Publications by authors named "Risa Shorr"

57 Publications

Effects of living kidney donation on arterial stiffness: a systematic review protocol.

BMJ Open 2021 03 8;11(3):e045518. Epub 2021 Mar 8.

Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Introduction: Kidney donors have been reported to have accelerated progression of aortic stiffness and decreased glomerular filtration compared with healthy non-donors. This is a concern because increased aortic stiffness is an independent predictor of overall cardiovascular disease and all-cause mortality in the general population. To confirm if arterial stiffness increases after donation, we will systematically review all studies that evaluated indices of arterial stiffness in healthy individuals who underwent unilateral nephrectomy for kidney donation compared with age-matched healthy non-nephrectomised controls.

Methods/analysis: We will comprehensively search for studies published between 1 January 1960 and 15 March 2021 in MEDLINE, EMBASE, Cochrane Central, OVID and EBM reviews. All prospective (cohort, case-control, case series and before-and-after studies) and retrospective non-randomised studies reporting indices of arterial stiffness in nephrectomised and non-nephrectomised healthy participants will be included. Primary outcome will be the difference in the functional metrics of arterial stiffness between donors and non-donors. Secondary outcomes will be the differences in systolic/diastolic blood pressures, serum creatinine, glomerular filtration, carotid artery intima-media thickness and vascular calcification. Study screening, selection and data extraction will be performed by two independent reviewers. Risk of bias will be independently assessed with the ROBINS-I tool and confidence in evidence by the Grading of Recommendations Assessment, Development and Evaluation recommendations. Qualitative and quantitative data syntheses as well as clinical and statistical heterogeneity (Forest plots, I and Cochran's Q statistics) will be evaluated. If clinical and statistical heterogeneity are acceptable, inverse variance-weighted effects will be analysed by random effect models.

Ethics And Dissemination: No ethical approval is necessary. Our results will be disseminated through peer-review publication and presentations to guide stakeholders on the evaluation and follow-up care of kidney donors.

Prospero Registration Number: CRD42020185551.
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http://dx.doi.org/10.1136/bmjopen-2020-045518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942241PMC
March 2021

MicroRNA in Human Acute Kidney Injury: A Systematic Review Protocol.

Can J Kidney Health Dis 2021 24;8:20543581211009999. Epub 2021 Apr 24.

Division of Nephrology, Department of Medicine and Kidney Research Centre, Ottawa Hospital Research Institute, The University of Ottawa and The Ottawa Hospital, ON, Canada.

Background: Acute kidney injury (AKI) is a common complication of hospitalization with high morbidity and mortality for which no effective treatments exist and for which current diagnostic tools have limitations for earlier identification. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in the pathogenesis of AKI, and some miRNAs have shown promise as therapeutic tools in animal models of AKI. However, less is known about the role of miRNAs in human AKI.

Objective: To evaluate the role of miRNAs in human subjects with AKI.

Design: Systematic review and meta-analysis.

Measurements: Quantification of miRNA levels from human blood, urine, or kidney biopsy samples, and measures of renal function as defined in the study protocol.

Methods: A comprehensive search strategy for Ovid MEDLINE All, Embase, Web of Science, and CENTRAL will be developed to identify investigational studies that evaluated the relationship between miRNA levels and human AKI. Primary outcomes will include measurements of kidney function and miRNA levels. Study screening, review and data extraction will be performed independently by 2 reviewers. Study quality and certainty of evidence will be assessed with validated tools. A narrative synthesis will be included and the possibility for meta-analysis will be assessed according to characteristics of clinical and statistical heterogeneity between studies.

Limitations: These include (1) lack of randomized trials of miRNAs for the prevention or treatment of human AKI, (2) quality of included studies, and (3) sources of clinical and statistical heterogeneity that may affect strength and reproducibility of results.

Conclusion: Previous studies of miRNAs in different animal models of AKI have generated strong interest on their use for the prevention and treatment of human AKI. This systematic review will characterize the most promising miRNAs for human research and will identify methodological constraints from miRNA research in human AKI to help inform the design of future studies.

Systematic Review Registration: PROSPERO CRD42020201253.
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http://dx.doi.org/10.1177/20543581211009999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072838PMC
April 2021

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

Hematol Oncol 2021 May 8. Epub 2021 May 8.

Cancer Therapeutics Program, The Ottawa Hospital Research Institute, Ottawa, ON, Canada.

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.
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http://dx.doi.org/10.1002/hon.2875DOI Listing
May 2021

Contemporary Neoadjuvant Therapies for High-Risk Melanoma: A Systematic Review.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Division of General Surgery, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.

Despite advances in adjuvant immuno- and targeted therapies, the risk of relapse for stage III melanoma remains high. With 43 active entries on clinicaltrials.gov (8 July 2020), there is a surge of interest in the role of contemporary therapies in the neoadjuvant setting. We conducted a systematic review of trials performed in the last decade evaluating neoadjuvant targeted, immuno- or intralesional therapy for resectable stage III or IV melanoma. Database searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials were conducted from inception to 13 February 2020. Two reviewers assessed titles, abstracts, and full texts. Trials investigating contemporary neoadjuvant therapies in high-risk melanoma were included. Eight phase II trials (4 randomized and 4 single-arm) involving 450 patients reported on neoadjuvant anti-BRAF/MEK targeted therapy (3), anti-PD-1/CTLA-4 immunotherapy (3), and intralesional therapy (2). The safest and most efficacious regimens were dabrafenib/trametinib and combination ipilimumab (1 mg/kg) + nivolumab (3 mg/kg). Pathologic complete response (pCR) and adverse events were comparable. Ipilimumab + nivolumab exhibited longer RFS. Contemporary neoadjuvant therapies are not only safe, but also demonstrate remarkable pCR and RFS-outcomes which are regarded as meaningful surrogates for long-term survival. Studies defining predictors of pCR, its correlation with oncologic outcomes, and phase III trials comparing neoadjuvant therapy to standard of care will be crucial.
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http://dx.doi.org/10.3390/cancers13081905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071293PMC
April 2021

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack-Protocol for a systematic review and network meta-analysis.

PLoS One 2021 28;16(4):e0250553. Epub 2021 Apr 28.

University of Ottawa, School of Epidemiology and Public Health, Ottawa, Ontario, Canada.

Introduction: Patients with minor ischemic stroke or transient ischemic attack represent a high-risk population for recurrent stroke. No direct comparison exists comparing dual antiplatelet therapy regimens-namely, Ticagrelor and Aspirin versus Clopidogrel and Aspirin. This systematic review and network meta-analysis (NMA) will examine the efficacy of these two different antiplatelet regimens in preventing recurrent stroke and mortality up to 30 days.

Methods And Analysis: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched with the assistance of a medical information specialist. Two independent reviewers will screen studies for inclusion; eligible studies will include randomized controlled trials that enrolled adults presenting with acute minor ischemic stroke or transient ischemic attack and compared one or more of the interventions against each other and/or a control. The primary outcomes will be recurrent ischemic stroke up to 30 days from symptom onset. Secondary outcomes will include safety outcomes (I.e. major bleeding and mortality), functional disability, and outcomes up to 90 days from symptom onset. A Bayesian approach to NMA will be implemented using the BUGSnet function in R Software. Between group comparisons for time-to-event (TTE) and dichotomous outcomes will be presented in terms of hazard ratios and odds ratios with 95% credible intervals, respectively. Secondary effect measures of treatment ranking will also be estimated.

Ethics And Dissemination: No formal research ethics approval are necessary. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will aid clinicians in decision-making on the choice of antithrombotic therapy in a high-risk stroke population and could be important in the development of future treatment trials and guidelines. Registration ID with Open Science Framework: 10.17605/OSF.IO/XDJYZ.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081237PMC
April 2021

MSC-Derived Extracellular Vesicles to Heal Diabetic Wounds: a Systematic Review and Meta-Analysis of Preclinical Animal Studies.

Stem Cell Rev Rep 2021 Apr 24. Epub 2021 Apr 24.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Introduction: Extracellular vesicles from mesenchymal stromal cells (MSC-EVs) have shown promise in wound healing. Their use in diabetic wounds specifically, however, remains pre-clinical and their efficacy remains uncertain less clear. A systematic review of preclinical studies is needed to determine the efficacy of MSC-EVs in the treatment of diabetic wounds to accelerate the clinical translation of this cell-based therapy.

Methods: PubMed and Embase were searched (to June 23, 2020). All English-language, full-text, controlled interventional studies comparing MSC-EVs to placebo or a "no treatment" arm in animal models of diabetic wounds were included. Study outcomes, including wound closure (primary outcome), scar width, blood vessel number and density, and re-epithelialisation were pooled using a random effects meta-analysis. Risk of bias (ROB) was assessed using the SYRCLE tool for pre-clinical animal studies.

Results: A total of 313 unique records were identified from our search, with 10 full text articles satisfying inclusion criteria (n = 136 animals). The administration of MSC-EVs improved closure of diabetic wounds compared to controls with a large observed effect (Standardized Mean Difference (SMD) 5.48, 95% Confidence Interval (CI) 3.55-8.13). Healing was further enhanced using MSC-EVs enriched in non-coding RNAs or microRNAs compared to controls (SMD 9.89, 95%CI 7.32-12.46). Other outcomes, such as blood vessel density and number, scar width, and re-epithelialisation were improved with the administration of MSC-EVs, with a large effect. ROB across studies was unclear.

Conclusion: MSC-EVs, particularly following enrichment for specific RNAs, are a promising treatment for diabetic wounds in pre-clinical studies and translation to the clinical domain appears warranted.

Registration: PROSPERO #CRD42020199327 [248]. Forest plot demonstrating increased wound closure rates of diabetic wounds receiving genetically modified MSC-EVs that were enriched for specific RNAs. DFO = deferoxamine. Control groups were inactive (no treatment or saline) except for 3 studies which used hydrogels without MSC-EVs as control (Li M 2016; Shi 2017; Tao 2016).
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http://dx.doi.org/10.1007/s12015-021-10164-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064883PMC
April 2021

Mesenchymal Stromal Cell-derived Extracellular Vesicles in Preclinical Animal Models of Tumor Growth: Systematic Review and Meta-analysis.

Stem Cell Rev Rep 2021 Apr 15. Epub 2021 Apr 15.

Clinical Epidemiology, Ottawa Hospital Research Institute, Box 704, 501 Smyth Rd, ON, K1H 8L6, Ottawa, Canada.

Background: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials.

Methods: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed.

Results: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied.

Conclusions: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.
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http://dx.doi.org/10.1007/s12015-021-10163-5DOI Listing
April 2021

The COVID-19 pandemic: An opportunity to rethink and harmonise the frequency of follow-up visits for patients with early stage breast cancer.

Cancer Treat Rev 2021 Jun 23;97:102188. Epub 2021 Mar 23.

Division of Medical Oncology (Department of Medicine), The Ottawa Hospital Cancer Centre, Ottawa, Canada; Ottawa Hospital Research Institute, Ottawa, Canada. Electronic address:

Purpose: While routine, in-person follow-up of early-stage breast cancer patients (EBC) after completion of initial treatment is common, the COVID-19 pandemic has resulted in unprecedented changes in clinical practice. A systematic review was performed to evaluate the evidence supporting different frequencies of routine follow-up.

Methods: MEDLINE and the Cochrane Collaboration Library were searched from database inception to July 16, 2020 for randomized controlled trials (RCTs) and prospective cohort studies (PCS) evaluating different frequencies of routine follow-up. Citations were assessed by pairs of independent reviewers. Risk of Bias (RoB) was assessed using the Cochrane RoB tool for RCTs and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. Findings were summarized narratively.

Results: The literature search identified 3316 studies, of which 7 (6 RCTs and 1 PCS) were eligible. Study endpoints included; quality of life (QoL; 5 RCTs and 1 PCS), disease free survival (DFS) (1 RCT), overall survival (OS) (1 RCT) and cost-effectiveness (1 RCT). The results showed reduction in follow-up frequency had no adverse effect on: QoL (6 studies, n = 920), DFS (1 trial, n = 472) or OS (1 trial, n = 472), but improved cost-effectiveness (1 trial, n = 472). Four RCTs specifically examined follow-up on-demand versus scheduled follow-up visits and found no statistically significant differences in QoL (n = 544).

Conclusion: While no evidence-based guidelines suggest that follow-up of EBC patients improves DFS or OS, routinely scheduled in-person assessment is common. RCT data suggests that reduced frequency of follow-up has no adverse effects.
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http://dx.doi.org/10.1016/j.ctrv.2021.102188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986467PMC
June 2021

Persistence of CRISPR/Cas9 gene edited hematopoietic stem cells following transplantation: A systematic review and meta-analysis of preclinical studies.

Stem Cells Transl Med 2021 Mar 5. Epub 2021 Mar 5.

Canadian Blood Services, Stem Cells and Centre for Innovation, Ottawa, Ontario, Canada.

Gene editing blood-derived cells is an attractive approach to cure selected monogenic diseases but remains experimental. A systematic search of preclinical controlled studies is needed to determine the persistence of edited cells following reinfusion. All studies identified in our systematic search (to 20 October 2020) examining the use of CRISPR/Cas9 gene editing in blood-derived cells for transplantation were included. Meta-analysis was performed to determine the engraftment and persistence of gene edited cells. A total of 3538 preclinical studies were identified with 15 published articles meeting eligibility for meta-analysis. These in vivo animal studies examined editing of hemoglobin to correct sickle cell disease (eight studies), inducing resistance to acquired immunodeficiency syndrome (two studies), and six other monogenic disorders (single studies). CRISPR-Cas9 edited hematopoietic stem and progenitor cells demonstrated equivalent early engraftment compared to controls in meta-analysis but persistence of gene-edited cells was reduced at later time points and in secondary transplant recipients. Subgroup analysis in studies targeting the hemoglobin gene revealed a significant reduction in the persistence of gene-edited cells whether homology-directed repair or nonhomologous end-joining were used. No adverse side effects were reported. Significant heterogeneity in study design and outcome reporting was observed and the potential for bias was identified in all studies. CRISPR-Cas9 gene edited cells engraft similarly to unedited hematopoietic cells. Persistence of gene edited cells, however, remains a challenge and improved methods of targeting hematopoietic stem cells are needed. Reducing heterogeneity and potential risk of bias will hasten the development of informative clinical trials.
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http://dx.doi.org/10.1002/sctm.20-0520DOI Listing
March 2021

Direct oral anticoagulants in treatment of cerebral venous thrombosis: a systematic review.

BMJ Open 2021 02 16;11(2):e040212. Epub 2021 Feb 16.

Department of Medicine, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objectives: Current guidelines do not recommend direct oral anticoagulants (DOACs) to treat cerebral venous thrombosis (CVT) despite their benefits over standard therapy. We performed a systematic review to summarise the published experience of DOAC therapy in CVT.

Data Sources: MEDLINE, Embase and COCHRANE databases up to 18 November 2020.

Eligibility Criteria: All published articles of patients with CVT treated with DOAC were included. Studies without follow-up information were excluded.

Data Extraction And Synthesis: Two independent reviewers screened articles and extracted data. A risk of bias analysis was performed.

Primary And Secondary Outcome Measures: Safety data included mortality, intracranial haemorrhage (ICH) or other adverse events. Efficacy data included recurrent CVT, recanalisation rates and disability by modified Rankin Scales (mRS).

Results: 33 studies met inclusion criteria. One randomised controlled trial, 5 observational cohorts and 27 case series or studies reported 279 patients treated with DOAC for CVT: 41% dabigatran, 47% rivaroxaban, 10% apixaban and 2% edoxaban, in addition to 315 patients treated with standard therapy. The observational cohorts showed a similar risk of death in DOAC and standard therapy arms (RR 2.12, 95% CI 0.29 to 15.59). New ICH was reported in 2 (0.7%) DOAC-treated patients and recurrent CVT occurred in 4 (1.5%). A favourable mRS between 0 and 2 was reported in 94% of DOAC-treated patients, more likely than standard therapy in observational cohorts (RR 1.13, 95% CI 1.02 to 1.25).

Conclusion: The evidence for DOAC use in CVT is limited although suggests sufficient safety and efficacy despite variability in timing and dose of treatment. This systematic review highlights that further rigorous trials are needed to validate these findings and to determine optimal treatment regimens.
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http://dx.doi.org/10.1136/bmjopen-2020-040212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888326PMC
February 2021

Optimising weight-loss interventions in cancer patients-A systematic review and network meta-analysis.

PLoS One 2021 4;16(2):e0245794. Epub 2021 Feb 4.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.

Background: Excess weight has been associated with increased morbidity and a worse prognosis in adult patients with early-stage cancer. The optimal lifestyle interventions to optimize anthropometric measures amongst cancer patients and survivors remain inconsistent.

Objective: To conduct a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing the effects of exercise and dietary interventions alone or in combination on anthropometric measures of adult cancer patients and survivors.

Methods: A systematic search of Medline, Embase and the Cochrane Trials Registry was performed. Outcomes of interest included changes in weight, body mass index (BMI), and waist circumference. Screening and data collection were performed by two reviewers. Bayesian NMAs were performed.

Results: Overall, 98 RCTs were included; 75 were incorporated in NMAs (n = 12,199). Groups of intervention strategies included: 3 exercise interventions, 8 dietary interventions, 7 combination interventions of diet and exercise and standard care. Median intervention duration was 26 weeks. NMA suggested that diet alone (mean difference [MD] -2.25kg, 95% CrI -3.43 to -0.91kg) and combination strategies (MD -2.52kg, 95% CrI -3.54 to -1.62kg) were associated with more weight loss compared to standard care. All dietary interventions achieved a similar magnitude of weight loss (MD range from -2.03kg to -2.52kg). Both diet alone and combination strategies demonstrated greater BMI reductions versus standard care, and each of diet alone, exercise alone and combination strategies demonstrated greater reductions in waist circumference than standard care.

Conclusion: Diet and exercise alone or in combination are effective lifestyle interventions to improve anthropometric measures in cancer patients and survivors. All reputable diets appear to be similarly effective to achieve weight loss.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245794PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861370PMC
February 2021

Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis.

Syst Rev 2021 01 21;10(1):35. Epub 2021 Jan 21.

Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Chimeric antigen receptor (CAR) T cell therapy has had great success in treating patients with relapsed or refractory B cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fails to respond or relapse after CD19 CAR T cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials. Given the heterogeneity and small size of CAR T cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T cell therapies targeting CD22, alone or in combination with other antigen targets, in B cell malignancies.

Methods: We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and cataloged. Interventional studies investigating CD22 CAR T cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B cell malignancies will be eligible for inclusion. Only full-text articles, conference abstracts, letters, and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate, a meta-analysis will be performed using a random effects model to synthesize results.

Discussion: The results of the proposed review will help inform clinicians, patients, and other stakeholders of the risks and benefits of CD22 CAR T cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T cells.

Systematic Review Registration: PROSPERO registration number: CRD42020193027.
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http://dx.doi.org/10.1186/s13643-021-01588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819297PMC
January 2021

Exploring Peaks in Hospital Blood Component Utilization: A 10-Year Retrospective Study at a Large Multisite Academic Centre.

Transfus Med Rev 2021 Jan 12;35(1):37-45. Epub 2020 Nov 12.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Canadian Blood Services, Ottawa, Ontario, Canada; Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

Peak demand analysis is common in industries such as the energy sector, but can also be applied to the field of transfusion to characterize the nature and timing of peak days in hospital blood utilization. This information can be used to forecast future peak days or to inform hospital emergency preparedness plans. The aims of this study are to characterize peak days in red blood cell (RBC) utilization over the past 10 years at our hospital, and to compare RBC peaks with peaks in platelet, plasma, and cryoprecipitate utilization. This was a retrospective cohort study of RBC, platelet, plasma, and cryoprecipitate transfusions in the inpatient and emergency department setting between May 2009 and April 2019 at a large academic hospital, containing regional trauma and cardiovascular surgery centers. For each blood product, a peak in utilization was defined as a day with a ≥50% increase in the number of units transfused compared to the previous 90-day average. Descriptive and inferential analyses were performed to characterize peak days. There were on average 20,501 RBCs transfused per year and 56 RBCs transfused per day over the 10-year period. A total of 134 peaks in RBC utilization occurred over the study period, with an average of 14 peaks per year. RBC peak days required on average 69% more RBC units compared to nonpeak days (P< .0001). 77% of RBC peaks were caused either solely or in part by surgical bleeding, 34% were caused entirely or in part by trauma, and other causes were infrequent. RBC peaks occurred most often on Fridays and least often on weekends (P< .0001). While there were 134 RBC peaks over the study period, there was a larger number of platelet (n = 292), plasma (n = 467), and cryoprecipitate peaks (n = 579). RBC peak days often coincided with plasma peak days, but less frequently with platelet and cryoprecipitate peaks. More studies are needed to determine whether analysis of peak usage will be of value to hospital blood banks for emergency planning and blood inventory management.
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http://dx.doi.org/10.1016/j.tmrv.2020.10.002DOI Listing
January 2021

Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults.

BMJ Open 2020 12 7;10(12):e040122. Epub 2020 Dec 7.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal yet treatable disease. Several advances in treatment of VTE have been made over the past decades, but definition and reporting of outcomes across those studies are inconsistent. Development of an international core outcome set for clinical studies of interventions for VTE addresses this lack of standardisation. The first step in the development of a core outcome set is to conduct a scoping review which aims to generate an inclusive list of unique outcomes that have been reported in previous studies.

Methods And Analysis: MEDLINE, Embase and the Cochrane Central Register of Controlled Trials will be searched with no language restriction for prospective studies reporting on interventions for treatment of VTE in patients who are adult and non-pregnant. Records will be sorted in reverse chronological order. Study screening and data extraction will be independently performed by two authors in blocks based on date of publication, starting with 2015 to 2020 and subsequent 1-year periods, until no new outcome measures are identified from the set of included studies. After homogenising spelling and combining outcomes with the same meaning, a list of unique outcomes will be determined. Those outcomes will be grouped into outcome domains. Qualitative analysis and descriptive statistics will be used to report results.

Ethics And Dissemination: Ethical approval is not required for this study. The results of this scoping review will be presented at scientific conferences, published in a peer-reviewed journal, and they will provide candidate outcome domains to be considered in subsequent steps in the development of a core outcome set for clinical studies of interventions for VTE. PROTOCOL REGISTRATION DETAILS: http://hdl.handle.net/10393/40459.
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http://dx.doi.org/10.1136/bmjopen-2020-040122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722803PMC
December 2020

Preclinical Studies of MSC-Derived Extracellular Vesicles to Treat or Prevent Graft Versus Host Disease: a Systematic Review of the Literature.

Stem Cell Rev Rep 2021 Apr 7;17(2):332-340. Epub 2020 Nov 7.

Department of Medicine (Blood and Marrow Transplantation), The Ottawa Hospital, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.

Introduction: Treating and preventing graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT) remains a significant challenge. The use of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) appears promising and a systematic review of preclinical studies is needed to accelerate the design of translational studies.

Methods: We identified 4 eligible studies from a systematic review performed on December 1, 2018. In brief, eligible studies included the treatment or prevention of GVHD in animal models and the use of MSC-EVs. Study design and outcome data were extracted and reporting was evaluated using the SYRCLE tool to identify potential bias.

Results: Two studies assessed the efficacy of MSC-EVs in treatment of GVHD and 2 studies address prevention. Mice treated with MSC-EVs showed improved median survival, GVHD clinical scores and histology scores as compared to untreated mice with GVHD. Prophylactic treatment with MSC-EVs attenuated GVHD severity and improved median survival as compared to no treatment or saline.

Conclusion: Our systematic review provides important insight regarding the potential of MSC-EVs to treat or prevent GVHD. Although few studies were identified, improved survival and attenuated histologic findings of GVHD were observed in mice after MSC-EV administration for the treatment and prevention of GVHD. Dosing of EVs and route of administration remain inconsistent, however, and scalability of EV isolation for clinical studies remains a challenge. Standardized outcome reporting is needed to pool results for metanalysis. Graphical abstract.
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http://dx.doi.org/10.1007/s12015-020-10058-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648545PMC
April 2021

A scoping review characterizing "Choosing Wisely®" recommendations for breast cancer management.

Breast Cancer Res Treat 2021 Feb 6;185(3):533-547. Epub 2020 Nov 6.

Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.

Purpose: Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient-physician conversations about unnecessary medical interventions. Similarly, other countries created their own panels of experts called "CW® campaigns" which review recommendations submitted by that country's oncology societies. We performed a scoping review to consolidate CW® recommendations from different groups with respect to breast cancer care.

Methods: A systematic search of Medline and Embase was designed by an information specialist for publications presenting CW® recommendations for breast cancer care practices from 2011-2020. We also reviewed the websites of all CW® campaigns and reference sections of each CW® recommendation. Two reviewers independently screened studies for inclusion and performed data extraction. Findings were summarized narratively.

Results: Review of ABIM CW® recommendations showed 19 breast cancer-related recommendations pertaining to; screening (n = 4), radiological staging (n = 2), treatment (n = 10), surveillance (n = 2), and miscellaneous (genetic testing; n = 1). Of 22 countries with CW® campaigns, 10 published recommendations for breast cancer. Over half (57%) of recommendations were supported by more than one country. No recommendations were refuted between campaigns. Two campaigns developed 3 novel recommendations on new topics, including chemotherapy in ductal carcinoma in situ (Italy) and comparison of screening imaging modalities (Portugal).

Conclusions: CW® recommendations focus on reducing overutilization of investigations and treatments. There was a high rate of consensus between different CW® campaigns. As health care systems globally move attention to reduce low-value care, further studies are required to address adherence to these current recommendations and develop new recommendations.
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http://dx.doi.org/10.1007/s10549-020-06009-2DOI Listing
February 2021

Transcatheter Mitral Valve Repair in Cardiogenic Shock and Mitral Regurgitation: A Patient-Level, Multicenter Analysis.

JACC Cardiovasc Interv 2021 01 14;14(1):1-11. Epub 2020 Oct 14.

Department of Cardiac Surgery, San Raffaele Scientific Institute, Milan, Italy.

Objectives: The aim of this study was to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR).

Background: Patients in cardiogenic shock with severe MR have a poor prognosis in the setting of conventional medical therapy. Because of its favorable safety profile, TMVr is being increasingly used as an acute therapy in this population, though its efficacy remains unknown.

Methods: A multicenter, collaborative, patient-level analysis was conducted. Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success.

Results: Between January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03).

Conclusions: TMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock.
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http://dx.doi.org/10.1016/j.jcin.2020.08.037DOI Listing
January 2021

Educational interventions are associated with improvements in colonoscopy quality indicators: a systematic review and meta-analysis.

Endosc Int Open 2020 Oct 22;8(10):E1321-E1331. Epub 2020 Sep 22.

Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Canada.

 The quality of screening-related colonoscopy depends on several physician- and patient-related factors. Adenoma detection rate (ADR) varies considerably between endoscopists. Educational interventions aim to improve endoscopists' ADRs, but their overall impact is uncertain. We aimed to assess whether there is an association between educational interventions and colonoscopy quality indicators. A comprehensive search was performed through August 2019 for studies reporting any associations between educational interventions and any colonoscopy quality indicators. Our primary outcome of interest was ADR. Two authors assessed eligibility criteria and extracted data independently. Risk of bias was also assessed for included studies. Pooled rate ratios (RR) with 95 % confidence intervals (CI) were reported using DerSimonian and Laird random effects models. From 2,253 initial studies, eight were included in the meta-analysis for ADR, representing 86,008 colonoscopies. Educational interventions were associated with improvements in overall ADR (RR 1.29, 95 % CI 1.25 to 1.42, 95 % prediction interval 1.09 to 1.53) and proximal ADR (RR 1.39, 95 % CI 1.29 to 1.48), with borderline increases in withdrawal time, ([WT], mean difference 0.29 minutes, 95 % CI - 0.12 to 0.70 minutes). Educational interventions did not affect cecal intubation rate ([CIR], RR 1.01, 95 % CI 1.00 to 1.01). Heterogeneity was considerable across many of the analyses. Educational interventions are associated with significant improvements in ADR, in particular, proximal ADR, and are not associated with improvements in WT or CIR. Educational interventions should be considered an important option in quality improvement programs aiming to optimize the performance of screening-related colonoscopy.
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http://dx.doi.org/10.1055/a-1221-4922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508648PMC
October 2020

Association Between Time to Colonoscopy After Positive Fecal Testing and Colorectal Cancer Outcomes: A Systematic Review.

Clin Gastroenterol Hepatol 2020 Oct 1. Epub 2020 Oct 1.

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Cancer Epidemiology and Prevention Research, Cancer Care Alberta, Alberta Health Services, Calgary, Alberta, Canada. Electronic address:

Background & Aims: Colonoscopy is required following a positive fecal screening test for colorectal cancer (CRC). It remains unclear to what extent time to colonoscopy is associated with CRC-related outcomes. We performed a systematic review to elucidate this relationship.

Methods: An electronic search was performed through April 2020 for studies reporting associations between time from positive fecal testing to colonoscopy and outcomes including CRC incidence (primary outcome), CRC stage at diagnosis, and/or CRC-specific mortality. Our primary objective was to quantify these relationships following positive fecal immunochemical testing (FIT). Two authors independently performed screening, abstraction, and risk of bias assessments.

Results: From 1,612 initial studies, 8 were included in the systematic review, with 5 reporting outcomes for FIT. Although meta-analysis was not possible, consistent trends between longer time delays and worse outcomes were apparent in all studies. Colonoscopy performed beyond 9 months from positive FIT compared to within 1 month was significantly associated with a higher incidence of CRC, with adjusted odds ratios (AORs) of 1.75 and 1.48 in the two largest studies. These studies also reported significant associations between colonoscopy performed beyond 9 months and higher incidence of advanced stage CRC (stage III or IV) at diagnosis, with AORs of 2.79 and 1.55, respectively.

Conclusions: Colonoscopy for positive FIT should not be delayed beyond 9 months. Given the additional time required for urgent referrals and surgical planning for CRC, colonoscopy should ideally be performed well in advance of 9 months following a positive FIT.
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http://dx.doi.org/10.1016/j.cgh.2020.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527352PMC
October 2020

Prevalence of non-contrast CT abnormalities in adults with reversible cerebral vasoconstriction syndrome: protocol for a systematic review and meta-analysis.

BMJ Open 2020 09 21;10(9):e041776. Epub 2020 Sep 21.

Neurology, The Ottawa Hospital, Ottawa, Ontario, Canada.

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is characterised by severe, recurrent thunderclap headaches (TCHs) and vasoconstriction of cerebral arteries that resolve within 3 months. Abnormalities on non-contrast CT (NCCT) such as ischaemic strokes, intracerebral haemorrhage and subarachnoid haemorrhages are frequently observed on brain imaging of patients with RCVS though their prevalence varies considerably between studies. The aim of this systematic review and meta-analysis is to estimate the prevalence of NCCT abnormalities seen on neuroimaging of adult patients with RCVS.

Methods And Analysis: We will search the Medline, Embase and the Cochrane Library databases for studies on the prevalence of NCCT abnormalities on neuroimaging of patients with RCVS. Search results will be screened for eligibility by title and abstract. Suitable studies will be fully reviewed and relevant data extracted using a data abstraction form. The studies will be assessed for methodological quality, risk of bias and heterogeneity. Prevalence estimates across studies will be pooled using a random-effects model and subgroup analysis will be performed to assess the impact of age, sex, publication year and study design on prevalence of vascular lesions. Sensitivity analysis will be used to investigate the robustness of the findings. This protocol has been devised using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist.

Ethics And Dissemination: Formal ethics is not required as primary data will not be collected. The findings of this study will be disseminated through a peer-reviewed publication and conference presentations.

Trial Registration Number: CRD42020190637.
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http://dx.doi.org/10.1136/bmjopen-2020-041776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507847PMC
September 2020

Plerixafor in combination with chemotherapy and/or hematopoietic cell transplantation to treat acute leukemia: A systematic review and metanalysis of preclinical and clinical studies.

Leuk Res 2020 10 27;97:106442. Epub 2020 Aug 27.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Canada; Department of Medicine (Hematology), Faculty of Medicine, University of Ottawa, Canada. Electronic address:

Leukemia-initiating cells localize to bone marrow niches via cell surface CXCR4 binding to stromal-derived factor 1 (SDF-1). Plerixafor, a CXCR4 antagonist, can mobilize and sensitize leukemia cells to cytotoxic therapy, and/or enhance the engraftment of healthy donor stem cells in the context of hematopoietic cell transplantation (HCT). A systematic review of preclinical and clinical studies was performed (updated May 1, 2020) to inform the design of definitive clinical trials and identified 19 studies. Pooled data from 10 preclinical in-vivo studies of AML and ALL in mouse models of leukemia revealed significant mobilization of leukemia cells into the peripheral circulation, decreased total blast burden and increased survival with plerixafor in addition to cytotoxic treatment compared to control animals. Two of 9 clinical studies compared outcomes to a control group. Plerixafor appears well tolerated and safe and can mobilize leukemia cells into the peripheral circulation. In patients with AML undergoing HCT, plerixafor given with the conditioning regimen appears safe and well tolerated. Engraftment, relapse and survival were not different from controls after limited follow-up. Studies in high risk patients with AML with longer follow-up are needed to understand the influence on relapse following treatment and on donor cell engraftment following HCT.
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http://dx.doi.org/10.1016/j.leukres.2020.106442DOI Listing
October 2020

Human endothelial colony-forming cells in regenerative therapy: A systematic review of controlled preclinical animal studies.

Stem Cells Transl Med 2020 11 18;9(11):1344-1352. Epub 2020 Jul 18.

Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Endothelial colony-forming cells (ECFCs) hold significant promise as candidates for regenerative therapy of vascular injury. Existing studies remain largely preclinical and exhibit marked design heterogeneity. A systematic review of controlled preclinical trials of human ECFCs is needed to guide future study design and to accelerate clinical translation. A systematic search of Medline and EMBASE on 1 April 2019 returned 3131 unique entries of which 66 fulfilled the inclusion criteria. Most studies used ECFCs derived from umbilical cord or adult peripheral blood. Studies used genetically modified immunodeficient mice (n = 52) and/or rats (n = 16). ECFC phenotypes were inconsistently characterized. While >90% of studies used CD31+ and CD45-, CD14- was demonstrated in 73% of studies, CD146+ in 42%, and CD10+ in 35%. Most disease models invoked ischemia. Peripheral vascular ischemia (n = 29), central nervous system ischemia (n = 14), connective tissue injury (n = 10), and cardiovascular ischemia and reperfusion injury (n = 7) were studied most commonly. Studies showed predominantly positive results; only 13 studies reported ≥1 outcome with null results, three reported only null results, and one reported harm. Quality assessment with SYRCLE revealed potential sources of bias in most studies. Preclinical ECFC studies are associated with benefit across several ischemic conditions in animal models, although combining results is limited by marked heterogeneity in study design. In particular, characterization of ECFCs varied and aspects of reporting introduced risk of bias in most studies. More studies with greater focus on standardized cell characterization and consistency of the disease model are needed.
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http://dx.doi.org/10.1002/sctm.20-0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581447PMC
November 2020

Associations between endoscopist feedback and improvements in colonoscopy quality indicators: a systematic review and meta-analysis.

Gastrointest Endosc 2020 11 21;92(5):1030-1040.e9. Epub 2020 Apr 21.

Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta; Department of Community Health Sciences, University of Calgary, Calgary, Alberta.

Background And Aims: Colonoscopy quality indicators such as adenoma detection rate (ADR) are surrogates for the effectiveness of screening-related colonoscopy. It is unclear whether endoscopist feedback on these indicators improves performance. We performed a meta-analysis to determine whether associations exist between endoscopist feedback and colonoscopy performance.

Methods: We conducted a search through May 2019 for studies reporting on endoscopist feedback and associations with ADR or other colonoscopy quality indicators. Pooled rate ratios (RRs) and weighted mean differences were calculated using DerSimonian and Laird random effects models. Subgroup, sensitivity, and meta-regression analyses were performed to assess for potential methodological or clinical factors associated with outcomes.

Results: From 1326 initial studies, 12 studies were included in the meta-analysis for ADR, representing 33,184 colonoscopies. Endoscopist feedback was associated with an improvement in ADR (RR, 1.21; 95% confidence interval [CI], 1.09-1.34). Low performers derived a greater benefit from feedback (RR, 1.62; 95% CI, 1.18-2.23) compared with moderate performers (RR, 1.19; 95% CI, 1.11-1.29), whereas high performers did not derive a significant benefit (RR, 1.06; 95% CI, 0.99-1.13). Feedback was not associated with increases in withdrawal time (weighted mean difference, +0.43 minutes; 95% CI, -0.50 to +1.36 minutes) or improvements in cecal intubation rate (RR, 1.00; 95% CI, 0.99-1.01).

Conclusion: Endoscopist feedback is associated with modest improvements in ADR. The implementation of routine endoscopist audit and feedback should be considered alongside other quality improvement interventions in institutions dedicated to the provision of high-quality screening-related colonoscopy.
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http://dx.doi.org/10.1016/j.gie.2020.03.3865DOI Listing
November 2020

Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol.

Syst Rev 2019 12 12;8(1):322. Epub 2019 Dec 12.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.

Background: Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury.

Methods: A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles.

Discussion: This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.
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http://dx.doi.org/10.1186/s13643-019-1242-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909572PMC
December 2019

The safety and efficacy of hypovolemic phlebotomy on blood loss and transfusion in liver surgery: a systematic review and meta-analysis.

HPB (Oxford) 2020 03 13;22(3):340-350. Epub 2019 Nov 13.

Liver and Pancreas Unit, Department of Surgery, The Ottawa Hospital, University of Ottawa, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Canada. Electronic address:

Background: Hypovolemic phlebotomy (HP) is a novel intervention that involves intraoperative removal of whole blood (7-10 mL/kg) without volume replacement. The subsequent central venous pressure (CVP) reduction is hypothesized to decrease blood loss and the need for blood transfusion. The objective was to conduct a systematic assessment of the safety and efficacy of HP on blood loss and transfusion in the liver surgery literature.

Methods: MEDLINE, EMBASE, and Cochrane Library databases were searched. Outcomes of interest included blood loss, allogenic red blood cell transfusion, postoperative adverse events, and CVP change. A qualitative synthesis and meta-analysis were performed as appropriate.

Results: Four cohort studies, one case series, and three randomized controlled trials involving 2255 patients were included. Meta-analysis of studies involving liver resections for any indication (n = 6) found no difference in transfusion (OR 0.38, p = 0.12) or incidence of adverse events with HP compared to non-use. Pooling of studies involving liver resections for an underlying pathology (n = 4) revealed HP was associated with significant reduction in transfusion (OR 0.25, p = 0.03) but no differences in blood loss (-173 mL, p = 0.17).

Conclusion: This review suggests HP is safe and associated with decreased transfusion in patients undergoing liver surgery. It supports further investigation.
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http://dx.doi.org/10.1016/j.hpb.2019.10.001DOI Listing
March 2020

Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy.

Cytotherapy 2019 11 3;21(11):1112-1121. Epub 2019 Oct 3.

Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address:

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.
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http://dx.doi.org/10.1016/j.jcyt.2019.08.004DOI Listing
November 2019

Endoscopic ultrasound-guided transmural approach versus ERCP-guided transpapillary approach for primary decompression of malignant biliary obstruction: a meta-analysis.

Endoscopy 2019 10 23;51(10):950-960. Epub 2019 May 23.

Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.

Background: Primary decompression in patients with malignant biliary obstruction can be achieved via endoscopic retrograde cholangiopancreatography (ERCP) with transpapillary stenting, or, more recently, via transmural endoscopic ultrasound-guided biliary drainage (EUS-BD). It is unclear whether either approach is superior in terms of clinical success or adverse events in the primary setting.

Methods: A comprehensive systematic electronic search was performed for studies comparing EUS-BD and ERCP as the primary approach with respect to clinical success and any other outcome(s). Pooled relative risks (RRs) and weighted mean differences were obtained as appropriate using DerSimonian and Laird random effects models. Sensitivity analyses were also performed.

Results: 5 out of 776 studies with a total of 396 patients were included. Overall clinical success was not significantly different between EUS-BD and ERCP (RR 0.98, 95 % confidence interval [CI] 0.93 to 1.03). There was no significant difference in overall adverse events (RR 0.84, 95 %CI 0.35 to 2.01), though results suggested that EUS-BD may be associated with a reduced risk of pancreatitis (RR 0.22, 95 %CI 0.05 to 1.02). There were no significant differences between EUS-BD and ERCP in terms of procedure time or the risk of stent occlusion.

Conclusions: EUS-BD had similar clinical success rates and occlusion rates to ERCP in the primary decompression of malignant biliary obstruction from meta-analysis including a modest number of patients. EUS-BD may be a practical alternative to the ERCP-guided approach in such patients, but further well-designed prospective studies with larger numbers of patients are required to more clearly delineate potential differences in adverse events and cost.
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http://dx.doi.org/10.1055/a-0901-7343DOI Listing
October 2019

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis.

Breast Cancer Res Treat 2019 Aug 11;176(3):507-517. Epub 2019 May 11.

Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Box 912, Ottawa, ON, K1H 8L6, Canada.

Purpose: Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA's in patients with bone metastases from breast cancer.

Methods: We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014-March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI).

Results: From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88-1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15-1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation.

Conclusions: These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05265-1DOI Listing
August 2019

Identifying stroke therapeutics from preclinical models: A protocol for a novel application of network meta-analysis.

F1000Res 2019 3;8:11. Epub 2019 Jan 3.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.

Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: in preclinical models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke.  : Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. PROSPERO number to be submitted following peer review.
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http://dx.doi.org/10.12688/f1000research.15869.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426098PMC
June 2020

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

Anesth Analg 2019 03;128(3):533-542

From the Department of Anesthesiology and Pain Medicine, The Ottawa Hospital and the University of Ottawa, Ottawa, Ontario, Canada.

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.
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http://dx.doi.org/10.1213/ANE.0000000000003942DOI Listing
March 2019