Extracellular Vesicles as a Cell-free Therapy for Cardiac Repair: a Systematic Review and Meta-analysis of Randomized Controlled Preclinical Trials in Animal Myocardial Infarction Models.

Stem cell therapy for cardiac regeneration has been gaining traction as a possible intervention for the reduction of the burden associated with MI and heart failure. However, stem cell therapies have several shortcomings, including poor engraftment, limited improvements in cardiac function, and possible teratogenicity. Recently, extracellular vesicles (EVs) from stem cell sources have been explored as a novel therapy to regenerate the injured myocardium in several animal MI trials. In this systematic review and meta-analysis, we investigate the use of stem cell-derived EVs for cardiac repair preclinical trials in animal MI models. Cochrane Library, Medline, Embase, PubMed, Scopus and Web of Science and grey literature (Canadian Agency for Drugs, Technologies in Health, and Google Scholar) were searched through August 20, 2020 and 37 articles were included in the final analysis. The overall effect size observed in EV-treated small animals after MI for ejection fraction (EF) was 10.85 [95 %CI: 8.79, 12.90] and for fractional shortening (FS) was 7.19 [95 %CI: 5.43, 8.96] compared to control-treated animals. The most abundant stem cell source used were mesenchymal stem cells which showed robust improvements in EF and FS (MD = 11.89 [95 % CI: 9.44, 14.34] and MD = 6.96 [95 % CI: 4.97, 8.96], respectively). Significant publication bias was detected for EF and FS outcomes. This study supports the use of EVs derived from stem cells as a novel therapy for cardiac repair after MI. Further investigation in larger animal studies may be necessary before clinical trials.PROSPERO registration number: CRD42019142218.

Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials.

The use of bioactive scaffolds in conjunction with stem cell therapies for cardiac repair after a myocardial infarction shows significant promise for clinical translation. We performed a systematic review and meta-analysis of preclinical trials that investigated the use of bioactive scaffolds to support stem cell-aided cardiac regeneration, in comparison to stem cell treatment alone. Cochrane Library, Medline, Embase, PubMed, Scopus, Web of Science, and grey literature were searched through April 23, 2020 and 60 articles were included in the final analysis. The overall effect size observed in scaffold and stem cell-treated small animals compared to stem cell-treated controls for ejection fraction (EF) was 7.98 [95% confidence interval (CI): 6.36, 9.59] and for fractional shortening (FS) was 5.50 [95% CI: 4.35, 6.65] in small animal models. The largest improvements in EF and FS were observed when hydrogels were used (MD = 8.45 [95% CI: 6.46, 10.45] and MD = 5.76 [95% CI: 4.46, 7.05], respectively). Subgroup analysis revealed that cardiac progenitor cells had the largest effect size for FS, and was significant from pluripotent, mesenchymal and endothelial stem cell types. In large animal studies, the overall improvement of EF favoured the use of stem cell-embedded scaffolds compared to direct injection of cells (MD = 10.49 [95% CI: 6.30, 14.67]). Significant publication bias was present in the small animal trials for EF and FS. This study supports the use of bioactive scaffolds to aid in stem cell-based cardiac regeneration. Hydrogels should be further investigated in larger animal models for clinical translation.

A systematic review and meta-analysis evaluating the impact of obesity on outcomes of abdominal aortic aneurysm treatment.

OBJECTIVE: We sought to evaluate the impact of obesity on perioperative mortality and complication rates in patients undergoing endovascular aortic repair (EVAR) and open surgical repair (OSR) for abdominal aortic aneurysms. METHODS: A systematic review of all studies reporting abdominal aortic aneurysm treatment perioperative (30-day) outcomes in obese patients (body mass index ≥30 kg/m2). The primary outcome was 30-day mortality. Secondary outcomes included cardiac complications, respiratory complications, wound complication, renal complications, and neurological complications at 30 days. These outcomes were pooled for meta-analysis. Analysis first compared obese vs nonobese patients undergoing EVAR and OSR then compared EVAR with OSR in obese patients. RESULTS: We identified seven observational studies with 14,971 patients (11,743 EVAR, 3228 OSR). Obese patients undergoing EVAR had lower 30-day mortality (1.5%) compared with nonobese patients (2.2%) (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.50-0.96; P = .03; I2 = 0%; Grade of evidence: low). In OSR, obese patients (5.0%) had similar 30-day mortality to nonobese patients (5.7%) (OR, 0.92; 95% CI, 0.70-1.20; P = .54; I2 = 0%; Grade of evidence: low). Wound complications were higher in obese patients undergoing OSR (OR, 2.30; 95% CI, 1.74-3.06; P < .001; I2 = 0%; Grade of evidence: low). EVAR was associated with a lower 30-day mortality (1.5%) compared with OSR (5.0%) in obese patients (OR, 0.23; 95% CI, 0.12-0.46; P < .001; I2 = 38%; Grade of evidence: low). Cardiac, respiratory, wound, renal, and neurological complications were also reduced in EVAR. CONCLUSIONS: Obese patients have lower 30-day mortality in EVAR compared with nonobese patients. In OSR, obese patients had similar 30-day mortality but higher wound complications compared with nonobese patients. Obese patients otherwise have similar cardiopulmonary complication rates compared with nonobese patients in both EVAR and OSR. EVAR offers lower 30-day mortality and morbidity compared with OSR in obese patients. This study suggests that EVAR is superior to OSR in obese patients.

Exercise intervention in cancer patients with sleep disturbances scheduled for elective surgery: Systematic review.

BACKGROUND & OBJECTIVES: Sleep disturbance is one of the patients' major complaints after major surgery and can impair postoperative recovery. Pre-operative exercise has been shown to increase functional capacity and resilience in cancer patients; scarce knowledge is available on the effects of pre-operative exercise on sleep disturbances. This systematic review aims to determine the impact of pre-operative exercise training alone or as part of multimodal prehabilitation on sleep disturbances and sleep quality in cancer patients. METHODS: A systematic search including Biosis, Cochrane Library and CENTRAL, EMBASE, MEDLINE, and clinical trial registries (clinicaltrials.gov, International Clinical Trials Registry Platform) was performed to identify studies involving a pre-operative exercise intervention in cancer patients awaiting surgery. Trials had to contain at least one sleep measure, assessed subjectively and objectively were included in the systematic review. The quality of the included trials was assessed using the Cochrane Risk of Bias Tool for assessing the risk of bias in randomized trials tool and the ROBINS-I tool for evaluating the risk of bias in non-randomized studies. RESULTS: Seven studies were included (1 RCT, 2 non-RCTs and 4 single-arm design). Due to substantial heterogeneity in the interventions across studies, a meta-analysis was not conducted. The available empirical evidence on the presurgical effect of exercise on sleep outcomes is scarce and, overall, suggests that it has a limited effect. Besides, non-significant improvement of the pre-operative exercise on sleep was unique to the studies that used subjective measures to assess sleep disturbances changes during cancer treatment. CONCLUSION: There are conflicting results and a lack of quality data proving the pre-operative exercise on sleep quality and disturbances. More research is needed in the pre-operative period using clinical sleep disturbances such as insomnia as an inclusion criterion, subjectively and objectively assessed.

Pharmacological intervention for diabetes after pregnancy prevention in women with prior gestational diabetes: A scoping review.

Women with previous gestational diabetes mellitus (GDM) are at increased risk of developing diabetes after pregnancy (DAP), especially 5-10 years postpartum. Two well-known diabetes prevention trials demonstrated a significant reduction in DAP incidence using metformin and troglitazone; however, since their publication, several novel classes of anti-hyperglycemic agents have emerged. This review aimed to conduct a systematic literature search for new evidence in support of pharmacotherapy in DAP prevention and to analyze the results based on special considerations for women of reproductive potential. The only studies whose primary outcome was DAP incidence were those examining metformin, the thiazolidinediones troglitazone and pioglitazone, and the dipeptidyl peptidase-4 inhibitor vildagliptin. Metformin was effective in DAP reduction and was well tolerated, but participants were on average 12 years beyond their GDM pregnancy. Troglitazone was also shown to prevent DAP, but was withdrawn from the market due to hepatotoxicity. There was no comparator arm in the pioglitazone study, which limits its interpretability. The vildagliptin study was underpowered. There are ongoing trials with glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, but none with diabetes incidence as a primary outcome. This review highlights the limited evidence base for pharmacological prevention of DAP.

Bioactive scaffolds in stem-cell-based therapies for cardiac repair: protocol for a meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models.

BACKGROUND: Acute myocardial infarction (MI) remains one of the leading causes of death worldwide with no curative therapy available. Stem cell therapies have been gaining interest as a means to repair the cardiac tissue after MI and prevent the onset of heart failure. Many in vivo reports suggest that the use of stem cells is promising, yet clinical trials suggest that the cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function and repair. To battle this limitation, the combination of using stem cells embedded in a bioactive scaffold that promotes cell retention is growing in interest. Yet, a systematic review of the literature on the use of stem cells embedded in bioactive scaffolds for cardiac repair has not yet been performed. In this protocol, we outline a systematic review and meta-analysis of preclinical trials in animal MI models that utilize stem cell-embedded scaffolds for cardiac repair and compare their effects to stem cell-treated animals without the use of a scaffold. METHODS/DESIGN: We will search the following electronic databases: Cochrane Library, MEDLINE, Embase, PubMed, Scopus and Web of Science, and gray literature: Canadian Agency for Drugs and Technologies in Health and Google Scholar. We will only include randomly controlled preclinical trials that have directly investigated the effects of stem cells embedded in a scaffold for cardiac repair in an animal MI model. Two investigators will independently review each article included in the final analysis. The primary endpoint that will be investigated is left ventricular ejection fraction. Secondary endpoints will include infarct size, end systolic volume, end diastolic volume, fractional shortening and left ventricular wall thickness. Pooled analyses will be conducted using the DerSimonian-Laird random effects and Mantel-Haenszel fixed-effect models. Between-studies heterogeneity will be quantified and determined using the Tau2 and I2 statistics. Publication bias will be assessed using visual inspection of funnel plots and complemented by Begg's and Egger's statistical tests. Possible sources of heterogeneity will be assessed using subgroup-meta analysis and meta-regression. DISCUSSION: To date, the use of scaffolds in myocardial repair has not yet been systematically reviewed. The results of this meta-analysis will aid in determining the efficacy of stem cell-embedded scaffolds for cardiac repair and help bring this therapy to the clinic.