may act as modifiers of CAR-T cell efficacy is of paramount importance and can help shape future clinical trials in the field. Results from this study will be submitted for publication in a peer-reviewed scientific journal, presented at relevant conferences and shared with relevant stakeholders.