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Chia-Yu Huang,1,2 Mei-Yao Wu,3– 5 Ming-Cheng Huang,2,3 Teng-Shun Yu,6,7 Peter Karl Mayer,3,8,&ast; Hung-Rong Yen2,3,5,8,9,&ast; 1Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; 2Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 3Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; 4School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 5Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 6Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 7College of Medicine, China Medical University, Taichung, Taiwan; 8International Master Program in Acupuncture, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen, School of Chinese Medicine, College of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung, 404, Taiwan, ext. 3001 Fax +886-4-22365141, Email hungrongyen@mail.cmu.edu.twPurpose: Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients.Patients and Methods: A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment.Results: A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60– 0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents.Conclusion: Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.Keywords: acupuncture, disability, dementia, traditional Chinese medicine

Sio-Ian Tou,1 Cheng-Li Lin,2,3 Chia-Yu Huang,4,5,&ast; Hung-Rong Yen5– 9,&ast; 1Department of Pediatrics, Chung Kang Branch, Cheng-Ching General Hospital, Taichung, Taiwan; 2Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 3College of Medicine, China Medical University, Taichung, Taiwan; 4Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; 5Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 6International Master Program in Acupuncture, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 7Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; 8Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen, China Medical University, 91 Hsueh-Shih Road, North District, Taichung, 404, Taiwan, Tel +886-4-22053366 ext. 3313, Fax +886-4-22365141, Email hungrongyen@gmail.com Chia-Yu Huang, Taichung Tzu Chi Hospital, 88, Sec 1, Fengxing Road, Tanzi Dist, Taichung, 427, Taiwan, Tel +886-4-36060666, Fax +886-4- 36026656, Email dochuangcharlie@gmail.comPurpose: Coprescription means that patients use different prescription medications at the same time, which can lead to polypharmacy and subsequent complications. In Taiwan, prescriptions can be ordered by Western physicians, traditional Chinese physicians and dentists. It is essential to disclose the trends in coprescription to prevent possible polypharmacy among children.Patients and Methods: We used the Longitudinal Health Insurance Database 2000 in Taiwan. Children < 18 years old who had coprescription from 2002 to 2012 are included. The odds ratio and 95% confidence interval are estimated by a logistic regression model to evaluate the correlation between basic characteristics and coprescription.Results: A total of 44,801 children are included in the analysis. The numbers of children with coprescription and the numbers of coprescriptions ordered for children increased with calendar years. Children aged 3– 5 year and 6– 8 years constituted the majority of coprescriptions, while those aged < 3 years constituted the minority of coprescriptions. Compared to those in the Western medication-alone group, aged 3– 5 years and children who lived in central and southern Taiwan are more likely to have coprescription.Conclusion: Coprescription among Taiwanese children is not uncommon. Healthcare providers, policymakers and parents should be aware of the real coprescription situation among the children.Keywords: pediatrics, Chinese herbal medicine, polypharmacy, big-data analysis

Hang-Tsung Liu,1,&ast; Cheng-Shyuan Rau,2,&ast; Yueh-Wei Liu,3 Ting-Min Hsieh,1 Chun-Ying Huang,1 Peng-Chen Chien,4 Hui-Ping Lin,4 Chia-Jung Wu,4 Pei-Chin Chuang,5 Ching-Hua Hsieh4 1Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 2Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 3Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 4Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 5Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan&ast;These authors contributed equally to this workCorrespondence: Pei-Chin Chuang; Ching-Hua Hsieh, Tel +886-7-3454746, Email pcjchuang@gmail.com; m93chinghua@gmail.comIntroduction: RNA modifications mediated by the m6A, m1A, and m5C regulatory genes are crucial for the progression of malignancy. This study aimed to explore the expression of regulator genes for m6A/m5C/m1A methylation at the single-cell level and to validate their expression in cancerous and adjacent para-cancerous liver tissues of adult patients with HCC who underwent tumor resection.Methods: The bulk sequencing from The Cancer Genome Atlas (TCGA) database and the single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database were used to identify the dysregulated m6A/m5C/m1A genes for hepatocellular carcinoma (HCC). A real-time polymerase chain reaction (real-time PCR) was used to measure the expression of dysregulated m6A/m5C/m1A genes in collected human HCC tissues and compared with adjacent para-cancerous liver tissues. Immune cell infiltration with these significantly expressed methylation-related genes was evaluated using Timer2.0.Results: A discrepancy in m6A/m5C/m1A gene expression was observed between bulk sequencing and scRNA-seq. The clustered heatmap of the scRNA-seq-identified dysregulated m6A/m5C/m1A genes in TCGA cohort revealed heterogeneous expression of these methylation regulators within the cancer, whereas their expression in the adjacent liver tissues was more homogeneous. The real-time PCR validated the significant overexpression of DNMT1, NSUN5, TRMT6, IGF2BP1, and IGFBP3, which were identified using scRNA-seq, and IGFBP2, which was identified using bulk sequencing. These dysregulated methylation genes are mainly correlated with the infiltration of natural killer cells.Discussion: This study suggests that cellular diversity inside tumors contributes to the discrepancy in the expression of methylation regulator genes between traditional bulk sequencing and scRNA-seq. This study identified five regulatory genes that will be the focus of further studies regarding the function of m6A/m5C/m1A in HCC.Keywords: hepatocellular carcinoma, HCC, methylation, N6-methyladenosine, m6A, N1-methyladenosine, m1A, 5-methylcytidine, m5C, bulk sequencing, single-cell RNA sequencing, scRNA-seq

Ching Yao Huang,1 Chih Ming Chen,1 Chao Kai Chang1,2 1Department of Optometry, Da-Yeh University, Changhua, Taiwan; 2Nobel Eye Institute, Taipei, TaiwanCorrespondence: Chao Kai Chang, Nobel Eye Institute, Taipei, 100008, Taiwan, Tel +886-4-7232105 Ext 3222, Email chaokai@nobelgroup.com.twPurpose: The prevalence of children myopia in Taiwan is among the highest in the world. The study aimed to understand the status of the final prescription of the spectacle prescribed by the Taiwan optometrists when they conducted the visual inspection of elementary school, middle school and high school students, and to evaluate the influencing factors of their decision-making behavior.Methods: Among the attendants of the continuing education course activities held by optometrist associations in Taiwan, an anonymous questionnaire survey was given on the spot to optometrists who have passed the national examination. This study received 442 questionnaire surveys, including 174 optometrists and 268 assistant optometrists. The data were analyzed by using chi-square test in IBM SPSS.Results: There are statistically significant differences in the decision-making of spectacle prescription for myopia of − 1.00D~− 1.50D and − 2.25D~− 2.50D in the primary school stage between optometrists and assistant optometrists. There are also significant differences for myopia of − 2.25D and above in the middle school students. By the time of high school, there are significant differences for myopia from − 0.75D to − 3.25D and above. The higher the grade, the greater the difference in the final prescription of the spectacles given. As for the judgment factors of the final prescription, only children among elementary school and junior high school show a statistically significant difference in professional judgment between optometrists and assistant optometrists. There is no significant difference in the judgment factors for high school children. Depending on the educational level of optometrists and assistant optometrists and their distribution area, the prescription decisions are also different.Conclusion: The optometrists prefer to prescribe full correction for schoolchildren, while the assistant optometrists mostly prescribe under-correction in prescriptions for low-degree myopia and lower grades. Further investigation is needed to study its impact on children’s visual health.Keywords: children myopia, optometrists, assistant optometrists, prescription

Bi-Hua Luo,&ast; Jian-Qing Huang,&ast; Chun-Yu Huang, Pan Tian, Ai-Zhen Chen, Wei-Hao Wu, Xiao-Mei Ma, Yue-Xing Yuan, Lian Yu Department of Hematology, Longyan First Hospital Affiliated Fujian Medical University, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lian Yu, Department of Hematology, Longyan First Hospital Affiliated Fujian Medical University, No. 105 of Jiuyibei Road, Xinluo District, Fujian, 364000, People’s Republic of China, Tel +86 13859572936, Email yulian_ly@126.comObjective: The objective of this study was to screen lymphoma radiotherapy-resistant genes using CRISPR activation (CRISPRa).Methods: The Human CRISPRa library virus was packaged and then transfected into lymphoma cells to construct an activation library cell line, which was irradiated at the minimum lethal radiation dose to screen radiotherapy-resistant cells. Radiotherapy-resistant cell single-guide RNA (sgRNA) was first amplified by quantitative polymerase chain reaction (qPCR) in the coding region and then subject to next-generation sequencing (NGS) and bioinformatics analysis to screen radiotherapy-resistant genes. Certain radiotherapy-resistant genes were then selected to construct activated cell lines transfected with a single gene so as to further verify the relationship between gene expression and radiotherapy resistance.Results: A total of 16 radiotherapy-resistant genes, namely, C20orf203, MTFR1, TAF1L, MYADM, NIPSNAP1, ZUP1, RASL11A, PSMB2, PSMA6, OR8H3, TMSB4Y, CD300LF, EEF1A1, ATP6AP1L, TRAF3IP2, and SNRNP35, were screened based on the NGS results and bioinformatics analysis of the radiotherapy-resistant cells. Activated cell lines transfected with a single gene were constructed using 10 radiotherapy-resistant genes. The qPCR findings showed that, when compared with the control group, the experimental group had significantly up-regulated mRNA expression of MTFR1, NIPSNAP1, ZUP1, PSMB2, PSMA6, EEF1A1, TMSB4Y and TAF1L (p < 0.05). No significant difference in the mRNA expression of AKT3 or TRAF3IP2 (p > 0.05) was found between the two groups (p > 0.05).Conclusion: The 16 genes screened are potential lymphoma radiotherapy-resistant genes. It was initially determined that the high expression of 8 genes was associated with lymphoma radiotherapy resistance, and these genes could serve as the potential biomarkers for predicting lymphoma radiotherapy resistance or as new targets for therapy.Keywords: lymphoma, radiotherapy resistance, gene, CRISPR/Cas9

Chu-Yu Huang,1– 3 Zih-Yin Lai,1– 3 Tzu-Jung Hsu,1– 3 Fong-In Chou,3 Hong-Ming Liu,3 Yung-Jen Chuang1– 3 1School of Medicine, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; 3Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, TaiwanCorrespondence: Yung-Jen Chuang, School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, Tel +886-3-5742764, Fax +886-3-5715934, Email yjchuang@life.nthu.edu.twIntroduction: For advanced hepatocellular carcinoma (HCC), resistance to conservative treatments remains a challenge. In previous studies, the therapeutic effectiveness and DNA damage responses of boric acid-mediated boron neutron capture therapy (BA-BNCT) in HCC have been demonstrated in animal models and HCC cell line. On the other hand, numerous studies have shown that high linear energy transfer (LET) radiation can overcome tumor resistance. Since BNCT yields a mixture of high and low LET radiation, we aimed to explore whether and how BA-BNCT could eliminate radioresistant HCC cells.Methods: Radioresistant human HCC (HepG2-R) cells were established from HepG2 cells via intermittent irradiation. HepG2 and HepG2-R cells were then irradiated with either γ-ray or neutron radiation of BA-BNCT. Colony formation assays were used to assess cell survival and the relative biological effectiveness (RBE). The expression of phosphorylated H2AX (γH2AX) was also examined by immunocytochemistry and Western blot assays to evaluate the extent of DNA double-strand breaks (DSBs). Finally, the expression levels of DNA damage response-associated proteins were determined, followed by cell cycle analysis and caspase-3 activity analysis.Results: Our data demonstrated that under the same dose by γ-ray, BNCT effectively eliminated radioresistant HCC by increasing the number of DNA DSBs (p < 0.05) and impeding their repair (p < 0.05), which verified the high RBE of BNCT. We also found that BNCT resulted in delayed homologous recombination (HR) and inhibited the nonhomologous end-joining (NHEJ) pathway during DNA repair. Markedly, BNCT increased cell arrest (p < 0.05) in the G2/M phase by altering G2 checkpoint signaling and increased PUMA-mediated apoptosis (p < 0.05).Conclusion: Our data suggest that DNA damage and repair responses could affect the anticancer efficiency of BNCT in radioresistant HepG2-R cells, which highlights the potential of BNCT as a viable treatment option for recurrent HCC.Keywords: boron neutron capture therapy, BNCT, hepatocellular carcinoma, HCC, radioresistance, DNA damage, DNA repair responses

Cheng-Shyuan Rau1 &ast;, Pao-Jen Kuo2 &ast;, Hui-Ping Lin,2 Chia-Jung Wu,2 Yi-Chan Wu,2 Peng-Chen Chien,2 Ting-Min Hsieh,3 Hang-Tsung Liu,3 Chun-Ying Huang,3 Ching-Hua Hsieh2 1Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Hua Hsieh, Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung City, 833, Taiwan, Tel +886-7-7327476, Fax +886-7-3450431, Email m93chinghua@gmail.comPurpose: Following major trauma, genes involved in adaptive immunity are downregulated, which accompanies the upregulation of genes involved in systemic inflammatory responses. This study investigated microRNA (miRNA)-mRNA interactome dysregulation in circulating T cells of patients with major trauma.Patients and Methods: This study included adult trauma patients who had an injury severity score ≥ 16 and required ventilator support for more than 48 h in the intensive care unit. Next-generation sequencing was used to profile the miRNAs and mRNAs expressed in CD3+ T cells isolated from patient blood samples collected during the injury and recovery stages.Results: In the 26 studied patients, 9 miRNAs (hsa-miR-16-2-3p, hsa-miR-16-5p, hsa-miR-185-5p, hsa-miR-192-5p, hsa-miR-197-3p, hsa-miR-23a-3p, hsa-miR-26b-5p, hsa-miR-223-3p, and hsa-miR-485-5p) were significantly upregulated, while 58 mRNAs were significantly downregulated in T cells following major trauma. A network consisting of 8 miRNAs and 22 mRNAs interactions was revealed by miRWalk, with three miRNAs (hsa-miR-185-5p, hsa-miR-197-3p, and hsa-miR-485-5p) acting as hub genes that regulate the network. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested that “chemokine signaling pathway” was the predominant pathway.Conclusion: The study revealed a miRNA-mRNA interactome consisting of 8 miRNAs and 22 mRNAs that are predominantly involved in chemokine signaling in circulating T cells of patients following major trauma.Keywords: miRNA, next-generation sequencing, T cells, adaptive immunity, major trauma, critical illness

Huang CY, Lai ZY, Hsu TJ, Chou FI, Liu HM, Chuang YJ. J Hepatocell Carcinoma. 2022;9:1385–1401. The authors have advised due to an error at the time of figure assembly, Figure 7A on page 1395 is incorrect. The western blots for the 10-hour timepoint in Figure 7A was duplicated from the western blots of the 24-hour timepoint in Figure 7B. The correct Figure 7 is shown below. Figure 7 Boron neutron capture therapy increased G2/M arrest by altering CHK2 and CDK1 (CDC2) checkpoint signaling. Western blot assay for the G2/M checkpoint regulation-related proteins pCHK2, CHK2, pCDK1 (CDC2) (Y15), pCDK1 (pCDC2) (T161), and CDK1 (CDC2) at 10 hours (A) and 24 hours (B) post-irradiation. *p

Miguel Cruz-Pimentel,1 Chyong Yng Huang,2 Lihteh Wu2,3 1Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada; 2Asociados de Macula, Vitreo y Retina de Costa Rica, Primer Piso Torre Mercedes Paseo Colon, San José, Costa Rica; 3Illinois Eye and Ear Infirmary, Department of Ophthalmology, School of Medicine, University of Illinois Chicago, Chicago, IL, USACorrespondence: Lihteh Wu, Asociados de Macula, Vitreo y Retina de Costa Rica, Primer Piso Torre Mercedes, Paseo Colon, San Jose, CR, USA, Tel +506 2222-1115, Email LW65@cornell.eduAbstract: Scleral buckling (SB) remains an important technique to master for those interested in treating rhegmatogenous retinal detachment (RRD). Several ways to repair RRD include pneumatic retinopexy (PR), pars plana vitrectomy (PPV), SB or a combination of these. There is a growing worldwide trend that favors PPV as the preferred method for retinal reattachment of primary uncomplicated RRD. Reimbursement issues, operating room access, and technological advances in PPV that improve retinal visualization and less exposure to SB during fellowship training may explain this trend. As the number of SB cases decreases over time, there is a risk that SB becomes a dying art and surgeons in training may not be trained in SB. SB is preferred in eyes with no posterior vitreous detachment and retinal dialysis. SB with minimal gas vitrectomy may be indicated for eyes with inferior pathology. Non-contact wide-angled visualization with chandelier assisted SB may be well suited for teaching new generations of aspiring vitreoretinal surgeons. Its functional and anatomic results compare favorably with conventional SB for primary uncomplicated primary RRD. The main advantage of this technique is the improved visualization even through small pupils. Better visualization ensures treatment of all breaks while avoiding complications during drainage of subretinal fluid and a safer placement of intrascleral sutures for scleral fixation of the buckling element. Recordings of the procedure are easily performed, allowing the surgeons involved to review the case and learn from it. The main disadvantage is the cost involved with the chandelier and the need to have a microscope or a 3D system with a wide angle viewing system. Photoreceptor re-alignment following retinal re-attachment is an important determinant of the post-operative functional outcomes. Different methods of retinal re-attachment apparently result in different degrees of photoreceptor re-alignment. SB may hold an advantage over PPV in this regard.Keywords: rhegmatogenous retinal detachment, chandelier assisted scleral buckling, wide-angled illumination assisted scleral buckling, scleral buckling, pars plana vitrectomy, photoreceptor integrity

Chia-Liang Tsai,1 Ching-Yun Huang,2 Yi-Ching Lu,1 Li-Mei Pai,3,4 Daniel Horák,5 Yunn-Hwa Ma1,6 1Department of Physiology and Pharmacology, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 2Institute of Biomedical Sciences, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 3Department of Biochemistry & Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan, Republic of China; 4Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of China; 5Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague 6, 162 06, Czech Republic; 6Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan, Republic of ChinaCorrespondence: Yunn-Hwa Ma, Department of Physiology and Pharmacology, Chang Gung University, Guishan, Taoyuan, 33302, Taiwan, Republic of China, Email yhma@mail.cgu.edu.twBackground: Intravascular delivery of nanoparticles for theranostic application permits direct interaction of nanoparticles and vascular cells. Since vascular smooth muscle cells (VSMCs), the major components of the vascular wall, are constantly subjected to mechanical stimulation from hemodynamic influence, we asked whether cyclic strain may modulate internalization of magnetic nanoparticles (MNPs) by cultured VSMCs.Methods: Cyclic strain (1 Hz and 10%) was applied with Flexcell system in cultured VSMCs from rats, with cell-associated MNPs (MNPcell) determined by a colorimetric iron assay. Transmission and scanning electron microscopy were used for morphology studies. Confocal microscopy was used to demonstrate distribution of actin assembly in VSMCs.Results: Incubation of poly(acrylic acid) (PAA)-coated MNPs with VSMCs for 4 h induced microvilli formation and MNP internalization. Application of cyclic strain for 4– 12 h significantly reduced MNPcell by up to 65% (p < 0.05), which was associated with blunted microvilli and reduced vesicle size/cell, but not vesicle numbers/cell. Confocal microscopy demonstrated that both cyclic strain and fibronectin coating of the culture plate reduced internalized MNPs, which were co-localized with vinculin. Furthermore, cytochalasin D reduced MNPcell, suggesting a role of actin polymerization in MNP uptake by VSMCs; however, a myosin II ATPase inhibitor, blebbistatin, exhibited no effect. Cyclic strain also attenuated uptake of PAA-MNPs by LN-229 cells and uptake of poly-L-lysine-coated MNPs by VSMCs.Conclusion: In such a dynamic milieu, cyclic strain may impede cellular internalization of nanocarriers, which spares the nanocarriers and augments their delivery to the target site in the lumen of vessels or outside of the circulatory system.Graphical Abstract: Keywords: cyclic strain, magnetic nanoparticles, endocytosis, actin

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

Dina Nur Anggraini Ningrum,1– 3 Woon-Man Kung,4 I-Shiang Tzeng,4– 6 Sheng-Po Yuan,1,7 Chieh-Chen Wu,4 Chu-Ya Huang,8 Muhammad Solihuddin Muhtar,2 Phung-Anh Nguyen,2,9 Jack Yu-Chuan Li,1,2,10,11 Yao-Chin Wang12,13 1Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 2International Center for Health Information Technology (ICHIT), Taipei Medical University, Taipei, Taiwan; 3Public Health Department, Faculty of Sport Science, Universitas Negeri Semarang, Semarang City, Indonesia; 4Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei, Taiwan; 5Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 6Department of Statistics, National Taipei University, Taipei, Taiwan; 7Department of Otorhinolaryngology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 8Taiwan College of Healthcare Executives, Taipei, Taiwan; 9Department of Healthcare Information and Management, Ming Chuan University, Taoyuan, Taiwan; 10Department of Dermatology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 11TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; 12Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan; 13Department of Emergency Medicine, Min-Sheng General Hospital, Taoyuan, TaiwanCorrespondence: Jack Yu-Chuan Li Email jack@tmu.edu.tw; jaak88@gmail.comYao-Chin Wang Email vkwang8888@yahoo.com.twPurpose: To develop deep learning model (Deep-KOA) that can predict the risk of knee osteoarthritis (KOA) within the next year by using the previous three years nonimage-based electronic medical record (EMR) data.Patients and Methods: We randomly selected information of two million patients from the Taiwan National Health Insurance Research Database (NHIRD) from January 1, 1999 to December 31, 2013. During the study period, 132,594 patients were diagnosed with KOA, while 1,068,464 patients without KOA were chosen randomly as control. We constructed a feature matrix by using the three-year history of sequential diagnoses, drug prescriptions, age, and sex. Deep learning methods of convolutional neural network (CNN) and artificial neural network (ANN) were used together to develop a risk prediction model. We used the area under the receiver operating characteristic (AUROC), sensitivity, specificity, and precision to evaluate the performance of Deep-KOA. Then, we explored the important features using stepwise feature selection.Results: This study included 132,594 KOA patients, 83,111 females (62.68%), 49,483 males (37.32%), mean age 64.2 years, and 1,068,464 non-KOA patients, 545,902 females (51.09%), 522,562 males (48.91%), mean age 51.00 years. The Deep-KOA achieved an overall AUROC, sensitivity, specificity, and precision of 0.97, 0.89, 0.93, and 0.80 respectively. The discriminative analysis of Deep-KOA showed important features from several diseases such as disorders of the eye and adnexa, acute respiratory infection, other metabolic and immunity disorders, and diseases of the musculoskeletal and connective tissue. Age and sex were not found as the most discriminative features, with AUROC of 0.9593 (− 0.76% loss) and 0.9644 (− 0.25% loss) respectively. Whereas medications including antacid, cough suppressant, and expectorants were identified as discriminative features.Conclusion: Deep-KOA was developed to predict the risk of KOA within one year earlier, which may provide clues for clinical decision support systems to target patients with high risk of KOA to get precision prevention program.Keywords: artificial intelligence, clinical decision support system, medical informatics application, precision medicine

Chia-Yu Huang,1– 3 Ming-Cheng Huang,3,4 Mao-Feng Sun,3,4 Cheng-Li Lin,5,6 Mei-Yao Wu,4,7 Wu-Chou Lin,3,8,&ast; Hung-Rong Yen3,4,9,10,&ast; 1Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 427, Taiwan; 2School of Medicine, Tzu Chi University, Hualien, 970, Taiwan; 3Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 4Department of Chinese Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 5Management Office for Health Data, China Medical University Hospital, Taichung, 404, Taiwan; 6College of Medicine, China Medical University, Taichung, 404, Taiwan; 7School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 8Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, 404, Taiwan; 9Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, 404, Taiwan; 10Chinese Medicine Research Center, China Medical University, Taichung, 404, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen Tel +886-4-22053366 ext. 3313Email hungrongyen@mail.cmu.edu.twWu-Chou Lin Tel +886-4-22052121Email d0562@mail.cmuh.org.twBackground: Major depressive disorder is a significant public health concern, which often leads to loss of productivity, functional decline, and various complications. The aim of this study was to investigate the effectiveness of acupuncture in the risk reduction of coronary heart disease (CHD) in patients with depression.Methods: We enrolled patients diagnosed with depression between January 1, 1997, and December 31, 2010, through the Taiwanese National Health Insurance Research Database (NHIRD). Propensity score was used to match equal numbers (n=14,647) of acupuncture cohort and no-acupuncture cohort based on characteristics including sex, age, baseline comorbidity and medication. Patients were followed up until December 31, 2013, or withdrawn from the NHIRD. The Cox regression model was used to compare the hazard ratios (HRs) of CHD in the two cohorts.Results: The basic characteristics of the two groups were similar. A lower cumulative incidence of CHD was noted in the acupuncture cohort (Log rank test, p < 0.001). Over time, 1626 patients in the acupuncture cohort (21.05 per 1000 person-years) and 2412 patients in the no-acupuncture cohort (39.84 per 1000 person-years) developed CHD (adjusted HR=0.50, 95% CI 0.47– 0.53). The decreased CHD incidence was independent of age, sex, comorbidities, and medications used. The cumulative incidence of CHD was significantly lower in the acupuncture cohort than in the no-acupuncture cohort (Log rank test, p< 0.001).Conclusion: The results provided a real-world evidence that acupuncture may have beneficial effect on CHD risk reduction in patients with depression.Keywords: acupuncture, depression, coronary heart disease, National Health Insurance Research Database, real-world evidence

Wei-Ti Su,1 Ching-Hua Tsai,1 Chun-Ying Huang,1 Sheng-En Chou,1 Chi Li,1 Shiun-Yuan Hsu,1 Ching-Hua Hsieh2 1Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanCorrespondence: Ching-Hua HsiehDepartment of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung City, 833, TaiwanTel +886-7-7327476Email m93chinghua@gmail.comBackground: The Geriatric Nutritional Risk Index (GNRI) is a simple and objective screening tool for clinicians to screen patients’ nutritional status based on serum albumin level and their weight and height. The original study had divided patients based on GNRI into quartiles of nutritional risk for death: a no-risk group (GNRI > 98), a low-risk group (GNRI 92– 98), a moderate-risk group (GNRI 82 to < 92), and a major-risk group (GNRI < 82). Given that the patients generally sustained traumatic brain injury (TBI) in an acute condition, the study aimed to explore whether GNRI presents a prognostic value for the mortality outcome of these patients.Methods: From January 1, 2009, to December 31, 2019, 581 elderly patients with moderate to severe TBI, which was defined as sustaining a head Abbreviated Injury Scale ≥ 3, was included in the study population. The collected data included age, sex, body mass index, serum albumin levels at admission, preexisting comorbidities, Glasgow Coma Scale, and Injury Severity Score. The primary outcome in the comparison was in-hospital mortality.Results: Multivariate logistic regression analysis revealed that GNRI, ESRD, and ISS were significant independent risk factors for mortality in patients with moderate to severe TBI. When subgrouping the study population into four nutritional risk categories according to the quartile deviation as Q1 (GNRI < 85, n = 145), Q2 (GNRI 85 to < 93.8 n = 145), Q3 (GNRI 93.8 to 103, n = 145), and Q4 (GNRI > 103, n = 146), Q1 patients had a significantly longer LOS in hospital (25.2 days vs 18.6 days, respectively; p = 0.004) and higher mortality rate (28.3% vs 11.7%, respectively; p < 0.001) than Q4 patients. The mortality rate was significantly higher in Q1 patients than in Q4 patients (OR, 2.8; 95% CI, 1.14– 6.78; p = 0.021).Conclusion: This study revealed that the GNRI is a significant independent risk factor and a promising simple assessment tool for mortality in elderly patients with moderate to severe TBI.Keywords: elderly, malnutrition, mortality, Geriatric Nutritional Risk Index, GNRI, trauma, traumatic brain injury, TBI

Dina Nur Anggraini Ningrum,1,2 Sheng-Po Yuan,1,3 Woon-Man Kung,4 Chieh-Chen Wu,4 I-Shiang Tzeng,4– 6 Chu-Ya Huang,7 Jack Yu-Chuan Li,1,8,9,* Yao-Chin Wang10,11,* 1Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 2Public Health Department, Universitas Negeri Semarang, Semarang City, Indonesia; 3Department of Otorhinolaryngology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 4Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei, Taiwan; 5Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 6Department of Statistics, National Taipei University, Taipei, Taiwan; 7Taiwan College of Healthcare Executives, Taipei, Taiwan; 8Department Dermatology, Wan Fang Hospital, Taipei, Taiwan; 9Taipei Medical University Research Center of Cancer Translational Medicine, Taipei, Taiwan; 10Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan; 11Department of Emergency Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Jack Yu-Chuan LiGraduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 15 F, No. 172-1, Sec 2, Kellung Road, Daan District, Taipei, 11031, TaiwanTel/Fax +886-2-2736-1661 Ext. 7600Email jack@tmu.edu.twYao-Chin WangDepartment of Emergency, Min-Sheng General Hospital, No. 168, ChingKuo Road, Taoyuan, 33044, TaiwanTel +886-3-317-9599 Ext. 8134Email vkwang8888@yahoo.com.twBackground: Incidence of skin cancer is one of the global burdens of malignancies that increase each year, with melanoma being the deadliest one. Imaging-based automated skin cancer detection still remains challenging owing to variability in the skin lesions and limited standard dataset availability. Recent research indicates the potential of deep convolutional neural networks (CNN) in predicting outcomes from simple as well as highly complicated images. However, its implementation requires high-class computational facility, that is not feasible in low resource and remote areas of health care. There is potential in combining image and patient’s metadata, but the study is still lacking.Objective: We want to develop malignant melanoma detection based on dermoscopic images and patient’s metadata using an artificial intelligence (AI) model that will work on low-resource devices.Methods: We used an open-access dermatology repository of International Skin Imaging Collaboration (ISIC) Archive dataset consist of 23,801 biopsy-proven dermoscopic images. We tested performance for binary classification malignant melanomas vs nonmalignant melanomas. From 1200 sample images, we split the data for training (72%), validation (18%), and testing (10%). We compared CNN with image data only (CNN model) vs CNN for image data combined with an artificial neural network (ANN) for patient’s metadata (CNN+ANN model).Results: The balanced accuracy for CNN+ANN model was higher (92.34%) than the CNN model (73.69%). Combination of the patient’s metadata using ANN prevents the overfitting that occurs in the CNN model using dermoscopic images only. This small size (24 MB) of this model made it possible to run on a medium class computer without the need of cloud computing, suitable for deployment on devices with limited resources.Conclusion: The CNN+ANN model can increase the accuracy of classification in malignant melanoma detection even with limited data and is promising for development as a screening device in remote and low resources health care.Keywords: skin cancer, convolutional neural network, artificial neural network, embedded artificial intelligence

Chen-Mao Liao,1,* Chih-Ming Lin,2,* Chin-Chia Kuo,1 Ming-Shu Chen,3 Chun-Yang Huang,4 Ching-Yuan Lin4 1Department of Applied Statistics and Information Science, Ming Chuan University, Taoyuan City 33352, Taiwan; R.O.C.; 2Department of Healthcare Information and Management, Ming Chuan University, Taoyuan City 33352, Taiwan; R.O.C.; 3Department of Healthcare Administration, College of Management and Healthcare, Oriental Institute of Technology, New Taipei City 22061, Taiwan; R.O.C.; 4Department of Laboratory Medicine, Ten Chan General Hospital, Chung-Li, Taoyuan City 32043, Taiwan; R.O.C.*These authors contributed equally to this workCorrespondence: Ming-Shu ChenDepartment of Healthcare Administration, College of Management and Healthcare, Oriental Institute of Technology, No58, Sec. 2, Sichuan Road, Pan-Chiao Dist., New Taipei City 22061, Taiwan; R.O.C.Tel +886-2-77388000 ext. 6223Email tree1013@gmail.comBackground: To continuously improve medical quality and provide clinicians with more accurate blood test reports, this study collected blood quality control data in 2017 from a medical examination laboratory in a teaching level hospital located in Taoyuan City, Taiwan.Material and Methods: The quality control data were arranged and analyzed from daily complete blood count (CBC), including white blood cells (WBC), red blood cells (RBC), hemoglobin (Hb), and platelets (PLT) recorded by a laboratory blood analyzer. Using the empirical Bayesian method, we estimated the variation of concentrations of the last and current batches to establish a novel control chart with adjusted upper and lower limits for the current batch, and then compared results with the traditional Shewhart method. The average run length (ARL) and sensitivity of the empirical Bayesian method were explored.Results: The study found that ARL showed a qualified capability for the four blood routine tests when using the empirical Bayesian method. Compared to the Levey–Jennings control chart, the novel control chart presents an alert earlier when a deviation occurs and shows a fake alert later when there is no deviation.Conclusion: The parallel tests showed that the longer the time is, the better the test’s proficiency. We concluded that the empirical Bayesian method could be applied effectively to improve the capability of daily control in CBC laboratory tests.Keywords: empirical Bayesian, EB, average run length, ARL, complete blood count, CBC, Levey–Jennings control chart

Chun-Ying Huang,1,* Sheng-En Chou,1,* Wei-Ti Su,1 Hang-Tsung Liu,1 Ting-Min Hsieh,1 Shiun-Yuan Hsu,1 Hsiao-Yun Hsieh,2 Ching-Hua Hsieh2 1Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University and College of Medicine, Kaohsiung 83301, Taiwan; 2Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University and College of Medicine, Kaohsiung 83301, Taiwan*These authors contributed equally to this workCorrespondence: Ching-Hua HsiehDepartment of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, TaiwanTel +886-7-7327476Email m93chinghua@gmail.comBackground: In June 2013, the legal blood alcohol concentration (BAC) limit for driving was lowered from 0.05 to 0.03 mg/mL in Taiwan. Thus, this study aimed to assess the epidemiological changes in terms of drinking among drivers in southern Taiwan before and after the law was imposed.Methods: Only patients who had undergone the BAC test at the emergency room were included in the study. The patients during the study period before (n = 2735) and after (n = 2413) the implementation of the law were selected for comparison. Drunk patients were defined as those who had a BAC ≥ 0.005 and were considered as driving under the influence (DUI) of alcohol. Meanwhile, driving while intoxicated (DWI) was defined as a BAC ≥ 0.05, which was the level adopted in the new law.Results: Since the BAC limit lowered to 0.03, the number of DUI patients significantly decreased from 340 (12.4%) to 171 (7.1%), and that of DWI patients significantly reduced from 273 (10.0%) to 146 (6.1%) based on the alcohol test. In addition, after the implementation of the law, the number of associated injuries did not significantly decrease from that before the law was implemented in patients involved in alcohol-related crashes.Conclusion: After lowering the legal BAC limit from 0.05 to 0.03, responsiveness to the change in law was observed among the studied population. However, such responsiveness may not be observed in some citizens who may need special interventions to help reduce their behavior of drinking and driving.Keywords: alcohol, blood alcohol concentration, BAC, driving under the influence (DUI) of alcohol, driving while intoxicated, DWI, alcohol-related crashes, law sanction, mortality

Chen-Yu Huang,1,2 Wen-Hsun Chang,3,4 Hsin-Yi Huang,5 Chao-Yu Guo,4,6 Yiing-Jenq Chou,4,6 Nicole Huang,4,6 Wen-Ling Lee,2,7,8 Peng-Hui Wang1,2,9,10 1Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 3Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan; 4Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan; 5Biostatics Task Force, Taipei Veterans General Hospital, Taipei, Taiwan; 6Institute of Public Health, National Yang-Ming University, Taipei, Taiwan; 7Department of Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan; 8Department of Nursing, Oriental Institute of Technology, New Taipei City, Taiwan; 9Female Cancer Foundation, Taipei, Taiwan; 10Department of Medical Research, China Medical University Hospital, Taichung, TaiwanCorrespondence: Wen-Ling LeeDepartment of Medicine, Cheng-Hsin General Hospital, 45, Cheng-Hsin Street, Taipei, TaiwanEmail johnweiwang@gmail.comPeng-Hui WangDepartment of Obstetrics and Gynecology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, 201, Section 2, Shih-Pai Road, Taipei 112, TaiwanFax +886-2-55702788Email pongpongwang@gmail.comPurpose: The goal of the current study is to determine the risk of subsequent development of epithelial ovarian cancer (EOC) in women after ovarian surgery for benign ovarian tumors.Patients and Methods: We conducted the nationwide population-based historic cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan. Eleven thousand six hundred twenty women who underwent ovarian surgery for ovarian benign diseases were analyzed. The collected data included age, types of ovarian surgery, medical history by Charlson comorbidity index (CCI), infertility (yes/no), pelvic inflammatory disease (PID) (yes/no), tubal ligation (yes/no), total/subtotal hysterectomy (TH/STH) (yes/no), and endometrioma (yes/no). We used the Kaplan–Meier method and the Log-rank test to evaluate the risk factors. Cox proportional hazard methods were used to evaluate risk factors for the subsequent development of EOC. Multivariate analysis using Cox stepwise forward regression was conducted for the covariate selected in univariate analysis. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using the Wald test.Results: Subsequent EOC incidence rate (IR, incidence per 10,000 person-years) of women after ovarian surgery for benign ovarian tumors was 2.98. Separating into four groups based on different age, IR of EOC was 1.57 (< 30 years), 4.71 (30– 39 years), 3.59 (40– 49 years) and 0.94 (≥ 50 years), respectively. Univariate and multivariate analyses identified only high level of CCI (≥ 2 or more) as an independent risk factor for subsequent development of EOC in women after ovarian surgery for benign ovarian tumors (HR 59.17, 95% CI 7.50– 466.80 in women with CCI level of 2 and HR 190.68, 95% CI 24.33– 2494.19, in women with CCI level ≥ 3, respectively).Conclusion: Our results, if confirmed, suggest that women with other comorbidities (CCI) should be well informed that they may have a higher risk of subsequent development of EOC when ovarian surgery is planned even though the final pathology showed a benign ovarian tumor.Keywords: benign ovarian tumor, cohort study, epidemiology, epithelial ovarian cancer, ovarian surgery, risk

Kuan-Lin Chen,1–3 Cheng-Te Chen,4 Chien-Ho Lin,5 Chien-Yu Huang,6 Ya-Chen Lee7 1Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan (R.O.C); 2Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan (R.O.C); 3Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan (R.O.C); 4Department of Educational Psychology and Counseling, National Tsing Hua University, Hsinchu, Taiwan (R.O.C); 5Department of Psychiatry, Chi Mei Medical Center, Youngkang Dist., Tainan City 710, Taiwan (R.O.C); 6Department of Occupational Therapy, I-Shou University, Yanchao District, Kaohsiung City 824, Taiwan (R.O.C); 7Department of Occupational Therapy, College of Medical and Health Science, Asia University, Wufeng, Taichung, Taiwan (R.O.C)Correspondence: Ya-Chen LeeDepartment of Occupational Therapy, College of Medical and Health Science, Asia University, No. 500, Lioufeng Road, Wufeng, Taichung, Taiwan (R.O.C)Tel +886-4-23323456 Ext. 20007Email jennyleenet@hotmail.comBackground: Children with autism spectrum disorder (ASD) often exhibit deficits in pretend play and have less playfulness. The purpose of this study was to evaluate the relationship between pretend play and playfulness in children with autism spectrum disorder, while controlling for severity of autism behaviors, verbal comprehension, and age.Methods: A sample of 72 children with ASD aged between 3 and 12 years were assessed with the Child-Initiated Pretend Play Assessment, Test of Playfulness, and Childhood Autism Rating Scale, respectively, for their pretend play, playfulness, and severity of autism behaviors. Correlation and multiple regression analyses were conducted.Results: The results of Pearson correlation coefficients revealed that the pretend play variables had mild to moderate associations with the playfulness variables (r = −0.25 to 0.68). The multiple regression analyses showed that, overall, the internal locus of control was the significant predictor of the pretend play variables (accounting for 5–47% of the variance, p < 0.001). The six pretend play variables were all important predictors of all playfulness variables (explaining 41–76% of the variance, p < 0.001–0.047). Particularly, the elaborate pretend play action was a significant predictor of all four playfulness variables. Our findings indicated that the more children with ASD engaged in pretend play, the more they experienced playfulness.Conclusion: Clinicians could help children with ASD improve their feeling of being in charge of their play in order to develop better performance in pretend play. Assisting children with ASD to engage in pretend play is important to promote their internal experience of playfulness.Keywords: autism spectrum disorder, pretend play, playfulness, severity of autism behaviors

Chia-Sui Weng,1,* Chao-Chih Wu,2,* Tze-Chien Chen,1 Jen-Ruei Chen,1 Chueh-Yi Huang,1 Chih-Long Chang1–3 1Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan; 2Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan; 3Department of Medicine, Mackay Medical College, New Taipei City, Taiwan*These authors contributed equally to this workCorrespondence: Chih-Long ChangDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei, TaiwanTel +886-2-25433535 Fax +886-2-25232448Email clchang@mmc.edu.twPurpose: The aim of this study is to analyze the outcomes of platinum-sensitive (PS) recurrent ovarian cancer treated with pegylated liposomal doxorubicin and carboplatin (CD) versus paclitaxel and carboplatin (CP). Clinical features were examined to characterize the patient population that would benefit from CD.Materials and methods: This is a retrospective review of 122 cases at a tertiary hospital. Patients with PS recurrent ovarian cancer who received CD or CP were included. Progression-free survival (PFS) and overall survival (OS) were evaluated through the Kaplan–Meier method and log-rank test. Cox proportional hazards regression was used to examine PFS predictors.Results: In total, 122 patients (75% with first recurrence and 25% with second recurrence) were included. The majority of the patients were diagnosed at an advanced stage and with the histology of serous carcinoma. Median PFS and OS were 14.8 and 55.5 months in the CD group and 13.5 and 56.8 months in the CP group. Subgroup analysis of patients revealed that the CD group had longer median PFS than the CP group among patients with PFI>12 months. Additionally, during the second recurrence, longer PFS was observed in the CD group than in the CP group (medians 22.3 and 13.5 months, respectively, p = 0.019).Conclusion: Comparable outcomes in recurrent platinum-sensitive ovarian cancer treated with CD versus CP were presented in this study. Longer PFS in CD group was observed among patients with PFI for more than 12 months or in second recurrence.Keywords: Lipo-Dox, platinum-sensitive ovarian cancer

Wei-Ke Kuo,1 Yu-Chih Liu,1,2 Chien-Ming Chu,1 Chung-Ching Hua,1,2 Chih-Yu Huang,1 Min-Hui Liu,2,3 Chao-Hung Wang2,3 1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; 2Chang Gung University, College of Medicine, Taoyuan, Taiwan; 3Heart Failure Research Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, TaiwanCorrespondence: Chao-Hung WangHeart Failure Research Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, No. 222, Maijin Road, Anle District, Keelung City 204, TaiwanTel +886-2-24313131 ext 2245Fax +886-2-24335342Email bearty54@gmail.comBackground: The BODE index is a multidimensional grading system for predicting the prognoses of patients with chronic obstructive pulmonary disease (COPD). This study investigated whether an amino acids-based metabolic profile developed for heart failure patients (including histidine, ornithine, phenylalanine, and leucine) could identify COPD patients and further discriminates COPD patients in advanced BODE stages.Methods: Ultra-performance liquid chromatography was performed on 119 participants, including 75 COPD patients at different BODE stages and 44 normal controls. Albumin, pre-albumin, transferrin, high sensitivity C-reactive protein, and hand grip strength were also measured. Receiver operating characteristic curves and area under curves were used for estimation.Results: The BODE points in our patients were 3.29 [95% confidence interval (CI) = 2.74–3.85]. Compared to normal controls, COPD patients had lower leucine but higher ornithine levels. A COPD score, developed based on leucine and ornithine, significantly discriminated COPD from normal controls [odds ratio (OR) = 2.71, 95% CI = 1.83–4.04, p

Chih-Yu Huang,1 Chung-Chieh Yu1,21Division of Pulmonary, Critical Care, and Sleep Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of ChinaObjective: Periodic leg movement in sleep (PLMS) is common among patients with obstructive sleep apnea (OSA). The PLMS frequency changes after continuous positive airway pressure (CPAP) titration. This study investigated the effects of two PLMS diagnostic criteria on PLMS prevalence and the restless leg syndrome (RLS) detection rate in patients with OSA before and after CPAP titration.Methods: This retrospective study included patients with OSA who received polysomnography (PSG) and successful CPAP titration from December 2012 to December 2014. Their clinical variables and sleep parameters were evaluated using the PLMS diagnostic criteria: PLMS index (PLMI) ≥5 and ≥15. PLMS prevalence and the RLS detection rate were analyzed according to the PLMI before and after CPAP.Results: In patients with OSA with a PLMI of ≥5 and ≥15 after PSG with CPAP titration, the PLMS prevalence was 20.1% (76/378) and 4.5% (17/378), respectively, which revealed CPAP titration increased PLMI. Moreover, in terms of PLMI ≥5 and ≥15, PSG with CPAP titration led to significantly higher PLMS prevalence than PSG alone (20.1% vs 7.1% and 4.5% vs 0.8%, respectively; both P

Chung-Chieh Yu,1–3 Chih-Yu Huang,1–3 Wei-Ke Kuo,1–3 Chung-Yao Chen2,4 1Division of Pulmonary Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; 2Department of Medicine, College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung, Taiwan; 4Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan Objectives: To assess the effect of continuous positive airway pressure (CPAP) on nocturia in ischemic stroke patients with obstructive sleep apnea (OSA).Methods: This was a prospective and non-randomized controlled study in which ischemic stroke patients with OSA being treated in a rehabilitation ward were enrolled. The participants who tolerated CPAP were classified as the CPAP group, while those who refused or could not tolerate CPAP were classified as the control group. The percentage change of nocturia before and after 2 weeks of CPAP therapy between the two groups were compared.Results: A total of 44 participants were enrolled in and 35 participants (mean age=59.8±11.7 years old; mean apnea hypopnea index=42.9±16.7/h) completed the study (control group: 14, CPAP group: 21). Overall, 69% of the participants had nocturnal polyuria and 69% of them had more than one nocturia episode per night. The baseline and initial nocturia characteristics did not differ significantly between the two groups. As compared to the control group, CPAP therapy significantly decreased the nocturnal polyuria index (mean percentage change: 9% vs -21% (P=0.005)) and nocturnal urine output (mean percentage change: 6% vs -26% (P=0.04)), but not the nocturia episodes or 24-hours total urine output.Conclusion: Nocturia due to nocturnal polyuria is very common in post-stroke patients with OSA. Treating OSA by CPAP significantly reduces nocturnal polyuria, but not nocturia frequency, in ischemic stroke patients. Keywords: nocturia, nocturnal polyuria index, nocturnal urine output, multiple comorbidities

Chung-Yu Huang,1,2 Wen-Shin Chang,3 Chia-Wen Tsai,3 Te-Chun Hsia,3 Te-Chun Shen,3,* Da-Tian Bau,3–5,* Hao-Ai Shui1,* 1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; 2Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; 3Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan; 4Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; 5Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan *These authors contributed equally to this work Background: The incidence rate of nasopharyngeal carcinoma (NPC) has been documented to be high in Southeast Asia. Interleukin-18 (IL-18) is a multifunctional cytokine that augments interferon-γ production and acts as an important immunomediator in the development of several types of cancer.Patients and methods: This case–control study evaluated the role of IL-18 in NPC at the DNA level by genotyping its promoter polymorphisms at positions -656, -607, and -137 in a Taiwanese population. A total of 176 patients with NPC and age- and gender-matched 352 noncancer controls were included in this study.Results: The CC genotype of the IL-18-607 polymorphism was found to be associated with significantly decreased risks of NPC compared to the AA genotype (crude OR =0.50, 95% CI =0.29–0.84, P=0.0093). This significant difference persisted even in the dominant and recessive models. A significantly lower C allele frequency at position -607 was detected in the NPC group (41.8% vs 50.3%; OR =0.77; 95% CI =0.63–1.04, P=0.0089). Regarding IL-18-656 and -137 polymorphisms, there were no differential distributions of their genotypes between the NPC and control groups. After substratification of the subjects according to their smoking, alcohol consumption, and areca chewing status, the genotype distribution of the IL-18-607 polymorphism was found to be different only among nonsmokers between the NPC and control subgroups.Conclusion: This study suggests that IL-18 plays an important role in the carcinogenesis of NPC in Taiwan and that the genotype–phenotype correlation of IL-18-607 polymorphism and its contribution to NPC need to be investigated further. Keywords: genotype, IL-18, nasopharyngeal carcinoma (NPC), polymorphism, Taiwan

Chun-Bing Chen,1–6 Ming-Ying Wu,1–4 Chau Yee Ng,1–5 Chun-Wei Lu,1–6 Jennifer Wu,1–4,6 Pei-Han Kao,1–4,6 Chan-Keng Yang,4–7 Meng-Ting Peng,4,6–7 Chen-Yang Huang,4,6–7 Wen-Cheng Chang,4,6–7 Rosaline Chung-Yee Hui,1–4 Chih-Hsun Yang,1–4 Shun-Fa Yang,8,9 Wen-Hung Chung,1–4,6,10,11 Shih-Chi Su1–4,10 1Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; 2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; 7Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 11Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China Abstract: With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management. Keywords: acute generalized exanthematous pustulosis, drug rash, eosinophilia, Stevens–Johnson syndrome, toxic epidermal necrolysis, targeted therapy, immunotherapy

Cynthia Y Huang,1 Jonathan B Thomas,2 Abdullah Alismail,3 Avi Cohen,1 Waleed Almutairi,3 Noha S Daher,4 Michael H Terry,5 Laren D Tan1,3 1Department of Medicine, Division of Pulmonary, Critical Care, Hyperbaric and Sleep Medicine, Loma Linda University, Loma Linda, CA, USA; 2Zapara School of Business, La Sierra University, Riverside, CA, USA; 3Cardiopulmonary Sciences Department, School of Allied Health Professions, Loma Linda University, Loma Linda, CA, USA; 4Department of Allied Health Studies, School of Allied Health Professions, Loma Linda University, Loma Linda, CA, USA; 5Department of Respiratory Care, Loma Linda University Medical Center, Loma Linda, CA, USA Objective: The aim of this study was to investigate the feasibility of using augmented reality (AR) glasses in central line simulation by novice operators and compare its efficacy to standard central line simulation/teaching. Design: This was a prospective randomized controlled study enrolling 32 novice operators. Subjects were randomized on a 1:1 basis to either simulation using the augmented virtual reality glasses or simulation using conventional instruction. Setting: The study was conducted in tertiary-care urban teaching hospital. Subjects: A total of 32 adult novice central line operators with no visual or auditory impairments were enrolled. Medical doctors, respiratory therapists, and sleep technicians were recruited from the medical field. Measurements and main results: The mean time for AR placement in the AR group was 71±43 s, and the time to internal jugular (IJ) cannulation was 316±112 s. There was no significant difference in median (minimum, maximum) time (seconds) to IJ cannulation for those who were in the AR group and those who were not (339 [130, 550] vs 287 [35, 475], p=0.09), respectively. There was also no significant difference between the two groups in median total procedure time (524 [329, 792] vs 469 [198, 781], p=0.29), respectively. There was a significant difference in the adherence level between the two groups favoring the AR group (p=0.003). Conclusion: AR simulation of central venous catheters in manikins is feasible and efficacious in novice operators as an educational tool. Future studies are recommended in this area as it is a promising area of medical education. Keywords: augmented reality, central line, simulation, medical education

Kuo-Chen Wei,1 Feng-Wei Lin,2 Chiung-Yin Huang,1 Chen-Chi M Ma,3 Ju-Yu Chen,1 Li-Ying Feng,1 Hung-Wei Yang2 1Department of Neurosurgery, Chang Gung Memorial Hospital, School of Medicine, Chang Gung University, Taoyuan, 2Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 3Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, Republic of China Abstract: To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM-1 s-1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM-1 s-1). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. Keywords: drug tracking, fluorescence imaging, MR imaging, BSA nanoparticles, cancer therapy

Barry J Allen,1,2 Chen-Yu Huang,3 Raymond A Clarke2 1Faculty of Physics, University of Sydney, Sydney, NSW, Australia; 2Faculty of Medicine, Ingham Institute, University of Western Sydney, Liverpool, NSW, Australia; 3Central Clinical School, University of Sydney, Sydney, NSW, AustraliaAbstract: Targeted alpha therapy (TAT) is an emerging option for local and systemic cancer treatment. Preclinical research and clinical trials show that alpha-emitting radionuclides can kill targeted cancer cells while sparing normal cells, thus reducing toxicity. 223RaCl2 (Xofigo®) is the first alpha emitting radioisotope to gain registration in the US for palliative therapy of prostate cancer bone metastases by indirect physiological targeting. The alpha emitting radioisotopes 211At, 213Bi, 225Ac and 227Th are being used to label targeting vectors such as monoclonal antibodies for specific cancer therapy indications. In this review, safety and tolerance aspects are considered with respect to microdosimetry, specific energy, Monte Carlo model calculations, biodosimetry, equivalent dose and mutagenesis. The clinical efficacy of TAT for solid tumors may also be enhanced by its capacity for tumor anti-vascular (TAVAT) effects. This review emphasizes key aspects of TAT research with respect to the PAI2-uPAR complex and the monoclonal antibodies bevacizumab, C595 and J591. Clinical trial outcomes are reviewed for neuroendocrine tumors, leukemia, glioma, melanoma, non-Hodgkins lymphoma, and prostate bone metastases. Recommendations and future directions are proposed.Keywords: biodosimetry, microdosimetry, mutagenesis, PAI2, bevacizumab, C595, J591, tumors, cancer, metastases

JiSheng Zhang,1,* CongYang Huang,1,* YanLi Li,1 Jun Chen,2 FangYuan Shen,1 Qiang Yao,3 JiaQi Qian,4 BeiYan Bao,1 XuPing Yao51Division of Nephrology, School of Medicine, Ningbo Urology and Nephrology Hospital, Ningbo University, Ningbo, Zhejiang, People's Republic of China; 2Blood Purification Center, School of Medicine, Ningbo Urology and Nephrology Hospital, Ningbo University, Ningbo, Zhejiang, People's Republic of China; 3Baxter Healthcare Pty Ltd, Shanghai, People's Republic of China; 4Division of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 5Division of Urology, School of Medicine, Ningbo Urology and Nephrology Hospital, Ningbo University, Ningbo, Zhejiang, People's Republic of China *These authors contributed equally to this workObjectives: To evaluate differences in the health-related quality of life (HRQoL) between patients with constipation receiving hemodialysis (HD) and those receiving peritoneal dialysis (PD).Methods: In this cross-sectional study, 605 dialysis patients (478 HD cases and 127 PD cases; all patients were older than 18 years) from our hospital were included. A questionnaire was used to evaluate their constipation statuses. The effect of constipation on HRQoL was assessed, using the Chinese version of the 12-item short-form (SF-12) general health survey. Karnofsky score, sociodemographic, and clinical data were also collected. We performed multiple logistic regression analysis to define independent risk factors for constipation and impaired HRQoL.Results: A total of 605 participants (326 men [53.9%] and 279 women [46.1%]) were surveyed. The incidence of constipation was 71.7% in HD patients and 14.2% in PD patients. Dialysis patients with constipation had significantly lower mean SF-12 Physical Component Summary scale and Mental Component Summary scale scores than the nonconstipation group (P < 0.05), whereas HD patients had better SF-12 Physical Component Summary and Mental Component Summary scores than PD patients (P < 0.05). When we performed multivariate logistic regression analysis, dialysis modality, diabetes, and the number of constipation-related medications were three independent risk factors associated with constipation. As for impaired HRQoL in the constipated dialysis population, dialysis modality was found to be another independent risk factor in addition to age and diabetes.Conclusion: PD patients with constipation had worse HRQoL than HD control participants. We should pay more attention to the patients with constipation receiving PD, as peritonitis caused by constipation was associated with a higher mortality.Keywords: constipation, health-related quality of life, dialysis, SF-12

Hung-Wei Yang,1,2 Mu-Yi Hua,1 Hao-Li Liu,3 Chiung-Yin Huang,2 Kuo-Chen Wei21Molecular Medicine Research Center, Department of Chemical and Materials Engineering, Chang Gung University, 2Department of Neurosurgery, Chang Gung University and Memorial Hospital, 3Department of Electrical Engineering, Chang Gung University, Taoyuan, TaiwanAbstract: Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications.Keywords: magnetic nanoparticles, drug delivery, biomedical applications, cancer therapy

Yu-Jen Lu1,2,#, Hung-Wei Yang1,#, Sheng-Che Hung3, Chiung-Yin Huang2, Shin-Ming Li4, Chen-Chi M Ma4, Pin-Yuan Chen2, Hong-Chieh Tsai2, Kuo-Chen Wei2, Jyh-Ping Chen1 1Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan, Taiwan; 2Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan; 3Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan#These authors contributed equally to this workBackground: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life.Methods: Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA–GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA–GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA–GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug.Results: Single layer PAA–GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA–GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 µg BCNU/mg PAA–GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA–GO–BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC50 value toward GL261 compared with the same dosage of free drug.Conclusion: Nanosized PAA–GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.Keywords: graphene oxide, BCNU, glioma cells, drug delivery, thermal stability

Drought- and heat-driven tree mortality, along with associated insect outbreaks, have been observed globally in recent decades and are expected to increase in future climates. Despite its potential to profoundly alter ecosystem carbon and water cycles, how tree mortality scales up to ecosystem functions and fluxes is uncertain. We describe a framework for this scaling where the effects of mortality are a function of the mortality attributes, such as spatial clustering and functional role of the trees killed, and ecosystem properties, such as productivity and diversity. We draw upon remote-sensing data and ecosystem flux data to illustrate this framework and place climate-driven tree mortality in the context of other major disturbances. We find that emerging evidence suggests that climate-driven tree mortality impacts may be relatively small and recovery times are remarkably fast (~4 years for net ecosystem production). We review the key processes in ecosystem models necessary to simulate the effects of mortality on ecosystem fluxes and highlight key research gaps in modeling. Overall, our results highlight the key axes of variation needed for better monitoring and modeling of the impacts of tree mortality and provide a foundation for including climate-driven tree mortality in a disturbance framework.

The projected responses of forest ecosystems to warming and drying associated with twenty-first-century climate change vary widely from resiliency to widespread tree mortality. Current vegetation models lack the ability to account for mortality of overstorey trees during extreme drought owing to uncertainties in mechanisms and thresholds causing mortality. Here we assess the causes of tree mortality, using field measurements of branch hydraulic conductivity during ongoing mortality in Populus tremuloides in the southwestern United States and a detailed plant hydraulics model. We identify a lethal plant water stress threshold that corresponds with a loss of vascular transport capacity from air entry into the xylem. We then use this hydraulic-based threshold to simulate forest dieback during historical drought, and compare predictions against three independent mortality data sets. The hydraulic threshold predicted with 75% accuracy regional patterns of tree mortality as found in field plots and mortality maps derived from Landsat imagery. In a high-emissions scenario, climate models project that drought stress will exceed the observed mortality threshold in the southwestern United States by the 2050s. Our approach provides a powerful and tractable way of incorporating tree mortality into vegetation models to resolve uncertainty over the fate of forest ecosystems in a changing climate.

The magnetic behavior of TiBe2 is found to be similar to that of strongly enhanced paramagnets like Pd and Ni3Ga. The susceptibility curves χ(H, T = 0) and χ(H, T = 0) both go through a smooth maximum, at 55 kOe and 10 K, respectively, which might be due to the electron-electron interaction. For TiBe2-xCux compounds the transition from paramagnetism to ferromagnetism is analyzed, starting from Arrott plots of the magnetization. A critical concentration xcr = 0.155 ± 0.005 is obtained. The Stoner-Edwards-Wohlfarth model of itinerant-electron magnetism is well followed near xcr. The low temperature behavior of the specific heat of TiBe2 is tentatively ascribed to the effect of the electron-phonon interaction on the electronic specific heat coefficient γ. © 1981.

We have measured the magnetic moment of (La0.9Ba0.1)2CuO4- as a function of temperature and magnetic field and have found the onset of superconductivity at a temperature T {reversed tilde equals} 35 K. From the magnetic field dependencies, we have shown that the sample is a type-II superconductor with ≲ {reversed tilde equals} 11. Specific heat measurements yield a finite electronic specific heat coefficient of ∼6 mJ/mole-K2 at 4 K and a Debye temperature of only 330 K, suggesting that a strong electron-phonon interaction may be responsible for the high T in our sample. © 1987.