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.

Technetium-99m dimercaptosuccinic acid scintigraphy studies of renal cortical scarring and renal length.

UNLABELLED: The aims of this study were to validate 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy appearances with histopathological features of scarring; to evaluate the sensitivity and specificity of 99mTc-DMSA and ultrasound for the detection of renal scarring; to compare planar, pinhole and SPECT techniques when using 99mTc-DMSA; and to compare 99mTc-DMSA and ultrasound renal length measurement. METHODS: Reflux nephropathy was induced in large white pigs using established methods. To ensure that the abnormalities detected were scars and not inflammatory changes, the pigs were not studied until 3 mo after the treated episode of acute pyelonephritis confirmed by 99mTc-DMSA. RESULTS: Twenty pigs were enrolled in the study. Eleven reached the end point, but only nine pigs (18 kidneys) were available for analysis. Thirty-four scars were identified pathologically; 24 were present macroscopically and a further 10 were seen only on microscopy. Technetium-99m-DMSA abnormalities correlated with scars histopathologically with an accuracy of 92% versus that of ultrasound, 75% (p < 0.001). Technetium-99m-DMSA more accurately identified scarring with a higher sensitivity (76% versus 29%) and specificity (98% versus 92%) than ultrasound. On the 99mTc-DMSA study, pinhole imaging had the highest accuracy (92%) when compared with planar (90%) and SPECT (87%) data. These differences were not statistically significant. Renal lengths as measured on 99mTc-DMSA more closely correlated with length measurement at pathological examination than ultrasound. Technetium-99m-DMSA measurement was, on average, 6% higher than pathology, and ultrasound was, on average, 22% lower. CONCLUSION: Technetium-99m-DMSA appears to be the preferred method for the detection of renal cortical scarring and accurate renal length measurement when compared with ultrasound examination.

Binary oscillatory cross-flow electrophoresis: theory and experiments.

In this article a novel electrophoretic separation technique, Binary Oscillatory Cross-flow Electrophoresis (BOCE), is described. The technique utilizes the interaction of an oscillatory electric field and a transverse oscillatory shear flow to create an active binary filter for the separation of charged protein species. An oscillatory electric field is applied across the narrow gap of a rectangular channel inducing a periodic motion of charged protein species. The amplitude of this motion depends on the dimensionless electrophoretic mobility, alpha = Eomu/omegad, where Eo is the amplitude of the electric field oscillations, mu is the dimensional mobility, omega is the angular frequency of oscillation, and d is the channel gap width. An oscillatory shear flow of the form u = Deltaxomega(beta + cos(2omegat)) where beta is the fraction of steady flow and Deltax is the tidal displacement, is induced along the length of the channel resulting in the separation of species with different mobilities. An analytic model is presented that predicts the induced convective velocity of solute species as a function of alpha and beta in the absence of diffusion. Numerical simulations including diffusion support these predictions, and determine the time history of the concentration profiles in a separation cell and connecting reservoirs. In experiments using a model protein system including bovine serum albumen (BSA) and bovine hemoglobin (BHb), solute throughputs of 37 mg/h of 92% pure BSA have been observed in a small separation cell with a volume of 3 mL. These results are in close agreement with theoretical predictions.

The occurrence and possible significance of diacylglyceryl ether lipids in abalone.

Gonadal and foot tissues of the green abalone, Haliotis fulgens, farm-raised on macroalgal [corrected] diets, were analyzed for lipids using thin-layer chromatography/flame-ionization detection and gas chromatography-mass spectrometry (GC-MS). Diacylglyceryl ether (DAGE) was 0.7% of total lipids in the gonad. The major alkyl constituents of the glyceryl ether diols in the gonad (as % of total diols) were 16:0 (38%) and 18:1 (36%). While levels of DAGE in the abalone foot were below flame-ionization detection limits, glyceryl ether diols from them were detected using the more sensitive GC-MS procedure. The major diol components in the foot were 18:0 (39%) and 18:1 (32%). To our knowledge, this is the first report of DAGE in abalone tissues. Although the precise role of DAGE in abalone remains to be determined, a possible structural role may exist.

Diuresis renography. The need for an additional view after gravity-assisted drainage.

The role of diuresis renography (DR) in the evaluation of pelvi-ureteric junction obstruction is well established. However, problems may be encountered when applying this technique to patients after pyeloplasty because of the role of gravity-assisted drainage (GAD) in this post-operative group. Twenty-three radionuclide studies that were performed in 21 children were reviewed. All children underwent standard DR and all then had an additional view performed after GAD. In 12 children evaluated in a preoperative assessment for possible obstruction, 5 were obstructed on both DR and after GAD, 1 was equivocal on DR but drained after GAD, and 6 were not obstructed in either part of the study. In 11 children assessed after pyeloplasty, 5 were obstructed on DR but not obstructed on GAD, 3 were not obstructed in both studies, 1 was obstructed in both, and 2 were equivocal on DR but not obstructed after GAD. It can be concluded that when assessing patients, particularly those who have undergone pyeloplasty, DR should be supplemented with an additional view acquired after gravity-assisted drainage.