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Background Klebsiella pneumoniae is a gram-negative opportunistic pathogen that causes diseases mostly in immunocompromised individuals. Recently, hypervirulent K. pneumoniae strains also cause severe disease in healthy individuals. Capsular polysaccharide (CPS) is the major virulence determinant in hypervirulent K. pneumoniae and protects the cell against the bactericidal activity of the immune system. Gallic acid (GA), a natural phenolic compound, is known to exhibit wide spectrum antibacterial activity; however, its effect on hypervirulent K. pneumoniae remains largely unresolved. We aimed to identify the effects of GA on CPS biosynthesis in hypervirulent K. pneumoniae. Methods Antibacterial activity of GA was evaluated by counting colonies. CPS amount was determined by glucuronic acid content. The transcriptions of cps gene cluster were measured by quantitative real time PCR (qRT-PCR) and the β-galactosidase activity. The effect of GA on the resistance of K. pneumoniae to streptonigrin (SNG), an iron-activated antibiotic, was evaluated. The effect of GA on the resistance of K. pneumoniae to serum killing and phagocytosis by macrophages was observed. Results GA inhibited the growth and CPS biosynthesis in K. pneumoniae. GA may affect the iron availability in K. pneumoniae, thus possibly repressing the cps transcription. In addition, GA reduced the resistance of K. pneumoniae to serum killing and enhanced its susceptibility to phagocytosis. Conclusion GA possesses bactericidal activity and inhibits the CPS biosynthesis in hypervirulent K. pneumoniae, thereby facilitating pathogen clearance by the host immune system. Therefore, GA may represent a promising strategy for the prevention or treatment of patients with hypervirulent K. pneumoniae infections.

In 1996, the National Health Insurance Administration of Taiwan applied a restrictive reimbursement criteria for erythropoiesis-stimulating agents (ESAs) use in patients with chronic kidney disease. The maximal ESAs dosage allowed by insurance is capped at 20,000 U of epoetin per month. Nephrologists avoided the use of high ESA dosages to achieve a hemoglobin level of 10–11 g/dL using iron supplementation. We assessed the association of anemia and iron parameters with mortality among peritoneal dialysis (AIM-PD) patients. A retrospective cohort study was conducted based on the Taiwan Renal Registry Data System. From January 1, 2000 to December 31, 2008, we enrolled 4356 well-nourished PD patients who were older than 20 years and had been receiving PD for more than 12 months. All patients were divided into subgroups according to different hemoglobin, ferritin and transferrin saturation (TSAT) values. Patients were followed until death or December 31, 2008. In a median 2.9-year study period, 694 (15.9%) patients died. By multivariate adjustment, a hemoglobin level lower than 10 g/dL was significantly associated with a higher risk for all-cause and cardiovascular deaths. Moreover, a serum ferritin level higher than 800 ng/mL was associated with a higher risk for all-cause deaths, and a TSAT value between 20 and 50% was associated with the lowest all-cause mortality. In conclusions, we recommend avoiding a low hemoglobin level and a serum ferritin level of more than 800 ng/mL and maintaining a TSAT value between 20 and 50%, as these conditions were associated with lower risks of all-cause mortality in the AIM-PD study.

Background/purpose Growth arrest-specific 6 (Gas6) protein is involved in cell proliferation, differentiation, adhesion, migration in response to inflammatory processes. Human immunodeficiency virus (HIV) infection induces a chronic inflammatory condition and combination of antiretroviral therapy improves immune function and decreases the inflammatory state. The aim of this study was to assess the implications of Gas6 in chronic inflammation status of HIV-infected patients undergoing different third regimens of antiretroviral therapy. The Gas6 may be a marker of chronic inflammation of HIV-infected patients. Methods A total of 356 adult males, including 258 HIV-infected patients and 98 healthy controls, were recruited. The demographic and clinical characteristics of the patients were collected. Laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), hepatitis B and C viruses, and serum biochemistry. Plasma Gas6 concentrations were determined. Results The values of Gas6 were lower in HIV patients compared to healthy subjects (14.3 ± 6.4 vs 21.5 ± 15.2, p = 0.01). HIV patients that received antiviral regimen with abacavir had similar Gas6 level than those who received antiviral regimens with tenofovir (14.3 ± 6.5 vs 13.8 ± 5.9, p = 0.99). HIV patients that received antiviral regimen with protease inhibitors (PIs) had lower Gas6 level (13.1 ± 3.5 vs 14.2 ± 6.6 vs 14.6 ± 6.5, p = 0.03) than those who received antiviral regimens with non-nucleoside reverse transcriptase inhibitors (nNRTIs) and integrase inhibitors (INSTIs), respectively. Conclusions Decreased plasma Gas6 concentrations were observed in HIV patients. Gas6 levels are associated with different third regimen of highly active antiretroviral therapy. Gas6 may represent a unique marker for assessing the chronic inflammation state difference among cART regimens in HIV patients.

Background Microcirculation is important for regulating ischemia-reperfusion (I/R) injury associated with skin flap transplantation surgery. We investigated whether co-culture with adipose-derived stem cells (ADSCs) could protect human dermal microvascular endothelial cells (HDMECs) from I/R injury by inhibiting cell apoptosis and enhancing cell proliferation. We also investigated the effects of hypoxic preconditioning on ADSCs. Materials and methods HDMECs were divided into four groups, control, HDMECs in normoxic culture conditions; hypoxia/reoxygenation (H/R), HDMECs in a hypoxic incubator for 8 h then in saturated aerobic culture medium for 24 h; H/R + ADSC(N), HDMECs treated similar to the H/R group then co-cultured with normoxic ADSCs; and H/R + ADSC(H), HDMECs treated similar to the H/R group then co-cultured with hypoxia preconditioned ADSCs. Results The rate of HDMECs apoptosis significantly increased in the H/R group, but decreased upon co-culture with ADSCs for 24 h, especially in the H/R + ADSC(H) group. Co-culture with ADSCs, especially hypoxia preconditioned ADSCs, significantly enhanced cell proliferation ability compared with that of the H/R group after 48 h and 72 h, but not after 24 h. Vascular endothelial growth factor levels were significantly higher in the H/R + ADSC(N) and H/R + ADSC(H) groups than in the H/R group. Conclusions ADSCs attenuated H/R injury in endothelial cells by promoting proliferation ability and reducing apoptosis, with an increase in Vascular endothelial growth factor level, especially in the context of hypoxic preconditioning. This approach suggests the potential for an easy and safe method to reduce I/R injury associated with skin flap transplantation surgery.

We performed a systematic review to identify the role of microRNAs (miRNAs) as biomarkers in the progression of cervical precancerous lesions. A comprehensive search of the Cochrane Controlled Register of Trials, PubMed, ScienceDirect, and Embase databases was performed for articles published between January 2010 and June 2020. The following Medical Subject Headings (MeSH) terms were searched: “microRNA” and “cervical” and “lesion.” All study designs that aimed to evaluate the correlation of miRNA expression with different precancerous cervical staging and/or cervical cancer were included, except for case reports and case series. Approximately 82 individual miRNAs were found to be significant in differentiating the stages of cervical carcinogenesis. Among the miRNAs, miR-21 is the most prevalent, and it is consistently upregulated progressively from normal cervical to worsening cervical lesion stages in both cell and serum samples. miR-205 has been shown to have a higher specificity than human papilloma virus testing in predicting the absence of high-grade squamous intraepithelial lesions (HSILs) in exfoliated cell samples. The tumor suppressor miRNAs miR-34, let-7, miR-203 miR-29, and miR-375 were significantly downregulated in low-grade squamous intraepithelial lesions, HSILs, and cervical cancer. We found significant dysregulated miRNAs in cervical carcinogenesis with their dynamic expression changes and ability to detect viral persistency, risk prediction of low-grade lesions (cervical intraepithelial neoplasia [CIN] 2) to high-grade lesions (CIN 3), and progression of CIN 3 to cancer. Their ability to discriminate HSILs from non-dysplastic lesions has potential implications in early diagnosis and reducing overtreatment of otherwise regressive early preinvasive lesions.

BACKGROUND Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours. AIM To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis. METHODS A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs. RESULTS All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival. CONCLUSION The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.

Background: Acute kidney injury (AKI) is the most frequent complication in critically ill neonatal and pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support. This study analyzed risk factors for in-hospital mortality and the incidence of AKI in neonatal and pediatric patients received ECMO support. Methods: We reviewed the medical records of 105 neonatal and 171 pediatric patients who received ECMO support at the intensive care unit (ICU) of a tertiary care university hospital between January 2008 and December 2015. Demographic, clinical, and laboratory data were retrospectively collected as survival and AKI predictors, utilizing the Kidney Disease Improving Global Outcome (KDIGO) consensus definition for AKI. Results: In the 105 neonatal and 171 pediatric patients, the overall in-hospital mortality rate were 58% and 55% respectively. The incidence of AKI at post-ECMO 24 h were 64.8% and 61.4%. A greater KDIGO24-h severity was associated with a higher in-hospital mortality rate (chi-square test; p

Chronic inflammation, a hallmark of gout, is implicated in the pathogenesis of atherosclerosis. Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (AMI). Yet, results from several epidemiological studies have been inconclusive. A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohort comprised 3581 patients with gout (the gout cohort) and 14,324 patients without gout (the non-gout cohort). The primary outcome was the incidence of AMI. To estimate the effect of gout on the risk of AMI, the Lunn-McNeil competing risk model was fitted to estimate cause-specific hazard ratios (HRs) and their 95% confidence intervals (CIs). The cumulative incidence of AMI was significantly higher in the gout cohort than in the non-gout cohort, resulting in an adjusted HR of 1.36 (95% CI 1.04 to 2.76). Further, HRs of gout with incident AMI were higher in patients without hypertension, diabetes mellitus, or hyperlipidemia (ranging from 1.63 to 2.09) than in those with each of these comorbidities (ranging from 0.95 to 1.13). The results of this study suggest that patients with gout have an increased risk of AMI. The AMI risk associated with gout was conditional on patients’ cardiovascular risk profile. Future work is needed to confirm these findings.

Objectives Previous literature has shown that chronic diseases and psychological distress are correlated. However, the mediating and moderating mechanisms underlying this relationship have not been sufficiently studied. The purpose of this study was to explore the role played by activities of daily living (ADL) and perceived social support. Method Face-to-face questionnaire-based surveys were conducted with 3250 valid participants (age ≥60 years). Participants were assessed using the Barthel Index, Perceived Social Support Scale, and Depression Anxiety Stress Scale-21. Results 1) Chronic diseases had a significant direct effect on psychological distress in older adults; 2) the relationship between chronic diseases and psychological distress was partially mediated by ADL; and 3) the impact of chronic diseases on psychological distress was significantly moderated by perceived social support. More importantly, perceived social support was a protective factor that could effectively alleviate the adverse effects of chronic diseases on psychological distress. Conclusion The results add to the existing literature by uncovering the underlying mechanisms between chronic diseases and mental health. These findings have implications for early intervention and prevention of mental health problems in older adults.

Summary Objective The vascularization of subchondral bone plays a significant role in the progression of knee osteoarthritis (OA). Treatment with platelet-rich plasma (PRP) has positive effects on cartilage lesions. However, PRP's efficacy for subchondral bone marrow lesions and the relationship of these lesions to cartilage are still undiscovered. Therefore, our aims were first to longitudinally investigate the change in subchondral flow by dynamic contrast enhanced MRI and degeneration of cartilage by MRI T2∗ in an anterior cruciate transection rodent (ACLT) model, and second to examine changes in parameters after intra-articular PRP injection. Design A 32-week investigation in 18 rats allocated to sham-control, ACLT with normal saline injection (ACLT + NS), and ACLT with PRP injection groups ended with histological evaluation. Another rat was used as a donor of allogenic PRP. Results Compared to the sham-control group, the ACLT + NS group had higher subchondral blood volume A (0.051, 95% confidence interval: 0.009, 0.092) and lower venous washout kel (−0.030: −0.055, −0.005) from week 4; lower permeability kep from week 18 (−0.954: −1.339, −0.569); higher cartilage T2∗ values (1.803: 1.504, 2.102) reflecting collagen loss beginning at week 10. For the PRP treatment group, subchondral bone marrow A and cartilage T2∗ decreased from week 10. Histological results confirmed and were correlated with the MRI findings. Conclusion Subchondral hyper-perfusion plays a vital role in the pathogenesis of OA and was associated with cartilage degeneration. The efficacy of PRP can be observed from reduced perfusion and MRI T2∗ values.

This study aimed to explore the epidemiological characteristics of breast cancer and establish an Exponential Smoothing (ETS) and Autoregressive Integrated Moving Average (ARIMA) models to predict the development of incidence in Shantou. This study has a large sample size, strong representativeness, and wide‐ranging and comprehensive medical insurance information, which can fill the gaps in basic epidemiological research on breast cancer in Shantou. Successful completion of this study is a helpful tool to understand the epidemiology of Guangdong Province and Southern China. This study also provides data and scientific references for the government and future research on breast cancer prevention and control. This retrospective study was conducted to describe the epidemic intensity, epidemic distribution, and epidemic trend of breast cancer in Shantou, Guangdong Province, from 2006 to 2017, gathered from the Shantou's Medical Security Bureau covers the whole districts of Shantou. ETS and ARIMA models were used to describe the regional distribution, time distribution, and population distribution of breast cancer in Shantou. Moreover, based on the ARIMA model and ETS model, the incidence trend of breast cancer was predicted during 2018–2022. This study included 5,681 breast cancer patients, majority of whom were aged 50–59 years. The male‐to‐female ratio of the breast cancer patients was about 1:107 (the same ratio of the insured population was 1:1). Female patients accounted for 98.61% of the total insured population. The incidence and mortality rates of female breast cancer were 16.42/100,000 and 0.66/100,000, respectively. Based on the ARIMA model or ARIMA and ETS model, a gradually decreasing trend in the incidence of breast cancer is expected in the future. Comparing the performances of the ARIMA model and ETS model, ARIMA (4, 0, 1) (0, 1, 0) model had a lower the root mean squared error and the mean absolute percentage error than ETS (M, N) model. This population‐based retrospective study showed that the high‐risk age for the age‐specific incidence of female breast cancer was 50–55 years. It is recommended that healthcare administration should strengthen program awareness and education regarding breast cancer prevention and control. It is also possible that feasibility of extrapolating the current methodology to other future studies or broader populations in which the cancer registry data are not available., This is the first population‐based retrospective study of breast cancer in Shantou, Guangdong Province of Southern China in the past 10 years. The result of the age‐specific incidence of female breast cancer indicated that the high‐risk age was from 50 to 55 years. It is recommended that the health administration strengthen the publicity and education regarding the prevention and control of breast cancer.

Depression is the most frequent psychiatric disorder among the older adults, the purpose of this study is to explore the mediation effect of health promoting lifestyle on the relationship between Socioeconomic Status (SES) and depression, so as to provide practical reference for effectively preventing and alleviating depression of the older adults.A multi-stage random sampling method was conducted in Shanxi Province. A total 8526 older adults were included in the analysis. Regression analysis was used to explore the relationship between the socioeconomic status, health promoting lifestyle and depression, and the mediation effect test process was used to verify the mediating mechanism of health promoting lifestyle on this relationship.62.1% of the older adults had depression symptoms in this study, and there were significant differences in depression scores among the older adults with gender, age, residence, marital status, endowment pattern, self-care ability, exercise frequency, physical examination frequency, daily diet rules(P0.05). The results of mediating effect analysis showed that health promoting lifestyle as mediation effect between social economic status and depression was established, and the mediating effect was accounted for (a*b/c) 63.1%.Given the cross-sectional study, it is not possible to make causal inferences.There were different degrees of depression in the older adults. The lower the SES is, the higher the risk of depression is. This result once again confirms the social causation theory. Combined with the theory of health risk behavior, the study further confirmed the applicability of lifestyle mechanism in the intermediate mechanism of the relationship between SES and depression in the elderly. Thus, in addition to providing material support and financial assistance, helping the elderly develop a healthy lifestyle is also effective measure to improve their depression.

Background The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in endemic regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations between smoking exposure and risk of NPC. Methods We obtained individual participant data of 334 935 male participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status. Results During 2 961 315 person-years of follow-up, 399 NPC evens were ascertained. Risks of NPC were higher in ever versus never smokers (HRone-stage = 1.32, 95% CI = 1.07-1.63, P = 0.0088; HRtwo-stage = 1.27, 1.01-1.60, 0.04). These positive associations appeared to be stronger in ever smokers who consumed 16+ cigarettes/day (HRone-stage = 1.67, 95% CI = 1.29-2.16, P = 0.0001), and in those who started smoking at age younger than 16 (2.16, 1.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for 5+ years: HRone-stage = 0.91, 95% CI = 0.60-1.39, P = 0.66; for former smokers: HRtwo-stage = 0.84, 0.61-1.14, 0.26). Conclusions This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12–16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.

Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133

Aim Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function. Methods We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke. Results Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3-5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m2. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60-89 mL/min/1.73 m2. Statin therapy in patients with an eGFR of 60-89 mL/min/1.73 m2 may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57). Conclusions In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.

Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP-13) expression are higher in prostate cancer patients than in healthy cancer-free individuals. Mechanistic investigations revealed that melatonin inhibits MMP-13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c-Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP-13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.

Background Lung adenocarcinoma (LUAD) is the most frequent histologic type of lung cancer and the morbidity of LUAD is increasing rapidly in the worldwide. But the mechanism of LUAD is still largely unknown. Methods In this study, we analyzed three microarrays of gene expression profiles, containing 196 LUAD samples and 137 normal samples, to explore the potential key candidate genes in LUAD by integrated bioinformatical analysis. Results A total of 240 shared differentially expressed genes (DEGs) were identified and pathways enrichment were analyzed. DEGs-associated protein-protein interaction (PPI) network was constructed and top 20 hub genes were established by calculating the degree of connectivity. We further validated these genes in TCGA and GTEx projects, and found all of these hub genes were differentially expressed in LUAD patients except TIMP1 and FOS. In these candidate genes, ten genes (TPX2, CENPF, TYMS, PRC1, NEK2, CCNB2, KIAA0101, CDC20, TOP2A and SPP1) were confirmed to associate with the prognosis of LUAD. Out of these ten genes, CENPF had the highest genetic alteration at a rate of 4% in LUAD patients, and the expression of CENPF was significantly increased in different subgroups of all age, gender, race, smoking condition and cancer stage groups of LUAD patients. Conclusions Our study contributes to comprehend the role of genes in LUAD and provides possible therapeutic targets for further clinical application.

Prostate cancer osteoblastic bone metastases are incurable and associated with chronic bone pain and a high mortality rate. Osteoclast-targeting drugs intended to prevent skeletal-related events associated with prostate cancer bone metastases do not prolong overall survival. Improved understanding of the bone-derived factors that contribute to prostate cancer osteoblastic bone metastases is required to design treatments that will improve morbidities and overall survival. Activated osteoblasts stimulate prostate cancer growth in bone. In this study, we report that prostate cancer conditioned medium (CM) promoted bone morphogenetic protein (BMP)-2, -4 and -7 production and the expression of osteogenic transcription factors Runx2 and osterix in osteoblasts. Treating the prostate cancer CM with antibody against CCN3 (nephroblastoma-overexpressed), a cysteine-rich protein that belongs to the CCN family, reduced all of these increases. Incubation of osteoblasts with CCN3 facilitated phosphorylation of GSK3β and β-catenin. GSK3β and β-catenin inhibitors or siRNAs all abolished CCN3-induced promotion of BMPs, Runx2 and osterix expression in osteoblasts. Our results indicate that prostate cancer-secreted CCN3 enhances BMP, Runx2 and osterix expression in osteoblasts via the GSK3β and β-catenin signaling pathways. This understanding of the role played by CCN3 in osteoblastic prostate bone metastasis may lead to more efficient targeted therapies.

Objectives Renal replacement therapy-requiring acute kidney injury frequently occurs in ICUs, which require evidence-based medical attention. However, in the postacute kidney injury patient population, the evidence regarding effective therapies to improve patient outcomes is lacking. Therefore, we aimed to examine whether the renin-angiotensin-aldosterone system blockade is effective in improving renal outcomes in postacute kidney injury patients who experienced temporary renal replacement therapy and have hypertension. Design A retrospective cohort study. Setting A nationwide database in Taiwan. Patients From January 1, 2000, to December 31, 2013, we identified 8,558 acute kidney injury patients with hypertension in the national registry database. All these patients experienced an acute kidney injury episode, which required temporary renal replacement therapy for at least once. Interventions Users (n = 3,885) and nonusers (n = 4,673) of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Measurements and main results We used Cox proportional hazards regression models to analyze hazard ratios for the commencement of end-stage renal disease and all-cause mortality for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users (n = 3,885) and nonusers (n = 4,673). In a median follow-up of 4.3 years, 5,880 patients (68.7%) required long-term dialysis, and 4,841 patients (56.6%) died. Compared with postacute kidney injury patients who did not use angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users are marginally less likely to progress to end-stage renal disease (adjusted hazard ratio 0.95; 95% CI 0.90-1.01; p = 0.06) and significantly less likely to suffer from all-cause mortality (adjusted hazard ratio 0.93; 95% CI 0.87-0.98; p = 0.011). Conclusions In patients who experienced renal replacement therapy-requiring acute kidney injury and have hypertension, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use is associated with better survival outcomes compared with nonuser.

Summary Objective This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. Design We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and Results Among patients with eGFR levels of Conclusions tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.

Chronic renal failure (CRF) is commonly associated with various adverse consequences including pathological vascular calcification (VC), which represents a significant clinical concern. Existing literature has suggested the involvement of histone deacetylases (HDACs) in the progression of CRF‐induced VC. However, the underlying molecular mechanisms associated with HDACs remain largely unknown. Therefore, we established the adenine‐induced CRF rat model and in vitro VC models based on vascular smooth muscle cells (VSMCs) to examine HDAC1/lysine demethylase 1A (LSD1)/SESN2 as a novel molecular pathway in CRF‐induced VC. Our initial results demonstrated that HDAC1 reduced the formation of VC in vivo and in vitro. HDAC1 was found to deacetylate LSD1, which subsequently led to impaired transcriptional activity in CRF‐induced VC. Moreover, our results illustrated that LSD1 diminished the enrichment of H3K4me2 at the SESN2 promoter. Autophagy was identified as a vasculo‐protective element against calcification in VC. Finally, we found that the inhibitory effects of HDAC1 overexpression on VC were partially abolished via over‐expressed LSD1 in adenine‐induced CRF model rats and in high phosphate‐induced VSMCs. Taken together, these results highlight the crucial role of HDAC1 as an antagonistic factor in the progression of VC in CRF, and also revealed a novel regulatory mechanism by which HDAC1 operates. These findings provide significant insight and a fresh perspective into promising novel treatment strategies by up‐regulating HDAC1 in CRF.

Purpose: This nationwide population-based retrospective cohort study evaluated the protective effect of N-acetylcysteine against prosthetic joint infection after hip or knee joint replacement. Methods: Patients receiving N-acetylcysteine after hip or knee joint replacement between 2000 and 2015 were identified from the Taiwan National Health Insurance Research Database. Each patient receiving N-acetylcysteine was matched to four controls based on age, sex, and index year. All subjects were followed-up from the index date to December 31, 2015. The Cox proportional hazards regression model was used to assess the risk of prosthetic joint infection. Results: A total of 1478 patients were included in the study group, and 5912 matched subjects not receiving N-acetylcysteine were included in the control group. After adjusting for age, sex, insured premium, comorbidities, and immunosuppressive agent use, no significant difference in the risk of prosthetic joint infection was found between the two groups. A higher N-acetylcysteine dose (>360 cumulative defined daily dose) significantly decreased the risk of prosthetic joint infection (adjusted hazard ratio = 0.891; 95% confidence interval = 0.599–0.989; p = 0.042). The protective effect of N-acetylcysteine was observed only in the group of prosthetic joint infection within 5 years (adjusted hazard ratio = 0.801; 95% confidence interval = 0.581–0.980; p = 0.040). Conclusions: High cumulative dose of N-acetylcysteine (>360 cumulative defined daily dose) can effectively reduce the risk of prosthetic joint infection in patients undergoing knee or hip joint replacement surgery within 5 years. Keywords: Biofilm, N-acetylcysteine, Prosthetic joint infection

Background The incidence of female stroke has increased gradually and has begun occurring at a younger age in recent years. Given that women live longer than men, stroke would cause more negative and longer-term impacts on the rest of the lives of women. There are few related studies on Asian women. We aimed to evaluate stroke risk in Asian women following hypertensive pregnancy disorders. Methods Using the Taiwan National Health Insurance database, we designed a retrospective study that included pregnant women between 2000 and 2013. We selected an age-matched control group of women without hypertensive pregnancy disorders at a 1:3 ratio. The endpoint was any episode of stroke; otherwise, the patients were tracked until December 31, 2013. After the index date until the end of 2013, Cox proportional hazards analysis was used to compare the risk of incident stroke. The risk factors for stroke were determined using Cox proportional regression to calculate the hazard ratio (HR) compared with the control group. Results During the follow-up period, the Kaplan-Meier analysis indicated that patients with hypertensive pregnancy disorders had a significantly higher risk of developing stroke than did patients without hypertensive pregnancy disorders (log-rank test P < 0.001). Multivariate Cox regression analysis demonstrated that the case group had a 2.134-fold increased risk of stroke (HR = 2.134; 95% CI = 1.817–2.505; P < 0.001). Conclusion Our study provided evidence of an increased risk of stroke in patients with hypertensive pregnancy disorders. Compared with those without such disorders, the patients who had experienced the disorders had a 2.134-fold (P

Scrub typhus is a zoonotic disease caused by the bacterium Orientia tsutsugamushi. In this study, the epidemiological characteristics of scrub typhus in Taiwan, including gender, age, seasonal variation, climate factors, and epidemic trends from 2010 to 2019 were investigated. Information about scrub typhus in Taiwan was extracted from annual summary data made publicly available on the internet by the Taiwan Centers for Disease Control. From 2010 to 2019, there were 4352 confirmed domestic and 22 imported cases of scrub typhus. The incidence of scrub typhus ranged from 1.39 to 2.30 per 100,000 from 2010–2019, and peaked in 2013 and 2015–2016. Disease incidence varied between genders, age groups, season, and residence (all p < 0.001) from 2010 to 2019. Risk factors were being male (odds ratio (OR) =1.358), age 40 to 64 (OR = 1.25), summer (OR = 1.96) or fall (OR = 1.82), and being in the Penghu islands (OR = 1.74) or eastern Taiwan (OR = 1.92). The occurrence of the disease varied with gender, age, and place of residence comparing four seasons (all p < 0.001). Weather, average temperature (°C) and rainfall were significantly correlated with confirmed cases. The number of confirmed cases increased by 3.279 for every 1 °C (p = 0.005) temperature rise, and 0.051 for every 1 mm rise in rainfall (p = 0.005). In addition, the total number of scrub typhus cases in different geographical regions of Taiwan was significantly different according to gender, age and season (all p < 0.001). In particular, Matsu islands residents aged 20–39 years (OR = 2.617) and residents of the Taipei area (OR = 3.408), northern Taiwan (OR = 2.268) and eastern Taiwan (OR = 2.027) were affected during the winter. Males and females in the 50–59 age group were at high risk. The total number of imported cases was highest among men, aged 20–39, during the summer months, and in Taipei or central Taiwan. The long-term trend of local cases of scrub typhus was predicted using the polynomial regression model, which predicted the month of most cases in a high-risk season according to the seasonal index (1.19 in June by the summer seasonal index, and 1.26 in October by the fall seasonal index). The information in this study will be useful for policy-makers and clinical experts for direct prevention and control of chigger mites with O. tsutsugamushi that cause severe illness and are an economic burden to the Taiwan medical system. These data can inform future surveillance and research efforts in Taiwan.

Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother-to-infant transmission in highly viremic HBV-infected women. Data on hepatitis B surface antigen (HBsAg) levels in pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV-infected mothers with HBV DNA ≥7.5 log10 IU/ml were tested for HBsAg and HBV DNA from baseline to 6 months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1 month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32 ± 0.47 vs. 4.54 ± 0.35 log10 IU/ml, p = .0004) and markedly lower HBV DNA (4.26 ± 0.97 vs. 8.11 ± 0.70 log10 IU/ml, p

BackgroundCigarette smoking is associated with nasopharyngeal cancer (NPC) risk. Whether quitting reduces the risk is unclear. We investigated the associations of NPC with duration of and age at quitting in an endemic region.MethodsWe investigated the associations between NPC and quitting in a multicenter case-control study in Hong Kong with 676 newly diagnosed NPC cases and 1,285 hospital controls between 2014 and 2017, using a computer-assisted self-administered questionnaire. Multivariable unconditional logistic regression yielded adjusted odds ratios (AORs) of NPC by quitting status, duration and age of quitting, combinations of duration and age of quitting, and quitting to smoking duration ratio, compared with current smoking.ResultsQuitting (AOR: 0.72; 95% CI: 0.53–0.98) and never smoking (0.73, 0.56–0.95) were associated with lower NPC risk. NPC risk decreased with (i) longer quitting duration (p < 0.01), reaching significance after 11–20 (0.62, 0.39–0.99) and 21+ years (0.54, 0.31–0.92) of quitting; (ii) younger quitting age (p = 0.01), reaching significance for quitting at p < 0.01), reaching significance when the ratio reached 1 (0.60, 0.39–0.93). Quitting younger (age ConclusionsWe have shown longer duration and younger age of quitting were associated with lower NPC risk, with dose-response relations. Our findings support including smoking as a cause of NPC. Stronger tobacco control measures and quitting services are needed to prevent NPC.

BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC). AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis. METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival. RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues. CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

BACKGROUND Maternal anti-viral treatment prevents mother-to-infant transmission of hepatitis B virus (HBV), but the role of neonatal viremia on subsequent HBV infection is not clear. AIMS To investigate the effect of maternal anti-viral treatment on neonatal serum HBV DNA and hepatitis B surface antigen (HBsAg) in infants born to highly viremic mothers and the roles of neonatal markers in predicting chronic HBV infection in children. METHODS Serum HBV DNA and HBsAg were tested in children. Of the 201 pregnant mothers, 110 received tenofovir during the third trimester. Chronic infection in children was defined by HBsAg seropositivity at 6 or 12 months lasting more than 6 months. RESULTS The maternal HBV viral loads from baseline to delivery were 8.25 ± 0.48 to 4.29 ± 0.98 log10 IU/mL; and 8.29 ± 0.49 to 8.12 ± 0.68 log10 IU/mL in the tenofovir and control group respectively. Of the 208 children, those in the tenofovir group had a lower rate of neonatal HBV DNA seropositivity at birth (5.22% vs 30.11%, P

Background Botulinum toxin type A (BTXA) has been reported to increase survival of critically ischemic skin flaps; however, the effect of BTXA in human dermal microvascular endothelial cells (HDMECs) remains to be investigated. This study aimed to investigate the protective effect of BTXA in HDMECs exposed to an in vitro model of ischemia/reperfusion injury. Methods HDMECs were isolated from human upper eyelid tissue and were randomly divided into 3 groups: 1. control group: culture under normoxic conditions (95% air and 5% CO2); 2. hypoxia/reoxygenation (H/R) group: culture in a hypoxic incubator (94% N2 + 5% CO2 + 5% O2) for 8 hours, followed by culture in saturated aerobic culture medium for 24 hours; and 3. BTXA group: treatment with BTXA for 12 hours before exposure to hypoxic conditions. Flow cytometry was used to analyze the apoptosis of HDMECs, and western blotting was used to detect the expression of apoptosis-related proteins. Results H/R leads to severe injury in HDMECs, as evidenced by an increase in the percentage of apoptosis and an increase in expression of apoptosis-related proteins (Bax, cleaved-caspase-3, and cytochrome C). Moreover, H/R results in a decrease in expression of anti-apoptotic protein (Bcl-2), which can be significantly attenuated with BTXA treatment. Conclusion BTXA protects against apoptosis in HDMECs exposed to an in vitro model of H/R-induced injury.

In the present study, we investigated the role of PKR-like endoplasmic reticular kinase (PERK), an endoplasmic reticulum (ER) stress kinase, in endothelin 1 (ET-1)- and thrombin-induced pulmonary fibrosis (PF), and the preventive effects of curcumin (CUR). Using the human embryonic WI-38 lung fibroblast cell line, ET-1 and thrombin induced the expression of ER stress-related proteins (CCAAT-enhancer-binding protein homologous protein, PERK, and binding immunoglobulin protein), a profibrogenic factor (cellular communication network factor 2 [CCN2]), and differentiation markers including α-smooth muscle actin (α-SMA), collagen I (Col I), and Col IV. Knockdown of PERK expression via small interfering RNA (siRNA) significantly reduced the increases in CCN2, α-SMA, Col I, and Col IV proteins in WI-38 cells according to western blot analysis and immunohistochemistry (IHC). Activation of c-Jun N-terminal kinase (JNK) was observed in ET-1- and thrombin-treated WI-38 cells, and the addition of a JNK inhibitor (SP) suppressed the induction of the indicated proteins by ET-1 and thrombin. Thapsigargin (TG), an ER stress inducer, elevated expressions of PERK and ER stress-related proteins with increased differentiation of WI-38 cells. Knockdown of PERK by siRNA or the PERK inhibitor glycogen synthesis kinase reduced expressions of the differentiation markers, α-SMA and Col IV, in WI-38 cells. CUR concentration-dependently inhibited ET-1- or thrombin-induced CCN2, α-SMA, and vimentin proteins with decreased levels of phosphorylated mitogen-activated protein kinase and PERK in WI-38 cells. An in vivo bleomycin-induced PF study showed that an intraperitoneal injection of CUR (30 mg/kg) reduced expressions of α-SMA, CCN2, Col IV, and vimentin in lung tissues via IHC staining using specific antibodies. This study is the first to demonstrate that PERK activation contributes to pulmonary fibroblast differentiation elicited by ET-1 or thrombin, and the inhibitory activity of CUR against PF is demonstrated herein.

Introduction: Multimorbidity has become one of the key issues in the public health sector. This study aimed to explore the urban–rural differences in patterns and associated factors of multimorbidity in China and to provide scientific reference for the development of health management strategies to reduce health inequality between urban and rural areas.Methods: A cross-sectional study, which used a multi-stage random sampling method, was conducted effectively among 3,250 participants in the Shanxi province of China. The chi-square test was used to compare the prevalence of chronic diseases among older adults with different demographic characteristics. The Apriori algorithm and multinomial logistic regression were used to explore the patterns and associated factors of multimorbidity among older adults, respectively.Results: The findings showed that 30.3% of older adults reported multimorbidity, with significantly higher proportions in rural areas. Among urban older adults, 10 binary chronic disease combinations with strong association strength were obtained. In addition, 11 binary chronic disease combinations and three ternary chronic disease combinations with strong association strength were obtained among rural older adults. In rural and urban areas, there is a large gap in patterns and factors associated with multimorbidity.Conclusions: Multimorbidity was prevalent among older adults, which patterns mainly consisted of two or three chronic diseases. The patterns and associated factors of multimorbidity varied from urban to rural regions. Expanding the study of urban–rural differences in multimorbidity will help the country formulate more reasonable public health policies to maximize the benefits of medical services for all.

Ching-Huang Lin,1 Hsien-Chang Lin,2 Chien-Yu Chen,3 Chong-Chung Lih4 1Department of Electronic Engineering, National Yunlin University of Science & Technology, Yunlin, 640, Taiwan; 2Graduate School of Engineering Science and Technology, National Yunlin University of Science & Technology, Yunlin, 640, Taiwan; 3Graduate Institute of Color and Illumination Technology, National Taiwan University of Science and Technology, Taipei, 106, Taiwan; 4Department of Optometry, Central Taiwan University of Science and Technology, Taichung, 406, TaiwanCorrespondence: Chong-Chung LihDepartment of Optometry, Central Taiwan University of Science and Technology, Taichung, 406, TaiwanTel +866 4 22391647 6981Email cclih@phys.nthu.edu.twPurpose: This study used low-level laser irradiation on auricular points for the eyes of junior college teenagers with myopia to observe the changes in refractive errors and eye accommodation. According to the Sterner’s study, we used the relationship between the amplitude and subjective symptoms to assess the degree of improvement in visual fatigue caused by changes in accommodation.Methods: Participants were 49 healthy junior college teenagers, with an average age of 16.04± 0.80 years old, and the refractive errors of both eyes were between − 1.50 D and − 5.00 D. All participants underwent refractive error tests before and after class and after a 30-min break. In a 30-min break, all participants underwent two tests of with (experimental group) and without (control group) low-level laser irradiation on the auricular points. Then, refractive error tests were conducted to evaluate the participants’ eye accommodation.Results: The results revealed that with treatment of the auricular points with and without low-level laser irradiation, the refractive error of the participants’ binocular left and right eyes decreased by − 0.12 D (− 0.18 D) in the experimental grou and by − 0.05 D (− 0.02D) in the control group. For the amplitudes of accommodation (AA) examination, the AA of the participants’ binocular in the experimental group became 7.98 ± 1.35 D (7.65 ± 1.37 D). The AA of participants’ binocular can recover to the level before the class.Conclusion: The results indicated that low-level laser irradiation at auricular points restored the eye accommodation faster than did natural closing of the eyes.Keywords: low-level laser irradiation, myopia, teenager, accommodation, auricular point

Macrophage migration inhibitory factor (MIF), an immunoregulatory cytokine plays an important role in inflammation and the immune response, and has been described as having a potential role in immune evasion by parasites. Thelazia callipaeda, a vector-borne zoonotic eye worm with a broad host range, has been documented as an agent of ocular infection of thelaziosis. The ability of T. callipaeda to persist in an immunologically competent host has led to the suggestion that it has evolved specific measures to counter immune defenses. To date, whether the immune evasion of T. callipaeda is related to MIF and the possible related signaling pathway and molecular mechanism have remained unclear. In the present study, we examined the effect of T. callipaeda MIF (T. cp-MIF) on macrophages. We analyzed the antigenic epitopes of the candidate T. cp-MIF and found that it exhibited an ideal antigenic index. Morphology, Flow cytometry, and cytokine analysis showed that T. cp-MIF induced the dynamic polarization of THP-1 macrophages from the M1-like phenotype to the M2-like phenotype. The chemotaxis assay revealed an inhibitory effect of T. cp-MIF on THP-1 macrophages. Western blotting suggested that, compared to the control, THP-1 macrophages exposed to T. cp-MIF had higher TLR4 protein expression and the phosphatidylinositol 3'-kinase (PI3K) -Akt pathway activation. In conclusion, T. cp-MIF induces M2-like macrophage polarization through TLR4-mediated activation of the PI3K-Akt pathway, which might provide a basis for future research on how it affects the immune system of the host.

Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17f/f/Cre+ mice compared to control mice. TGF-β- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-β and thrombin through an aberrant ADAM17/EGFR signalling pathway.

This study introduced satellite-derived aerosol optical depth (AOD) in land use regression (LUR) modeling to predict ambient concentrations of fine particulate matter (PM2.5) and its elemental composition. Twenty-four daily samples were collected from 17 air quality monitoring sites (N = 408) in Taiwan in 2014. A total of 12 annual LUR models were developed for PM2.5 and 11 elements, including aluminum, calcium, chromium, iron, potassium, manganese, sulfur, silicon, titanium, vanadium, and zinc. After applied AOD and a derived-predictor, AOD percentage, in modeling, the number of models with leave-one-out cross-validation R2 > 0.40 significantly increased from 5 to 9, indicating the substantial benefits for the construction of spatial prediction models. Sensitivity analyses of using data stratified by PM2.5 concentrations revealed that the model performances were further improved in the high pollution season.

In this large-scale prospective cohort study, a propensity score matching method was applied in a natural experimental design to investigate how post-acute care (PAC) after stroke affects functional status and to identify predictors of functional status. The main objective of this study was to examine longitudinal changes in various measures of functional status in stroke patients and predictors of scores for these measures before and after PAC. A group of patients who had received PAC for stroke at one of two medical centers (PAC group, n = 273) was compared with a group who had received standard care for stroke at one of four hospitals (three regional hospital and one district hospital, non-PAC group, n = 273) in Taiwan from March, 2014, to October, 2018. The patients completed the functional status measures before rehabilitation, the 12th week and the 1st year after rehabilitation. Generalized estimating equations were used to estimate differences-in-differences models for examining the effects of PAC. The average age was 68.0 (SD = 8.1) years, and males accounted for 57.9%. During the follow-up period, significant risk factors for poor functional outcomes were advanced age, hemorrhagic stroke, and poor function scores before rehabilitation (p &lt, 0.05). Between-group comparisons at subsequent time points revealed significantly higher functional status scores in the PAC group versus the non-PAC group (p &lt, 0.001). Notably, for all functional status measures, between-group differences in total scores significantly increased over time from baseline to 1 year post-rehabilitation (p &lt, 0.001). The contribution of this study is its further elucidation of the clinical implications and health policy implications of rehabilitative care after stroke. Specifically, it improves understanding of the effects of PAC in stroke patients at different follow-up times. Therefore, a policy implication of this study is that standard care for stroke should include intensive rehabilitative PAC to maximize recovery of overall function.

Acute diarrhea is mainly caused by norovirus and rotavirus. Numerous factors modify the risk of diarrhea cluster infections and outbreaks. The purpose of this study was to explore the epidemiological characteristics, differences, and trends in the distribution of viral and bacterial pathogens that cause diarrhea cluster events as well as the public places where diarrhea cluster events took place in Taiwan from 2011 to 2019. We examined publicly available, annual summary data on 2865 diarrhea clusters confirmed by the Taiwan Centers for Disease Control (CDC) from 2011 to 2019. There were statistically significant differences (p &lt, 0.001) in event numbers of diarrhea clusters among viral and bacterial pathogens, and statistically significant differences (p &lt, 0.001) in event numbers of diarrhea clusters among bacterial pathogens. There were also statistically significant differences (p &lt, 0.001) in the event numbers of diarrhea clusters among public places. Norovirus infections were the first most numerous (77.1%, 1810/2347) diarrhea clusters among viral and bacterial infections. Among bacterial infections, Staphylococcus aureus infections accounted for the greatest number of diarrhea clusters (35.5%, 104/293). Schools were the places with the greatest number of diarrhea clusters (49.1%, 1406/2865) among various institutions. Norovirus single infection (odds ratio, OR = 4.423), Staphylococcus aureus single infection (OR = 2.238), and school (OR = 1.983) were identified as risk factors. This is the first report of confirmed events of diarrhea clusters taken from surveillance data compiled by Taiwan’s CDC (2011–2019). This study highlights the importance of long-term and geographically extended studies, particularly for highly fluctuating pathogens, to understand the implications of the transmission of diarrhea clusters in Taiwan’s populations. Importantly, big data have been identified that can inform future surveillance and research efforts in Taiwan.

PURPOSE: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. METHODS: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120–360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. RESULTS: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. CONCLUSIONS: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. TRIAL REGISTRATION: NCT01749384 (First posted 12/13/2012).

Background Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. Methods The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. Results ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. Conclusions ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.

The purpose of present study was to longitudinally investigate the alterations in infrapatellar fat pad (IPFP) vascularity in 5/6 nephrectomized rats by using dynamic contrast enhanced (DCE) MRI and IPFP degeneration by using MRI T2* relaxation time. Twelve male Sprague–Dawley rats were assigned to a control group and a 5/6 nephrectomy CKD group. The right knees of all rats were longitudinally scanned by 4.7 T MRI, and serial changes in the IPFP were assessed at 0, 8, 16, 30, and 44 weeks by DCE-MRI (parameters A, kel and kep) and MRI T2* mapping. After MRI measurements, knee specimens were obtained and evaluated histologically. The CKD group had IPFPs with lower blood volume A and lower permeability kep values from 16 weeks (p kel value from 30 weeks (p * values reflecting adipocyte degeneration beginning at 16 weeks (p

Summary Background & aims Little is known about the risk of nasopharyngeal carcinoma (NPC) in relation to vitamin D exposure. The aim of this study was to examine the associations of NPC risk with serum level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD, and potential effect modification by several putative risk factors of NPC. Methods Our multicenter case–control study in Hong Kong recruited 815 NPC cases and 1502 frequency-matched (by sex and age) hospital controls from five major regional hospitals, and recruited 299 healthy subjects from blood donation centers (2014–2017). Circulating level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD (rs12785878, rs11234027, rs12794714, rs4588 and rs6013897) were measured by validated enzyme immunoassay and the iPLEX assay on the MassARRAY System, respectively. Data were also collected on demographics, lifestyle factors, ultraviolet radiation exposure, and potential confounders using a computer-assisted, self-administered questionnaire with satisfactory test-retest reliability. Unconditional logistic regression models were used to estimate ORs and 95% CIs. Results Despite no significant association of NPC risk with circulating 25OHD and genetic predicted 25OHD, there was evidence for an inverse association in participants with normal body mass index (between 18.5 and 27.5) across categories of 25OHD (Ptrend = 0.003), and a positive association in those with low socioeconomic status across categories based on the genetic score (Ptrend = 0.005). In addition, risk of NPC diagnosed at an early stage was higher for genetically lower 25OHD level (adjusted OR = 3.09, 95% CI = 1.04–9.21, Ptrend = 0.022). Conclusions Findings of this first comprehensive study to investigate the positive association of NPC risk with vitamin D deficiency need to be confirmed and be best interpreted with results of further similar studies. Our findings may inform possible etiological mechanisms of the associations with several putative risk/protective factors of NPC.

This study investigated the usefulness of ventilator parameters in the prediction of development and outcome of acute respiratory distress syndrome (ARDS) in postoperative patients with esophageal or lung cancer on admission to the surgical intensive care unit (SICU). A total of 32 post-operative patients with lung or esophageal cancer from SICU in a tertiary medical center were retrospectively analyzed. The study patients were divided into an ARDS group (n = 21) and a non-ARDS group (n = 11). The ARDS group contained the postoperative patients who developed ARDS after lung or esophageal cancer surgery. The ventilator variables were analyzed in this study. Principal component analysis (PCA) was performed to reduce the correlated ventilator variables to a small set of variables. The top three ventilator variables with large coefficients, as determined by PCA, were considered as sensitive variables and included in the analysis model based on the rule of 10 events per variable. Firth logistic regression with selective stepwise elimination procedure was performed to identify the most important predictors of morbidity and mortality in patients with ARDS. Ventilator parameters, including rapid shallow breath index during mechanical ventilation (RSBIv), rate pressure product of ventilation (RPPv), rate pressure volume index (RPVI), mechanical work (MW), and inspiration to expiration time ratio (IER), were analyzed in this study. It was found that the ARDS patients had significantly greater respiratory rate (RR), airway resistance (Raw), RSBIv, RPPv, RPVI, positive end-expiratory pressure (PEEP), and IER and significantly lower respiratory interval (RI), expiration time (Te), flow rate (V˙), tidal volume (VT), dynamic compliance (Cdyn), mechanical work of ventilation (MW), and MW/IER ratio than the non-ARDS patients. The non-survivors of ARDS had significantly greater peak inspiratory pressure above PEEP (PIP), RSBIv, RPPv, and RPVI than the survivors of ARDS. By using PCA, the MW/IER was found to be the most important predictor of the development of ARDS, and both RPPv and RPVI were significant predictors of mortality in patients with ARDS. In conclusion, some ventilator parameters, such as RPPv, RPVI, and MW/IER defined in this study, can be derived from ventilator readings and used to predict the development and outcome of ARDS in mechanically ventilated patients on admission to the SICU.

Chronic obstructive asthma is characterized by airway fibrosis. Hypoxia and connective tissue growth factor (CTGF) play important roles in airway fibrosis. Preadipocyte factor-1 (Pref-1) participates in adipocyte differentiation and liver fibrosis. Herein, we investigated the role of Pref-1 in airway fibrosis in chronic obstructive asthma. We found that Pref-1 was overexpressed in lung tissues from chronic obstructive asthma patients compared to normal subjects. Extracellular matrix proteins were inhibited by Pref-1 small interfering (si)RNA in airway fibroblasts from chronic obstructive asthma patients. Furthermore, ovalbumin induced prominent Pref-1 expression and fibronectin coexpression. Hypoxia induced Pref-1 upregulation and its release into medium of WI-38 cells. Hypoxia-induced CTGF expression was inhibited by Pref-1 siRNA. We also found that Pref-1-stimulated fibrotic protein expressions were reduced by ATN-161, curcumin, U0126, and c-Jun siRNA in WI-38. Furthermore, ATN161 inhibited Pref-1-induced ERK phosphorylation, and ITGA5 siRNA inhibited c-Jun phosphorylation. Moreover, expression of CTGF, Fibronectin, α-SMA, and ERK and c-Jun phosphorylation were all increased in fibroblasts from patients with chronic obstructive asthma. Taken together, these results suggest that Pref-1 participates in airway fibrosis and hypoxia-induced CTGF expression via the integrin receptor α5β1/ERK/AP-1 pathway.

Mei Zhao,1,* Jun-Xian Song,2,* Fang-Fang Zheng,2 Lin Huang,1 Yu-Fei Feng1 1Department of Pharmacy, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department of Cardiology, Peking University People’s Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Fei FengDepartment of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, People’s Republic of ChinaTel +86-13611010053Email fengyufei@126.comPurpose: Medication therapy is crucial in the management of chronic coronary syndrome (CCS). The use of potentially inappropriate medications (PIMs) contributes to poor outcomes in older patients, making it a major public health concern. However, few studies are available on PIMs use in older Chinese CCS patients. To investigate the frequency of prescribed PIMs at discharge and explore risk factors in older adults with CCS.Patients and Methods: The cross-sectional study was conducted in a tertiary hospital in China over three months, from 1st October to 31st December, 2019. CCS patients aged over 60 years who were discharged alive were recruited. Information on demographics and medications at discharge was collected. Clinical data including diagnoses, frailty status, New York Heart Association (NYHA) class and age-adjusted Charlson Comorbidity Index (ACCI) were evaluated in each patient. PIMs were identified using the 2019 Beers criteria. Binary logistic regression was performed to recognize variables related to PIMs.Results: A total of 447 eligible patients with 2947 medications were included. The prevalence of PIMs use was 38%. Medications to be avoided, to be used with caution, and with drug–drug interactions were 38.4%, 48.9% and 12.7% of the PIMs, respectively. Medications with drug–disease/syndrome interactions and those adjusted for kidney function were not identified. The common PIMs were diuretics (37.1%), benzodiazepines and benzodiazepine receptor agonist hypnotics (15.2%), glimepiride (13.1%), and co-prescription of potassium-sparing diuretics and renin-angiotensin system (RAS) inhibitors (9.7%). Individuals with frailty syndrome, polypharmacy, multiple comorbidities, atrial fibrillation, psychiatric disorders and greater NYHA class severity were more likely to receive PIMs.Conclusion: Prescription of PIMs was a common burden in older adults. A CCS multidisciplinary team is needed to control PIMs, especially in vulnerable older patients.Keywords: potentially inappropriate medication, Beers criteria, chronic coronary syndrome, older adults, discharge