Systematic online living evidence summaries: emerging tools to accelerate evidence synthesis.

Systematic reviews and meta-analysis are the cornerstones of evidence-based decision making and priority setting. However, traditional systematic reviews are time and labour intensive, limiting their feasibility to comprehensively evaluate the latest evidence in research-intensive areas. Recent developments in automation, machine learning and systematic review technologies have enabled efficiency gains. Building upon these advances, we developed Systematic Online Living Evidence Summaries (SOLES) to accelerate evidence synthesis. In this approach, we integrate automated processes to continuously gather, synthesise and summarise all existing evidence from a research domain, and report the resulting current curated content as interrogatable databases via interactive web applications. SOLES can benefit various stakeholders by (i) providing a systematic overview of current evidence to identify knowledge gaps, (ii) providing an accelerated starting point for a more detailed systematic review, and (iii) facilitating collaboration and coordination in evidence synthesis.

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.

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.

INTRODUCTION: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine. METHODS AND ANALYSIS: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments. ETHICS AND DISSEMINATION: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants. TRIAL REGISTRATION NUMBERS: European Clinical Trials Registry (2019-000099-41); NCT04302870.

A systematic review of non-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva. AIM/HYPOTHESIS: We aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments. METHODS: We reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied. RESULTS: 237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms. CONCLUSIONS: Non-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs. PROPSERO REGISTRATION: CRD42020223648.

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Effectiveness of Insole Colour on Impact Loading and Lower-Limb Kinematics When Running at Preferred and Nonpreferred Speeds.

While colour of red can play a significant role in altering human perception and performances, little is known about its perceptual-motor effect on running mechanics. This study examined the effects of variations in insole colours on impact forces, ankle kinematics, and trial-to-trial reliability at various running speeds. Sixteen male recreational runners ran on instrumented treadmill at slow (90%), preferred (100%), and fast (110%) running speeds when wearing insoles in red, blue, and white colours. We used synchronized force platform and motion capturing system to measure ground reaction force, ankle sagittal and frontal kinematics, and movement variability. A two-way (colour x speed) ANOVA with repeated measures was performed with Bonferroni adjusted post hoc comparisons, with alpha set at 0.05. Data analyses indicated that participants demonstrated higher impact and maximum loading rate of ground reaction force, longer stride length, shorter contact time, and smaller touchdown ankle inversion as well as larger ankle sagittal range of motion (RoM), but smaller frontal RoM in fast speed as compared with preferred (P < 0.05) and slow speeds (P < 0.001). Although insole colour had minimal effect on mean values of any tested variables (P > 0.05), participants wearing red-coloured orthoses showed higher coefficient of variation values for maximum loading rate than wearing blue insoles (P=0.009). These results suggest that running at faster speed would lead to higher impact loading and altered lower-limb mechanics and that colour used on the tops of insoles influences the wearers' movement repeatability, with implications for use of foot insole in running.

A systematic review of neuropsychiatric and cognitive assessments used in clinical trials for amyotrophic lateral sclerosis.

BACKGROUND: Up to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning. METHODS: We reviewed the past 25 years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted. RESULTS: 216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (n = 6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (n = 8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials. CONCLUSIONS: Trials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS. PROPSERO REGISTRATION: CRD42020175612.

Effectiveness and Reliability of Foot Orthoses on Impact Loading and Lower Limb Kinematics When Running at Preferred and Nonpreferred Speeds.

This study examined the effect of foot orthoses used on ground reaction forces, ankle, and knee kinematics when running at preferred and nonpreferred speeds. Sixteen runners ran on instrumented treadmills at various speeds (90%, 100%, and 110% of preferred speed) when wearing arch-support and flat-control orthoses. Two-way repeated analysis of variance (ANOVA) was performed on the mean and coefficient of variation of all variables. Results indicated that arch-support orthoses experienced larger maximum loading rates than flat-control orthoses (P = .017, 95% CI, 2.22 to 19.53). Slower speed was related to smaller loading rates (preferred: P = .002, 95% CI, -17.02 to -4.20; faster: P = .003, 95% CI, -29.78 to -6.17), shorter stride length (preferred: P < .001, 95% CI, -0.204 to -0.090; faster: P < .001, 95% CI, -0.382 to -0.237), and longer contact time (preferred: P < .001, 95% CI, 0.006-0.021; faster: 95% CI, 0.012-0.042). In arch-support condition, preferred speed induced higher stride length coefficient of variation (P = .046, 95% CI, 0.035-1.117) than faster speed, while displaying no differences in flat-control condition. These findings suggest that the use of arch-support orthoses would influence impact loading, but not spatial-temporal and joint kinematics in recreational runners.

Effects of arch-support orthoses on ground reaction forces and lower extremity kinematics related to running at various inclinations.

While foot orthoses are commonly used in running, little is known regarding biomechanical risk potentials during uphill running. This study investigated the effects of arch-support orthoses on kinetic and kinematic variables when running at different inclinations. Sixteen male participants ran at different inclinations (0°, 3° and 6°) when wearing arch-support and flat orthoses on an instrumented treadmill. Arch-support orthoses induced longer contact time, larger initial ankle dorsiflexion, maximum ankle eversion, and knee sagittal range of motion (RoM) (p < 0.05). As incline slopes increased, vertical impact peak and loading rate, stride length, and ankle coronal RoM decreased, but contact time, stride frequency, initial ankle dorsiflexion and inversion, maximum dorsiflexion, initial knee flexion, and ankle sagittal RoM increased (p < 0.05). Furthermore, knee sagittal RoM was lowest when running at an inclination of 3°. The interaction effect indicated that in arch-support condition, participants running at 6° induced higher maximum ankle eversion than running at 0° (p < 0.05), while no differences were found in flat orthosis condition. These findings suggest that the use of arch-support orthoses would influence running biomechanics that is related to injury risks. Running at higher inclination led to more alterations to biomechanical variables than at lower inclination.

Elderly woman with subacute lower limb weakness and rapid systemic decline.

A 74-year-old woman developed bilateral leg weakness, with fluctuating cognitive and systemic symptoms that progressed despite treatment. Her diagnosis was confirmed at autopsy. Her case was discussed at the Edinburgh Clinical Neurology Course 2019 Clinicopathological Conference.

Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis.

Importance: The c9orf72 repeat expansion (c9 or c9orf72RE) confers a survival disadvantage in amyotrophic lateral sclerosis (ALS); its effect on prognosis in frontotemporal dementia (FTD) remains uncertain. Data on prognostic factors in c9orf72RE disorders could inform patient care, genetic counseling, and trial design. Objective: To examine prognostic factors in c9ALS, c9FTD, c9ALS-FTD, and atypical phenotypes. Data Sources: The MEDLINE, Embase, Amed, ProQuest, PsychINFO, CINAHL, and LILACS databases were searched between January 2011 and January 2019. Keywords used were c9orf72 and chromosome 9 open reading frame 72. Reference lists, citations of eligible studies, and review articles were also searched by hand. Study Selection: Studies reporting disease duration for patients with a confirmed c9orf72RE and a neurological and/or psychiatric disorder were included. A second author independently reviewed studies classified as irrelevant by the first author. Analysis began in January 2019. Data Extraction and Synthesis: Data were extracted by 1 author; a further author independently extracted 10% of data. Data were synthesized in univariate and multivariable Cox regression and are displayed as hazard ratios (HR) and 95% confidence intervals. Main Outcomes and Measures: Survival after symptom onset. Results: Overall, 206 studies reporting on 1060 patients were included from 2878 publications identified (c9ALS: n = 455; c9FTD: n = 296; c9ALS-FTD: n = 198; atypical phenotypes: n = 111); 197 duplicate cases were excluded. The median (95% CI) survival (in years) differed significantly between patients with c9ALS (2.8 [2.67-3.00]), c9FTD (9.0 [8.09-9.91]), and c9ALS-FTD (3.0 [2.73-3.27]); survival in atypical phenotypes varied substantially. Older age at onset was associated with shorter survival in c9ALS (HR, 1.03; 95% CI, 1.02-1.04; P < .001), c9FTD (HR, 1.04; 95% CI, 1.02-1.06; P < .001), and c9ALS-FTD (HR, 1.02; 95% CI, 1.004-1.04; P = .016). Bulbar onset was associated with shorter survival in c9ALS (HR, 1.64; 95% CI, 1.27-2.08; P < .001). Age at onset and bulbar onset ALS remained significant in multivariable regression including variables indicating potential diagnostic ascertainment bias, selection bias, and reporting bias. Family history, sex, study continent, FTD subtype, or the presence of additional pathogenic sequence variants were not significantly associated with survival. Clinical phenotypes in patients with neuropathologically confirmed frontotemporal lobar degeneration-TDP-43, motor neuron disease-TDP-43 and frontotemporal lobar degeneration-motor neuron disease-TDP-43 were heterogenous and impacted on survival. Conclusions and Relevance: Several factors associated with survival in c9orf72RE disorders were identified. The inherent limitations of our methodological approach must be considered; nonetheless, the reported prognostic factors were not significantly associated with the bias indicators examined.

The Role of Selective Peripheral Neurectomy in the Treatment of Upper Limb Spasticity.

BACKGROUND: Management of upper limb spasticity remains challenging. Selective peripheral neurectomy (SPN) is a relatively recent intervention for cases refractory to medical therapy. The aim of this study was to conduct a systematic review looking at the efficacy and outcomes of SPN, in order to clarify the patient selection criteria and surgical technique. METHODS: A search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science Core Collection, Open Grey and CINAHL was conducted. Inclusion criteria included studies comparing pre- and post-operative outcomes for SPN, neurectomy, fasciculotomy and upper limb spasticity. RESULTS: Only case series were reported with no randomised controlled trials found. 7 studies met the inclusion criteria with a total of 174 patients. A meta-analysis was not possible due to the degree of baseline heterogeneity. All studies had no control arm for comparison of outcomes, with a high risk of bias due to poor internal and external validity, as well as design and performance bias. Surgical techniques differ vastly between studies, with percentage of fascicles ablated between 30-80% and length of neurectomy between 5-10 mm. Some advocated removing end branches while others performed fascicular SPN proximally. 13 patients underwent orthopaedic or neurosurgical procedures, which are both confounding factors. All studies reported an improvement in spasticity although functional outcomes were reported with non-standardized measures. Recurrence rates were reported to be 0-16.1% (mean 3.72%). CONCLUSIONS: From this systematic review, SPN appeared to be a useful technique in selected cases, but overall no firm conclusions can be drawn regarding the best surgical technique, or the extent of functional improvement.