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Frontiers in Neuroscience 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the upper and lower motor neurons. Though the pathogenesis of ALS is still unclear,...
OBJECTIVE
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the upper and lower motor neurons. Though the pathogenesis of ALS is still unclear, exploring the associations between risk factors and ALS can provide reliable evidence to find the pathogenesis. This meta-analysis aims to synthesize all related risk factors of ALS to understand this disease comprehensively.
METHODS
We searched the following databases: PubMed, EMBASE, Cochrane library, Web of Science, and Scopus. Moreover, observational studies, including cohort studies, and case-control studies, were included in this meta-analysis.
RESULTS
A total of 36 eligible observational studies were included, and 10 of them were cohort studies and the rest were case-control studies. We found six factors exacerbated the progression of disease: head trauma (OR = 1.26, 95% CI = 1.13, 1.40), physical activity (OR = 1.06, 95% CI = 1.04, 1.09), electric shock (OR = 2.72, 95% CI = 1.62, 4.56), military service (OR = 1.34, 95% CI = 1.11, 1.61), pesticides (OR = 1.96, 95% CI = 1.7, 2.26), and lead exposure (OR = 2.31, 95% CI = 1.44, 3.71). Of note, type 2 diabetes mellitus was a protective factor for ALS. However, cerebrovascular disease (OR = 0.99, 95% CI = 0.75, 1.29), agriculture (OR = 1.22, 95% CI = 0.74, 1.99), industry (OR = 1.24, 95% CI = 0.81, 1.91), service (OR = 0.47, 95% CI = 0.19, 1.17), smoking (OR = 1.25, 95% CI = 0.5, 3.09), chemicals (OR = 2.45, 95% CI = 0.89, 6.77), and heavy metal (OR = 1.5, 95% CI = 0.47, 4.84) were not risk factors for ALS based on meta-analyses.
CONCLUSIONS
Head trauma, physical activity, electric shock, military service, pesticides, and lead were risk factors for ALS onset and progression. But DM was a protective factor. This finding provides a better understanding of ALS risk factors with strong evidence for clinicians to rationalize clinical intervention strategies.
INPLSY REGISTRATION NUMBER
https://inplasy.com/inplasy-2022-9-0118/, INPLASY202290118.
PubMed: 37284659
DOI: 10.3389/fnins.2023.1196722 -
Clinical Science (London, England :... May 2023Systematic reviews and meta-analysis are the cornerstones of evidence-based decision making and priority setting. However, traditional systematic reviews are time and... (Meta-Analysis)
Meta-Analysis
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.
Topics: Software; Technology; Data Mining; Machine Learning; Evidence-Based Medicine; Automation
PubMed: 37219941
DOI: 10.1042/CS20220494 -
Frontiers in Veterinary Science 2023Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently...
BACKGROUND AND OBJECTIVES
Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently understood how much findings from these model systems can be translated to humans. Thus, we aimed at systematically assessing the translational value of MND animal models to probe their external validity with regards to magnetic resonance imaging (MRI) features.
METHODS
In a comprehensive literature search in PubMed and Embase, we retrieved 201 unique publications of which 34 were deemed eligible for qualitative synthesis including risk of bias assessment.
RESULTS
ALS animal models can indeed present with human ALS neuroimaging features: Similar to the human paradigm, (regional) brain and spinal cord atrophy as well as signal changes in motor systems are commonly observed in ALS animal models. Blood-brain barrier breakdown seems to be more specific to ALS models, at least in the imaging domain. It is noteworthy that the G93A-SOD1 model, mimicking a rare clinical genotype, was the most frequently used ALS proxy.
CONCLUSIONS
Our systematic review provides high-grade evidence that preclinical ALS models indeed show imaging features highly reminiscent of human ALS assigning them a high external validity in this domain. This opposes the high attrition of drugs during bench-to-bedside translation and thus raises concerns that phenotypic reproducibility does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS therapy development thereby benefiting refinement of animal experiments.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022373146.
PubMed: 37205225
DOI: 10.3389/fvets.2023.1135282 -
Journal of Neuromuscular Diseases 2023Recent pharmaceutical breakthroughs in neuromuscular diseases may considerably change the prognosis and natural history these diseases. The ability to measure clinically...
BACKGROUND
Recent pharmaceutical breakthroughs in neuromuscular diseases may considerably change the prognosis and natural history these diseases. The ability to measure clinically relevant outcomes such as motor function is critical for the assessment of therapeutics and the follow up of individuals. The Motor Function Measure (MFM) is a quantitative scale designed to measure motor function in adult and children with neuromuscular disease (NMD).
OBJECTIVE
The objective of this study is to assess the quality and level of evidence of the MFM's published measurement properties by completing a systematic review of the validation and responsiveness studies of the MFM20 (a 20-item version of MFM adapted for children 2 to 6 years of age) and the MFM32 (the original 32 item version), in all NMDs and in specific diseases.
METHODS
A search for MFM responsiveness and MFM validation studies was completed in February 2023 in EMBASE, MEDLINE, SCOPUS and Web of Science databases. The PRISMA guidelines and the COSMIN manual for systematic reviews were followed for databases searches, articles screening and selection, study quality and measurement properties evaluation.
RESULTS
49 studies were included in analysis. In studies including individuals with all NMDs, MFM's internal consistency, reliability, convergent validity, construct validity and responsiveness were rated as sufficient with a high quality of evidence. Structural validity was rated sufficient with a moderate quality of evidence In SMA in particular, MFM's reliability, internal consistency, convergent validity, discriminant validity and responsiveness are sufficient with a high quality of evidence. More studies would be required to assess specific measurement properties in different diseases. MFM32's minimal clinically relevant difference has been defined between 2 and 6%.
CONCLUSION
MFM's structural validity, internal consistency, reliability, construct validity, convergent validity and responsiveness have been verified with moderate to high level of evidence.
Topics: Adult; Child; Humans; Psychometrics; Reproducibility of Results; Neuromuscular Diseases
PubMed: 37125561
DOI: 10.3233/JND-230001 -
International Journal of Molecular... Apr 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and... (Meta-Analysis)
Meta-Analysis Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the "C" allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Aminopeptidases; Genome-Wide Association Study; Neurodegenerative Diseases; Prognosis; Biomarkers
PubMed: 37108335
DOI: 10.3390/ijms24087169 -
International Journal of Molecular... Feb 2023Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived... (Meta-Analysis)
Meta-Analysis Review
Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95% CI (0.32, 0.74), < 0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), < 0.0001), astrogliosis (GM, SMD 0.56; 95% CI (0.12, 1.01), = 0.01), microglial activation (WM, SMD 1.03; 95% CI (0.40, 1.66), = 0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), < 0.0001); as well as improved neuron number (SMD 0.86; 95% CI (0.39, 1.33), = 0.0003), oligodendrocyte number (GM, SMD 3.35; 95 %CI (1.00, 5.69), = 0.005) and motor function (cylinder test, SMD 0.49; 95 %CI (0.23, 0.76), = 0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.
Topics: Animals; Pregnancy; Female; Fetal Blood; Brain; Brain Injuries
PubMed: 36901781
DOI: 10.3390/ijms24054351 -
Sensors (Basel, Switzerland) Feb 2023This systematic review documents the protocol characteristics of studies that used neuromuscular electrical stimulation protocols (NMES) on the plantar flexors [through...
This systematic review documents the protocol characteristics of studies that used neuromuscular electrical stimulation protocols (NMES) on the plantar flexors [through triceps surae (TS) or tibial nerve (TN) stimulation] to stimulate afferent pathways. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, was registered to PROSPERO (ID: CRD42022345194) and was funded by the Greek General Secretariat for Research and Technology (ERA-NET NEURON JTC 2020). Included were original research articles on healthy adults, with NMES interventions applied on TN or TS or both. Four databases (Cochrane Library, PubMed, Scopus, and Web of Science) were systematically searched, in addition to a manual search using the citations of included studies. Quality assessment was conducted on 32 eligible studies by estimating the risk of bias with the checklist of the Effective Public Health Practice Project Quality Assessment Tool. Eighty-seven protocols were analyzed, with descriptive statistics. Compared to TS, TN stimulation has been reported in a wider range of frequencies (5-100, vs. 20-200 Hz) and normalization methods for the contraction intensity. The pulse duration ranged from 0.2 to 1 ms for both TS and TN protocols. It is concluded that with increasing popularity of NMES protocols in intervention and rehabilitation, future studies may use a wider range of stimulation attributes, to stimulate motor neurons via afferent pathways, but, on the other hand, additional studies may explore new protocols, targeting for more optimal effectiveness. Furthermore, future studies should consider methodological issues, such as stimulation efficacy (e.g., positioning over the motor point) and reporting of level of discomfort during the application of NMES protocols to reduce the inherent variability of the results.
Topics: Adult; Animals; Humans; Afferent Pathways; Checklist; Electric Stimulation; Fishes; Leg; Tibial Nerve
PubMed: 36850945
DOI: 10.3390/s23042347 -
The Cochrane Database of Systematic... Feb 2023Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge... (Review)
Review
BACKGROUND
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), causes increasing physical impairment and disability. People with ALS/MND face huge physical challenges, and the diagnosis can be a source of great psychological distress for both people with ALS/MND and their carers. In such a context, how news of the diagnosis is broken is important. At present, there are no systematic reviews of methods for informing people with ALS/MND of their diagnosis.
OBJECTIVES
To examine the effects and effectiveness of different methods for informing people of a diagnosis of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), including effects on the person's knowledge and understanding of their disease, its treatment, and care; and on coping and adjustment to the effects of ALS/MND, its treatment, and care.
SEARCH METHODS
We searched the Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers (February 2022). We contacted individuals or organisations to locate studies. We contacted study authors to obtain additional unpublished data.
SELECTION CRITERIA
We planned to include randomised controlled trials (RCTs) and quasi-RCTs of techniques for informing people with ALS/MND of their diagnosis. We planned to include adults (aged 17 years or over) with ALS/MND, according to the El Escorial criteria.
DATA COLLECTION AND ANALYSIS
Three review authors independently reviewed the results of the search to identify RCTs, and three review authors identified non-randomised studies to include in the discussion section. We planned that two review authors would independently extract data, and three would assess the risk of bias in any included trials.
MAIN RESULTS
We did not identify any RCTs that met our inclusion criteria.
AUTHORS' CONCLUSIONS
There are no RCTs that evaluate different communication strategies for breaking the bad news for people diagnosed with ALS/MND. Focused research studies are needed to assess the effectiveness and efficacy of different communication methods.
Topics: Adult; Humans; Amyotrophic Lateral Sclerosis; Motor Neuron Disease
PubMed: 36812393
DOI: 10.1002/14651858.CD007593.pub2 -
BMJ Open Feb 2023Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying... (Review)
Review
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.
Topics: Humans; Consensus; Induced Pluripotent Stem Cells; Motor Neuron Disease; Randomized Controlled Trials as Topic
PubMed: 36725099
DOI: 10.1136/bmjopen-2022-064169 -
Frontiers in Pharmacology 2022Parkinson's disease (PD) is the most common neurodegenerative disease closely related to the immune system, among whose prodromes constipation is a representative...
Parkinson's disease (PD) is the most common neurodegenerative disease closely related to the immune system, among whose prodromes constipation is a representative symptom. Recent Randomized Controlled Trials (RCTs) have proved that probiotics can be used to effectively treat PD constipation, but the results are inconsistent. We performed a meta-analysis to assess the efficacy and safety of probiotic therapy on Parkinson's constipation. Questions about the research focus were constructed based on the . We searched electronic databases such as PubMed, Web of Science, EMBASE, Scopus, EBSCO, Cochrane and Google Scholar until March 2022 for eligible literatures. Our primary endpoints were stool frequency, stool consistency, the number of laxatives uses, UPDRS-III scores and adverse events. 12 eligible studies (n = 818 patients) met the inclusion and endpoint criteria. Meta-analysis results showed that constipation symptoms were improved after probiotic treatment, including an increased stool frequency (WMD = 0.94, 95% CI:0.53 to 1.34; OR = 3.22, 95% CI:1.97-5.29), an improved stool consistency (WMD = 1.46, 95% CI:0.54-2.37), a reduced use of laxatives (WMD = -0.72, 95%CI: -1.04 to-0.41), and also a reduced Parkinson's UPDRS-III score (WMD = -6.58, 95%CI: -12.02 to -1.14); there was no significant difference in total adverse events (OR = 0.82, 95%CI:0.39-1.72). Our analysis suggests that probiotics can be used to improve the constipation and motor symptoms for patients with Parkinson's constipation, possibly by reducing the inflammatory response and improving gut-brain axis neuron function, whose safety also proved to be good.
PubMed: 36703760
DOI: 10.3389/fphar.2022.1007654