Update on Myositis Therapy: From Today's Standards to Tomorrow's Possibilities.

Inflammatory myopathies, in short, myositis, are heterogeneous disorders that are characterized by inflammation of skeletal muscle and weakness of arms and legs. Research over the past few years has led to a new understanding regarding the pathogenesis of myositis. The new insights include different pathways of the innate and adaptive immune response during the pathogenesis of myositis. The importance of non-inflammatory mechanisms such as cell stress and impaired autophagy has been recently described. New target-specific drugs for myositis have been developed and are currently being tested in clinical trials. In this review, we discuss the mechanisms of action of pharmacological standards in myositis and provide an outlook of future treatment approaches.

A community-powered search of machine learning strategy space to find NMR property prediction models.

The rise of machine learning (ML) has created an explosion in the potential strategies for using data to make scientific predictions. For physical scientists wishing to apply ML strategies to a particular domain, it can be difficult to assess in advance what strategy to adopt within a vast space of possibilities. Here we outline the results of an online community-powered effort to swarm search the space of ML strategies and develop algorithms for predicting atomic-pairwise nuclear magnetic resonance (NMR) properties in molecules. Using an open-source dataset, we worked with Kaggle to design and host a 3-month competition which received 47,800 ML model predictions from 2,700 teams in 84 countries. Within 3 weeks, the Kaggle community produced models with comparable accuracy to our best previously published 'in-house' efforts. A meta-ensemble model constructed as a linear combination of the top predictions has a prediction accuracy which exceeds that of any individual model, 7-19x better than our previous state-of-the-art. The results highlight the potential of transformer architectures for predicting quantum mechanical (QM) molecular properties.

Improved Scaffold Hopping in Ligand-Based Virtual Screening Using Neural Representation Learning.

Deep learning has demonstrated significant potential in advancing state of the art in many problem domains, especially those benefiting from automated feature extraction. Yet, the methodology has seen limited adoption in the field of ligand-based virtual screening (LBVS) as traditional approaches typically require large, target-specific training sets, which limits their value in most prospective applications. Here, we report the development of a neural network architecture and a learning framework designed to yield a generally applicable tool for LBVS. Our approach uses the molecular graph as input and involves learning a representation that places compounds of similar biological profiles in close proximity within a hyperdimensional feature space; this is achieved by simultaneously leveraging historical screening data against a multitude of targets during training. Cosine distance between molecules in this space becomes a general similarity metric and can readily be used to rank order database compounds in LBVS workflows. We demonstrate the resulting model generalizes exceptionally well to compounds and targets not used in its training. In three commonly employed LBVS benchmarks, our method outperforms popular fingerprinting algorithms without the need for any target-specific training. Moreover, we show the learned representation yields superior performance in scaffold hopping tasks and is largely orthogonal to existing fingerprints. Summarily, we have developed and validated a framework for learning a molecular representation that is applicable to LBVS in a target-agnostic fashion, with as few as one query compound. Our approach can also enable organizations to generate additional value from large screening data repositories, and to this end we are making its implementation freely available at https://github.com/totient-bio/gatnn-vs.

Dyspnea in Patients with Stiff-Person Syndrome.

BACKGROUND: Stiff-person syndrome (SPS) is a rare autoimmune disorder that leads to progressively worsening stiffness and spasm of thoracic and proximal-limb musculature. Dyspnea has been reported but not analyzed in patients with SPS. MATERIALS AND METHODS: For this prospective study, 17 patients were recruited from a university-based neurology clinic. History and exam were performed, demographic information collected and available imaging reviewed. Dyspnea was assessed using vertical visual analog scales (VAS), the University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) and dyspnea "descriptors". Standardized assessments of SPS severity were performed by an experienced neurologist. Forced vital capacity (FVC) spirometric analysis was performed on all patients. RESULTS: Fifteen of 17 patients complained of dyspnea, including dyspnea at rest, with exertion, and disturbing sleep. A restrictive pattern was the most common abnormality noted on spirometry. FVC (r = -0.67; P < 0.01) and forced expiratory volume in 1-second (FEV1) (r = -0.76; P < 0.01) percent predicted correlated with dyspnea measured by VAS over the preceding 2 weeks. Pulmonary function did not correlate with UCSB-SOBQ or standardized measures of SPS severity. CONCLUSIONS: Dyspnea in SPS is common and occurs at rest with exertion and disturbs sleep. The finding of restrictive physiology and correlation between pulmonary function variables and dyspnea support the hypothesis that thoracic cage constriction by rigidity and/or spasm of the muscles of the trunk causes or contributes to the sensation of dyspnea. The possibility of diaphragmatic involvement requires further study.

Fast and accurate genomic analyses using genome graphs.

The human reference genome serves as the foundation for genomics by providing a scaffold for alignment of sequencing reads, but currently only reflects a single consensus haplotype, thus impairing analysis accuracy. Here we present a graph reference genome implementation that enables read alignment across 2,800 diploid genomes encompassing 12.6 million SNPs and 4.0 million insertions and deletions (indels). The pipeline processes one whole-genome sequencing sample in 6.5 h using a system with 36 CPU cores. We show that using a graph genome reference improves read mapping sensitivity and produces a 0.5% increase in variant calling recall, with unaffected specificity. Structural variations incorporated into a graph genome can be genotyped accurately under a unified framework. Finally, we show that iterative augmentation of graph genomes yields incremental gains in variant calling accuracy. Our implementation is an important advance toward fulfilling the promise of graph genomes to radically enhance the scalability and accuracy of genomic analyses.

Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder.

BACKGROUND: Stiff Person Syndrome (SPS) is an under-diagnosed disorder that affects mobility and the quality of life of affected patients. The aim of the study is to describe the natural history of SPS, the extent of accumulated disability and the associated clinical and immunological features in patients followed for up to 8 years in a single center. METHODS: Our collective cohort included 57 SPS patients. Additionally, 32 of these patients were examined every 6 months for a two-year period in a longitudinal study protocol, to assess disease progression using quantitative measures of stiffness and heightened sensitivity. RESULTS: The most frequent initial symptom was leg stiffness, followed by paraspinal muscle rigidity and painful spasms in 95% of the patients. Although none of the patients required assistance for ambulation during the first 2 years of disease onset, 46 patients (80%) lost the ability to walk independently during our follow-up, despite symptomatic medications. In the longitudinal cohort, the number of stiff areas increased (p < 0.0001), consistent with worsening functional status and quality of life. High-titer anti-GAD antibodies were present in serum and CSF with elevated intrathecal GAD-specific IgG synthesis, but they did not correlate with clinical severity or progression. CONCLUSIONS: This large study on SPS patients, combining an eight-year follow-up at a single center by the same leading neurologist and his team, is the first to provide longitudinal data in a large patient subgroup using objective clinical measures. One of the main findings is that SPS is a progressive disease leading to physical disability over time.

Comparing complex variants in family trios.

Motivation: Several tools exist to count Mendelian violations in family trios by comparing variants at the same genomic positions. This naive variant comparison, however, fails to assess regions where multiple variants need to be examined together, resulting in reduced accuracy of existing Mendelian violation checking tools. Results: We introduce VBT, a trio concordance analysis tool, which identifies Mendelian violations by approximately solving the 3-way variant matching problem to resolve variant representation differences in family trios. We show that VBT outperforms previous trio comparison methods by accuracy. Availability and implementation: VBT is implemented in C++ and source code is available under GNU GPLv3 license at the following URL: https://github.com/sbg/VBT-TrioAnalysis.git. Supplementary information: Supplementary data are available at Bioinformatics online.

A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome.

OBJECTIVE: In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. METHODS: This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. RESULTS: Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. INTERPRETATION: This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271-277.

Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment?

BACKGROUND: Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy. METHODS: Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment. RESULTS: Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia. CONCLUSION: An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients.

Propofol as a Risk Factor for ICU-Acquired Weakness in Septic Patients with Acute Respiratory Failure.

BACKGROUND: Critical illness polyneuropathy (CIN) and critical illness myopathy (CIM), together "ICU-Acquired weakness (ICUAW)," occur frequently in septic patients. One of the proposed mechanisms for ICUAW includes prolonged inactivation of sodium channels. Propofol, used commonly in patients with acute respiratory failure (ARF), primarily acts via enhancement of GABAergic transmission but may also increase sodium channel inactivation, suggesting a potential interaction. METHODS: Electronic medical records and EMG reports of patients with ICUAW and a diagnosis of either sepsis, septicaemia, severe sepsis, or septic shock, concurrent with a diagnosis of acute respiratory failure (ARF), were retrospectively analyzed in a single center university hospital. RESULTS: 74 cases were identified (50.0% men, age 58±14 years), and compared to age- and sex-matched controls. Of these, 51 (69%) had CIN, 19 (26%) had CIM, and 4 (5%) had both. Propofol exposure was significantly higher in patients with ICUAW compared to controls (63.5% vs. 33.8%, p<0.001). The odds ratio of developing ICUAW with propofol exposure was 3.4 (95% CI:1.7-6.7, p<0.001). Patients with ICUAW had significantly more days in hospital (59±44 vs. 30±23) and ICU (38±26 vs. 17±13), days dependent on mechanical ventilation (27±21 vs. 13±16), and rates of tracheostomy (79.7% vs. 36.5%) and gastrostomy (75.7% vs. 25.7%) (all p<0.001). They also received a significantly higher number of distinct intravenous antibiotics, cumulative days of antibiotic therapy, and exposure to vasopressors and paralytics. CONCLUSIONS: Propofol exposure may increase the risk of ICUAW in septic patients. An interaction through sodium channel inactivation is hypothesized.

Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Molecular treatment effects of alemtuzumab in skeletal muscles of patients with IBM.

BACKGROUND: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. METHODS: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. RESULTS: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-ß, TNF-α, and IL-1ß. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1ß and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and ß-amyloid. CONCLUSIONS: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM.

Higher expression of IL-12Rß2 is associated with lower risk of relapse in relapsing-remitting multiple sclerosis patients on interferon-ß1b therapy during 3-year follow-up.

Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-ß alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-ß1b treatment initiation and at 6, 12, 24 and 36 months of therapy. All mRNA levels changed significantly during the IFN-ß1b therapy. Higher IL-12Rß2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level.

Severe acute inflammatory demyelinating polyradiculoneuropathy with persistent weakness associated with tumor-like nerve root enlargement.

We report a 23-year-old woman with rapid onset of proximal and distal limb weakness and areflexia, associated with tumor-like spinal nerve root enlargement and markedly elevated cerebrospinal fluid protein. Our patient developed the inability to walk within days, without preceding illness. Within two weeks, she had near-complete bilateral wrist and foot drop. Her cranial nerves and respiratory function remained intact. She received intravenous immunoglobulin early on for suspected Guillain-barre syndrome but remained wheelchair-bound until 6 Plasma exchange sessions were completed. After that, she continued to improve with intravenous immunoglobulin dosed every 3-4 weeks. Prominent demyelinating features were found on NCS, with cerebrospinal fluid protein of 415 mg/dL. Comprehensive infectious work-up was negative. Magnetic resonance imaging of lumbosacral and cervical spine showed tumor-like masses mistaken for neurofibromatosis (axial diameter, 7.5-10 mm). Repeated magnetic resonance imaging 6 months later showed persistent nerve root enlargement, despite the patient's improved functional status.

Lower extremity peak force and gait kinematics in individuals with inclusion body myositis.

OBJECTIVE: To determine the relationship between peak isometric muscle force and temporal characteristics of gait in individuals with sporadic inclusion body myositis (s-IBM). METHODS: An observational study of 42 individuals with s-IBM (12 women; mean ± SD age 61.8 ± 7.3 years and mean ± SD disease duration 8.9 ± 4.3 years) was conducted at a federal hospital. Peak isometric force measurements for lower extremity (LE) muscle groups were obtained using quantitative muscle testing. Temporal characteristics of gait during habitual and fast walking conditions were measured using a portable gait analysis system. RESULTS: All observed muscle force values were significantly lower than predicted values (P ≤ 0.001). During habitual walking, the subjects' gait speed and cadence were ≤83% of normative literature values. During fast walking, total gait cycle time was 133% of normal, while gait speed and cadence were 58% and 78% of normative literature values, respectively. Scaled LE peak muscle forces showed significant moderate correlations with temporal gait variables. Weaker subjects had greater limitations in gait speed and cadence compared with stronger subjects (P < 0.05). Peak isometric force of the knee flexors and ankle plantar flexors was significantly correlated with most temporal features of habitual gait. CONCLUSION: Muscle weakness associated with s-IBM disease activity may contribute to diminished gait kinematics. Temporal features of gait were not substantially influenced by knee extensor weakness alone, considering the knee flexors and ankle plantar flexors played a compensatory role in maintaining the walking ability of individuals with s-IBM.

Paraplegia following lumbosacral steroid epidural injections.

Spinal cord ischemia is a rare but possible neurological complication following routine conservative treatment of lumbosacral radiculopathy. A case of a 46 year old woman with chronic L5 radiculopathy, who developed spinal cord ischemia following epidural steroid injection, is reported. Two months after the epidural injection, she required crutches for walking and had neurogenic bladder and bowel.

Validity of the single limb heel raise test to predict lower extremity disablement in patients with sporadic inclusion body myositis.

PURPOSE: To determine the validity of the single limb heel raise (SLHR) test as a potential screening tool to detect lower extremity disability in patients with sporadic inclusion body myositis (sIBM). METHODS: We compared gait speed and fall history between subjects with sIBM who either could complete one SLHR (SLHR group) or could not complete one SLHR. Discriminative validity was established by comparing between group differences in functional measures based on group assignment. Receiver operating characteristics curve analysis was used to determine the predictive validity of completing one repetition on the SLHR test. Spearman correlations were used to determine the association between gait kinematics and number of repetitions achieved on the SLHR test. RESULTS: Forty-three subjects (13 females) were studied. The SLHR group (n = 21) showed significantly greater gait speed (p < 0.001) and decreased gait aid use (p < 0.05) compared to the no SLHR group (n = 22). SLHR cut scores of 1, 20, and 22 repetitions maximized positive likelihood ratios (+LR) for the ability to walk at 54.9 (+LR. 2.2), 63.2 (+LR. 9.5), and 73.1 m/min (+LR. 5.0), respectively. CONCLUSION: The SLHR test demonstrates adequate discriminative and predictive validity as a screening tool for lower extremity disablement in patients with sIBM. Implications for Rehabilitation The SLHR test has adequate reliability and validity to screen for the presence of lower extremity disablement in patients with sIBM. Results of this rapid field test may be used to guide the need for rehabilitation services to mitigate the effects of slow gait speeds in patients with sIBM.

Are repeated single-limb heel raises and manual muscle testing associated with peak plantar-flexor force in people with inclusion body myositis?

BACKGROUND: Repeated heel raises have been proposed as a method of ankle plantar-flexor strength testing that circumvents the limitations of manual muscle testing (MMT). OBJECTIVE: The study objective was to examine the relationships among ankle plantar-flexion isometric maximum voluntary contraction (MVC), repeated single-limb heel raises (SLHRs), and MMT in people with myositis. DESIGN: This was a cross-sectional study with a between-group design. The ability to complete 1 SLHR determined group assignment (SLHR group, n=24; no-SLHR group, n=19). METHODS: Forty-three participants with myositis (13 women; median age=64.9 years) participated. Outcome measures included MVC, predicted MVC, Kendall MMT, and Daniels-Worthingham MMT. RESULTS: The Kendall MMT was unable to detect significant ankle plantar-flexor weakness established by quantitative methods and was unable to discriminate between participants who could and those who could not perform the SLHR task. Ankle plantar-flexion MVC was not associated with the number of heel-raise repetitions in the SLHR group (pseudo R(2)=.13). No significant relationship was observed between MVC values and MMT grades in the SLHR and no-SLHR groups. However, a moderate relationship between MVC values and MMT grades was evident in a combined-group analysis (ρ=.50-.67). LIMITATIONS: The lower half of both MMT grading scales was not represented in the study despite the profound weakness of the participants. CONCLUSIONS: Both Kendall MMT and Daniels-Worthingham MMT had limited utility in the assessment of ankle plantar-flexor strength. Repeated SLHRs should not be used as a proxy measure of ankle plantar-flexion MVC in people with myositis.