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Ling-ling Zhu,1 Yan-hong Wang,2 Jian-hua Feng,3 Quan Zhou2 1VIP Geriatric Ward, Division of Nursing, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 3Department of Pediatrics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou, 310009, Zhejiang Province, People’s Republic of China, Email zhouquan142602@zju.edu.cn Jian-hua Feng, Department of Pediatrics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou, 310009, Zhejiang Province, People’s Republic of China, Email hzhz87083886@zju.edu.cnBackground: Bacterial lysates are known for having immunomodulatory properties and have been used mainly for the prevention and treatment of respiratory tract infections (RTIs). However, rigorous studies are needed to confirm the clinical efficacy of bacterial lysates with various bacterial antigen components, preparation methods, administration routes and course of treatment. OM-85, an oral standardized lysate prepared by alkaline lysis of 21 strains from 8 species of common respiratory tract pathogens, is indicated as immunotherapy for prevention of recurrent RTIs and acute infectious exacerbations of chronic bronchitis. OM-85 acts on multiple innate and adaptive immune targets and can restore type 1 helper T (Th1)/Th2 balance. Sporadic studies have shown advances in pharmacology and therapeutics of OM-85, and thus an update review is necessary.Methods: Literature was retrieved by searching PubMed, Web of science, Embase, CNKI, and Full Text Database of Chinese Medical Journals.Results: New roles of OM-85 were discovered in prevention and treatment of lung cancer, pulmonary tuberculosis, SARS-CoV-2 infection, allergic rhinitis, pulmonary fibrosis, atopic dermatitis, and nephrotic syndrome. Pharmacoeconomic values of OM-85 were demonstrated in prophylaxis and treatment of RTIs, chronic obstructive pulmonary disease, asthma, chronic bronchitis, rhinosinusitis and allergic rhinitis. Two consecutive courses of OM-85 (6 or 12 months apart) could prevent recurrent RTIs in children. Maternal OM-85 treatment could offer benefits for offspring. Product-specific response was observed. The efficacy of OM-85 may be associated with patient’s characteristics (eg, severity of the disease, age, immune response pattern, malignancy risk stratification).Conclusion: OM-85 can improve effectiveness of standard care for some primary diseases, and carry significant pharmacoeconomic implications. The benefits shown by OM-85 in vitro and in vivo, when extrapolated to humans, are exciting but also require caution. Individualized treatment may need to be considered. It is necessary to compare the efficacy and safety of various bacterial lysate preparations.Keywords: airway inflammatory disease, allergic diseases, bacterial lysates, immunomodulator, OM-85, pharmacoeconomic evaluation

Chien-Hui Pan,1,2 Tzen-Yuh Chiang,2 Hui-Chi Hsieh,1 Ya-Huei Wang3,4 1Education Center, National Cheng Kung University Hospital, Tainan, Taiwan; 2Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan; 3Department of Applied Foreign Languages, Chung Shan Medical University, Taichung, Taiwan; 4Department of Medical Education, Chung Shan Medical University Hospital, Taichung, TaiwanCorrespondence: Ya-Huei Wang, Chung Shan Medical University, Department of Applied Foreign Languages, 110, Sec. 1, Jian-Koa N. Road, Taichung, 402, Taiwan, Tel +886-4-24730022 Ex 12003, Email yhuei@csmu.edu.twObjective: In Taiwanese clinical and healthcare environments, there is a dearth of appropriate and effective tools to evaluate clinical teachers’ occupational well-being. Therefore, this study aimed to develop a culturally adapted scale, a Taiwanese version of the Clinical Teachers’ Occupational Well-Being Dimensions Scale (CTOWDS), to accurately measure the occupational well-being of clinical teachers in Taiwan.Methods: Following a comprehensive literature review and expert panel discussions, the study developed the CTOWDS and conducted exploratory factor analysis (EFA) with 346 participants using SPSS to identify its underlying dimensional structure and psychometric properties. Confirmatory factor analysis (CFA) was then performed with 255 participants using AMOS to validate the EFA results. The study also assessed internal consistency, convergent and discriminant validities, and goodness-of-fit indexes to ensure that the scale was valid and reliable in the Taiwanese cultural setting.Results: The EFA refined the scale from 51 to 29 items across five dimensions: personal qualities (11 items), academic research and career development pressure (6 items), teaching experience (4 items), learning experience (4 items), and teaching and communication pressure (4 items). These five dimensions explained 65.279% of the total variance. The CFA confirmed the five dimensions and 29 items, with good convergent and discriminant validities, goodness-of-fit indexes, and Cronbach’s alpha values exceeding 0.70.Conclusion: The findings affirm the utility of the developed CTOWDS as a reliable and culturally relevant instrument for assessing the occupational well-being of clinical teachers.Keywords: occupational well-being, clinical teachers, scale development, psychometric validation

Yang Zhao,1,* Yi-Han Wang,2,* Wei-Chao Tu,1 Da-Wei Wang,1 Mu-Jun Lu,3,4 Yuan Shao1 1Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, 201800, People’s Republic of China; 2Department of Urology, Sixth People’s Hospital South Campus Affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Urology and Andrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Shanghai Institute of Andrology, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mu-Jun Lu; Yuan Shao, Email lumujun@163.com; shaoyuan10772@163.comBackground: Chronic kidney disease (CKD) is a significant worldwide health concern that leads to high mortality rates. The bioactive substance costunolide (CTD) has demonstrated several pharmacological effects and holds promise as a CKD treatment. This study aims to investigate the impact of CTD on CKD and delve into its mechanisms of action.Methods: Unilateral ureteral obstruction (UUO) methods and renal fibrosis mice models were created. Various concentrations of CTD were injected into UUO mice models to investigate the therapeutic effects of CTD on renal fibrosis of mice. Then, renal morphology, pathological changes, and the expression of genes related to fibrosis, inflammation and ferroptosis were analysed. RNA sequencing was utilized to identify the main biological processes and pathways involved in renal injury. Finally, both overexpression and inhibition of IKKβ were studied to examine their respective effects on fibrosis and inflammation in both in vitro and in vivo models.Results: CTD treatment was found to significantly alleviate fibrosis, inflammation and ferroptosis in UUO-induced renal fibrosis mice models. The results of RNA sequencing suggested that the IKKβ acted as key regulatory factor in renal injury and the expression of IKKβ was increased in vitro and in vivo renal fibrosis model. Functionally, down-regulated IKKβ expression inhibits ferroptosis, inflammatory cytokine production and collagen deposition. Conversely, IKKβ overexpression exacerbates progressive renal fibrosis. Mechanistically, CTD alleviated renal fibrosis and inflammation by inhibiting the expression of IKKβ and attenuating IKKβ/NF-κB pathway.Conclusion: This study demonstrates that CTD could mitigate renal fibrosis, ferroptosis and inflammation in CKD by modulating the IKKβ/NF-κB pathway, which indicates targeting IKKβ has an enormous potential for treating CKD. Keywords: chronic kidney disease, costunolide, renal fibrosis, IKKβ/NF-κB pathway

Yan-hong Wang,1,* Ling-ling Zhu,2,* Tian-lang Li,3 Quan Zhou1 1Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2VIP Geriatric Ward, Division of Nursing, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 3Department of VIP Care and Geriatric Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Shangcheng District, Hangzhou, 310009, Zhejiang Province, People’s Republic of China, Email zhouquan142602@zju.edu.cn Tian-lang Li, Department of VIP Care and Geriatric Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China, Email 2194012@zju.edu.cnAbstract: Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.Keywords: cyclooxygenase-2, efficacy, imrecoxib, non-steroidal anti-inflammatory drug, older adults, osteoarthritis, safety

Abstract The TAROGE-M radio observatory is a self-triggered antenna array on top of the ∼2700 m high Mt. Melbourne in Antarctica, designed to detect impulsive geomagnetic emission from extensive air showers induced by ultra-high energy (UHE) particles beyond 1017 eV, including cosmic rays, Earth-skimming tau neutrinos, and particularly, the “ANITA anomalous events” (AAE) from near and below the horizon. The six AAE discovered by the ANITA experiment have signal features similar to tau neutrinos but that hypothesis is in tension either with the interaction length predicted by Standard Model or with the flux limits set by other experiments. Their origin remains uncertain, requiring more experimental inputs for clarification. The detection concept of TAROGE-M takes advantage of a high altitude with synoptic view toward the horizon as an efficient signal collector, and the radio quietness as well as strong and near vertical geomagnetic field in Antarctica, enhancing the relative radio signal strength. This approach has a low energy threshold, high duty cycle, and is easy to extend for quickly enlarging statistics. Here we report experimental results from the first TAROGE-M station deployed in January 2020, corresponding to approximately one month of livetime. The station consists of six receiving antennas operating at 180-450 MHz, and can reconstruct source directions of impulsive events with an angular resolution of ∼0.3°, calibrated in situ with a drone-borne pulser system. To demonstrate TAROGE-M's ability to detect UHE air showers, a search for cosmic ray signals in 25.3-days of data together with the detection simulation were conducted, resulting in seven identified candidates. The detected events have a mean reconstructed energy of 0.95-0.31+0.46 EeV and zenith angles ranging from 25° to 82°, with both distributions agreeing with the simulations, indicating an energy threshold at about 0.3 EeV. The estimated cosmic ray flux at that energy is 1.2-0.9+0.7 × 10-16 eV-1 km-2 yr-1 sr-1, also consistent with results of other experiments. The TAROGE-M sensitivity to AAEs is approximated by the tau neutrino exposure with simulations, which suggests comparable sensitivity as ANITA's at around 1 EeV energy with a few station-years of operation. These first results verified the station design and performance in a polar and high-altitude environment, and are promising for further discovery of tau neutrinos and AAEs after an extension in the near future.

Ling-Ling Zhu,1 Yan-Hong Wang,2 Mei-Juan Lan,3 Quan Zhou2 1VIP Geriatric Ward, Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 3Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou, 310009, People’s Republic of China, Email zhouquan142602@zju.edu.cn Mei-Juan Lan, Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou, 310009, People’s Republic of China, Email lanmj@zju.edu.cnAbstract: Medication reconciliation (MR) is the process of comparing a patient’s medication orders to all of the medications that the patient has been taking in order to identify and resolve medication discrepancies. It is an effective means of risk management to avoid medication errors (eg, omissions, duplication, dosage errors, or drug interactions). Some guidelines explicitly state that MR is a pharmacist-led transition of care; however, there is a shortage of qualified pharmacists to meet the increasing clinical needs, and clinical nurses’ roles have not been clearly described. This paper aimed to enable nurses to gain confidence in contributing to MR at discharge and to make the industry aware of the potential risks if nurses do not actively intervene in this area. A narrative approach was used to introduce experiences in identifying discrepancies and medication errors through MR at discharge in a geriatric ward of an academic medical center hospital in China. The nurses’ main roles in MR involve chasing, checking, and education. Clinical nurses, an untapped hospital resource, can actively engage in MR at discharge if they receive effective training and motivation. Multidisciplinary collaboration at discharge allowed many discrepancies to be reconciled before harming older patients. It is worth conducting further research in MR when discharging older adults, such as the cost-effectiveness of nurses’ efforts, the value of electronic tools and the impact of MR-targeted education and training for nursing students and nursing staff.Keywords: hospital discharge, medication reconciliation, multidisciplinary collaboration, older adults, patient safety

Ling-Ling Zhu,1,* Yan-Hong Wang,2,* Quan Zhou2 1VIP Geriatric Ward, Division of Nursing, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan Zhou, Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Shangcheng District, Hangzhou, Zhejiang Province, 310009, People’s Republic of China, Email zhouquan142602@zju.edu.cnBackground: Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration.Methods: Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase.Results: Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer’s disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel.Conclusion: Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.Keywords: musculoskeletal pain, skeletal muscle relaxants, neuropathic pain, older adults, tizanidine

Jia-Jia Hu,* Yu-Sen Lin,* Jing-Cong Zhang, Yan-Hong Wang Medical Intensive Care Unit, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Hong Wang, Email wangyh28@mail.sysu.edu.cnBackground: In the context of progressively uncontrolled drug resistance of bacteria, the difficulty of treating Klebsiella (KP)-induced pneumonia increases. Searching for drugs other than antibiotics has become an urgent task. Vitamin D (VD), meanwhile, is shown to be capable of treating pneumonia. Therefore, we aimed to explore the effects and mechanisms of VD on KP-infected rats.Methods: Male Sprague Dawley rats were divided into the Control, VD, KP and KP+VD groups. A rat pneumonia model was induced using an intratracheal drop of 2.4× 108 CFU/mL KP. VD treatment was performed by gavage using 5 μg/kg. Subsequently, the survival of the rats was recorded, and the lungs, bronchoalveolar lavage fluid, and feces of the rats were collected 4 days after KP infection. Next, the water content of lung tissues was measured by the wet-to-dry weight ratio. Histopathological changes of lung tissues were observed by Hematoxylin and Eosin staining and the levels of inflammatory factors (TNF-α, IL-1β, MCP1) were detected using ELISA. The feces of rats in each group were also subjected to 16S rDNA gene analysis of intestinal microbiota.Results: Compared with the KP group, the KP+VD group showed a significant increase in survival, a significant decrease in water content and bacterial counts in the lungs, a significant improvement in lung injury, and a significant decline in the levels of TNF-α, IL-1β, and MCP1. According to the 16S rDNA sequencing, VD altered the structure of the intestinal bacterial community in the KP-infected rats and made the species richness similar to that of healthy rats. Additionally, the abundance of Anaeroglobus was significantly increased in the KP+VD group.Conclusion: VD modulates intestinal microbiota to increase the resistance of rats to pneumonia caused by Klebsiella infection.Keywords: severe pneumonia, Klebsiella, intestinal microbiota, vitamin D

Abstract Collapse of the edge flow shear as the line-averaged density approaches the Greenwald density limit has been observed as a precursor to the enhanced edge particle flux characteristic of proximity to the density limit regime. Here, we report the use of a biased electrode to sustain the edge shear layer in high density discharges, in which the shear layer would otherwise collapse. A stable increase in line-averaged density is observed along with a strong increase in edge density. These experiments were carried out on the J-TEXT tokamak. The Reynolds stress at the edge is enhanced, and the zonal flow sustained, while density perturbation levels, the flux of turbulence internal energy (i.e., turbulence spreading), and particle and heat flux all decrease significantly. Electron adiabaticity increases, and bias voltage modulation experiments show that an increase in the edge shear leads the increase in adiabaticity. These results suggest that external edge E × B flow shear drive may be of interest for sustaining edge plasma states at high density, and support the hypothesis that collapse of the edge shear layer triggers the onset of the strong transport and turbulence characteristic of the density limit regime.

Zhi-Feng Liu,* Yang Zhang,* Jing Liu, Yu-Yan Wang, Mo Chen, Er-Yang Liu, Jun-Ming Guo, Yan-Hua Wang, Zhi-Wen Weng, Chang-Xin Liu, Chang-He Yu, Xi-You Wang Tuina and Pain Management Department, Beijing University of Chinese Medicine Affilliated Dongzhimen Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chang-He Yu; Xi-You Wang, Email yakno2@163.com; dwxy658@163.comAbstract: Knee osteoarthritis (KOA) stands as a degenerative ailment with a substantial and escalating prevalence. The practice of traditional Chinese non-pharmacological therapy has become a prevalent complementary and adjunctive approach. A mounting body of evidence suggests its efficacy in addressing KOA. Recent investigations have delved into its underlying mechanism, yielding some headway. Consequently, this comprehensive analysis seeks to encapsulate the clinical application and molecular mechanism of traditional Chinese non-pharmacological therapy in KOA treatment. The review reveals that various therapies, such as acupuncture, electroacupuncture, warm needle acupuncture, tuina, and acupotomy, primarily target localized knee components like cartilage, subchondral bone, and synovium. Moreover, their impact extends to the central nervous system and intestinal flora. More perfect experimental design and more comprehensive research remain a promising avenue in the future.Keywords: knee osteoarthritis, traditional Chinese non-pharmacological therapy, mechanism, acupuncture, tuina, acupotomy

Chen-Yu Chen,1,2 Ying-Hao Wang,1 Chie-Pein Chen,1 Fang-Ju Sun,3 Yi-Yung Chen,1 Yu-Jun Huang,1 Nan-Fu Chiu4,5 1Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, 10449, Taiwan; 2Department of Medicine, MacKay Medical College, New Taipei City, 252005, Taiwan; 3Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan; 4Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, Taipei, 11677, Taiwan; 5Department of Life Science, National Taiwan Normal University, Taipei, 11677, TaiwanCorrespondence: Chen-Yu Chen, Department of Obstetrics and Gynecology, MacKay Memorial Hospital, No. 92, Section 2, Zhong-Shan North Road, Taipei, 10449, Taiwan, Tel +886-2-25433535, Fax +886-2-25433642, Email f122481@mmh.org.tw Nan-Fu Chiu, Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, No. 88, Section 4, Ting-Chou Road, Taipei, 11677, Taiwan, Tel +886-2-77496722, Fax +886-2-86631954, Email nfchiu@ntnu.edu.twBackground: Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor.Methods: This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups.Results: Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73– 0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96– 1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68– 0.81, P < 0.001).Conclusion: Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia. Keywords: graphene oxide, surface plasmon resonance, biosensor, preeclampsia, PAPP-A/PAPP-A2 ratio

Ling-Ling Zhu,1 Yan-hong Wang,2 Quan Zhou2 1VIP Geriatric Ward, Division of Nursing, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Quan Zhou, Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Jiefang Road No. 88, Hangzhou, Zhejiang Province, 310009, People’s Republic of China, Email zhouquan142602@zju.edu.cnBackground: Phlebitis is a common complication of intravenous administration and greatly affects clinical outcomes, patient satisfaction, and health-care expenditure. Numerous studies have revealed venous injuries only through visual and histopathological examination. Although sporadic studies have explored the cellular and molecular biological mechanisms of phlebitis and the outcomes of pharmacological interventions, an updated review over the last decade is not available.Methods: Progress in research on the mechanisms and interventions of phlebitis was summarized from the perspective of endothelial cells and signaling pathways by retrieving the PubMed, Web of Science Core Collection, MEDLINE, Embase, and CNKI.Results: Phlebitis involves multiple signaling pathways (eg, nuclear factor kappa B, Wnt/β-catenin, focal adhesion kinase/protein kinase B, Toll-like receptor, protein kinase C beta/NADPH oxidase, PI3K/AKT/TNF, and JAK2/STAT3), upregulation of E-selectin, GBP5/NLRP3 inflammasome axis, cell apoptosis, intracellular ROS generation, SOD reduction, stimulation of angiogenesis, and induction of autophagy-associated cell death. Preventive and curative interventions included α-solanine, baicalein, escin, intermedin, Y15, micro-ribonucleic acid-223, sotrastaurin, cimetidine, aescin, resveratrol, α-chaconine, Chahuang ointment, QingLuoTongMai, Mailuo Shutong, and N-acetylcysteine. Laboratory models included vascular endothelial cells, real-time cell-monitoring analysis, network pharmacology analysis and experimental verification in vivo, animal models of phlebitis (rat, rabbit, and mouse), rabbit models with peripherally inserted central catheters (PICC) catheterization, models of PICC/central venous catheter indwelling with combined drugs in human umbilical vein endothelial cells, and compatibility with endothelial cells. Factors affecting vascular endothelial cell injury include difference in the same class of drugs, concentration and exposure time of precipitant, and infusion strategy.Conclusion: Phlebitis is accompanied by endothelial dysfunction and may involve multiple molecular and cellular mechanisms. These findings improve our understanding of the molecular targets of interventions and help identify effective candidates for the prophylaxis and treatment of phlebitis. Vascular health and risk management should be considered when initiating intravenous administration.Keywords: endothelial cells, intravenous infusion therapy, phlebitis, pharmacological interventions, peripherally inserted central catheters, signaling pathway

Hsin-Hua Li,1,&ast; Hanoch Livneh,2,&ast; Hua-Lung Huang,3 Yu-Han Wang,4,&ast; Ming-Chi Lu,5,6 Wei-Jen Chen,1,4,7,8 Tzung-Yi Tsai9– 11 1Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 2Rehabilitation Counseling Program, Portland State University, Portland, OR, 97207-0751, USA; 3Department of Rehabilitation, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 4Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 5Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 6School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan; 7School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, 97004, Taiwan; 8Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, 33301, Taiwan; 9Department of Medical Research, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 10Department of Nursing, Tzu Chi University of Science and Technology, Hualien, 97004, Taiwan; 11Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, 70428, Taiwan&ast;These authors contributed equally to this workCorrespondence: Wei-Jen Chen; Tzung-Yi Tsai, Tel +886-5-2648000-5003 ; +886-5-2648000-3209, Fax +886-5-2648006, Email tough2915@hotmail.com; dm732024@tzuchi.com.twObjective: Sarcopenia is a frequently observed comorbidity of rheumatoid arthritis (RA) due to the chronic activation of the innate immune system. Accumulating evidence has indicated that Chinese herbal medicine (CHM) safely suppresses proinflammatory pathways and controls inflammation-associated disease, but its effect in reducing the risk of developing sarcopenia among RA subjects has not been established. We conducted a population-level cohort study to compare the sarcopenia risk in patients with RA who use or do not use CHM.Methods: Using claims from a nationwide insurance database, we recruited patients with newly diagnosed RA and without sarcopenia between 2002 and 2010. Propensity score matching was applied to randomly select sets of CHM users and non-CHM users to compare the sarcopenia risk until the end of 2013. The risk of new-onset sarcopenia was assessed using the Cox proportional hazards model.Results: As compared to non-CHM users, those receiving CHM treatment had a lower incidence of sarcopenia (7.69 vs 9.83 per 1000 person-years). CHM was correlated with a decreased chance of sarcopenia after controlling for potential covariates. Notably, use of CHM for more than two years may diminish the risk of getting sarcopenia by about 47% when taken as prescribed. Prescriptions of several herbal formulae may benefit the reduction of sarcopenia risk, such as Yan-Hu-Suo, Bei-Mu, Da-Huang, Huang Qin, Ping-Wei-San (PWS), Shu-Jing-Huo-Xue-Tang (SJHXT) and Chuan-Xiong-Cha-Tiao-San (CXCTS).Conclusion: This study produced new evidence as it is the first to show that the longer duration of CHM use was correlated to reduced risk of sarcopenia in a dose-dependent manner, implying that CHM treatment could be embraced as a routine care strategy for preventing sarcopenia.Keywords: sarcopenia, rheumatoid arthritis, Chinese herbal medicine, cohort study

Ya-Huei Wang,1,2 Hung-Chang Liao3,4 1Department of Applied Foreign Languages, Chung Shan Medical University, Taichung, Taiwan; 2Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan; 3Department of Health Policy and Management, Chung Shan Medical University, Taichung, Taiwan; 4Department of Medical Management, Chung Shan Medical University Hospital, Taichung, TaiwanCorrespondence: Hung-Chang Liao, Department of Health Policy and Management, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung, Taiwan, Tel +886-4-2473-0022 (ext. 12125), Email hcliao@csmu.edu.twObjective: Viewing that there is a lack of valid and reliable measures to assess visual literacy in clinical and healthcare settings, this study aimed to develop a visual literacy scale to assess health students’ and professionals’ visual literacy, by which teachers can further help them sharpen their visual literacy skills and sensitivity to let them reach effective communication in clinical and healthcare settings.Methods: The scale was constructed according to Slavec and Drnovšek’s three-phase scale development process: theoretical significance and existence of the scale construct, representative data collection and appropriate data collection methods, and statistical analysis of data collection and statistical evidence of the scale construct. To investigate the psychometrical properties, the researchers first performed a pilot study on randomly selected 464 health students and professionals, using exploratory factor analysis (EFA) with SPSS to derive the hidden factor structure, and then on randomly selected 303 participants, using confirmatory factor analysis (CFA) with AMOS to validate the derived factor structure. Internal consistency, convergent validities, discriminant validities, and goodness-of-fit indices were also examined in the study.Results: After going through the EFA, 30 items in three factors were identified: “allegorical meaning” (12 items), “explicit meaning” (10 items), and “symbolic meaning” (8 items). The three factors explained 73.191 of the total variance. The CFA generated the same three factors and 22 items: “allegorical meaning” (12 items), “explicit meaning” (4 items), and “symbolic meaning” (6 items). The three factors accounted for 75.022% of variance. Both the EFA and CFA models demonstrated satisfactory goodness-of-fit and good convergent and discriminant validities. Regarding the reliabilities, the Cronbach’s alpha values in the EFA and CFA models were all above 0.90.Conclusion: The findings have demonstrated that the VLS-HSP can be a formal instrument to measure visual literacy on health students and professionals.Keywords: humanistic professional awareness, healthcare students and providers, scale development, psychometric properties

Yen-Ming Huang,1– 3 Yao-Hsing Wang,1,4 Hsun-Yu Chan,5 Yunn-Fang Ho1,2 1Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan; 3Department of Pharmacy, National Taiwan University Hospital, Taipei, 100229, Taiwan; 4Honest Pharmacy, Taichung, 408483, Taiwan; 5Department of Industrial Education, National Taiwan Normal University, Taipei, 106308, TaiwanCorrespondence: Hsun-Yu Chan, Department of Industrial Education, National Taiwan Normal University, Taipei, 106308, Taiwan, Tel +886 2 77493550, Email hsunyuchan@ntnu.edu.tw Yunn-Fang Ho, Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, 100025, Taiwan, Tel +886 2 33668794, Fax +886 2 33668780, Email yfho@ntu.edu.twPurpose: This study aimed to thoroughly document the process and cost factors involved in dispensing services within a community pharmacy.Methods: Using a cross-sectional design, this study incorporated a pragmatic and descriptive qualitative approach to outline pharmacists’ viewpoints on providing dispensing services in community settings. A purposive sampling was employed to recruit pharmacists from geographically different community pharmacies, spanning from March to July 2022. Semi-structured interviews with direct content analysis were conducted through face-to-face interactions to gather firsthand insights into pharmacists’ professional dispensing services. The data underwent analysis through descriptive and in vivo coding techniques to categorize, define, and label themes, thereby identifying key steps and cost components in the prescription dispensing process. The qualitative data management software, MAXQDA 2020, was utilized for data management and maintenance.Results: Ten community pharmacists participated in the study, cooperatively completing the interview process. Of these, 7 were male and 3 were female, with age ranging from 29 to 62 years. The average length of pharmacy practice experience was 11.4 years. The study revealed six integral steps in the dispensing process: (1) receiving and clarifying legality and completeness of prescriptions, (2) profiling and verifying patient prescriptions, (3) preparing prescription labels and containers, (4) dispensing right medications with right quantity, (5) inspecting dispensing accuracy, (6) handing over medications and providing counseling. Along with these processes, pharmacists emphasized that pharmacy manpower, representing a substantial portion of the associated costs, determines the success and quality of the dispensing service. Additionally, rental, utilities, consumables, and physical equipment were identified as other important cost factors associated with carrying out pharmacy dispensing services.Conclusion: The study offers a comprehensive understanding of the dispensing service workflow within community pharmacies. The findings may inform key stakeholders and policymakers about required resources for enhancing and sustaining quality dispensing services for the public in Taiwan.Keywords: community pharmacy, dispensing service, pharmacist, prescription, refill

Yin-Han Wang,1 Tsung-Ming Yang,2,3 Ming-Szu Hung,2– 4 Yu-Ching Lin,2– 4 Tien-Pei Fang,1,3 Tzu-Tzu Kuo,5,&ast; Mark D Griffiths,6 Chung-Ying Lin7– 10,&ast; 1Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 3Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 4Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan; 6International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK; 7Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chung-Ying Lin, Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tel +886-6-2353535 ext. 5106, Fax +886-6-2367981, Email cylin36933@gmail.com Tzu-Tzu Kuo, Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan, Email ed101231@gmail.comPurpose: Inhaled medication adherence is an important issue for patients with chronic obstructive pulmonary disease (COPD) because adhering to inhaled medications could substantially improve their health. However, patients with COPD may not be always adhere to the prescribed inhaled medications. Therefore, understanding the underlying reasons for patients with COPD adhering to inhaled medications is important. The present study used Theory of Planned Behavior (TPB) as a theoretical framework to develop the Intention of Inhaled Medication Adherence Scale (IMAS) and assess its psychometric properties.Patients and Methods: After reviewing papers using the TPB to design psychometric scales and the TPB scale development guidelines, 28 items were generated for expert evaluation. Eight experts reported that the 28 items all had good content validity (content validity index ranged from 0.88 to 1.00 at item-level; and from 0.981 to 0.987 at scale-level) comprising four factors. Following initial development, 235 patients with COPD (mean age 73.12 years; 93.6% males) completed the IMAS via interview with a respiratory therapist and a research assistant. The four-factor structure of the IMAS was evaluated using confirmatory factor analysis (CFA).Results: Nine IMAS items were removed because of low factor loadings or offending estimates. The 19-item IMAS was confirmed as having a four-factor structure supported by the CFA results (comparative fit index=1.00; Tucker-Lewis index=1.00; root mean square error of approximation=0.00; standardized root mean square residual=0.06).Conclusion: The 19-item IMAS had satisfactory psychometric properties in construct validity. The 19-item IMAS is an instrument that could help healthcare providers understand potential factors associated with adherence to inhaled medications among people with COPD.Keywords: adherence, confirmatory factor analysis, COPD, psychometrics

Wei-Jen Chen,1– 4,&ast; Hanoch Livneh,5 Hsin-Hua Li,1 Yu-Han Wang,4,&ast; Ming-Chi Lu,6,7 Tzung-Yi Tsai,8– 10 Kuei-Yu Chien2 1Department of Chinese Medicine, Dalin Tzu chi Hospital, The Buddhist Tzu chi Medical Foundation, Chiayi, 62247, Taiwan; 2Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, 33301, Taiwan; 3School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, 97004, Taiwan; 4Center of Sports Medicine, Dalin Tzu chi Hospital, The Buddhist Tzu chi Medical Foundation, Chiayi, 62247, Taiwan; 5Rehabilitation Counseling Program, Portland State University, Portland, OR, 97207-0751, USA; 6Division of Allergy, Immunology and Rheumatology, Dalin Tzu chi Hospital, The Buddhist Tzu chi Medical Foundation, Chiayi, 62247, Taiwan; 7School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan; 8Department of Medical Research, Dalin Tzu chi Hospital, The Buddhist Tzu chi Medical Foundation, Chiayi, 62247, Taiwan; 9Department of Nursing, Tzu Chi University of Science and Technology, Hualien, 97004, Taiwan; 10Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, 70428, Taiwan&ast;These authors contributed equally to this workCorrespondence: Kuei-Yu Chien; Tzung-Yi Tsai, Tel +886-3-3283201-2421 ; +886-5-2648000-3209, Fax +886-3-3280592 ; +886-5-2648006, Email chienkueiyu@gmail.com; dm732024@tzuchi.com.twIntroduction: With population aging, sarcopenia and its accompanying risk of osteoporotic fracture has drawn increased attention. Nowadays, while Chinese herbal medicine (CHM) is often used as complementary therapy for many medical conditions, its effect against likelihood of osteoporotic fracture among sarcopenia subjects was not fully elucidated yet. We therefore conducted a population-level study to compare osteoporotic fracture risk for sarcopenia persons with or without CHM use.Methods: Using the patient record from a nationwide insurance database, we recruited persons with newly diagnosed sarcopenia and simultaneously free of osteoporotic fracture between 2000 and 2010. Propensity score matching was then applied to randomly select sets of CHM users and non-CHM users. All of them were tracked until end of 2013 to measure the incidence and adjusted hazard ratios (HRs) for new new-onset fracture in multivariable Cox proportional hazards model.Results: Compared to non-CHM users, the CHM users indeed had a lower incidence of osteoporotic fracture (121.22 vs 156.61 per 1000 person-years). Use of CHM correlated significantly with a lower fracture likelihood after adjusting for potential covariates, and those receiving CHM treatment for more than two years experienced a remarkably lower risk by 73%. Uses of several herbal formulae were correlated to reduced risk of osteoporotic fracture, such as Caulis Spatholobi, Xuduan, Duzhong, Danshen, Shu-Jing-Huo-Xue-Tang, Du-Huo-Ji-Sheng-Tang, Shao-Yao-Gan-Cao-Tang, and Shen-Tong-Zhu-Yu -Tang.Conclusion: Our study depicted that cumulative CHM exposure was inversely associated with osteoporotic fracture risk in a duration-dependent manner, implying that CHM treatment may be embraced as routine care in preventing incident osteoporotic fracture.Keywords: sarcopenia, osteoporotic fracture, risk, Chinese herbal medicines, cohort study

Yan Xiao,1 Xin-Yue Yao,1 Yong-Hui Wang,1 Lan-Wen Han,1 Lian-Xia Li,1 Ming Li,2 Shan Gao3 1Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Shan Gao, Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xuanwu District, Beijing, 100053, People’s Republic of China, Tel +8613910599635, Email gaoshanmw@163.comPurpose: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular disease which increases the risk of heart failure. This study aimed to determine whether clinical characteristics and subclinical cardiovascular disease (CVD) features are correlated with echocardiographic morpho-functional parameters of T2DM patients.Patients and Methods: Two hundred and fifty-five T2DM patients without a history of coronary heart disease were enrolled in this cross-sectional study. The demographic characteristics, glucose and lipid levels were assessed for each patient. Carotid ultrasonography and peripheral artery examination were performed to measure carotid intima-media thickness (cIMT), carotid plaque, ankle-brachial index (ABI), brachial artery pulse wave velocity (baPWV), and carotid-femoral pulse wave velocity (cfPWV). Furthermore, echocardiography was conducted to evaluate cardiac morphology and systolic and diastolic function. The relationship between clinical characteristics, subclinical cardiovascular diseases, and cardiac morpho-functional parameters was explored with the Pearson and stepwise multivariable linear regression analyses.Results: A total of 255 subjects aged 18– 80 years were enrolled in the study. Multiple regression analysis revealed that left ventricular mass index (LVMI) was correlated with age (β=0.463, p = 0.000) and systolic blood pressure (SBP) (β=0.179, p = 0.003). Relative wall thickness (RWT) was related to cfPWV (β=0.006, p = 0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (β=0.000, p = 0.036). In contrast, left ventricular ejection fraction (LVEF) was inversely related to cIMT (β=− 0.925, p = 0.019). The ratio of the peak flow velocity of early diastole to atrial contraction (peak E/A) was correlated with age (β=− 0.014, p = 0.000), diastolic blood pressure (DBP) (β=− 0.006, p = 0.001) and cfPWV (β=− 0.025, p = 0.044).Conclusion: In preclinical stage A/B heart failure adults with T2DM, age, BP, HOMA-IR, cfPWV and cIMT are correlated with cardiac morpho-functional parameters.Keywords: type 2 diabetes mellitus, preclinical stage A/B heart failure, subclinical cardiovascular diseases, echocardiography

Chia-Jung Chen,1 Hanoch Livneh,2 Wei-Jen Chen,1,3– 5 Yu-Han Wang,5 Ming-Chi Lu,6,7 Chia-Chou Yeh,1,4 Chieh-Tsung Yen,8 Tzung-Yi Tsai9– 11 1Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 2Rehabilitation Counseling Program, Portland State University, Portland, OR, USA; 3Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, Taiwan; 4School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; 5Center of Sports Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 6Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 7School of Medicine, Tzu Chi University, Hualien, Taiwan; 8Department of Neurology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 9Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan; 10Department of Medical Research, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 11Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, TaiwanCorrespondence: Chieh-Tsung Yen; Tzung-Yi Tsai, Tel +886-5-2648000-5003 ; +886-5-2648000-3209, Fax +886-5-2648006, Email dm335164@tzuchi.com.tw; dm732024@tzuchi.com.twPurpose: The systemic inflammation is believed to provide an outline of the association between rheumatoid arthritis (RA) and endometriosis. This retrospective cohort study aimed to explore the association of Chinese herbal medicine (CHM) use with the prevention of endometriosis onset in women diagnosed with RA.Methods: We utilized the claims data from the National Health Insurance of Taiwan from 2000 to 2009 and excluded individuals diagnosed with endometriosis before being diagnosed with RA, using age at clinical diagnosis. After selection and propensity-score matching, a total of 5992 females aged ≧20 years old and with newly diagnosed RA but without endometriosis at baseline were included, which contained 2996 CHM users and 2996 non-CHM users. All of them were followed until the end of 2013 to measure the incidence of endometriosis.Results: During the study period, we noticed that CHM users had a substantially lower incidence of endometriosis compared to non-CHM users (2.54 vs 5.19 per 1000 person-years). Use of CHM correlated significantly with a lower endometriosis likelihood even after adjusting for potential covariates, with the adjusted hazard ratio of 0.47 (95% confidence interval, 0.35– 0.65). A longer duration of CHM use was associated with a reduction in endometriosis risk, especially in those using CHM for more than 730 days. Uses of several herbal products may be associated with a lower risk of endometriosis, like Ge-Gen, Da-Huang, Huang-Qin, Ye-Jiao-Teng, Chuan-Niu-Xi, Shu-Jing-Huo-Xue-Tang, Du-Huo-Ji-Sheng-Tang, Ge-Gen-Tang, Shao-Yao-Gan-Cao-Tang, Ping-Wei-San, Gan-Lu-Yin, and Dang-Gui-Nian-Tong-Tang.Conclusion: Taken together, adding CHM to conventional therapy may reduce the incidence of endometriosis in women with RA. The therapeutic mechanisms and safety of these natural products may be a direction for future clinical studies.Keywords: endometriosis, rheumatoid arthritis, Chinese herbal medicines, propensity score match

Qin-Yu Cai,1,2 Yin Yang,3 Yong-Heng Wang,1,2 Han-Lin Cui,1,2 Xue-Peng Wu,2 Kai-Mai Liao,1 Xin Luo,2,4 Tai-Hang Liu1,2 1Department of Bioinformatics, The School of Basic Medicine, Chongqing Medical University, Chongqing, People’s Republic of China; 2The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Infection Controlling Section, Women and Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Tai-Hang Liu; Xin Luo, Chongqing Medical University, Box 197, No. 1 Yixueyuan Road, Chongqing, 400016, People’s Republic of China, Tel +86 023 68485008, Fax +86 023 68485000, Email liuth@cqmu.edu.cn; lxcqmu@outlook.comObject: COVID-19 pandemic and worldwide quarantine seriously affected the physical and mental health of the general public. Our study aimed to investigate the effects of the COVID-19 quarantine on pregnancy outcomes among pregnant women with hypertensive disorders of pregnancy (HDP).Methods: This single-center retrospective cohort study collected complete clinical data of HDP patients with a history of home quarantine in The First Affiliated Hospital of Chongqing Medical University (Chongqing, China) in 2020 as well as the patients without home quarantine in 2018 and 2019. Then, the maternal and neonatal outcomes of two subtypes of HDP, gestational hypertension (GH) and preeclampsia/eclampsia (PE/E), were analyzed over the three years.Results: The incidence of HDP increased from 0.84% in 2018 and 0.51% in 2019 to 2.30% in 2020. The data suggested that home quarantine was associated with higher gestational weight gain, obesity rates, blood pressure, and uric acid among the patients with HDP in 2020. Furthermore, HDP patients with a history of home quarantine may have worse neonatal outcomes, including lower newborn weight, shorter body length, lower Apgar score, and higher risk of fetal growth restriction.Conclusion: Our results suggested that COVID-19 quarantine may be a risk factor for poor pregnancy outcomes in HDP patients. Lifestyle guidance and antenatal care may be necessary for HDP patients with home quarantine in an epidemic outbreak.Keywords: COVID-19, home quarantine, pregnancy outcomes, HDP, obesity

Xiao Jun Wang,1 Yi-Ho Wang,2 Matthew Jian Chun Ong,1 Christina Gkitzia,3 Shui Yen Soh,4 William Ying Khee Hwang5– 7 1Novartis Singapore Pte Ltd, Singapore; 2Novartis Asia Pacific Pharmaceuticals Pte Ltd, Singapore; 3Novartis Pharma AG, Basel, Switzerland; 4KK Women’s & Children’s Hospital, Singapore; 5National Cancer Centre Singapore, Singapore; 6Singapore General Hospital, Singapore; 7Duke-NUS Medical School, SingaporeCorrespondence: Xiao Jun Wang, Novartis Singapore Pte Ltd, 20 Pasir Panjang Road, #10-25/28 Mapletree Business City (West Tower), 117439, Singapore, Tel +65 67226010, Email nick-1.wang@novartis.comPurpose: Children and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) have poor survival due to ineffective therapy options. The newly approved chimeric antigen receptor T-cell (CAR-T) therapy, tisagenlecleucel, has demonstrated improved survival but at a high up-front cost. The study aims to evaluate the cost-effectiveness and budget impact of tisagenlecleucel versus salvage chemotherapy regimen (SCR) or blinatumomab (BLN) for the treatment of pediatric and young adult patients with relapsed/refractory B-cell ALL from the Singapore healthcare system perspective.Patients and Methods: A three-health state partitioned survival model was constructed to analyze the cost-effectiveness of tisagenlecleucel vs SCR/BLN with/without allogenic hematopoietic stem cell transplantation (allo-HSCT) over a lifetime period. Clinical efficacy for tisagenlecleucel, SCR and BLN were based on pooled data from ELIANA, ENSIGN and B2101J trials, the study by von Stackelberg et al 2011, and MT103-205 respectively. Medical costs from pre-treatment until terminal care, including treatment, side effects, follow-up, subsequent allo-HSCT and relapse, were considered. Incremental cost-effectiveness ratios (ICERs) were estimated as the incremental costs per quality-adjusted life-year (QALY) gain. Additionally, the financial impact of tisagenlecleucel introduction in Singapore was estimated, comparing the present treatment scenario (without tisagenlecleucel) with a future scenario (with tisagenlecleucel), over 5 years.Results: In the base-case analysis, tisagenlecleucel treatment demonstrated cost-effectiveness with an ICER of S$45,840 (US$34,762) per QALY (vs SCR) and S$51,978 (US$39,315) per QALY (vs BLN). The estimated budget ranges from S$477,857 (US$361,438) to S$1.4 million (US$1.05 million) annually for the initial 5 years.Conclusion: Tisagenlecleucel is likely to be a cost-effective treatment option with limited budget implications while treating r/r ALL patients who have failed at least 2 lines of prior therapies.Keywords: tisagenlecleucel, acute lymphocytic leukemia, partition survival model, cost-effectiveness, budget impact, Singapore

Zhen-Ni Liu,1– 3,&ast; Qian-Qian Su,4,&ast; Yu-Hui Wang,1– 3,&ast; Xue Wu,1– 3 Xiong-Wen Lv1– 3 1Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, People’s Republic of China; 3Institute for Liver Diseases of Anhui Medical University, Hefei, People’s Republic of China; 4Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiong-Wen Lv, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province, 230032, People’s Republic of China, Email xiongwen_lv2019@163.comPurpose: It is well known that inflammation plays a key role in complex pathological progressions of alcohol-associated liver disease (ALD). To date, effective therapy for ALD is lacking. P2Y2 receptor (P2Y2R), a G protein-coupled P2Y purinergic receptor, represents a novel pharmacological target in many inflammations.Methods: The alcohol-associated liver injury and inflammation mouse model was established. The effect of P2Y2R on alcohol-induced liver injury and inflammation was evaluated using quantitative real-time PCR, Western blot and immunohistochemical assay. An alcohol-stimulated (100 mmol/L, for 24 h) AML-12 cell model was established. Different agonists, antagonists and P2Y2R siRNA were used to explore the possible mechanisms of P2Y2R.Results: In vivo, results showed that the hepatoprotective effect of P2Y2R blockade by significantly suppressed liver structural abnormalities and lipid infiltration, and decreased levels of ALT/AST and TNF-α/IL-1β in the high dosage group of suramin (20 mg/kg) compared to control diet (CD)-fed mice. At the same time, we found that alcohol feeding promoted the phosphorylation of EGFR and ERK1/2, both of which were effectively inhibited by suramin (20 mg/kg). In vitro, suramin or P2Y2R silencing effectively inhibited the phosphorylation of EGFR and ERK1/2, similar to the down-regulated effects of their corresponding inhibitors (EGFR inhibitor AG1478 and ERK1/2 inhibitor U0126) accompanied by reduced levels of TNF-α and IL-1β compared to alcohol-induced AML-12 cell. In addition, we found that silencing P2Y2R attenuated the apoptosis of hepatocyte.Conclusion: Our findings suggest that P2Y2R regulates alcoholic liver inflammation by targeting the EGFR-ERK1/2 signaling pathway and plays an important role in hepatocyte apoptosis, which may provide new ideas for the development of methods to treat ALD.Keywords: P2Y2 receptor, alcoholic liver inflammation, EGFR, ERK1/2

Li-li Hu,1 Qing Wang,2,3 Yan-hu Wang,1 Ling-xi Gu,1 Tian-gui Yu1 1Department of Public Health, Shandong Mental Health Center, Jinan, People’s Republic of China; 2Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Institute for Medical Dataology, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Tian-gui Yu, Department of Public Health, Shandong Mental Health Center, Jinan, People’s Republic of China, Tel +86-531-86336798, Email sdyutg@163.comPurpose: To describe the mortality rate and cause of death among Han Chinese schizophrenia patients and to explore the risk factors affecting survival.Methods: We performed a retrospective analysis of death among patients with schizophrenia from Jan 1, 2012, to Dec 31, 2019, using the Severe Mental Disorders Information System of Shandong Province (henceforth referred to as the SMDI system) in Shandong, China. The cohort included 72,102 patients, and 11,766 patients died during follow-up. The data in this cohort study were derived from the SMDI system. We calculated the crude mortality rate and standardized mortality rate (SMR, standardized according to the sex and age composition of the population in Shandong Province) for patients with schizophrenia. Cox regression analysis was used to analyze the risk factors affecting patient survival, and the statistical index was the hazard ratio (HR).Results: The mean age of the cohort patients was 47.21± 14.05 years; 51.79% were males, and 48.21% were females. Among them, 68.98% (49,735) had only a primary education level, 85.36% (61,549) were farmers, 64.37% (46,413) were married, and 94.01% (67,775) received community management. A total of 16.32% of the cohort died. The SMR in patients with schizophrenia was 4.9, and it was higher for males than females (4.99 versus 4.82). Among the 6 registered causes of death, physical illness had the highest SMR (5.15), followed by other causes of death (4.86), mental illness-related complications (4.57), homicide (4.31), accidents (4.13), and suicide (3.87). Higher levels of education, employment (in-service status), marriage, and urban residence were protective factors for survival among patients with schizophrenia.Conclusion: In China, the SMR of schizophrenia is relatively high, and physical diseases are the main cause of death. We suggest that a variety of measures should be taken early to treat somatic diseases and reduce SMR in patients with schizophrenia.Keywords: schizophrenia, cause of death, mortality, physical illness

James Cheng-Chung Wei,1– 3 Yi-Jung Chang,4 Yu-Hsun Wang,5 Chih-Jung Yeh6 1Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan; 2Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; 4Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan; 5Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Department of Public Health, Chung Shan Medical University, Taichung, TaiwanCorrespondence: Chih-Jung Yeh, Department of Public Health, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, South District, Taichung, 40201, Taiwan, Tel +886 4 24739595 #11794, Fax +886 4 24637389, Email alexyeh@csmu.edu.twBackground: Previous research has pointed to the relationship between psoriasis and the development of gout. However, most previous studies had either small sample sizes or short study durations. Therefore, in this nationwide cohort study, we investigated the effect of psoriasis on the risk of gout development.Methods: The study group included one million patients from Taiwan, whom we followed for 14 years. The participants were divided into two cohorts designated as psoriasis and non-psoriasis. A 1:4 propensity score matching test was used to compare age, sex, and index year between the two cohorts. Cox proportional hazard regression was used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of gout. Sensitivity analyses were conducted to evaluate the HR for gout after the occurrence of psoriasis.Results: The incidence densities of gout in the psoriasis and non-psoriasis cohorts were 6.96 and 5.09 per 1000 person-years, respectively. After adjusting for age, sex, urbanization, comorbidities, and nonsteroidal anti-inflammatory drug (NSAID) use, the adjusted hazard ratio (aHR) with 95% CI for incidental gout in the psoriasis group was 1.38 (1.2– 1.6). Moreover, the aHR (95% CI) values for gout risk in patients with psoriasis using NSAIDs and those who did not were 1.21 (1.0– 1.47) and 1.65 (1.33– 2.05), respectively.Conclusion: This study demonstrated an association between psoriasis and risk of developing gout. Clinically, patients with psoriasis should be evaluated for incidental gout.Keywords: psoriasis, gout, epidemiology, corticosteroids, NHIRD, cohort

© 2018. The American Astronomical Society. All rights reserved. The Kepler-9 system harbors three known transiting planets. The system holds significant interest for several reasons. First, the outer two planets exhibit a period ratio that is close to a 2:1 orbital commensurability, with attendant dynamical consequences. Second, both planets lie in the planetary mass "desert" that is generally associated with the rapid gas agglomeration phase of the core accretion process. Third, there exist attractive prospects for accurately measuring both the sky-projected stellar spin-orbit angles as well as the mutual orbital inclination between the planets in the system. Following the original Kepler detection announcement in 2010, the initially reported orbital ephemerides for Kepler-9 b and c have degraded significantly, due to the limited time base-line of observations on which the discovery of the system rested. Here, we report new ground-based photometric observations and extensive dynamical modeling of the system. These efforts allow us to photometrically recover the transit of Kepler-9 b and thereby greatly improve the predictions for upcoming transit mid-times. Accurate ephemerides of this system are important in order to confidently schedule follow-up observations of this system, for both in-transit Doppler measurements as well as for atmospheric transmission spectra taken during transit.

Hung-Chang Liao,1,2 Cheng-Yi Huang,3,4 Ya-huei Wang5,6 1Department of Health Policy and Management, Chung Shan Medical University, Taichung, Taiwan; 2Department of Medical Management, Chung Shan Medical University Hospital, Taichung, Taiwan; 3School of Nursing, Chung Shan Medical University, Taichung, Taiwan; 4Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan; 5Department of Applied Foreign Languages, Chung Shan Medical University, Taichung, Taiwan; 6Department of Medical Education, Chung Shan Medical University Hospital, Taichung, TaiwanCorrespondence: Ya-huei WangDepartment of Applied Foreign Languages, Chung Shan Medical University, Taichung, TaiwanEmail yhuei@csmu.edu.twObjective: This study aimed to develop an appropriate scale accessing healthcare students’ and providers’ humanistic professional awareness (HPAS-HSP).Methods: Following a literature review, stakeholder interviews, and panel discussions for item generation, 65 items for the HPAS-HSP scale were created based on a nine-point Likert scale, with 9 indicating “strongly agree” and 1 indicating “strongly disagree.” A pilot study using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), with seven hundred twenty-five medical care students and providers in Taiwan as the total sample number of the study, was administered to examine the practicability of the HPAS-HSP scale. The statistics software SPSS and AMOS 24.0 were used to examine the psychometric properties of the scale, including internal consistency, convergent validities, discriminant validities, and exploratory and confirmatory factor analysis.Results: The EFA resulted in 21 items in three factors, with 66.221% of the total variance explained: “personal integrity and accountability” (9 items; 51.763% of the variance explained), “sensitivity to others” (6 items; 8.667% of the variance explained), and “medical professional competence” (6 items; 5.791% of the variance explained). The Cronbach’s alphas for the three subscales and the entire questionnaire ranged from 0.892 to 0.949. The CFA results yielded 20 items, with the same three factors, and demonstrated good model fit in the χ2/df ratio (1.130; p = 0.140), CFI (0.998), TFI (0.998), and RMSEA (0.013). The composite alphas ranged between 0.900 and 0.969. Convergent and discriminant validity also confirmed the stability and consistency of the scale.Conclusion: The statistical results demonstrated that the HPAS-HSP scale can be a measure to assess healthcare students’ and providers’ humanistic professional awareness.Keywords: humanistic professional awareness, healthcare students and providers, scale development, psychometric properties

Yi Wang,1,&ast; Na Li,1,&ast; Di Tian,1,&ast; Chang-Wu Zhou,1 You-Hua Wang,2 Chun Yang,1 Meng-Su Zeng1 1Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, 200032, People’s Republic of China; 2Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng-Su Zeng; Chun YangDepartment of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Xuhui District, Shanghai, 200032, People’s Republic of ChinaTel +86 13501922963; Tel +86 18702135336Email zhudahuaidan@yeah.net; dryangchun@hotmail.comIntroduction: N6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play pivotal roles in the progression of hepatocellular carcinoma (HCC). However, how their interaction is involved in the prognostic value of HCC and immune checkpoint inhibitors (ICIs) therapy remains unclear.Methods: The RNA sequencing and clinical data of HCC patients were collected from TCGA database. The prognostic m6A-related lncRNAs were screened out with Pearson correlation test, univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. Patients with HCC were classified into 2 subtypes by consensus clustering. Survival analyses were performed to assess the prognostic value of different clusters and risk models. Potential tumor correlated biological pathways correlated with different clusters were explored through gene set enrichment analysis. We also identified the relationship of the risk model and clusters with response to immune checkpoint inhibitors (ICIs) therapy and tumor microenvironment (TME). Furthermore, the prognostic value of the 9 m6A-related lncRNAs was validated in the external cohort. Finally, the role of SNHG4 was explored by silencing and overexpression of SNHG4 through conducting proliferation, migration and invasion experiments.Results: Patients from 2 clusters and different risk groups based on m6A-related lncRNAs had significantly different clinicopathological characteristics and overall survival outcomes. Tumor-correlated biological pathways were found to be correlated with Cluster 2 through GSEA. Moreover, we found that patients from different clusters and risk groups expressed higher levels of immune checkpoint genes and had distinct TME and different responses for ICIs therapy. Prognostic value of this risk model was further confirmed in the external cohort. Finally, consistent with the discovery, SNHG4 played an oncogenic role in vitro.Conclusion: Our study demonstrated that the 9 m6A-related lncRNA signature may serve as a novel predictor in the prognosis of HCC and optimize (ICIs) therapy. SNHG4 plays an oncogenic role in HCC.Keywords: N6-methyladenosine, long non-coding RNAs, prognosis, immune checkpoints inhibitors therapy, hepatocellular carcinoma

Yun-Hong Wang,1 Tong Qu,2 Xue-Lian Wang,3 Rong-Ping Yang3 1Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, People’s Republic of China; 2Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China; 3Department of Pharmacy College, Southwest University, Chongqing, 400715, People’s Republic of ChinaCorrespondence: Rong-Ping YangDepartment of Pharmacy College, Southwest University, No. 2 of Tiansheng Street, Beibei District, Chongqing, 400715, People’s Republic of ChinaTel +86 023-68251225Fax +86 023-68251225Email yangrongping1119@163.comObjective: This study aims to investigate the preparation of sustained-release microcapsules of salvianolic acid.Methods: The stability of salvianolic acid microcapsules was improved, and the time of action was prolonged in the present study. This was prepared using the spray-drying method, with chitosan as the carrier. In the preparation process, the prescription and process were optimized by L9 (34) using an orthogonal design, with yield and drug loading as indexes, in order to obtain optimum conditions.Results: The optimal process and prescription for the preparation of salvianolic acid microcapsules were found to be as follows: mass concentration of chitosan, 1.5%; mass ratio of salvianolic acid to chitosan, 1:3; inlet air temperature, 190°C; and peristaltic pump speed, 300 mL·h-1. The surface of the microcapsules was round, the drug loading was 25.99% ± 2.14%, the yield was 51.88% ± 2.84%, the entrapment efficiency was 86.21% ± 2.89%, and the average particle size was 105.6 ± 2.56 nm. The microcapsules in vitro had certain sustained release characteristics. The internally fitted first-order release model equation was ln(1-Q) = − 0.236 t + 4.591 7, r = 0.920. In addition, the results of differential scanning calorimetry show that the properties of salvianolic acid were not changed by the microcapsules.Conclusion: Sustained-release microcapsules of salvianolic acid can be successfully prepared by adopting marine polysaccharide as a carrier.Keywords: salvianolic acid sustained-release microcapsule, marine polysaccharides, chitosan, Salvia miltiorrhiza, salvianolic acid B

Nan-Fu Chiu,1,2 Ming-Jung Tai,1 Devi Taufiq Nurrohman,1,3 Ting-Li Lin,1 Ying-Hao Wang,1 Chen-Yu Chen4,5 1Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, Taipei City, Taiwan; 2Department of Life Science, National Taiwan Normal University, Taipei City, Taiwan; 3Department of Electronics Engineering, State Polytechnic of Cilacap, Cilacap, Indonesia; 4Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City, Taiwan; 5Department of Medicine, Mackay Medical College, Taipei City, TaiwanCorrespondence: Nan-Fu ChiuLaboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, No. 88, Sec. 4, Ting-Chou Road, Taipei City, 11677, TaiwanTel +886-2-77496722Fax +886-2-86631954Email nfchiu@ntnu.edu.twChen-Yu ChenDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Taipei City, 10449, TaiwanTel +886-2-25433535Fax +886-2-25433642Email f122481@mmh.org.twBackground: Due to educational, social and economic reasons, more and more women are delaying childbirth. However, advanced maternal age is associated with several adverse pregnancy outcomes, and in particular a high risk of Down’s syndrome (DS). Hence, it is increasingly important to be able to detect fetal Down’s syndrome (FDS).Methods: We developed an effective, highly sensitive, surface plasmon resonance (SPR) biosensor with biochemically amplified responses using carboxyl-molybdenum disulfide (MoS2) film. The use of carboxylic acid as a surface modifier of MoS2 promoted dispersion and formed specific three-dimensional coordination sites. The carboxylic acid immobilized unmodified antibodies in a way that enhanced the bioaffinity of MoS2 and preserved biorecognition properties of the SPR sensor surface. Complete antigen pregnancy-associated plasma protein-A2 (PAPP-A2) conjugated with the carboxyl-MoS2-modified gold chip to amplify the signal and improve detection sensitivity. This heterostructure interface had a high work function, and thus improved the efficiency of the electric field energy of the surface plasmon. These results provide evidence that the interface electric field improved performance of the SPR biosensor.Results: The carboxyl-MoS2-based SPR biosensor was used successfully to evaluate PAPP-A2 level for fetal Down’s syndrome screening in maternal serum samples. The detection limit was 0.05 pg/mL, and the linear working range was 0.1 to 1100 pg/mL. The women with an SPR angle > 46.57 m° were more closely associated with fetal Down’s syndrome. Once optimized for serum Down’s syndrome screening, an average recovery of 95.2% and relative standard deviation of 8.5% were obtained. Our findings suggest that carboxyl-MoS2-based SPR technology may have advantages over conventional ELISA in certain situations.Conclusion: Carboxyl-MoS2-based SPR biosensors can be used as a new diagnostic technology to respond to the increasing need for fetal Down’s syndrome screening in maternal serum samples. Our results demonstrated that the carboxyl-MoS2-based SPR biosensor was capable of determining PAPP-A2 levels with acceptable accuracy and recovery. We hope that this technology will be investigated in diverse clinical trials and in real case applications for screening and early diagnosis in the future.Keywords: carboxyl-functionalized molybdenum disulfide, carboxyl-MoS2, surface plasmon resonance, SPR, pregnancy-associated plasma protein A2, PAPP-A2, Down’s syndrome, DS, fetal Down’s syndrome, FDS

Nan-Fu Chiu,1,2 Ying-Hao Wang,1,3 Chen-Yu Chen3,4 1Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, Taipei City 11677, Taiwan; 2Department of Life Science, National Taiwan Normal University, Taipei City 11677, Taiwan; 3Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei City 10449, Taiwan; 4Department of Medicine, Mackay Medical College, Taipei City 25245, TaiwanCorrespondence: Nan-Fu ChiuLaboratory of Nano-photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, No. 88, Sec. 4, Ting-Chou Road, Taipei 11677, TaiwanTel +886-2-77496722Fax +886-2-86631954Email nfchiu@ntnu.edu.twChen-Yu ChenDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Taipei City 10449, TaiwanTel +886-2-25433535Fax +886-2-25433642Email f122481@mmh.org.twBackground: Advanced medical detection technology requires high sensitivity and accuracy to increase the disease detection rate. We showed that carboxyl-functionalized graphene oxide (carboxyl-GO) biosensing materials are capable of accurate detection.Methods: We developed a carboxylated GO-based surface plasmon resonance (SPR) aptasensor suitable for screening Down’s syndrome in clinical serum. This biosensing material could rapidly and accurately detect hCG protein with a low concentration to identify fetal Down’s syndrome. The developed carboxyl-GO-based SPR aptasensor showed excellent sensitivity and limit of detection without the use of antibodies and without any specific preference.Results: hCG protein detection limits of 1 pM in buffer samples and 1.9 pM in clinical serum samples were achieved. The results showed that the carboxyl-GO-based chip could detect hCG well below the normal physiological level of serum protein (5.0 mIU/mL). High affinity, sensitivity, and better detection limit were obtained in the range of 1.9 pM to 135 pM. The results showed a 5k-fold dilution factor, and that an SPR angle shift of more than 20 millidegrees (mo) was associated with a significant risk of fetal Down’s syndrome compared to normal pregnant women. The results clearly showed that the detection of hCG protein in serum samples from pregnant women at 12– 19 weeks could be used to screen Down’s syndrome with high selectivity and sensitivity.Conclusion: Our findings suggest the potential application of carboxyl-GO film in proof-of-concept studies for serum assays as a new type of SPR material. In addition, peptide and carboxyl-GO films may be conducive to the development of future point of care testing and rapid diagnostic devices for other diseases such as cancer.Keywords: surface plasmon resonance, SPR, aptasensor, carboxyl-functionalized graphene oxide, GO-COOH, peptides, human chorionic gonadotropin, hCG, Down’s syndrome, DS

Different approaches to obtaining uncertainty estimates of the North Atlantic Oscillation (NAO) are explored. The resulting estimates are used to enhance the understanding of spatial variability of the NAO over different time periods. Among the parametric and nonparametric approaches investigated in this study, the bootstrap is nonparametric and not confined to the assumption of normally distributed data. It gives physically plausible uncertainty estimates. The NAO uncertainty estimates depend on sample sizes with greater sampling variability as sample size is smaller. The NAO uncertainty varies with time but common features include that the most uncertain values are centered between the centers of action of theNAOand are asymmetric in the zonal direction (more uncertainty in the eastward direction or downstream). The bootstrap can also be used to provide direct measures of uncertainty regarding the location of the NAO action centers. The uncertainty of the location of the NAO action centers not only helps assess the shift in the NAO but also provides evidence of more than two action centers. The methods reported on here could in principle be applied to any EOF-derived climate pattern. © 2014 American Meteorological Society.

Chih-Cheng Lai,1 Cheng-Hsin Chen,2 Charlotte Yu Hsuan Lin,3 Cheng-Yi Wang,2 Ya-Hui Wang41Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA; 4Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, TaiwanBackground: This study aims to compare the effects of single inhaler triple therapy comprised of inhaled corticosteroids (ICSs), long-acting β2-agonists (LABAs), and long-acting muscarinic receptor antagonists (LAMAs) with dual therapies comprised of either LABA/LAMA, ICS/LABA or separate ICS/LABA plus LAMA triple therapy.Methods: The Pubmed, Embase, and Cochrane databases were searched up to October 31st 2018. Only randomized controlled trials were included in the meta-analysis. The primary outcome was the rate of moderate-to-severe chronic obstructive pulmonary disease (COPD) exacerbations.Results: Seven studies fulfilling the inclusion criteria were included in the meta-analysis. Single inhaler triple therapy was associated with a significantly lower risk of COPD exacerbation compared with LABA/LAMA (rate ratio, 0.69; 95% confidence interval [CI] 0.55 to 0.87, I2=85%), and ICS/LABA (rate ratio, 0.81; 95% CI 0.73 to 0.89, I2=29%) dual therapy. Single inhaler triple therapy led to a more significant improvement in lung function and quality of life compared with LABA/LAMA and ICS/LABA dual therapy. Single inhaler triple therapy was associated with a higher risk of pneumonia compared with LABA/LAMA (risk ratio, 1.38, 95% CI 1.14 to 1.67, I2=0) dual therapy.Conclusions: The use of single inhaler triple therapy for COPD patients can result in lower rates of moderate or severe exacerbations of COPD as well as improved lung function and quality of life compared with dual therapy with LABA/LAMA or ICS/LABA.Keywords: COPD, triple therapy, randomized controlled trials, single inhaler

Cheng-Yi Wang,1,* Yin-Lan Hu,2,* Ya-Hui Wang,3 Cheng-Hsin Chen,1 Chih-Cheng Lai,4 Kun-Lun Huang51Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-jen Catholic University, New Taipei City, Taiwan; 2Department of Dentistry, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 5Division of Pulmonary Medicine, Tri-service General Hospital, Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, Taipei, Taiwan*These authors contributed equally to this workBackground: Latent tuberculosis infection (LTBI) is a precursor of active tuberculosis diseases and an important issue in the United States and worldwide. The association between vitamin D deficiency and LTBI is poorly understood.Methods: From 2011 to 2012, the National Health and Nutrition Examination Survey (NHANES) assessed LTBI (according to tuberculin skin testing and QuantiFERON®,-TB Gold In-Tube) and measured serum levels of vitamin D. We evaluated the association between LTBI and vitamin D using multivariate logistic regression models adjusted for known confounders.Results: The LTBI group had a lower 25-hydroxyvitamin D [25(OH)D] level than the non-LTBI group (p=0.0012). The adjusted risk of LTBI was significantly higher among participants with serum 25(OH)D levels

Yi-Hong Wang,1,* Ching Yee Chan,2,* Qing-Hua Liu11Department of Otorhinolaryngology, The Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 2Department of Otolayngology, KK Women’s and Children’s Hospital, Duke-NUS Medical School, Singapore*These authors contributed equally to this work Background: Benign paroxysmal positional vertigo (BPPV) is a common cause of vertigo that can be easily diagnosed and treated in primary care.Purpose: We describe our experience with a large cohort of patients and include recommendations for diagnosis and treatment in the primary care setting.Patients and methods: Three hundred and fifty-nine patients were diagnosed with BPPV between June 2011 and March 2017 at the dizziness clinic of Fujian Provincial Hospital, Fuzhou, China. We mainly used Epley’s maneuver and barbecue roll for the treatment of PSC-BPPV and HSC-BPPV respectively.Results: Our results show that posterior semicircular canal (PSC) involvement is the most common (n=264, 73.5%), followed by horizontal semicircular canal (HSC, n=81, 22.5%) and multicanal (n=12, 3.3%) involvement. Anterior semicircular canal (ASC) BPPV is the rarest (n=2). Particle repositioning maneuvers (PRM) are the treatment of choice and have a high success rate (1 month after treatment), from 75% (9 out of 12) for multicanal to 95.8% (253 out of 264) for PSC, and to 100% for HSC and ASC involvement respectively.Conclusion: We recommend the use of the Epley’s maneuver and barbecue roll for the treatment of PSC-BPPV and HSC-BPPV, respectively. Patients should be reviewed regularly and repeated maneuvers can be performed. Unresolving symptoms require tertiary evaluation.Keywords: giddiness, benign paroxysmal positional vertigo, Epley’s maneuver, diagnosis, treatment

Ding-Yun Feng,1,* Yu-Qi Zhou,1,* Xiao-Ling Zou,1 Mi Zhou,2 Jia-Xin Zhu,1 Yan-Hong Wang,1 Tian-Tuo Zhang11Department of Pulmonary and Critical Care Medicine, Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Surgery Intensive Care Unit, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this work Purpose: Nosocomial pneumonia is a common nosocomial infection that includes hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia(VAP). It is an important cause of morbidity and mortality in hospitalized patients. This study aimed to evaluate the differences in microbial etiology and outcomes between HAP and VAP, particularly in related risk factors of multidrug-resistant organism (MDRO) causing HAP and VAP.Patients and methods: This single-center retrospective, observational study included patients with HAP/VAP. Clinical and epidemiological data of nosocomial pneumonia confirmed by microbial etiology that occurred in the Third Affiliated Hospital of Sun Yat-sen University, China, from January 2014 to December 2017 were obtained.Results: A total of 313 HAP cases and 106 VAP cases were included. The leading pathogens of HAP and VAP were similar, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Antimicrobial susceptibility of the pathogens was low, and P. aeruginosa in VAP was less susceptible. In the multivariate logistic regression analysis, the risk factors associated with MDRO-HAP were chronic obstructive pulmonary disease, antibiotic therapy in the preceding 90 days, and prior endotracheal tracheostomy. The risk factor of MDRO-VAP was ≥5 days of hospitalization. The 30-day mortality rates of HAP and VAP were 18.5% and 42.5%.Conclusion: The leading pathogens were similar in both HAP and VAP, and antimicrobial susceptibility of the pathogens was low. The risk factors associated with MDRO infection in HAP and VAP have significant variability; hence, attention should be paid to improve prognosis. VAP was associated with poorer outcomes compared with HAP.Keywords: hospital-acquired pneumonia, ventilator-associated pneumonia, epidemiology, microbial etiology

Chih-Cheng Lai,1 Che-Hsiung Wu,2,3 Ya-Hui Wang,4 Cheng-Yi Wang,4 Vin-Cent Wu,5 Likwang Chen6 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan; 3School of Medicine, Tzu Chi University, Hualien, Zhunan, Taiwan; 4Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 6Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objective: The aim of this study was to investigate the impact of COPD on the outcomes of patients with advanced chronic kidney disease (CKD).Patients and methods: All patients with advanced CKD from 2000 to 2010 were identified from the Taiwanese National Health Insurance Research Database. Associations between COPD and the risk of long-term dialysis and all-cause mortality were assessed.Results: A total of 33,399 advanced CKD patients were enrolled, of whom 31,536 did not have COPD (non-COPD group) and 1,863 had COPD (COPD group). The incidence of end-stage renal disease (ESRD) was higher for those with COPD than those without COPD (744.2 per 1,000 person-years vs 724.6 per 1,000 person-years, adjusted HR [aHR] 1.04; 95% CI 0.96–1.12). The cumulative incidence rates of ESRD were similar between the COPD and non-COPD groups (log-rank test, P=0.356). Overall, the patients with COPD had a higher risk of death than those without COPD (151.7 per 1,000 person-years vs 125.5 per 1,000 person-years, aHR 1.22; 95% CI 1.11–1.33). The cumulative mortality rate was higher in the COPD group than in the non-COPD group (log-rank test, P

Chi-Ho Chan,1 Shun-Fa Yang,2,3 Han-Wei Yeh,4 Ying-Tung Yeh,5–7 Yu-Hsun Wang,2 Ying-Hock Teng,8,9 Chao-Bin Yeh8,9 1Department of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 2Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 3Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 4School of Medicine, Chang Gung University, Taoyuan City, Taiwan, Republic of China; 5Graduate School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 6School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 7Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 8Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 9Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China Background: Burns are the main cause of accidental injury, and pneumonia is a common respiratory disease in humans.Aim: The purpose of this study was to investigate the relationship between burn injury and pneumonia.Patients and methods: A nationwide population-based cohort study was conducted using data from the National Health Insurance Research Database in Taiwan. We identified and enrolled 2,893 subjects with burn injury, who were individually matched to 2,893 subjects in the comparison group by using the propensity score. Furthermore, we used a self-controlled case-series design to estimate the temporal association between burn injury and pneumonia.Results: Exposure to burn injury revealed a higher risk of pneumonia than that to non-burn injury within 1 year. The Cox proportional hazards model revealed that, compared with the non-burn injury, burn injury yielded a 2.39-fold (95% CI=1.44–3.96) increase in risk of pneumonia. The exposure period of burn injury within 30 days showed 2.76-fold increase in risk of pneumonia (95% CI=1.44–3.96) compared with that in the baseline period.Conclusion: Burn injury was associated with a significant increased risk of pneumonia, especially occurring within 30 days. Keywords: burn injury, pneumonia, odds ratio

Chang-Liang Luo,1,* Zhi-Gao Xu,2,* Hao Chen,2 Jia Ji,1 Yu-Hui Wang,1 Wei Hu,1 Kun Wang,3 Wu-Wen Zhang,1 Chun-Hui Yuan,4 Fu-Bing Wang1 1Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; 2Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China; 3Department of Laboratory Medicine, Hubei Cancer Hospital, Wuhan, China; 4Department of Laboratory Medicine, Wuhan Children’s Hospital, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Background: Tissue biopsy-based cancer diagnosis has limitations because of the fact that tumor tissues are in constant evolution and extremely heterogeneous. The current study was aimed to examine whether tumor-educated blood platelets (TEPs) might be a potential all-in-one source for blood-based cancer diagnostics to overcome the limitations of conventional cancer biopsy.Methods: In the present study, we evaluated the expression pattern of MAGI2 antisense RNA 3 (MAGI2-AS3) and ZNFX1 antisense RNA 1 (ZFAS1) in both plasma and platelets of 101 non-small-cell lung cancer (NSCLC) patients. Receiver operating characteristic (ROC) curve was generated to evaluate their diagnostic potential. In addition, epidermal growth factor receptor (EGFR) mutations were detected in DNA and RNA samples of platelets for companion diagnostics.Results: Our results showed that the levels of MAGI2-AS3 and ZFAS1 in both plasma and platelets of NSCLC patients were significantly downregulated than those in healthy controls. A positive correlation of long noncoding RNA expression was observed between platelets and plasma (r=0.738 for MAGI2-AS3, r=0.751 for ZFAS1, respectively). By ROC analysis, we found that molecular interrogation of MAGI2-AS3 and ZFAS1 in TEPs and plasma can offer valuable diagnostic performance for NSCLC patients (area under the ROC curve [AUC]MAGI2-AS3=0.853/0.892, and AUCZFAS1=0.780/0.744 for diagnosing adenocarcinoma and squamous cell carcinoma cases from controls, respectively). Clinicopathologic characteristic analysis further revealed that MAGI2-AS3 level significantly correlated with tumor–node–metastasis (TNM) stage (p=0.001 in TEPs, p=0.003 in plasma), lymph-node metastasis (p=0.016 in TEPs, p=0.023 in plasma), and distant metastasis (p=0.045 in TEPs, p=0.045 in plasma), while ZFAS1 level was only correlated with TNM stage (p=0.005 in TEPs, p=0.044 in plasma). Furthermore, EGFRvIII RNA existed in both TEPs and plasma, but EGFR intracellular mutations cannot be detected in DNA of TEPs isolated from NSCLC.Conclusion: Our data suggested that TEP is a promising source for NSCLC diagnosis and companion diagnostics. Keywords: tumor-educated platelets, lncRNA-MAGI2-AS3, lncRNA-ZFAS1, EGFR mutations, NSCLC

Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1) of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29) than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21) than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring hospitalization (aHR, 1.24; 95% CI, 1.21–1.28) or emergency department visits (aHR, 1.16; 95% CI, 1.13–1.18), pneumonia requiring mechanical ventilation (aHR, 1.35; 95% CI, 1.24–1.47), and mortality (aHR, 1.33; 95% CI, 1.26–1.42).Conclusion: ARBs were associated with lower rates of pneumonia, severe pneumonia, and mortality than ACEis in patients with COPD. Keywords: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, COPD, severe exacerbation, pneumonia, mortality

Pseudogout and gout are common types of inflammatory joint disease in the elderly. However, the existence of both in a single joint in a patient is relatively rare. This case report describes an interesting case of a 42-year old man who presented with simultaneous gout and pseudogout in the knee joint, diagnosed via polarised light microscopy. There was no radiographic evidence of pseudogout. This case report serves to illustrate the need to actively exclude concomitant pseudogout, especially in patients suffering from recurrent attacks of gout.

Yueh Lan Huang,1 Chih-Cheng Lai,2 Ya-Hui Wang,3 Cheng-Yi Wang,1 Jen-Yu Wang,1 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 2Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan Background: There is conflicting information regarding the effects of selective and nonselective beta-blocker treatment in patients with COPD.Participants and methods: This nested case–control study used the Taiwan National Health Insurance Research Database. We included COPD patients who used inhalation steroid and beta-blockers between 1998 and 2010. From this cohort, there were 16,067 patients with severe exacerbations included in the analysis and 55,970 controls matched on age, sex, COPD diagnosis year, and beta-blockers treatment duration by risk set sampling.Results: For the selective beta-blocker users, the current users had a lower risk of severe exacerbations than the nonusers (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85–0.96). In contrast, for the nonselective beta-blocker users, the current users had a higher risk of severe acute exacerbations than the nonusers (OR, 1.21; 95% CI, 1.14–1.27). A higher risk of severe exacerbation during increasing mean daily dose or within about the initial 300 days was found in nonselective beta-blockers, but not in selective beta-blockers. One selective beta-blocker, betaxolol, had a significantly lower risk of severe exacerbations (OR, 0.75; 95% CI, 0.60–0.95). Two nonselective beta-blockers (labetalol and propranolol) were associated with a significantly higher risk of exacerbations (OR, 1.49; 95% CI, 1.32–1.67 for labetalol; OR, 1.16; 95% CI, 1.10–1.23 for propranolol).Conclusion: Selective beta-blockers can be cautiously prescribed for patients with COPD and cardiovascular disease (CVD), however, nonselective beta-blockers should not be prescribed for patients with COPD. Betaxolol may be the preferred choice of suitable selective beta-blocker for patients with COPD, however, labetalol and propranolol should be avoided for patients with COPD. Keywords: beta-blocker, COPD, selective, nonselective

Yu-Guo Yuan,1 Yan-Hong Wang,1 Hui-Hui Xing,1 Sangiliyandi Gurunathan2 1Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China; 2Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea Background: Graphene and graphene-related materials have gained substantial interest from both academia and industry for the development of unique nanomaterials for biomedical applications. Graphene oxide (GO) and silver nanoparticles (AgNPs) are a valuable platform for the development of nanocomposites, permitting the combination of nanomaterials with different physical and chemical properties to generate novel materials with improved and effective functionalities in a single platform. Therefore, this study was conducted to synthesize a graphene oxide–silver nanoparticle (GO-AgNPs) nanocomposite using the biomolecule quercetin and evaluate the potential cytotoxicity and mechanism of GO-AgNPs in human neuroblastoma cancer cells (SH-SY5Y).Methods: The synthesized GO-AgNPs were characterized using various analytical techniques. The potential toxicities of GO-AgNPs were evaluated using a series of biochemical and cellular assays. The expression of apoptotic and anti-apoptotic genes was measured by quantitative real-time reverse transcription polymerase chain reaction. Further, apoptosis was confirmed by caspase-9/3 activity and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and GO-AgNPs-induced autophagy was also confirmed by transmission electron microscopy.Results: The prepared GO-AgNPs exhibited significantly higher cytotoxicity toward SH-SY5Y cells than GO. GO-AgNPs induced significant cytotoxicity in SH-SY5Y cells by the loss of cell viability, inhibition of cell proliferation, increased leakage of lactate dehydrogenase, decreased level of mitochondrial membrane potential, reduced numbers of mitochondria, enhanced level of reactive oxygen species generation, increased expression of pro-apoptotic genes, and decreased expression of anti-apoptotic genes. GO-AgNPs induced caspase-9/3-dependent apoptosis via DNA fragmentation. Finally, GO-AgNPs induced accumulation of autophagosomes and autophagic vacuoles.Conclusion: In this study, we developed an environmentally friendly, facile, dependable, and simple method for the synthesis of GO-AgNPs nanocomposites using quercetin. The synthesized GO-AgNPs exhibited enhanced cytotoxicity compared with that of GO at very low concentrations. This study not only elucidates the potential cytotoxicity against neuroblastoma cancer cells, but also reveals the molecular mechanism of toxicity. Keywords: neuroblastoma, cell viability, cytotoxicity, graphene oxide–silver nanoparticles nanocomposite, apoptosis, autophagy