Abstract Background Dysregulation of N6-methyladenosine (m6A) has been implicated in the pathophysiology of various autoimmune diseases. However, its role in dermatomyositis (DM), particularly in cases associated with anti-MDA5 antibodies, remains unclear. This study aimed to elucidate the potential involvement of m6A modifications of mRNAs in the pathogenesis of anti-MDA5+DM. Methods We assessed mRNA m6A methylation levels in peripheral blood mononuclear cells (PBMCs) from anti-MDA5+DM patients and healthy controls (HC) using LC-MS/MS assay. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting were conducted to determine the mRNA and protein expression levels of YTHDF2 in PBMCs and monocytes from anti-MDA5+DM patients and HC. RNA sequencing (RNA-seq) was performed to identify differentially expressed genes and signaling pathways in siYTHDF2-THP-1 cells. RNA immunoprecipitation and quantitative PCR (RIP-qPCR) were used to explore the interaction between YTHDF2 protein and IFNB mRNA in THP-1 cells. Results The overall level of mRNA m6A methylation was found to be decreased in PBMCs of anti-MDA5+ DM compared to HC. The expression levels of YTHDF2 were downregulated in PBMCs and monocytes of anti-MDA5+DM patients compared with HC. The expression of IFNB was increased in PBMCs and monocytes of anti-MDA5+DM. Knockdown of YTHDF2 in THP-1 cells significantly increased IFNB expression and activated the JAK-STAT signaling pathway. The interaction between YTHDF2 protein and IFNB mRNA was confirmed by RIP-qPCR. The upregulated expression of type I IFN caused by YTHDF2 knockdown in THP-1 cells could be inhibited by JAK inhibitors. Conclusions Our findings suggest a decrease in YTHDF2 expression in anti-MDA5+DM monocytes, potentially enhancing IFNB expression and promoting the activation of JAK-STAT signaling pathway.
Abstract The SH2 domain-containing protein tyrosine phosphatase 2 (SHP2, also known as PTP2C), encoded by PTPN11, is ubiquitously expressed and has context-specific effects. It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases, cytokine receptors, and extracellular matrix proteins, and was shown in various lineages to modulate cell survival, proliferation, differentiation, and migration. Over the past decade, PTPN11 inactivation in chondrocytes was found to cause metachondromatosis, a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions. Moreover, SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice, and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis, during which its expression and activity are tightly regulated transcriptionally and posttranslationally, and by varying sets of functional partners. Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments. We here review current knowledge, highlight recent discoveries and controversies, and propose new research directions to answer remaining questions.
Emilie Schurenberg, Edward M. Huddleston, Kenneth G. Saag
Primary care physicians (PCPs) play a critical role in the management of gout worldwide. However, significant gaps in gout care persist, underscoring the need for improved approaches to its management. While some guidelines, such as those from the American College of Physicians (ACP) published in 2016, support a more reactive treat-to-symptoms approach, others from the American College of Rheumatology (ACR) and the European Alliance Of Associations For Rheumatology advocate for a proactive treat-to-target (TTT) strategy—focused on achieving optimal serum urate levels through urate lowering therapy (ULT). This divergence reflects differing clinical priorities and differential interpretation of the evidence and it may contribute to variability in care delivery. Improving gout management requires greater engagement from both patients and healthcare providers, with particular emphasis on increasing adherence to ULT. Patients need enhanced support to better understand the importance of sustained urate lowering treatment, while healthcare providers may benefit from clearer guidance aligned with evidence-based strategies to foster greater patient trust and confidence. This article provides an overview of the current state of guidelines, highlights areas of agreement and discordance between them, and identifies key areas for improving care delivery. It additionally offers insight into alternative care delivery strategies, such as those involving non-physician health professionals, which have shown promise in enhancing patient outcomes. Future research should focus on continued development of innovative, multi-modal interventions to improve ULT adherence, including health system-based initiatives and collaborative care models.
Calcium pyrophosphate crystal deposition disease is a prevalent and impactful form of crystal arthropathy. It usually targets the large joints of the extremities, significantly affecting daily life. Progression of this disease, commonly observed in older individuals and often mistaken for septic arthritis, osteoarthritis, or several rheumatic conditions, remains poorly understood. The disease can present in various forms, from asymptomatic to severe joint deformity. The primary goal of treating this disease is to firmly control inflammation, prevent joint deformities, and decisively stop attacks. Medications used to treat the disease include anti-rheumatic drugs such as non-steroidal anti-inflammatory drugs, oral, intramuscular, or intra-articular steroids, hydroxychloroquine, colchicine, methotrexate, and interleukin-1 receptor antagonists. Radiosynovectomy is a radioactive technique that effectively targets and eliminates inflamed synovium. This article highlights the importance of awareness and early intervention to manage this condition effectively.
O. A. Katsaraba, R. M. Sachuk, O. Ya. Dmytriv
et al.
Laboratory studies were conducted to determine the subacute toxicity of the veterinary drug Loxidev in dogs. 1 ml of the drug contains the active substance: meloxicam – 20 mg, excipients – glycine, sodium hydroxide, meglumine, and water for injection – up to 1 ml. The drug Loxidev, based on meloxicam, is used in diseases of European fallow deer, treatment of animals for non-infectious diseases of the musculoskeletal system (acute aseptic myositis to reduce symptoms of lameness and inflammation), as well as for diseases of the respiratory system (in the case of appropriate antibiotic therapy). Red deer: treatment of animals for non-infectious diseases of the musculoskeletal system (arthritis of the metatarso-metatarsal joint to reduce symptoms of lameness and inflammation). It was established that subcutaneous administration of the drug Loxidev (solution for injection) to dogs in doses of 0.03; 0.15 and 0.3 ml/kg of body weight for 3 days in general does not affect the clinical and biochemical parameters of the blood and does not cause hepato- and nephrotoxic effects on the animal body under the conditions of a subacute toxicological experiment. The exceptions were the tendencies to reduce the concentration of total hemoglobin, hematocrit and erythrocyte count, as well as a significant decrease (P < 0.05) in the number of leukocytes by 6.6 %, respectively, relative to the control in the blood and an increase (P < 0.05) in the enzymatic activity of ALT and AST and the concentration of urea in the blood serum of dogs after three days of administration of the drug at a dose of 0.30 mg/kg of body weight by 19.4; 19.3 and 14.5 %, respectively, however, 7 days after discontinuation of the drug, these indicators did not significantly differ from the control. Further research directions will include the following: studying the long-term effects of meloxicam on the body of dogs to determine possible cumulative effects when used in long-term therapeutic courses; analysis of the molecular and cellular mechanisms underlying the identified toxic effects, for example, effects on enzyme systems, oxidative stress or immunological reactions; expanding studies with an emphasis on the specific effects of the drug on the liver, kidneys, cardiovascular system and digestive tract, which are the primary targets for NSAIDs; studying the effects of meloxicam on animal reproductive function, embryo development and potential risks to offspring.
Alexis Ogdie, Nicole Middaugh, Taylor Blachley
et al.
Abstract Introduction This study evaluated the real-world effectiveness of tofacitinib monotherapy versus combination therapy in patients with psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry. Methods This study (NCT05195814) included adult patients with PsA initiating tofacitinib (from December 14, 2017 to October 1, 2023) as monotherapy, or in combination with oral small molecules (OSMs: methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and apremilast). Patients with baseline and 6-month follow-up visits (± 3 months) were included. Outcomes: mean change from baseline (∆) in/proportions achieving, disease activity measures (including body surface area [BSA] = 0%), and patient-reported outcomes. Continuous endpoints at month 6 were analyzed as ∆ with an analysis of covariance model including treatment and baseline value as covariates. ∆ in least squares (LS) means and adjusted LS means/odds ratios are presented. Results The study included 141 patients (66/141 monotherapy; 75/141 combination therapy). Patients were predominantly female (61.0%) and white (94.3%), and average age was 56.7 years. More monotherapy initiators were OSM treatment-naïve and had higher mean Patient Global Assessment of Arthritis, compared with combination therapy initiators. By 6 ± 3 months, 28.8% and 25.3% of monotherapy and combination therapy initiators, respectively, discontinued tofacitinib. At 6 ± 3 months, 15.0% of monotherapy initiators achieved minimal disease activity, and 27.1% had BSA = 0%. Corresponding data for combination therapy initiators were 20.7%, and 22.0%, respectively. Differences between groups were not significant. LS mean differences from baseline in overall work impairment/activity impairment were − 13.0/− 21.8 and 1.4/− 2.9 for monotherapy and combination therapy initiators, respectively. Conclusion Monotherapy and combination therapy initiators demonstrated improvements across effectiveness outcomes. Tofacitinib monotherapy initiators experienced numerical improvements in overall work impairment/activity impairment. This highlights tofacitinib effectiveness as monotherapy/combination therapy for a diverse PsA population. However, the small sample size limited the statistical power, and so results should be interpreted cautiously. Trial Registration ClinicalTrials.gov identifier, NCT05195814.
Wearable sensor technologies and deep learning are transforming healthcare management. Yet, most health sensing studies focus narrowly on physical chronic diseases. This overlooks the critical need for joint assessment of comorbid physical chronic diseases and depression, which is essential for collaborative chronic care. We conceptualize multi-disease assessment, including both physical diseases and depression, as a multi-task learning (MTL) problem, where each disease assessment is modeled as a task. This joint formulation leverages inter-disease relationships to improve accuracy, but it also introduces the challenge of double heterogeneity: chronic diseases differ in their manifestation (disease heterogeneity), and patients with the same disease show varied patterns (patient heterogeneity). To address these issues, we first adopt existing techniques and propose a base method. Given the limitations of the base method, we further propose an Advanced Double Heterogeneity-based Multi-Task Learning (ADH-MTL) method that improves the base method through three innovations: (1) group-level modeling to support new patient predictions, (2) a decomposition strategy to reduce model complexity, and (3) a Bayesian network that explicitly captures dependencies while balancing similarities and differences across model components. Empirical evaluations on real-world wearable sensor data demonstrate that ADH-MTL significantly outperforms existing baselines, and each of its innovations is shown to be effective. This study contributes to health information systems by offering a computational solution for integrated physical and mental healthcare and provides design principles for advancing collaborative chronic disease management across the pre-treatment, treatment, and post-treatment phases.
In the context of the rising share of new energy generation, accurately generating new energy output scenarios is crucial for day-ahead power system scheduling. Deep learning-based scenario generation methods can address this need, but their black-box nature raises concerns about interpretability. To tackle this issue, this paper introduces a method for day-ahead new energy scenario generation based on an improved conditional generative diffusion model. This method is built on the theoretical framework of Markov chains and variational inference. It first transforms historical data into pure noise through a diffusion process, then uses conditional information to guide the denoising process, ultimately generating scenarios that satisfy the conditional distribution. Additionally, the noise table is improved to a cosine form, enhancing the quality of the generated scenarios. When applied to actual wind and solar output data, the results demonstrate that this method effectively generates new energy output scenarios with good adaptability.
Calcium pyrophosphate deposition disease (CPPD) is a cause of inflammatory arthropathy that increases in prevalence with increasing age, presents in acute and chronic forms, and is characterized by the finding of positively birefringent crystals on polarized microscopy of synovial fluid. This review finds that although strides are being made in CPPD diagnosis and classification, CPPD remains a poorly understood, unrecognized, and debilitating disease. As a consequence, treatment options usually lack supportive evidence and there has been little progress in novel drug development for the condition. This article aims to discuss the updated evidence on treatment options for CPPD and identifies promising future areas for improvement.
A. I. Bogatyreva, E. V. Gerasimova, T. V. Kirichenko
et al.
The pathogenesis of immunoinflammatory rheumatic diseases (IRDs) is based on chronic inflammation, one of the key mechanisms of which may be abnormal activation of macrophages, leading to further disruption of the immune system.The aim – to evaluate the pro-inflammatory activation of circulating monocytes in patients with IRDs.Material and methods. The study included 149 participants: 53 patients with rheumatoid arthritis (RA), 45 – with systemic lupus erythematosus (SLE), 34 – with systemic scleroderma (SSc) and 17 participants without IRD, aged 30 to 65 years. Basal and lipolysaccharide (LPS)-stimulated secretion of monocytes was studied in a primary culture of monocytes obtained by immunomagnetic separation from blood. Quantitative assessment of the cytokines tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and the monocyte chemoattractant protein-1 (MCP-1) was carried out in the culture fluid by ELISA. Pro-inflammatory activation of monocytes was calculated as the ratio of LPS-stimulated and basal secretions.Results. It was shown that the basal secretion of all studied cytokines was significantly increased in all groups of patients with IRDs, except for the secretion of IL-1β in the SLE group, compared with the control. LPS-stimulated secretion of TNF-α was increased and MCP-1 was decreased in patients with IRDs compared to the control group; LPS-stimulated IL-1β secretion only in the SSc group was significantly different from the control group. In the RA group, monocyte activation was reduced for all cytokines compared to the control, in the SLE group – for TNF-α and MCP-1, in the SSc group – for MCP-1.Conclusion. The decrease in pro-inflammatory activation of monocytes in patients with IRDs is due to a high level of basal secretion of cytokines, which can lead to disruption of the adequate immune response in these diseases and is an important link in the pathogenesis of chronic inflammation.
Giulia Di Martino, Stefano Giommoni, Fosco Esposito
et al.
<b>Background:</b> This study aimed to evaluate the effects of a six-week visual training protocol, based on the Science Vision Training Academy (SVTA) method, on reaction times and executive functions in high-ranking fencers. <b>Methods:</b> Twenty-seven fencers, aged 17.34 ± 3.63 years, were randomly assigned to an experimental Visual Training Group (VTG = 16) and a Control Group (CG = 11). The VTG, in addition to regular fencing training, underwent SVTA training two times per week using six different visual modules, while the CG followed only their traditional fencing training. Simple and complex reaction times and movement times were assessed before and after the intervention using the Fit-Light System. <b>Results:</b> Both groups showed a significant improvement in all four reaction time tests: simple reaction time with and without a weapon and complex reaction time ability (motor inhibition ability) with and without a weapon (<i>p</i> < 0.001). No significant differences were observed between the groups. A significant Time* Group interaction was found in the short reaction time and movement time (<i>p</i> < 0.001). This trend suggests that, although genetically determined and difficult to significantly improve through training, short reaction time can be stimulated through SVTA protocols. <b>Conclusions:</b> Training in realistic conditions is always preferable to non-ecological protocols; however, the SVTA method may be beneficial to enhance simple reaction time in elite fencers.
Pierluigi Colli, Gabriela Marinoschi, Elisabetta Rocca
et al.
Partial differential equation (PDE) models for infectious disease have received renewed interest in recent years. Most models of this type extend classical compartmental formulations with additional terms accounting for spatial dynamics, with Fickian diffusion being the most common such term. However, while diffusion may be appropriate for modeling vector-borne diseases, or diseases among plants or wildlife, the spatial propagation of airborne diseases in human populations is heavily dependent on human contact and mobility patterns, which are not necessarily well-described by diffusion. By including an additional chemotaxis-inspired term, in which the infection is propagated along the positive gradient of the susceptible population (from regions of low- to high-density of susceptibles), one may provide a more suitable description of these dynamics. This article introduces and analyzes a mathematical model of infectious disease incorporating a modified chemotaxis-type term. The model is analyzed mathematically and the well-posedness of the resulting PDE system is demonstrated. A series of numerical simulations are provided, demonstrating the ability of the model to naturally capture important phenomena not easily observed in standard diffusion models, including propagation over long spatial distances over short time scales and the emergence of localized infection hotspots
Ghazaleh Babanejaddehaki, Aijun An, Manos Papagelis
Infectious diseases occur when pathogens from other individuals or animals infect a person, resulting in harm to both individuals and society as a whole. The outbreak of such diseases can pose a significant threat to human health. However, early detection and tracking of these outbreaks have the potential to reduce the mortality impact. To address these threats, public health authorities have endeavored to establish comprehensive mechanisms for collecting disease data. Many countries have implemented infectious disease surveillance systems, with the detection of epidemics being a primary objective. The clinical healthcare system, local/state health agencies, federal agencies, academic/professional groups, and collaborating governmental entities all play pivotal roles within this system. Moreover, nowadays, search engines and social media platforms can serve as valuable tools for monitoring disease trends. The Internet and social media have become significant platforms where users share information about their preferences and relationships. This real-time information can be harnessed to gauge the influence of ideas and societal opinions, making it highly useful across various domains and research areas, such as marketing campaigns, financial predictions, and public health, among others. This article provides a review of the existing standard methods developed by researchers for detecting outbreaks using time series data. These methods leverage various data sources, including conventional data sources and social media data or Internet data sources. The review particularly concentrates on works published within the timeframe of 2015 to 2022.
Zsuzsanna H. McMahan, Subhash Kulkarni, Felipe Andrade
et al.
Objective Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti‐ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction. Methods Serum from a patient with SSc with GI dysfunction but without defined SSc‐associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on‐bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry. Results We identified gephyrin as a novel SSc autoantigen. Anti‐gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti‐gephyrin antibody–positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15 % , P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti‐gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00 ; P = 0.001) and severe distention and bloating (0.03 vs 0.004 ; P = 0.010). Severe constipation was associated with anti‐gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility. Conclusion Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti‐gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.
Aniket A. Tolpadi, Jinhee J. Lee, Valentina Pedoia
et al.
AbstractKnee Osteoarthritis (OA) is a common musculoskeletal disorder in the United States. When diagnosed at early stages, lifestyle interventions such as exercise and weight loss can slow OA progression, but at later stages, only an invasive option is available: total knee replacement (TKR). Though a generally successful procedure, only 2/3 of patients who undergo the procedure report their knees feeling “normal” post-operation, and complications can arise that require revision. This necessitates a model to identify a population at higher risk of TKR, particularly at less advanced stages of OA, such that appropriate treatments can be implemented that slow OA progression and delay TKR. Here, we present a deep learning pipeline that leverages MRI images and clinical and demographic information to predict TKR with AUC 0.834 ± 0.036 (p < 0.05). Most notably, the pipeline predicts TKR with AUC 0.943 ± 0.057 (p < 0.05) for patients without OA. Furthermore, we develop occlusion maps for case-control pairs in test data and compare regions used by the model in both, thereby identifying TKR imaging biomarkers. As such, this work takes strides towards a pipeline with clinical utility, and the biomarkers identified further our understanding of OA progression and eventual TKR onset.
Tonia K. Tsinman, Yuming Huang, Saima Ahmed
et al.
AbstractExternally applied forces, such as those generated through skeletal muscle contraction, are important to embryonic joint formation, and their loss can result in gross morphologic defects including joint fusion. While the absence of muscle contraction in the developing chick embryo leads to dissociation of dense connective tissue structures of the knee and ultimately joint fusion, the central knee joint cavitates whereas the patellofemoral joint does not in murine models lacking skeletal muscle contraction, suggesting a milder phenotype. These differential results suggest that muscle contraction may not have as prominent of a role in the growth and development of dense connective tissues of the knee. To explore this question, we investigated the formation of the menisci, tendon, and ligaments of the developing knee in two murine models that lack muscle contraction. We found that while the knee joint does cavitate, there were multiple abnormalities in the menisci, patellar tendon, and cruciate ligaments. The initial cellular condensation of the menisci was disrupted and dissociation was observed at later embryonic stages. The initial cell condensation of the tendon and ligaments were less affected than the meniscus, but these tissues contained cells with hyper‐elongated nuclei and displayed diminished growth. Interestingly, lack of muscle contraction led to the formation of an ectopic ligamentous structure in the anterior region of the joint as well. These results indicate that muscle forces are essential for the continued growth and maturation of these structures during this embryonic period.
Masanori Tsubosaka, Masahiro Maruyama, Elaine Lui
et al.
AbstractNontraumatic osteonecrosis of the femoral head (ONFH) is a refractory condition that commonly results in femoral head collapse and degenerative arthritis of the hip. In the early stages, surgical procedures for hip preservation, including core decompression (CD), have been developed to prevent progressive collapse of the femoral head. Optimization of bone regeneration and biological augmentation may further enhance the therapeutic efficacy of CD for ONFH. Thus, combining CD with cell‐based therapy has recently been proposed. In fact, patients treated with cell‐based therapy using autologous bone marrow concentrate demonstrate improved survivorship of the femoral head, compared with conventional CD alone. Preclinical research studies to investigate adjunctive therapies for CD often utilize the rabbit model of corticosteroid‐induced ONFH. Mesenchymal stem cells (MSCs) are known to promote osteogenesis and angiogenesis, and decrease inflammation in bone. Local drug delivery systems have the potential to achieve targeted therapeutic effects by precisely controlling the drug release rate. Scaffolds can provide an osteoconductive structural framework to facilitate the repair of osteonecrotic bone tissue. We focused on the combination of both cell‐based and scaffold‐based therapies for bone tissue regeneration in ONFH. We hypothesized that combining CD and osteoconductive scaffolds would provide mechanical strength and structural cell guidance; and that combining CD and genetically modified (GM) MSCs to express relevant cytokines, chemokines, and growth factors would promote bone tissue repair. We developed GM MSCs that overexpress the anti‐inflammatory, pro‐reconstructive cytokines platelet‐derived growth factor‐BB to provide MSCs with additional benefits and investigated the efficacy of combinations of these GM MSCs and scaffolds for treatment of ONFH in skeletally mature male New Zealand white rabbits. In the future, the long‐term safety, efficacy, durability, and cost‐effectiveness of these and other biological and mechanical treatments must be demonstrated for the patients affected by ONFH.