Sequencing large number of individuals, which is often needed for population genetics studies, is still economically challenging despite falling costs of Next Generation Sequencing (NGS). Pool-seq is ...an alternative cost- and time-effective option in which DNA from several individuals is pooled for sequencing. However, pooling of DNA creates new problems and challenges for accurate variant call and allele frequency (AF) estimation. In particular, sequencing errors confound with the alleles present at low frequency in the pools possibly giving rise to false positive variants. We sequenced 996 individuals in 83 pools (12 individuals/pool) in a targeted re-sequencing experiment. We show that Pool-seq AFs are robust and reliable by comparing them with public variant databases and in-house SNP-genotyping data of individual subjects of pools. Furthermore, we propose a simple filtering guideline for the removal of spurious variants based on the Kolmogorov-Smirnov statistical test. We experimentally validated our filters by comparing Pool-seq to individual sequencing data showing that the filters remove most of the false variants while retaining majority of true variants. The proposed guideline is fairly generic in nature and could be easily applied in other Pool-seq experiments.
Background and Purpose
The COVID‐19 pandemic has significantly impacted health systems worldwide. Here, we assessed the pandemic's impact on clinical service, curricular training, and financial ...burden from a neurological viewpoint during the enforced lockdown periods and the assumed recovery by 2023.
Methods
An online 18‐item survey was conducted by the European Academy of Neurology (EAN) NeuroCOVID‐19 Task Force among the EAN community. The survey was online between February and March 2023. Questions related to general, demographic, clinical, work, education, and economic aspects.
Results
We collected 430 responses from 79 countries. Most health care professionals were aged 35–44 years, with >15 years of work experience. The key findings of their observations were as follows. (i) Clinical services were cut back in all neurological subspecialties during the most restrictive COVID‐19 lockdown period. The most affected neurological subspecialties were services for patients with dementia, and neuromuscular and movement disorders. The levels of reduction and the pace of recovery were distinct for acute emergencies and in‐ and outpatient care. Recovery was slow for sleep medicine, autonomic nervous system disorders, neurorehabilitation, and dementia care. (ii) Student and residency rotations and grand rounds were reorganized, and congresses were converted into a virtual format. Conferences are partly maintained in a hybrid format. (iii) Affordability of neurological care and medication shortage are emerging issues.
Conclusions
Recovery of neurological services up to spring 2023 has been incomplete following substantial disruption of neurological care, medical education, and health economics in the wake of the COVID‐19 pandemic. The continued limitations for the delivery of neurological care threaten brain health and call for action on a global scale.
Mitoxantrone for multiple sclerosis Martinelli Boneschi, Filippo; Vacchi, Laura; Rovaris, Marco ...
Cochrane database of systematic reviews,
05/2013, Letnik:
2013, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Background
Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients.
This is an update of the ...Cochrane review "Mitoxantrone for multiple sclerosis" (published on Cochrane Database of Systematic Reviews 2013, Issue 5).
Objectives
The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing‐remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants.
Search methods
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (23 May 2013). We also undertook handsearching and contacted trialists and pharmaceutical companies.
Selection criteria
Randomised, double‐blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included.
Data collection and analysis
The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed‐effect model was used.
Main results
Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow‐up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD ‐0.36, 95% CI‐ 0.70 to ‐0.02; P = 0.04). Significant results were found regarding the reduction in annualised relapse rate (MD ‐0.85, 95% CI ‐1.47 to ‐0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001).
Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the limited number of included subjects the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long‐term efficacy and safety of MX.
Authors' conclusions
MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short‐term follow‐up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow‐up (not included in this review) have raised concerns about the risk of systolic disfunction and therapy‐related acute leukaemias, occurring in about 12% and 0.8% of MX‐treated patients respectively.
MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients’ risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.
Abstract
Background
As the coronavirus pandemic spreads, more and more people are infected with severe acute respiratory syndrome coronavirus 2. The short- and medium-term effects of the infection ...have been described, but the description of the long-term sequelae is lacking in the literature.
Methods
Patients healed from coronavirus disease 2019 (COVID-19) from February 2020 to May 2020 were considered for inclusion in this study, regardless of the severity of the disease during the acute phase. Eligible patients were consecutively contacted and a semistructured interview was administered between February and March 2021 by trained medical staff.
Results
Three hundred three patients were eligible and accepted to participate in the study and were enrolled. Of those surveyed, most patients (81%) reported at least 1 symptom, and the most prevalent symptoms were fatigue (52%), pain (48%), and sleep disorders (47%). Sensory alterations were present in 28% of surveyed patients, but in most of these cases (74% of those affected by sensory alterations or 20% of the overall sample) symptoms reported were either anosmia or dysgeusia. Higher prevalence was generally observed with increasing age, although the most relevant differences were observed when comparing young versus middle-aged adults.
Conclusions
At 12 months after acute infection, COVID-19 survivors were still suffering from symptoms identified at shorter follow-up, and the most frequent symptoms included fatigue, pain, and sleep disorders. A more severe impairment in the acute phase did not seem to predict more severe complications.
One year after SARS-CoV-2 infection, most patients (81%) presented at least 1 symptom with the most prevalent being fatigue and weakness (52%), muscle and joint pain (48%), sleep disorders (47%), neurological and cognitive impairment (36%), and respiratory disorders (36%).
Objective
Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). ...However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.
Methods
We examined whole‐genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.
Results
WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP‐related mutations in PPMS patients compared to controls (risk ratio RR = 1.95; 95% confidence interval CI, 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.
Interpretation
This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63
Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of ...neuregulin 1 type III upregulated the prostaglandin D2 synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein-coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective:
To investigate resting state (RS) functional connectivity (FC) abnormalities within the principal brain networks in a large cohort of multiple sclerosis (MS) patients, to define the ...trajectory of FC changes over disease stages and their relation with clinical and structural magnetic resonance imaging (MRI) measures.
Methods:
RS functional magnetic resonance imaging (fMRI), clinical, and neuropsychological evaluation were obtained from 215 MS patients and 98 healthy controls. Connectivity abnormalities and correlations with clinical/neuropsychological/imaging measures were evaluated. We analyzed seed-voxel FC with seven major hubs, producing one visual/sensory, one motor, two cognitive, one cerebellar, and two subcortical networks.
Results:
MS patients showed reduced network average RS FC versus controls in the default-mode network. At regional level, a complex pattern of decreased and increased RS FC was found. Reduced RS FC mainly involved sensorimotor, cognitive, thalamic, and cerebellar networks, whereas increased RS FC involved visual/sensory and subcortical networks. Reduced RS FC correlated with T2 lesions. Reduced thalamic RS FC correlated with better neuropsychological performance, whereas for all remaining networks reduced FC correlated with more severe clinical/cognitive impairment.
Conclusion:
Increased and decreased RS FC occurs in MS and contributes to a wide spectrum of clinical manifestations. RS FC reduction is related to T2 lesions. Such a paradigm is inverted for the thalamic network.
Background and purpose
Health risks associated with SARS‐CoV‐2 infection are undisputed. Moreover, the capability of vaccination to prevent symptomatic, severe, and fatal COVID‐19 is recognized. ...There is also early evidence that vaccination can reduce the chance for long COVID‐19. Nonetheless, the willingness to get vaccinated and receive booster shots remains subpar among people with neurologic disorders. Vaccine scepticism not only jeopardizes collective efforts to end the COVID‐19 pandemic but puts individual lives at risk, as some chronic neurologic diseases are associated with a higher risk for an unfavorable COVID‐19 course.
Methods
In this position paper, the NeuroCOVID‐19 Task Force of the European Academy of Neurology (EAN) summarizes the current knowledge on the prognosis of COVID‐19 among patients with neurologic disease, elucidates potential barriers to vaccination coverage, and formulates strategies to overcome vaccination hesitancy. A survey among the Task Force members on the phenomenon of vaccination hesitancy among people with neurologic disease supports the lines of argumentation.
Results
The study revealed that people with multiple sclerosis and other nervous system autoimmune disorders are most skeptical of SARS‐CoV‐2 vaccination. The prevailing concerns included the chance of worsening the pre‐existing neurological condition, vaccination‐related adverse events, and drug interaction.
Conclusions
The EAN NeuroCOVID‐19 Task Force reinforces the key role of neurologists as advocates of COVID‐19 vaccination. Neurologists need to argue in the interest of their patients about the overwhelming individual and global benefits of COVID‐19 vaccination. Moreover, they need to keep on eye on this vulnerable patient group, its concerns, and the emergence of potential safety signals.
Background and purpose
Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic ...factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing–remitting MS (RRMS) patients.
Methods
Ninety‐nine PMS and 214 RRMS patients underwent a 3‐T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis.
Results
Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p = 0.002), whereas inflammatory‐related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p = 0.004 and p = 0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (β = −0.731, p = 3.2*10−7) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (β = 22.04, p = 5.5*10−6) in RRMS.
Conclusions
Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.
This study evaluated the genetic contribution to brain MRI outcomes in patients of Italian origin affected by multiple sclerosis (MS), investigating T2 lesion volume measurements and white matter and whole and regional grey matter volume measurements. We stratified analyses in 214 relapsing‐remitting and 99 progressive MS patients, adopting a knowledge‐driven candidate pathways approach, selecting processes deemed as relevant to neurodegeneration and neuroinflammation. Analyses revealed a differential pattern of association across the two cohorts, with evidence of association for variants in SPON1 gene in the progressive cohort.
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