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Background and Purpose Hypoxia-mediated neovascularization plays an important role in age-related macular degeneration ( AMD). There are few animal models or effective treatments for AMD. Here, we investigated the effects of the flavonoid silibinin on hypoxia-induced angiogenesis in a rat AMD model. Experimental Approach Retinal pigmented epithelial ( RPE) cells were subjected to hypoxia in vitro and the effects of silibinin on activation of key hypoxia-induced pathways were examined by elucidating the hypoxia-inducible factor-1 alpha ( HIF-1 α) protein level by Western blot. A rat model of AMD was developed by intravitreal injection of VEGF in Brown Norway rats, with or without concomitant exposure of animals to hypoxia. Animals were treated with oral silibinin starting at day 7 post- VEGF injection and AMD changes were followed by fluorescein angiography on days 14 and 28 post-injection. Key Results Silibinin pretreatment of RPE cells increased proline hydroxylase-2 expression, inhibited HIF-1 α subunit accumulation, and inhibited VEGF secretion. Silibinin-induced HIF-1 α and VEGF down-regulation required suppression of hypoxia-induced phosphatidylinositol 3-kinase/ Akt/mammalian target of rapamycin ( mTOR) pathway. In the rat model of AMD, silibinin administration prevented VEGF- and VEGF plus hypoxia-induced retinal oedema and neovascularization. Conclusion and Implications The effects of silibinin, both in vitro and in vivo, support its potential as a therapeutic for the prevention of neovascular AMD. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are medications with anti-inflammatory effects used to treat type 2 diabetes mellitus (T2DM). Cervical cancer is the most common gynecological cancer and is characterized by elevated inflammatory status. Accordingly, this study aimed to investigate the potential association between SGLT2 inhibitor use and cervical cancer development. In this retrospective cohort study, female patients with T2DM were divided into 2 groups: SGLT2 inhibitor users and a control group of non-SGLT2 inhibitor users. After propensity score matching, the SGLT2 inhibitor group and control group each had 136 212 patients. Cox proportional hazards regression was conducted to obtain the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for cervical cancer between the 2 groups. Overall, 148 and 191 cases of cervical cancer were identified in the SGLT2 inhibitor and control groups, respectively. The incidence of cervical cancer was significantly lower in the SGLT2 inhibitor group than in the control group (aHR, 0.77; 95% CI, 0.62-0.96, P = 0.0179). In a subgroup analysis stratified by type of oral medication, the effect of SGLT2 inhibitors on cervical cancer development exhibited a significant difference compared with a biguanide group (aHR, 0.77; 95% CI, 0.63-0.95) and a sulfonylurea group (aHR, 0.69; 95% CI, 0.50-0.94) groups. In conclusion, the use of SGLT2 inhibitors in patients with T2DM is associated with reduced risk of cervical cancer development., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Imperatorin is a naturally occurring furocoumarin derivative found in traditional Chinese medicine Angelica dahurica for its anticancer, antihypertensive, and antidiabetic properties. Chronic kidney disease (CKD) is a global health issue, characterized by a high prevalence, significant morbidity and mortality, and a range of related complications., Objective: This study aims to investigate the protective effects of imperatorin treatment and the specific underlying mechanisms in progressive CKD., Methods: Imperatorin was orally administrated for 14 consecutive days to mice with unilateral ureteral obstruction (UUO) to investigate the renal pathological alternations, pro-inflammatory mediators, antioxidant response, and ferroptotic death signaling. Imperatorin was also tested in the erastin-induced injury of renal proximal tubular cells (NRK-52E). Cell viability, ferroptosis protein markers, erastin-induced oxidative stress, and lipid peroxidation were assessed., Results: In vivo, imperatorin treatment alleviated kidney histology alternations and attenuated the protein expression of fibrotic markers. Furthermore, imperatorin administration reduced inflammatory cell infiltration, and alleviated the oxidative stress burden by downregulating protein markers such as catalase, superoxide dismutase 2 (SOD-2), NADPH oxidase 4 (NOX-4), and thioredoxin reductase 1 (Trxr-1). It also mitigated ferroptosis markers such as glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11/cystine transporter (SLC7A11/xCT), and transferrin receptor 1 (TFR-1), and attenuated renal cell apoptosis. In vitro, imperatorin treatment effectively decreased erastin-induced feroptotic cell death, restored the antioxidant enzyme levels, and mitigated lipid peroxidation as well as the expression of ferroptosis-related markers (XCT, GPX4, and p-p53) in a dose-dependent manner., Conclusion: Our finding demonstrated for the first time, that imperatorin treatment holds therapeutic potential in a UUO mouse model of CKD and inhibits the erastin-induced oxidative stress, ferroptosis, and subsequent lipid peroxidation in vitro. This highlights the potential of imperatorin as a future therapeutic target for ferroptosis to improve the progression of CKD., Competing Interests: Declaration of competing interest 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, (Copyright © 2024. Published by Elsevier GmbH.)

Background: Tinnitus and uveitis have shared commonality in pathophysiology in terms of autoimmunity. However, no studies that have linked any association between the conditions of tinnitus and uveitis., Methods: This is a retrospective study conducted from the Taiwan National Health Insurance database in order to investigate whether tinnitus patients are at increased risk of uveitis. Patients newly diagnosed with tinnitus between 2001 and 2014 were recruited and followed up until 2018. The endpoint of interest was a diagnosis of uveitis., Results: A total of 31,034 tinnitus patients and 124,136 matched comparisons were analyzed. Tinnitus patients were found to have a significantly higher cumulative incidence for uveitis than those without the diagnosis of tinnitus with incidence rate of 1.68 (95% CI 1.55-1.82) per 10 000 person-months for tinnitus group and 1.48 (95% CI 1.42-1.54) per 10 000 person-months for non-tinnitus group., Conclusion: Tinnitus patients were found to have increased risk of developing uveitis.

Background: The associations of coronavirus disease (COVID-19) with Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) remain unclear. Few large-scale studies have estimated the cumulative incidence of MIS-C and KD after COVID-19 in children., Methods: Data were obtained from TriNetX. After propensity score matching was completed, data from 258 645 patients with COVID-19 (COVID-19 group) and 258 645 patients without COVID-19 (non-COVID-19 group) were analyzed using Cox regression. Hazard ratio (HR), 95% CI, and cumulative incidence of MIS-C and KD were calculated for both groups. A stratified analysis was performed to validate the results., Results: After matching for age at baseline and sex, the risks of MIS-C and KD were higher in the COVID-19 group than in the non-COVID-19 group (HR: 3.023 [95% CI, 2.323-3.933] and 1.736 [95% CI, 1.273-2.369], respectively). After matching for age at baseline, sex, race, ethnicity, and comorbidities, the risks of MIS-C and KD remained significantly higher in the COVID-19 group than in the non-COVID-19 group (HR: 2.899 [95% CI, 2.173-3.868] and 1.435 [95% CI, 1.030-2.000]). When stratified by age, the risk of MIS-C was higher in the COVID-19 group-for patients aged >5 years and ≤5 years (HR: 2.399 [95% CI, 1.683-3.418] and 2.673 [95% CI, 1.737-4.112], respectively)-than in the non-COVID-19 group. However, the risk of KD was elevated only in patients aged ≤5 years (HR: 1.808; 95% CI, 1.203-2.716). When stratified by COVID-19 vaccination status, the risks of MIS-C and KD were elevated in unvaccinated patients with COVID-19 (HR: 2.406 and 1.835, respectively)., Conclusion: Patients with COVID-19 who are aged <18 and ≤5 years have increased risks of MIS-C and KD, respectively. Further studies are required to confirm the role of COVID-19 in the pathogenesis of MIS-C and KD., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Clinical studies have investigated the effects of using sodium-glucose co-transporter-2 (SGLT2) inhibitors on the development of new-onset stroke (NOS) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), but the findings are inconsistent. This study aimed to examine the association between the use of SGLT2 inhibitors and NOS risk in patients with T2D and CKD. We conducted a nationwide retrospective cohort study using data from the Taiwan Health Insurance Review and Assessment Service database for the years 2004 to 2019. The primary outcome was the risk of incident stroke, which was estimated using hazard ratios (HRs) and 95% confidence intervals (CIs). We used multiple Cox regression modeling to analyze the association between SGLT2 inhibitor use and the risk of stroke in patients with T2D and CKD. In a cohort of 113,710 patients with T2D and CKD who were using SGLT2 inhibitors and 227,420 patients with T2D and CKD who were not using SGLT2 inhibitors, after applying a 1:2 sex- and age-matching strategy, 2,842 and 7,169 NOS events were recorded, respectively. The event rate per 10,000 person-months was 10.60 (95% CI 10.21 to 11.03) for SGLT2 inhibitor users and 13.71 (13.39-14.03) for non-SGLT2 inhibitor users. After adjusting for the index year, sex, age, comorbidities, and concurrent medication, there was a decreased risk of NOS for SGLT2 inhibitor users (adjusted HR 0.80; 95% CI 0.77-0.84) compared with non-SGLT2 inhibitor users. The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.80; 95% CI 0.76-0.84). The type of SGLT2 inhibitor subgroup analysis for incident stroke showed consistent results. We concluded that the use of SGLT2 inhibitors in patients with T2D and CKD was associated with significantly low rates of NOS. The significantly low rates of NOS in patients with T2D and CKD were greater among females and less than 50 years patients., (© 2023. The Author(s).)

Objective: To investigate the relationships of sleep patterns and respiratory disturbance index (RDI) with key physiological parameters (height, body mass index (BMI), bone age (BA), and IGF-1 levels) in children aged 6 to 16 years with self-perceived short stature., Methods: For this cross-sectional study, conducted from October 2019 to November 2021, 238 children aged 6 to 16 years with self-perceived short stature were enrolled. The primary outcomes of sleep patterns and the RDI were non-invasively collected at home using the LARGAN Health AI-Tech Sleep Apnea and Sleep Quality Examination System, which operates based on polygraphy. Additionally, various physiological parameters, including height, BMI, bone age, and IGF-1 levels, were measured to assess their associations with sleep patterns and RDI., Results: Significant age-related reductions were observed in both the total and deep sleep durations. Children aged 6-9 years averaged 8.5 ± 1.0 h of total sleep, which decreased to 8.1 ± 1.1 h in ages 10-11 and further to 7.5 ± 0.9 h in ages 12-16 ( p < 0.0001). Deep sleep followed a similar pattern, decreasing from 4.4 ± 1.1 h in the youngest group to 3.3 ± 1.0 h in the oldest ( p < 0.0001). Notably, girls experienced significantly longer deep sleep than boys, averaging 4.0 ± 1.2 h compared to 3.6 ± 1.2 h ( p = 0.0153). In a multivariable regression analysis, age (beta = 4.89, p < 0.0001) and RDI (beta = -0.54, p = 0.0022) were significantly associated with body height. Age and deep sleep duration (beta = -0.02, p = 0.0371) were significantly associated with BMI., Conclusions: The results demonstrate significant age-related decreases in the total and deep sleep duration among children with self-perceived short stature, along with a notable association between RDI and body height and an association between deep sleep duration and BMI. These findings suggest that sleep disturbances in pediatric endocrine patients are intricately linked with physiological growth parameters. The identified correlations underline the importance of monitoring sleep patterns in this demographic to better understand the impact of endocrine disorders on developmental health. Further research is needed to explore interventions that could alleviate these sleep disturbances, thereby potentially improving outcomes for the affected children.

Aim: Patients with rheumatoid arthritis (RA) are at a higher risk of osteoporotic fractures. Studies have shown that patients with Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE) experienced an increase in bone mineral density (BMD) after receiving hydroxychloroquine (HCQ) treatment, indicating a potential protective effect against osteoporosis. Therefore, this study is to examine the relationship between HCQ usage and the risk of osteoporosis in patients diagnosed with RA., Methods: The retrospective cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) covering the period from January 2010 to December 2018, which included 14 050 newly diagnosed RA patients, subsequently divided into two groups: HCQ users and non-users. Propensity score matching (PSM) based on sex, age, urbanization, insured unit type, insured area, and comorbidities was conducted to match the groups. The primary outcome assessed was the evaluation of the risk of osteoporosis by employing a multivariable Cox proportional hazard regression model to calculate the adjusted hazard ratio (aHR)., Results: After PSM, a total of 6408 RA patients were included in the analysis (3204 HCQ users and 3204 non-users). There was no significantly higher risk of osteoporosis in HCQ users compared with non-users, aHR = 0.99 (95% CI: 0.82-1.196). Additionally, different durations of HCQ usage demonstrated a neutral effect on the risk of osteoporosis [HCQ <90 days, aHR = 0.88 (95% CI: 0.585-1.324); HCQ 90-180 days, aHR = 0.941 (95% CI: 0.625-1.418); HCQ >180 days, aHR = 1.019 (95% CI: 0.832-1.249)]., Conclusions: The study indicates that there is no significant association between the use of HCQ and the risk of osteoporosis in patients with RA., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: To verify our hypothesis that psoriatic arthritis (PsA) is mainly genetically predetermined and distinct from psoriasis (PsO), we use the TriNetX database to investigate whether intrinsic factors outweigh externals in PsA emergence in PsO patients., Methods: We conducted three retrospective cohort studies utilizing information from the TriNetX network, whether (a) PsO patients with type 2 diabetes mellitus (DM) face an elevated risk of developing PsA compared to those without type 2 DM; (b) PsO patients who smoke face a higher risk of PsA; and (c) PsO patients with type 2 DM who smoke are more likely to develop PsA than those who do not smoke., Results: PsO patients with type 2 DM exhibited an elevated risk of developing PsA [hazard ratio (HR), 1.11; 95% CI 1.03-1.20], with the combined outcome demonstrating a heightened HR of 1.31 (95% CI 1.25-1.37). PsO patients with a smoking history exhibited an elevated risk of developing PsA (HR, 1.11; 95% CI 1.06-1.17), with the combined outcome demonstrating a heightened HR of 1.28 (95% CI 1.24-1.33). PsO patients with type 2 DM and a history of smoking were not found to be associated with an increased risk of developing PsA (HR, 1.05; 95% CI 0.92-1.20). However, the combined result revealed a higher risk of 1.15 (95% CI 1.06)., Discussion: These findings suggested that intrinsic factors outweigh external factors in PsA emergence in PsO patients. Further studies may focus on genetic disparities between PsO and PsA as potential risk indicators rather than solely on phenotypic distinctions., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Huo, Liao, Leong and Wei.)

Patients with type 2 diabetes (T2D) are at a higher risk of developing renal cell carcinoma (RCC) than the general population. In vitro and in vivo investigations of the effects of sodium glucose cotransporter-2 inhibitors (SGLT2I) have shown a significantly reduced risk of RCC. However, the impact of these drugs on the incidence of RCC in the human population is unclear. This study aimed to examine the association between SGLT2I use and RCC risk in patients with T2D. We undertook a nationwide retrospective cohort study using the Health and Welfare Data Science Center database (2016-2020). The primary outcome was the risk of incident RCC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression modeling was applied to analyze the association between SGLT2I use and RCC risk in patients with T2D. In a cohort of 241,772 patients with T2D who were using SGLT2Is and 483,544 participants who were not, 220 and 609 RCC cases, respectively, were recorded. The mean follow-up period of the study subjects was 2 years. There was a decreased risk of RCC for SGLT2I users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.68; 95% CI, 0.58-0.81). The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.67; 95% CI, 0.55-0.81). The subgroup analysis revealed consistent results for sex, age (<70 years), and comorbidity with chronic kidney disease. The present study indicates that SGLT2I therapy significantly decreases RCC risk in patients with T2D. This finding was also consistent among the sensitivity test and subgroup analysis for those with or without chronic kidney disease/hypertension., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Previous research has explored theories regarding the vertical transmission of human papillomavirus (HPV) infection and its association with adverse pregnancy and perinatal outcomes. However, the impact of maternal HPV infection on congenital anomalies (CAs) in offspring remains relatively understudied. We conducted a population-based cohort study linking the Taiwan Birth Registry, Taiwan Death Registry, and National Health Insurance Research Database, in which newborns born in Taiwan between 2009 and 2015 were included. We established a maternal HPV infection cohort comprising 37 807 newborns and matched them with a comparison group of 151 228 newborns at a 1:4 ratio based on index year, age, and sex. The study examined a composite outcome and subgroups of different types of congenital malformations. Differences in cumulative incidence of CAs were assessed using Kaplan-Meier curves and log-rank tests. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazard regressions. No significant association was found between HPV infection and the broad spectrum of CAs (aHR: 1.04, 95% confidence interval [CI]: 0.98-1.10; log-rank test p = 0.14). However, we observed a 19% increased risk of musculoskeletal CAs in the maternal HPV infection group (aHR: 1.19; 95% CI: 1.05-1.34) compared to those without maternal HPV exposure. Other factors, including the type of HPV (aHR: 0.65; 95% CI: 0.16-2.63), the timing of exposure (during or before pregnancy), and maternal age (aHR for <30 years: 1.02, 95% CI: 0.94-1.1; aHR for 30-39 years: 1.05, 95% CI: 0.99-1.11; aHR for ≥40 years: 0.88, 95% CI: 0.67-1.17), did not significantly affect the risk for any CA. In conclusion, gestation detection of HPV infection was associated with musculoskeletal CAs but not other major CAs. Prospective studies are warranted to elucidate the necessity of prenatal screening in populations at risk., (© 2024 Wiley Periodicals LLC.)

Background: The mortality rate associated with nontraumatic intracranial hemorrhage (NTICrH) remains consistently high under the current care modality. The effectiveness of tranexamic acid (TXA) as a treatment option is still a subject of debate. This study aims to assess the association between TXA administration and both short-term and long-term mortality rates in patients with NTICrH. Methods: We conducted a retrospective cohort study using data from the Taiwan National Health Insurance Research Database (NHIRD) spanning from January 2000 to December 2017. The study population consists of NTICrH patients admitted to the ICU, divided into two groups: patients who were treated with TXA and those who were not. Propensity score matching (PSM) was conducted to balance the baseline characteristics of the two groups. Cox proportional hazard analysis was conducted to estimate the hazard ratio (HR) for the all-cause mortality. Sensitivity analyses were performed using the inverse probability of treatment-weighted hazard ratio (IPTW-HR). To assess the timing of TXA use, we compared the risk of all-cause mortality within 180 days between patients receiving early TXA treatment and those receiving late TXA treatment. Results: There was no significant difference in 180-day all-cause mortality between the groups; the hazard ratio was 1.07 (95% CI: 0.96-1.20) in patients treated with TXA compared to those without TXA treatment. Within 7 days of admission, patients treated with TXA had a lower hazard ratio of 0.81 (95% CI: 0.74-0.90) for all-cause mortality. Conclusions: Lower mortality within the first 7 days was observed in patients with NTICrH who received TXA.

Calvisia is a colorful winged stick insect genus consisting of 6 subgenera and 44 species widely distributed in temperate and tropical Asia. C. medogensis syn. nov. was discovered in Mdog, Xizang (Tibet), China and is so far the only species recorded from China. We here propose that C. medogensis syn. nov. is a synonym of C. fuscoalata after checking type specimens of both species. New materials studied are deposited in Yunnan Agricultural University, China (YNAU).

Objective: Uveitis is a common manifestation of various autoimmune diseases and can lead to severe visual impairment. Hydroxychloroquine (HCQ) is an antimalarial drug that is also used to treat autoimmune diseases. The aim of this study was to investigate the association between HCQ use and the incidence of uveitis in patients with autoimmune diseases, as well as to identify potential risk factors for the development of uveitis in this study., Methods: We conducted a population-based cohort study using a nationwide database to investigate the incidence of uveitis in patients with autoimmune diseases who received HCQ treatment. We selected non-HCQ comparison cohort at a 1:1 ratio by propensity score matching on age, sex, index date, urbanization, income, comorbidities, and medications. The data were analyzed using Cox proportional hazards models, and propensity score matching (PSM) was used to reduce selection bias., Results: Our study included 15 822 patients with autoimmune diseases. After 1:1 PSM, there were 4555 individuals in both the HCQ group (n = 4555) and the non-HCQ group (n = 4555). The multiple Cox proportional hazard regression analysis was used for the estimation of adjusted hazard ratios on uveitis. After PSM, the adjusted hazard ratio for the HCQ group was 0.74 (95% CI = 0.58-0.95). These findings suggest that HCQ may play a protective role in reducing the risk of uveitis in patients with autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus groups. The Kaplan-Meier survival curves also showed a significantly lower incidence of uveitis in the HCQ group (log-rank = 0.0229) after PSM., Conclusion: HCQ use is associated with a lower incidence of uveitis in patients with autoimmune diseases. Further studies are needed to confirm this association and to investigate the underlying mechanisms., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The QuEChERS (quick, easy, cheap, effective, rugged and safe) conditions were optimized for efficient determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) for the categories of grains, tuber & starchy vegetables, soy beans and products, fish & seafood, and poultry & meat, including raw materials and their corresponding products. The PAHs were analyzed using ultrahigh-performance liquid chromatography with temperature-controlled fluorescence detection and gas chromatography with tandem mass spectrometry. The established conditions had good accuracy, repeatability, and precision. Environmental pollution and processing methods influence the level of PAHs in samples. The low molecular weight PAHs were present in all raw materials, and processing increased high and low molecular weight PAHs in the products. The excess cancer risk for consumption of PAHs in cooked samples was mostly acceptable; a small number of samples might be of slight concern in certain age groups.

Purple Pennisetum ( Pennisetum purpureum Schumach), a hybrid between Taihucao No. 2 and the local wild species of purple Pennisetum , has dark red stems and leaves due to its anthocyanin content. This study explores the potential of purple napiergrass extracts (PNE) in alleviating obesity and metabolic disorders induced by a high-fat diet in mice, where 50% of the caloric content is derived from fat. Mice were orally administered low-dose or high-dose PNE alongside a high-fat diet. Experimental findings indicate that PNE attenuated weight gain, reduced liver, and adipose tissue weight, and lowered blood cholesterol, triglyceride, low-density lipoprotein, and blood sugar levels. Stained sections showed that PNE inhibited lipid accumulation and fat hypertrophy in the liver. Immunoblotting analysis suggested that PNE improved the inflammatory response associated with obesity, dyslipidemia, and hyperglycemia induced by a high-fat diet. Furthermore, PNE potentially functions as a PPAR-γ agonist, increasing the adiponectin (ADIPOQ) concentration and suppressing inflammatory factors, while elevating the anti-inflammatory factor interleukin-10 (IL-10) in the liver. PNE-treated mice showed enhanced activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways and increased fatty acid oxidation and liver lipolysis. In conclusion, this study elucidated the mechanisms underlying the anti-inflammatory, PI3K/Akt, and AMPK pathways in a high-fat diet-induced obesity model. These findings highlight the potential of PNE in reducing weight, inhibiting inflammation, and improving blood sugar and lipid levels, showing the potential for addressing obesity-related metabolic disorders in humans.

Objective: Previous studies have indicated a bidirectional correlation between diabetes and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, no investigation has comprehensively explored the potential of coronavirus disease 2019 (COVID-19) vaccination to reduce the risk of new-onset diabetes in infected individuals., Research Design and Methods: In the first of 2 cohorts, we compared the risk of new-onset diabetes between individuals infected with SARS-CoV-2 and noninfected individuals (N = 1,562,606) using the TriNetX database to validate findings in prior literature. For the second cohort, we identified 83,829 vaccinated and 83,829 unvaccinated COVID-19 survivors from the same period. Diabetes, antihyperglycemic drug use, and a composite of both were defined as outcomes. We conducted Cox proportional hazard regression analysis for the estimation of hazard ratios (HRs) and 95% CIs. Kaplan-Meier analysis was conducted to calculate the incidence of new-onset diabetes. Subgroup analyses based on age (18-44, 45-64, ≥65 years), sex (female, male), race (White, Black or African American, Asian), and BMI categories (<19.9, 20-29, 30-39, ≥40), sensitivities analyses, and a dose-response analysis were conducted to validate the findings., Results: The initial cohort of patients infected with SARS-CoV-2 had a 65% increased risk (HR 1.65; 95% CI 1.62-1.68) of developing new-onset diabetes relative to noninfected individuals. In the second cohort, we observed that vaccinated patients had a 21% lower risk of developing new-onset diabetes in comparison with unvaccinated COVID-19 survivors (HR 0.79; 95% CI 0.73-0.86). Subgroup analyses by sex, age, race, and BMI yielded similar results. These findings were consistent in sensitivity analyses and cross-validation with an independent data set from TriNetX., Conclusions: In conclusion, this study validates a 65% higher risk of new-onset diabetes in SARS-CoV-2-infected individuals compared to noninfected counterparts. Furthermore, COVID-19 survivors who received COVID-19 vaccinations experienced a reduced risk of new-onset diabetes, with a dose-dependent effect. Notably, the protective impact of COVID-19 vaccination is more pronounced among the Black/African American population than other ethnic groups. These findings emphasize the imperative of widespread vaccination to mitigate diabetes risk and the need for tailored strategies for diverse demographic groups to ensure equitable protection., (© 2023 by the American Diabetes Association.)

Sulfide-containing wastewater, characterized by its foul odor, corrosiveness, and toxicity, can endanger human health. Fluidized-bed homogeneous crystallization (FBHC) avoids the excessive sludge production commonly associated with conventional chemical precipitation methods. In this study, FBHC is used to treat sulfur-containing synthetic wastewater. Furthermore, nickel-containing wastewater was utilized as a precipitant in the system, hence the advantage of simultaneous sulfur and nickel removal from the wastewater. The operating parameters, including pH, a precipitant dosage of [Ni 2+ ] 0 /[S 2- ] 0 , and cross-sectional surface loading (L S , kg/m 2 h) are optimized. The optimum operating conditions of pH 9.8 ± 0.3, [Ni 2+ ] 0 /[S 2- ] 0  = 0.8, and L S  = 1.5 kg/m 2 h results in total sulfur removal (TR) of 95.7% and crystallization ratio (CR) of 94.8%. The effect of organic compounds (acetic acid, oxalic acid, EDTA, and citric acid) and inorganic ions (NO 3 - , CO 3 2- , PO 4 3- , F - , and Cl - ) on the nickel sulfide granulation process was discussed., Competing Interests: Declaration of competing interest 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., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.

Introduction: Coronavirus disease 2019 (COVID-19) has caused more than 690 million deaths worldwide. Different results concerning the death rates of the Delta and Omicron variants have been recorded. We aimed to assess the secular trend of case fatality rate (CFR), identify risk factors associated with mortality following COVID-19 diagnosis, and investigate the risks of mortality and hospitalization during Delta and Omicron waves in the United States., Methods: This study assessed 2,857,925 individuals diagnosed with COVID-19 in the United States from January 2020, to June 2022. The inclusion criterion was the presence of COVID-19 diagnostic codes in electronic medical record or a positive laboratory test of the SARS-CoV-2. Statistical analysis was bifurcated into two components, longitudinal analysis and comparative analysis. To assess the discrepancies in hospitalization and mortality rates for COVID-19, we identified the prevailing periods for the Delta and Omicron variants., Results: Longitudinal analysis demonstrated four sharp surges in the number of deaths and CFR. The CFR was persistently higher in males and older age. The CFR of Black and White remained higher than Asians since January 2022. In comparative analysis, the adjusted hazard ratios for all-cause mortality and hospitalization were higher in Delta wave compared to the Omicron wave. Risk of all-cause mortality was found to be greater 14-30 days after a COVID-19 diagnosis, while the likelihood of hospitalization was higher in the first 14 days following a COVID-19 diagnosis in Delta wave compared with Omicron wave. Kaplan-Meier analysis revealed the cumulative probability of mortality was approximately 2-fold on day 30 in Delta than in Omicron cases (log-rank p  < 0.001). The mortality risk ratio between the Delta and Omicron variants was 1.671 (95% Cl 1.615-1.729, log-rank p  < 0.001). Delta also had a significantly increased mortality risk over Omicron in all age groups. The CFR of people aged above 80 years was extremely high as 17.33%., Conclusion: Male sex and age seemed to be strong and independent risk factors of mortality in COVID-19. The Delta variant appears to cause more hospitalization and death than the Omicron variant., 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 Li, Liao, Wei, Hsu and Yeh.)

The relationship between Helicobacter pylori infection and rheumatoid arthritis has been investigated, but the results remain controversial. This study aims to determine the association between the two diseases via a 17-year retrospective cohort study. Using the National Health Insurance Research Database, a nationwide population based in Taiwan, we identified 97,533 individuals with H. pylori infection and matched controls between 2000 and 2017 using propensity score matching at a 1:1 ratio. The adjusted hazard ratio of rheumatoid arthritis was determined by multiple Cox regression. The incidence rate of rheumatoid arthritis was 1.28 per 10,000 person-months in the H. pylori cohort, with a higher risk compared to the control group. In the < 30 years old subgroup, the risk was highest, especially in women < 30 years old with H. pylori infection. Patients with < 1 year follow-up showed 1.58 times higher susceptibility to rheumatoid arthritis. Individuals with follow-ups of 1-5 years and over 5 years demonstrated 1.43 and 1.44 times higher risks of rheumatoid arthritis, respectively. Our study showed H. pylori infection was associated with the development of rheumatoid arthritis. Clinicians should note higher risk, especially < 30 years old. More research needed to understand underlying mechanism., (© 2023. Springer Nature Limited.)

Objectives: In previous reports, proton pump inhibitor (PPI) use increased the risk of gout. However, there is no epidemiological study investigating this association. We aimed to examine the potential impact of PPI treatment on the risk of developing gout., Methods: A population-based case-control study was performed using a Longitudinal Health Insurance Database 2000 from Taiwan (population 23 million). We identified gout cases and non-gout controls through propensity score matching at 1:1, which was matched by sex and age. We used a conditional logistic regression model to estimate an odds ratio and 95% confidence intervals (CI) for gout population versus controls., Results: Esomeprazole increased the risk of gout after adjusting confounding variables (adjusted odds ratio [aOR] 1.3; 95% CI 1.0-1.6). The risk of gout was highest within 30 days of PPI treatment (aOR 1.7; 95% CI 1.4-1.9) and attenuated thereafter. The risk of gout was increased among female users of PPI compared with male users (aOR 2.2; 95% CI 1.7-2.8). The aOR of gout in people with PPI use was higher in middle-aged individuals (41-60 years: aOR 2.1; 95% CI 1.7-2.7) than in the older group (≥60 years: aOR 1.8; 95% CI 1.5-2.2)., Conclusions: Our findings provide population-level evidence for the hypothesis that PPI treatment is positively associated with the risk of developing gout. Further research on the mechanism underlying this association is warranted., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The optimal conditions for simultaneous determination of the U.S. Environmental Protection Agency (US EPA) and European Union (EU) priority polycyclic aromatic hydrocarbons (PAHs) in coffee beans and coffee brews were developed. The QuEChERS (quick, easy, cheap, effective, rugged and safe) technology combined with high performance liquid chromatography - temperature-controlled fluorescence detection and gas chromatography - tandem mass spectrometry were used in the investigation. PAHs could be determined in commercially available green coffee beans (possibly caused by environmental contamination), and their PAHs content increased with the degree of roasting. Coffee beans brewed with the coffee machine released more PAHs into their brews than those brewed with the drip bag. The PAHs consumption risk of the brewed coffee samples was not high due to their low PAH level. Nevertheless, the methods of roasting and brewing and the amount of drinking could still be considered to reduce the intake of PAHs., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effect of SGLT2is, pioglitazone, and their combination on the risk of major adverse cardiovascular events (MACE) and heart failure in type 2 diabetes mellitus (T2DM) patients without a history of cardiovascular disease., Research Design and Methods: Using Taiwan National Health Insurance Research Database, we identified four groups based on medication use, including 1) both SGLT2is and pioglitazone, 2) SGLT2i, 3) pioglitazone and 4) non-study drugs (reference group). The four groups were matched by propensity score. The primary outcome was 3-point MACE, which included myocardial infarction, stroke, cardiovascular death, and the secondary outcome was incidence of heart failure., Results: After propensity-matching, each group included 15,601 patients. Compared with the reference group, the pioglitazone/SGLT2i combination group had a significantly lower risk for MACE (aHR 0.76, 95 % CI 0.66-0.88) and heart failure (aHR 0.67, 95 % CI 0.55-0.82). Pioglitazone was associated with a lower risk of MACE (aHR 0.82, 95 % CI 0.71-0.94) and there was no difference in risk of heart failure compared with the reference group. The incidence of heart failure was significantly decreased in the SGLT2i group (aHR 0.7, 95 % CI 0.58-0.86)., Conclusion: Combination therapy with pioglitazone and SGLT2is is an effective treatment in the primary prevention of MACE and heart failure in patients with type 2 diabetes., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Atopic dermatitis (AD) contributes to substantial social and financial costs in public health care systems. Antibiotic exposure during pregnancy has been proposed as a risk factor, but findings remain inconsistent. The aim of this study was to investigate the association between prenatal antibiotic use and childhood AD., Methods: We performed a population-based cohort study using data collected from the Taiwan Maternal and Child Health Database from 2009 to 2016. Associations were determined using Cox proportional hazards model and were adjusted for several potential covariates, including maternal atopic disorders and gestational infections. Children with and without maternal predispositions of atopic diseases and postnatal antibiotic/acetaminophen exposures within 1 year were stratified to identify the subgroups at risk., Results: A total of 1,288,343 mother-child pairs were identified and 39.5% received antibiotics prenatally. Maternal antibiotic use during pregnancy was slightly positively associated with childhood AD (aHR 1.04, 95% CI 1.03-1.05), especially in the first and second trimesters. An apparent dose-response pattern was observed with an 8% increased risk when the exposure was ≥5 courses prenatally (aHR 1.08, 95% CI 1.06-1.11). Subgroup analysis showed the positive association remained significant regardless of postnatal infant antibiotic use, but the risk attenuated to null in infants who were not exposed to acetaminophen (aHR 1.01, 95% CI 0.96-1.05). The associations were higher in children whose mothers were without AD compared to those whose mothers were with AD. In addition, postnatal antibiotic or acetaminophen exposure of infants was associated with an increased risk of developing AD after 1 year of age., Conclusion: Maternal antibiotic use during pregnancy was associated with an increased risk of childhood AD in a dose-related manner. Further research may be warranted to investigate this variable using a prospectively designed study, and also to examine whether or not this association is specifically related to pregnancy., (© 2023 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Aim: The incidence of type 1 diabetes continues to increase. However, the strategies to prevent or reduce its occurrence are inadequate. Therefore, we attempted to investigate if mothers with autoimmune disease were more likely to have children with type 1 diabetes., Methods: We identified 1,288,347 newborns from the Taiwan Maternal and Child Health Database between January 1, 2009, and December 31, 2016, and followed them up to December 31, 2019. We used a multivariable Cox regression model to compare the childhood-onset type 1 diabetes risk between children whose mother had or did not have an autoimmune disease., Results: The multivariable model demonstrated significantly higher risks of type 1 diabetes in the children with maternal autoimmune disease (aHR 1.55, 95% CI 1.16-2.08), type 1 diabetes (aHR 11.33, 95% CI 4.62-27.77), Hashimoto's thyroiditis (aHR 3.73, 95% CI 1.70-8.15), and inflammatory bowel diseases (aHR 2.00, 95% CI 1.07-3.76)., Conclusion: This nationwide mother and child cohort study showed a higher risk of type 1 diabetes in the children whose mothers had autoimmune disease, including Hashimoto's thyroiditis, and inflammatory bowel diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear., Aim: The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function., Methods: Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10-/- mice were used to study the role of PPIs in intestinal permeability., Results: PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10-/- enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK-/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients., Conclusions: Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with chronic kidney disease (CKD) are at a higher risk for developing dementia than the general population. Clinical studies have investigated the effects of statin use on new-onset dementia (NOD) in patients with CKD; however, the findings are inconsistent. This study examines the association between the use of statins and NOD in patients with CKD. We conducted a nationwide retrospective cohort study using the Taiwan Health Insurance Review and Assessment Service database (2003-2016). The primary outcome assessed the risk of incident dementia by estimating the hazard ratios and 95% confidence intervals. Therefore, multiple Cox regression models were conducted to analyse the association between statin use and NOD in patients with CKD. There were 24,090 participants with statin use and 28,049 participants without statin use in patients with new-diagnosed CKD; the NOD event was 1390 and 1608, respectively. There was a trend of reduction association between statin users and NOD events after adjusted sex, age, comorbidities, and concurrent medication (adjusted HR 0.93, 95% CI 0.87 to 1.00) in the 14 years of the follow-up. Sensitivity test for the propensity score 1:1 matched analyses showed similar results (adjusted HR 0.91, 95% CI 0.81 to 1.02). The subgroup analysis also identified the use of statins as having a trend against developing NOD in patients with hypertension. In conclusion, statin therapy may effectively reduce the risk of NOD in patients with CKD. More studies are needed to credibly evaluate the effects of statin therapy on the prevention of NOD in patients with CKD.

Objective: This study investigated whether patients with history of dental caries are associated with an increased risk of newly-onset systemic lupus erythematosus (SLE)., Methods: A total of 501,461 carious patients and 258,918 controls without carious teeth were enrolled between 1997 and 2013 from the National Health Insurance Research Database. Subgroup analyses were conducted based on restorative materials including amalgam, composite resins, or both. The cumulative incidence and hazard ratios (HRs) of SLE development were derived after adjusting for age, sex, socioeconomic status, income, insured classification, comorbidities, and frequency of dental visit in a multivariable model., Results: The risk of SLE was significantly higher in carious patients (HR = 1.98, 95% confidence interval [CI] = 1.65-2.38) compared to controls. Dose-dependent relationship between caries and risk of SLE was identified. The risk of SLE was higher among those who had dental visits ≧11 (HR = 2.53, 95% CI = 1.86-3.43), followed by those with 3-10 dental visits (HR = 1.86, 95% CI = 1.36-2.54), when compared to those with 1-2 visits, and was higher among those who had carious teeth extractions ≧5 (HR = 1.88, 95% CI = 1.19-2.97), followed by those with 1-4 carious teeth extractions (HR = 1.36, 95% CI = 1.17-1.59) than those without extraction. The risk of SLE for dental caries management among different restorative materials, including amalgam, composite resins, or both, was not statistically different., Conclusions: Patients with dental caries were associated with higher SLE risks. The relationship between dental caries and risk of SLE was dose-dependent, regardless of the material used for the restoration.

Lacticaseibacillus paracasei strain PS23 (PS23) exhibits some probiotic properties. In this study, a genomic analysis of PS23 revealed no genes related to virulence or antibiotic resistance. Moreover, ornithine decarboxylase activity was not detected in vitro. In addition, PS23 was sensitive to the tested antibiotics. Genotoxicity tests for PS23 including the Ames test and chromosomal aberrations in vitro using Chinese hamster ovary cells and micronuclei in immature erythrocytes of ICR mice were all negative. Moreover, following a 28-day study involving repeated oral dose toxicity tests (40, 400, and 4000 mg/kg equal 1.28 × 10 10 , 1.28 × 10 11 , and 1.28 × 10 12 CFU/kg body weight, respectively) using an ICR mouse model, no adverse effects were observed from any doses. In addition, supplementation with live or heat-killed PS23 ameliorates DSS-induced colonic inflammation in mice. Our findings suggest that PS23 is safe and has anti-inflammatory effects and may therefore have therapeutic implications.

Objectives: Recent research has demonstrated the commonality of several biological markers between Kawasaki disease (KD) and juvenile idiopathic arthritis (JIA), including interleukin-1β and -6. Therefore, in this cohort study, we assessed whether KD increases the risk of JIA., Methods: This study enrolled 7009 patients with and 56 072 individuals without KD in the period 2010-2018 from Taiwan's National Health Insurance Research Database. On the basis of sex, age, and comorbidities, we executed propensity score matching at the ratio 1:8. The adjusted hazard ratio (aHR) for JIA was determined through multiple Cox regression. Stratified analysis and sensitivity tests were also employed., Results: When adjusting for age, sex, and comorbidities, the JIA risk was noted to be 2.02-fold greater in children with KD than it was in those without (aHR: 2.02, 95% confidence interval: 1.12-3.67, p = 0.0205). The sensitivity test and subgroup analysis obtained consistent findings in the different sex and comorbidity subgroups., Conclusion: Children's risk of JIA is higher if they have KD. Pediatricians should consider the possibility of JIA in this population. More investigations are necessary to identify the pathological mechanisms that link JIA and KD., 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 Liao, Fu, Chuang, Liao, Wei and Fu.)

Aims: This study evaluates the effectiveness of an interactive E-book app training program in improving nurses' knowledge, attitudes, and confidence to prevent and care for pressure injury., Design: Randomized experimental study., Methods: Participants were recruited from a teaching hospital in Taiwan. The study was carried out between 20 March 2014 to 1 April 2016. In total, 164 participants were randomly assigned to a pressure injury E-book app training program (n = 86) or a conventional education program (n = 78) with a one-month follow-up. Outcome variables were levels of pressure injury knowledge, attitudes, and confidence of pressure injury care., Results: Participants answered 51.96% of the pressure injury knowledge questions correctly before the intervention and 75.5% after the intervention. The pressure injury attitude score was slightly positive, with moderate confidence in pressure injury care. The knowledge, attitudes, and confidence of pressure injury care of the two groups in the pretest and posttest groups increased significantly. Analysis of covariance indicated that nurses in the pressure injury E-book app group had significantly greater improvement in knowledge, attitudes, and pressure injury care confidence as compared with the control group., Conclusion: The pressure injury E-book app interactive training program was effective in improving nurses' knowledge and attitudes toward pressure injury care and in enhancing their confidence in pressure injury care; therefore, this program has potential for nurses' in-service education in both Taiwan and worldwide., Impact: E-book apps allow individuals to control the time and place of learning. Direct observation of procedural skills can provide feedback to trainees on techniques to ensure learning effectiveness and pressure injury care quality.

Background: Epidemiological evidence suggests the association of diabetes with an increased risk of stroke. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on new-onset stroke (NOS), but the results are inconsistent., Objectives: To determine the association between the use of SGLT2 inhibitors and NOS in patients with type 2 diabetes mellitus (DM)., Methods: We conducted a retrospective longitudinal cohort study based on the Taiwan Health Insurance Review and Assessment Service database (2016-2019). The primary outcome of the assessment was the risk of incident stroke by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression was applied to estimate the adjusted HR of NOS. Subgroup analysis was also conducted., Results: Among the 232,101 eligible patients with type 2 DM aged ≥ 20 years, SGLT2-inhibitor users were compared with non-SGLT2-inhibitor users based on age, sex, and the duration of type 2 DM matching at a ratio of 1:2. The event rate per 10 000 person-months was 9.20 (95% CI 8.95 to 9.45) for SGLT2-inhibitor users and 10.5(10.3-10.6) for non-SGLT2-inhibitor users. There was a decreased risk of NOS for SGLT2-inhibitor users (adjusted HR 0.85, 95% CI 0.82-0.88) compared with non-SGLT2-inhibitor users. Results for the propensity score-matched analyses showed similar results (adjusted HR 0.87, 95% CI 0.84-0.91 for both SGLT2-inhibitor users and non-SGLT2-inhibitor users)., Conclusion: The risk of developing NOS was lower in patients with SGLT2-inhibitor users than in non-SGLT2-inhibitor users. The decreased risk of NOS in patients with type 2 DM was greater among patients with concurrent use of statins, biguanides, thiazolidinediones, and glucagon-like peptide-1 receptor agonists. We, therefore, suggest that the long-term use of SGLT2 inhibitors may help reduce the incidence of NOS in patients with type 2 DM., 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 Lin, Chen, Huang, Liao, Chen, Pan and Jong.)

The optimal conditions for QuEChERS (quick, easy, cheap, effective, rugged and safe) with superior performance were established to rapidly extract 21 heterocyclic amines (HAs) from 9 categories of food matrices including meat and poultry, eggs, soy beans and products, composite foods, fish and seafood, grains, beer, dairy foods, and coffee. The QuEChERS conditions and the developed ultra-high performance liquid chromatography-tandem mass spectrometry analysis conditions were then applied to the determination of HAs in popular food products sold in the Taiwan market. The conditions comply with the food chemical analysis specifications of Taiwan Food and Drug Administration. Coffee products and braised products that require a longer cooking time contained relatively high content of HAs (mainly Harman and Norharman), and their consumption is relatively high resulting in relatively high intake of HAs from these products. The dietary intake of HAs in plant-based protein food products should also be of concern., (Copyright © 2022. Published by Elsevier Ltd.)

Thiazide diuretics have long been widely used as antihypertensive agents. In addition to reducing blood pressure, thiazides also control calcium homeostasis and increase bone density. We hypothesized that the use of thiazides in patients with hypertension would reduce overall fracture risk. We used the Taiwan National Health Insurance Research Database to find patients with a hypertension diagnosis who accepted antihypertensive treatment from 2000 to 2017. The patients were further classified into thiazide users and nonthiazide users. Multivariable Cox regression analysis and Kaplan-Meier survival analysis were performed to estimate the adjusted hazard ratios (aHRs) and cumulative probability of fractures. After 1:1 propensity score matching by sex, age, urbanization level of place of residence, income, comorbidities, and medications, there were 18,483 paired thiazide users and non-users, respectively. The incidence densities of fractures (per 1000 person-months) were 1.82 (95% CI: 1.76-1.89) and 1.99 (95% CI: 1.92-2.06) in the thiazide and nonthiazide groups, respectively. The results indicated a lower hazard ratio for fractures in thiazide users (aHR = 0.93, 95% CI: 0.88-0.98). Kaplan-Meier survival analysis revealed a significantly lower cumulative incidence of fractures in the thiazide group (log-rank test; p = 0.0012). In conclusion, our results reveal that thiazide use can reduce fracture risk. When antihypertensive agents are being considered, thiazide may be a better choice if the patient is at heightened risk of fracture.

A method using UPLC-MS/MS and a core-shell C18 column was developed to simultaneously determine 21 heterocyclic amines (HAs) in 15 min. Appropriate QuEChERS conditions were also established to conveniently extract HAs from soy products cooked with various methods. These conditions presented good analytical performance; limit of detection, limit of quantification, recovery (%), repeatability (coefficient of variation (CV) %) and intermediate precision (CV%) were 0.008 ∼ 0.150 ng/g, 0.025 ∼ 0.500 ng/g, 62 ∼ 91%, ≤ 28% and ≤ 23% for tofu sample, and 0.003 ∼ 0.100 ng/g, 0.010 ∼ 0.350 ng/g, 64 ∼ 93%, ≤ 19% and ≤ 20% for soy milk sample, respectively. HAs contents in the samples increased with cooking temperature and time. The tofu samples cooked by frying had much higher HAs content than those cooked by boiling and roasting. Norharman and Harman mainly contributed HAs content in all samples. For the general population in Taiwan, the highest estimated level of HAs consumed from the samples is 373.67 ng/day., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tranexamic acid (TXA) is an antifibrinolytic pharmacological agent, but its use in gastrointestinal bleeding remains contentious. Moreover, studies on the timing of TXA administration are limited. We examined whether early TXA administration reduced the risk of mortality in patients with gastrointestinal bleeding in a Taiwanese population. We used the National Health Insurance Research Database to identify patients diagnosed with gastrointestinal bleeding with early and late TXA treatment. We defined early treatment as initial TXA treatment in an emergency department and late treatment as initial TXA treatment after hospitalization. Mortality within 52 weeks was the primary outcome. A multivariable analysis using a multiple Cox regression model was applied for data analysis. Propensity score matching (PSM) was performed to reduce the potential for bias caused by measured confounding variables. Of the 52,949 selected patients with gastrointestinal bleeding, 5127 were assigned to either an early or late TXA treatment group after PSM. The incidence of mortality was significantly decreased during the first and fourth weeks (adjusted HR (aHR): 0.65, 95% CI: 0.56−0.75). A Kaplan−Meier curve revealed a significant decrease in cumulative incidence of mortality in the early TXA treatment group (log-rank test: p < 0.0001). Multiple Cox regression analysis revealed significantly lower mortality in the early TXA treatment group compared with the late treatment group (aHR: 0.64, 95% CI: 0.57−0.73). Thromboembolic events were not significantly associated with early or late TXA treatment (aHR: 1.03, 95% CI: 0.94−1.12). A Kaplan−Meier curve also revealed no significant difference in either venous or arterial events (log-rank test: p = 0.3654 and 0.0975, respectively). In conclusion, early TXA treatment was associated with a reduced risk of mortality in patients with gastrointestinal bleeding compared with late treatment, without an increase in thromboembolic events. The risk of rebleeding and need for urgent endoscopic intervention require further randomized clinical trials.

Abstract: Although uveitis can be an intraocular presentation of systemic lymphoma, it may be associated with direct lymphomatous infiltration and immune-mediated alterations. There have been no published studies describing the incidence of uveitis after systemic lymphoma. We conducted a nationwide cohort study to investigate the incidence of uveitis after systemic lymphoma diagnosis in Taiwan. Data were collected from the Taiwan National Health Insurance system and included patients newly diagnosed with systemic lymphoma between 2000 and 2017. We observed the risk of uveitis among study population since the index date until December 2017. The 1:8 of systemic lymphoma patient and paired comparison was identified by time distribution matching and individual paired with sex and age. Subsequent propensity score matching (PSM) was used to select the 1:1 of systemic lymphoma patient and paired comparison by greedy algorism with caliper of 0.05. The multiple Cox proportional hazard regression model was used to compare the developmental risk of uveitis (time-to-uveitis) between the systemic lymphoma and non-systemic lymphoma, while controlling for selected covariates. After time distribution matching, we selected 6846 patients with systemic lymphoma, and 54,768 comparisons. Among patients with systemic lymphoma groups, there were more men than women (52.94% vs 47.06%) and the mean age was 53.32 ± 21.22 years old. Systemic lymphoma incidence rates (per 10,000 person-months) of uveitis were 1.94 (95% confidence interval [CI], 1.60-2.35) in the systemic lymphoma cohort and 1.52 (95% CI, 1.42-1.63) in the non-systemic lymphoma cohort. Compared with the non-systemic lymphoma cohort, adjusted hazard ratio (aHR) of developing uveitis were 1.24 (95% CI, 1.00-1.52) in people with systemic lymphoma. But not significant in after PSM, aHR of developing uveitis were 1.17 (95% CI, 0.90-1.53). This 18-year nationwide population-based cohort study in Taiwan, showed that the risk of uveitis in patients' systemic lymphoma was not significantly higher than non-systemic lymphoma after PSM. In elderly and rheumatic patients with intraocular inflammation, it is important to first exclude uveitis masquerade syndrome, which could be a harbinger of intraocular involvement from systemic lymphoma. Further large-scale prospective clinical studies to investigate whether systemic lymphoma influences the incidence of uveitis are warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27 Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.

Hard-to-heal wounds (HHW) represent wound beds that are at high risk of stagnating during the inflammatory or proliferative phase because of various internal or external factors. A wound area reduction of less than 40% in 4 weeks is an indicator of HHW. With the acceleration of population aging, an increasing number of older adults are developing various chronic diseases with comorbidities. Although many older adults are affected by HHW, patients are regularly expected to recuperate at home or in long-term care institutions rather than in hospitals because of shortened hospitalization periods and changes in the medical insurance system. The provision of healthcare to patients with HHW in home settings is currently complicated by the lack of systematic nursing education on wound care, the lack of evidence-based guidelines for home wound care, and the inadequate wound care skills of nurses. HHW have major physical, psychological, and economic impacts on patients and their families and increase stress and frustration in nurses. Inappropriate wound care interventions increase medical expenditures and have multifaceted effects that are largely ignored by the medical care system. This phenomenon, which encompasses HHW, has been called a silent epidemic. In this paper, HHW are defined, the current status of home wound healing worldwide is analyzed, the relevant challenges and strategy implementations are discussed, and recommendations for the home care of HHW are provided.

Objective. Developments in electroencephalography (EEG) technology have allowed the use of the brain-computer interface (BCI) outside dedicated labratories. In order to achieve long-term monitoring and detection of EEG signals for BCI application, dry electrodes with good signal quality and high bio compatibility are essential. In 2016, we proposed a flexible dry electrode made of silicone gel and Ag flakes, which showed good signal quality and mechanical robustness. However, the Ag components used in our previous design made the electrode too expensive for commercial adaptation. Approach. In this study, we developed an affordable dry electrode made of silicone gel, metal flakes and graphene/GO based on our previous design. Two types of electrodes with different graphene/GO proportions were produced to explore how the amount of graphene/GO affects the electrode. Main results. During our tests, the electrodes showed low impedance and had good signal correlation to conventional wet electrodes in both the time and frequency domains. The graphene/GO electrode also showed good signal quality in eyes-open EEG recording. We also found that the electrode with more graphene/GO had an uneven surface and worse signal quality. This suggests that adding too much graphene/GO may reduce the electrods' performance. Furthermore, we tested the proposed dry electrodes' capability in detecting steady state visually evoked potential. We found that the dry electrodes can reliably detect evoked potential changes even in the hairy occipital area. Significance. Our results showed that the proposed electrode has good signal quality and is ready for BCI applications., (© 2021 IOP Publishing Ltd.)

Patients with pelvic fractures could encounter various complications during or after treatments. This cohort study investigated the risk of mortality and readmissions in patients with pelvic fractures, with or without urinary tract infections (UTIs), within 30 days following the pelvic fractures. This retrospective cohort study examined claim records from the Longitudinal Health Insurance Database 2000 (LHID2000). We selected patients hospitalized with pelvic fractures between 1997 and 2013 for study. Patients who had index data before 2000 or after 2010 ( n = 963), who died before the index date ( n = 64), who were aged <18 years ( n = 94), or who had a pelvic injury ( n = 31) were excluded. In total, the study cohort comprised 1623 adult patients; 115 had UTIs, and 1508 patients without UTIs were used as a comparison cohort. Multivariate analysis with a multiple Cox regression model and Kaplan-Meier survival analysis were performed to analyze the data. Our results showed that the 1-year mortality rate (adjusted hazard ratio [HR]: 2.32; 95% CI: 1.25-4.29) and readmission rate (adjusted HR: 1.72; 95% CI: 1.26-3.34) of the UTI group were significantly higher than those of the non-UTI group. Moreover, the Kaplan-Meier curve for the 1-year follow-up indicated that the UTI group had a higher cumulative risk of both mortality and hospital readmission compared with the non-UTI group. In conclusion, among patients with pelvic fracture, patients with UTI were associated with increased risks of mortality and readmission. Physicians must pay more attention to such patients to prevent UTIs among patients with pelvic fractures during hospitalization and conduct a follow-up after discharge within at least 1 year.

This study evaluated the association between long-term low-dose aspirin use and decreased risk of pneumonia in patients with cardio-cerebra-vascular ischemic diseases (CCVDs). This retrospective cohort study used records from Taiwan's National Health Insurance Research Database of claims made between 1997 and 2013. After propensity score matching (PSM), patients who took a low dose of aspirin for more than 90 days within 1 year of diagnosis with CCVDs were identified as the exposure group ( n = 15,784). A matched total of 15,784 individuals without aspirin use were selected for the non-aspirin group. The main outcome was the development of pneumonia after the index date. Multivariable Cox regression analysis and Kaplan-Meier survival analysis were performed to estimate the adjusted hazard ratio (aHR) and cumulative probability of pneumonia. The result after PSM indicated a lower hazard ratio for pneumonia in aspirin users (aHR = 0.890, 95% confidence interval = 0.837-0.945). Therefore, patients with CCVDs who took aspirin had a lower risk of developing pneumonia than those who did not. In conclusion, this population-based cohort study demonstrated that long-term low-dose aspirin use is associated with a slightly decreased risk of pneumonia in patients with CCVDs., 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, Chen, Yeh, Yeh, Huang, Liao, Yeh, Yang, Chou and Yeh.)

Background: Depending on their distinct properties, titanium dioxide nanoparticles (TiO 2 -NPs) are manufactured extensively and widely present in our daily necessities, with growing environmental release and public concerns. In sunscreen formulations, supplementation of TiO 2 -NPs may reach up to 25% (w/w). Ocular contact with TiO 2 -NPs may occur accidentally in certain cases, allowing undesirable risks to human vision. This study aimed to understand the barrier integrity of retinal endothelial cells in response to TiO 2 -NP exposure. bEnd.3 cells and human retinal endothelial cells (HRECs) were exposed to TiO 2 -NP, followed by examination of their tight junction components and functions., Results: TiO2-NP treatment apparently induced a broken structure of the junctional plaques, conferring decreased transendothelial electrical resistance, a permeable paracellular cleft, and improved cell migration in vitro. This might involve rapid activation of metalloproteinase, a disintegrin and metalloproteinase 17 (ADAM17), and ADAM17-mediated claudin-5 degradation. For the in vivo study, C57BL/6 mice were administered a single dose of TiO2-NP intravitreally and then subjected to a complete ophthalmology examination. Fluorescein leakage and reduced blood flow at the optical disc indicated a damaged inner blood-retinal barrier induced by TiO 2 -NPs. Inappreciable change in the thickness of retinal sublayers and alleviated electroretinography amplitude were observed in the TiO 2 -NP-treated eyes., Conclusions: Overall, our data demonstrate that TiO2-NP can damage endothelial cell function, thereby affecting retinal electrophysiology.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder worldwide. In addition to the chief feature of long-standing hyperglycemia, dyslipidemia, hyperinsulinemia, and a number of complications develop in parallel. It is believed that an adequate control of blood glucose levels can cause these complications to go into remission. This study was performed to evaluate the antidiabetic activity of Eurycoma longifolia Jack (EL) in vivo. The blood-glucose-lowering activity of EL was studied in db/db mice administered crude powdered EL root (25, 50, and 100 mg/kg) orally for eight weeks. At the end of the study, HbA 1c , insulin, plasma lipid levels, and histopathology were performed. Powdered EL root showed significant antihyperglycemic activity along with the control of body weight. After eight weeks of treatment, both the blood cholesterol level and the glycogen deposit in hepatocytes were remarkably lower, whereas the secreting insulin level was elevated. An improvement in islet performance was manifested as an increase in beta-cell number and pancreatic and duodenal homeobox 1 (PDX1) expression. Neogenesis or formation of new islets from pancreatic duct epithelial cells seen in the EL-treated group was encouraging. This study confirms the antihyperglycemic activity of EL through PDX1-associated beta-cell expansion resulting in an enhancement of islet performance.

High-risk neuroblastoma is associated with low long-term survival rates due to recurrence or metastasis. Retinoids, including 13-cis-retinoic acid (13cRA), are commonly used for the treatment of high-risk neuroblastoma after myeloablative therapy; however, there are significant side effects and resistance rates. In this study, we demonstrated that 13cRA has a better antiproliferative effect in MYCN-amplified neuroblastoma cells than in MYCN-nonamplified neuroblastoma cells. In MYCN-amplified SK-N-DZ cells, 13cRA induced significant upregulation of toll-like receptor 3 (TLR3) and mitochondrial antiviral-signaling protein (MAVS) expression in a time-dependent manner. Furthermore, poly (I:C), a synthetic agonist of TLR3, effectively synergized with 13cRA to enhance antiproliferative effects through upregulation of the innate immune signaling and the mitochondrial stress response, leading to augmentation of the apoptotic response in 13cRA-responsive cancer cells. In addition, the 13cRA/poly (I:C) combination induced neural differentiation through activation of retinoic acid receptors beta (RAR-β), restoring expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein, and inhibiting vessel formation, leading to retarded tumor growth in a mouse xenograft model. These results suggest that the combination of poly (I:C) and RA may provide synergistic therapeutic benefits for treatment of patients with high-risk neuroblastoma.