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.

Does Changing Examiner Stations During UK Postgraduate Surgery Objective Structured Clinical Examinations Influence Examination Reliability and Candidates' Scores?

OBJECTIVE: Objective structured clinical examinations (OSCE) are widely used for summative assessment in surgery. Despite standardizing these as much as possible, variation, including examiner scoring, can occur which may affect reliability. In study of a high-stakes UK postgraduate surgical OSCE, we investigated whether examiners changing stations once during a long examining day affected marking, reliability, and overall candidates' scores compared with examiners who examined the same scenario all day. DESIGN, SETTING, AND PARTICIPANTS: An observational study of 18,262 examiner-candidate interactions from the UK Membership of the Royal College of Surgeons examination was carried at 3 Surgical Colleges across the United Kingdom. Scores between examiners were compared using analysis of variance. Examination reliability was assessed with Cronbach's alpha, and the comparative distribution of total candidates' scores for each day was evaluated using t-tests of unit-weighted z scores. RESULTS: A significant difference was found in absolute scores differences awarded in the morning and afternoon sessions between examiners who changed stations at lunchtime and those who did not (p < 0.001). No significant differences were found for the main effects of either broad content area (p = 0.290) or station content area (p = 0.450). The reliability of each day was not affected by examiner switching (p = 0.280). Overall, no difference was found in z-score distribution of total candidate scores and categories of examiner switching. CONCLUSIONS: This large study has found that although the range of marks awarded varied when examiners change OSCE stations, examination reliability and the likely candidate outcome were not affected. These results may have implications for examination design and examiner experience in surgical OSCEs and beyond.