Human Arm Workout Classification by Arm Sleeve Device Based on Machine Learning Algorithms.

Wearables have been applied in the field of fitness in recent years to monitor human muscles by recording electromyographic (EMG) signals. Understanding muscle activation during exercise routines allows strength athletes to achieve the best results. Hydrogels, which are widely used as wet electrodes in the fitness field, are not an option for wearable devices due to their characteristics of being disposable and skin-adhesion. Therefore, a lot of research has been conducted on the development of dry electrodes that can replace hydrogels. In this study, to make it wearable, neoprene was impregnated with high-purity SWCNTs to develop a dry electrode with less noise than hydrogel. Due to the impact of COVID-19, the demand for workouts to improve muscle strength, such as home gyms and personal trainers (PT), has increased. Although there are many studies related to aerobic exercise, there is a lack of wearable devices that can assist in improving muscle strength. This pilot study proposed the development of a wearable device in the form of an arm sleeve that can monitor muscle activity by recording EMG signals of the arm using nine textile-based sensors. In addition, some machine learning models were used to classify three arm target movements such as wrist curl, biceps curl, and dumbbell kickback from the EMG signals recorded by fiber-based sensors. The results obtained show that the EMG signal recorded by the proposed electrode contains less noise compared to that collected by the wet electrode. This was also evidenced by the high accuracy of the classification model used to classify the three arms workouts. This work classification device is an essential step towards wearable devices that can replace next-generation PT.

Safety and tolerability of bone marrow-derived mesenchymal stem cells in lupus animal models and a phase I clinical trial in humans.

OBJECTIVE: Several clinical trials aimed at treating various autoimmune diseases, including systemic lupus erythematosus (SLE), by introducing mesenchymal stem cells (MSCs) have been conducted. However, with refractory lupus nephritis (LN), the outcomes of MSC transplantation are not well known, and further validation is required. In particular, data concerning the safety and efficacy of LN treatment using bone marrow-derived MSCs (BM-MSCs) are still lacking. METHODS: We identified characteristics of BM-MSCs in terms of cell morphology, chromosomal stability, differentiation capacity, and phenotype through cell passages. The in vivo stability of BM-MSCs was evaluated by single-dose and repeated-dose toxicity tests, tumorigenicity tests, and biodistribution tests using lupus mouse models. Based on the encouraging nonclinical results, we conducted a nonrandomized, open-label, single-arm phase I clinical trial to evaluate the tolerability and safety of a single administration of haploidentical allogeneic BM-MSCs (CS20AT04) in seven LN patients (NCT03174587). We used a classical three + three design to find the optimal dosage. The starting dose was 2.0×106 cells/kg and escalated to 3.0×106 cells/kg if there was no dose-limiting toxicity (DLT). Evaluation of the safety and tolerability was assessed 28 days after the infusion, and the maximum tolerated dose was determined. RESULTS: Properly cultured BM-MSCs showed high proliferation and multipotency, but chromosomal changes were not found. There were two deaths by a rapid administration rate in the high-dose group (2.0×106 cells/head) in a single administration test. BM-MSCs were distributed in the kidneys until Day 7. In the phase I clinical trial, seven LN patients were enrolled. Participants received BM-MSCs through intravenous infusion. There was no DLT at both initial dose (2.0×106 cells/kg) and escalated dose (3.0×106 cells/kg). One patient was not administered the full 2.0×106 cells/kg dose because of a technical error during infusion. This patient did not show DLT. Three adverse events were reported, namely, one diarrhea, one toothache, and one arthralgia, and all were considered NCI-CTC grade I events. CONCLUSION: We defined the characteristics of BM-MSCs and identified their safety and tolerability in both animal models and a phase I clinical trial. The maximum tolerated dose was determined to be 3.0×106 cells/kg in patients with LN.

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Objective: Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. Methods: A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Results: Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. Conclusion: The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.

Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial.

BACKGROUND: A single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS. METHODS: ALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months. DISCUSSION: Lenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745299 . Registered on Feb 9, 2021. Clinical Research Information Service (CRIS) KCT0005954 . Registered on Mar 4, 2021.

Allele-Specific Quantification of HLA-DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA-DRß1.

OBJECTIVE: HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRß1 structure-associated trait in RA. METHODS: We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRß1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA. RESULTS: The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRß1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10-3 ). CONCLUSION: Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.

Deletion at 2q14.3 is associated with worse response to TNF-α blockers in patients with rheumatoid arthritis.

BACKGROUND: Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers. METHODS: A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment. RESULTS: The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10- 5 ≤ P ≤ 4.07 × 10- 4) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK. CONCLUSIONS: This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.