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Background: Collaborative learning is an essential pedagogy in medical education, within which small group learning constitutes an integral component. Online small group teaching has been widely applied and blended with in-person sessions in the aftermath of the Covid-19 pandemic. This study examined whether group metacognition was associated with teamwork satisfaction in an online small group teaching curriculum for medical students., Methods: We enrolled medical students of the 2nd and 4th years during the 2021 fall semester after they participated in 3 consecutive sessions of online small group tutorials (SGTs), which have been implemented in our medical school for more than 20 years. The students completed a group metacognitive scale (GMS) and a teamwork satisfaction scale (TSS) after the sessions. We analyzed whether group metacognition in 4 dimensions (knowledge of cognition, planning, evaluating, and monitoring) could be connected with medical students' teamwork satisfaction using partial least squares-structural equation modeling (PLS-SEM)., Results: A total of 263 medical students participated in this study. Both GMS and TSS exhibited good reliability and validity. Three of the 4 dimensions of group metacognition (cognition, planning, and evaluating) positively correlated with teamwork satisfaction (path coefficients 0.311, 0.279, and 0.21; p = 0.002, 0.002, and 0.043, respectively) following the online SGT curriculum, whereas the monitoring dimension did not (path coefficient 0.087; p = 0.357). The model achieved an adjusted R square of 0.683., Conclusion: We discovered that group metacognition correlated positively with better teamwork satisfaction, supporting the importance of group metacognitive competency for online collaborative learning., (© 2024. The Author(s).)

Background: Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine., Methods: We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database., Results: Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10 - 7 ): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10 - 9 ). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure., Conclusion: The identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology., Trial Registration: Not applicable., (© 2024. The Author(s).)

Background: Rapid recognition of frailty in older patients in the ED is an important first step toward better geriatric care in the ED. We aimed to develop and validate a novel frailty assessment scale at ED triage, the Emergency Department Frailty Scale (ED-FraS)., Methods: We conducted a prospective cohort study enrolling adult patients aged 65 years or older who visited the ED at an academic medical center. The entire triage process was recorded, and triage data were collected, including the Taiwan Triage and Acuity Scale (TTAS). Five physician raters provided ED-FraS levels after reviewing videos. A modified TTAS (mTTAS) incorporating ED-FraS was also created. The primary outcome was hospital admission following the ED visit, and secondary outcomes included the ED length of stay (EDLOS) and total ED visit charges., Results: A total of 256 patients were included. Twenty-seven percent of the patients were frail according to the ED-FraS. The majority of ED-FraS was level 2 (57%), while the majority of TTAS was level 3 (81%). There was a weak agreement between the ED-FraS and TTAS (kappa coefficient of 0.02). The hospital admission rate and charge were highest at ED-FraS level 5 (severely frail), whereas the EDLOS was longest at level 4 (moderately frail). The area under the Receiver Operating Characteristic curve (AUROC) in predicting hospital admission for the TTAS, ED-FraS, and mTTAS were 0.57, 0.62, and 0.63, respectively. The ED-FraS explained more variation in EDLOS (R 2  = 0.096) compared with the other two methods., Conclusions: The ED-Fras tool is a simple and valid screening tool for identifying frail older adults in the ED. It also can complement and enhance ED triage systems. Further research is needed to test its real-time use at ED triage internationally., (© 2024. The Author(s).)

Background: Accurate pain assessment is essential in the emergency department (ED) triage process. Overestimation of pain intensity, however, can lead to unnecessary overtriage. The study aimed to investigate the influence of pain on patient outcomes and how pain intensity modulates the triage's predictive capabilities on these outcomes., Methods: A prospective observational cohort study was conducted at a tertiary care hospital, enrolling adult patients in the triage station. The entire triage process was captured on video. Two pain assessment methods were employed: (1) Self-reported pain score in the Taiwan Triage and Acuity Scale, referred to as the system-based method; (2) Five physicians independently assigned triage levels and assessed pain scores from video footage, termed the physician-based method. The primary outcome was hospitalization, and secondary outcomes included ED length of stay (EDLOS) and ED charges., Results: Of the 656 patients evaluated, the median self-reported pain score was 4 (interquartile range, 0-7), while the median physician-rated pain score was 1.5 (interquartile range, 0-3). Increased self-reported pain severity was not associated with prolonged EDLOS and increased ED charges, but a positive association was identified with physician-rated pain scores. Using the system-based method, the predictive efficacy of triage scales was lower in the pain groups than in the pain-free group (area under the receiver operating curve, [AUROC]: 0.615 vs. 0.637). However, with the physician-based method, triage scales were more effective in predicting hospitalization among patients with pain than those without (AUROC: 0.650 vs. 0.636)., Conclusions: Self-reported pain seemed to diminish the predictive accuracy of triage for hospitalization. In contrast, physician-rated pain scores were positively associated with longer EDLOS, increased ED charges, and enhanced triage predictive capability for hospitalization. Pain, therefore, appears to modulate the relationship between triage and patient outcomes, highlighting the need for careful pain evaluation in the ED., (© 2023. Norwegian Air Ambulance Foundation.)

Objectives: Little is known about the recent status of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in the U.S. emergency department (ED). This study aimed to describe the disease burden (visit and hospitalization rate) of AECOPD in the ED and to investigate factors associated with the disease burden of AECOPD., Methods: Data were obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2010-2018. Adult ED visits (aged 40 years or above) with AECOPD were identified using International Classification of Diseases codes. Analysis used descriptive statistics and multivariable logistic regression accounting for NHAMCS's complex survey design., Results: There were 1,366 adult AECOPD ED visits in the unweighted sample. Over the 9-year study period, there were an estimated 7,508,000 ED visits for AECOPD, and the proportion of AECOPD visits in the entire ED population remained stable at approximately 14 per 1,000 visits. The mean age of these AECOPD visits was 66 years, and 42% were men. Medicare or Medicaid insurance, presentation in non-summer seasons, the Midwest and South regions (vs. Northeast), and arrival by ambulance were independently associated with a higher visit rate of AECOPD, whereas non-Hispanic black or Hispanic race/ethnicity (vs. non-Hispanic white) was associated with a lower visit rate of AECOPD. The proportion of AECOPD visits that were hospitalized decreased from 51% to 2010 to 31% in 2018 (p = 0.002). Arrival by ambulance was independently associated with a higher hospitalization rate, whereas the South and West regions (vs. Northeast) were independently associated with a lower hospitalization rate. The use of antibiotics appeared to be stable over time, but the use of systemic corticosteroids appeared to increase with near statistical significance (p = 0.07)., Conclusions: The number of ED visits for AECOPD remained high; however, hospitalizations for AECOPD appeared to decrease over time. Some patients were disproportionately affected by AECOPD, and certain patient and ED factors were associated with hospitalizations. The reasons for decreased ED admissions for AECOPD deserve further investigation., (© 2023. The Author(s).)

Background: Small group tutorials (SGT) promotes self-directed learning and is widely used in medical education. The coronavirus pandemic (COVID-19) has accelerated the trend toward SGT digitalization, with unclear effect. We hypothesize that team dynamics and facilitator support influence SGT satisfaction in digital versus conventional SGT., Methods: During the spring semester of year 2021, medical students (the second, third, and fourth year; n = 433) participating in conventional face-to-face and digital SGT curricula were enrolled. Participating students completed the collaborative learning attitude scale (including team dynamics, team acquaintance, and facilitator support dimensions) and teamwork satisfaction scale, previously validated for small-group collaborative learning, and chose preference between conventional or digital SGT in future curricula. Exploratory factor analysis (EFA) was performed to extract the essential structural factors of these scales. Paired t-tests were conducted to compare differences in different dimensions and satisfaction between the conventional and digital SGT settings. Two sets of multiple regression analyses were done; one with team satisfaction scale results and the other with preference for digital SGT as the dependent variable were used to evaluate determinants of these two variables., Results: The EFA results revealed that the original collaborative learning attitude scale was concentrated on two dimensions: team dynamics and facilitator support. No significant differences were noted between the SGT settings for the two dimensions and teamwork satisfaction. Regression analyses showed that teamwork dynamics was independently correlated with teamwork satisfaction in both conventional and digital SGT. Facilitator support was positively correlated with teamwork satisfaction in conventional, but not digital SGT. Higher teamwork satisfaction was an important determinant of preference for digital SGT among medical students., Conclusions: Team dynamics were closely linked to teamwork satisfaction among medical students in both conventional and digital SGT, while the role of facilitator support became less obvious during digital SGT., (© 2022. The Author(s).)

Background: Cancer therapy has evolved from non-specific cytotoxic agents to a selective, mechanism-based approach that includes targeted agents and immunotherapy. Although the response to targeted therapies for unresectable hepatocellular carcinoma (HCC) is acceptable with the improved survival, the high tumor recurrence rate and drug-related side effects continue to be problematic. Given that immune checkpoint inhibitor alone are not robust enough to improve survival in unresectable HCC, growing evidence supports the combination of targeted therapy and immunotherapy with synergistic effect., Methods: Online databases including PubMed, EMBASE, Cochrane Library, and Web of Science were searched for the studies that compared targeted monotherapy with the combination therapy of targeted drug and checkpoint inhibitors in unresectable HCC patients. Eligibility criteria were the presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (version 1.1) for unresectable HCC patients, an Eastern Cooperative Oncology Group performance status of 0-2, and a Child-Pugh score ≤ 7. Outcome measurements include overall survival (OS), progression-free survival (PFS), and treatment-related adverse event (TRAE)., Results: Three phase II/III randomized controlled trials were included in this study. The pooled results showed that combination therapy significantly improved survival than targeted monotherapy, in terms of OS (hazard ratio (HR) = 0.67; 95% confidence interval [CI]: 0.50-0.91) and PFS (HR = 0.58; 95% CI: 0.51-0.67), respectively. In the incidence of grade 3-5 TRAEs, the combination therapy was significantly higher than targeted monotherapy (odds ratio = 1.98; 95% CI: 1.13-3.48)., Conclusion: For unresectable HCC, combined targeted drug and immunotherapy significantly improved survival compared with targeted monotherapy. However, the incidences of AEs of combinational therapy were higher than targeted monotherapy., (© 2022. The Author(s).)

Background: Post-resuscitation hemodynamic level is associated with outcomes. This study was conducted to investigate if post-resuscitation diastolic blood pressure (DBP) is a favorable prognostic factor., Methods: Using TaIwan Network of Targeted Temperature ManagEment for CARDiac Arrest (TIMECARD) registry, we recruited adult patients who received targeted temperature management in nine medical centers between January 2014 and September 2019. After excluding patients with extracorporeal circulation support, 448 patients were analyzed. The first measured, single-point blood pressure after resuscitation was used for analysis. Study endpoints were survival to discharge and discharge with favorable neurologic outcomes (CPC 1-2). Multivariate analysis, area under the receiver operating characteristic curve (AUC), and generalized additive model (GAM) were used for analysis., Results: Among the 448 patients, 182 (40.7%) patients survived, and 89 (19.9%) patients had CPC 1-2. In the multivariate analysis, DBP > 70 mmHg was an independent factor for survival (adjusted odds ratio [aOR] 2.16, 95% confidence interval [CI, 1.41-3.31]) and > 80 mmHg was an independent factor for CPC 1-2 (aOR 2.04, 95% CI [1.14-3.66]). GAM confirmed that DBP > 80 mmHg was associated with a higher likelihood of CPC 1-2. In the exploratory analysis, patients with DBP > 80 mmHg had a significantly higher prevalence of cardiogenic cardiac arrest (p = 0.015) and initial shockable rhythm (p = 0.045)., Conclusion: We found that DBP after resuscitation can predict outcomes, as a higher DBP level correlated with cardiogenic cardiac arrest., (© 2022. The Author(s).)

Background: To enhance tutors' teaching skills, tutor shadowing for novice tutors of problem-based learning (PBL) in addition to conventional faculty development (FD) was applied. This study aimed to develop a tutoring-skill scale (TS-scale) and evaluate the effect of shadowing on PBL tutors., Methods: This study employed a before-and-after study design with three phases. In phase 1, a TS-scale was elaborated. A validity examination was performed in phase 2. Phase 3 was a study of the effectiveness using a TS-scale survey of novice PBL tutors before and after the FD course. The FD course for novice PBL tutors included an FD workshop and PBL shadowing activities., Results: A TS-scale with a 32-item questionnaire of self-rated confidence for PBL tutors was identified in phase 1. In phase 2, 7 experienced specialists in medical education were invited to evaluate the content validity of the scale. The item content validity index (I-CVI) ranged from 0.86 to 1, and the scale-CVI (S-CVI) was 0.95. A total of 85 novice PBL tutors completed the TS-scale before the FD course, yielding a Cronbach's alpha of 0.98. An exploratory factor analysis with varimax rotation was performed. The twenty-four items with significant loadings greater than 0.5 were incorporated into a new TS-scale and were grouped into three factors: student contact, medical expertise, and teaching expertise. In phase 3, 76 novice PBL tutors completed the 24-item TS-scale before (pretest) and after (posttest) the FD course. Their self-rated confidence improved significantly across the three factors after the FD course. The pretest and posttest scores did not differ according to the tutors' gender, the grades they taught, or their specialty background., Conclusions: Novice PBL tutors benefit from FD that incorporates tutor shadowing in the 3 key domains of tutoring competencies. The TS-scale developed in this study can be applied in future research on FD design., (© 2022. The Author(s).)

Background: Considering the involvement of genetics in migraine pathogenesis in diverse ethnic populations, genome-wide association studies (GWAS) are being conducted to identify migraine-susceptibility genes. However, limited surveys have focused on the onset age of migraine (AoM) in Asians. Therefore, in this study, we aimed to identify the susceptibility loci of migraine considering the AoM in an Asian population., Methods: We conducted a GWAS in 715 patients with migraine of Han Chinese ethnicity, residing in Taiwan, to identify the susceptibility genes associated with AoM. Based on our standard demographic questionnaire, the population was grouped into different subsets. Single-nucleotide polymorphism (SNP) associations were examined using PLINK in different AoM onset groups., Results: We discovered eight novel susceptibility loci correlated with AoM that reached the GWAS significance level in the Han Chinese population. First, rs146094041 in ESRRG was associated with AoM [Formula: see text] 12 years. The other SNPs including rs77630941 in CUX1, rs146778855 in CDH18, rs117608715 in NOL3, rs150592309 in PRAP1, and rs181024055 in NRAP were associated with the later AoM., Conclusions: To our knowledge, this is the first GWAS to investigate the AoM in an Asian Han Chinese population. Our newly discovered susceptibility genes may have prospective associations with migraine pathogenesis., (© 2021. The Author(s).)

Background: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare and heterogeneous clinico-neuroradiological syndrome characterized by headache, altered mental status, seizures, and visual disturbances. Hypertension and immunosuppression are two of the main factors that predispose an individual to RPLS. However, RPLS can develop when no major risk factors are present. RPLS has been reported in pediatric nephrotic patients, but rarely in adults., Case Presentation: A 42-year-old Asian woman with nephrotic syndrome presented with seizures, headaches, and nausea. Her blood pressure was controlled, and no immunosuppressants had been prescribed. All symptoms and tests indicated RPLS following infection with pneumonia, which was successfully treated by immediate administration antibiotic and anti-epileptic medications. Seizures did not recur during a 2-year follow-up period., Conclusions: When patients with nephrotic syndrome have an infection, RPLS symptoms should be investigated thoroughly. With early diagnosis and appropriate treatment of RPLS, morbidity and mortality can be prevented.

Background: Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analgesic activity. A striking therapeutic target for arterial thrombosis is inhibition of platelet activation because platelet activation significantly contributes to these diseases. The current study examined the influence of CBN on human platelet activation in vitro and vascular thrombotic formation in vivo., Methods: Aggregometry, immunoblotting, immunoprecipitation, confocal microscopic analysis, fibrin clot retraction, and thrombogenic animals were used in this study., Results: CBN markedly inhibited platelet aggregation in washed human platelets stimulated only by collagen, but was not effective in platelets stimulated by other agonists such as thrombin, arachidonic acid, and U46619. CBN evidently inhibited ATP release, intracellular ([Ca 2+ ]i) mobilization, and P-selectin expression. It also inhibited the phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), Akt (protein kinase B), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK] 1/2 and c-Jun N-terminal kinase [JNK] 1/2, but not p38 MAPK) in collagen-activated platelets. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the CBN-mediated inhibition of platelet aggregation. CBN had no significant effect in triggering vasodilator-stimulated phosphoprotein phosphorylation. Moreover, it markedly hindered integrin α IIb β 3 activation by interfering with the binding of PAC-1; nevertheless, it had no influences on integrin α IIb β 3 -mediated outside-in signaling such as adhesion number and spreading area of platelets on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Additionally, CBN did not attenuate FITC-triflavin binding or phosphorylation of proteins, such as integrin β 3 , Src, and focal adhesion kinase, in platelets spreading on immobilized fibrinogen. In experimental mice, CBN increased the occlusion time of thrombotic platelet plug formation., Conclusion: This study demonstrated that CBN exhibits an exceptional activity against platelet activation through inhibition of the PLCγ2-PKC cascade, subsequently suppressing the activation of Akt and ERKs/JNKs and influencing platelet aggregation. Consequently, this work provides solid evidence and considers that CBN has the potential to serve as a therapeutic agent for the treatment of thromboembolic disorders.

Background: Sublethal radiation induces matrix metalloproteinase 9 (MMP-9)-mediated radioresistance in Lewis lung carcinoma (LLC) cells and their metastatic dissemination. We aim to determine if EGFR/HER2 activation associates with MMP-9-mediated radioresistance and invasiveness in irradiated LLC cells., Methods: LLC cells were treated with erlotinib or afatinib followed by sublethal radiation. After irradiation, we examined the phosphorylation of EGFR/HER2 and MMP-9 expression. Colony formation assay determined if the kinase inhibitors sensitize LLC cells to radiation. Matrigel-coated Boyden chamber assay assessed cellular invasiveness. Resulting tumors of wild-type LLC cells or HER2 knock-down mutant cells were irradiated to induce pulmonary metastases., Results: Afatinib more effectively sensitized LLC cells to radiation and decreased invasiveness by inhibiting phosphorylation of EGFR, HER2, Akt, ERK, and p38, and down-regulating MMP-9 when compared to erlotinib. Afatinib abolished radiation-induced lung metastases in vivo. Furthermore, LLC HER2 knock-down cells treated with radiation had growth inhibition., Conclusion: Dual inhibition of radiation-activated EGFR and HER2 signaling by afatinib suppressed the proliferation and invasion of irradiated LLC cells. Increased radiosensitivity and decreased metastatic dissemination were observed by pharmacological or genetic HER2 inhibition in vivo. These findings indicate that HER2 plays a pivotal role in enhancing radioresistance and reducing metastatic potential of LLC cells.

Background: Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology, METHODS: We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE)., Results: Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E + C 12.3%, E + P 17.3%, C + P 4.9%), and 27 patients (11.1%) had all three criteria (E + C + P). Overall, 49.4% of patients had pathology from lung biopsy compared to 31.6% with CT scan., Conclusions: Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.

Background: Iliopsoas abscess (IPA) is a rare clinical entity and is difficult to diagnose due to its insidious onset and nonspecific symptoms. The association between IPA and cardiovascular disorders (CVD) has been rarely reported. Computed tomographic (CT) scan can provide a definitive diagnosis of IPA and associated foci of adjacent structures. IPA is a life-threatening condition, especially when associated with CVD., Materials and Methods: We conducted a hospital-based observational study of IPA associated with CVD. Data were collected from the electronic clinical database of Taichung Veterans General Hospital (1520-bed tertiary referral hospital in central Taiwan) between July 2007 and December 2017. The diagnosis of IPA associated with CVD was confirmed by classical findings on CT and transesophageal echocardiography with compatible clinical presentation and cultures from pus/tissue and blood., Results: Fifteen patients of IPA associated with CVD were studied. They included 12 males (80%) and 3 females (20%), with a mean age 63.2 ± 16.9 years (31-85 years). CVD included stent-graft/endograft infection of abdominal aortic aneurysm (AAA) (40%), primary mycotic AAA (33.3%), and infective endocarditis (26.7%). Staphylococcus aureus is the most common microorganism in pus/tissue cultures (n = 3, 37.5%) and in blood cultures (n = 6, 40%). The average length of hospital stay was 33.1 ± 20.5 days (range, 3-81 days; median, 33 days). Hospital stay lasted 42.6 ± 19.2 days in the survival group and 19.0 ± 14.1 days (P = 0.018) in the non-survival group. Incidence of patients staying in the intensive care unit (ICU) with intubation > 3 days was 33% in the survival group and 100% (P = 0.028) in the non-survival group. Intra-hospital mortality rate was 40%. Poor prognostic factors in the non-survival group were hypoalbuminemia, hyponatremia, involved disc/vertebral body and/or epidural abscess, and ICU stay with intubation > 3 days. Cumulative survival rate was 25% under conservative treatments and 66.3% under aggressive treatments (P = 0.038)., Conclusion: Due to high mortality rates, clinicians should keep a high suspicion index for IPA associated with CVD through clinical presentation, physical examination, and imaging study. Timely empiric antibiotics for common bacteria, drainage for IPA, endovascular repair, or vascular reconstruction by graft replacement or bypass with intensive care should be mandatory to shorten the hospital stay, reduce medical costs, and lower mortality rate.

Background: Primary aortoduodenal fistula (ADF) is a rare cause of gastrointestinal (GI) bleeding and is difficult to diagnose as the clinical presentation is subtle. Clinicians should keep a high level of suspicion for an unknown etiology of GI bleeding, especially in older patients with or without abdominal aortic aneurysm (AAA). Computed tomographic angiography (CTA) can be used to detect primary ADF. Open surgery or endovascular aortic repair (EVAR) for ADF with bleeding will improve the survival rate., Case Presentation: We report a rare case of AAA complicating ADF with massive GI bleeding in a 73-year-old Taiwanese man. He presented with abdominal pain and tarry stool for 5 days and an initial upper GI endoscopy at a rural hospital showed gastric ulcer only, but hypotension with tachycardia and a drop in hemoglobin of 9 g/dl from 12 g/dl occurred the next day. He was referred to our hospital for EVAR and primary closure of fistula defect due to massive GI bleeding with shock from ADF caused by AAA. Diagnosis was made by CTA of aorta., Conclusions: A timely and accurate diagnosis of primary ADF may be challenging due to insidious episodes of GI bleeding, which are frequently under-diagnosed until the occurrence of massive hemorrhage. Clinical physicians should keep a high index of awareness for primary ADF, especially in elderly patients with unknown etiology of upper GI bleeding with or without a known AAA.

Background: Mineral trioxide aggregate (MTA) is widely used for pulp-capping procedures in permanent teeth and as a gold standard material in endodontics. The aim of the study was to investigate the effect of MTA on cell viability and apoptosis when MTA is directly in contact with Stem Cells from Human Exfoliated Deciduous Teeth (SHEDs)., Methods: MTA was mixed and coated in the bottom of a 24-well plate. SHEDs collected and cultured from normal exfoliated human deciduous teeth (passages 3-4) were seeded on square cover glasses. The glasses with seeded SHEDs were incubated in the plates with or without MTA coating. They were divided into four groups: MTA direct contact, direct control, MTA indirect contact, and indirect control. After 1, 2 and 3 days of culturing, cell morphology was observed and cell viability was assessed by the WST-1 cell cytotoxicity assay. TUNEL assay, immunofluorescent labeling and western blot analysis were used to study the effects of MTA on SHEDs apoptosis., Results: MTA impaired cell viability of SHEDs in 1, 2 and 3 days, and the effect of direct contact was more severe. Cell apoptosis with positive Annexin V and TUNEL staining was noted when there was direct contact with MTA. Western blot analysis revealed that Bcl-2 and Bcl-xL decreased after SHEDs were in contact with MTA., Conclusions: This study shows that direct contact with 1 week post-set MTA significantly decreases the viability of SHEDs and induced cell apoptosis. The results suggest that there is a possible cytotoxic effect of pulp tissue when there is direct contact with MTA. Different responses would be expected due to the strong alkaline characteristics of fresh mixed MTA.

Background: Mycotic aortic aneurysm (MAA) is a rare clinical entity with an incidence of 1-3%, but it is a life-threatening infection of aorta characterized by dilatation of aorta with false lumen. Multiple MAAs have been reported rarely with an incidence of 0.03% and associated with a high mortality rate of 80% if ruptured., Case Presentation: A hypertensive and diabetic 78-year-old man visited our emergency department complaining intermittent dull and tingled pain over the left flank region for 1 week. Chest X-ray showed left pleural effusion and hemothorax was confirmed by thoracocentesis. Computed tomography (CT) of chest demonstrated multiple thoracic aortic aneurysms and the pathological findings disclosed the diagnosis of multiple MAAs. He was discharged under an uneventful condition post-surgical aortic repair with adequate intravenous antibiotics for 4 weeks., Conclusions: CT scan may make a definite diagnosis of multiple MAAs and management with surgical debridement, aortic repair and full-course antibiotics for Gram-positive coccus and/or Gram-negative bacillus is recommended.

Background: Headache such as migraine is associated with stroke. Studies focused on primary headache disorders (PHDs) as a risk factor for stroke are limited. The purpose of this population-based cohort study was to explore whether patients with PHDs were at a high risk for developing stroke., Methods: A total of 1346 patients with PHDs were enrolled and compared with 5384 age-, gender- and co-morbidity-matched control cohorts. International Classification of Diseases, Clinical Modification codes were administered for the definition of PHDs, stroke, and stroke risk factors. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR)., Results: PHDs patients exhibited a 1.49 times (95% CI :1.15-1.98, p < 0.01) higher risk for developing ischaemic stroke compared with that of control cohorts. Both migraine (HR = 1.22, 95% CI :1.13-1.97, p < 0.05) and tension-type headache (HR = 2.29, 95% CI :1.22-2.80, p < 0.01) were associated with an increased risk of ischemic stroke. Females with PHDs were at greater risk of developing ischaemic stroke (HR = 1.49, 95% CI :1.13-1.90, p < 0.01) than those without PHDs. PHDs patient aged 45 to 64 years displayed significantly higher risk to develop ischaemic stroke (HR = 1.50, 95% CI: 1.11-2.10, p < 0.05) than the matched controls. The impact of PHDs on ischaemic stroke risk became gradually apparent by different following time intervals beyond 2 years after first diagnosis., Conclusion: PHDs is suggestive of an incremental risk for ischaemic stroke with gender-dependent, age-specific and time-dependent characteristics.

Background: Hericium erinaceus (HE) is a well-known mushroom in traditional Chinese food and medicine. HE extracts from the fruiting body and mycelia not only exhibit immunomodulatory, antimutagenic and antitumor activity but also have neuroprotective properties. Here, we purified HE polysaccharides (HEPS), composed of two high molecular weight polysaccharides (1.7 × 10(5) Da and 1.1 × 10(5) Da), and evaluated their protective effects on amyloid beta (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells., Methods: HEPS were prepared and purified using a 95 % ethanol extraction method. The components of HEPS were analyzed and the molecular weights of the polysaccharides were determined using high-pressure liquid chromatography (HPLC). The neuroprotective effects of the polysaccharides were evaluated through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and an MTT assay and by quantifying reactive oxygen species (ROS) and mitochondrial membrane potentials (MMP) of Aβ-induced neurotoxicity in cells., Result: Our results showed that 250 μg/ml HEPS was harmless and promoted cell viability with 1.2 μM Aβ treatment. We observed that the free radical scavenging rate exceeded 90 % when the concentration of HEPS was higher than 1 mg/mL in cells. The HEPS decreased the production of ROS from 80 to 58 % in a dose-dependent manner. Cell pretreatment with 250 μg/mL HEPS significantly reduced Aβ-induced high MMPs from 74 to 51 % and 94 to 62 % at 24 and 48 h, respectively. Finally, 250 μg/mL of HEPS prevented Aβ-induced cell shrinkage and nuclear degradation of PC12 cells., Conclusion: Our results demonstrate that HEPS exhibit antioxidant and neuroprotective effects on Aβ-induced neurotoxicity in neurons.

Background: Cholix toxin is an ADP-ribosyltransferase found in non-O1/non-O139 strains of Vibrio cholera. The catalytic fragment of cholix toxin was characterized as a diphthamide dependent ADP-ribosyltransferase., Results: Our studies on the enzymatic activity of cholix toxin catalytic fragment show that the transfer of ADP-ribose to toxin takes place by a predominantly intramolecular mechanism and results in the preferential alkylation of arginine residues proximal to the NAD+ binding pocket. Multiple arginine residues, located near the catalytic site and at distal sites, can be the ADP-ribose acceptor in the auto-reaction. Kinetic studies of a model enzyme, M8, showed that a diffusible intermediate preferentially reacted with arginine residues in proximity to the NAD+ binding pocket. ADP-ribosylarginine activity of cholix toxin catalytic fragment could also modify exogenous substrates. Auto-ADP-ribosylation of cholix toxin appears to have negatively regulatory effect on ADP-ribosylation of exogenous substrate. However, at the presence of both endogenous and exogenous substrates, ADP-ribosylation of exogenous substrates occurred more efficiently than that of endogenous substrates., Conclusions: We discovered an ADP-ribosylargininyl activity of cholix toxin catalytic fragment from our studies in auto-ADP-ribosylation, which is mediated through diffusible intermediates. The lifetime of the hypothetical intermediate exceeds recorded and predicted lifetimes for the cognate oxocarbenium ion. Therefore, a diffusible strained form of NAD+ intermediate was proposed to react with arginine residues in a proximity dependent manner.

Background: We aimed to evaluate early clinical and pathological results for treating locally advanced rectal cancer with bevacizumab and neoadjuvant concurrent chemoradiotherapy using the technique of prone-position volumetric modulated arc therapy and to compare the toxicity of volumetric modulated arc therapy with that of supine-position four-field box radiotherapy., Methods: Twelve patients with stage IIA to IVA rectal adenocarcinoma, treated with neoadjuvant concurrent chemoradiotherapy (45 Gy in 25 fractions to the rectal tumor and pelvic lymphatics) and bevacizumab, were prospectively enrolled. Chemotherapy included FOLFOX (leucovorin, fluorouracil, and oxaliplatin) (n=11) and 5-fluorouracil (n=1). All patients received prone-position volumetric modulated arc therapy. A historical cohort treated with supine-position box radiotherapy, including six other patients treated with bevacizumab-based concurrent chemoradiotherapy in our hospital, was used for comparison. Setup errors, toxicities, and potential biomarkers were evaluated., Results: All patients completed neoadjuvant concurrent chemoradiotherapy and underwent total mesorectal excision. Four (33.3%) patients had pathological complete response. Significantly more grade 2 or 3 diarrhea was associated with the supine-box technique (5/6 versus 2/12, P=0.01). The magnitude of setup errors was similar between the supine-box and prone volumetric modulated arc therapy techniques. The estimated 2-year survival and 2-year failure-free survival rates were 100% and 72.9% in the prone volumetric modulated arc therapy group and 66.7% and 66.7% in the supine box group, respectively., Conclusions: The early clinical outcome has been encouraging. Volumetric modulated arc therapy in prone-positioned patients was technically advantageous and reduced bowel toxicity.

Background: Matrix metalloproteinase-9 (MMP-9) has been shown to be induced by cytokines including TNF-α and may contribute to bone inflammatory diseases. However, the mechanisms underlying MMP-9 expression induced by TNF-α in MC3T3-E1 cells remain unclear., Results: We applied gelatin zymography, Western blot, RT-PCR, real-time PCR, selective pharmacological inhibitors of transcription (actinomycin D, Act.D), translation (cycloheximide, CHI), c-Src (PP1), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), and NF-κB (Bay11-7082), respective siRNAs transfection, promoter assay, immunofluorescence staining, and ELISA to investigate the MMP-9 expression and soluble ICAM-1 (sICAM-1) release induced by TNF-α in MC3T3-E1 cells. Here we demonstrated that TNF-α-induced MMP-9 expression was attenuated by Act.D, CHI, PP1, U0126, SB202190, SP600125, and Bay11-7082, and by the transfection with siRNAs for ERK2, p38 MAPK, and JNK2. TNF-α-stimulated TNFR1, TRAF2, and c-Src complex formation was revealed by immunoprecipitation and Western blot. Furthermore, TNF-α-stimulated NF-κB phosphorylation and translocation were blocked by Bay11-7082, but not by PP1, U0126, SB202190, or SP600125. TNF-α time-dependently induced MMP-9 promoter activity which was also inhibited by PP1, U0126, SB202190, SP600125, or Bay11-7082. Up-regulation of MMP-9 was associated with the release of sICAM-1 into the cultured medium, which was attenuated by the pretreatment with MMP-2/9i, an MMP-9 inhibitor., Conclusions: In this study, we demonstrated that TNF-α up-regulates MMP-9 expression via c-Src, MAPKs, and NF-κB pathways. In addition, TNF-α-induced MMP-9 expression may contribute to the production of sICAM-1 by MC3T3-E1 cells. The interplay between MMP-9 expression and sICAM-1 release may exert an important role in the regulation of bone inflammatory diseases.

Cases of an endovascular treatment for traumatic aortic injury are extremely rare. A prompt diagnosis of traumatic thoracic aortic pseudoaneurysm through a 3-dimensional computed tomographic angiography of aorta and emergency repair are mandatory to rescue the life-threatening condition. An endovascular treatment is a trend for traumatic aortic injury because of lower invasivity, morbidity and mortality. We reported a rare case of traumatic aortic injury with thoracic aortic pseudoaneurysm definitively diagnosed by the reconstructional computed tomographic angiography of aorta and successfully treated with endovascular stent-graft.

Background: The efficacy and tolerability of 500-730 kDa sodium hyaluronate (Hyalgan®) for treatment of osteoarthritis (OA) pain has been established in clinical trials, but few data are available in the Asian population. We conducted a randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy and tolerability of this preparation in a Taiwanese population., Methods: Two hundred patients with mild to moderate OA of the knee were randomized to receive five weekly intra-articular injections of sodium hyaluronate or placebo. The primary efficacy outcome was the change from baseline to Week 25 in patients' evaluation of pain using a 100-mm visual analog scale (VAS) during the 50-foot walking test. Additional outcomes included Western Ontario and McMaster Universities (WOMAC) scores, time on the 50-foot walking test, patient's and investigator's subjective assessment of effectiveness, acetaminophen consumption, and the amounts of synovial fluid., Results: The Hyalgan® treatment group showed a significantly greater improvement from baseline to Week 25 in VAS pain on the 50-foot walking test than the placebo group (p = 0.0020). The Hyalgan® group revealed significant improvements from baseline to week 25 in WOMAC pain and function score than the placebo group (p = 0.005 and 0.0038, respectively) Other outcomes, such as time on the 50-foot walking test and subjective assessment of effectiveness, did not show any significant difference between groups. Both groups were safe and well tolerated., Conclusions: The present study suggests that five weekly intra-articular injections of sodium hyaluronate are well tolerated, can provide sustained relief of pain, and can improve function in Asian patients with osteoarthritis of the knee., Trial Registration: Therapeutic study, Level I-1a (randomized controlled trial with a significant difference).

Background: Although several chronic obstructive pulmonary disease (COPD) practice guidelines have been published, there is sparse data on the actual emergency department (ED) management of acute exacerbation of COPD (AECOPD)., Aims: Our objectives were to examine concordance of ED care of AECOPD in older patients with guideline recommendations and to evaluate whether concordance has improved over time in two academic EDs., Methods: Data were obtained from two cohort studies on AECOPD performed in two academic EDs during two different time periods, 2000 and 2005-2006. Both studies included ED patients, aged 55 and older, who presented with AECOPD, and cases were confirmed by emergency physicians. Data on ED management and disposition were obtained from chart review for both cohorts., Results: The analysis included 272 patients: 72 in the 2000 database and 200 in the 2005-2006 database. The mean age of the patients was 72 years; 50% were women and 80% white. In 2005-2006, overall concordance with guideline recommendations was high (for chest radiography, pulse oximetry, bronchodilators, all >/= 90%), except for arterial blood gas testing (7% among the admitted) and discharge medication with systemic corticosteroids (42%). Compared to the 2000 data, the use of systemic corticosteroids in the ED improved from 53 to 77% [absolute improvement: 24%, 95% confidence interval (CI): 11-37%], and the use of antibiotics among the patients with respiratory infection symptoms improved from 56 to 78% (absolute improvement: 22%, 95% CI: 6-38%)., Conclusions: Overall concordance with guideline-recommended care for AECOPD was high in two academic EDs, and some emergency treatments have improved over time.

Background: Combination of CHD (chromo-helicase-DNA binding protein)-specific polymerase chain reaction (PCR) with electrophoresis (PCR/electrophoresis) is the most common avian molecular sexing technique but it is lab-intensive and gel-required. Gender determination often fails when the difference in length between the PCR products of CHD-Z and CHD-W genes is too short to be resolved., Results: Here, we are the first to introduce a PCR-melting curve analysis (PCR/MCA) to identify the gender of birds by genomic DNA, which is gel-free, quick, and inexpensive. Spilornis cheela hoya (S. c. hoya) and Pycnonotus sinensis (P. sinensis) were used to illustrate this novel molecular sexing technique. The difference in the length of CHD genes in S. c. hoya and P. sinensis is 13-, and 52-bp, respectively. Using Griffiths' P2/P8 primers, molecular sexing failed both in PCR/electrophoresis of S. c. hoya and in PCR/MCA of S. c. hoya and P. sinensis. In contrast, we redesigned sex-specific primers to yield 185- and 112-bp PCR products for the CHD-Z and CHD-W genes of S. c. hoya, respectively, using PCR/MCA. Using this specific primer set, at least 13 samples of S. c. hoya were examined simultaneously and the Tm peaks of CHD-Z and CHD-W PCR products were distinguished., Conclusion: In this study, we introduced a high-throughput avian molecular sexing technique and successfully applied it to two species. This new method holds a great potential for use in high throughput sexing of other avian species, as well.