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Research Question: Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients?, Design: Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition., Results: In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM., Conclusions: YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients., Competing Interests: Declaration of competing interest All authors have declared that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Aim: To evaluate real-world abatacept retention and clinical outcomes in patients with rheumatoid arthritis in Taiwan., Methods: This prospective, observational study enrolled patients with rheumatoid arthritis aged ≥20 years who received abatacept in real-world practice. The primary endpoint was the abatacept retention rate at 24 months. Patients were categorized into subgroups based on abatacept treatment status and previous biological disease-modifying antirheumatic drug (bDMARD) therapy. Risk factors affecting abatacept retention were determined by regression analysis., Results: A total of 212 patients were enrolled. The overall abatacept retention rate at 24 months among all patients was 59.9% (95% confidence interval 53.0%-66.6%). Patients who were ongoing users of abatacept and bDMARD-naïve had the highest retention rate (76.3%); of these, 31.6% achieved low disease activity or remission after 2 years. Previous treatment with bDMARDs was associated with an increased risk of abatacept discontinuation (hazard ratio 1.99; p = .002). The most common reasons for abatacept discontinuation were drug switch (11.3%) and loss to follow-up (6.1%). Abatacept was well-tolerated with no new safety signals., Conclusion: The 24-month retention rate of abatacept was 59.9%; abatacept was associated with improved clinical outcomes and was well-tolerated in the real-world setting in Taiwan., (© 2024 Bristol‐Myers Squibb and The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The number of patients with chronic kidney disease (CKD) is increasing. Oral toxin adsorbents may provide some value. Several uremic toxins, including indoxyl sulfate (IS), p-cresol (PCS), acrolein, per- and poly-fluoroalkyl substances (PFAS), and inflammation markers (interleukin 6 [IL-6] and tumor necrosis factor [TNF]-alpha) have been shown to be related to CKD progression. A total of 81 patients taking oral activated charcoal toxin adsorbents (AC-134), which were embedded in capsules that dissolved in the terminal ileum, three times a day for 1 month, were recruited. The renal function, hemoglobulin (Hb), inflammation markers, three PFAS (PFOA, PFOS, and PFNA), and acrolein were quantified. Compared with the baseline, an improved glomerular filtration rate (GFR) and significantly lower acrolein were noted. Furthermore, the CKD stage 4 and 5 group had significantly higher concentrations of IS, PCS, IL-6, and TNF but lower levels of Hb and PFAS compared with the CKD Stage 3 group at baseline and after the intervention. Hb was increased only in the CKD Stage 3 group after the trial (p = .032). Acrolein did not differ between the different CKD stage groups. Patients with improved GFR (responders) (about 77%) and nonresponders had similar baseline GFR. Responders had higher acrolein and PFOA levels throughout the study and a more significant reduction in acrolein, indicating a better digestion function. Both the higher PFOA and lower acrolein may be related to improved eGFR (and possibly to improvements in proteinuria, which we did not measure. Proteinuria is associated with PFAS loss in the urine), AC-134 showed the potential to improve the GFR and decrease acrolein, which might better indicate renal function change. Future studies are needed with longer follow-ups., (© 2024 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)

The Fracture Risk Assessment Tool (FRAX®) is a widely utilized country-specific calculator for identifying individuals with high fracture risk; its score is calculated from 12 variables, but its formulation is not publicly disclosed. We aimed to decompose and simplify the FRAX® by utilizing a nationwide community survey database as a reference module for creating a local assessment tool for osteoporotic fracture community screening in any country. Participants ( n  = 16384; predominantly women (75%); mean age = 64.8 years) were enrolled from the Taiwan OsteoPorosis Survey, a nationwide cross-sectional community survey collected from 2008 to 2011. We identified 11 clinical risk factors from the health questionnaires. BMD was assessed via dual-energy X-ray absorptiometry in a mobile DXA vehicle, and 10-year fracture risk scores, including major osteoporotic fracture (MOF) and hip fracture (HF) risk scores, were calculated using the FRAX®. The mean femoral neck BMD was 0.7 ± 0.1 g/cm 2 , the T-score was -1.9 ± 1.2, the MOF was 8.9 ± 7.1%, and the HF was 3.2 ± 4.7%. Following FRAX® decomposition with multiple linear regression, the adjusted R 2 values were 0.9206 for MOF and 0.9376 for HF when BMD was included and 0.9538 for MOF and 0.9554 for HF when BMD was excluded. The FRAX® demonstrated better prediction for women and younger individuals than for men and elderly individuals after sex and age stratification analysis. Excluding femoral neck BMD, age, sex, and previous fractures emerged as 3 primary clinical risk factors for simplified FRAX® according to the decision tree analysis in this study population. The adjusted R 2 values for the simplified country-specific FRAX® incorporating 3 premier clinical risk factors were 0.8210 for MOF and 0.8528 for HF. After decomposition, the newly simplified module provides a straightforward formulation for estimating 10-year fracture risk, even without femoral neck BMD, making it suitable for community or clinical osteoporotic fracture risk screening., Competing Interests: C.-C.L., I.-T.L., T.-T.C., F.-W.L., Z.-J.S., Y.-F.C., C.-S.C., Y.-C.Y., T.-H.L., and L.-C.K. declare that they have no conflicts of interest. C.-H.W.: honoraria for lectures, attending meetings, research grant or travel from Eli Lilly, Novartis, Roche, Abbott, Pfizer, Boehringer, Bayers, Takeda, Merck, Sanofi-Aventis, GlaxoSmithKline, Servier laboratories, GE Lunar, Schering-Plough, Harvester, TCM Biotch, Alvogen/Lotus, Teijin Pharma, Amgen, Der-Zeng, Sankyo Daiichi, Alnylam, and AstraZeneca. This study was presented in part as a poster at the 2023 IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases on May 4, 2023, in Barcelona, Spain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

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.

Objectives: To assess the efficacy of cord blood-assisted haploid peripheral blood stem cell transplantation (haplo-cord-PBSCT) versus unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in the treatment of malignant hematological diseases. Methods: A retrospective analysis was performed on one hundred and four patients with malignant hematological diseases who underwent haplo-cord-PBSCT and fifty-two patients who underwent UD-PBSCT at Xiangya Hospital of Central South University between January 2016 and December 2021. Results: ①The median implantation time for neutrophils in the haplo-cord-PBSCT and UD-PBSCT groups was 13 (9-22) days and 13 (10-24) days, respectively ( P =0.834), whereas the median implantation time for platelets was 15 (7-103) days and 14 (8-38) days, respectively ( P =0.816). The cumulative implantation rate of neutrophils at 30 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group was 100% ( P =0.314), and the cumulative platelet implantation rate at 100 days after transplantation was 95.2% (95% CI 88.3% - 98.1% ) and 100% ( P =0.927), respectively. 30 days after transplantation, both groups of patients achieved complete donor chimerism, and no umbilical cord blood stem cells were implanted. ②The cumulative incidence rates of grade Ⅱ-Ⅳ acute GVHD within 100 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group were 29.1% (95% CI 20.1% -38.1% ) and 28.8% (95% CI 17.2% -41.6% ( P =0.965), respectively. The cumulative incidence rates of grade Ⅲ/Ⅳ acute GVHD were 7.8% (95% CI 3.6% -14.0% ) and 9.6% (95% CI 3.5% -19.5% ) ( P =0.725). The cumulative incidence rates of 2-year chronic GVHD in the haplo-cord-PBSCT group and the UD-PBSCT group were 45.3% (95% CI 36.1% -56.1% ) and 35.1% (95% CI 21.6% -44.1% ), respectively ( P =0.237). The cumulative incidence rates of severe chronic GVHD at 2 years after transplantation were 13.6% (95% CI 7.6% -21.3% ) and 12.9% (95% CI 5.1% -24.3% ), respectively ( P =0.840). ③The 2-year CIR after transplantation in the haplo-cord-PBSCT group and UD-PBSCT group were 12.8% (95% CI 7.0% -20.5% ) and 10.0% (95% CI 3.6% -20.2% ), respectively ( P =0.341), and the NRM were 14.7% (95% CI 8.4% -22.6% ) and 16.2% (95% CI 7.4% -28.0% ), respectively ( P =0.681). ④The 2-year OS rates in the haplo-cord-PBSCT and UD-PBSCT groups after transplantation were 82.2% (95% CI 74.8% -90.3% ) and 75.5% (95% CI 64.2% -88.7% ), respectively ( P =0.276). The 2-year DFS rates were 69.9% (95% CI 61.2% -79.8% ) and 73.8% (95% CI 62.4% -87.3% ), respectively ( P =0.551). The 2-year rates of GVHD-free/recurrence-free survival (GRFS) were 55.3% (95% CI 44.8% -64.8% ) and 64.7% (95% CI 52.8% -79.3% ), respectively ( P =0.284) . Conclusion: The findings of this study indicate that haplo-cord-PBSCT and UD-PBSCT have comparable efficacy and safety in the treatment of malignant hematological diseases and can be used as an alternative treatment options.

While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis., Purpose: Fracture risk assessment tool (FRAX) is useful in classifying the fracture risk level, and precise prediction can be achieved by estimating both clinical risk factors and bone mineral density (BMD) using dual X-ray absorptiometry (DXA). However, DXA is not frequently feasible because of its cost and accessibility. This study aimed to establish the reliability of deep learning (DL)-based alternative tools for screening patients at a high risk of fracture and osteoporosis., Methods: Participants were enrolled from the National Bone Health Screening Project of Taiwan in this cross-sectional study. First, DL-based models were built to predict the lowest T-score value in either the lumbar spine, total hip, or femoral neck and their respective BMD values. The Bland-Altman analysis was used to compare the agreement between the models and DXA. Second, the predictive model to classify patients with a high fracture risk was built according to the estimated BMD from the first step and the FRAX score without BMD. The performance of the model was compared with the classification based on FRAX with BMD., Results: Approximately 10,827 women (mean age, 65.4 ± 9.4 years) were enrolled. In the prediction of the lumbar spine BMD, total hip BMD, femoral neck BMD, and lowest T-score, the root-mean-square error (RMSE) was 0.099, 0.089, 0.076, and 0.68, respectively. The Bland-Altman analysis revealed a nonsignificant difference between the predictive models and DXA. The FRAX score with femoral neck BMD for major osteoporotic fracture risk was 9.7% ± 6.7%, whereas the risk for hip fracture was 3.3% ± 4.6%. Comparison between the classification of FRAX with and without BMD revealed the accuracy rate, positive predictive value (PPV), and negative predictive value (NPV) of 78.8%, 64.6%, and 89.9%, respectively. The area under the receiver operating characteristic curve (AUROC), accuracy rate, PPV, and NPV of the classification model were 0.913 (95% confidence interval: 0.904-0.922), 83.5%, 71.2%, and 92.2%, respectively., Conclusion: While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines., Objective: This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells., Methods: Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells., Results: FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9., Conclusion: Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Context: Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine's active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD's major components remains unclear., Objective: This study evaluates the herb-drug interaction between DBD's major components and gemcitabine and validates the underlying pharmacokinetic mechanism., Materials and Methods: The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis., Results: The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD's major components in rats. The C max and AUC of calycosin-7- O -β-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life ( t 1/2 ) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression., Discussion and Conclusions: Gemcitabine could modulate the pharmacokinetics of DBD's major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.

This article proposes two adaptive asymptotic tracking control schemes for a class of interconnected systems with unmodeled dynamics and prescribed performance. By applying an inherent property of radial basis function (RBF) neural networks (NNs), the design difficulties aroused from the unknown interactions among subsystems and unmodeled dynamics are overcome. Then, in order to ensure that the tracking errors can be suppressed in the specified range, the constrained control problem is transformed into the stabilization problem by using an auxiliary function. Based on the adaptive backstepping method, a time-triggered controller is constructed. It is proven that under the framework of Barbalat's lemma, all the variables in the closed-loop system are bounded and the tracking errors are further ensured to converge to zero asymptotically. Furthermore, the event-triggered strategy with a variable threshold is adopted to make more precise control such that the better system performance can be obtained, which reduces the system communication burden under the condition of limited communication resources. Finally, an illustrative example is provided to demonstrate the effectiveness of the proposed control scheme.

Background: Membrane-bound P-selectin induces endothelial adhesion of leucocytes and amplifies organ inflammations during major trauma, while soluble P-selectin (sP-sel) mediates survival rescue properties. This study characterized the differential effects of P-selectin in a "2-hit" model of hemorrhagic shock (HS) and partial hepatectomy (PH)., Materials and Methods: HS was induced by withdrawing blood (0.3 mL) directly from the mouse femoral arteries. 70% or 50% of liver volumes were resected after inducing HS. Time of survival in P-selectin deficient (Selp -/-) mice treated with and without intraperitoneal injections of recombinant P-sel IgG-Fc fusion proteins (rP-sel-Fc, 1.5 mg/kg) were recorded for up to 72h after injury. In addition, liver regeneration at 72h after HS and 50% PH was assessed in wild-type and Selp -/- mice., Results: Compared to wild-types, Selp -/- mice had significantly higher mortality rates post HS and 70% PH, as none of these animals survived up to 48h postoperatively. The survival curve was restored in Selp -/- mice pre-treated with rP-sel-Fc. In the HS followed by 50% PH experimental arm, liver remnant growth ratios were significantly higher in Selp -/- mice (15.7 ± 3.1 vs 11.7 ± 4.9, P = 0.040). The elevated serum concentrations of alanine aminotransferase post-PH were significantly reduced in Selp -/- mice. Hepatocyte proliferation indices (CYP7a1 and PCNA) expression were enhanced and myeloperoxidase activity in the regenerated remnant liver was reduced in the Selp -/- mice., Conclusion: In critical conditions induced by HS and PH, P-selectin mediates two distinct phenotypic characteristics. Soluble-form circulating P-selectin improves survival in the acute stage of HS and extensive loss of liver parenchyma; membrane-bound P-selectin induces regional pro-inflammatory reactions in the remnant liver after the acute stage of two insults, thereby inhibiting hepatic regeneration. The results of this pre-clinical study may provide molecular mechanistic insight and clinical therapeutic applications of P-selectin in the acute and regenerative phases of traumatic hepatic injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Objective: To investigate the association between long-term fasting blood glucose (FPG) variability and all-cause mortality in patients with type 2 diabetes. Methods: A total of 7 174 type 2 diabetic patients included in National Basic Public Health Service Program in Changshu of Jiangsu Province were recruited as participants. Long-term glucose variability was assessed using standard deviation ( SD ), coefficient of variation ( CV ), average real variability ( ARV ), and variability independent of the mean ( VIM ) across FPG measurements at the more than three visits. Death information were mainly obtained from the death registry system in Jiangsu. Then Cox proportional hazards regression models were used to estimate the associations of four variability indicators and all-cause mortality's hazard ratios ( HR s) and their 95% CI s. Results: Among 55 058.50 person-years of the follow-up, the mean follow-up time was 7.67 years, and 898 deaths occurred during the follow-up period. After adjustment, compared with T 1 group, the Cox regression model showed that HR s of T 3 group in SD , CV , ARV and VIM were 1.24 (95% CI : 1.03-1.49), 1.20 (95% CI : 1.01-1.43), 1.28 (95% CI : 1.07-1.55) and 1.20 (95% CI :1.01-1.41), respectively. HR s of per 1 SD higher SD , CV , ARV and VIM were 1.13 (95% CI : 1.06-1.21), 1.08 (95% CI : 1.01-1.15), 1.05 (95% CI : 1.00-1.12) and 1.09 (95% CI : 1.02-1.16) for all-cause mortality, respectively. In the stratified analysis, age, gender, hypoglycemic agent and insulin uses had no effect on the above associations (all P for interaction >0.05). Conclusion: Long-term FPG glycemic variability was positively associated with the risk of all-cause mortality in type 2 diabetes patients.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival., Materials and Methods: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models., Results: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS., Conclusion: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB., Plain Language Summary: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts., (© 2023 American Cancer Society.)

To fully exploit the economic value of the Chinese endemic species Pteroceltis tatarinowii and provide new resources for forage production, the forage nutritional value of P. tatarinowii leaves from different populations was analyzed and evaluated. The results were as follows: 1) There were significant differences in the forage nutrient indices of leaves from different populations. The crude protein content was 10.77%-18.65%, with an average of 14.58%, and the SDJN population had the highest crude protein content. The average crude fat, crude fiber content was 7.62%; the average neutral detergent fiber content was 25.33%; and the average acid detergent fiber contents were 6.79%, 7.62%, 25.33%, and 17.52%, respectively. The average phosphorus and calcium content in the leaves was 0.785 g·kg -1 and 58.01 g·kg -1 , respectively. The tannin content was much lower than the antifeedant standard, at an average of 4.97 g·kg -1 . The average total amounts of hydrolyzed and free amino acids in the leaves were 108.20 mg·g -1 and 47.87 mg·g -1 , respectively. Thus, P. tatarinowii leaves have high crude protein, crude fat, and calcium contents, and low fiber, tannin contents, and are protein-rich. These results provide evidence that this species can be developed into an excellent woody forage tree. 2) There were significant differences in the forage quality evaluation indices among the populations. The forage indices of NDP, ADP, DMI, DDM, and RFV of 21 populations all met the super standard of the American Grass and Grassland Association (AFGC) for hay, two crude protein indices met the grade 1 standard, and 12 crude protein indices met the grade 2 standard. Four high-protein and high-RFV forage populations (SDJN, SDZZ, SXLQ, and AHXX) were selected. 3) The results of the correlation analysis showed that there was no significant correlation between the forage characteristics of P. tatarinowii leaves and latitude and longitude, indicating no significant geographical variation. However, the forage characteristics were strongly correlated with elevation, average annual temperature, and annual precipitation. Thus, high elevation, low temperatures, and rainy weather can improve the forage value of the leaves. P. tatarinowii can be planted to provide leaf forage in cold and wet areas at a specific elevation. Moreover, the forage value of P. tatarinowii leaves can be further improved by increasing nitrogen fertilizer and reducing K and Ca fertilizers during cultivation. 4) Cluster analysis revealed obvious regionalism. Taking the Yangtze River Basin as the limit, cluster analysis divided the species into four population groups: the Yangtze River Basin and northern, southwestern, and eastern coastal populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Cheng, Zhang, Yan, Zhang, Liu, Liu and Qiao.)

Background: To evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity., Methods: Gray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation., Results: There were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%., Conclusions: There was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation., (© 2023. The Author(s).)

Background: To determine the effects of adalimumab on health-related quality of life (HRQoL) in Taiwanese patients with moderate-to-severe rheumatoid arthritis (RA) (NCT02616380)., Methods: During a 24-week observational period, 100 biologic-naive patients with RA received 40 mg adalimumab subcutaneously, every 2 weeks. The primary endpoint was a change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at 24 weeks. The secondary endpoints included change in HAQ-DI at week 12, number and percentage of patients achieving a meaningful improvement in HAQ-DI at weeks 12 and 24, and changes in the 36-Item Short Form Health Survey (SF-36), EuroQol 5-dimension 3-level version (EQ-5D-3L) index, and Work Productivity and Activity Impairment (WPAI) questionnaire scores at weeks 12 and 24., Results: At weeks 12 and 24, mean changes in HAQ-DI from baseline were -0.34 ± 0.46 and -0.44 ± 0.59 (both p < 0.001), and clinically meaningful improvement in HAQ-DI was achieved by 60.4% and 59.6% of patients, respectively. SF-36, EQ-5D-3L index, and WPAI scores significantly improved ( p < 0.001) from baseline to weeks 12 and 24. Exploratory analyses showed diabetes was significantly associated with changes in HAQ-DI, EQ-5D-3L, and WPAI scores whereas peptic ulcer correlated with changes in the SF-36 physical component summary T-score., Conclusion: HRQoL improved after initiation of adalimumab therapy in Taiwanese patients with moderate-to-severe RA., Competing Interests: Conflicts of interest: Dr. Chang-Youh Tsai, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Background: Nursing experts regularly visited the community to deliver safety education on the prevention of unintentional injuries in children to the parents of children aged 0-6 years and to pregnant women in a maternity school. This was undertaken to explore the effects of the measure on preventing unintentional injuries in children in Chizhou, China., Methods: Using the convenience sampling method, the guardians(it means mother in this study)of children were investigated. The nursing experts visited communities in which the number of nursing experts is declining. Data on unintentional injuries in children in the previous year were collected retrospectively., Results: After the nursing experts delivered safety education to the community, the scores of the questionnaire on unintentional injury prevention knowledge completed by children's guardians increased significantly (p < 0.01). Among the children whose guardians completed the questionnaire, there were 157 cases of unintentional injury in 2020 and 103 cases in 2021 (p < 0.05). The types of unintentional injuries included scratches, falls, sharp object injuries, swallowing of foreign bodies, burns and traffic accidents; there was no statistical difference (p > 0.05). However, there were significant differences in terms of gender ratio and location (p < 0.05)., Conclusion: In conjunction with the maternity school for pregnant women and the vaccination programme, nursing experts delivered safety education regarding unintentional injuries in children; this may have promoted safety and protection awareness in the children's guardians and reduced unintentional injuries., (© 2022. The Author(s).)

Osteoporosis greatly increases the risk of fractures. Osteoporotic fractures negatively impact quality of life, increase the burden of care, and increase mortality. Taiwan is an area with a high prevalence of osteoporosis. This updated summary of guidelines has been developed by experts of the Taiwan Osteoporosis Association with the intention of reducing the risks of osteoporotic fractures and improving the quality of care for patients with osteoporosis. The updated guidelines compile the latest evidence to provide clinicians and other healthcare professionals with practical recommendations for the prevention, diagnosis, and management of osteoporosis under clinical settings in Taiwan., Competing Interests: Declaration of competing interest The authors declared that there was no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Osteoporotic vertebral fractures may predict the future occurrence of fractures and increase mortality. Treating underlying osteoporosis may prevent second fractures. However, whether anti-osteoporotic treatment can reduce the mortality rate is not clear. The aim of this population study was to identify the degree of decreased mortality following the use of anti-osteoporotic medication after vertebral fractures., Methods: We identified patients who had newly diagnosed osteoporosis and vertebral fractures from 2009 to 2019 using the Taiwan National Health Insurance Research Database (NHIRD). We used national death registration data to determine the overall mortality rate., Results: There were 59,926 patients with osteoporotic vertebral fractures included in this study. After excluding patients with short-term mortality, patients who had previously received anti-osteoporotic medications had a lower refracture rate as well as a lower mortality risk (hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.81-0.88). Patients receiving treatment for more than 3 years had a much lower mortality risk (HR: 0.53, 95% CI: 0.50-0.57). Patients who used oral bisphosphonates (alendronate and risedronate, HR: 0.95, 95% CI: 0.90-1.00), intravenous zoledronic acid (HR: 0.83, 95% CI: 0.74-0.93), and subcutaneous denosumab injections (HR: 0.71, 95% CI: 0.65-0.77) had lower mortality rates than patients without further treatment after vertebral fractures., Conclusion: In addition to fracture prevention, anti-osteoporotic treatments for patients with vertebral fractures were associated with a reduction in mortality. A longer duration of treatment and the use of long-acting drugs was also associated with lower mortality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is an uncommon but increasing complication that is challenging to diagnose due to its varied symptoms and delayed onset, usually from months to years after radiation exposure. For patients undergoing cardiac catheterization, high-risk factors for radiodermatitis include obesity, the presence of complex or chronic total occlusion lesions, the use of a fixed large beam angulation, and a procedure time of more than 2 hours. We present an individual with FICRD that had an indurated plaque on his back for 7 years to familiarize physicians with high-risk groups and early recognition of the disease.

Background: Osteoporosis increases the risk of fractures. Visceral fat is associated with cardiovascular disease (CVD). There is inadequate knowledge on the relationship between osteoporosis and visceral fat. The study aimed to evaluate the relationship between bone mineral density (BMD) and visceral fat mass in the elderly., Methods: This was a prospective cohort study. Subjects were enrolled from the Rheumatology Clinic. All subjects underwent baseline bone mineral density and body composition measurements using dual-energy X-ray absorptiometry., Results: A total of 321 patients including 288 females and 33 males were enrolled in this study. We followed up DEXA for 1 year for fat and muscle mass change and found that 162 (50.5%) had a decrease in fat mass, 129 (40.2%) had decreased visceral fat, and 138 (43%) had decreased muscle mass. Furthermore, we found that the baseline hip T score was correlated with visceral fat decrease. Using visceral fat decrease as the outcome, we found that hip T score could predict visceral fat loss: the higher the T score, the more visceral fat loss was found [ p  < 0.001, OR: 1.6, CI: (1.3-2.1)]., Conclusion: A high hip T score was associated with a future decrease in visceral fat, which may decrease the risk of atherosclerosis and CV risk. Therefore, evaluation of visceral fat may be useful for assessing CVD risk in patients with osteoporosis. Effective management of the risk of atherosclerosis and CVD is important in improving the life expectancy of these patients., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Danazol is a treatment option for autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Three patients with AIHA and eight patients with ITP between 2008 and 2022 were enrolled in the Rheumatology Outpatient Clinic of Chang Gung Memorial Hospital, Kaohsiung. Those patients were refractory or intolerant to conventional therapy and were treated with danazol. All the patients received an initial dose of danazol (200-400 mg). The observation period was 6 months. Three patients (100%) with AIHA and six (75%) with ITP achieved treatment response after 6 months of danazol therapy. The dose of glucocorticoid for responders could be reduced to ≤5 mg/day of prednisolone, and the immunosuppressants, except hydroxychloroquine and azathioprine for systemic lupus erythematosus, could be discontinued. Adverse events were acne in two (18.2%) patients and transient dose-related liver function impairment in one (9.1%) patient in the current series. Danazol therapy appears to be a favorable alternative for refractory AIHA and ITP by altering the erythrocyte membrane to resist osmotic lysis and protecting platelets against complement-mediated lysis. In this report, we also performed a literature review and searched the PubMed/Cochrane Library for articles published from 1984 to January 2022 on danazol therapy for patients with AIHA and ITP.

Shared decision making (SDM) is an interactive process that involves patients and their healthcare professionals reaching joint decisions about medical care through negotiation. As the initiators of medical decision-making in daily routine, physicians should be aware of and concerned about the SDM process. Thus, professional competency development for SDM has become increasingly critical for physicians' training. Therefore, this study investigates the professional competency and the important competency development aspects/criteria of SDM tasks through expert interviews and literature research. The study adopts the SAA (satisfaction-attention analysis) method to assess the status of competency development aspects/criteria and determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The results demonstrate that the CE (concept and evaluation) aspect is the dominant aspect, and the CR (communication and relationship) aspect is the aspect being dominated. The CE aspect influences the aspects of SP (skill and practice), JM (joint information and decision making) and CR, and the SP aspect affects the aspects of JM and CR. Then, the JM aspect affects the CR aspect. The study also suggests suitable adoption paths of competency development for SDM tasks using the NRM approach. It provides recommendations and strategic directions for SDM competency development and sustainable training programs.

Shared decision making (SDM) is a collaborative process involving patients and their healthcare workers negotiating to reach a shared decision about medical care. However, various physician stakeholders (attending physicians, medical residents, and doctors in post-graduate years) may have different viewpoints on SDM processes. The purpose of this study is to explore the core competence of physicians in performing SDM tasks and to investigate the significant competency development aspects/criteria by applying the literature research and expert interviews. We adopt the IAA (importance awareness analysis) technique for different stakeholders to evaluate the status of competency development aspects/criteria and to determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The study combines the IAA and NRM methods and suggests using the IAA-NRM approach to evaluate the adoption strategies and common suitable paths for different levels of physicians. Our findings reveal that SDM perception and practice is the primary influencer of SDM competence development for all stakeholders. The current model can help hospital administrators and directors of medical education understand the diverse stakeholders' perspectives on the core competence of SDM tasks and determine common development plans. It provides strategic directions for SDM competency development and talent cultivation programs.

The outcomes of 80 patients with hematologic malignancies who received haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) combined with unrelated cord blood (UCB) from March 2017 to June 2020 were analyzed in this retrospective study. Anti-thymocyte globulin(ATG) was administered at a dose of 7.5 mg/kg. The median time for neutrophil and platelet engraftment was 13(range: 8-22) days and 14(range: 8-103) days, respectively. The 30-day cumulative incidence of neutrophil engraftment was 100%, and the 100-day cumulative incidence of platelet engraftment was 95%. All patients achieved complete haploidentical peripheral blood stem cell engraftment, and no cord blood chimerism was observed. The cumulative incidence of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) on 100-day was 26.3%(95%CI: 17.2%-36.3%) and 5.0%(95%CI: 1.6%-11.4%), respectively. The estimated cumulative incidence of chronic GVHD (cGVHD) and moderate-severe cGVHD at 3-year was 43.3%(95%CI: 31.6%-54.4%) and 16.0%(95%CI: 8.7%-25.2%), respectively. The estimated 3-year cumulative incidence of relapse and non-relapse mortality was 18.8%(95%CI: 10.0%-29.7%) and 17.8%(95%CI: 9.9%-27.5%), respectively. The estimated 3-year probabilities of overall survival, disease-free survival, GVHD/relapse-free survival were 77.6%(95%CI: 68.3%-88.1%), 63.4%(95%CI: 52.6%-76.5%), and 55.5%(95%CI: 44.8%-68.7%), respectively. These satisfying results suggested that haplo-PBSCT combined with UCB is an alternative transplantation protocol for hematologic malignancies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Chen, Hua, Liu, Cheng, Ma, Chen, Wang and Xu.)

Background: Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Accumulating evidence suggests that imbalanced Treg/Th17 ratio accelerates the progression of aGVHD. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor activated through cognate ligand binding. Current evidence supports that AhR plays a critical regulatory role in the differentiation of Treg and Th17 cells. However, the relationship between AhR and aGVHD remains unclear., Results: Our results showed that AhR expression was downregulated significantly in CD4 + T cells from patients with aGVHD compared with the non-aGVHD group. We also discovered that after activating AhR deficient CD4 + T cells, the expression levels of the activation markers-CD40L, CD134 and CD137 and cell proliferation activity were significantly higher than those of AhR-expressing CD4 + T cells. Restoring the expression of AhR in aGVHD CD4 + T cells resulted in significantly increased percentage of Tregs and associated gene transcripts, including Foxp3, IL-10 and CD39. In contrast, Th17 cell amounts and the transcription of related genes, including RORγt, IL-17A and IL-17F, were significantly reduced. We confirmed that CTCF recruited EP300 and TET2 to bind to the AhR promoter region and promoted AhR expression by mediating histone H3K9/K14 hyperacetylation and DNA demethylation in this region. The low expression of CTCF caused histone hypoacetylation and DNA hypermethylation of the AhR promoter, resulting in insufficient expression in aGVHD CD4 + T cells., Conclusions: CTCF is an important inducer of AhR transcription. Insufficient expression of CTCF leads to excessive AhR downregulation, resulting in substantial CD4 + T cell activation and Th17/Treg ratio increase, thereby mediating the occurrence of aGVHD., (© 2022. The Author(s).)

Objective: To explore the impact of seropositivity on systemic bone loss in rheumatoid arthritis (RA)., Methods: We conducted an interim analysis of the RA registry. Patients were examined with dual-energy X-ray absorptiometry at baseline and again 3 years later. Participants were grouped into seropositive (SPRA) and seronegative (SNRA) based on the presence or absence of rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (ACPA). After matching (1:2) for age and sex, SNRA and SPRA patients were divided into groups A and B. Each matched group (A or B) was further subdivided according to the number of antibodies present (0, group I; 1, group II; 2, group III). Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict bone mineral density (BMD) change., Results: A total of 477 participants who completed a 3-year observation period were included. After matching, 312 participants were enrolled (group A, 104; group B, 208). Three years later, group B had significant BMD reduction in the femoral neck (FN) ( p < 0.001), total hip (TH) ( p = 0.001), and first through fourth lumbar vertebrae (L1-4) ( p = 0.006), while group A had bone loss only at FN ( p = 0.002). Groups I, II, and III included 104, 52, and 156 participants, respectively. Compared to baseline, BMD decreased significantly at FN ( p = 0.002) in group I, FN ( p < 0.001) in group II, and FN ( p < 0.001), TH ( p = 0.002), and L1-4 ( p = 0.016) in group III. In terms of regression-adjusted percent change in BMD, more significantly negative changes were found at all measured sites in group B ( p < 0.001, all) and at TH and L1-4 within groups I-III ( p for trend < 0.001 and < 0.001, respectively). Regardless of antibodies, anti-osteoporotic therapy can preserve bone density in RA patients., Conclusion: After 3 years, SPRA patients lost more bone density than SNRA patients. More attention should be paid to SPRA patients, especially those with double-positive antibodies, including a vigorous evaluation of BMD and fracture risk. Anti-osteoporotic therapy can prevent BMD loss irrespective of autoantibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Chen, Chen, Wang, Hsu, Lai, He, Ko, Chiu and Cheng.)

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO 2 and SaO 2 ) and reduced CO 2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The shapeshifting behavior for synthetic matters was found at either the molecular or supramolecular level, but the connection between shapeshifting at the two hierarchical levels remains missing. In this study, an 8-arm star giant molecule, NPOSS , was synthesized to connect the molecular and supramolecular shapeshifting. Controlling the conditions of bulk self-assembly allowed us to bring NPOSS into three different Ostwald's stages of nucleation. The high conformational flexibility of NPOSS facilitates molecular shapeshifting and allows NPOSS to take the discotic, rod-like and star-like geometries in different Ostwald's stages. Simultaneous changes in the supramolecular scaffolds were observed as the discotic, rod-like and star-like NPOSS molecules self-assembled into the supramolecular scaffolds of 1D columns, 2D lamellae, and 3D networks, respectively. These changes in the hierarchical structures also affect the CO 2 affinity of NPOSS . Therefore, the connection between the molecular/supramolecular shapeshifting and the structure-driven property changes of NPOSS were established by taking advantage of the high conformational freedom of the 8-arm star giant molecule and its diverse self-assembly pathways leading to the different Ostwald's stages.

Objective: Because mitochondrial dysfunction is a key factor in the progression of pulmonary hypertension, this study tested the hypothesis that transplantation of exogenous viable mitochondria can reverse pulmonary artery remodeling and restore right ventricular performance in pulmonary hypertension., Methods: Pulmonary hypertension was induced by parenteral injection of monocrotaline (60 mg/kg) and creation of a left-to-right shunt aortocaval fistula in rats. Three weeks after creation of fistula, the animals were randomly assigned to receive intravenous delivery of placebo solution or allogeneic mitochondria once weekly for 3 consecutive weeks. Mitochondria (100 μg) were isolated from the freshly harvested soleus muscles of naïve rats. Transthoracic echocardiography was performed at 3 weeks after mitochondrial delivery., Results: Ex vivo heart-lung block images acquired by an IVIS Spectrum (PerkinElmer, Waltham, Mass) imaging system confirmed the enhancement of MitoTracker (Invitrogen, Carlsbad, Calif) fluorescence in the pulmonary arteries. Mitochondria transplantation significantly increased lung tissue adenosine triphosphate concentrations and improved right ventricular performance, as evidenced by a reduction in serum levels of B-type natriuretic peptide and ventricular diameter. Right ventricular mass and wall thickness were restored in the mitochondrial group. In the pulmonary arteries of rats that received mitochondrial treatment, vascular smooth muscle cells expressed higher levels of α-smooth muscle actin and smooth muscle myosin heavy chain II, indicating the maintenance of the nonproliferative, contractile phenotype. The hyper-reactivity of isolated pulmonary arteries to α-adrenergic stimulation was also attenuated after mitochondrial transplantation., Conclusions: Transplantation of viable mitochondria can restore the contractile phenotype and vasoreactivity of the pulmonary artery, thereby reducing the afterload and right ventricular remodeling in rats with established pulmonary hypertension. The improvement in overall right ventricular performance suggests that mitochondrial transplantation can be a revolutionary clinical therapeutic option for the management of pulmonary hypertension., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

In nature, many different factors cause plants to develop variegated leaves. To explore the mechanism of variegated leaf formation in Pteroceltis tatarinowii , a mutant variety ('Jinyuyuan'), which was induced by ethylmethylsulfone, was selected, and its morphological structure, physiology, biochemistry, transcription and metabolism were analysed. According to differences in colour values, the colours were divided into two regions: a green region and a yellow-green region. The chlorophyll content of the two regions was significantly different. Moreover, the yellow-green regions of the leaves were significantly thinner than the green regions. The chloroplast ultrastructure in the yellow-green region revealed small chloroplasts, large vacuoles, small starch grains, obviously increased numbers of osmophilic grains, loose lamellae of the inner capsule and thin lamellae. Moreover, the yellow-green region was accompanied by oxidative stress, and the activity of the oxidative phosphorylation pathway related to oxidative activity in the transcriptome showed an upward trend. Vitamin B6 and proline contents also increased, indicating that the antioxidant activity of cells in the yellow-green region increased. Transcriptomic and metabolomic analysis showed that the differentially expressed genes (DEGs) related to chlorophyll synthesis and metabolism led to a decrease in the photosynthesis and then a decrease in the assimilation ability and contents of sucrose, starch and other assimilates. Amino acid synthesis and metabolism, lipid synthesis and the activity of metabolic pathways were obviously downregulated, and the contents of differentially accumulated metabolites associated with amino acids and lipids were also reduced. At the same time, 31 out of 32 DEGs involved in the flavonoid synthesis pathway were downregulated, which affected leaf colour. We hypothesized that the variegated leaves of P. tatarinowii 'Jinyuyuan' are caused by transcriptional and post-transcriptional regulation. Mutations in pigment and flavonoid synthesis pathway genes and transcription factor genes directly affect both pigment and flavonoid synthesis and degradation rate, which in turn affect carbon assimilation, carbon fixation, related protein synthesis and enzyme activity, lipid synthesis and degradation and the activity of other metabolic pathways, eventually leading to the formation of different colour regions.

Despite advantages of arsenic trioxide (ATO) in oncological practice, its clinical applications have been hampered by severe cardiotoxicity. The general mechanism of ATO-induced cardiotoxicity has been attributed to its damage to mitochondria, resulting in cardiac remodeling. Honokiol (HKL) is a naturally occurring compound derived from Magnolia bark. Previous studies have demonstrated that HKL exerts cardio-protective effects on ischemia/reperfusion (I/R) or chemical-induced cardiotoxicity by counteracting the toxic effects on mitochondria. The present study was conducted to investigate whether HKL pretreatment protects against ATO-induced cardiac oxidative damage and cell death. For the in vitro study, we evaluated the effects of ATO and/or Honokiol on reactive oxygen species (ROS) production and apoptosis induction in primary cultured cardiomyocytes; for the in vivo study, BALB/c mice were administrated with ATO and/or HKL for a period of 4 weeks, myocardial apoptosis, cardiac function, and cardiac remodeling (cardiac hypertrophy and cardiac fibrosis) were assessed at the end of administration. Our results demonstrated Honokiol pretreatment alleviated the ATO-induced boost in ROS concentration and the following apoptosis induction in primary cultured cardiomyocytes. In the mouse model, Honokiol pretreatment ameliorated ATO-induced myocardial apoptosis, cardiac dysfunction, and cardiac remodeling. Collectively, these results indicated that Honokiol provide a protection against ATO-induced cardiotoxicity by reducing mitochondrial damage. In addition, given that Honokiol has shown considerable suppressive effects on leukemia cells, our data also imply that ATO and Honokiol combination may possibly be a superior avenue in leukemia therapy., (© 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Competing Interests: There are no conflicts of interest.

Objective: Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organs, including the kidneys. There is a lack of long-term renal prognosis studies on patients with SSc. The aim of this study was to assess the risk of end-stage renal disease (ESRD) in patients with SSc., Method: We designed a prospective cohort study based on the National Health Insurance Research Database of Taiwan. Patients with SSc and a non-SSc control group were selected from 1 January 2000 to 31 December 2013. The SSc cohort and control group were matched on the propensity score in a 1:2 ratio. The primary outcome was development of ESRD. Cox proportional hazard regression was performed to assess the effects of SSc on ESRD., Results: After propensity score matching, we enrolled 2012 patients in the SSc group and 4024 patients in the control group. During a mean follow-up of 6.5 years, 86 individuals [SSc group, n = 41 (2.04%); control group, n = 45 (1.12%)] had developed ESRD. The risk of ESRD in the SSc group was approximately two times higher than that in the control group [hazard ratio (HR) = 2.12, 95% confidence interval (CI) 1.39-3.24]. Subgroup analysis revealed that the higher risk of ESRD was predominantly in males (HR = 4.14, 95% CI 1.97-8.71) and the younger population (HR = 7.09, 95% CI 2.31-21.80)., Conclusion: There was a significantly higher risk of ESRD among SSc patients than among the general population, with males and younger generations being the most vulnerable groups.

Background: To establish a FRAX®-based prediction model for rheumatoid arthritis (RA)-associated fragility fracture., Methods: This study is a longitudinal, real-world, registry cohort study. Patients with RA were registered to start in September 2014. The baseline demographics, bone mineral density (BMD), and risk factors of osteoporosis or fragility fracture were recorded. Subsequent fragility fractures during the 3-year observation period were also recorded. We developed a fixed intervention threshold (FITD) to identify fractures by choosing an optimal cut-off point on the receiver operating characteristic (ROC) curve and FRAX®. Several models for intervention thresholds (IT), including fixed intervention threshold (Taiwan) (FITT), age-specific individual intervention threshold (IIT), and hybrid intervention threshold (HIT), were compared to evaluate which IT model will have better discriminative power., Results: As of December 2020, a total of 493 RA participants have completed the 3-year observation study. The mean age of the participants was 59.3 ± 8.7, and 116 (23.5%) new fragility fractures were observed during the study period. In terms of pairwise comparisons of area under the curve ( n , 95% confidence interval) in the ROC curve, the FITD (0.669, 0.610-0.727, p  < 0.001) with a value of 22% in major osteoporotic fracture and FITT (0.640, 0.582-0.699, p  < 0.001) is significantly better than reference, but not for IIT (0.543, 0.485-0.601, p  = 0.165) and HIT (0.543, 0.485-0.601, p  = 0.165)., Conclusion: An optimal FIT is established for intervention decisions in RA-associated fragility fractures. This model can offer an easy and simple guide to aid RA caregivers to provide interventions to prevent fragility fractures in patients with RA., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

A salicylaldehyde Schiff base hybrid lead iodide perovskite [SAPD]PbI 3 (SAPD = 1-((2-hydroxybenzylidene)amino)pyridin-1-ium) was found to show a robust nonlinear optical response and large spontaneous polarization. We expect this work to inspire researchers to investigate the optical control of ferroelectricity in hybrid perovskites.

Purpose: To evaluate the clinical features, diagnostic techniques, various treatment strategies and prognosis of primary intraocular lymphoma (PIOL)., Methods: The databases PubMed, EMBASE, and Ovid were searched from inception to March 2021 to identify relevant studies. Statistical analyses were performed with R version 3.3.1., Results: 87 studies involving 1484 patients (aged from 14 to 90 years old) were finally included. The pooling results indicated PIOL patients were female, elderly, binocular and B cell type dominated. About 19% have central nervous system (CNS) involvement at the first visit. During follow-up, the incidence of CNS involvement, death rate, 2-year and 5-year survival rate, 1-year and 2-year progression-free survival, and recurrence rate were 58%, 33%, 82%, 70%, 88%, 70%, 44%, respectively. The most common recurrent site was CNS. The delayed diagnosis rate was 85%, the misdiagnosed rate was 64%. The diagnostic technique with the highest positive rate was IL10:IL6>1 of aqueous (98%). The most common symptoms, signs, FFA and OCT features were blurring of vision (72%), vitreous inflammatory opacity (92%), FA/FAF reversal (91%) and hyper-reflective foci in posterior vitreous (53%), respectively. The prognosis of PIOL patients without CNS involvement was obviously better than those with CNS involvement. Overall, intravitreal injection of chemotherapy drug plus systemic chemotherapy (IV+CT) could achieve satisfactory prognosis, the combination of local radiotherapy (RT) could further decrease the recurrent and death rate., Conclusion: PIOL patients with CNS involvement had significantly worse prognosis. The aqueous humor examination should be regarded as first-line and routine diagnostic technique. IV+CT could achieve satisfactory prognosis, the combination of RT was also beneficial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Cheng, Meng, Zhang and Chen.)

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., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis factor-α inhibitors (TNFi), and abatacept., Methods: Patients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD., Results: A total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA., Conclusion: Compared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Yu, Chen, Chen, Liou, Chou, Hsu, Lai, Chen, Tsai and Cheng.)

Ferroelectrics usually exhibit temperature-triggered structural changes, which play crucial roles in controlling their physical properties. However, although light is very striking as a non-contact, non-destructive, and remotely controlled external stimuli, ferroelectric crystals with light-triggered structural changes are very rare, which holds promise for optical control of ferroelectric properties. Here, an organic molecular ferroelectric, N-salicylidene-2,3,4,5,6-pentafluoroaniline (SA-PFA), which shows light-triggered structural change of reversible photoisomerization between cis-enol and trans-keto configuration is reported. SA-PFA presents clear ferroelectricity with the saturate polarization of 0.84 μC cm -2 , larger than those of some typical organic ferroelectrics with thermodynamically structural changes. Benefit from the reversible photoisomerization, the dielectric real part of SA-PFA can be reversibly switched by light. More strikingly, the photoisomerization enables SA-PFA to show reversible optically induced ferroelectric polarization switching. Such intriguing behaviors make SPFA a potential candidate for application in next-generation photo-controlled ferroelectric devices. This work sheds light on further exploration of more excellent molecular ferroelectrics with light-triggered structural changes for optical control of ferroelectric properties., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Although the self-assessment tools for predicting osteoporosis are convenient for clinicians, they are not commonly used among men. We developed the Male Osteoporosis Self-Assessment Tool for Taiwan (MOSTAi) to identify the patients at risk of osteoporosis. Methods: All the participants completed a questionnaire on the clinical risk factors for the fracture risk assessment tool. The risk index was calculated by the multivariate regression model through the item reduction method. The receiver operating characteristic (ROC) curve was used to analyze its sensitivity and specificity, and MOSTAi was developed and validated. Results: A total of 2,290 men participated in the bone mineral density (BMD) survey. We chose a model that considered two variables (age and weight). The area under the curve (AUC) of the model was 0.700. The formula for the MOSTAi index is as follows: 0.3 × (weight in kilograms) - 0.1 × (years). We chose 11 as the appropriate cut-off value for the MOSTAi index to identify the subjects at the risk of osteoporosis. Conclusions: The MOSTAi is a simple, intuitive, and country-specific tool that can predict the risk of osteoporosis in Taiwanese men. Due to different demographic characteristics, each region of the world can develop its own model to identify patients with osteoporosis more effectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Hsu, Wu, Chen, Chen, Chen, Yu and Cheng.)

Background and Objectives: In the intensive care unit (ICU), renal failure and respiratory failure are two of the most common organ failures in patients with systemic inflammatory response syndrome (SIRS). These clinical symptoms usually result from sepsis, trauma, hypermetabolism or shock. If this syndrome is caused by septic shock, the Surviving Sepsis Campaign Bundle suggests that vasopressin be given to maintain mean arterial pressure (MAP) > 65 mmHg if the patient is hypotensive after fluid resuscitation. Nevertheless, it is important to note that some studies found an effect of various mean arterial pressures on organ function; for example, a MAP of less than 75 mmHg was associated with the risk of acute kidney injury (AKI). However, no published study has evaluated the risk factors of mortality in the subgroup of acute kidney injury with respiratory failure, and little is known of the impact of general risk factors that may increase the mortality rate. Materials and Methods: The objective of this study was to determine the risk factors that might directly affect survival in critically ill patients with multiple organ failure in this subgroup. We retrospectively constructed a cohort study of patients who were admitted to the ICUs, including medical, surgical, and neurological, over 24 months (2015.1 to 2016.12) at Chiayi Chang Gung Memorial Hospital. We only considered patients who met the criteria of acute renal injury according to the Acute Kidney Injury Network (AKIN) and were undergoing mechanical ventilator support due to acute respiratory failure at admission. Results: Data showed that the overall ICU and hospital mortality rate was 63.5%. The most common cause of ICU admission in this cohort study was cardiovascular disease (31.7%) followed by respiratory disease (28.6%). Most patients (73%) suffered sepsis during their ICU admission and the mean length of hospital stay was 24.32 ± 25.73 days. In general, the factors independently associated with in-hospital mortality were lactate > 51.8 mg/dL, MAP ≤ 77.16 mmHg, and pH ≤ 7.22. The risk of in-patient mortality was analyzed using a multivariable Cox regression survival model. Adjusting for other covariates, MAP ≤ 77.16 mmHg was associated with higher probability of in-hospital death [OR = 3.06 (1.374-6.853), p = 0.006]. The other independent outcome predictor of mortality was pH ≤ 7.22 [OR = 2.40 (1.122-5.147), p = 0.024]. Kaplan-Meier survival curves were calculated and the log rank statistic was highly significant. Conclusions: Acute kidney injury combined with respiratory failure is associated with high mortality. High mean arterial pressure and normal blood pH might improve these outcomes. Therefore, the acid-base status and MAP should be considered when attempting to predict outcome. Moreover, the blood pressure targets for acute kidney injury in critical care should not be similar to those recommended for the general population and might prevent mortality.

Objectives: To explore the risk factors for fragility fractures in rheumatoid arthritis (RA) patients using a 3-year longitudinal, observational cohort study., Methods: This RA registry study included consecutive RA patients in the outpatient clinic of Chang Gung Memorial Hospital since September 1, 2014. The demographics, clinical characteristics, lifestyle, evidence of previous fracture, risk factors according to the Fracture Risk Assessment Tool (FRAX®), and the FRAX score of each participant were recorded. The participants were categorized into the new incident fracture (group A) and no incident fracture (group B) groups based on evidence or absence of new incident fractures and propensity score matching (age and gender, 1:2)., Results: Overall, 477 participants completed the 3-year observation period. After matching, 103 and 206 participants were allocated to groups A and B, respectively. The non-adjusted model revealed, presented as hazard ratio (HR) (95% confidence interval [CI]), that the presence of co-morbidity (1.80 [1.17-2.78], p = 0.008), Health Assessment Questionnaire Disability Index (1.35 [1.07-1.69], p = 0.010), lower baseline hip bone mineral density (0.11 [0.02-0.48], p = 0.004), longer disease duration (1.02 [1.00-1.04], p = 0.026), higher FRAX score of major fracture (1.03 [1.02-1.04], p<0.001) or hip fracture (1.03 [1.02-1.04], p<0.001), and previous fracture history (2.65 [1.79-3.94], p<0.001) were associated with new incident fracture. After adjustment, it was disclosed that a previous fracture is an independent risk factor for fragility fractures in RA patients (2.17 [1.20-3.90], p = 0.010)., Conclusions: In addition to aging and disease-related factors, previous fracture history is the most important risk factor for fragility fractures in RA patients., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To identify risk factors for recurrent shoulder instability after arthroscopic stabilization in adolescent athletes., Methods: A retrospective case-control study was undertaken of all patients younger than 18 years undergoing arthroscopic shoulder stabilization for anterior instability between 2009 and 2016. Two patient cohorts were identified: (1) patients with recurrent instability (frank dislocations or subluxations) after arthroscopic stabilization and (2) an age- and sex-matched cohort of patients with no recurrent instability at a minimum of 2 years' follow-up from index surgery. Patient demographic, injury, radiographic, and surgical variables were recorded. Variables with P < .10 on univariate analysis were entered into a binary logistic multivariate regression analysis., Results: We identified 35 patients (20.5%) in whom arthroscopic stabilization failed at a mean of 1.2 ± 1.0 years after their index surgical procedure. A separate age- and sex-matched cohort of 35 patients with no evidence of recurrent instability was identified (mean follow-up, 5.4 ± 2.0 years; minimum follow-up, 2 years). Univariate analysis identified increased glenoid bone loss (P = .039), decreased glenoid retroversion (P = .024), and more than 1 instability event prior to surgery (P = .017) as significant risk factors for recurrent instability. Multivariate regression analysis revealed that glenoid retroversion less than 6°, skeletal immaturity, and more than 1 prior instability event significantly and independently predicted future recurrence. The risk of recurrence after arthroscopic stabilization was increased by 3 times in patients with 2 risk factors and by 4 times in patients with all 3 risk factors., Conclusions: Anterior glenoid bone loss, glenoid version, skeletal immaturity, and multiple preoperative instability events are risk factors for failed arthroscopic stabilization in adolescent athletes with anterior instability., Level of Evidence: Level III, case-control study., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background Cardiovascular disease is the most common cause of death in patients with rheumatoid arthritis. It is believed that using disease-modifying antirheumatic drugs (DMARDs) to control inflammation can reduce the risk of cardiovascular disease. In this study, we investigated whether patients who responded differently to DMARDs might sustain different cardiovascular events. Methods and Results We designed a cohort study using the Chang Gung Research Database. We identified 7114 patients diagnosed with rheumatoid arthritis. After strict exclusion criteria, we collected 663 individuals as an inadequate response to DMARDs group. Then, 2034 individuals were included as the control group. The end point was composite vascular outcomes, including acute coronary syndrome or ischemic stroke. We used the inverse probability of treatment weighting to keep the covariates between these 2 groups well balanced. We compared the risk of these outcomes using the Cox proportional hazards model. The mean follow-up time was 4.7 years. During follow-up, there were 7.5% and 6.4% of patients with composite vascular outcomes in the DMARD-inadequate response and control groups, respectively. There was no significant difference in the risk of composite vascular outcomes (95% CI, 0.94-1.41) and ischemic stroke (95% CI, 0.84-1.36). The risk of acute coronary syndrome was significantly higher in the DMARD-inadequate response group (hazard ratio, 1.45; 95% CI, 1.02-2.05). Conclusions Patients with DMARD-inadequate response rheumatoid arthritis have a higher risk of developing acute coronary syndrome than those whose disease can be controlled by DMARDs.

Post-weaning diarrhea due to enterotoxigenic Escherichia coli (ETEC) is a common disease of piglets and causes great economic loss for the swine industry. Over the past few decades, decreasing effectiveness of conventional antibiotics has caused serious problems because of the growing emergence of multidrug-resistant (MDR) pathogens. Various studies have indicated that antimicrobial peptides (AMPs) have potential to serve as an alternative to antibiotics owing to rapid killing action and highly selective toxicity. Our previous studies have shown that AMP GW-Q4 and its derivatives possess effective antibacterial activities against the Gram-negative bacteria. Hence, in the current study, we evaluated the antibacterial efficacy of GW-Q4 and its derivatives against MDR ETEC and their minimal inhibition concentration (MIC) values were determined to be around 2~32 μg/mL. Among them, AMP Q4-15a-1 with the second lowest MIC (4 μg/mL) and the highest minimal hemolysis concentration (MHC, 256 μg/mL), thus showing the greatest selectivity (MHC/MIC = 64) was selected for further investigations. Moreover, Q4-15a-1 showed dose-dependent bactericidal activity against MDR ETEC in time-kill curve assays. According to the cellular localization and membrane integrity analyses using confocal microscopy, Q4-15a-1 can rapidly interact with the bacterial surface, disrupt the membrane and enter cytosol in less than 30 min. Minimum biofilm eradication concentration (MBEC) of Q4-15a-1 is 4× MIC (16 μg/mL), indicating that Q4-15a-1 is effective against MDR ETEC biofilm. Besides, we established an MDR ETEC infection model with intestinal porcine epithelial cell-1 (IPEC-1). In this infection model, 32 μg/mL Q4-15a-1 can completely inhibit ETEC adhesion onto IPEC-1. Overall, these results suggested that Q4-15a-1 may be a promising antibacterial candidate for treatment of weaned piglets infected by MDR ETEC.