Effectiveness of oral prednisone tapering following intravenous methylprednisolone for acute optic neuritis in multiple sclerosis.

Acute optic neuritis treatment lacks standardized protocols. The value of oral prednisone taper (OPT) following intravenous methylprednisolone (IVMP) on visual outcome parameters in optic neuritis (ON) has never been explored. In the present retrospective study, we investigated whether OPT after IVMP affects the structural and functional visual outcomes of inaugural clinically isolated syndrome (CIS)- or multiple sclerosis (MS)-ON. Adult patients with acute, inaugural, unilateral CIS- or MS-ON, treated with IVMP in Germany and Israel were stratified into patients treated with IVMP alone-versus IVMP and OPT. Inclusion criteria were age ≥18, CIS or MS diagnosis according to McDonald criteria 2017, available visual acuity (VA) at nadir before treatment initiation and at follow-up ≥5 months, as well as a spectral domain optic coherence tomography (OCT) data scan at follow-up. Exclusion criteria included recurrent ON, concomitant ophthalmological comorbidities, optical coherence tomography (OCT) of insufficient quality and ON-related escalation therapy after IVMP. The structural outcome was defined as the average retinal nerve fiber layer (RNFL) difference between the ON-affected and the unaffected eye, while the functional outcome was defined as the final high-contrast best-corrected VA (HC-BCVA) at follow-up compared to nadir. The comparative analysis was performed using linear regression analysis, adjusted for sex, age, and days-to-treatment. Fifty-one patients met the inclusion criteria (25% male). The mean age was 33.9 (±10.23) years. Twenty-six patients (51%) received OPT following IVMP. There was no difference in nadir HC-BCVA between the groups (0.39 No OPT; 0.49 With OPT, P = 0.36). Adjusted linear regression analysis did not indicate an influence of OPT on RNFL thickness or on HC-BCVA (beta coefficient for RNFL difference in percentages: 0.51, 95%-CI: [-4.58, 5.59], beta coefficient for logMAR: 0.11, 95%; CI [-0.12, 0.35] at follow-up. In conclusion, the addition of OPT to IVMP did not affect RNFL thickness or the final VA in a retrospective cohort of 51 patients with inaugural acute CIS- or MS-ON. The results of this exploratory study are currently being re-examined in a large-scale, demographically diverse, prospective study.

Early safety and tolerability profile of the BNT162b2 COVID-19 vaccine in myasthenia gravis.

Although the COVID-19 vaccines are currently recommended for people with myasthenia gravis (MG), there is no data regarding the safety of the vaccines in this population. In order to investigate the real-life safety data of the BNT162b2 COVID-19 vaccine in people with MG, an anonymous survey was distributed to 142 MG patients. Fifty-six MG patients completed the questionnaire. The median age was 53 years (range 23-83 years); 35 (62.5%) were males, and 25 (44.6%) had associated comorbidities. Thirty-seven participants (66.1%) were treated with immunotherapies. Fifty-five participants (98.2% of the responders) received the BNT162b2 COVID-19 vaccine. Of these, 32 (58.2%) were < 55 years old, and 23 (41.8%) were > 55 years old. Adverse events were more common in patients younger than 55 years old (46.9% Vs. 17.4%; p = 0.0428). Eight participants (14.5%) reported worsening neurological symptoms following the vaccination. Three of those who reported worsening of neurological symptoms (37.5%) required additional treatment. Most events occurred within the first few days after vaccination and resolved within a few weeks. This survey indicates an overall favorable safety and tolerability profile of the BNT162b2 vaccine in people with MG. Additional prospective, large-scale studies are warranted to confirm these findings.

Safety of the BNT162b2 COVID-19 vaccine in multiple sclerosis (MS): Early experience from a tertiary MS center in Israel.

BACKGROUND AND PURPOSE: Although the COVID-19 vaccines are currently recommended for people with multiple sclerosis (MS), the fact that they were not specifically tested in people with MS raises uncertainty regarding their safety in this population. The purpose of this study was to report real-life safety data of the BNT162b2 COVID-19 vaccine in a cohort of MS patients. METHODS: An anonymous survey was distributed to 425 MS patients. Participants were asked general demographic and disease-related questions and specific questions regarding the safety profile of the COVID-19 vaccine. RESULTS: Of the 425 MS patients, 262 completed the questionnaire. The median (range) participant age was 42 (22-79) years, 199 participants were women (75.9%), and 66 participants (25.2%) had associated comorbidities. A total of 198 participants (75.6%) were treated with disease-modifying therapies. In all, 239 participants (91.2% of the responders) had received the BNT162b2 COVID-19 vaccine. Of these, 182 (76.1%) were aged <55 years, and 57 (23.9%) were aged >55 years. Adverse events were reported by 136 participants (56.9%; 52.5% of those aged <55 years and 40.3% of those aged >55 years; p = 0.1517) and 36 participants (15.1%) reported new or worsening neurological symptoms following the vaccination, the most frequent being sensory disturbances (21 participants, 58.3%). Most symptoms occurred within the first 24 h after vaccination and resolved within 3 days. A total of 28 participants (77.8%) did not require any medication to treat their symptoms. CONCLUSIONS: This survey indicates an overall favorable safety profile of the BNT162b2 vaccine in people with MS. These data should be confirmed in further prospective, large-scale studies.

miRror-Suite: decoding coordinated regulation by microRNAs.

MicroRNAs (miRNAs) are short, non-coding RNAs that negatively regulate post-transcriptional mRNA levels. Recent data from cross-linking and immunoprecipitation technologies confirmed the combinatorial nature of the miRNA regulation. We present the miRror-Suite platform, developed to yield a robust and concise explanation for miRNA regulation from a large collection of differentially expressed transcripts and miRNAs. The miRror-Suite platform includes the miRror2.0 and Probability Supported Iterative miRror (PSI-miRror) tools. Researchers who performed large-scale transcriptomics or miRNA profiling experiments from cells and tissues will benefit from miRror-Suite. Our platform provides a concise, plausible explanation for the regulation of miRNAs in such complex settings. The input for miRror2.0 may include hundreds of differentially expressed genes or miRNAs. In the case of miRNAs as input, the algorithm seeks the statistically most likely set of genes regulated by this input. Alternatively, for a set of genes, the miRror algorithm seeks a collection of miRNAs that best explains their regulation. The miRror-Suite algorithm designates statistical criteria that were uniformly applied to a dozen miRNA-target prediction databases. Users select the preferred databases for predictions and numerous optional filters/parameters that restrict the search to the desired tissues, cell lines, level of expression and predictor scores. PSI-miRror is an advanced application for refining the input set by gradually enhancing the degree of pairing of the sets of miRNAs with the sets of targets. The iterations of PSI-miRror probe the interlinked nature of miRNAs and targets within cells. miRror-Suite serves experimentalists in facilitating the understanding of miRNA regulation through combinatorial- cooperative activity. The platform applies to human, mouse, rat, fly, worm and zebrafish. Database URL: http://www.mirrorsuite.cs.huji.ac.il.

miRror2.0: a platform for assessing the joint action of microRNAs in cell regulation.

microRNAs (miRNAs) are short, noncoding RNAs that negatively regulate the levels of mRNA post-transcriptionally. Recent experiments revealed thousands of mRNA-miRNA pairs in which multiple miRNAs may bind the same transcript. These results raised the notion of miRNAs teamwork for a wide range of cellular context. miRror2.0 utilizes the miRNA-target predictions from over a dozen programs and resources and unifies them under a common statistical basis. The platform, called miRror2.0, considers the combinatorial regulation by miRNAs in different tissues, cell lines and under a broad range of conditions. A flexible setting permits the selection of the preferred combination of miRNA-target prediction resources as well as the statistical parameters for the analysis. miRror2.0 covers six major model organisms including human and mouse. Importantly, the system is capable of analyzing hundreds of genes that were subjected to miRNAs' regulation. Activating miRror2.0 by introducing thousands of genes from miRNA overexpression experiments successfully identified the objective miRNAs. The output from miRror2.0 is a list of genes that is optimally regulated by a defined set of miRNAs. A symmetric application of miRror2.0 starts with a set of miRNAs, and the system then seeks the preferred set of genes that are regulated by that miRNA composition. The results from miRror2.0 are empowered by an iterative procedure called PSI-miRror. PSI-miRror tests the robustness of miRror2.0 prediction. It allows a refinement of the initial list of genes in view of the miRNAs that optimally regulate this list. We present miRror2.0 as a valuable resource for supporting cellular experimentalists that seek recovery of combinatorial regulation by miRNAs from noisy experimental data. miRror2.0 is available at http://www.mirrorsuite.cs.huji.ac.il .

Working together: combinatorial regulation by microRNAs.

MicroRNAs (miRNAs) negatively regulate gene expression level of mRNA post-transcriptionally. Deep sequencing and large-scale screening methods have yielded about 1,500 miRNA sequences in human. Each miRNA contains a seed sequence that is required, but not sufficient, for the correct matching with its targets. Recent technological advances make it possible to capture the miRNAs with their cognate mRNAs at the RISC complex. These experiments have revealed thousands of validated mRNA-miRNA pairing events. In the context of human stem cells, 90% of the identified transcripts appear to be paired with at least two different miRNAs.In this chapter, we present a comprehensive outline for a combinatorial regulation mode by miRNAs. Initially, we summarize the computational and experimental evidence that support a combined effect of multiple miRNAs. Then, we describe miRror2.0, a platform specifically convened to consider the likelihood of miRNAs cooperativity in view of the targets, tissues and cell lines. We show that results from miRror2.0 can be further refined by an iterative procedure, calls Psi-miRror that gauges the robustness of the regulation. We illustrate the combinatorial regulation projected onto graphs of human pathways and show that these pathways are amenable to disruption by a small set of miRNAs. Finally, we propose that miRNA combinatorial regulation is an attractive regulatory strategy not only at the level of single target, but also at the level of pathways and cellular homeostasis. The joint operation of miRNAs is a powerful means to overcome the low specificity inherent in each individual miRNA.

Toward a combinatorial nature of microRNA regulation in human cells.

MicroRNAs (miRNAs) negatively regulate the levels of messenger RNA (mRNA) post-transcriptionally. Recent advances in CLIP (cross-linking immunoprecipitation) technology allowed capturing miRNAs with their cognate mRNAs. Consequently, thousands of validated mRNA-miRNA pairs have been revealed. Herein, we present a comprehensive outline for the combinatorial regulation by miRNAs. We implemented combinatorial and statistical constraints in the miRror2.0 algorithm. miRror estimates the likelihood of combinatorial miRNA activity in explaining the observed data. We tested the success of miRror in recovering the correct miRNA from 30 transcriptomic profiles of cells overexpressing a miRNA, and to identify hundreds of genes from miRNA sets, which are observed in CLIP experiments. We show that the success of miRror in recovering the miRNA regulation from overexpression experiments and CLIP data is superior in respect to a dozen leading miRNA-target prediction algorithms. We further described the balance between alternative modes of joint regulation that are executed by pairs of miRNAs. Finally, manipulated cells were tested for the possible involvement of miRNA in shaping their transcriptomes. We identified instances in which the observed transcriptome can be explained by a combinatorial regulation of miRNA pairs. We conclude that the joint operation of miRNAs is an attractive strategy to maintain cell homeostasis and overcoming the low specificity inherent in individual miRNA-mRNA interaction.

Susceptibility of the human pathways graphs to fragmentation by small sets of microRNAs.

MOTIVATION: MicroRNAs (miRNAs) are short sequences that negatively regulate gene expression. The current understanding of miRNA and their corresponding mRNA targets is primarily based on prediction programs. This study addresses the potential of a coordinated action of miRNAs to manipulate the human pathways. Specifically, we investigate the effectiveness of disrupting the topology of human pathway graphs through a regulation by miRNAs. RESULTS: From a set of miRNA candidates that is associated with a pathway, an exhaustive search for all possible doubles and triplets (coined miR-Duo, miR-Trios) is performed. The impact of each miR-combination on the connectivity of the pathway graph was quantified. About 170 human pathways were tested, and the miR-Duos and miR-Trios were scored for their ability to disrupt these pathway graphs. We show that 75% of all pathways are effectively disconnected by a small number of pathway-specific miR-Trios. Only 15% of the human pathways are resistant to fragmentation by miR-Duos or miR-Trios. Significantly, the combination of the most effective miR-Trios is unique. Thus, a specific regulation of a pathway within the cell is guaranteed. The impact of the selected miR-Duo/Trios on various diseases is discussed. CONCLUSIONS: The methodology presented shows that the synthesis of the topology of a network with a detailed understanding of the miRNAs' regulation is useful in exposing critical nodes of the network. We propose the miR-Trio approach as a basis for rationally designed perturbation experiments. CONTACT: michall@cc.huji.ac.il SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MiRror: a combinatorial analysis web tool for ensembles of microRNAs and their targets.

SUMMARY: The miRror application provides insights on microRNA (miRNA) regulation. It is based on the notion of a combinatorial regulation by an ensemble of miRNAs or genes. miRror integrates predictions from a dozen of miRNA resources that are based on complementary algorithms into a unified statistical framework. For miRNAs set as input, the online tool provides a ranked list of targets, based on set of resources selected by the user, according to their significance of being coordinately regulated. Symmetrically, a set of genes can be used as input to suggest a set of miRNAs. The user can restrict the analysis for the preferred tissue or cell line. miRror is suitable for analyzing results from miRNAs profiling, proteomics and gene expression arrays. AVAILABILITY: http://www.proto.cs.huji.ac.il/mirror