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.

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.

A Systematic Review and Meta-analysis Examining the Impact of Age on Perioperative Inflammatory Biomarkers.

BACKGROUND: Dysregulation of immune responses to surgical stress in older patients and those with frailty may manifest as differences in inflammatory biomarkers. We conducted a systematic review and meta-analysis to examine differences in perioperative inflammatory biomarkers between older and younger patients, and between patients with and without frailty. METHODS: MEDLINE, Embase, Cochrane, and CINAHL databases were searched (Inception to June 23, 2020). Observational or experimental studies reporting the perioperative level or activity of biomarkers in surgical patients stratified by age or frailty status were included. The primary outcome was inflammatory biomarkers (grouped by window of ascertainment: pre-op; post-op: <12 hours, 12-24 hours, 1-3 days, 3 days to 1 week, and >1 week). Quality assessment was conducted using the Newcastle-Ottawa Scale. Inverse-variance, random-effects meta-analysis was conducted. RESULTS: Forty-five studies (4263 patients) were included in the review, of which 36 were pooled for meta-analysis (28 noncardiac and 8 cardiac studies). Two studies investigated frailty as the exposure, while the remaining investigated age. In noncardiac studies, older patients had higher preoperative levels of interleukin (IL)-6 and C-reactive protein (CRP), lower preoperative levels of lymphocytes, and higher postoperative levels of IL-6 (<12 hours) and CRP (12-24 hours) than younger patients. In cardiac studies, older patients had higher preoperative levels of IL-6 and CRP and higher postoperative levels of IL-6 (<12 hours and >1 week). CONCLUSIONS: Our findings demonstrate a paucity of frailty-specific studies; however, the presence of age-associated differences in the perioperative inflammatory response is consistent with age-associated states of chronic systemic inflammation and immunosenescence. Additional studies assessing frailty-specific changes in the systemic biologic response to surgery may inform the development of targeted interventions.

Airway recommendations for perioperative patients during the COVID-19 pandemic: a scoping review.

PURPOSE: Numerous guideline recommendations for airway and perioperative management during the COVID-19 pandemic have been published. We identified, synthesized, and compared guidelines intended for anesthesiologists. SOURCE: Member society websites of the World Federation of Societies of Anesthesiologists and the European Society of Anesthesiologists were searched. Recommendations that focused on perioperative airway management of patients with proven or potential COVID-19 were included. Accelerated screening was used; data were extracted by one reviewer and verified by a second. Data were organized into themes based on perioperative phase of care. PRINCIPAL FINDINGS: Thirty unique sets of recommendations were identified. None reported methods for systematically searching or selecting evidence to be included. Four were updated following initial publication. For induction and airway management, most recommended minimizing personnel and having the most experienced anesthesiologist perform tracheal intubation. Significant congruence was observed among recommendations that discussed personal protective equipment. Of those that discussed tracheal intubation methods, most (96%) recommended videolaryngoscopy, while discordance existed regarding use of flexible bronchoscopy. Intraoperatively, 23% suggested specific anesthesia techniques and most (63%) recommended a specific operating room for patients with COVID-19. Postoperatively, a minority discussed extubation procedures (33%), or care in the recovery room (40%). Non-technical considerations were discussed in 27% and psychological support for healthcare providers in 10%. CONCLUSION: Recommendations for perioperative airway management of patients with COVID-19 overlap to a large extent but also show significant differences. Given the paucity of data early in the pandemic, it is not surprising that identified publications largely reflected expert opinion rather than empirical evidence. We suggest future efforts should promote coordinated responses and provide suggestions for studying and establishing best practices in perioperative patients. STUDY REGISTRATION: Open Science Framework ( https://osf.io/a2k4u/ ); date created, 26 March 2020.

RéSUMé: OBJECTIF: De nombreuses recommandations ont été publiées pour la prise en charge des voies aériennes et périopératoires pendant la pandémie de COVID-19. Nous avons identifié, synthétisé et comparé les lignes directrices destinées aux anesthésiologistes. SOURCES: Les sites internet des sociétés membres de la Fédération mondiale des sociétés d'anesthésiologistes et de la Société européenne d'anesthésiologie ont été consultés. Les recommandations axées sur la prise en charge périopératoire des voies aériennes des patients atteints de COVID-19 prouvée ou potentielle ont été incluses. Une sélection accélérée a été utilisée; les données ont été extraites par un examinateur et vérifiées par un second. Les données ont été thématiquement organisées en fonction de la phase périopératoire des soins. CONSTATATIONS PRINCIPALES: Trente ensembles uniques de recommandations ont été identifiés. Aucun de ces ensemble n'a fait état de méthodes de recherche ou de sélection systématiques des données probantes à inclure. Quatre ont été mis à jour après leur publication initiale. Pour l'induction et la prise en charge des voies aériennes, la plupart ont recommandé de minimiser le personnel et de demander à l'anesthésiologiste le plus expérimenté de réaliser l'intubation trachéale. Une congruence significative a été observée parmi les recommandations qui portaient sur les équipements de protection individuelle. Parmi les lignes directrices évoquant les méthodes d'intubation trachéale, la plupart (96 %) ont recommandé la vidéolaryngoscopie, alors qu'il existait une discordance concernant l'utilisation de bronchoscopes flexibles. En peropératoire, 23 % ont suggéré des techniques d'anesthésie spécifiques et la plupart (63 %) ont recommandé une salle d'opération spécifique pour les patients atteints de COVID-19. En postopératoire, une minorité a abordé le sujet des procédures d'extubation (33 %) ou des soins en salle de réveil (40 %). Les considérations non techniques ont été traitées dans 27 % des cas et le soutien psychologique aux fournisseurs de soins de santé dans 10 %. CONCLUSION: Les recommandations pour la prise en charge périopératoire des voies aériennes des patients atteints de COVID-19 se chevauchent dans une large mesure, mais montrent également des différences significatives. Compte tenu de la rareté des données au début de la pandémie, il n'est pas surprenant que les publications identifiées reflètent en grande partie l'opinion d'experts plutôt que de se fonder sur des données probantes empiriques. Nous suggérons que les efforts futurs soient déployés de manière à promouvoir des réponses coordonnées et proposer des suggestions pour étudier et établir les meilleures pratiques chez les patients en période périopératoire. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/a2k4u/ ); date de création, 26 mars 2020.

Building a Platform for Meaningful Patient Partnership to Accelerate "Bench-to-Bedside" Translation of Promising New Therapies.

Engaging patients as partners in the design and execution of early-phase clinical trials offers a unique opportunity to ensure patient perspectives are considered. Here we describe our experience partnering with four individuals with lived experience of blood cancer to co-develop documents and services to support participants of an early-phase trial. Through regular team meetings, patient partners co-developed a visual informed consent document and a non-technical summary of the informed consent document to facilitate participant understanding of trial procedures. Overall, patient partners highlighted important trial components that would not have been identified without their input.

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis.

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.

Implementation of the Canadian Cardiovascular Society guidelines for perioperative risk assessment and management: an interrupted time series study.

PURPOSE: The Canadian Cardiovascular Society (CCS) guidelines for patients undergoing non-cardiac surgery address the lack of standardized management for patients at risk of perioperative cardiovascular complications. Our interdisciplinary group evaluated the implementation of these guidelines. METHODS: We used an interrupted time series design to evaluate the effect of implementation of the CCS guidelines, using routinely collected hospital data. The study population consisted of elective, non-cardiac surgery patients who were: i) inpatients following surgery and ii) age ≥ 65 or age 45-64 yr with a Revised Cardiac Risk Index ≥ 1. Outcomes included adherence to troponin I (TnI) monitoring (primary) and adherence to appropriate consultant care for patients with elevated TnI (secondary). Exploratory outcomes included cost measures and clinical outcomes such as length of stay. RESULTS: We included 1,421 patients (706 pre- and 715 post-implementation). We observed a 67% absolute increase (95% confidence interval, 55 to 80; P < 0.001) in adherence to TnI testing following the implementation of the guidelines. In patients who had elevated TnI following guideline implementation (n = 64), the majority (85%) received appropriate follow-up care in the form of a general medicine or cardiology consult, all received at least one electrocardiogram, and half received at least one advanced cardiac test (e.g., cardiac perfusion scan, or percutaneous intervention). CONCLUSIONS: Our study showed the ability to implement and adhere to the CCS guidelines. Large-scale multicentre evaluations of CCS guideline implementation are needed to gain a better understanding of potential effects on clinically relevant outcomes.

RéSUMé: OBJECTIF: Les lignes directrices de la Société canadienne de cardiologie (SCC) concernant les patients subissant une chirurgie non cardiaque ont été conçues pour pallier l'absence de standardisation dans la prise en charge des patients à risque de complications cardiovasculaires périopératoires. Notre groupe interdisciplinaire a évalué la mise en œuvre de ces lignes directrices. MéTHODE: Nous avons utilisé une méthodologie de série chronologique interrompue pour évaluer l'effet de la mise en œuvre des lignes directrices de la SCC, à l'aide des données hospitalières habituellement recueillies. La population à l'étude se composait de patients de chirurgies non cardiaques non urgentes qui étaient : i) hospitalisés après leur chirurgie et ii) âgés de ≥ 65 ans ou de 45 à 64 ans avec un Indice de risque cardiaque révisé ≥ 1. Les critères d'évaluation comprenaient l'observance du monitorage de la troponine I (TnI) (critère d'évaluation primaire) et l'observance des soins spécialisés appropriés aux patients présentant un taux élevé de TnI (critère secondaire). Les critères exploratoires comprenaient des mesures de coûts et des résultats cliniques tels que la durée de séjour. RéSULTATS: Nous avons inclus 1421 patients (706 avant et 715 après la mise en œuvre). Nous avons observé une augmentation absolue de 67 % (intervalle de confiance de 95 %, 55 à 80; P < 0,001) de l'observance des tests de la TnI suite à la mise en œuvre des lignes directrices. Parmi les patients présentant un taux élevé de TnI suite à la mise en œuvre des lignes directrices (n = 64), la majorité (85%) a reçu des soins de suivi appropriés sous la forme d'une consultation en médecine générale ou en cardiologie; tous ont subi au moins un électrocardiogramme, et la moitié ont passé au moins un examen cardiaque subséquent (p. ex., évaluation de la perfusion myocardique par scintigraphie ou cathétérisme percutané). CONCLUSION: Notre étude a montré qu'il est possible de mettre en œuvre et d'adhérer aux nouvelles lignes directrices de la SCC. Des évaluations multicentriques à grande échelle portant sur la mise en œuvre des lignes directrices de la SCC sont nécessaires pour mieux comprendre ses effets potentiels sur les devenirs cliniquement pertinents.

The effects of resistant starches on inflammatory bowel disease in preclinical and clinical settings: a systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a debilitating chronic disease with limited treatment options. Resistant starches may represent a novel treatment for IBD. However, its efficacy and safety remain unclear. Our objective was to perform a systematic review to summarize the preclinical and clinical effects of resistant starch, which may help guide future studies. METHODS: Medline, EMBASE, and the Cochrane Central Register were searched. Included studies investigated the use of resistant starch therapy in in vivo animal models of IBD or human patients with IBD. Articles were screened, and data extracted, independently and in duplicate. The primary outcomes were clinical remission (clinical) and bowel mucosal damage (preclinical). RESULTS: 21 preclinical (n = 989 animals) and seven clinical (n = 164 patients) studies met eligibility. Preclinically, resistant starch was associated with a significant reduction in bowel mucosal damage compared to placebo (standardized mean difference - 1.83, 95% CI - 2.45 to - 1.20). Clinically, five studies reported data on clinical remission but clinical and methodological heterogeneity precluded pooling. In all five, a positive effect was seen in patients who consumed resistant starch supplemented diets. The majority of studies in both the preclinical and clinical settings were at a high or unclear risk of bias due to poor methodological reporting. CONCLUSIONS: Our review demonstrates that resistant starch is associated with reduced histology damage in animal studies, and improvements in clinical remission in IBD patients. These results need to be tempered by the risk of bias of included studies. Rigorously designed preclinical and clinical studies are warranted. Trial registration The review protocols were registered on PROSPERO (preclinical: CRD42019130896; clinical: CRD42019129513).

A Systematic Review of the Impact of Surgical Special Care Units on Patient Outcomes and Health Care Resource Utilization.

Perioperative intermediate care units (termed surgical special care units) have been widely implemented across health systems because they are believed to improve surveillance and management of high-risk surgical patients. Our objective was to conduct a systematic review to investigate the effects of a 3-level model of perioperative care delivery (ie, ward, surgical special care unit, or intensive care unit) compared to a 2-level model of care (ie, ward, intensive care unit) on postoperative outcomes. Our protocol was registered with PROSPERO, the international prospective register of systematic reviews (CRD42015025155). Randomized controlled studies and nonrandomized comparator studies were included. We performed a systematic search of Medline, Cumulative Index to Nursing and Allied Health Literature, Embase, and the Cochrane library (inception - 11/2017). The primary outcome was mortality; secondary outcomes included length of stay and hospital costs. We identified 1995 citations with our search, and 21 studies met eligibility criteria (2 randomized controlled studies and 19 nonrandomized comparator studies; 44,134 patients in total). Surgical special care units were characterized by continuous monitoring (12 studies), the absence of mechanical ventilation (8 studies), nurse-to-patient ratios (range, 1:2-1:4), and number of beds (median: 5; range: 3-33). Thirteen studies reported on mortality. Notable findings included no observed difference in overall in-hospital mortality, but an apparent increase in intensive care unit mortality in a 3-level model of care. This may reflect a decanting of lower acuity patients from the intensive care unit to the surgical special care unit. No significant difference was found in hospital length of stay; however, 2 studies demonstrated reductions in hospital costs with the implementation of a surgical special care unit. Significant clinical and methodological heterogeneity precluded pooled analysis. Given the prevalence of surgical special care units, the results of our review suggest that additional methodologically rigorous investigations are needed to understand the effect of these units on the surgical population.

Postoperative shared-care for patients undergoing non-cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Collaborative ("shared-care") models of postoperative care improve outcomes in patients undergoing surgery for hip fracture. Despite being widely adopted, it is unclear if similar benefits of shared-care models exist for other at-risk surgical patient populations. Thus, we performed a systematic review to understand the impact of shared-care models. METHODS: EMBASE, MEDLINE, CINAHL, and Cochrane Central Register databases were searched for prospective studies examining an in-hospital shared-care approach to postoperative management of adult non-cardiac surgery patients. The primary outcome was a composite of in-hospital mortality and mortality of up to 30 days. Secondary outcomes were long-term mortality (> 90 days) and hospital length of stay. Tertiary outcomes included quality of life and health utility measures. Risk of bias was assessed using Cochrane Collaboration tools. RESULTS: Six thousand eight hundred and ninety-six citations were reviewed and four studies (n = 987 patients) met the inclusion criteria-two randomized-controlled trials (RCT, n = 729 patients) and two non-randomized-controlled trials (NRCT, n = 258 patients). All studies were conducted in the elective surgical setting. There was no association between shared-care and control groups for in-hospital mortality (Peto odds ratio, 1.76; 95% confidence interval [CI], 0.65 to 4.80), or hospital length of stay (mean difference, -1.41; 95% CI, -3.18 to 0.35). Reporting of other outcomes was limited. Both RCTs were judged to be at high risk of bias for blinding and both NRCTs were judged to be at moderate risk of bias for reported outcomes. CONCLUSION: Overall, there was limited high-quality evidence to evaluate the effect of postoperative shared-care. Well-designed interventional studies, perhaps targeting higher risk surgical populations, are needed. REGISTRATION: PROSPERO (CRD42018094943); registered 16 May, 2018.

Active surveillance in Canadian men with low-grade prostate cancer.

BACKGROUND: Recent guidelines recommend against routine screening for prostate cancer, partly because of the risks associated with overtreatment of clinically indolent tumours. We aimed to determine the proportion of patients whose low-grade prostate cancer was managed by active surveillance instead of immediate treatment. METHODS: We reviewed data for patients who were referred to the Ottawa regional Prostate Cancer Assessment Clinic with abnormal results for prostate-specific antigen (PSA) or prostate examination between Apr. 1, 2008, and Jan. 31, 2013. Patients with subsequent biopsy-proven low-grade (Gleason score 6) cancer were included. Active surveillance was defined a priori as monitoring by means of PSA, digital rectal examination and repeat biopsies, with the potential for curative-intent treatment in the event of disease progression. RESULTS: Of 477 patients with low-grade cancer, active surveillance was used for 210 (44.0%), and the annual proportion increased from 32% (11/34) in 2008 to 67% (20/30) in 2013. Factors associated with immediate treatment were palpable tumour, PSA density above 0.2 ng/mL(2) and more than 2 positive biopsy cores. Factors associated with surveillance were age over 70 years and higher Charlson comorbidity index. Of 173 men who received immediate surgical treatment, 103 (59.5%) had higher-grade or advanced-stage disease on final pathologic examination. Of the 210 men with active surveillance, 62 (29.5%) received treatment within a median of 1.3 years, most commonly (52 [84%]) because of upgrading of disease on the basis of surveillance biopsy. INTERPRETATION: Active surveillance has become the most common management strategy for men with low-grade prostate cancer at our regional diagnostic centre. Factors associated with immediate treatment reflected those that increase the risk of higher-grade tumours.

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence.

Background: Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9-20 years, and acknowledging the use of an alternative off-label single dose schedule. Objective: The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines. Methods: To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence. Results: Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection. Conclusion: While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.

A systematic assessment of preclinical multilaboratory studies and a comparison to single laboratory studies.

Background: Multicentric approaches are widely used in clinical trials to assess the generalizability of findings, however, they are novel in laboratory-based experimentation. It is unclear how multilaboratory studies may differ in conduct and results from single lab studies. Here, we synthesized the characteristics of these studies and quantitatively compared their outcomes to those generated by single laboratory studies. Methods: MEDLINE and Embase were systematically searched. Screening and data extractions were completed in duplicate by independent reviewers. Multilaboratory studies investigating interventions using in vivo animal models were included. Study characteristics were extracted. Systematic searches were then performed to identify single lab studies matched by intervention and disease. Difference in standardized mean differences (DSMD) was then calculated across studies to assess differences in effect estimates based on study design (>0 indicates larger effects in single lab studies). Results: Sixteen multilaboratory studies met inclusion criteria and were matched to 100 single lab studies. The multicenter study design was applied across a diverse range of diseases, including stroke, traumatic brain injury, myocardial infarction, and diabetes. The median number of centers was four (range 2-6) and the median sample size was 111 (range 23-384) with rodents most frequently used. Multilaboratory studies adhered to practices that reduce the risk of bias significantly more often than single lab studies. Multilaboratory studies also demonstrated significantly smaller effect sizes than single lab studies (DSMD 0.72 [95% confidence interval 0.43-1]). Conclusions: Multilaboratory studies demonstrate trends that have been well recognized in clinical research (i.e. smaller treatment effects with multicentric evaluation and greater rigor in study design). This approach may provide a method to robustly assess interventions and the generalizability of findings between laboratories. Funding: uOttawa Junior Clinical Research Chair; The Ottawa Hospital Anesthesia Alternate Funds Association; Canadian Anesthesia Research Foundation; Government of Ontario Queen Elizabeth II Graduate Scholarship in Science and Technology.

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.

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.

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.