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Hsin-Yi Huang,1,2,* Ming-Chen Wang,2,* Zhi-Yu Chen,1 Wen-Ying Chiu,1 Ko-Hua Chen,3,4 I-Chan Lin,4,5 Wei-Chung Vivian Yang,6 Chi-Chang Wu,7 Ching-Li Tseng1,8,9 1Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 2Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan City, Taiwan; 3Department of Ophthalmology, Taipei Veterans General Hospital, Taipei City, Taiwan; 4Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; 5Department of Ophthalmology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 6PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan; 7Department of Electronic Engineering, Feng Chia University, Taichung City, Taiwan; 8International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 9International PhD Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan *These authors contributed equally to this work Introduction: Dry-eye syndrome (DES) is a general eye disease. Eye drops are the common ophthalmological medication. However, the ocular barrier makes it difficult to attain high drug bioavailability. Nanomedicine is a promising alternative treatment for ocular diseases and may increase drug content in the affected eye. Methods: To explore this potential, we constructed nanoparticles (NPs) containing an anti-inflammatory agent for DES treatment. The NPs were made of gelatin–epigallocatechin gallate (EGCG) with surface decoration by hyaluronic acid (HA) and designated “GEH”. The particle size, surface charge, and morphology were evaluated. The in vitro biocompatibility and anti-inflammation effect of nanoparticles were assayed via culturing with human corneal epithelium cells (HCECs) and in vivo therapeutic effect was examined in a DES rabbit’s model. Results: The synthesized GEH NPs had a diameter of approximately 250 nm and were positively charged. A coculture experiment revealed that 20 µg/mL GEH was not cytotoxic to HCECs and that an EGCG concentration of 0.2 µg/mL downregulated the gene expression of IL1B and IL6 in inflamed HCECs. Large amounts of GEH NPs accumulated in the cytoplasm of HCECs and the ocular surfaces of rats and rabbits, indicating the advantage of GEH NPs for ocular delivery of medication. Twice-daily topical treatment with GEH NPs was performed in a rabbit model of DES. The ocular surface of GEH-treated rabbits displayed normal corneal architecture with no notable changes in inflammatory cytokine levels in the cornea lysate. The treatment improved associated clinical signs, such as tear secretion, and fluorescein staining recovered. Conclusion: We successfully produced GEH NPs with high affinity for HCECs and animal eyes. The treatment can be delivered as eye drops, which retain the drug on the ocular surface for a longer time. Ocular inflammation was effectively inhibited in DES rabbits. Therefore, GEH NPs are potentially valuable as a new therapeutic agent delivered in eye drops for treating DES. Keywords: gelatin nanoparticles, epigallocatechin gallate, EGCG, hyaluronic acid, HA, dry-eye syndrome, DES, anti-inflammation

Aim: Antiresorptive therapy (ART) is commonly used in osteoporotic patients to prevent bone loss. This retrospective cohort study aimed to identify the risk factors associated with medication-related osteonecrosis of the jaw (MRONJ) in osteoporotic patients receiving dental extraction during ART., Materials and Methods: Data were collected from 937 patients with 1067 dental extractions conducted between January 2003 and May 2022, including 519 patients on oral alendronate, 276 on denosumab, and 172 on zoledronate. Multivariate logistic regression analysis was employed to assess potential risk factors., Results: Regression model analysis revealed older age (AOR 1.09 per year; 95% CI, 1.06-1.12) and drug treatment exceeding 24 months (AOR 2.07; 95% CI, 1.29-3.30) as significant risk factors. A drug interruption of 3 or more months prior to tooth extraction lowered MRONJ risk (AOR 0.11; 95% CI, 0.07-0.17). Stratified by drug type, denosumab users had significantly lower risk of MRONJ after extraction (AOR 0.14; 95% CI, 0.07-0.27) compared to those on other medications. Factors of drug duration ≥ 24 months, < 3 months of interruption, and posterior mandibular tooth extraction posed the highest synergistic MRONJ risk (AOR 80.29; 95% CI, 33.05-195.09)., Conclusion: Our results suggest an association between a three-month ART interruption prior to tooth extraction and reduced MRONJ risk, especially in long-term ART patients undergoing posterior mandibular extractions. However, these findings require validation through prospective randomized controlled trials., Clinical Relevance: Scientific Rationale for Study: The study fills crucial knowledge gaps regarding MRONJ risks in osteoporotic patients undergoing dental extraction during antiresorptive therapy (ART), providing a foundation for informed clinical decisions., Principal Findings: Noteworthy findings include elevated MRONJ risk with older age and prolonged ART, the protective effect of a 3-month ART interruption, and denosumab users showing significantly reduced postextraction MRONJ risk., Practical Implications: Implementing a 3-month ART interruption before dental extraction is recommended to reduce MRONJ occurrences., (© 2024 Wiley Periodicals LLC.)

Introduction: This study examines the impact of COVID-19 on older adults in traditional nursing homes, Green Houses (GHs), and Continuing Care Retirement Communities-Nursing Homes (CCRCNHs)., Methods: COVID-19 cases and deaths from CMS and LTCFocus data across 11 states from 6/2020 to 9/2022 were used, and Poisson regressions to compare care settings while adjusting for covariates., Results: CCRCNH and GH residents were older (84.4 and 83.1 years) than those in traditional NHs (77.5 and 77.6 years, p < 0.0001), with more female and White individuals. COVID-19 risk was higher in CCRCNHs (RR 1.51, 95 % CI 1.10-2.07), large NHs (RR 1.57, 95 % CI 1.14-2.15), and highest in small NHs (RR 1.80, 95 % CI 1.32-2.47). Mortality rates across NH types showed no significant difference., Conclusion: The study shows that smaller, person-centered GHs are more effective in controlling COVID-19 infection, suggesting a need to rethink care models to incorporating GH features for better outcomes. GEORGE2 07-AUG-2024 11:31., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Medical device-associated infection remains a critical problem in the healthcare setting. Different clinical- or device-related methods have been attempted to reduce the infection rate. Among these approaches, creating a surface with bactericidal cationic functionality has been proposed. To do so, a sophisticated multi-step chemical procedure would be needed. Instead, a simple immersion approach was utilized in this investigation to render the titanium and polypropylene surface with the quaternary ammonium functionality by using a mussel-inspired novel lab-synthesized biomimetic catechol-terminated polymer, PQA-C8. The chemical oxidants, CuSO 4 /H 2 O 2 , as well as dopamine, were added into the novel PQA-C8 polymer immersion solution for one-step surface modification. Additionally, a two-step immersion scheme, in which the polypropylene substrate was first immersed in the dopamine solution and then in the PQA-C8 solution, was also attempted. Surface analysis results indicated the surface characteristics of the modified substrates were affected by the immersion solution formulation as well as the procedure utilized. The antibacterial assay has shown the titanium substrates modified by the one-step dopamine + PQA-C8 mixtures with the oxidants added and the polypropylene modified by the two-step scheme exhibited bacterial reduction percentages greater than 90% against both Gram-positive S. aureus and Gram-negative E. coli and these antibacterial substrates were non-cytotoxic.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) represents a formidable challenge due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, rendering it unresponsive to conventional hormonal and targeted therapies. This study introduces the development of mesoporous nanoreactors (NRs), specifically mPDA@CuO 2 NRs, as acid-triggered agents capable of self-supplying H 2 O 2 for chemodynamic therapy (CDT). To enhance therapeutic efficacy, these NRs were further modified with immune checkpoint antagonists, specifically anti-PD-L1 and anti-CD24 antibodies, resulting in the formation of dual antibody-aided mesoporous nanoreactors (dAb PD-L1/CD24 -mPDA@CuO 2 NRs). These NRs were designed to combine CDT and checkpoint blockade immunotherapy (CBIT) for precise targeting of 4T1 TNBC cells. Remarkably, dAb PD-L1/CD24 -mPDA@CuO 2 NRs exhibited tumor-targeted CDT triggered by H 2 O 2 and successfully activated immune cells including T cells and macrophages. This integrated approach led to a remarkable inhibition of tumor growth by leveraging the collaborative effects of the therapies. The findings of this study introduce a novel and promising strategy for the integrative and collaborative treatment of refractory cancers, providing valuable insights into addressing the challenges posed by aggressive breast cancer, particularly TNBC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Vesicular trafficking involving SNARE proteins play a crucial role in the delivery of cargo to the target membrane. Arf-like protein 1 (Arl1) is an important regulator of the endosomal trans -Golgi network (TGN) and secretory trafficking. In yeast, ER stress-enhances Arl1 activation and Golgin Imh1 recruitment to the late-Golgi. Although Arl1 and Imh1 are critical for GARP-mediated endosomal SNARE-recycling transport in response to ER stress, their downstream effectors are unknown. Here, we report that the SNARE-associated protein Sft2 acts downstream of the Arl1-Imh1 axis to regulate SNARE recycling upon ER stress. We first demonstrated that Sft2 is required for Tlg1/Snc1 SNARE-recycling transport under tunicamycin-induced ER stress. Interestingly, we found that Imh1 regulates Tlg2 retrograde transport to the late-Golgi under ER stress, which in turn is required for Sft2 targeting to the late-Golgi. We further showed that Sft2 with 40 amino acids deleted from the N-terminus exhibits defective mediation of SNARE recycling and decreased association with Tlg1 under ER stress. Finally, we demonstrated that Sft2 is required for GARP-dependent endosome-to-Golgi transport in the absence of Rab protein Ypt6. This study highlights Sft2 as a critical downstream effector of the Arl1-Imh1 axis, mediating the endosome-to-Golgi transport of SNAREs.

Background: The public health strategy of increasing access to comprehensive home or community-based healthcare services and emergency home visits is intent on reducing the overcrowding of emergency departments. However, scientific evidence regarding the association between home-based healthcare services and emergency department uses is surprisingly insufficient and controversial so far. The present retrospective study identified the risk factors for emergency department visits among patients receiving publicly-funded homecare services., Methods: The personal demographic and medical information, caregiver characteristics, and behaviours related to homecare services and emergency department visits from the medical records and structured questionnaires of 108 patients who were recipients of integrated homecare services in a regional hospital in southern Taiwan between January 1, 2020, and December 31, 2020, were collected. After screening the potential predictor variables using the preliminary univariate analyses, the multivariate logistic regression with best subset selection approach was conducted to identify best combination of determinants to predict unplanned emergency department utilizations., Results: Best subset selection regression analysis showed Charlson Comorbidity Index (odds ratio (OR)=1.33, 95% CI=1.05 to 1.70), male caregiver (OR=0.18, 95% CI=0.05 to 0.66), duration of introducing homecare services (OR=0.97, 95% CI=0.95 to 1.00), working experience of dedicated nurses (OR=0.89, 95% CI=0.79 to 0.99) and number of emergency department utilizations within previous past year before enrollment (OR=1.54, 95% CI=1.14 to 2.10) as significant determinants for unplanned emergency department visits., Conclusions: The present evidence may help government agencies propose supportive policies to improve access to integrated homecare resources and promote appropriate care recommendations to reduce unplanned or nonurgent emergency department visits among patients receiving homecare services., (© 2023 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

When it comes to predicting experimental values of molecular properties with deep learning, the key problem is the lack of sufficient experimental data for training. We propose a method that consists of pretraining a graph neural network that aims to reproduce first-principles quantum mechanical results, followed by fine-tuning of a fully connected neural network against experimental results. The combined pretraining and fine-tuning model is expected to yield molecular properties close to experimental accuracy. This is made possible because first-principles quantum mechanical methods are often qualitatively correct or semiquantitatively accurate; thus, a calibration of the calculation results against high-precision but limited experiment data can improve accuracy greatly. Moreover, the method is highly efficient, as first-principles quantum mechanical calculation is bypassed. To demonstrate this, we apply the combined model to determine the experimental heats of formation of organic molecules made of H, C, O, N, or F atoms (up to 30 atoms), where mere 405 experimental data are used. The overall mean absolute error is 1.8 kcal/mol for these molecules.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR), which acts through various mechanisms to reduce ER stress. While the UPR has been well studied for its effects on the ER, its impact on the Golgi is less understood. The Golgi complex receives transport vesicles from the endosome through two types of tethering factors: long coiled-coil golgin and the multisubunit Golgi-associated retrograde protein (GARP) complex. Here, we report that ER stress increases the phosphorylation of golgin Imh1 to maintain the GARP-mediated recycling of the SNAREs Snc1 and Tlg1. We also identify a specific function of the Golgi affected by ER stress and elucidate a homeostatic response to restore this function, which involves both an Ire1-dependent and a MAP kinase Slt2/ERK2-dependent mechanism. Furthermore, our findings advance a general understanding of how two different types of tethers act cooperatively to mediate a transport pathway., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Researchers have emphasized the importance of examining how different factors affect men's and women's functional status over time. To date, the literature is unclear about whether sex affects the rate of change in disability in middle to older age. Researchers have further emphasized the importance of examining how different factors affect men's and women's functional status over time. We examined (a) sex differences in disability trends and (b) the determinants of the rate of change in disability for men and women 50 years and older., Methods: This study utilized the Taiwan Longitudinal Study on Aging Survey, a nationally representative database (four waves of survey data 1996-2007, N = 3429). We modeled and compared the differences in disability trends and the influences of determinants on trends among men and women using multiple-indicator and multiple-group latent growth curves modeling (LGCM). Equality constraints were imposed on 10 determinants across groups., Results: Once disability began, women progressed toward greater disability 18% faster than men. Greater age added about 1.2 times the burden to the rate of change in disability for women than men (p < 0.001). More comorbidities also added significantly more burden to baseline disability and rate of change in disability among women than men (p < 0.001), but women benefited more from higher education levels in lower baseline disability and slower rate of change. Having a better social network was associated with lower baseline disability among women only (p < 0.05). For both men and women, physically active leisure-time activities were beneficial in lower baseline disability (p men and women  < 0.001) and rate of change in disability (p men  < 0.01; p women  < 0.05), with no significant differences between groups., Conclusions: Age may widen the sex gap in the rate of change in disability. However, both sexes benefit from participating in leisure-time activities. Promoting health literacy improves health outcomes and physical function among women., (© 2021. The Author(s).)

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA's actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.

Objectives: The aim of this study was to find out the prognosis of medication-related osteonecrosis of the jaws (MRONJ) in prostate cancer patients who received two different types of antiresorptive agents for bone metastasis., Materials and Methods: We retrospectively surveyed a cohort of 95 metastatic prostate cancer patients with 122 MRONJ lesions treated in a single medical center. Treatment outcomes and prognostic factors were investigated. The cumulative complete response rate was calculated with the Kaplan-Meier method, and significance was examined with the log-rank and Breslow tests. Cox regression was used for the univariate and multivariate analyses of prognostic factors., Results: The cumulative complete response rate of all patients at 12 months was 37.8%, and that of patients treated with zoledronic acid and denosumab was 22.9% and 70.5%, respectively. Denosumab, pretreatment C-terminal telopeptide of collagen I (CTX) level > 150 pg/ml, and anemia were identified as independent prognostic factors in a multivariate analysis with adjusted hazard ratios of 3.18 (95% confidence interval [CI], 1.24-8.11), 3.24 (95% CI, 1.39-7.53), and 0.42 (95% CI, 0.19-0.93), respectively., Conclusion: A higher pretreatment level of CTX, using denosumab as the antiresorptive agent and without anemia, indicates a better treatment outcome of MRONJ in prostate cancer patients., (© 2020 Wiley Periodicals LLC.)

With the development of Internet, the number of people with symptoms of Internet gaming disorder (IGD) has increased. In the past, psychologists used retrospective questionnaires to diagnose IGD. However, it is difficult to diagnose IGD symptoms instantaneously using retrospective questionnaires due to the requirement of an Internet gaming experience of greater than 6 months and the limitations of retrospective memory. Observing the physiological regulation system might instantaneously diagnose IGD. However, observation of instantaneous physiological response is limited due to the lack of appropriate techniques. Our previous study successfully combined complimentary ensemble empirical mode decomposition and normalized direct quadrature to obtain respiratory instantaneous frequency (IF) to overcome this limitation. This study uses game-related films as stimulus materials to observe the difference in respiratory IF response per second of gamers with high-risk IGD (HIGD) and low-risk IGD (LIGD). The result showed that the respiratory IF of gamers with HIGD is lower than those of gamers with LIGD at the time of stimulation. In addition, the study also observes the dynamic change in respiratory IF per second (IF diff ). The results showed that the instant at which a significant difference is observed in IF diff between HIGD and LIGD can be matched to the stimulation of the films. In summary, this study demonstrated that the IF diff of gamers with HIGD and LIGD are different when stimulated. Therefore, this suggests that IF diff might be used as a potential physiological marker to instantaneously distinguish and diagnosis the risk of IGD.Clinical Relevance- This study investigates the dynamically psychophysiological response regulation by analyzing the respiratory IF of gamers diagnosed with IGD.

Background/purpose: Anti-resorptive agents are commonly used in cancer patients with bone metastasis or multiple myeloma (MM). An adverse event termed medication-related osteonecrosis of the jaws (MRONJ) was discovered in patients using these agents but relatively little attention has been paid to its prognosis. Our aims were to find out the treatment outcomes and prognostic indicators of MRONJ in cancer patients who received zoledronic acid as antiresorptive therapy., Methods: We retrospectively surveyed a cohort of 133 cancer patients who received zoledronic acid. A total of 150 MRONJ lesions were included for investigation. Cumulative complete response rate after treatment was calculated with the Kaplan-Meier method, and significance was examined with the log-rank tests. Cox regression was used for univariate and multivariate analyses of prognostic factors., Results: The cumulative complete response rate of all patients at 24 months was 53.2%, and those of patients with MM, breast cancer and prostate cancer were 27.8%, 60.7% and 68.0%, respectively. Having MM was identified as an independent prognostic factor in a multivariate analysis with adjusted hazard ratios of 0.28 (95% confidence interval, 0.09-0.83)., Conclusion: For cancer patients with ONJ related to zoledronic acid, patients with MM endure a worse treatment outcome., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

This study analysed the landing performance and muscle activity of athletes in forefoot strike (FFS) and rearfoot strike (RFS) patterns. Ten male college participants were asked to perform two foot strikes patterns, each at a running speed of 6 km/h. Three inertial sensors and five EMG sensors as well as one 24 G accelerometer were synchronised to acquire joint kinematics parameters as well as muscle activation, respectively. In both the FFS and RFS patterns, according to the intraclass correlation coefficient, excellent reliability was found for landing performance and muscle activation. Paired t tests indicated significantly higher ankle plantar flexion in the FFS pattern. Moreover, biceps femoris (BF) and gastrocnemius medialis (GM) activation increased in the pre-stance phase of the FFS compared with that of RFS. The FFS pattern had significantly decreased tibialis anterior (TA) muscle activity compared with the RFS pattern during the pre-stance phase. The results demonstrated that the ankle strategy focused on controlling the foot strike pattern. The influence of the FFS pattern on muscle activity likely indicates that an athlete can increase both BF and GM muscles activity. Altered landing strategy in cases of FFS pattern may contribute both to the running efficiency and muscle activation of the lower extremity. Therefore, neuromuscular training and education are required to enable activation in dynamic running tasks.

Background: The literature emphasizes the importance of matching the demand and supply of endocrinology and metabolism (EM) specialists. This study analyzed the current status of EM specialists in Taiwan. The gender effects on the workplace of EM specialists were also evaluated., Methods: The number of internal medicine (IM) specialists was obtained from the websites of the Ministry of Health and Welfare. Data about EM specialists were retrieved from the database of the Endocrine Society of the Republic of China (ESROC; Taiwan). Differences in age distribution and workplace levels or locations between female and male EM specialists were analyzed., Results: Since 1988, 809 physicians were certified as EM specialists. The average age of 739 EM specialists (509 male, 230 female) who remained as active members of the ESROC was 49.9 ± 11.1 years. The age distribution (p < 0.001) and workplace location (p = 0.043) were significantly different between male and female EM specialists. Divided by decades, the ratio of female-to-male EM specialists revealed an increasing tendency (p < 0.001). The percentage of EM specialists among IM specialists, certified 2 years previously, declined from 14.0% in 2017 to 7.9% and 8.3% in 2018 and 2019, respectively., Conclusion: The female-to-male ratio of EM specialists increased gradually. Compared to males, female EM specialists were relatively younger, and more of them had clinical practice in northern Taiwan. The percentage of IM specialists becoming EM specialists declined in the last 2 years. The equilibrium between the supply and demand of EM specialists deserves further investigation., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/purpose: This study analyzed the effects of the General Medicine Faculty Training Program (GMFTP), which was implemented in 2009. The training program includes a 7-hour basic training (BT) to introduce ways of teaching and assessing the 6 core competencies identified by the Accreditation Council for Graduate Medical Education, and a 40-hour clinical training program., Methods: Physicians from different hospitals attended the GMFTPs. Since 2010, we have been using quick tests to assess trainees' familiarity of core competencies. Knowledge improvement (KI) was defined as the difference between post-BT and pre-BT test scores. Since 2013, we have been annually mailing questionnaires to assess trainees' teaching confidence (TC) of core competencies. We analyzed the correlations between trainees' characteristics, KIs, and TCs., Results: Between year 2009 and 2017, a total of 319 attending physicians (257 male, 62 female), with a mean age of 39.1 ± 6.2 years, completed the GMFTPs. Significant KI (32.6-55.4) was noted. There were no correlations between trainees' characteristics and KIs. The mean TCs for the 6 core competences were all above 4.0 (based on a 5-point Likert scale). TCs were positively correlated with age during GMFTP training, age when responding to the questionnaire, and duration between training and the last time responding to the questionnaire. TC showed no correlation with sex, hospitals, departments, or KI., Conclusion: Knowledge of teaching core competencies improved immediately after BT, but KIs did not correlate with TCs in long-term follow-up. After the training program, physicians' teaching confidence increased over time., (Copyright © 2019 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Following 150 mg of oral ibandronate, Taiwanese females have greater serum and urine levels of this drug and bone resorption marker suppression than Caucasian women. These inter-ethnic differences seems to be partly explained by a 2.48-fold higher bioavailability of ibandronate in Taiwanese postmenopausal women., Introduction: Interethnic differences in the pharmacokinetics of oral ibandronate for osteoporosis are unknown. We compared the disposition of oral ibandronate between Caucasian and Taiwanese postmenopausal women., Methods: Ibandronate 150 mg was administered to 35 Caucasian and 16 Taiwanese postmenopausal women in two separate phase 1 studies. Interethnic comparisons were performed to assess pharmacokinetic properties, including the area under the concentration-time curve (AUC), peak concentration (Cmax), elimination half-life, urinary drug recovery (Ae%), renal clearance (CLr), apparent total clearance (CL/F), and apparent volume of distribution (Vd/F)., Results: The mean AUC, Cmax, and Ae% were 2.41-, 1.69-, and 2.95-fold greater in the Taiwanese than in the Caucasian subjects, and the average CL/F and Vd/F were 2.48- and 2.46-fold smaller. There were no significant differences in mean CLr and half-life between both groups. As bisphosphonates are not biotransformed but are mainly excreted in the urine, the total body clearance is close to the CLr. These results suggested a larger bioavailability in the Taiwanese group which resulted in the differences in the CL/F and Vd/F. Multiple linear regression analysis demonstrated ethnicity influences of the pharmacokinetic properties after adjusting for the other variables., Conclusions: Bioavailability was largely responsible for the interethnic pharmacokinetic differences following oral administration of 150 mg ibandronate and seemed greater in the Taiwanese compared with the Caucasian subjects. Further dose-ranging studies are warranted to determine the optimal dosages of oral ibandronate in patients of Asian or Taiwanese ethnicity.

The Arf and Rab/Ypt GTPases coordinately regulate membrane traffic and organelle structure by regulating vesicle formation and fusion. Ample evidence has indicated that proteins in these two families may function in parallel or complementarily; however, the manner in which Arf and Rab/Ypt proteins perform interchangeable functions remains unclear. In this study, we report that a Golgi-localized Arf, Arl1, could suppress Ypt6 dysfunction via its effector golgin, Imh1, but not via the lipid flippase Drs2. Ypt6 is critical for the retrograde transport of vesicles from endosomes to the trans-Golgi network (TGN), and its mutation leads to severe protein mislocalization and growth defects. We first overexpress the components of the Arl3-Syt1-Arl1-Imh1 cascade and show that only Arl1 and Imh1 can restore endosome-to-TGN trafficking in ypt6-deleted cells. Interestingly, increased abundance of Arl1 or Imh1 restores localization of the tethering factor Golgi associated retrograde-protein (GARP) complex to the TGN in the absence of Ypt6. We further show that the N-terminal domain of Imh1 is critical for restoring GARP localization and endosome-to-TGN transport in ypt6-deleted cells. Together, our results reveal the mechanism by which Arl1-Imh1 facilitates the recruitment of GARP to the TGN and compensates for the endosome-to-TGN trafficking defects in dysfunctional Ypt6 conditions.

Patient-reported experience measures (PREMs) are integral component of care for fracture patients. Using a multicenter cohort, we showed that the presence of chronic kidney disease (CKD) attenuated the probability of PREM improvement in fracture patients., Introduction: Assessing PREM can assist physicians in improving patients' experiences. Patients with CKD are at an increased risk of exhibiting poor PREM and developing fractures. We aimed to assess whether CKD influences the probability of PREM improvement during follow-up among patients with fractures., Methods: We prospectively enrolled patients with hip or vertebral fractures from different institutes into a fracture liaison service program. After registering clinical histories, they received a baseline PREM assessment based on EuroQol group-5 dimension content, including self-care, daily activity, and pain severity using a 5-point Likert scale. A follow-up PREM assessment was arranged 4 months later, and we evaluated whether baseline CKD was predictive of PREM improvement., Results: Among 593 fracture patients (18% with CKD), 37.3% and 62.7% presented with hip and vertebral fractures, respectively. Self-care, daily activity, and pain severity improved after follow-up in 32%, 27%, and 43% participants; those with CKD exhibited worse self-care ability and daily activity than those without. Multivariate logistic regression analyses showed that baseline CKD was significantly associated with lower possibility of improvement in daily activity (odds ratio [OR] 0.58, p = 0.049) and pain severity (OR 0.52, p = 0.01), and an insignificant change in the possibility of improvement in self-care ability (OR 0.61, p = 0.09)., Conclusions: The presence of CKD predicts a significantly lower probability of PREM improvement among fracture patients. An early emphasis on renal function during fracture care should be considered.

Background: Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors., Methods: We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls]., Results: For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis., Conclusion: Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.

Background: Although bisphosphonate-related osteonecrosis of the jaw (ONJ) develops mainly after tooth extractions (TEs), the strength of the association between them and how the existence of the disease among bisphosphonate (BP)-treated osteoporotic patients exposed to TE remain uncertain., Methods: A nationwide retrospective cohort study investigated the influence of alendronate and TE on the development of ONJ., Results: Incidence of ONJ following long-term alendronate therapy was 262/100,000 person-years, while no event developed in the control group on raloxifene. Overall prevalence of ONJ in osteoporotic subjects receiving alendronate was estimated at 0.34% which rose to 2.16% after TE. Multiple logistic regression analysis, adjusted for the potential confounders, showed TE (adjusted odds ratio, 9.60 [4.33-21.29]), drug duration exceeding 3 years (3.00 [1.33-6.76]), and concomitant rheumatoid arthritis (4.94 [1.64-14.90]) were independent predictors of ONJ., Conclusions: This article strengthens the relationship between ONJ and BPs. Among osteoporotic patients exposed to alendronate, TE confers a 9.6-fold increased risk for ONJ and it should be performed with caution irrespective of drug duration.

Exploring the ordering mechanism and dynamics of self-assembled block copolymer (BCP) thin films under confined conditions are highly essential in the application of BCP lithography. In this study, it is aimed to examine the self-assembling mechanism and kinetics of silicon-containing 3-arm star-block copolymer composed of polystyrene (PS) and poly(dimethylsiloxane) blocks as nanostructured thin films with perpendicular cylinders and controlled lateral ordering by directed self-assembly using topographically patterned substrates. The ordering process of the star-block copolymer within fabricated topographic patterns with PS-functionalized sidewall can be carried out through the type of secondary (i.e., heterogeneous) nucleation for microphase separation initiated from the edge and/or corner of the topographic patterns, and directed to grow as well-ordered hexagonally packed perpendicular cylinders. The growth rate for the confined microphase separation is highly dependent upon the dimension and also the geometric texture of the preformed pattern. Fast self-assembly for ordering of BCP thin film can be achieved by lowering the confinement dimension and also increasing the concern number of the preformed pattern, providing a new strategy for the design of BCP lithography from the integration of top-down and bottom-up approaches., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This paper reports the development of colored-yarn mixed woven fabrics by using raw white warps and multicolored-wefts, as well as a study of the influential factors on the color attributes of the resultant fabrics. Weft yarns in six colors, together with the white warp yarns, were used to create a series of fabric colors. Two types of new weft-backed structures were designed to assign the desired wefts for color mixing, as well as to reduce the white warp floats on the surface and thus, the lightness of the fabric. The effects of the proportion of yarn color components, weft density, and the introduction of black weft floats on the color attributes of fabrics, were investigated. The results show that through varying the proportion of mixing yarn color components, via fabric structure, a series of mixed red-blue and green-yellow colors for fabrics are created, respectively. Colored yarn mixed fabric presents a lowered lightness after a middle regulating layer is introduced into the structure. Compared to fabrics with a lower density, higher density fabrics possess lower lightness, higher redness and blueness in the blue-red fabrics, and higher greenness and yellowness in the yellow-green fabric. The lightness of fabric lowers after adding black yarn., Competing Interests: The authors declare no conflict of interest.

This randomized controlled trial aimed to test the effectiveness of brief face-to-face patient education in increasing influenza vaccination rate among elderly in the community. Recruitment and intervention were conducted at two general outpatient clinics in Hong Kong. 529 eligible patients were randomly assigned to intervention or control group with 1:1 allocation ratio. Patients in the intervention group received 3-min one-on-one verbal education by medical students and a pamphlet regarding influenza vaccination. Neither verbal health education nor pamphlet was given to the control group. Intention-to-treat analysis showed significantly higher vaccination rate in the intervention group compared with the control group (33.6 versus 25.0%) and the adjusted relative risk was 1.34 (95% CI 1.04-1.72; P = 0.021). Hence, brief face-to-face patient education was effective in increasing influenza vaccine uptake rate of community-dwelling elderly patients. Participants who were undecided whether to receive vaccination seemed to demonstrate larger beneficial effect (RR = 7.84; 95% CI 1.06-57.76) compared with patients who were certain of either receiving (RR = 1.16; 95% CI 0.90-1.48) or not receiving (RR = 2.18; 95% CI 0.68-6.99) the vaccine. The study also revealed that patients' intention for vaccination may not translate into action, reasons for which should be explored in future research., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Amyloidogenic processing of APP by β- and γ-secretases leads to the generation of amyloid-β peptide (Aβ), and the accumulation of Aβ in senile plaques is a hallmark of Alzheimer's disease (AD). Understanding the mechanisms of APP processing is therefore paramount. Increasing evidence suggests that APP intracellular domain (AICD) interacting proteins influence APP processing. In this study, we characterized the overexpression of AICD interactor GULP1 in a Drosophila AD model expressing human BACE and APP695. Transgenic GULP1 significantly lowered the levels of both Aβ1-40 and Aβ1-42 without decreasing the BACE and APP695 levels. Overexpression of GULP1 also reduced APP/BACE-mediated retinal degeneration, rescued motor dysfunction and extended longevity of the flies. Our results indicate that GULP1 regulate APP processing and reduce neurotoxicity in a Drosophila AD model., Competing Interests: CONFLICTS OF INTEREST There is no conflict of interest.

Magnetically and thermally sensitive poly(N-isopropylacrylamide) (PNIPAAm)/Fe3O4-NH2 microgels with the encapsulated anti-cancer drug curcumin (Cur) were designed and fabricated for magnetically triggered release. PNIPAAm-based magnetic microgels with a spherical structure were produced via a temperature-induced emulsion followed with physical-crosslinking by mixing PNIPAAm, polyethylenimine (PEI), and Fe3O4-NH2 magnetic nanoparticles. Because of their dispersity, the Fe3O4-NH2 nanoparticles were embedded inside the polymer matrix. The amine groups exposed on the Fe3O4-NH2 and PEI surface supported the spherical structure by physically crosslinking with the amide groups of the PNIPAAm. The hydrophobic anti-cancer drug curcumin can be dispersed in water after encapsulation into the microgels. The microgels were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and UV-Vis spectral analysis. Furthermore, magnetically triggered release was studied under an external high frequency magnetic field (HFMF). A significant "burst release" of curcumin was observed after applying the HFMF to the microgels due to the magnetic inductive heating (hyperthermia) effect. This manuscript describes the magnetically triggered controlled release of Cur-PNIPAAm/Fe3O4-NH2 encapsulated curcumin, which can be potentially applied for tumor therapy.

The ingestion of a foreign body is a common occurrence. Psychiatric patients and prisoners may swallow objects on purpose. Occasionally emergent exploratory laparotomy may be indicated if the diagnosis is uncertain, and emergent removal of the foreign body may be needed to prevent substantial risk of serious complications including perforation, fistula, or gastrointestinal bleeding.

A series of novel p-type conjugated copolymers, PTTVBDT, PTTVBDT-TPD, and PTTVBDT-DPP, cooperating benzo[1,2-b:4,5-b']dithiophene (BDT) and terthiophene-vinylene (TTV) units with/without thieno[3,4- c ]pyrrole-4,6-dione (TPD) or pyrrolo[3,4- c ]pyrrole-1,4-dione (DPP) via Stille polymerization were synthesized and characterized. Copolymer PTTVBDT shows a low-lying HOMO energy level and ordered molecular-packing behavior. Furthermore, two terpolymers, PTTVBDT-TPD and PTTVBDT-DPP, display stronger absorption ability, alower-lying HOMO energy level, and preferred molecular orientation, due to the replacement TTV-monomer units with electron-deficient groups. Furthermore, bulk-heterojunction organic solar cells were fabricated using blends of the PTTVBDT-TPD, and PC 61 BM gave the best power conversion efficiency of 5.01% under the illumination of AM 1.5G, 100 mW·cm -2 ; the short circuit current ( J sc ) was 11.65 mA·cm -2 which displayed a 43.8% improvement in comparison with the PTTVBDT/PC 61 BM device. These results demonstrate a valid strategy combining the two-dimensional molecular structure with random copolymerization strikes promising conjugated polymers to achieve highly efficient organic photovoltaics.

The incidence of obesity is increasing in Asia, with implications on gastrointestinal (GI) and liver diseases. The Gut and Obesity in Asia Workgroup comprises regional experts with the aim of studying relationship between obesity and the GI and liver diseases in Asia. Through literature review and the modified Delphi process, consensus statements examining the impact of obesity on esophageal, gastric, pancreatic, colorectal, and liver diseases, exploring relationship between gut microbiome and obesity, and assessing obesity therapies have been produced by the Gut and Obesity in Asia Workgroup. Sixteen experts participated with 9/15 statements having strong consensus (>80% agreement). The prevalence of obesity in Asia is increasing (100% percentage agreement in brackets), and this increased prevalence of obesity will result in a greater burden of obesity-related GI and liver diseases (93.8%). There was consensus that obesity increases the risk of gastric cancer (75%) and colorectal neoplasia (87.5%). Obesity was also associated with Barrett's esophagus and esophageal adenocarcinoma (66.7%) and pancreatic cancer (66.7%) in Asia. The prevalence of non-alcoholic fatty liver disease (NAFLD) in Asia is on the rise (100%), and the risk of NAFLD in Asia (100%) is increased by obesity. Obesity is a risk factor for the development of hepatocellular carcinoma (93.8%). Regarding therapy, it was agreed that bariatric surgery was an effective treatment modality for obesity (93.8%) but there was less agreement on its benefit for NAFLD (62.5%). These experts' consensus on obesity and GI diseases in Asia forms the basis for further research, and its translation into addressing this emerging issue., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

It is unclear whether the use of moxifloxacin (MFX), a newer synthetic fluoroquinolone, results in better outcomes in patients with ofloxacin (OFX)-resistant multidrug-resistant tuberculosis (MDR-TB). During the period from April 2006 to December 2013, a total of 2,511 patients with culture-confirmed tuberculosis (TB) were treated at a TB referral hospital in southern Taiwan. Of the 2,511 patients, 325 (12.9%) had MDR-TB, and of those 325 patients, 81 (24.9%) had OFX-resistant MDR-TB and were included in the study. Among the 81 patients with OFX-resistant MDR-TB, 50 (61.7%) were successfully treated and 31 (38.3%) had unfavorable outcomes, including treatment failure (n = 25; 30.9%), loss to follow-up (n = 2; 2.5%), and death (n = 4; 4.9%). Patients treated with MFX had a significantly higher rate of treatment success (77.3% versus 43.2%; odds ratio [OR] = 4.46, 95% confidence interval [CI] = 1.710 to 11.646, P = 0.002) than patients not treated with MFX, especially among those infected with MFX-susceptible isolates (40.7%) or isolates with low-level resistance to MFX (28.4%). Multivariate logistic regression analysis showed that treatment with MFX (adjusted odds ratio = 6.54, 95% CI = 1.44 to 29.59, P = 0.015) was the only independent factor associated with treatment success. Mutation at codon 94 in the gyrA gene was the most frequent mutation (68.0%) associated with high-level MFX resistance. Multivariate Cox proportional hazards regression analysis showed that treatment with MFX was also an independent factor associated with early culture conversion (hazard ratio = 3.12, 95% CI = 1.48 to 6.54, P = 0.003). Our results show that a significant proportion of OFX-resistant MDR-TB isolates were susceptible or had low-level resistance to MFX, indicating that patients with OFX-resistant MDR-TB benefit from treatment with MFX., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Magnetic silica core/shell nanovehicles presenting atherosclerotic plaque-specific peptide-1 (AP-1) as a targeting ligand (MPVA-AP1 nanovehicles) have been prepared through a double-emulsion method and surface modification. Amphiphilic poly(vinyl alcohol) was introduced as a polymer binder to encapsulate various drug molecules (hydrophobic, hydrophilic, polymeric) and magnetic iron oxide (Fe3O4) nanoparticles. Under a high-frequency magnetic field, magnetic carriers (diameter: ca. 50 nm) incorporating the anti-cancer drug doxorubicin collapsed, releasing approximately 80% of the drug payload, due to the heat generated by the rapidly rotating Fe3O4 nanoparticles, thereby realizing rapid and accurate controlled drug release. Simultaneously, the magnetic Fe3O4 themselves could also kill the tumor cells through a hyperthermia effect (inductive heating). Unlike their ungrafted congeners (MPVA nanovehicles), the AP1-grafted nanovehicles bound efficiently to colorectal cancer cells (CT26-IL4Rα), thereby displaying tumor-cell selectivity. The combination of remote control, targeted dosing, drug-loading flexibility, and thermotherapy and chemotherapy suggests that magnetic nanovehicles such as MPVA-AP1 have great potential for application in cancer therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In order to correlate the mutations inside the entiregyrAandgyrBgenes with the level of resistance to ofloxacin (OFX) and moxifloxacin (MFX) in isolates of multidrug-resistantMycobacterium tuberculosis(MDR-TB), a total of 111 isolates were categorized into OFX-susceptible (MIC, ≤2 μg/ml) and low-level (MIC, 4 to 8 μg/ml) and high-level (MIC, ≥16 μg/ml) OFX-resistant isolates and MFX-susceptible (MIC, ≤0.5 μg/ml) and low-level (MIC, 1 to 2 μg/ml) and high-level (MIC, ≥4 μg/ml) MFX-resistant isolates. Resistance-associated mutations inside thegyrAgene were found in 30.2% of OFX-susceptible and 72.5% and 72.2% of low-level and high-level OFX-resistant isolates and in 28.6% of MFX-susceptible and 58.1% and 83.9% of low-level and high-level MFX-resistant isolates. Compared with OFX-susceptible isolates, low-level and high-level OFX-resistant isolates had a significantly higher prevalence of mutations atgyrAcodons 88 to 94 (17.0%, 65.0%, and 72.2%, respectively;P< 0.001) and a higher prevalence of thegyrBG512R mutation (0.0%, 2.5%, and 16.7%, respectively;P= 0.006). Similarly, compared with MFX-susceptible isolates, low-level and high-level MFX-resistant isolates had a significantly higher prevalence of mutations atgyrAcodons 88 to 94 (14.3%, 51.6%, and 80.6%, respectively;P< 0.001) as well as a higher prevalence of thegyrBG512R mutation (0.0%, 0.0%, and 12.9%, respectively;P= 0.011). D94G and D94N mutations ingyrAand the G512R mutation ingyrBwere correlated with high-level MFX resistance, while the D94A mutation was associated with low-level MFX resistance. The prevalence of mutations atgyrAcodons 88 to 94 and thegyrBG512R mutation were higher among fluoroquinolone (FQ)-susceptible East Asian (Beijing) and Indo-Oceanic strains than they were among Euro-American strains, implying that molecular techniques to detect FQ resistance may be less specific in areas with a high prevalence of East Asian (Beijing) and Indo-Oceanic strains., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

After anterior cruciate ligament reconstruction (ACLR), the biological healing of the graft is a rate-limiting step which can contribute to graft failure. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu) is a well-known activator of tissue remodeling. We investigated whether GHK-Cu can improve graft healing following ACLR. Seventy-two rats underwent unilateral ACLR were randomized to saline, 0.3 or 3 mg/ml GHK-Cu groups (n = 24). Post-operational intra-articular injections were given from week 2, once a week, for 4 weeks. Gait analysis was performed pre-injury and at harvesting time. At 6 or 12 weeks post-operation, knee specimens were harvested for knee laxity test, graft pull-out test, and histology. At 6 weeks post-ACLR, GHK-Cu groups resulted in a smaller side-to-side difference in knee laxity as compared to the saline group (p = 0.009), but there was no significant difference at 12 weeks post-operation. The graft complex in the 0.3 mg/ml GHK-Cu group had higher stiffness than saline group at 6 weeks post-operation (p = 0.026), but there was no significant difference in ultimate load, gait parameters, and histological scores among treatment groups. All grafts failed mid-substance during pull-out test. Intra-articular supplementation with a bioactive small molecule GHK-Cu improved graft healing following ACLR in rat, but the beneficial effects could not last as treatment discontinued., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Thyroid cancer is the most common endocrine gland malignancy and fine-needle aspiration biopsy is widely used for thyroid nodule evaluation. Repeated aspiration biopsies are needed due to plausible false-negative results. This study aimed to investigate the overall relationship between aspiration biopsy and thyroid cancer diagnosis, and to explore factors related to shorter diagnostic time., Methods: This nationwide retrospective cohort study retrieved data from the Longitudinal Health Insurance Database in Taiwan. Subjects without known thyroid malignancies and who received the first thyroid aspiration biopsy after 2004 were followed-up from 2004 to 2009 (n = 7700). Chi-square test, Kaplan-Meier survival analysis, and Cox proportional hazards model were used for data analysis., Results: Of 7700 newly-aspirated patients, 276 eventually developed thyroid cancer (malignancy rate 3.6%). Among the 276 patients with thyroid cancer, 61.6% underwent only one aspiration biopsy and 81.2% were found within the first year after the initial aspiration. Cox proportional hazards model revealed that aspiration frequency (HR 1.07, 95% CI 1.06-1.08), ultrasound frequency (HR 1.02, 95% CI 1.01-1.03), older age, male sex, and aspiration biopsies arranged by surgery, endocrinology or otolaryngology subspecialties were all associated with shorter time to thyroid cancer diagnosis., Conclusions: About 17.4% of thyroid cancer cases received more than two aspiration biopsies and 18.8% were diagnosed one year after the first biopsy. Regular follow-up with repeated aspiration or ultrasound may be required for patients with clinically significant thyroid nodules.

The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), which was designed to simultaneously detect Mycobacterium tuberculosis (MTB), rifampin- and isoniazid-resistant MTB, and nontuberculous mycobacteria (NTM) was first evaluated with 950 consecutive positive cultures in Mycobacterium Growth Indicator Tube (MGIT) system (BACTEC, MGIT 960 system, Becton-Dickinson, Sparks) from clinical respiratory specimens. The discrepant results between kit and culture-based identification were finally assessed by 16S rRNA gene sequencing and clinical diagnosis. The accuracy rate of this kit for identification of all Mycobacterium species was 96.3% (905/940). For MTB identification, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the kit were 99.7%, 99.3%, 99.0% and 99.8%, respectively. For rifampicin-resistant MTB identification, the sensitivity, specificity, PPV, and NPV of the kit were 100.0%, 99.4%, 91.3%, and 100.0%, respectively, while the corresponding values of isoniazid-resistant MTB identification were 82.6%, 99.4%, 95.0%, and 97.6%, respectively. In identifying specific NTM species, the kit correctly identified 99.3% of M. abscessus (147/148) complex, 100% of M. fortuitum (32/32), M. gordonae (38/38), M. avium (39/39), M. intracellulare (90/90), M. kansasii (36/36), and M. avium complex species other than M. avium and M. intracellulare (94/94). In conclusions, the diagnostic value of the BluePoint MycoID plus kit was superior to culture method for recoveries and identification of NTM to species level. In addition, the diagnostic accuracy of BluePoint MycoID plus kit in MTB identification was similar to conventional culture method with high accuracy rate of rifampicin-resistant M. tuberculosis identification.

Environmentally sensitive composite nanofibrous mats capable of metal ion adsorption were successfully prepared via electrospinning. The composite nanofibers were fabricated with different ratios of chitosan to thermo-responsive polymer, poly(N-isopropylacrylamide-co-N-methylolacrylamide) (poly(NIPAAm-co-NMA), PNN). NMA provided the function of thermal crosslinking of the nanofibrous mats to form water-stable nanofibers in aqueous solution. Subsequently, glutaraldehyde was used as a secondary crosslinking agent to increase the gel fraction of the nanofibrous mats. The morphology changes of the nanofibers in different environments were studied. Comparing the nanofibrous mats and films of the same material, the fibrous mats showed significantly increased adsorption of Cu(II). The adsorption amount of Cu(II) on the chitosan/PNN (50/50) nanofibrous mats could reach 79±2 mg/g-mats, and its desorption was relatively effective. The incorporation of poly(NIPAAm-co-NMA) significantly improved the desorption of Cu(II) from the nanofibrous mats. The chitosan/PNN fibrous mats maintained the capacity of Cu(II) adsorption for 4-time regeneration., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Spontaneous pneumomediastinum is defined as presence of air in the mediastinum without obvious cause such as esophageal perforation or abscess formation. It is a benign condition and usually resolved by itself in 1 to 2 weeks. The main symptom of spontaneous pneumomediastinum is retrosternal chest pain. Here, we present a young adult who complained about sore throat initially. Marked retropharyngeal emphysema was noted by neck x-ray. Pneumomediastinum was confirmed with chest x-ray and computed tomographic scan later on.We want to emphasize the importance of thorough history taking and lateral soft tissue neck radiograph on retropharyngeal emphysema in real time, which is key to the diagnostic workup for patients who present with persistent sore throat and dysphagia in young adult.

Recent studies have confirmed the utility of massively parallel sequencing (MPS) in addressing genetically heterogeneous hereditary hearing impairment. By applying a MPS diagnostic panel targeting 129 known deafness genes, we identified a novel frameshift GATA3 mutation, c.149delT (p.Phe51LeufsX144), in a hearing-impaired family compatible with autosomal dominant inheritance. The GATA3 haploinsufficiency is thought to be associated with the hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome. The pathogenicity of GATA3 c.149delT was supported by its absence in the 5400 NHLBI exomes, 1000 Genomes, and the 100 normal hearing controls of the present study; the co-segregation of c.149delT heterozygosity with hearing impairment in 9 affected members of the family; as well as the nonsense-mediated mRNA decay of the mutant allele in in vitro functional studies. The phenotypes in this family appeared relatively mild, as most affected members presented no signs of hypoparathyroidism or renal abnormalities, including the proband. To our knowledge, this is the first report of genetic diagnosis of HDR syndrome before the clinical diagnosis. Genetic examination for multiple deafness genes with MPS might be helpful in identifying certain types of syndromic hearing loss such as HDR syndrome, contributing to earlier diagnosis and treatment of the affected individuals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The effects of the spatial arrangement of the conjugated side chains of two-dimensional polymers on their optical, electrochemical, molecular-packing, and photovoltaic characteristics were investigated. Accordingly, novel polythiophenes with horizontally (PBTTTV-h) and vertically (PBTTTV-v) grafted terthiophene–vinylene (TTV) conjugated side chains were synthesized that display two and one UV-vis peaks, respectively; the difference is due to the different constitutions of the conjugated side-chains. Because the spatial arrangement affects the molecular self-assembly, PBTTTV-h shows stronger crystallinity than PBTTTV-v, which enhances the charge mobility in devices. Moreover, PBTTTV-h has a lower HOMO energy level (−5.49 eV) than PBTTTV-v (−5.40 eV). Bulk heterojunction solar cells fabricated from PBTTTV-h/PC71BM and PBTTTV-v/PC71BM exhibit power conversion efficiencies of 4.75% and 4.00%, respectively, and Voc values of 800 and 730 mV, respectively, under AM1.5G illumination (100 mW cm(−2)). Thus, the architecture of the TTV conjugated side chains affects the optical, electrochemical, and photovoltaic properties; this study provides more ideas for improving 2-D conjugated polymers for semiconductor devices.

Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. It has been associated with malignancies in rare cases. High serum levels of fibroblast growth factor (FGF) 23 reported in a group of patients with ovarian cancer had normal serum phosphate levels. There had been no ovarian cancer-related hypophosphatemic osteomalacia in a search of the literature., Objective: We investigated a 57-year-old woman with progressive low back pain., Design and Intervention: Clinical, biochemical, and radiological assessments were performed. The patient's serum phosphate and FGF23 levels were evaluated at baseline and after treatment for ovarian cancer., Results: The patient presented with progressive low back pain and weight loss during the previous 6 months. Imaging studies revealed low bone mineral density and multiple suspicious spinal metastatic lesions. Laboratory examination showed hypophosphatemia, hyperphosphaturia, normocalcemia, an elevated serum alkaline phosphatase level, and an elevated serum FGF23 level. Because TIO was suspected, a tumor survey was performed, and ovarian carcinoma with multiple metastasis was detected. After surgery and chemotherapy treatments for ovarian cancer, the serum phosphate and FGF23 levels returned to normal, and the low back pain improved., Conclusions: To our knowledge, this is the first case of ovarian cancer-related hypophosphatemic osteomalacia reported in the literature. TIO should be considered in patients with ovarian cancer presenting with weakness, bone pain, and fractures. Investigation of TIO is appropriate when these patients present hypophosphatemia.