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Abstract Background Sepsis is the leading cause of death worldwide, and a number of biomarkers have been developed for early mortality risk stratification. Red blood cell distribution width (RDW) is a routinely available hematological data and has been found to be associated with mortality in a number of diseases; therefore, we aim to address the association between RDW and mortality in critically ill patients with sepsis. Methods We analyzed data of critically ill adult patients with sepsis on the TriNetX platform, excluding those with hematologic malignancies, thalassemia, and iron deficiency anemia. Propensity score-matching (PSM) (1:1) was used to mitigate confounding effects, and hazard ratio (HR) with 95% confidence (CI) was calculated to determine the association between RDW and 30-day mortality. We further conducted sensitivity analyses through using distinct cut-points of RDW and severities of sepsis. Results A total of 256,387 critically ill septic patients were included in the analysis, and 40.0% of them had RDW equal to or higher than 16%. After PSM, we found that high RDW was associated with an increased 30-day mortality rate (HR: 1.887, 95% CI 1.847–1.928). The associations were consistent using distinct cut-points of RDW, with the strength of association using cut-points of 12%, 14%, 16%, 18% and 20% were 2.098, 2.204, 1.887, 1.809 and 1.932, respectively. Furthermore, we found consistent associations among critically ill septic patients with distinct severities, with the association among those with shock, receiving mechanical ventilation, bacteremia and requirement of hemodialysis being 1.731, 1.735, 2.380 and 1.979, respectively. Conclusion We found that RDW was associated with 30-day mortality in critically ill septic patients, underscoring the potential as a prognostic marker in sepsis. More studies are needed to explore the underlying mechanisms.

Abstract Background To investigate the association between maternal sepsis during pregnancy and poor pregnancy outcome and to identify risk factors for poor birth outcomes and adverse perinatal events. Methods We linked the Taiwan Birth Cohort Study (TBCS) database and the Taiwanese National Health Insurance Database (NHID) to conduct this population-based study. We analysed the data of pregnant women who met the criteria for sepsis-3 during pregnancy between 2005 and 2017 as the maternal sepsis cases and selected pregnant women without infection as the non-sepsis comparison cohort. Sepsis during pregnancy and fulfilled the sepsis-3 definition proposed in 2016. The primary outcome included low birth weight (LBW,

Abstract Background Outdoor air pollution has been found to trigger systemic inflammatory responses and aggravate the activity of certain rheumatic diseases. However, few studies have explored the influence of air pollution on the activity of ankylosing spondylitis (AS). As patients with active AS in Taiwan can be reimbursed through the National Health Insurance programme for biological therapy, we investigated the association between air pollutants and the initiation of reimbursed biologics for active AS. Methods Since 2011, hourly concentrations of ambient air pollutants, including PM2.5, PM10, NO2, CO, SO2, and O3, have been estimated in Taiwan. Using Taiwanese National Health Insurance Research Database, we identified patients with newly diagnosed AS from 2003 to 2013. We selected 584 patients initiating biologics from 2012 to 2013 and 2336 gender-, age at biologic initiation-, year of AS diagnosis- and disease duration-matched controls. We examined the associations of biologics initiation with air pollutants exposure within 1 year prior to biologic use whilst adjusting for potential confounders, including disease duration, urbanisation level, monthly income, Charlson comorbidity index (CCI), uveitis, psoriasis and the use of medications for AS. Results are shown as adjusted odds ratio (aOR) with 95% confidence intervals (CIs). Results The initiation of biologics was associated with exposure to CO (per 1 ppm) (aOR, 8.57; 95% CI, 2.02–36.32) and NO2 (per 10 ppb) (aOR, 0.23; 95% CI, 0.11–0.50). Other independent predictors included disease duration (incremental year, aOR, 8.95), CCI (aOR, 1.31), psoriasis (aOR, 25.19), use of non-steroidal anti-inflammatory drugs (aOR, 23.66), methotrexate use (aOR, 4.50; 95% CI, 2.93–7.00), sulfasalazine use (aOR, 12.16; 95% CI, 8.98–15.45) and prednisolone equivalent dosages (mg/day, aOR, 1.12). Conclusions This nationwide, population-based study revealed the initiation of reimbursed biologics was positively associated with CO levels, but negatively associated with NO2 levels. Major limitations included lack of information on individual smoking status and multicollinearity amongst air pollutants.

Abstract Background Sepsis is a frequent complication in critically ill patients, is highly heterogeneous and is associated with high morbidity and mortality rates, especially in the elderly population. Utilizing RNA sequencing (RNA-Seq) to analyze biological pathways is widely used in clinical and molecular genetic studies, but studies in elderly patients with sepsis are still lacking. Hence, we investigated the mortality-relevant biological features and transcriptomic features in elderly patients who were admitted to the intensive care unit (ICU) for sepsis. Methods We enrolled 37 elderly patients with sepsis from the ICU at Taichung Veterans General Hospital. On day-1 and day-8, clinical and laboratory data, as well as blood samples, were collected for RNA-Seq analysis. We identified the dynamic transcriptome and enriched pathways of differentially expressed genes between day-8 and day-1 through DVID enrichment analysis and Gene Set Enrichment Analysis. Then, the diversity of the T cell repertoire was analyzed with MiXCR. Results Overall, 37 patients had sepsis, and responders and non-responders were grouped through principal component analysis. Significantly higher SOFA scores at day-7, longer ventilator days, ICU lengths of stay and hospital mortality were found in the non-responder group, than in the responder group. On day-8 in elderly ICU patients with sepsis, genes related to innate immunity and inflammation, such as ZDHCC19, ALOX15, FCER1A, HDC, PRSS33, and PCSK9, were upregulated. The differentially expressed genes (DEGs) were enriched in the regulation of transcription, adaptive immune response, immunoglobulin production, negative regulation of transcription, and immune response. Moreover, there was a higher diversity of T-cell receptors on day-8 in the responder group, than on day-1, indicating that they had better regulated recovery from sepsis compared with the non-response patients. Conclusion Sepsis mortality and incidence were both high in elderly individuals. We identified mortality-relevant biological features and transcriptomic features with functional pathway and MiXCR analyses based on RNA-Seq data; and found that the responder group had upregulated innate immunity and increased T cell diversity; compared with the non-responder group. RNA-Seq may be able to offer additional complementary information for the accurate and early prediction of treatment outcome.

Abstract Background Previous studies have shown systemic lupus erythematosus (SLE) patients had a significantly higher prevalence of thyroid diseases and hypothyroidism than matched controls, and some case reports showed SLE may occur after Hashimoto’s thyroiditis (HT). Objective This study aimed to investigate the subsequent risk of SLE in patients with HT. Methods In this retrospective cohort study done by the Taiwan National Health Insurance Research Database, the HT group (exposure group) and the non-HT group (comparator group) were propensity score matched at a ratio of 1:2 by demographic data, comorbidities, medications, and the index date. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Several sensitivity analyses were done for cross-validation of our findings. Results We identified 15,512 HT patients and matched 31,024 individuals. The incidence rate ratio of SLE was 3.58 (95% CI, 2.43–5.28; p < 0.01). Several sensitivity analyses show adjusted hazard ratio (aHR) (CIs) of 4.35 (3.28–5.76), 4.39 (3.31–5.82), 5.11 (3.75–6.98), and 4.70 (3.46–6.38), consistent with the results of the main model. Conclusion Our study showed an increased risk of SLE in the HT group after adjustment for baseline characteristics, comorbidities, and medical confounders compared with the reference group.

Abstract Background Rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) are autoimmune rheumatic diseases that share a complex genetic background and common clinical features. This study’s purpose was to construct machine learning (ML) models for the genomic prediction of RA and SLE. Methods A total of 2,094 patients with RA and 2,190 patients with SLE were enrolled from the Taichung Veterans General Hospital cohort of the Taiwan Precision Medicine Initiative. Genome-wide single nucleotide polymorphism (SNP) data were obtained using Taiwan Biobank version 2 array. The ML methods used were logistic regression (LR), random forest (RF), support vector machine (SVM), gradient tree boosting (GTB), and extreme gradient boosting (XGB). SHapley Additive exPlanation (SHAP) values were calculated to clarify the contribution of each SNPs. Human leukocyte antigen (HLA) imputation was performed using the HLA Genotype Imputation with Attribute Bagging package. Results Compared with LR (area under the curve [AUC] = 0.8247), the RF approach (AUC = 0.9844), SVM (AUC = 0.9828), GTB (AUC = 0.9932), and XGB (AUC = 0.9919) exhibited significantly better prediction performance. The top 20 genes by feature importance and SHAP values included HLA class II alleles. We found that imputed HLA-DQA1*05:01, DQB1*0201 and DRB1*0301 were associated with SLE; HLA-DQA1*03:03, DQB1*0401, DRB1*0405 were more frequently observed in patients with RA. Conclusions We established ML methods for genomic prediction of RA and SLE. Genetic variations at HLA-DQA1, HLA-DQB1, and HLA-DRB1 were crucial for differentiating RA from SLE. Future studies are required to verify our results and explore their mechanistic explanation.

Abstract Background Infectious disease is an increasing threat to patients with systemic lupus erythematosus (SLE); however, the long-term outcome in critically ill septic patients with SLE remains unclear, and we aimed to address the impact of SLE on 5-year survival in critically ill septic patients. Methods We used the 2003–2017 nationwide data with 825,556 patients with sepsis in Taiwan. We identified lupus cases with sepsis that required admission to the intensive care unit and mechanical ventilation and selected controls matched (1:4) for age, sex, and index-year. Conditional logistic regression analysis was used to determine risk factors for mortality risk and shown as odds ratios (HRs) with 95% confidence intervals (CIs). Results A total of 513 SLE-sepsis patients and 2052 matched non-SLE septic individuals were enrolled. The mortality rate was higher in the SLE group (38.5 per 100,000 person-year) than that in the non-SLE group (13.7 per 100,000 person-year), with an IRR of 2.8 (95% CI, 2.5–3.2). We found that SLE was independently associated with a high mortality rate after adjusting relevant variables (HR 1.47, 95% CI 1.27–1.77). In addition to SLE, a higher age (HR 1.02, 95% CI 1.02–1.02), more comorbidities, and receiving prednisolone equivalent dose higher than 5 mg/day (HR 1.55, 95% CI 1.27–1.90), methotrexate (HR 2.19, 95% CI 1.61–2.99), and immunosuppressants (HR 1.45, 95% CI 1.22–1.74) were also independent risks for mortality. Conclusions We identified that SLE affects the long-term mortality in critically ill septic patients, and more studies are warranted for the underlying mechanism.

Abstract Background Pneumocystis pneumonia (PCP) is increasingly being diagnosed in patients with systemic lupus erythematosus (SLE), and hydroxychloroquine (HCQ) has been found to possess antifungal activities. We hence aimed to investigate the association between HCQ and PCP risk among patients with SLE. Methods Using the 1997–2013 nationwide claim data, we identified 24,343 newly-diagnosed SLE patients. We then identified 58 PCP cases and selected 348 non-PCP controls matching (1:6) by age, sex, disease duration and the year of PCP diagnosis date. The risk of PCP was assessed by determing odds ratios (ORs) with 95% confidence intervals (CIs) by using multivariable conditional logistic regression. Results The risk of PCP was associated with moderate to severe renal disease (OR 6.73, 95% CI 1.98–22.92), higher doses of glucocorticoids (≤5 mg/day, reference; 5–10 mg/day, OR 25.88, 95% CI 2.97–225.33; > 10 mg/day, OR 286.58, 95% CI 28.58–> 999), higher 3-month cumulative dose of cyclophosphamide (not use, reference; ≤1.4 g, OR 0.64, 95% CI 0.14–3.01; > 1.4 g, OR 11.52, 95% CI 1.97–67.39) and use of mycophenolate mofetil/mycophenolic acid (OR 50.79, 95% CI 5.32–484.77), whereas 3-month cumulative dose of HCQ was associated with a reduced risk of PCP among patients with SLE (not use, reference; ≤14 g, OR 0.69, 95% CI 0.21–2.24; > 14 g, OR 0.20, 95% CI 0.05–0.71). Conclusions This study demonstrated incident PCP was associated with mycophenolate mofetil/mycophenolic acid use and higher doses of cyclophosphamide or glucocorticoid, whereas the use of a higher dose of HCQ was associated with a reduced risk of PCP in lupus patients.

Abstract Background Previous case reports have demonstrated the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). Methods A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the study period were enrolled in the study cohort. Enrollees were divided into three groups according to the categorized levels of injection number (first level: 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyses were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to the different levels of injection numbers. The confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). Results In total, the study cohort included 77,210 patients. Of these, 26,520, 38,010, and 12,680 were in the first-, second-, and third-level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second- and third-level groups were 1.91 (95% confidence interval [CI], 1.32–2.76) and 2.20 (95% CI, 1.42–3.43), respectively, compared with those in the first-level group. Conclusions Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections have a significantly higher risk of developing ION compared with individuals who receive a lower number of injections.

Abstract Background Increasing prevalence of childhood allergic diseases including asthma is a global health concern, and we aimed to investigate prenatal risk factors for childhood asthma and to address the potential shared prenatal impacts among childhood asthma, allergic rhinitis (AR) and atopic dermatitis (AD). Methods We used two claim databases, including Taiwan Birth Cohort Study (TBCS) and National Health Insurance Research Database (NHIRD), to identify independent paired mother–child data (mother–child dyads) between 2006 and 2009. The association between prenatal factors and asthma was determined by calculating adjusted odds ratio (aOR) with 95% confidence interval (CI) using conditional logistic regression analysis. Results A total of 628,878 mother–child dyads were included, and 43,915 (6.98%) of children developed asthma prior to age 6. We found that male gender (aOR 1.50, 95% CI 1.47–1.53), maternal asthma (aOR 1.80, 95% CI 1.71–1.89), maternal AR (aOR 1.33, 95% CI 1.30–1.37), preterm birth (aOR 1.32, 95% CI 1.27–1.37), low birth weight (aOR 1.14, 95% CI 1.10–1.19) and cesarean section (aOR 1.10, 95% CI 1.08–1.13) were independent predictors for childhood asthma. A high urbanization level and a low number of older siblings were associated with asthma in a dose–response manner. Notably, we identified that the association between maternal asthma and childhood asthma (aOR 1.80, 95% CI 1.71–1.89) was stronger compared with those between maternal asthma and childhood AR (aOR 1.67, 95% CI 1.50–1.87) as well as childhood AD (aOR 1.31, 95% CI 1.22–1.40). Similarly, the association between maternal AR and childhood AR (aOR 1.62, 95% CI 1.53–1.72) was higher than those between maternal AR and childhood asthma (aOR 1.33, 95% CI 1.30–1.37) as well as childhood AD (aOR 1.35, 95% CI 1.31–1.40). Furthermore, the number of maternal allergic diseases was associated with the three childhood allergic diseases in a dose–response manner. Conclusions In conclusion, this population-based study provided evidence of prenatal impacts on childhood asthma and demonstrated the shared maternal impacts among childhood asthma, AR, and AD. These findings highlight the shared prenatal impacts among allergic diseases, and studies are warranted to address the pivotal pathway in allergic diseases.

Abstract Objective To investigate the risk of immune-mediated inflammatory diseases (IMIDs) in patients with ankylosing spondylitis (AS). Methods Using 2003–2012 claims data from the Taiwanese National Health Insurance Research Database, we identified 30,911 newly diagnosed AS patients requiring medical therapy from 2006 to 2012. In addition, we randomly selected 309,110 non-AS individuals matching (1:10) the AS patients with regard to age, sex and the year of the index date. After excluding subjects with the corresponding prior IMIDs, we calculated the incidence rates (IRs) of various IMIDs in the AS and non-AS cohorts and estimated the hazard ratios (HRs) with 95% confidence intervals after adjusting for age, sex, the Charlson comorbidity index, the frequency of ambulatory visits during the follow-up period and medications. We conducted sensitivity analyses by excluding those who developed IMIDs within 3 months after the index date. Results In the follow-up period, we found that newly diagnosed AS patients had significantly increased risks of acute anterior uveitis, psoriasis, Sjögren’s syndrome, thromboangiitis obliterans, Behcet’s disease and sarcoidosis. However, the risk of Sjögren’s syndrome did not increase in AS patients in the sensitivity analysis. In the same period, this study found no significant differences in the risks of Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, pemphigus and vitiligo between newly diagnosed AS patients and non-AS individuals. AS patients had a significantly reduced risk of rheumatoid arthritis. Conclusion Newly diagnosed Taiwanese AS patients had increased risks of acute anterior uveitis, psoriasis, thromboangiitis obliterans, Behcet’s disease and sarcoidosis, but a reduced risk of rheumatoid arthritis.

Abstract Background Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. Methods In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. Results Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p

Abstract Background Previous cross-sectional studies revealed a higher prevalence of depression among glaucoma patients. However, cohort studies were in lack to build the risk of incident depression after the diagnosis of glaucoma. The aim of our study was to investigate the association between glaucoma and the subsequent risk of developing depression and to assess risk factors associated with depression in glaucoma patients. Methods A population-based retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from January 1, 2001 through December 31, 2011. Glaucoma patients (n = 8777) and age- and gender-matched control subjects without glaucoma (n = 35,108) were enrolled in the study. Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent depression between the glaucoma and control groups. A Cox regression analysis estimated the crude and adjusted hazard ratios (HRs) for depression. Risk factors leading to depression were investigated among the glaucoma patients. Results Glaucoma patients had a significantly higher cumulative hazard of depression compared to the control group (p-value

Abstract Background Nontuberculous mycobacterial (NTM) infection in immunocompromized patients is currently a growing health concern, and we aimed to examine the relative risk of NTM infection in patients with Sjögren’s syndrome (SS) compared with that in non-SS individuals. Methods We used the 2003–2012 Taiwanese National Health Insurance Research Database to identify 6554 incident SS cases during 2007–2012 and selected 98,310 non-SS controls matched (1:15) for age, gender, and the year of first SS diagnosis date after excluding those who had rheumatoid arthritis or systemic lupus erythematosus. Results We identified four NTM-infected patients in the SS group (three in the first year) and nine in the non-SS group (three in the first year). SS patients had a higher incidence rate of NTM infection than that in non-SS individuals (IRR, 7.56; 95% CI, 2.33–24.55), especially during the first year (IRR, 16.05; 95% CI, 3.24–79.51). After adjusting for potential confounders, the risk of NTM infection was not increased in SS patients during the entire follow-up period or during the first year, but the risk increased in SS patients treated with immunosuppressants during the entire follow-up period (HR, 17.77; 95% CI, 4.53–69.61), especially during the first year (HR, 33.33; 95% CI, 4.37–254.23). Conclusion An increased risk of NTM infection was found in SS patients treated with immunosuppressants during the first year after SS diagnosis.