Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Comparison of outcomes of trans-subclavian versus trans-apical approaches in transcatheter aortic valve implantation.

BACKGROUND: Many patients are unsuitable for conventional femoral transcatheter aortic valve implantation (TAVI) but there is limited evidence as to which alternative approach has the best outcomes. We compared clinical outcomes in patients undergoing trans-subclavian (TS) or trans-apical (TA) TAVI. METHODS: This was a national retrospective observational study of patients undergoing surgical TAVI in Scotland between January 2013 and March 2020. The pre-operative patient characteristics, intraoperative details and post-operative outcomes were compared between TS and TA cohorts using data from the National Institute of Cardiovascular Outcomes Research (NICOR) registry. RESULTS: Among 1055 patients who underwent TAVI, TS or TA access was used in 50 (4.7%) and 90 (8.5%) patients respectively. Self-expanding Medtronic Evolut R valves were used in 84% of TS procedures, while balloon-expandable Edwards SAPIEN valves were used in all TA procedures. The TS group had a lower mean logistic EuroSCORE than the TA group (27.31 ± 19.44% vs 34.92 ± 19.61% p = 0.029). The TS approach was associated with a higher incidence of moderate postprocedural aortic regurgitation (12.5% vs 2.4%, p = 0.025). There was no significant difference in 30-day, 1-year or overall all-cause mortality. CONCLUSIONS: Both trans-subclavian and trans-apical access are viable approaches for patients requiring non-transfemoral TAVI. Differences in peri-procedural indices reflect the disparate patient populations and factors governing prosthesis choice, and short- and long-term mortality was similar.

Variations in human pulmonary vein ostia morphology: A systematic review with meta-analysis.

This study aimed to establish the most accurate and up-to-date anatomical knowledge of pulmonary veins (PV), ostia variations, diameters and ostial area, to provide physicians, especially heart and thoracic surgeons with exact knowledge concerning this area. The main online medical databases, such as PubMed, Embase, Scopus, Web of Science, and Google Scholar, were searched to gather all studies in which the variations, maximal diameter, and ostial area of the PVs were investigated. During the study, the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. Additionally, the critical appraisal tool for anatomical meta-analysis (CATAM) was used to provide the highest quality findings. The most common ostia variation is the classical one, which contains the left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV) and right inferior pulmonary vein (RIPV). The mean diameter and ostial area of each pulmonary vein were established in the general population and in multiple variations considering the method of collecting the data and geographical location. Significant variability in PV ostia is observed. Left-sided PVs have smaller ostia than the corresponding right-sided PVs, and the inferior PVs ostia are smaller than the superior. The LCPV ostium size is the largest among all veins analyzed, while the RMPV ostium is the smallest. The results of this meta-analysis are hoped to help clinicians in planning and performing procedures that involve the pulmonary and cardiac areas, especially catheter ablation for atrial fibrillation.