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.

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 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.

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.

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.

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.

Assessing the impact of predatory journals on policy and guidance documents: a cross-sectional study protocol.

INTRODUCTION: Many predatory journals fail to follow best publication practices. Studies assessing the impact of predatory journals have focused on how these articles are cited in reputable academic journals. However, it is possible that research from predatory journals is cited beyond the academic literature in policy documents and guidelines. Given that research used to inform public policy or government guidelines has the potential for widespread impact, we will examine whether predatory journals have penetrated public policy. METHODS AND ANALYSIS: This is a descriptive study with no hypothesis testing. Policy documents that cite work from the known predatory publisher OMICS will be downloaded from the Overton database. Overton collects policy documents from over 1200 sources worldwide. Policy documents will be evaluated to determine how the predatory journal article is used. We will also extract epidemiological details of the policy documents, including: who funded their development, the discipline the work is relevant to and the name of the organisations producing the policy. The record of scholarly citations of the identified predatory articles will also be examined. Findings will be reported with descriptive statistics using counts and percentages. ETHICS AND DISSEMINATION: No ethical approval was required for this study since it does not involve human or animal research. Study findings will be discussed at workshops on journalology and predatory publishing and will be disseminated through preprint, peer-reviewed literature and conference presentations.

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.

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.

MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair. METHODS: English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF). RESULTS: Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8-28.5%, p < 0.001) and NBF (26.1% MD; 10.3-41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20). CONCLUSION: Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.

Tolerability and SCFA production after resistant starch supplementation in humans: a systematic review of randomized controlled studies.

BACKGROUND: Resistant starches (RSs) have been advocated as a dietary supplement to address microbiota dysbiosis. They are postulated to act through the production of SCFAs. Their clinical tolerability and effect on SCFA production has not been systematically evaluated. OBJECTIVES: We conducted a systematic review of RS supplementation as an intervention in adults (healthy individuals and persons with medical conditions) participating in randomized controlled trials. The primary outcome was tolerability of RS supplementation, the secondary outcome was SCFA production. METHODS: MEDLINE, Embase, and the Cochrane Central Register were searched. Articles were screened, and data extracted, independently and in duplicate. RESULTS: A total of 39 trials met eligibility criteria, including a total of 2263 patients. Twenty-seven (69%) studies evaluated the impact of RS supplementation in healthy subjects whereas 12 (31%) studies included individuals with an underlying medical condition (e.g., obesity, prediabetes). Type 2 RS was most frequently investigated (29 studies). Of 12 studies performed in subjects with health conditions, 11 reported on tolerability. All studies showed that RS supplementation was tolerated; 9 of these studies used type 2 RS with doses of 20-40 g/d for >4 wk. Of 27 studies performed in healthy subjects, 20 reported on tolerability. In 14 studies, RS supplementation was tolerated, and the majority used type 2 RS with a dose between 20 and 40 g/d. Twenty-one (78%) studies reporting SCFAs used type 2 RS with a dose of 20-40 g/d for 1-4 wk. In 16 of 23 studies (70%), SCFA production was increased, in 7 studies there was no change in SCFA concentration before and after RS supplementation, and in 1 study SCFA concentration decreased. CONCLUSIONS: Available evidence suggests that RS supplementation is tolerated in both healthy subjects and in those with an underlying medical condition. In addition, SCFA production was increased in most of the studies.

Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: A meta-analysis.

Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC-EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta-research methods, we determined the effectiveness of MSC-EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta-analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC-EVs markedly reduced lung injury (SMD -4.33, CI -5.73 to -2.92), vascular permeability (SMD -2.43, CI -3.05 to -1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC-EVs (SMD -1.45, CI -2.08 to -0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD -4.16, CI -5.68 to -2.64) and hypertrophy (SMD -2.80, CI -3.68 to -1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC-EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334.

Patient engagement in preclinical laboratory research: A scoping review.

BACKGROUND: 'Patient engagement' involves meaningful collaboration between researchers and 'patient partners' to co-create research. It helps ensure that research being conducted is relevant to its ultimate end-users. Although patient engagement within clinical research has been well documented, the prevalence and effects of patient engagement in translational preclinical laboratory research remain unclear. The aim of this scoping review is to present current patient engagement activities reported in preclinical laboratory research. METHODS: MEDLINE, Embase, and grey literature were systematically searched from inception to April 2021. Studies that described or investigated patient engagement in preclinical laboratory research were included. Patient engagement activities where patients (i.e. patients, family members, caregivers or community members) provided input, or consultation on at least one element of the research process were eligible for inclusion. Study characteristics and outcomes were extracted and organized thematically. FINDINGS: 32 reports were included (30 primary studies, 1 narrative review, and 1 researcher guide). Most studies engaged patients at the education or priority setting stages (n=26). The most frequently reported benefit of patient engagement was 'providing a mutual learning opportunity'. Reported barriers to patient engagement reflected concerns around 'differences in knowledge and research experience' and how this may challenge communication and limit meaningful collaboration. INTERPRETATION: Patient engagement is feasible and beneficial for preclinical laboratory research. Future work should focus on assessing the impacts of patient engagement in this area of research. FUNDING: None.

The Effects of Biological Sex on Sepsis Treatments in Animal Models: A Systematic Review and a Narrative Elaboration on Sex- and Gender-Dependent Differences in Sepsis.

Preclinical studies provide an opportunity to evaluate the relationship between sex and sepsis, and investigate underlying mechanisms in a controlled experimental environment. The objective of our systematic review was to assess the impact of biological sex on treatment response to fluid and antibiotic therapy in animal models of sepsis. Furthermore, we provide a narrative elaboration of sex-dependent differences in preclinical models of sepsis. DATA SOURCES: MEDLINE and Embase were searched from inception to March 16, 2020. STUDY SELECTION: All studies reporting sex-stratified data comparing antibiotics and/or fluid resuscitation with a placebo or no treatment arm in an in vivo model of sepsis were included. DATA EXTRACTION: Outcomes of interest were mortality (primary) and organ dysfunction (secondary). Risk of bias was assessed. Study selection and data extraction were conducted independently and in duplicate. DATA SYNTHESIS: The systematic search returned 2,649 unique studies, and two met inclusion criteria. Both studies used cecal ligation and puncture models with imipenem/cilastatin antibiotics. No eligible studies investigated fluids. In one study, antibiotic therapy significantly reduced mortality in male, but not female, animals. The other study reported no sex differences in organ dysfunction. Both studies were deemed to be at a high overall risk of bias. CONCLUSIONS: There is a remarkable and concerning paucity of data investigating sex-dependent differences in fluid and antibiotic therapy for the treatment of sepsis in animal models. This may reflect poor awareness of the importance of investigating sex-dependent differences. Our discussion therefore expands on general concepts of sex and gender in biomedical research and sex-dependent differences in key areas of sepsis research such as the cardiovascular system, immunometabolism, the microbiome, and epigenetics. Finally, we discuss current clinical knowledge, the potential for reverse translation, and directions for future studies. REGISTRATION: PROSPERO CRD42020192738.

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.

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.

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.

Hematologists' barriers and enablers to screening and recruiting patients to a chimeric antigen receptor (CAR) T cell therapy trial: a theory-informed interview study.

BACKGROUND: Novel therapies often fail to reach the bedside due to low trial recruitment rates. Prior to conducting one of the first chimeric antigen receptor (CAR) T cell therapy trials in Canada, we used the Theoretical Domains Framework, a novel tool for identifying barriers and enablers to behavior change, to identify physician-related barriers and enablers to screening and recruiting patients for an early phase immunotherapy trial. METHODS: We conducted interviews with hematologists across Canada and used a directed content analysis to identify relevant domains reflecting the key factors that may affect screening and recruitment. RESULTS: In total, we interviewed 15 hematologists. Physicians expressed "cautious hope"; while expressing safety, feasibility, and screening criteria concerns, 14 out of 15 hematologists intended to screen for the trial (domains: knowledge, goals, beliefs about consequences, intentions). Physicians underscored the "challenging contexts," identifying resources, workload, forgetting, and patient wait times to receive CAR T cells as key practical barriers to screening (domains: environmental context and resources, memory, attention and decision-making, behavioral regulation). They also highlighted "variability in roles and procedures" that may lead to missed trial candidates (domain: social and professional role). Left unaddressed, these barriers may undermine trial recruitment. CONCLUSIONS: This study is among the first to use the Theoretical Domains Framework from the physician perspective to identify recruitment challenges to early phase trials and demonstrates the value of this approach for identifying barriers to screening and recruitment that may not otherwise have been elicited. This approach can optimize trial procedures and may serve to inform future promising early phase cancer therapy trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03765177 . Registered on December 5, 2018.