Explainable Deep Learning Model for Predicting Serious Adverse Events in Hospitalized Geriatric Patients Within 72 Hours.

Background: The global aging population presents a significant challenge, with older adults experiencing declining physical and cognitive abilities and increased vulnerability to chronic diseases and adverse health outcomes. This study aims to develop an interpretable deep learning (DL) model to predict adverse events in geriatric patients within 72 hours of hospitalization. Methods: The study used retrospective data (2017-2020) from a major medical center in Taiwan. It included non-trauma geriatric patients who visited the emergency department and were admitted to the general ward. Data preprocessing involved collecting prognostic factors like vital signs, lab results, medical history, and clinical management. A deep feedforward neural network was developed, and performance was evaluated using accuracy, sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC). Model interpretation utilized the Shapley Additive Explanation (SHAP) technique. Results: The analysis included 127,268 patients, with 2.6% experiencing imminent intensive care unit transfer, respiratory failure, or death during hospitalization. The DL model achieved AUCs of 0.86 and 0.84 in the validation and test sets, respectively, outperforming the Sequential Organ Failure Assessment (SOFA) score. Sensitivity and specificity values ranged from 0.79 to 0.81. The SHAP technique provided insights into feature importance and interactions. Conclusion: The developed DL model demonstrated high accuracy in predicting serious adverse events in geriatric patients within 72 hours of hospitalization. It outperformed the SOFA score and provided valuable insights into the model's decision-making process.

Multivariate analysis of carcinogenic equivalence (CEQ) to characterize carcinogenic VOC emissions in a typical petrochemical industrial park in Taiwan.

Large industrial emissions of volatile organic compounds (VOCs) from the petrochemical industry are a critical concern due to their potential carcinogenicity. VOC emissions vary in composition depending on the source and occur in mixtures containing compounds with varying degrees of toxicity. We proposed the use of carcinogenic equivalence (CEQ) and multivariate analysis to identify the major contributors to the carcinogenicity of VOC emissions. This method weights the carcinogenicity of each VOC by using a ratio of its cancer slope factor to that of benzene, providing a carcinogenic equivalence factor (CEF) for each VOC. We strategically selected a petrochemical industrial park in southern Taiwan that embodies the industry's comprehensive nature and serves as a representative example. The CEQs of different emission sources in three years were analyzed and assessed using principal component analysis (PCA) to characterize the major contributing sectors, vendors, sources, and species for the carcinogenicity of VOC emissions. Results showed that while the study site exhibited a 20.7 % (259.8 t) decrease in total VOC emissions in three years, the total CEQ emission only decreased by 4.5 % (15.9 t), highlighting a potential shift in the emitted VOC composition towards more carcinogenic compounds. By calculating CEQ followed by PCA, the important carcinogenic VOC emission sources and key compounds were identified. More importantly, the study compared three approaches: CEQ followed by PCA, PCA followed by CEQ, and PCA only. While the latter two methods prioritized sources based on emission quantities, potentially overlooking less abundant but highly carcinogenic compounds, the CEQ-first approach effectively identified vendors and sources with the most concerning cancer risks. This distinction underscores the importance of selecting the appropriate analysis method based on the desired focus. Our study highlighted how prioritizing CEQ within the analysis framework empowered the development of precise control measures that address the most carcinogenic VOC sources.

Development and Comparison of Treatment Decision Tools for Glucocorticoid-Induced Osteoporosis.

Long-term Glucocorticoid (GC) use results in compromised bone strength and fractures, and several treatment recommendations have been developed to prevent fractures, but none have been validated in a real-world setting. This study aims to create a treatment decision tool and compares this tool to the treatment suggestions from the American College of Rheumatology (ACR), International Osteoporosis Foundation and European Calcified Tissue Society (IOF-ECTS), and GC-adjusted Fracture Risk Assessment Tool (GC-FRAX), above the intervention threshold. We utilized registry data gathered at Chang Gung Memorial Hospital at Kaohsiung, Taiwan, between September 2014 and April 2021. This research is a single-center, observational, and case-controlled study. We recruited participants using prednisone for at least 2.5 mg/day or the equivalent dose for over 3 months, excluding those younger than 40, those with malignancies, or those currently undergoing anti-osteoporosis therapy. The primary endpoint was new fragility fractures within 3 years, including morphometric vertebral fractures detected at baseline and with a follow-up thoracic-lumbar spine X-ray. Participants were randomly allocated into derivation and validation sets. We developed the Steroid-Associated Fracture Evaluation (SAFE) tool in the derivation cohort by assessing the weights of exploratory variables via logistic regression. Prediction performance was compared in the validation set by the receiver operating characteristic (ROC) curve, the area under the curve (AUC), and sensitivity and specificity. A total of 424 treatment-naïve subjects were enrolled, and 83 (19.6%) experienced new fractures within 3 years. The final formula of the SAFE tool includes osteoporosis (1 point), an accumulated GC dose ≥ 750 mg within 6 months (or equivalent prednisolone of ≥4.5 mg/day for 6 months) (1 point), a BMI ≥ 23.5 (1 point), previous fractures (1 point), and elderliness of ≥70 years (2 points). In the validation set, a treatment decision based on the SAFE ≥ 2 points demonstrated an AUC of 0.65, with a sensitivity/specificity/accuracy of 75.9/54.0/58.9, with an ACR of 0.56 (100.0/11.0/31.0), IOF-ECTS 0.61 (75.9/46.0/52.7), and GC-FRAX 0.62 (82.8/42.0/51.2). Among current GIOP recommendations, the SAFE score serves as an appropriate treatment decision tool with increased accuracy and specificity.

Analyzing the risk of osteoporosis and fracture in rheumatoid arthritis patients who have been treated with various biologics.

BACKGROUND: Rheumatoid arthritis (RA) is a major risk factor for osteoporosis/osteoporotic fractures. We aimed to elucidate the role of treatment choices among osteoporosis/osteoporotic fractures. METHODOLOGY: We utilized the Chang-Gung Research Database to assess the risks of osteoporosis/osteoporotic fractures among independently treated RA patients, using retrospective time-to-event outcomes analysis. RESULTS: A total of 3509 RA patients with a mean of 63.1 ± 8.6 years were analyzed. Among all, 1300 RA patients (37%) were diagnosed with newly diagnosed osteoporosis. The crude incidence of newly diagnosed osteoporosis was the highest among those treated with other conventional disease-modifying anti-rheumatic drugs (cDMARDs; 74.1 events/1000-PYs, 95%CI 66.0-82.3), followed by those with a non-treatment period (68 events/1000-PYs, 95%CI 63.1-72.9), methotrxate (MTX) monotherapy (60.7 events/1000-PYs, 95%CI 41.2-80.3), MTX plus other cDMARDs (51.9 events/1000-PYs, 95%CI 43.4-60.3), and abatacept/rituximab (48.6 events/1000-PYs, 95%CI 14.9-82.3). The lowest crude incidence was found in patients treated with anti-TNFi biologics (40.4 events/1000-PYs, 95%CI 28.6-52.2) and other biologic disease-modifying anti-rheumatic drugs (bDMARDs; 40.1 events/1000-PYs, 95%CI 8.0-72.1). A total of 270 patients (20.8%) suffered from an incident fracture during follow-ups. The crude incidence of fracture was the highest among those treated with abatacept/rituximab (49.0 events/1000-PYs, 95%CI 6.0-91.9), followed by those with non-treatment periods (24.3 events/1000-PYs, 95%CI 19.3-29.4), other cDMARDs (24.2 events/1000-PYs, 95%CI 18.1-30.2), anti-TNFi biologics (20.2 events/1000-PYs, 95%CI 8.8-31.6). Other bDMARDs (13.3 events/1000-PYs, 95%CI 0-39.2), MTX mono (12.5 events/1000-PYs, 95%CI 0.3-24.8), and MTX plus other cDMARDs (11.4 events/1000-PYs, 95%CI 5.4-17.4) were low incidences. CONCLUSION: The treatment option has emerged as a critical determinant in the context of future osteoporosis and osteoporotic fracture risks among RA. These findings offer a valuable resource for clinicians, empowering them to tailor bespoke treatment strategies for RA patients, thereby mitigating the potential for future osteoporosis and fractures.

Disease-modifying anti-rheumatic drugs associated with different diabetes risks in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis are prone to developing diabetes, which may lead to various sequelae and even cardiovascular diseases, the most common cause of death in such patients. Previous research has shown that some rheumatoid arthritis treatments may help prevent the development of diabetes. This study aimed to investigate whether patients using disease-modifying anti-rheumatic drugs (DMARDs) may have different levels of risk for diabetes and to analyse other risk factors for diabetes. METHODS: This cohort study used data from the Chang Gung Research Database. 5530 adults with rheumatoid arthritis but without diabetes were eligible for the analysis. The endpoint of this study was new-onset diabetes, defined as an HbA1c value ≥7% during follow-up. The entire follow-up period was divided into monthly subunits. These 1-month units were then divided into methotrexate (MTX) monotherapy, any biological DMARDs (bDMARDs), MTX combination, other conventional DMARDs (cDMARDs) and non-DMARDs. RESULTS: A total of 546 participants (9.87%) developed diabetes between 2001 and 2018. The risk of diabetes was significantly lower in the bDMARD periods (HR 0.51; 95% CI 0.32 to 0.83), MTX combination periods (HR 0.50; 95% CI 0.32 to 0.78) and other cDMARD periods (HR 0.56; 95% CI 0.37 to 0.84) than in the MTX monotherapy periods. Individual drug analysis showed that hydroxychloroquine (HR 0.52; 95% CI 0.42 to 0.65) reduced the risk of diabetes. Tumour necrosis factor-α inhibitors (HR 0.69; 95% CI 0.46 to 1.03) tended to be protective. CONCLUSION: Patients with rheumatoid arthritis may have different levels of risk of diabetes depending on the treatment options.

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation.

AIMS/HYPOTHESIS: The mitochondrial chaperonin heat shock protein (HSP) 60 is indispensable in protein folding and the mitochondrial stress response; however, its role in nutrient metabolism remains uncertain. This study investigated the role of HSP60 in diet-induced non-alcoholic fatty liver disease (NAFLD). METHODS: We studied human biopsies from individuals with NAFLD, murine high-fat-diet (HFD; a diet with 60% energy from fat)-induced obesity (DIO), transgenic (Tg) mice overexpressing Hsp60 (Hsp60-Tg), and human HepG2 cells transfected with HSP60 cDNA or with HSP60 siRNA. Histomorphometry was used to assess hepatic steatosis, biochemistry kits were used to measure insulin resistance and glucose tolerance, and an automated home cage phenotyping system was used to assess energy expenditure. Body fat was assessed using MRI. Macrophage infiltration, the lipid oxidation marker 4-hydroxy-2-nonenal (4-HNE) and the oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were detected using immunohistochemistry. Intracellular lipid droplets were evaluated by Nile red staining. Expression of HSP60, and markers of lipogenesis and fatty acid oxidation were quantified using RT-PCR and immunoblotting. Investigations were analysed using the two-way ANOVA test. RESULTS: Decreased HSP60 expression correlated with severe steatosis in human NAFLD biopsies and murine DIO. Hsp60-Tg mice developed less body fat, had reduced serum triglyceride levels, lower levels of insulin resistance and higher serum adiponectin levels than wild-type mice upon HFD feeding. Respiratory quotient profile indicated that fat in Hsp60-Tg mice may be metabolised to meet energy demands. Hsp60-Tg mice showed amelioration of HFD-mediated hepatic steatosis, M1/M2 macrophage dysregulation, and 4-HNE and 8-OHdG overproduction. Forced HSP60 expression reduced the mitochondrial unfolded protein response, while preserving mitochondrial respiratory complex activity and enhancing fatty acid oxidation. Furthermore, HSP60 knockdown enhanced intracellular lipid formation and loss of sirtuin 3 (SIRT3) signalling in HepG2 cells upon incubation with palmitic acid (PA). Forced HSP60 expression improved SIRT3 signalling and repressed PA-mediated intracellular lipid formation. SIRT3 inhibition compromised HSP60-induced promotion of AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferator-activated receptor α (PPARα levels), while also decreasing levels of fatty acid oxidation markers. CONCLUSION/INTERPRETATION: Mitochondrial HSP60 promotes fatty acid oxidation while repressing mitochondrial stress and inflammation to ameliorate the development of NAFLD by preserving SIRT3 signalling. This study reveals the hepatoprotective effects of HSP60 and indicates that HSP60 could play a fundamental role in the development of therapeutics for NAFLD or type 2 diabetes.

Association of Systemic Sclerosis With Incident Clinically Evident Heart Failure.

OBJECTIVE: Primary myocardial involvement is an important cause of death in systemic sclerosis (SSc). Subclinical diastolic/systolic heart dysfunction is recognized; however, whether this indicates a subsequent increased risk of clinically overt heart failure (HF) remains largely unknown. We aimed to investigate the risk of clinically overt HF in a large, unselected SSc cohort. METHODS: This matched, retrospective cohort study was conducted using a nationwide insurance database in Taiwan. Incident SSc patients with no history of HF were identified, and non-SSc comparison groups were selected and matched to the SSc groups by age, sex, and cohort entry time. The cumulative HF incidence was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (HRs) for HF hospitalization. RESULTS: A total of 1,830 SSc patients and 27,981 controls were identified. The cumulative incidence of hospitalized HF at 3, 5, and 10 years among patients with SSc were 3.5%, 5.3%, and 9.7%, respectively. Compared with non-SSc individuals, SSc patients had an increased risk of HF (adjusted HR 3.26 [95% confidence interval (95% CI) 2.49-4.28]). Subgroup analyses revealed that the impact of SSc on the occurrence of HF was greater among patients ages <50 years than those ages ≥50 years (HR 7.8 [95% CI 4.03-15.1] versus HR 2.78 [95% CI 2.06-3.76]). CONCLUSION: SSc is associated with a markedly higher risk of clinically evident HF and not asymptomatic ventricular dysfunction alone. These findings provide real-world evidence suggesting the use of appropriate screening strategies to detect these lethal complications early in SSc.

Comparison of glucocorticoids and painkiller prescribed days between rheumatoid arthritis patients receiving early and late treatment with a biological agent via a population-based cohort study.

Comparison between early biologics treatment and late biologics treatment of rheumatoid arthritis (RA) patients in decreasing prescription days of glucocorticoids and painkillers by using the Taiwan National Health Insurance Research database from January 1, 1997 to December 31, 2013. We defined early use of biologics as biologics prescribed within 2.24 years after the RA diagnosis, and the late use of biologics was defined as those prescribed after 2.24 years of the RA diagnosis. These definitions are based on previous studies defining early arthritis as arthritis within 2 years of diagnosis, while we needed another 3 months for application biologics here in Taiwan, which equals a total of 2.24 years. Among the 821 patients, 410 patients (50%) were classified in the Early group, and the other 411 patients (50%) were classified in the Late group. The use of any of these 3 types of medication, including steroids, disease modifying antirhuematic drugs, and nonsteroid anti-inflammatory drug (NSAID) was changed significantly after biologics treatment. Comparing between before and after biologics treatment, oral medication was significantly tapered (all P < .0001). The results show that men are 1.81 times more likely than women to taper oral glucocorticoids and NSAIDs. Younger age (<45) patients are 1.91 times more likely to taper steroids and NSAIDs than those aged over 65 years old. Both gender and age were found to be independent factors that could decrease days of prescription of both steroids and NSAIDs in early use of biologics agents. This study indicates that younger patients only need short-term (2.53 ±â€…1.92 years, P = .03) and early treatment with biologics (within 2.24 years of diagnosis of RA), just in order to taper steroids and NSAIDs to less than 50% compared to the steroids and NSAIDs doses before biologics treatment.

A Study on MDA5 Signaling in Splenic B Cells from an Imiquimod-Induced Lupus Mouse Model with Proteomics.

INTRODUCTION: Several environmental stimuli may influence lupus, particularly viral infections. In this study, we used an imiquimod-induced lupus mouse model focused on the TLR7 pathway and proteomics analysis to determine the specific pathway related to viral infection and the related protein expressions in splenic B cells to obtain insight into B-cell responses to viral infection in the lupus model. MATERIALS AND METHODS: We treated FVB/N wild-type mice with imiquimod for 8 weeks to induce lupus symptoms and signs, retrieved splenocytes, selected B cells, and conducted the proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another week before performing Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and the protein-protein interactome was analyzed by the STRING database in this lupus murine model. RESULTS: The lupus model was well established and well demonstrated with serology evidence and pathology proof of lupus-mimicking organ damage. Proteomics data of splenic B cells revealed that the most important activated pathways (fold enrichment > 100) demonstrated positive regulation of the MDA5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production, and positive regulation of the RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 were demonstrated to be downstream effectors of MDA5 signaling. Finally, we found B-cell intracellular cytosolic proteins via Western blot experiment and continued to observe MDA5-related pathway activation. CONCLUSION: In this experiment, we confirmed that the B cells in the lupus murine model focusing on the TLR7 pathway were activated through the MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmunity. The MDA5 agonist/antagonist RNAs and the detailed molecular interactions within B cells are worthy of further investigation for lupus therapy.

Serum parabens and its correlations with immunologic and cellular markers in Southern Taiwan industrialized city systemic lupus erythematosus patients.

BACKGROUND: Although the immune systems of patients with systemic lupus erythematosus (SLE) are affected by both personal characteristics and environmental factors, the effects of parabens on patients with SLE have not been well studied. We investigated the indirect effects of four parabens-methylparaben (MP), ethylparaben (EP), propylparaben (n-PrP), and butylparaben (n-BuP)-on several immunological markers. METHODS: We assessed the serum levels of MP, EP, n-PrP, and n-BuP in 25 SLE patients and correlated the concentration of each paraben with available clinical and laboratory markers, including intracellular markers of antiviral immunity and apoptosis. RESULTS: The expression of aryl hydrocarbon receptor (AhR) was significantly negatively correlated with n-PrP levels (p = 0.03, r = -0.434). In monocytes, APO2.7 was significantly positively correlated with n-BuP levels (p = 0.019, r = 0.467). Glutathione levels were significantly negatively correlated with n-BuP levels (p = 0.019, r = -0.518). Anti- ß2 glycoprotein I IgM was significantly positively correlated with both MP (p = 0.011, r = 0.585) and EP levels (p = 0.032, r = 0.506). Anti-cardiolipin IgA was significantly positively correlated with both MP (p = 0.038, r = 0.493) and n-PrP levels (p = 0.031, r = 0.508). On CD8 T cells, the early apoptotic marker annexin V was significantly negatively correlated with both MP (p < 0.05, r = -0.541) and n-BuP levels (p = 0.02, r = -0.616), and L-selectin was significantly positively correlated with both MP (p < 0.05, r = 0.47) and n-PrP levels (p = 0.02, r = 0.556). CONCLUSION: Our findings suggest that higher parabens levels were associated with lower AhR expression in leukocytes, increased monocyte apoptosis, lower serum glutathione levels, reduced annexin V expression on CD8 T cells, and higher L-selectin levels on leukocytes.

Sulfonylureas or biguanides is associated with a lower risk of rheumatoid arthritis in patients with diabetes: A nationwide cohort study.

Objective: Diabetes mellitus (DM) is associated with immune dysregulation, while sulfonylureas or biguanides have been linked to anti-inflammatory mechanisms. In this study, we aimed to examine the occurrence rate of rheumatoid arthritis (RA) among DM patients and its incidence rate between different treatments. Methods: This cohort study used the Taiwan National Health Insurance Research Database between 1997 and 2013 to evaluate the primary outcomes of the preventive role of sulfonylureas or biguanides in the development of RA. We used the Chi-square test for categorical variables and Cox proportional hazard regression and log-rank test to explore the time for development of RA in DM patients. Logistic regression was adopted to estimate the odds ratio of RA in different dosages of medication exposure. Results: Our cohort study included 94,141 DM cases. The risk of RA development of non-sulfonylureas/biguanides users among the DM group in each analysis was set as the reference, and the adjusted hazard ratio of RA in DM patients who were using sulfonylureas or biguanides was 0.73 (95% confidence interval 0.60-0.90). Within 1 year before the index date, compared with no-biguanides users, patients with more than 180 days of prescription of biguanides had a significantly lower RA risk. Similarly, the significantly lower risk of RA was still observed in DM patients who had more than 365 days of prescription of sulfonylurea within 2 or 3 years before the index date of first RA visit (all p < 0.05). Conclusion: Our data suggest that sulfonylureas or biguanides are associated with a lower rate of RA development in patients with DM; the effect of biguanides appeared more rapid than that of sulfonylureas, but the sulfonylureas might have a longer effect on lowering RA development incidence.

Identify differential inflammatory cellular and serology pathways between children and adult patients in the lupus registry.

BACKGROUND: Age variances in systemic lupus erythematosus (SLE) may reflect different patterns and consequences. Monocyte differentiation is critical, and cytokine and chemokine milieu may be associated with long term outcome and treatment responses. This study aims to evaluate the inflammatory cellular and serology pathways associated with age in our lupus registry. METHODS: We included patients with SLE and divided them into 2 groups according to age, ≤18 or >18 years old. We performed flow cytometry analysis to define the peripheral blood monocyte differentiation pattern and phenotypes and used the multiplex method to detect cytokine and chemokine panels. The results were then compared between the 2 subgroups. RESULTS: In total, 47 SLE patients were included in this study. Of those, 23 patients were 18 years old or younger, and 24 patients were over the age of 18 years old. An increased distribution of circulating Type 2b macrophage (M2b) subsets was found in patients over 18 years old (P < 0.01), and we found the Type 1 macrophage (M1) to demonstrate a marked increase in those patients ≤18 years old (P = .05). Eotaxin values were significantly higher in patients >18 years old (P = .03), and Macrophage Inflammatory Protein (MIP)-1alpha, MIP-1beta, Interleukine (IL)-1Ra, Interferon (IFN)-alpha2, IL-12, IL-13, IL-17A, IL-1beta, IL-2, IL-4, IL-5, IL-7, IL-9, Monocyte Chemoattractant Protein (MCP)-3, Transforming Growth Factor (TGF)-alpha, and Tumor necrosis factor (TNF)-beta were significantly higher in patients ≤18 years old (all P < .05). CONCLUSIONS: We found significant M2b polarization in adult SLE patients, and several cytokines and chemokines were significantly higher in SLE patients ≤ 18 years old. Peripheral blood mononuclear cell differentiation and cytokine milieu could represent composite harm from both Type 2 helper T cells (Th2) and Type 17 helper T cells (Th17) pathways and may thus be a potential therapeutic target in younger SLE patients.

Sjögren syndrome is a hidden contributor of macrovascular and microvascular complications in patients with type 2 diabetes.

OBJECTIVE: To investigate cardiovascular risk among diabetic patients with Sjögren syndrome. METHODS: This study was a nationwide population-based case-control study from 1997 to 2013, in which the association between autoimmune diseases and diabetes was investigated. The study population consisted of individuals with newly diagnosed type 2 diabetes with macrovascular or microvascular complications with at least two outpatient visits or one hospitalization as the outcome variables, and the exposure variables included traditional risk factors, medications, and autoimmune diseases. The odds ratio of cardiovascular events among each prevalent autoimmune disease and hydroxychloroquine's effect on cardiovascular risk were analyzed. RESULTS: The study included a total of 7026 individuals with diabetes with microvascular and macrovascular complications and the same number of patients in the control group. Sjögren syndrome was significantly higher in the diabetes complication group than in the non-complication group (0.8% vs 0.5%, P = 0.036). By using multivariate analysis, we found hypertension, hyperlipidemia, and Sjögren syndrome to be three independent risk factors for diabetes vascular complications (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.82-2.10; OR 1.53, 95% CI 1.42-1.64; and OR 1.67, 95% CI 1.06-2.65; respectively, all P < 0.05). Treatment with traditional statins and aspirin might be able to overcome the increased risk of developing cardiovascular events while comparing between diabetes patients with and without Sjögren syndrome. CONCLUSION: Sjögren syndrome is an unrecognized independent risk factor for cardiovascular events among diabetes patients, which indicates that patients with diabetes combined with Sjögren syndrome require closer follow up regarding cardiovascular complications in clinical settings. Treatment with hydroxychloroquine might not be enough to lower the cardiovascular risk significantly in diabetes patients with Sjögren syndrome.

Time-dependent risk of mortality and end-stage kidney disease among patients with granulomatosis with polyangiitis.

Objective: To describe the time-dependent impact of granulomatosis with polyangiitis (GPA) on the risk of mortality and end-stage kidney disease (ESKD). The results would provide valuable insight regarding the most vulnerable period for patients with GPA. Methods: We conducted a retrospective cohort study using a nationally representative database in Taiwan. Patients with incident GPA without prior ESKD were identified, and non-GPA control cohorts were selected and matched to GPA cohorts based on sex, age, entry time and comorbidities in a 1:4 ratio. Cox regression model was used to estimate hazard ratios (HR) for mortality and ESKD stratified by the follow-up period. Results: We identified a total of 142 GPA patients and 568 matched controls. Of those, 52 GPA patients died during follow-up, 48.1% of whom did so within the first 6 months after diagnosis. The 1-, 3-, 5-, and 10-year survival rates of GPA were 78.2, 71.2, 62.6, and 54.7%, respectively. Patients with GPA exhibited the greatest risk of mortality within the first 6 months after follow-up compared with non-GPA cohorts (HR: 21.9, 95% CI: 8.41-57.5). The mortality risk diminished after 1 year and to a marginally significant level during the follow-up period of 5-10 years (HR: 2.71, 95% CI: 0.97-7.62). Ten (7.1%) of the GPA patients experienced ESKD, and these cases occurred exclusively in the first 3 years following diagnosis. Conclusion: Our findings suggest that physicians should closely monitor the treatment response and complications of patients with GPA in the first critical 6-month period after diagnosis to improve long-term survival outcome.

Gut microbiota differences between psoriatic arthritis and other undifferentiated arthritis: A pilot study.

BACKGROUND: Psoriatic arthritis (PSA) is a form of immune-mediated inflammatory arthritis that predominantly begins with enthesitis. Studying the gut microbiota of PSA patients may offer new insights into the pathogenesis of enthesitis, compared to other arthritis. We designed a prospective study to examine gut microbiome of patients with PSA, primarily with enthesitis and dactylitis, and compared the data with other undifferentiated types of arthritis (NO PSA) patients, without enthesitis or dactylitis. METHODS: We enrolled 9 PSA patients and 10 NO PSA patients in this study. We excluded rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis, mixed connective tissue disease, polymyositis, dermatomyositis, ANCA-associated vasculitis, and gouty arthritis patients. The fecal samples were investigated using 16S rRNA amplicon sequencing, followed by bioinformatics and statistical analyses. RESULTS: None of the available objective clinical laboratory data could differentiate PSA group from the NO PSA subgroup. The microbiota result shows that Family: XIII_AD3011 is significantly higher in NO PSA patients' than in PSA patients' stool samples (P = .039). Megasphaera elsdenii in the PSA group was 10,000 times higher than in the NO PSA group.Our results demonstrated high intragroup homogeneous and high intergroup heterogeneous microbiota. The clinical symptoms of either enthesitis or dactylitis are associated with higher presence of specific microbiota in the current study. The PSA and other undifferentiated arthritis could be differentiated with microbiota analysis. In the future, a larger cohort and thorough biochemical study are needed for confirmation.The microbiota is different between PSA and NO PSA patients, and the species could be used as a differential diagnostic tool between these 2 diseases. The clinically available serum markers may not be enough to reflect the details of patients with different patterns of arthritis. Megasphaera elsdenii species could be a link between gut flora and enthesitis and/or dactylitis clinically in PSA. We confirm the fact that the Bifidobacterium longum correlates negatively with eosinophils.

Association of primary Sjögren's syndrome with incident heart failure: a secondary analysis of health claims data in Taiwan.

OBJECTIVE: Mounting evidence has demonstrated that various chronic inflammatory diseases are associated with incident heart failure (HF). However, there is scarce evidence about the association between primary Sjögren's syndrome (pSS) and HF. We aimed to explore this association using a nationwide database in Taiwan. METHODS: We selected patients with incident pSS and no history of HF. Using propensity score matching based on age, sex, cohort entry time, comorbidities, and concomitant medications, cohorts of patients with and without pSS (as controls) were created in a 1:1 ratio and the groups were compared. The cumulative incidence of HF was calculated using Kaplan-Meier estimation. Cox proportional hazard regression analysis was used to measure the hazard ratio (HR) of HF-related hospitalization for the pSS cohort compared with the comparison group. RESULTS: A total of 16,466 pairs of patients with pSS and those without pSS were identified. The cumulative incidence of HF-related hospitalization at 3, 5, and 10 years in patients with pSS was 1.05%, 1.89%, and 4.33%, respectively. The risk of HF-related hospitalization was not higher in patients with pSS than in the general population (HR: 0.98, 95% confidence interval [CI]: 0.84-1.14). There was no difference in survival probability after the first episode of HF-related hospitalization between pSS and non-pSS groups. CONCLUSION: Our results suggest that distinct inflammatory spectrums in each chronic inflammatory disease might have differential impacts on cardiac function and subsequent risk of HF. Future studies are needed to elucidate the complex and diverse mechanisms of HF in various chronic autoimmune diseases.

Consensus recommendations on managing the selected comorbidities including cardiovascular disease, osteoporosis, and interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed. RA-related comorbidities affect disease control and lead to impairment in quality of life. We aimed to develop consensus recommendations for managing RA-related comorbidities. METHODS: The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises. The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement. Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities. RESULTS: Based on experts' consensus, eleven recommendations were developed. CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy. Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously. The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA. The FRAX-based approach with intervention threshold is a useful strategy for managing OP. RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity. A treat-to-target strategy would limit RA-related comorbidities. CONCLUSIONS: These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities.

Mitochondrial haplogroups have a better correlation to insulin requirement than nuclear genetic variants for type 2 diabetes mellitus in Taiwanese individuals.

AIMS/INTRODUCTION: Identifying diabetes-susceptible genetic variants will help to provide personalized therapy for the management of type 2 diabetes. Previous studies have reported a genetic risk score (GRS), computed by the sum of nuclear DNA (nDNA) risk alleles, that may predict the future requirement for insulin therapy. Although mitochondrial dysfunction has a close association with insulin resistance (IR), there are few studies investigating whether genetic variants of mitochondrial DNA (mtDNA) will affect the clinical characteristics of type 2 diabetes. MATERIALS AND METHODS: Mitochondrial haplogroups were determined using mtDNA whole genome next generation sequencing and 13 single nucleotide polymorphisms (SNPs) in nDNA susceptibility loci of 13 genes in 604 Taiwanese subjects with type 2 diabetes. A GRS of nDNA was computed by summation of the number of risk alleles. The correlation between the mtDNA haplogroup and the clinical characteristics of type 2 diabetes was assessed by logistic regression analysis. The results were compared with the GRS subgroups for the risk of insulin requirement. RESULTS: Mitochondrial haplogroups modulate the clinical characteristics of type 2 diabetes, in which patients harboring haplogroup D4, compared with those harboring non-D4 haplotypes, were less prone to require insulin treatment, after adjusting for age, gender, and diabetes duration. However, there was no association between insulin requirement and GRS calculated from nuclear genetic variants. CONCLUSIONS: Mitochondrial haplogroups, but not nuclear genetic variants, have a better association with the insulin requirement. The results highlight the role of mitochondria in the management of common metabolic diseases.

Time-Dependent Analysis of Risk of New-Onset Heart Failure Among Patients With Polymyositis and Dermatomyositis.

OBJECTIVE: To determine the risk and time trends of heart failure (HF) leading to hospitalization in individuals newly diagnosed as having polymyositis/dermatomyositis (PM/DM) relative to non-PM/DM controls at the general population level. METHODS: A retrospective cohort study was conducted using data from a nationwide insurance database in Taiwan. Patients with incident PM/DM and without a history of HF were selected between 2000 and 2013. Unmatched and propensity score-matched cohorts were established separately. A multivariable Cox proportional hazards regression model was used to estimate the adjusted hazard ratio (HR) for the risk of HF in the unmatched cohort. In the propensity score-matched cohort, general population controls were selected and matched at a 1:1 ratio to the patients with PM/DM based on propensity scores, which accounted for the confounding factors of age, sex, index date (year) of first diagnosis, comorbidities, and medication usage. The cumulative incidence of HF was estimated using the Kaplan-Meier method. A stratified Cox proportional hazards model was used to calculate the HR for the risk of HF events at different follow-up time points among patients with PM/DM compared with non-PM/DM controls in the propensity score-matched cohort. RESULTS: In the unmatched cohort, the study assessed 2,025 patients with PM/DM and 196,109 general population controls. Results of multivariable Cox regression analysis, adjusted for age, sex, comorbidities, and medication usage, revealed a greater risk of HF leading to hospitalization in the PM/DM group than in the control group (adjusted HR 3.29, 95% confidence interval [95% CI] 2.60-4.18). After matching based on propensity score, a total of 1,997 pairs of PM/DM patients and general population controls were identified. In this propensity score-matched cohort, the cumulative incidence of HF in patients with PM/DM at 3 years, 5 years, and 10 years was 3.3%, 4.4%, and 7.4%, respectively. The absolute difference in HF risk in the PM/DM group compared with the control group was 1.8% at 3 years, 2.1% at 5 years, and 3.0% at 10 years. Compared with general population controls, patients with PM/DM exhibited an augmented risk of HF (HR 2.06, 95% CI 1.36-3.12). Analyses stratified according to follow-up time point revealed that the increased risk of HF persisted for up to 10 years after the PM/DM diagnosis. CONCLUSION: These results indicate that the risk of HF leading to hospitalization was increased in patients with PM/DM throughout the study period, supporting the need for greater vigilance in the monitoring of patients with PM/DM for the development of this potentially lethal complication.

Is Behçet's syndrome associated with an increased risk of ischemic heart disease? A real-world evidence in Taiwan.

BACKGROUND: A variety of chronic inflammatory diseases are linked to ischemic heart disease (IHD); however, this association is less well studied in patients with Behçet's syndrome (BS). The primary objective of this study was to examine the impact of BS on the risk of IHD. The secondary objective was to estimate the long-term mortality risk in patients with BS. METHODS: Using a retrospective cohort design based on the Taiwan National Health Insurance Database, patients diagnosed with BS between 2000 and 2013, without prior history of IHD, were compared to non-BS individuals. The BS and non-BS cohorts were matched with a 1:2 ratio by propensity score, accounting for the following confounders: age, sex, year of index date, comorbidities, and drug exposure. Cox proportional hazard regression was used to derive the hazard ratio (HR) for IHD and mortality. The long-term survival rate was estimated using the Kaplan-Meier method. RESULTS: After propensity score matching, a total of 1554 patients newly diagnosed with BS and 3108 control subjects were identified. The incidence rate of IHD in the BS and control groups was 2.7 and 2.9 per 1000 person-years, respectively. The risk of IHD was comparable between BS and control cohorts [adjusted HR, 1.03; 95% confidence interval (CI), 0.66 to 1.62]. The 5- and 10-year survival rate of BS patients was 96.8% and 95.0%, respectively. Patients with BS exhibited a significantly higher risk of mortality than the sex- and age-matched general population (adjusted HR, 1.73; 95% CI, 1.30 to 2.32). CONCLUSION: Unlike other chronic systemic autoimmune disorders, BS does not appear to be associated with an excess risk of IHD.