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Objectives To determine the bidirectional relationship between macrophage activation syndrome (MAS) and SLE. Methods Using the 1997–2013 Taiwan National Health Insurance Research Database, we identified patients with newly diagnosed SLE from 2001 to 2013 and selected individuals without SLE from a 1 million representative population. Propensity score (PS) matching was performed to balance incident SLE patients and individuals without SLE according to age, sex, comorbidities and medical utilization. The association between a history of MAS and SLE was studied using conditional logistic regression analysis shown as an adjusted odds ratio (aOR). The risk of MAS associated with SLE was analysed using Cox proportional regression analysis, shown as an adjusted hazard ratio (aHR), and we conducted a sensitivity analysis using various definitions of MAS. Results We included 10 481 SLE patients and 20 962 PS-matched (1:2) non-SLE individuals. The correlation between a history of MAS and SLE did not reach statistical significance after adjustment for potential confounders [aOR 1.18 (95% CI, 0.80, 1.75)] in the age-/sex-matched populations. In the 1:2 PS-matched populations, the risk of MAS markedly increased in patients with SLE [aHR 7.18 (95% CI 4.97, 10.36)]. Other risk factors for MAS included female gender, age ≥65 years, low income, a history of inflammatory bowel disease and a history of MAS. Conclusion This nationwide, population-based study revealed that a history of MAS was not significantly associated with SLE risk. However, the risk of MAS was markedly associated with SLE and a history of MAS.

The purposes of the study were (1) to assess the physical activity (PA) status, muscle strength (MS), and flexibility of survivors of head and neck cancer (HNC) and compare these findings with normative data from national labor fitness measures; (2) to examine the differences among PA subgroups, as categorized using Godin’s scores; and (3) to examine the association between stretching exercises and cervical range of motion (CROM). A cross-sectional study with consecutive sampling was used to recruit HNC survivors from a medical center in Northern Taiwan who had completed either radiation therapy (RT) or multimodality treatments including RT within the current 5 years. The level of PA, daily function, fatigue, quality of life (QOL), MS (handgrip and hip flexor), BMI, and flexibility (CROM and fingertip-to-floor tests) of the participants were assessed. A total of 108 participants completed the assessments from 135 eligible patients (80% response rate). Although 60.2% reported engaging in PA, only 16.7% met WHO guidelines. Compared to subjects in the normative data, the survivors of HNC in this study had poorer handgrip strength, BMI, and CROM, but better forward flexion. The participants who were consistent with WHO PA guidelines reported less fatigue, better right hip flexor MS, and better QOL than those who did not engage in any PA. Lack of sufficient PA and generally poorer fitness were found in study subjects. Longitudinal research to explore changes in fitness and barriers to PA compliance is strongly suggested to better enhance HNC patients’ PA and fitness.

Human HLTF participates in the lesion-bypass mechanism through the fork reversal structure, known as template switching of post-replication repair. However, the mechanism by which HLTF promotes the replication progression and fork stability of damaged forks remains unclear. Here, we identify a novel protein–protein interaction between HLTF and PARP1. The depletion of HLTF and PARP1 increases chromosome breaks, further reduces the length of replication tracks, and concomitantly increases the number of stalled forks after methyl methanesulfonate treatment according to a DNA fiber analysis. The progression of replication also depends on BARD1 in the presence of MMS treatment. By combining 5-ethynyl-2′-deoxyuridine with a proximity ligation assay, we revealed that the HLTF, PARP1, and BRCA1/BARD1/RAD51 proteins were initially recruited to damaged forks. However, prolonged stalling of damaged forks results in fork collapse. HLTF and PCNA dissociate from the collapsed forks, with increased accumulation of PARP1 and BRCA1/BARD1/RAD51 at the collapsed forks. Our results reveal that HLTF together with PARP1 and BARD1 participates in the stabilization of damaged forks, and the PARP1–BARD1 interaction is further involved in the repair of collapse forks.

Systemic lupus erythematosus (SLE) is an autoimmune disease that develops mainly in women of reproductive age. We aimed to explore the risk of pregnancy complications in Asian patients with SLE.From January 2005 to December 2014, we conducted a nationwide case-control study, using Taiwan's National Health Insurance Research Database. Obstetric complications and perinatal outcomes in SLE patients were compared with those without SLE.2059 SLE offspring and 8236 age-matched, maternal healthy controls were enrolled. We found increased obstetric and perinatal complications in SLE population compared with healthy controls. SLE patients exhibited increased risk of preeclampsia/eclampsia (8.98% vs.1.98%, odds ratio [OR]: 3.87, 95% confidence interval [95% CI]: 3.08-4.87, p0.0001). Their offspring tended to have lower Apgar scores (7) at both 1 min (10.7% vs. 2.58%, p0.0001) and 5 min (4.25% vs. 1.17%, p0.0001), as well as higher rates of intrauterine growth restriction (IUGR, 9.91% vs. 4.12%, OR: 2.24, 95% CI: 1.85-2.71, p0.0001), preterm birth (23.70% vs 7.56%, OR: 3.00, 95% CI: 2.61-3.45, p0.0001), and stillbirth (4.23% vs. 0.87%, OR: 3.59, 95% CI: 2.54-5.06, p0.0001). The risks of preterm birth and stillbirth were markedly increased in SLE patients with concomitant preeclampsia/eclampsia or IUGR. Preterm birth of SLE patients was 1~4 gestational weeks earlier than that of healthy controls and the peak occurrence of stillbirth in SLE population was at 20~30 gestational weeks.Asian SLE patients exhibited increased risks of maternal complications and adverse birth outcomes. Frequent antenatal visits before 20 gestational weeks are recommended in high-risk SLE patients.

The risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after glucocorticoid (GC) pulse therapy remains unclear. Aims: Our study aimed to examine the safety of GC pulse therapy in HBsAg-negative, anti-HBc-positive rheumatic patients. Methods: Medical records of HBsAg-negative, anti-HBc-positive patients receiving GC pulse therapy to treat rheumatic diseases were reviewed. The primary outcome was HBV-associated hepatitis occurring within the first year after GC pulse therapy, the secondary outcome was HBsAg seroreversion occurring during the follow-up period. Results: We identified 5222 HBsAg-negative, anti-HBc-positive patients with rheumatic diseases who had attended Taichung Veterans General Hospital from October 2006 to December 2018. A total of 689 patients had received GC pulse therapy, with 424 patients being analyzed. Hepatitis was noted in 28 patients (6.6%) within the first year after GC pulse therapy, but none had been diagnosed as HBV-associated hepatitis. Three patients (0.7%) later developed HBsAg seroreversion, with a median interval of 97 months from the first episode of GC pulse therapy. These cases concurrently had maintained high dose oral prednisolone (≥20 mg prednisolone daily for over 4 weeks). Conclusions: Amongst the HBsAg-negative, anti-HBc-positive rheumatic patients treated with GC pulse therapy, the risk of HBV-associated hepatitis within the first year was low. HBsAg seroreversion may have developed in the later stage, but only in those patients who had maintained high-dose oral steroid.

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs 15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p 15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.

Primary congenital hypothyroidism is a disease associated with low serum thyroxine and elevated thyroid-stimulating hormone (TSH) levels. The processes of screening and treating congenital hypothyroidism, in order to prevent neurodevelopmental impairment (NDI) in newborns, have been well investigated. Unlike term infants, very preterm infants (VPIs) may experience low thyroxine with normal TSH levels (&lt, 10.0 μIU/mL) during long-stay hospitalization. In the current literature, thyroxine treatment has been evaluated only for TSH-elevated VPIs. However, the long-term impact of low thyroxine levels in certain VPIs with normal TSH levels deserves more research. Since July 2007, VPIs of this study unit received screenings at 1 month postnatal age (PNA) for serum TSH levels and total thyroxine (TT4), in addition to two national TSH screenings scheduled at 3–5 days PNA and at term equivalent age. This study aimed to establish the correlation between postnatal 1-month-old TT4 concentration and long-term NDI at 24 months corrected age among VPIs with serial normal TSH levels. VPIs born in August 2007–July 2016 were enrolled. Perinatal demography, hospitalization morbidities, and thyroid function profiles were analyzed, and we excluded those with congenital anomalies, brain injuries, elevated TSH levels, or a history of thyroxine treatments. In total, 334 VPIs were analyzed and 302 (90.4%) VPIs were followed-up. The postnatal TT4 concentration was not associated with NDI after multivariate adjustment (odd ratios 1.131, 95% confidence interval 0.969–1.32). To attribute the NDI of TSH-normal VPIs to a single postnatal TT4 concentration measurement may require more research.

MicroRNA-27 is a critical non-coding metabolic gene that is often aberrantly overexpressed in non-alcoholic fatty livers (NAFLD). However, the pathogenic role of miR-27 in NAFLD remains unknown. In this study, we attempted to identify the mechanism by which miR-27 was regulated in the context of insulin resistance, a predisposed metabolic disorder in NAFLD. Our data from cell culture and animal studies showed that insulin, CREB, and Hippo signalings coordinately regulated miR-27. First, miR-27 was upregulated in palmitate-treated cells and high fat diet-fed mouse livers, which exhibited insulin resistance and CREB overexpression. Second, miR-27 peaked in the mouse liver at the post-absorptive phase when CREB activity was increased. Also, miR-27 was increased rapidly in cell lines when CREB was deactivated by insulin treatment. Third, miR-27 was decreased in cultured cells when CREB was downregulated by siRNA or metformin treatment. In contrast, Forskolin-mediated activation of CREB promoted miR-27 expression. Fourth, Hippo signaling repressed miR-27 in a CREB-independent manner: miR-27 was reduced in cells at full confluence but was inhibited in cells transfected with siRNA against Lats2 and Nf2, which were two positive regulators of Hippo signaling. Lastly, bioinformatics and luciferase assay showed that miR-27 inhibited Akt phosphorylation by targeting Pdpk1 and Pik3r1. Overexpression of miR-27 impaired Akt phosphorylation in cell lines and primary mouse hepatocytes upon insulin stimulation. In conclusion, our data suggest that insulin, CREB, and Hippo signalings contribute to aberrant miR-27 overexpression and eventually lead to insulin resistance in NAFLD.

Introduction Fecal immunochemical testing (FIT) is the most commonly used colorectal cancer (CRC) screening tool worldwide and accounts for 10% of all CRC screening in the United States. Potential vulnerabilities for patients enrolled to facilities within the military health system have recently come to light requiring reassessment of best practices. We studied the impact of a process improvement initiative designed to improve the safety and quality of care for patients after a positive screening FIT given previously published reports of poor organization performance. Methods During a time of increased utilization of nonendoscopic means of screening, we assessed rates of colonoscopy completion and time to colonoscopy after positive FIT after a multi-faceted process improvement initiative was implemented, compared against an institutional control period. The interventions included mandatory indication labeling at the time of order entry, as well as utilization of subspecialty nurse navigators to facilitate rapid follow-up even the absence of a referral from primary care. Results Preintervention, 34.8% of patients did not have appropriate follow-up of a positive FIT. Those that did had a variable and prolonged wait time of 140.1 ± 115.9 days. Postintervention, a standardized order mandating test indication labeling allowed for proactive gastroenterology involvement. Colonoscopy follow-up rate increased to 91.9% with an average interval of 21.9 ± 12.3 days. Conclusion The addition of indication labels and patient navigation after positive screening FIT was associated with 57.1% absolute increase in timely diagnostic colonoscopy. Similar highly reliable systems-based solutions should be adopted for CRC screening, and further implementation for other preventative screening interventions should be pursued.

Human milk (HM) must be accurately fortified for extremely low birth weight (ELBW) preterm infants with human milk fortifiers (HMFs). Powdered HMF has some limitations in terms of sterilization and accuracy. A concentrated preterm formula (CPF) may serve as a safe liquid HMF to facilitate growth. Hence, we launched a quality improvement project for fortification accuracy of minute volume HM. A CPF, Similac Special Care 30 (SSC30), was newly introduced as an HMF when daily feeding reached 100 cm3/kg. CPF + HM (1:2 volume ratio), CPF + HM (1:1 volume ratio), and powdered HMF + HM (1 packet in 25 cm3) represented three fortification stages. Fortification shifted to powdered HMF while tolerable feeding reached 25 cm3/meal. The outcome was compared before (Period-I, January 2015 to June 2016, n = 37) and after the new implement (Period-II, July 2016 to December 2017, n = 36). Compared with the Period-I group, the Period-II group had significantly higher daily enteral milk intake in the first 4 weeks of life, and higher percentages of fortification in the HM-fed infants in the first 8 weeks after birth. The Period-II group also significantly increased in body weight growth in terms of z-score at term equivalent age (p = 0.04) and had better language and motor performance at 24 months old (p = 0.048 and p = 0.032, respectively). Using the liquid CPF as a strategical alternative fortification of HM might be beneficial for extremely preterm infants in terms of growth as well as neurodevelopment.

BACKGROUND Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. AIMS To explore genetic variants associated with chronic HBV infection. METHODS The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method. RESULTS Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10-35 ) was significantly associated with HBV chronicity (Pcorrected

Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

No standard treatment for Bacille Calmette–Guérin (BCG)-associated osteomyelitis, a rare but serious complication of the BCG vaccine, has been established. This study explored the short- and long-term outcomes of surgical intervention for BCG-associated osteomyelitis. Four patients with BCG osteomyelitis aged 9–21 months when diagnosed and treated at the Department of Orthopedics, Kaohsiung Veterans General Hospital, Taiwan, between January 2001 and April 2019 were analysed. Radiography revealed osteolytic lesions of the involved sites. Magnetic resonance imaging revealed physeal involvement in three patients. Debridement was performed for all four patients. One patient then underwent additional arthroscopy because of suspect intra-articular involvement. Specimens obtained intraoperatively were sent for pathology, culture, and to the national reference mycobacterial laboratory for BCG detection using polymerase chain reaction. All four patients had positive results for Mycobacterium bovis and satisfactory short-term results. Functional monitoring using QuickDASH or the Lower Extremity Functional Scale revealed excellent long-term outcomes despite tiny limb length discrepancy observed during follow-up in two patients. Prompt diagnosis plus proper intervention is required to prevent further major complications of BCG osteomyelitis. Minimally invasive debridement led to positive clinical outcomes and is therefore recommended.

To examine the effects of emotional distress, illness perception, and mental adjustment on return to work (RTW) among patients with head and neck cancer (HNC) and identify factors associated with RTW. A cross-sectional study with convenience sampling was conducted in Taiwan. Structured questionnaires were used to collect data on RTW status and to explore possible factors related to RTW. RTW status was assessed by a single question. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, illness perception was assessed by the Brief Illness Perception Questionnaire, and mental adjustment was assessed using the Mini-mental Adjustment to Cancer Scale. Sociodemographic and disease background data were also collected and analyzed. Factors related to RTW were identified by multivariate logistic regression. A total of 150 patients with HNC were recruited into the study. Of them, 58 (38.7%) returned to work after treatment. Compared to those who did not RTW, patients who did RTW had lower levels of emotional distress (anxiety and depression), better illness perception (cognitive illness representations and illness comprehensibility), and better mental adjustment (hopelessness and helplessness, anxious preoccupation, avoidance, and fatalism). Multivariable analysis indicated that anxiety (OR = 0.863, p < 0.05), avoidance (OR = 1.280, p < 0.001), cognitive illness representations (OR = 0.891, p < 0.01), illness comprehensibility (OR = 1.271, p < 0.05), higher education level (OR = 3.048–3.609, p < 0.05), married status (OR = 5.220, p < 0.05), tumor site in oral cavity (OR = 5.057, p < 0.05), and no reconstruction (OR = 3.415, p < 0.05) were significantly associated with RTW. The issue of RTW among patients with HNC is related to multidimensional factors, including sociodemographic, psychological, and disease-related situations. We suggest that programs for emotional rehabilitation and occupational counseling need to be developed to assist patients with HNC to RTW at an early stage.

Indomethacin has been widely used in preterm infants with hemodynamically significant patent ductus arteriosus (PDA). Gastrointestinal complications of indomethacin have been reported in 5% of treated neonates. However, massive gastric mucosa hemorrhage is a rarely reported complication. To the best of our knowledge, the infant in this report is the smallest reported in the literature to have undergone successful surgery for such a complication. A male preterm infant weighing 566 g was born at 252/7 weeks of gestational age without a complicated maternal history. Soon after birth, he received nasal noninvasive respiratory support and minimal feeding. PDA was observed since the first day of life (DOL), treatments were initiated on the second DOL for the hemodynamical significance, and PDA was closed after two courses of indomethacin therapy (0.2 mg/kg). At midnight on the seventh DOL, generalized pallor, bloody gastric drainage, and a distended stomach were observed. Massive gastric bleeding was suspected. He suffered from intermittent hypotension, which was corrected with blood products and fluid resuscitation under monitoring with a radial arterial line. Gastric lavage with cooling saline was performed twice but in vain. Prior to surgical consultation, intravascular volume transfusion was given twice. An exploratory laparotomy was arranged after obtaining the parents’ consent. Blood oozing from the gastric mucosa was observed through gastrostomy and was successfully stopped via epinephrine-soaked gauze compression. After the operation, his clinical course remained uneventful, and he was discharged without neurological anomaly at two-year follow-up. Physicians need to be cautious of indomethacin’s effect on platelet dysfunction in preterm infants with multiple predisposing factors. The tendency for mucosal bleeding should be continuously monitored after indomethacin therapy.

Background/purpose The purposes of this three-phase study were to: (1) translate and evaluate the burden, content, and face validity of the Chinese version of the University of Washington Quality of Life Scale, version 4 (UWQOL-v4-C); and (2) examine the psychometric properties of the UWQOL-v4-C in oral cancer and laryngeal cancer patients in Taiwan. Methods This instrument translation and validation study was part of a major research project. The first phase of this study developed and validated the content of the UWQOL-v4-C. The second phase sought to validate the internal consistency, reliability, and construct and discriminant validity in two major groups of head and neck cancer (HNC) patients: oral cavity cancers (n = 109) and laryngeal cancer (n = 102). Construct validity was measured using theoretically supported correlations between the UWQOL and related constructs. Discriminant validity was also assessed. In the third phase, test–retest reliability of UWQOL-v4-C was examined through the 1-week interval in another group of HNC patients (n = 50). Results The translated UWQOL-v4-C demonstrated satisfactory face validity, content validity, and minimal patient burden. Additionally, the UWQOL-v4-C showed excellent construct validity in patient testing, supported by significant correlations between the UWQOL-v4-C and hypothesized constructs, including generic measures of QOL and performance status. The developed scale correlated inversely with symptom severity and psychological distress. Discriminant validity was seen in patients with different cancer diagnoses, stages, and treatments. Finally, excellent stability was supported by a 1-week test–retest reliability of 0.88. Conclusion The UWQOL-v4-C was a brief, low-burden, and valid instrument to measure the QOL in Chinese-speaking HNC patients in Taiwan.

The tumor microenvironment (TME) is a key determinant of metastatic efficiency. We performed a quantitative high-throughput screen (qHTS) of diverse medicinal chemistry tractable scaffolds (44,420 compounds) and pharmacologically active small molecules (386 compounds) using a layered organotypic, robust assay representing the ovarian cancer metastatic TME. This 3D model contains primary human mesothelial cells, fibroblasts, and extracellular matrix, to which fluorescently labeled ovarian cancer cells are added. Initially, 100 compounds inhibiting ovarian cancer adhesion/invasion to the 3D model in a dose-dependent manner were identified. Of those, eight compounds were confirmed active in five high-grade serous ovarian cancer cell lines and were further validated in secondary in vitro and in vivo biological assays. Two tyrosine kinase inhibitors, PP-121 and milciclib, and a previously unreported compound, NCGC00117362, were selected because they had potency at 1 μmol/L in vitro. Specifically, NCGC00117362 and PP-121 inhibited ovarian cancer adhesion, invasion, and proliferation, whereas milciclib inhibited ovarian cancer invasion and proliferation. Using in situ kinase profiling and immunoblotting, we found that milciclib targeted Cdk2 and Cdk6, and PP-121 targeted mTOR. In vivo, all three compounds prevented ovarian cancer adhesion/invasion and metastasis, prolonged survival, and reduced omental tumor growth in an intervention study. To evaluate the clinical potential of NCGC00117362, structure–activity relationship studies were performed. Four close analogues of NCGC00117362 efficiently inhibited cancer aggressiveness in vitro and metastasis in vivo. Collectively, these data show that a complex 3D culture of the TME is effective in qHTS. The three compounds identified have promise as therapeutics for prevention and treatment of ovarian cancer metastasis.

Aim and objectives To determine whether the virtual reality as a distracting intervention could reduce pain and fear in school-age children receiving intravenous injections at an emergency department. Background An intravenous injection is the most common invasive procedure that paediatric patients encounter in emergency department. School-age children seldom show their fear or discomfort during the procedure which may be ignored. Design A randomised controlled trial was conducted from December 2017-May 2018 and performed according to the CONSORT guidelines. Methods One hundred and thirty-six children aged 7-12 years were randomly allocated to receive either a routine intravenous injection procedure or one with an immersive virtual reality experience. Children were asked to rate their pain and fear along with their caregivers and nurses on the Wong-Baker FACES Pain Rating Scale and Children's Fear Scale, respectively. The time required for successful intravenous insertion was also assessed in the emergency department. Clinical trial registration was done (ClinicalTrials.gov.: NCT04081935). Results Pain and fear scores were significantly lower in the virtual reality group, as were the children's ratings as perceived by their caregivers and nurses. The children's ratings of pain and fear were positively correlated with the caregivers' ratings and the nurses' ratings as well. The time required for successful intravenous insertion was significantly lower in the virtual reality group. Conclusion Visual reality intervention can effectively reduce the pain and fear during intravenous procedure in school-age children in emergency department. Relevance to clinical practice The results of this study indicate the feasible clinical value of virtual reality interventions during the administration of intravenous injections in school-age children in emergency departments.

Objective Head and neck cancer (HNC) patients suffer from symptoms and fear of recurrence (FoR), which both affect their quality of life (QoL). Based on a self-regulation model, the purpose of the study was to examine patients' FoR as a mediator of the relation between symptoms and QoL, and to identify which symptoms may trigger FoR. Methods A cross-sectional study was conducted, using convenience sampling. Structured questionnaires were used to collect data at a medical centre in Northern Taiwan. The analytic methods included descriptive statistics, structural equation modelling and linear regression. Results A total of 103 participants were recruited. Patients experienced a medium level of symptom severity and QoL but a moderate to high level of FoR. Symptom severity, FoR and QoL were significantly correlated. FoR was a significant partial mediator between symptom severity and QoL. The significant factors of the overall FoR and the subscale of health worry were "pain in general" and "pain in the mouth, throat or neck." "Pain in general" was a significant factor for the subscale of cancer worry. Conclusions This theory-driven study supports a mediation model of FoR among HNC patients and provides a more comprehensive understanding of the antecedents and consequences of FoR.

Oncology outpatient care centers generally subjugate patients' psychosocial needs to their physical care requirements. Consequently, the patients' self-management (SM) ability and utilization of social resources are essential in regulating their psychological distress (anxiety and depression). The study aims were (1) to examine the prevalence and severity of psychological distress in female cancer patients in outpatient settings in Taiwan and (2) to identify the major factors of psychological distress. Female cancer patients were recruited from oncology outpatient settings in Taiwan. Patients completed the questionnaires of anxiety, depression, social support, and utilization of social resources, and SM ability. In total, 116 patients were included. A total of 17.2% and 21.6% of the patients were at risk of anxiety and depression, respectively. Patients' mean anxiety and depression scores were 4.2 (SD = 4.1) and 4.1 (SD = 4.0), respectively. The patients' physical function, attendance of social support groups, degree of social support, and SM ability had a significant effect on their anxiety and depression. Patients' anxiety was intensified by the presence of comorbidity. Health professionals in oncology outpatient care centers should assess the patients' physical function, comorbidity, SM ability, and social support/engagement in order to reduce their psychological distress and devise appropriate follow-up interventions.

This study aimed to investigate the associations between Walk Score&reg, and lifestyle behaviors and health outcomes in older Taiwanese adults. A nationwide survey was conducted through telephone-based interviews with older adults (65 years and older) in Taiwan. Data on Walk Score&reg, lifestyle behaviors (physical activity, sedentary behavior, healthy eating behavior, alcohol use, and smoking status), health outcomes (overweight/obesity, hypertension, type 2 diabetes, and cardiovascular disease), and personal characteristics were obtained from 1052 respondents. A binary logistic regression adjusting for potential confounders was employed. None of the Walk Score&reg, categories were related to the recommended levels of total physical activity. The categories &ldquo, very walkable&rdquo, and &ldquo, walker&rsquo, s paradise&rdquo, were positively related to total sedentary time and TV viewing among older adults. No significant associations were found between Walk Score&reg, and other lifestyle health behaviors or health outcomes. While Walk Score&reg, was not associated with recommended levels of physical activity, it was positively related to prolonged sedentary time in the context of a non-Western country. The different associations between the walk score and health lifestyle behaviors and health outcomes in different contexts should be noted.

cope An elevated intracellular lipid contents resulted from lipid oversupply links obesity to insulin resistance. Flavanol-rich lychee fruit extract, oligonol, exhibited anti-obesity property in vitro and in vivo; however, the effects of oligonol on peripheral lipid metabolism and insulin sensitivity have not been fully investigated. We hypothesized that oligonol alleviated insulin resistance via decreasing intracellular lipid contents in peripheral tissues. Methods and results Dietary oligonol supplementation (20 or 200 mg/kg bw) reduced glucose and insulin levels, improved oral glucose tolerance, and suppressed inflammatory markers, MCP-1 and IL-6, in High-Fat diet (HFD) induced obese mice. Marked decreases in subcutaneous and visceral fat area, adipocyte size, and adipocyte released hormones including leptin and resistin by high-dose oligonol treatment were associated with downregulation of PPARγ gene expression. Significantly reduced intrahepatocellular lipid contents and hepatic triglyceride levels by oligonol (both doses) were associated with downregulation of mTOR/SREBP-1-mediated de novo lipogenesis. In skeletal muscle, oligonol enhanced Sirtuin1 protein expression and AMPKα activation, consequently resulted in reductions of intramuscular lipid contents and triglyceride levels and restoration of IRS-1 and AS160 phosphorylation. Conclusion Oligonol reduced intracellular lipid contents in liver and skeletal muscle and suppressed inflammatory markers, thereby alleviating HFD-induced insulin resistance.

Topical steroids are first-line treatment agents for eosinophilic esophagitis; however, some studies have demonstrated modest efficacy in inducing histologic remission.The aim of this study was to determine response to two topical steroids (fluticasone and budesonide), compare their efficacy, and examine patient characteristics which could predict non-response to topical steroids.We performed a retrospective review of an established EoE registry. Inclusion criteria were patients1 year of age who were diagnosed with EoE as defined by the most recent consensus guidelines. All patients were treated with an 8-week course of either swallowed fluticasone or viscous budesonide. Responders were defined as achieving15 eosinophils per high-power field (eos/hpf) in both proximal and distal esophageal biopsies. Demographic, clinical, endoscopic, and histologic features were examined.The study cohort included 75 EoE patients with a median age of 33 years (range 2-64 years), 71 % adults, 84 % male, and 76 % Caucasian. Overall histologic response rate to topical steroids was 51 %, while clinical response was 71 %. There was no significant differences in histologic response to treatment between children and adults (68 vs. 44 %, p = 0.111). There was no significant difference in response between males and females (47 vs. 73 %, p = 0.191) and between the two types of steroids (48 vs. 56 %, p = 0.632). Responders and non-responders were similar in clinical presentation and baseline endoscopic findings. Following treatment, responders had significantly less peak proximal (4.0 ± 4.4 vs. 46 ± 53, p 0.001) and distal eosinophil counts (3.5 ± 3.8 vs. 60 ± 47, p 0.001) compared to non-responders. There were no predictors of response to steroids identified.Histologic response to treatment was observed in approximately half the cohort, while more than two-thirds experienced clinical response to topical steroids. Response was similar between fluticasone and budesonide. Given the lack of differences in clinical presentation or endoscopic features, predictors of non-response were not seen.

Avicennia marina is the most abundant and common mangrove species and has been used as a traditional medicine for skin diseases, rheumatism, ulcers, and smallpox. However, its anticancer activities and polyphenol contents remain poorly characterized. Thus, here we investigated anticancer activities of secondary A. marina metabolites that were purified by sequential soxhlet extraction in water, ethanol, methanol, and ethyl acetate (EtOAc). Experiments were performed in three human breast cancer cell lines (AU565, MDA-MB-231, and BT483), two human liver cancer cell lines (HepG2 and Huh7), and one normal cell line (NIH3T3). The chemotherapeutic potential of A. marina extracts was evaluated in a xenograft mouse model. The present data show that EtOAc extracts of A. marina leaves have the highest phenolic and flavonoid contents and anticancer activities and, following column chromatography, the EtOAc fractions F2-5, F3-2-9, and F3-2-10 showed higher cytotoxic effects than the other fractions. 1H-NMR and 13C-NMR profiles indicated that the F3-2-10 fraction contained avicennones D and E. EtOAc extracts of A. marina leaves also suppressed xenograft MDA-MB-231 tumor growth in nude mice, suggesting that EtOAc extracts of A. marina leaves may provide a useful treatment for breast cancer.

Nasopharyngeal carcinoma (NPC) is a malignancy derived from the epithelial cells of the nasopharynx. Although a combination of radiotherapy with chemotherapy is effective for therapy, relapse and metastasis after remission remain major causes of mortality. Epstein-Barr virus (EBV) is believed to be one of causes of NPC development. We demonstrated previously that EBV reactivation is important for the carcinogenesis of NPC. We sought, therefore, to determine whether EBV reactivation can be a target for retardation of relapse of NPC. After screening, we found luteolin is able to inhibit EBV reactivation. It inhibited EBV lytic protein expression and repressed the promoter activities of two major immediate-early genes, Zta and Rta. Furthermore, luteolin was shown to reduce genomic instability induced by recurrent EBV reactivation in NPC cells. EBV reactivation-induced NPC cell proliferation and migration, as well as matrigel invasiveness, were also repressed by luteolin treatment. Tumorigenicity in mice, induced by EBV reactivation, was decreased profoundly following luteolin administration. Together, these results suggest that inhibition of EBV reactivation is a novel approach to prevent the relapse of NPC.

In clinical trials of tofacitinib for rheumatoid arthritis (RA), Japanese and Korean patients had higher incidence of herpes zoster (HZ) than subjects from elsewhere; however, post-market data from Asia are lacking. Hence, we investigated the incidence of HZ and its risk factors in Taiwanese RA patients receiving tofacitinib. At a medical center in Taichung, Taiwan, we enrolled patients with active RA treated with tofacitinib between January 4, 2015 and December 9, 2017, following unsuccessful methotrexate therapy and no tofacitinib exposure RA patients as a control group. Demographic characteristics, interferon-gamma levels, and lymphocyte counts were compared. Among 125 tofacitinib-treated RA patients, 7 developed HZ, an incidence rate of 3.6/100 person-years. Patients with HZ had shorter disease duration than those without, but higher frequency of prior HZ. Baseline interferon-gamma levels and HLA-DR+ activated T cell counts were positively correlated and significantly lower in patients with HZ than without. Strikingly, 5/7 HZ cases occurred within 4 months of starting tofacitinib therapy. Incidence of HZ in tofacitinib-treated Taiwanese RA patients is lower than rates in Japan or Korea, and commensurate with the global average. HZ may occur soon after commencing tofacitinib therapy. The role of interferon-gamma and activated T cells in tofacitinib-related HZ deserves further investigation.

Pharmacokinetic studies of maxacalcitol in healthy Taiwanese subjects have been conducted. This study to compare the pharmacokinetic properties of maxacalcitol in healthy Taiwanese and Japanese subjects. Healthy male Taiwanese subjects (n = 24) and healthy male Japanese subjects (n = 24) were enrolled in separate single-center and received a single intravenous dose of 1.25, 2.5 and 5 μg maxacalcitol. Male subjects were exclusively employed in the study due to the first administration of maxacalcitol to Taiwanese. Serum samples were collected for up to 72 h for pharmacokinetic analysis, and safety was assessed. Exposures to maxacalcitol as mean C5 and AUCinf appeared to increase with increase of doses in Taiwanese subjects (C5: 74.0, 159, and 321 pg/mL; AUCinf: 473, 763, and 1460 h･pg/mL) and Japanese subjects (C5: 92.9, 174, and 346 pg/mL; AUCinf: 312, 588, and 1040 h･pg/mL). After single bolus IV administration, linearity in maxacalcitol exposure was shown over the dose range of 1.25–5 μg in both Taiwanese and Japanese male healthy subjects. C5 of maxacalcitol was slightly lower (85%) in Taiwanese compared with that in Japanese and AUCinf of maxacalcitol in Taiwanese subjects was contrarily 15.0 (41.6%) higher than that in Japanese subjects, resulted in not much difference in pharmacokinetics of maxacalcitol between Taiwanese and Japanese. Moreover, maxacalcitol was well tolerated in both healthy Taiwanese and Japanese subjects., Maxacalcitol, Pharamcokinetics, Phase I study, Oxarol, Direct comparison study, Physical chemistry; Pharmaceutical science; Musculoskeletal system; Renal system; Pharmacology.

Gamma knife treatment outcome of large pituitary tumors which are only partially irradiated secondary to immediate proximity to critical structures such as the optic apparatus have not been rigorously studied.From July 2003 to December 2013, there were 41 cases of recurrent or residual nonfunctioning pituitary macroadenoma partially treated with gamma knife radiosurgery (GKRS) because the adenoma obscured part of the optic apparatus on planning SRS MR imaging.The follow up period after GKRS was 92.3 ± 5.6 months. The percentage of tumor coverage with the full dose was 88.5 ± 0.7%. Five of 43 (11.6%) patients experienced a transient visional decrease and one patient experienced a permanent visual field defect. During the follow up, two patients underwent transphenoidal surgery and one patient had a craniotomy due to tumor progression. Seven patients (16.2%) developed cortisol and thyroxine deficiencies. In multiple variant analyses, transient visual decline was correlated to the tumor volume ( 3.5 cc), percentage of tumor coverage ( 90%), the distance from the optic apparatus to the pituitary stalk ( 15 mm) and percentage of tumor above the orbital apex (65%).In the limited case of this cohort, we found that partially treated pituitary nonfunctioning macroadenoma yielded a high tumor control rate. However, visual decline as a result of tumor progression or radiation effect can occur in a minority of patients. The radiosurgical technique warrants further study to better define the long-term risk to benefit profile for its use in complex pituitary macroadenoma obscuring part of the optic apparatus.

The membrane-bound serine proteases prostasin and matriptase and the Kunitz-type protease inhibitors HAI-1 and HAI-2 are all expressed in human skin and may form a tightly regulated proteolysis network, contributing to skin pathophysiology. Evidence from other systems, however, suggests that the relationship between matriptase and prostasin and between the proteases and the inhibitors can be context-dependent. In this study the in vivo zymogen activation and protease inhibition status of matriptase and prostasin were investigated in the human skin. Immunohistochemistry detected high levels of activated prostasin in the granular layer, but only low levels of activated matriptase restricted to the basal layer. Immunoblot analysis of foreskin lysates confirmed this in vivo zymogen activation status and further revealed that HAI-1 but not HAI-2 is the prominent inhibitor for prostasin and matriptase in skin. The zymogen activation status and location of the proteases does not support a close functional relation between matriptase and prostasin in the human skin. The limited role for HAI-2 in the inhibition of matriptase and prostasin is the result of its primarily intracellular localization in basal and spinous layer keratinocytes, which probably prevents the Kunitz inhibitor from interacting with active prostasin or matriptase. In contrast, the cell surface expression of HAI-1 in all viable epidermal layers renders it an effective regulator for matriptase and prostasin. Collectively, our study suggests the importance of tissue distribution and subcellular localization in the functional relationship between proteases and protease inhibitors.

Adenosine-to-inosine (A-to-I) editing is widespread across the kingdom Metazoa. However, for the lack of comprehensive analysis in nonmodel animals, the evolutionary history of A-to-I editing remains largely unexplored. Here, we detect high-confidence editing sites using clustering and conservation strategies based on RNA sequencing data alone, without using single-nucleotide polymorphism information or genome sequencing data from the same sample. We thereby unveil the first evolutionary landscape of A-to-I editing maps across 20 metazoan species (from worm to human), providing unprecedented evidence on how the editing mechanism gradually expands its territory and increases its influence along the history of evolution. Our result revealed that highly clustered and conserved editing sites tended to have a higher editing level and a higher magnitude of the ADAR motif. The ratio of the frequencies of nonsynonymous editing to that of synonymous editing remarkably increased with increasing the conservation level of A-to-I editing. These results thus suggest potentially functional benefit of highly clustered and conserved editing sites. In addition, spatiotemporal dynamics analyses reveal a conserved enrichment of editing and ADAR expression in the central nervous system throughout more than 300 Myr of divergent evolution in complex animals and the comparability of editing patterns between invertebrates and between vertebrates during development. This study provides evolutionary and dynamic aspects of A-to-I editome across metazoan species, expanding this important but understudied class of nongenomically encoded events for comprehensive characterization.

Human immunodeficiency virus (HIV)-1 epidemics in Asian countries are driven by varying exposures. The epidemiology of the regional pandemic has been changing with the spread of HIV-1 to lower-risk populations through sexual transmission. Common HIV-1 genotypes include subtype B and circulating recombinant form (CRF) 01_AE. Our objective was to use HIV-1 genotypic data to better quantify local epidemics. TASER-M is a multicenter prospective cohort of HIV-infected patients. Associations between HIV exposure, patient sex, country of sample origin and HIV-1 genotype were evaluated by multivariate logistic regression. Phylogenetic methods were used on genotypic data to investigate transmission relationships. A total of 1086 patients from Thailand, Hong Kong, Malaysia and the Philippines were included in analyses. Proportions of male patients within countries varied (Thailand: 55.6%, Hong Kong: 86.1%, Malaysia: 81.4%, Philippines: 93.8%; p

Background Gamma Knife radiosurgery (GKRS) is an important part of the neurosurgical armamentarium in the treatment of acoustic neuromas. However, the treatment outcome related to the morphology of the tumor has not been rigorously studied. In this cohort, we evaluated the morphological features of the tumor in the tumor response and neurological outcomes after GKRS. Material and methods From July 2003 to December 2008, there were 93 cases of acoustic neuromas treated upfront with GKRS with 64 cases with serviceable hearing and 29 cases without serviceable hearing to fulfill the margin dose of 12Gy with at least follow up 5 years. Results The duration of symptom before GKRS in serviceable /no serviceable hearing was 7.9 ± 1.2 and 15.3 ± 3.1 months (p

Transcriptionally non-co-linear (NCL) transcripts can originate from trans-splicing (trans-spliced RNA; ‘tsRNA’) or cis-backsplicing (circular RNA; ‘circRNA’). While numerous circRNAs have been detected in various species, tsRNAs remain largely uninvestigated. Here, we utilize integrative transcriptome sequencing of poly(A)- and non-poly(A)-selected RNA-seq data from diverse human cell lines to distinguish between tsRNAs and circRNAs. We identified 24,498 NCL events and found that a considerable proportion (20–35%) of them arise from both tsRNAs and circRNAs, representing extensive alternative trans-splicing and cis-backsplicing in human cells. We show that sequence generalities of exon circularization are also observed in tsRNAs. Recapitulation of NCL RNAs further shows that inverted Alu repeats can simultaneously promote the formation of tsRNAs and circRNAs. However, tsRNAs and circRNAs exhibit quite different, or even opposite, expression patterns, in terms of correlation with the expression of their co-linear counterparts, expression breadth/abundance, transcript stability, and subcellular localization preference. These results indicate that tsRNAs and circRNAs may play different regulatory roles and analysis of NCL events should take the joint effects of different NCL-splicing types and joint effects of multiple NCL events into consideration. This study describes the first transcriptome-wide analysis of trans-splicing and cis-backsplicing, expanding our understanding of the complexity of the human transcriptome.

By using RNA-immunoprecipitation assay following next-generation sequencing, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Overexpressed hnRNP Q1 can upregulate Aurora-A protein, but not alter the mRNA level, through enhancing the translational efficiency of Aurora-A mRNA, either in a cap-dependent or -independent manner, by interacting with the 5′-UTR of Aurora-A mRNA through its RNA-binding domains (RBDs) 2 and 3. By ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1. Overexpression of hnRNP Q1 promotes cell proliferation and tumor growth. HnRNP Q1/ΔRBD23-truncated mutant, which loses the binding ability and translational regulation of Aurora-A mRNA, has no effect on promoting tumor growth. The expression level of hnRNP Q1 is positively correlated with Aurora-A in colorectal cancer. Taken together, our data indicate that hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A mRNA 5′-UTRs and regulates its translation, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer.

BACKGROUND The diagnosis and management of eosinophilic esophagitis (EoE) often requires multiple endoscopies. Serum biomarkers can be elevated in EoE patients, but their clinical utility in diagnosis and assessing response to treatment is not well established. GOALS To evaluate serum biomarkers in EoE subjects compared with controls and assess longitudinally in response to treatment. STUDY We conducted a prospective cohort study of children and adults undergoing esophagogastroduodenoscopy for suspected EoE. After completing an 8-week course of proton-pump inhibitor therapy, esophageal mucosal biopsies were obtained, as well as, serum analysis of absolute eosinophil count (AEC), eotaxin-3, eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and interleukin-5. Subjects with normal endoscopic and histologic findings constituted controls. Those meeting criteria for EoE underwent repeat esophagogastroduodenoscopy and biomarker measurements following treatment with topical steroids for 8 weeks. RESULTS Median levels of AEC (263.50 vs. 102 cu/mm, P

BACKGROUND Some patients with a phenotypic appearance of eosinophilic oesophagitis (EoE) respond histologically to PPI, and are described as having PPI-responsive oesophageal eosinophilia (PPI-REE). It is unclear if PPI-REE is a GERD-related phenomenon, a subtype of EoE, or a completely unique entity. AIM To compare demographic, clinical and histological features of EoE and PPI-REE. METHODS Two databases were reviewed from the Walter Reed and Swiss EoE databases. Patients were stratified into two groups, EoE and PPI-REE, based on recent EoE consensus guidelines. Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least a 6-week course of treatment. RESULTS One hundred and three patients were identified (63 EoE and 40 PPI-REE; mean age 40.2 years, 75% male and 89% Caucasian). The two cohorts had similar dysphagia (97% vs. 100%, P = 0.520), food impaction (43% vs. 35%, P = 0.536), and heartburn (33% vs. 32%, P = 1.000) and a similar duration of symptoms (6.0 years vs. 5.8 years, P = 0.850). Endoscopic features were also similar between EoE and PPI-REE; rings (68% vs. 68%, P = 1.000), furrows (70% vs. 70%, P = 1.000), plaques (19% vs. 10%, P = 0.272), strictures (49% vs. 30%, P = 0.066). EoE and PPI-REE were similar in the number of proximal (39 eos/hpf vs. 38 eos/hpf, P = 0.919) and distal eosinophils (50 vs. 43 eos/hpf, P = 0.285). CONCLUSIONS EoE and PPI-responsive oesophageal eosinophilia are similar in clinical, histological and endoscopic features and therefore are indistinguishable without a PPI trial. Further studies are needed to determine why a subset of patients with oesophageal eosinophilia respond to PPI.