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.

Dispersion reduction in pressure-driven flow through microetched channels.

Fluid is often moved about microetched channels in lab-on-a-chip applications using electrokinetic flows (electrophoresis or electroosmosis) rather than pressure-driven flows because the latter result in large Taylor dispersion. However, small pressure gradients may arise unintentionally in such systems due to a mismatch in electroosmotic flow rates or hydrostatic pressure differentials along the microetched channel. Under laminar flow conditions, Doshi et al. (Chem. Eng. Sci. 1978, 33, 795-804) have shown that for a channel with rectangular cross-section of width W and depth d, longitudinal diffusivities can attain values as large as approximately 8 K0 for small values of the aspect ratio d/W, where K0 is the value of the longitudinal diffusivity obtained by ignoring all variations across the channel. Microchannels in lab-on-a-chip geometries are often not rectangular in cross-section. Isotropic etching techniques, for example, lead to channels with quarter-circular ends. In this paper we examine the effect of this geometry on the magnitude of longitudinal dispersivity for pressure-driven flows and also investigate modifications to this design which may minimize such dispersion. Optimal channel profiles are shown to lead to dispersivities approaching K0, the theoretical minimum, for small values of d/W.

Generating theory from the client's experience of same day laparoscopic sterilisation.

A grounded theory methodology was used to generate theory about the experiences of women undergoing laparoscopic sterilisation in a day surgery unit. Theories were developed on the role of client education in relieving anxiety, and the importance of privacy in all stages of client care. The grounded theory approach offered a client-centered model for day surgery planning.

CT of blunt trauma bowel and mesenteric injury: typical findings and pitfalls in diagnosis.

Detection of bowel and mesenteric injury can be challenging in patients after blunt abdominal trauma. Early diagnosis and treatment are critical to decrease patient morbidity and mortality. Computed tomography (CT) has become the primary modality for the imaging of these patients. Signs of bowel perforation such as free air and contrast material are virtually pathognomonic. Bowel-wall thickening, free fluid, and mesenteric infiltration may be seen with this type of injury and partial thickness injuries. The authors present and discuss the range of CT findings seen with bowel and mesenteric injuries. Examples of observation and interpretation errors are also provided to highlight pitfalls encountered in the evaluation of abdominopelvic CT scans in patients after blunt trauma.

Work-based musculoskeletal problems: initiatives to improve health.

Musculoskeletal disorders (MSD) are the leading cause of occupational ill-health in the UK and the level of suffering and costs associated with the current prevalence of MSD is of concern. In partnership with others, the Health and Safety Executive (HSE) is committed to tackling MSD. This will be achieved in part through the implementation of new wide-ranging, integrated policy initiatives and strategies, and through the HSE's core activities of publication of guidance, publicity campaigns and workplace visits by inspectors. A summary of these activities is presented, demonstrating that with new initiatives and partnerships, the HSE will continue to work towards greater awareness of occupational health issues and more effective management of health risks in the workplace.

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.

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.

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.

Epidemiological aspects of back pain: the incidence and prevalence of back pain in nurses compared to the general population.

Two studies using retrospective questionnaires were conducted to obtain epidemiological information from nursing personnel (n = 1134) and among an age- and gender-matched cross-section of the general population (n = 315). The point and annual prevalence of back pain did not differ between the two sample groups. Nurses demonstrated a greater annual incidence of back pain (14.7%, compared to 11.5% in non-nurses). The point prevalence of back pain increased with age in both sample groups. Nurses considered patient-handling tasks instrumental in the onset of back pain symptoms. Comparison of results with those obtained from a similar study published in 1983 indicated an increase of almost 40% in the prevalence of back pain symptoms in nurses, although the linearity of the rise was not ascertained. The implementation of guidelines on the manual handling of loads has led to revised training procedures and these may have influenced the epidemiological findings.

Radiological abnormalities in children born as a result of assisted conception.

Over 15,000 children are born each year as a result of the various techniques of assisted conception. In 1991, there were 2083 live births in Australia and New Zealand as a result of these techniques. Radiological abnormalities relating to the increased rate of prematurity, a probable increase in the risk of congenital malformations and a number of cases of neural crest tumours seen in these infants will be presented.

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.

Evaluation of acute urinary tract infection in children by dimercaptosuccinic acid scintigraphy: a prospective study.

A prospective study examining the incidence of dimercaptosuccinic acid (DMSA) abnormalities in children at the time of acute urinary tract infection, the progression of these abnormalities following treatment and their correlation with the presence of vesicoureteral reflux is reported. DMSA scans performed within 72 hours of presentation in 65 previously healthy children with acute urinary tract infection were abnormal in 34 (52%). The scan appearances of 30 of 36 (83%) initially abnormal kidneys improved or became normal on the repeat DMSA study performed at 3 to 6 months after the acute urinary tract infection. A cystogram demonstrated significant vesicoureteral reflux in 11 of 45 cases (24%). Of these 11 cases 10 had abnormal DMSA studies and 1 had dilated upper tracts on ultrasound. Several conclusions may be drawn from our study. The incidence of DMSA abnormalities at the time of acute urinary tract infection is high but these abnormalities tend to resolve with time. An abnormal DMSA study at the time of urinary tract infection identifies most children with significant vesicoureteral reflux, and in our series a combination of ultrasound and DMSA identified all cases. This study may have major implications for the clinical investigation of children with urinary tract infection.

The detection of reflux nephropathy in infants by 99mtechnetium dimercaptosuccinic acid studies.

Dimercaptosuccinic acid (DMSA) studies were performed in 113 infants less than 1 year old at risk of renal scarring. Of these patients 86 presented with urinary tract infection and 27 were asymptomatic. A voiding cystourethrogram was performed in all cases and excretory urography (IVP) was done in 99. More abnormalities were detected by DMSA study when compared to scars on IVP. When both studies were abnormal there was an excellent correlation on a site by site basis. Fever or systemic disorder was not a reliable sign to determine whether there was upper tract involvement with infection. The incidence of DMSA abnormalities in infants increased with high grade vesicoureteral reflux and decreased with low grade reflux. There was no significant difference in the incidence of abnormal kidneys between the infected and noninfected groups, suggesting that renal scarring may occur with sterile reflux.

A case of rectal bleeding in infancy.

A case of colonic haemangioma in a 3 month old girl presenting with rectal bleeding and anaemia is presented. A colonic mass lesion was suspected on barium follow through and confirmed by enema and surgical excision.

Obstruction in the refluxing urinary tract--a common phenomenon.

Dilatation of the urinary tract may be due to vesicoureteric reflux, urinary tract obstruction, or to primary dilatation. In a proportion of patients these factors may coexist. A retrospective review was carried out to estimate the incidence and features of coexisting reflux and obstruction. Our review indicates that the coexistence of urinary tract obstruction and primary reflux is more common than previously reported, occurring in approximately 1 in 20 patients with reflux. Any patients with reflux who has a dilated and/or tortuous ureter must be suspected of having obstruction. This may be ruled out in the majority of cases by a drainage film after a micturating cystourethrogram and the importance of this simple procedure is emphasised.

Uses of direct coronal pelvic CT.

A technique for performing direct coronal computed tomography (CT) of the pelvis on conventional CT equipment is described. Eighteen patients have been examined by this technique and its possible applications in the evaluation of patients with anorectal and genitourinary anomalies, pre and postoperatively, are discussed.