The Utility of Miniaturized Adsorbers in Exploring the Cellular and Molecular Effects of Blood Purification: A Pilot Study with a Focus on Immunoadsorption in Multiple Sclerosis.

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of patients with MS in vitro. The plasma was screened before and after adsorption with regard to disease-specific mediators, and the effect of the IA treatment on the migration of neutrophils and the integrity of the endothelial cell barrier was tested in cell-based models. The in vitro IA treatment with miniaturized adsorbers resulted in reduced plasma levels of cytokines and chemokines. We also found a reduced migration of neutrophils towards patient plasma treated with the adsorbers. Furthermore, the IA-treated plasma had a positive effect on the endothelial cell barrier's integrity in the cell culture model. Our findings suggest that IA results in a reduced infiltration of cells into the central nervous system by reducing leukocyte transmigration and preventing blood-brain barrier breakdown. This novel approach of performing in vitro blood purification therapies on actual patient samples with miniaturized adsorbers and testing their effects in cell-based assays that investigate specific hypotheses of the pathophysiology provides a promising platform for elucidating the mechanisms of action of those therapies in various diseases.

Interferon beta-1a sc at 25 years: a mainstay in the treatment of multiple sclerosis over the period of one generation.

INTRODUCTION: Interferon beta (IFN beta) preparations are an established group of drugs used for immunomodulation in patients with multiple sclerosis (MS). Subcutaneously (sc) applied interferon beta-1a (IFN beta-1a sc) has been in continuous clinical use for 25 years as a disease-modifying treatment. AREAS COVERED: Based on data published since 2018, we discuss recent insights from analyses of the pivotal trial PRISMS and its long-term extension as well as from newer randomized studies with IFN beta-1a sc as the reference treatment, the use of IFN beta-1a sc across the patient life span and as a bridging therapy, recent data regarding the mechanisms of action, and potential benefits of IFN beta-1a sc regarding vaccine responses. EXPERT OPINION: IFN beta-1a sc paved the way to effective immunomodulatory treatment of MS, enabled meaningful insights into the disease process, and remains a valid therapeutic option in selected vulnerable MS patient groups.

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. OBJECTIVES: The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. METHODS: B cells were obtained from blood samples of patients with relapsing-remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. RESULTS: Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. CONCLUSIONS: We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

Depression and Anxiety in Association with Polypharmacy in Patients with Multiple Sclerosis.

Polypharmacy (intake of ≥5 drugs) is an important issue for patients with chronic diseases such as multiple sclerosis (MS). We aimed to assess the prevalence of polypharmacy with regard to the severity of anxiety/depression and to comorbidities. Therefore, 374 MS patients from two German neurological sites were examined for drug burden, comorbidities, disability level and psychopathological measures capturing depression and anxiety using the Hospital Anxiety and Depression Scale (HADS-A and HADS-D). We found that patients with a higher HADS-D score take more medication (r = 0.217, p < 0.001). Furthermore, patients with higher depression severity were more likely to show polypharmacy (p < 0.001). These differences were not significant for anxiety. (p = 0.413). Regarding the frequency of ≥1 comorbidities, there were no significant differences between patients with different HADS-A (p = 0.375) or HADS-D (p = 0.860) severity levels, whereas the concrete number of comorbidities showed a significant positive linear correlation with HADS-A (r = 0.10, p = 0.045) and HADS-D scores (r = 0.19, p < 0.001). In conclusion, symptoms of depression pose a relevant issue for MS patients and are correlated with polypharmacy and comorbidities. Anxiety is not correlated with polypharmacy but with the frequency of several comorbidity groups in MS patients.

Therapy of women with multiple sclerosis: an analysis of the use of drugs that may have adverse effects on the unborn child in the event of (unplanned) pregnancy.

Background: Although effective contraception is strongly recommended during the therapy of women with multiple sclerosis (MS) with some immunomodulatory drugs, unplanned pregnancies still occur. Adequate medication management is essential to avoid foetal harm in the event of an unplanned pregnancy. Objective: The aim was to screen for medications used in women of childbearing age with MS that may pose a risk of side effects on foetal development. Methods: Sociodemographic, clinical and medication data were collected from 212 women with MS by structured interviews, clinical examinations and medical records. Using the databases from Embryotox, Reprotox, the Therapeutic Goods Administration and on the German summaries of product characteristics, we assessed whether the taken drugs were potentially harmful regarding the foetal development. Results: The majority of patients (93.4%) were taking one or more drugs for which a possible harmful effect on the foetus is indicated in at least one of the four databases used. This proportion was even higher in patients who used hormonal contraceptives (birth control pills or vaginal rings) (PwCo, n = 101), but it was also quite high in patients who did not use such contraceptives (Pw/oCo, n = 111) (98.0% and 89.2%, respectively). PwCo were significantly more likely to take five or more medications with potential foetal risk according to at least one database than Pw/oCo (31.7% versus 6.3%). PwCo were also more severely disabled (average Expanded Disability Status Scale score: 2.8 versus 2.3) and more frequently had comorbidities (68.3% versus 54.1%) than Pw/oCo. Conclusion: Data on the most commonly used drugs in MS therapy were gathered to study the risk of possible drug effects on foetal development in female MS patients of childbearing age. We found that the majority of drugs used by patients with MS are rated as having a potential risk of interfering with normal foetal development. More effective contraception and special pregnancy information programmes regarding the therapy management during pregnancy should be implemented to reduce potential risks to mother and child. Plain Language Summary: Use of drugs not recommended during pregnancy by women with multiple sclerosis Introduction: Patients with multiple sclerosis (MS) often have to take different drugs simultaneously. During the therapy with some immunomodulatory drugs, effective contraception is strongly recommended. Nevertheless, unplanned pregnancies occur regularly in women with MS.Methods: Here, we investigated whether the 212 patients included in this study were taking drugs with known possibility of harm to the development of an unborn child. This was done using four different drug databases.Results: A subset of 111 patients was not taking hormonal contraceptives (birth control pills or vaginal rings). Of those, 99 patients were taking at least one drug that is not recommended during pregnancy according to at least one of the four databases. Most of the medications taken have the potential to affect normal foetal development.Conclusion: To ensure safe use of medications, the patients should be reminded of the importance of effective contraception.

Vector-based SARS-CoV-2 vaccination is associated with improved T-cell responses in hematological neoplasia.

In order to elucidate mechanisms for severe acute respiratory syndrome coronavirus 2 vaccination success in hematological neoplasia, we, herein, provide a comprehensive characterization of the spike-specific T-cell and serological immunity induced in 130 patients in comparison with 91 healthy controls. We studied 121 distinct T-cell subpopulations and the vaccination schemes as putative response predictors. In patients with lymphoid malignancies an insufficient immunoglobulin G (IgG) response was accompanied by a healthy CD4+ T-cell function. Compared with controls, a spike-specific CD4+ response was detectable in fewer patients with myeloid neoplasia whereas the seroconversion rate was normal. Vaccination-induced CD4+ responses were associated to CD8+ and IgG responses. Vector-based AZD1222 vaccine induced more frequently detectable specific CD4+ responses in study participants across all cohorts (96%; 27 of 28), whereas fully messenger RNA-based vaccination schemes resulted in measurable CD4+ cells in only 102 of 168 participants (61%; P < .0001). A similar benefit of vector-based vaccination was observed for the induction of spike-specific CD8+ T cells. Multivariable models confirmed vaccination schemes that incorporated at least 1 vector-based vaccination as key feature to mount both a spike-specific CD4+ response (odds ratio, 10.67) and CD8+ response (odds ratio, 6.56). Multivariable analyses identified a specific CD4+ response but not the vector-based immunization as beneficial for a strong, specific IgG titer. Our study reveals factors associated with a T-cell response in patients with hematological neoplasia and might pave the way toward tailored vaccination schemes for vaccinees with these diseases. The study was registered at the German Clinical Trials Register as #DRKS00027372.

Update and Application of a Deep Learning Model for the Prediction of Interactions between Drugs Used by Patients with Multiple Sclerosis.

Patients with multiple sclerosis (MS) often take multiple drugs at the same time to modify the course of disease, alleviate neurological symptoms and manage co-existing conditions. A major consequence for a patient taking different medications is a higher risk of treatment failure and side effects. This is because a drug may alter the pharmacokinetic and/or pharmacodynamic properties of another drug, which is referred to as drug-drug interaction (DDI). We aimed to predict interactions of drugs that are used by patients with MS based on a deep neural network (DNN) using structural information as input. We further aimed to identify potential drug-food interactions (DFIs), which can affect drug efficacy and patient safety as well. We used DeepDDI, a multi-label classification model of specific DDI types, to predict changes in pharmacological effects and/or the risk of adverse drug events when two or more drugs are taken together. The original model with ~34 million trainable parameters was updated using >1 million DDIs recorded in the DrugBank database. Structure data of food components were obtained from the FooDB database. The medication plans of patients with MS (n = 627) were then searched for pairwise interactions between drug and food compounds. The updated DeepDDI model achieved accuracies of 92.2% and 92.1% on the validation and testing sets, respectively. The patients with MS used 312 different small molecule drugs as prescription or over-the-counter medications. In the medication plans, we identified 3748 DDIs in DrugBank and 13,365 DDIs using DeepDDI. At least one DDI was found for most patients (n = 509 or 81.2% based on the DNN model). The predictions revealed that many patients would be at increased risk of bleeding and bradycardic complications due to a potential DDI if they were to start a disease-modifying therapy with cladribine (n = 242 or 38.6%) and fingolimod (n = 279 or 44.5%), respectively. We also obtained numerous potential interactions for Bruton's tyrosine kinase inhibitors that are in clinical development for MS, such as evobrutinib (n = 434 DDIs). Food sources most often related to DFIs were corn (n = 5456 DFIs) and cow's milk (n = 4243 DFIs). We demonstrate that deep learning techniques can exploit chemical structure similarity to accurately predict DDIs and DFIs in patients with MS. Our study specifies drug pairs that potentially interact, suggests mechanisms causing adverse drug effects, informs about whether interacting drugs can be replaced with alternative drugs to avoid critical DDIs and provides dietary recommendations for MS patients who are taking certain drugs.

Abnormal Pre-mRNA Splicing in Exonic Fabry Disease-Causing GLA Mutations.

Fabry disease (FD) is a rare X-linked disease due to a multiverse of disrupting mutations within the GLA gene encoding lysosomal α-galactosidase A (AGAL). Absent AGAL activity causes the accumulation of complex glycosphingolipids inside of lysosomes in a variety of cell types and results in a progressive multisystem disease. Known disease-associated point mutations in protein-coding gene regions usually cause translational perturbations and result in premature chain termination, punctual amino acid sequence alterations or overall altered sequence alterations downstream of the mutation site. However, nucleotide exchanges at the border between introns and exons can affect splicing behavior and lead to abnormal pre-mRNA processing. Prediction with the Human Splicing Finder (HSF) revealed an indication of a significant change in splicing-relevant information for some known FD-associated GLA mutations. To experimentally determine the extent of the change, we made use of a minigene reporter assay and verified alternative splicing events for the exonic mutations c.194G>T and c.358C>G, which led to the usage of alternative donor splice sites at exon 1 and exon 2, respectively. In addition, the mutations c.548G>T and c.638A>T led to significant exon 4 skipping. We conclude that splicing phenotype analysis should be employed in the in vitro analysis of exonic GLA gene mutations, since abnormal splicing may result in a reduction of enzyme activity and alter the amenability for treatment with pharmacological chaperone (PC).

Genetic risk variants for multiple sclerosis are linked to differences in alternative pre-mRNA splicing.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system to which a genetic predisposition contributes. Over 200 genetic regions have been associated with increased disease risk, but the disease-causing variants and their functional impact at the molecular level are mostly poorly defined. We hypothesized that single-nucleotide polymorphisms (SNPs) have an impact on pre-mRNA splicing in MS. Methods: Our study focused on 10 bioinformatically prioritized SNP-gene pairs, in which the SNP has a high potential to alter alternative splicing events (ASEs). We tested for differential gene expression and differential alternative splicing in B cells from MS patients and healthy controls. We further examined the impact of the SNP genotypes on ASEs and on splice isoform expression levels. Novel genotype-dependent effects on splicing were verified with splicing reporter minigene assays. Results: We were able to confirm previously described findings regarding the relation of MS-associated SNPs with the ASEs of the pre-mRNAs from GSDMB and SP140. We also observed an increased IL7R exon 6 skipping when comparing relapsing and progressive MS patients to healthy subjects. Moreover, we found evidence that the MS risk alleles of the SNPs rs3851808 (EFCAB13), rs1131123 (HLA-C), rs10783847 (TSFM), and rs2014886 (TSFM) may contribute to a differential splicing pattern. Of particular interest is the genotype-dependent exon skipping of TSFM due to the SNP rs2014886. The minor allele T creates a donor splice site, resulting in the expression of the exon 3 and 4 of a short TSFM transcript isoform, whereas in the presence of the MS risk allele C, this donor site is absent, and thus the short transcript isoform is not expressed. Conclusion: In summary, we found that genetic variants from MS risk loci affect pre-mRNA splicing. Our findings substantiate the role of ASEs with respect to the genetics of MS. Further studies on how disease-causing genetic variants may modify the interactions between splicing regulatory sequence elements and RNA-binding proteins can help to deepen our understanding of the genetic susceptibility to MS.

Screening for severe drug-drug interactions in patients with multiple sclerosis: A comparison of three drug interaction databases.

Background: Patients with multiple sclerosis (MS) often undergo complex treatment regimens, resulting in an increased risk of polypharmacy and potential drug-drug interactions (pDDIs). Drug interaction databases are useful for identifying pDDIs to support safer medication use. Objective: To compare three different screening tools regarding the detection and classification of pDDIs in a cohort of MS patients. Furthermore, we aimed at ascertaining sociodemographic and clinical factors that are associated with the occurrence of severe pDDIs. Methods: The databases Stockley's, Drugs.com and MediQ were used to identify pDDIs by screening the medication schedules of 627 patients. We determined the overlap of the identified pDDIs and the level of agreement in pDDI severity ratings between the three databases. Logistic regression analyses were conducted to determine patient risk factors of having a severe pDDI. Results: The most different pDDIs were identified using MediQ (n = 1,161), followed by Drugs.com (n = 923) and Stockley's (n = 706). The proportion of pDDIs classified as severe was much higher for Stockley's (37.4%) than for Drugs.com (14.4%) and MediQ (0.9%). Overall, 1,684 different pDDIs were identified by at least one database, of which 318 pDDIs (18.9%) were detected with all three databases. Only 55 pDDIs (3.3%) have been reported with the same severity level across all databases. A total of 336 pDDIs were classified as severe (271 pDDIs by one database, 59 by two databases and 6 by three databases). Stockley's and Drugs.com revealed 47 and 23 severe pDDIs, respectively, that were not included in the other databases. At least one severe pDDI was found for 35.2% of the patients. The most common severe pDDI was the combination of acetylsalicylic acid with enoxaparin, and citalopram was the drug most frequently involved in different severe pDDIs. The strongest predictors of having a severe pDDI were a greater number of drugs taken, an older age, living alone, a higher number of comorbidities and a lower educational level. Conclusions: The information on pDDIs are heterogeneous between the databases examined. More than one resource should be used in clinical practice to evaluate pDDIs. Regular medication reviews and exchange of information between treating physicians can help avoid severe pDDIs.

Associated factors of potential drug-drug interactions and drug-food interactions in patients with multiple sclerosis.

Background: Multiple sclerosis (MS) is the most common immune-mediated demyelinating disease in younger adults. Patients with MS (PwMS) are vulnerable to the presence of potential drug-drug interactions (pDDIs) and potential drug-food interactions (pDFIs) as they take numerous medications to treat MS, associated symptoms and comorbidities. Knowledge about pDDIs and pDFIs can increase treatment success and reduce side effects. Objective: We aimed at determining the frequency and severity of pDDIs and pDFIs in PwMS, with regard to polypharmacy. Methods: In the cross-sectional study, we analysed pDDIs and pDFIs of 627 PwMS aged ⩾18 years. Data collection was performed through patient record reviews, clinical examinations and structured patient interviews. pDDIs and pDFIs were identified using two DDI databases: Drugs.com Interactions Checker and Stockley's Interactions Checker. Results: We identified 2587 pDDIs (counted with repetitions). Of 627 PwMS, 408 (65.1%) had ⩾ 1 pDDI. Polypharmacy (concomitant use of ⩾ 5 drugs) was found for 334 patients (53.3%). Patients with polypharmacy (Pw/P) were found to have a 15-fold higher likelihood of having ⩾ 1 severe pDDI compared with patients without polypharmacy (Pw/oP) (OR: 14.920, p < 0.001). The most frequently recorded severe pDDI was between citalopram and fingolimod. Regarding pDFIs, ibuprofen and alcohol was the most frequent severe pDFI. Conclusion: Pw/P were particularly at risk of severe pDDIs. Age and educational level were found to be factors associated with the occurrence of pDDIs, independent of the number of medications taken. Screening for pDDIs/pDFIs should be routinely done by the clinical physician to increase drug safety and reduce side effects.

Pan-cancer proteomic map of 949 human cell lines.

The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted the identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence of cell-type and post-transcriptional modifications. Integrating multi-omics, drug response, and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline reveals thousands of protein biomarkers of cancer vulnerabilities that are not significant at the transcript level. The power of the proteome to predict drug response is very similar to that of the transcriptome. Further, random downsampling to only 1,500 proteins has limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger) is a comprehensive resource available at https://cellmodelpassports.sanger.ac.uk.

Vaccination Coverage against Tetanus, Diphtheria, Pertussis and Poliomyelitis and Validity of Self-Reported Vaccination Status in Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic immune-mediated disease with a neurodegenerative component of the central nervous system. Immunomodulatory therapy can increase the risk of infection, which is a particular risk for MS patients. Therefore, a complete vaccination status is of utmost importance as protection against vaccine-preventable infectious diseases. Our aim was to investigate the vaccination status, vaccination card knowledge and the vaccination behavior of MS patients with regard to vaccinations against tetanus, diphtheria, pertussis and poliomyelitis. Three hundred twenty-seven patients with MS were evaluated by anamnesis, clinical examination, structured interview and vaccination card control in this two-center study. Based on the recommendations of the Robert Koch Institute, we assessed the completeness of the vaccination status of the examined vaccinations. Furthermore, a comparative analysis of patients with complete/incomplete or correctly/wrongly self-reported vaccination status was performed. In the cohort analyzed, the vaccination coverage was 79.5% for tetanus, 79.2% for diphtheria, 74.8% for pertussis and 84.8% for poliomyelitis. The assumed vaccination status was higher for tetanus (86.5%) and lower for diphtheria (69.4%), pertussis (61.2%) and poliomyelitis (75.9%). Patients who were unvaccinated or only partially vaccinated against tetanus had received vaccination advice from a physician less often in the past year (13.4 vs. 36.9%, p < 0.001) and had no one to check the vaccination card more often (35.8 vs. 12.3%, p < 0.001). High sensitivity (93.7%) and low specificity (30.3%) were determined regarding the validity of self-reported tetanus vaccination status. Patients with a correctly reported tetanus vaccination status were more likely to have their vaccination card checked by a physician than those who overestimated or underestimated their vaccination status (76.7 vs. 63.0/43.8%, p = 0.002). Similar findings were seen with regard to diphtheria, pertussis and poliomyelitis vaccination. Patients without a regular vaccination card control (17.1%) were more likely to be male (44.6 vs. 29.4%, p = 0.037), had fewer siblings on average (1.1 vs. 1.6, p = 0.016), dealt less frequently with the issue of vaccination in the past year (32.1 vs. 69.3%, p < 0.001) and more frequently had the wish to receive vaccination advice (48.2 vs. 34.4%, p = 0.030) than patients in whom the vaccination card was checked regularly by a physician. To minimize the risk of infection in MS patients, treating physicians should provide regular vaccination counseling and perform vaccination card controls, as these factors are associated with a higher vaccination coverage and a higher validity of self-reported vaccination statuses.

Implication of genetic variants in primary microRNA processing sites in the risk of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a well-established genetic contribution to susceptibility. Over 200 genetic regions have been linked to the inherited risk of developing MS, but the disease-causing variants and their functional effects at the molecular level are still largely unresolved. We hypothesised that MS-associated single-nucleotide polymorphisms (SNPs) affect the recognition and enzymatic cleavage of primary microRNAs (pri-miRNAs). METHODS: Our study focused on 11 pri-miRNAs (9 primate-specific) that are encoded in genetic risk loci for MS. The levels of mature miRNAs and potential isoforms (isomiRs) produced from those pri-miRNAs were measured in B cells obtained from the peripheral blood of 63 MS patients and 28 healthy controls. We tested for associations between SNP genotypes and miRNA expression in cis using quantitative trait locus (cis-miR-eQTL) analyses. Genetic effects on miRNA stem-loop processing efficiency were verified using luciferase reporter assays. Potential direct miRNA target genes were identified by transcriptome profiling and computational binding site assessment. FINDINGS: Mature miRNAs and isomiRs from hsa-mir-26a-2, hsa-mir-199a-1, hsa-mir-4304, hsa-mir-4423, hsa-mir-4464 and hsa-mir-4492 could be detected in all B-cell samples. When MS patient subgroups were compared with healthy controls, a significant differential expression was observed for miRNAs from the 5' and 3' strands of hsa-mir-26a-2 and hsa-mir-199a-1. The cis-miR-eQTL analyses and reporter assays pointed to a slightly more efficient Drosha-mediated processing of hsa-mir-199a-1 when the MS risk allele T of SNP rs1005039 is present. On the other hand, the MS risk allele A of SNP rs817478, which substitutes the first C in a CNNC sequence motif, was found to cause a markedly lower efficiency in the processing of hsa-mir-4423. Overexpression of hsa-mir-199a-1 inhibited the expression of 60 protein-coding genes, including IRAK2, MIF, TNFRSF12A and TRAF1. The only target gene identified for hsa-mir-4423 was TMEM47. INTERPRETATION: We found that MS-associated SNPs in sequence determinants of pri-miRNA processing can affect the expression of mature miRNAs. Our findings complement the existing literature on the dysregulation of miRNAs in MS. Further studies on the maturation and function of miRNAs in different cell types and tissues may help to gain a more detailed functional understanding of the genetic basis of MS. FUNDING: This study was funded by the Rostock University Medical Center (FORUN program, grant: 889002), Sanofi Genzyme (grant: GZ-2016-11560) and Merck Serono GmbH (Darmstadt, Germany, an affiliate of Merck KGaA, CrossRef Funder ID: 10.13039/100009945, grant: 4501860307). NB was supported by the Stiftung der Deutschen Wirtschaft (sdw) and the FAZIT foundation. EP was supported by the Landesgraduiertenförderung Mecklenburg-Vorpommern.

Prevalence and Severity of Potential Drug-Drug Interactions in Patients with Multiple Sclerosis with and without Polypharmacy.

Polypharmacy (PP) is a common problem in modern medicine, especially known to affect patients with chronic diseases such as multiple sclerosis (MS). With an increasing number of drugs taken, the risk of potential drug-drug interactions (pDDIs) is rising. This study aims to assess the prevalence and clinical relevance of polypharmacy and pDDIs in patients with MS. Pharmacological data of 627 patients with MS were entered into two drug-drug-interaction databases to determine the number and severity of pDDIs for each patient. The patients were divided into those with and without PP (total PP and prescription medication PP (Rx PP)). Of the 627 patients included, 53.3% and 38.6% had total PP and Rx PP, respectively. On average, every patient took 5.3 drugs. Of all patients, 63.8% had at least one pDDI with a mean of 4.6 pDDIs per patient. Less than 4% of all pDDIs were moderately severe or severe. Medication schedules should be checked for inappropriate medication and for possible interacting drugs to prevent pDDIs. Physicians as well as pharmacists should be more sensitive towards the relevance of pDDIs and know how they can be detected and avoided.

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis.

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

Systematic Review of Studies on Telomere Length in Patients with Multiple Sclerosis.

Telomeres are protective cap structures at the end of chromosomes that are essential for maintaining genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases. We aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS). A comprehensive literature search was conducted to identify original studies that presented data on TL in samples from persons with MS. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies. A total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in patients with MS were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes. Despite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.

Rituximab versus mitoxantrone: comparing effectiveness and safety in advanced relapsing multiple sclerosis.

BACKGROUND: Rituximab (RTX), a CD20 depleting agent, is a frequently used off-label treatment for multiple sclerosis (MS), while mitoxantrone (MTX) is approved, albeit rarely used for active relapsing MS (RMS). However, observational data comparing RTX and MTX effectiveness and safety are scarce. OBJECTIVE: We aimed to compare effectiveness and safety of MTX and RTX in patients with active RMS. METHODS: From combined retrospective clinical data of three MS centers, we selected patients who had received at least one infusion of RTX or MTX and had at least a 6-month clinical follow-up available. Treatment groups were compared by propensity score (PS)-adjusted regression and inverse PS-weighted generalized estimated equation models regarding disability progression, relapse activity, and adverse events (AEs). RESULTS: We included 292 RMS patients (mean age 41.8 years, 71.6% female) who received RTX (119 patients, mean age 36.8 years, 74.8% female) or MTX (173 patients mean age 45.3 years, 69.4% female). Using both PS methods, we did not find a significant effect favoring RTX or MTX treatment regarding the probability of disability worsening or relapse occurrence. However, RTX treatment was associated with a significantly lower probability of severe AEs and AEs. CONCLUSIONS: RTX shows comparable effectiveness but a favorable safety profile compared with MTX in active RMS.

Polypharmacy in Chronic Neurological Diseases: Multiple Sclerosis, Dementia and Parkinson's Disease.

Polypharmacy is an important aspect of medication management and particularly affects elderly and chronically ill people. Patients with dementia, Parkinson's disease (PD), or multiple sclerosis (MS) are at high risk of multi medication due to their complex symptomatology. Our aim was to provide an overview of different definitions of polypharmacy and to present the current state of research on polypharmacy in patients with dementia, PD, or MS. The most common definition of polypharmacy in the literature is the concomitant use of ≥5 medications (quantitative definition approach). Polypharmacy rates of up to >50% have been reported for patients with dementia, PD, or MS, although MS patients are on average significantly younger than those with dementia or PD. The main predictor of polypharmacy is the complex symptom profile of these neurological disorders. Potentially inappropriate medication (PIM), drug-drug interactions, poor treatment adherence, severe disease course, cognitive impairment, hospitalisation, poor quality of life, frailty, and mortality have been associated with polypharmacy in patients with dementia, PD, or MS. For patients with polypharmacy, either the avoidance of PIM (selective deprescribing) or the substitution of PIM with more suitable drugs (appropriate polypharmacy) is recommended to achieve a more effective therapeutic management.

Improved identification and quantification of peptides in mass spectrometry data via chemical and random additive noise elimination (CRANE).

MOTIVATION: The output of electrospray ionization-liquid chromatography mass spectrometry (ESI-LC-MS) is influenced by multiple sources of noise and major contributors can be broadly categorized as baseline, random and chemical noise. Noise has a negative impact on the identification and quantification of peptides, which influences the reliability and reproducibility of MS-based proteomics data. Most attempts at denoising have been made on either spectra or chromatograms independently, thus, important 2D information is lost because the mass-to-charge ratio and retention time dimensions are not considered jointly. RESULTS: This article presents a novel technique for denoising raw ESI-LC-MS data via 2D undecimated wavelet transform, which is applied to proteomics data acquired by data-independent acquisition MS (DIA-MS). We demonstrate that denoising DIA-MS data results in the improvement of peptide identification and quantification in complex biological samples. AVAILABILITY AND IMPLEMENTATION: The software is available on Github (https://github.com/CMRI-ProCan/CRANE). The datasets were obtained from ProteomeXchange (Identifiers-PXD002952 and PXD008651). Preliminary data and intermediate files are available via ProteomeXchange (Identifiers-PXD020529 and PXD025103). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.