What Went Wrong with VEGF-A in Peripheral Arterial Disease? A Systematic Review and Biological Insights on Future Therapeutics.

BACKGROUND: Of the 200 million patients worldwide affected by peripheral arterial disease (PAD), 4% will inevitably require major limb amputation. Previous systematic reviews presented a conflicting body of evidence in terms of vascular endothelial growth factor (VEGF) family member effects upon PAD natural progression. Despite that, modulation of intrinsic angiogenesis mechanisms targeting the VEGF family members still confers an attractive therapeutic target. The aim of the present study was to evaluate current evidence of VEGF modulation in the context of PAD. METHODS: This is a systematic literature review conducted according to the PRISMA guidelines and registered under PROSPERO database [CRD42021285988]. Independent literature search was performed up to April 1, 2022, on six databases. A total of 22 eligible studies were identified [N: 3, interventional patient studies; N: 19, animal studies]. Animal studies were appraised by the SYRCLE risk of bias tool, while human participant studies were assessed by the Newcastle Ottawa scale. Overall, quality of evidence was deemed fair for both animal and human studies. Main study outcomes were percentage change of injured vessel lumen stenosis and neointimal area formation upon VEGF modulation (inhibition or activation) in comparison with control group. FINDINGS: Nineteen animal models and three human participant studies were included in the systematic review and assessed separately. Positive modulation of VEGF-A in animal models resulted in a median decrease of 65.58% [95% CI 45.2; 71.87] in lumen stenosis [14 studies]. Furthermore, positive modulation of VEGF-A was found to reduce neointimal area proliferation by a median decrease of 63.41% [95% CI 41.6; 79.59] [14 studies]. Median end of study duration was 28 days [range: 14-84 days]. Data were insufficient to assess these outcomes with respect to VEGF-B or VEGF-C modulation. The limited number of available human studies presented inadequate outcome assessment despite their overall fair NOS grading. INTERPRETATION: VEGF-A-positive modulation decreases lumen stenosis and neointimal hyperplasia in PAD simulation animal models. Previously identified variability among outcomes was found to strongly stem from the variability of experimental designs. Clinical applicability and safety profile of VEGF-A in the context of PAD remain to be defined by a robust and uniformly designed body of further animal model-based experiments.

Fertility and reproductive outcomes following high-energy pelvic fractures: A systematic review and meta-analysis.

BACKGROUND: There is a need to decipher the effect of pelvic fractures (PFs) upon female fertility and live birth rate, as data including treatment regimens in large, unselected populations remain scarce. OBJECTIVES: To assess the effect of high energy PFs upon female fertility and live birth rate. SEARCH STRATEGY: Literature search for relevant studies was performed up to March 2022 in five databases: Embase, MEDLINE, CAB Abstracts, ClinicalTrials.gov, and Google Scholar. SELECTION CRITERIA: Retrospective studies assessing live birth, infertility, and dyspareunia rates following PFs. DATA COLLECTION AND ANALYSIS: Data were extracted from studies independently by two authors. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. MAIN RESULTS: A total of 763 female patients of median age 27.8 years (95% CI 22-38 years) were included with median follow up of 5 years. Among PF patients, infertility hazard ratio (HR) 1.18 (95% CI 0.76-1.84, P = 0.47; I2  = 18%) and dyspareunia HR 0.60 (95% CI 0.34-1.08, P = 0.09; I2  = 66%), did not significantly differ from the age-matched literature-reported rates among non-PF patients. CONCLUSIONS: No significant differences of live birth, infertility, and dyspareunia rates across patients with PFs were found compared with non-PF counterparts.