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Background: Given the significant advancements in the management of hepatocellular carcinoma (HCC) and the emergence of novel treatment approaches, establishing reliable predictors has become crucial for optimizing patient selection and therapeutic sequencing in HCC. In this study, we aimed to investigate the prognostic factors and treatment efficacy associated with lenvatinib-based therapy., Methods: We retrospectively enrolled 53 patients receiving lenvatinib monotherapy, and 19 patients receiving lenvatinib plus immune checkpoint inhibitor combination therapy as their first-line systemic treatment for unresectable HCC at a single medical center. We employed univariate and multivariate Cox regression analyses to ascertain the factors influencing survival in these cohorts., Results: For lenvatinib monotherapy and the combination therapy, the objective response rates were 30.2% and 63.2%, respectively (P=0.03); the median progression-free survival (PFS) durations were 7 months [95% confidence interval (CI): 4.5-9.5] and 12 months (95% CI: 6.4-17.6), respectively (P=0.74); and the median overall survival (OS) was not reached in either group (P=0.93). Although patients receiving the combination therapy had a greater treatment response, no significant survival differences were observed between the lenvatinib monotherapy and combination therapy subgroups, even after inverse probability of treatment weighting (IPTW). Patients who received lenvatinib monotherapy could be stratified based on a combination of albumin-bilirubin (ALBI) grade (either grade 1 or 2a) and a neutrophil-lymphocyte ratio (NLR) of ≤5.8. Compared to the other subgroups combined, those who met both of these criteria exhibited PFS with a hazard ratio (HR) of 0.382 (95% CI: 0.168-0.871; P=0.02), corresponding to 11 and 5 months, respectively; and an OS (HR: 0.198, 95% CI: 0.043-0.920; P=0.04) of not reached versus 12 months, respectively, according to multivariate Cox regression analysis., Conclusions: In our study cohort, there were no statistically significant differences observed in the survival rates between patients treated with lenvatinib monotherapy and those treated with a combination of lenvatinib and immunotherapy. The incorporation of ALBI grade and NLR facilitates the stratification of survival outcomes in patients with unresectable HCC undergoing lenvatinib monotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-351/coif). C.Y.P. reports that this study was supported by a grant from China Medical University Hospital (DMR-101-011). C.Y.P. has been a member of the advisory committee for companies such as AbbVie, Bristol-Myers Squibb, Gilead, and Roche. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background/purpose: There are limited studies performing paired liver biopsies in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAA). We aimed to investigate the predictors of liver fibrosis changes assessed by paired liver biopsies in these patients., Methods: From March 2017 to March 2020, 113 CHC patients were prospectively enrolled to receive DAA therapy at our hospital. Paired liver biopsies were performed at baseline and 12 weeks after the end of treatment., Results: Among the entire cohort, the rate of sustained virological response (SVR) was 100%. Four baseline variables independently predicted fibrosis regression, including age <65 years [odds ratio (OR) = 2.725, p = 0.036], fibrosis stages (METAVIR scores) < 3 (OR = 4.874, p = 0.040), hemoglobin levels ≥12.5 g/dL (OR = 3.538, p = 0.029), and platelet counts ≥160 10 3 /μL (OR = 2.958, p = 0.023). Besides, five independent predictors of fibrosis progression included baseline age ≥66 years (OR = 16.351, p = 0.024), body mass index (BMI) ≥26.5 kg/m 2 (OR = 21.666, p = 0.009), sofosbuvir/ribavirin use (OR = 29.465, p = 0.031), platelet counts <119 10 3 /μL (OR = 33.739, p = 0.026), and the absence of alanine aminotransferase (ALT) levels declining from >35 U/L at baseline to ≤35 U/L at 4 weeks after baseline (OR = 284.534, p = 0.026)., Conclusion: For DAA-treated CHC patients, those with baseline age <65 years, fibrosis stages <3, hemoglobin levels ≥12.5 g/dL, or platelet counts ≥160 10 3 /μL are more likely to attain fibrosis regression. There is a higher risk of fibrosis progression in those with baseline age ≥66 years, BMI ≥26.5 kg/m 2 , sofosbuvir/ribavirin use, platelet counts <119 10 3 /μL, or the absence of early ALT normalization at 4 weeks after baseline., Competing Interests: Conflict of interest disclosure The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients., (© 2024 Asian Pacific Society of Nephrology.)

Background: The standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification., Methods: Medical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival., Results: A total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67-58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07-0.7, p = 0.01). Kaplan-Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups., Conclusions: R1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward., (© 2024. The Author(s).)

Background: /Purpose: This study aimed to directly compare the utility of liver stiffness (LS) and spleen stiffness (SS) at sustained virologic response (SVR) for predicting hepatocellular carcinoma (HCC) and non-HCC events in patients with chronic hepatitis C (CHC) after direct-acting antiviral therapy., Methods: This retrospective study included 695 CHC patients who achieved SVR and underwent LS and SS measurements. LS and SS were measured using point shear wave elastography and compared head-to-head., Results: During a median follow-up of 29.5 months, 49 (7.1%) patients developed liver-related events (LREs), including 28 HCC and 22 non-HCC events after SVR. Multivariable Cox regression analysis revealed that age, albumin level, and LS (≥ versus <1.46 m/s) at SVR (adjusted hazard ratio [aHR]: 5.390; 95% confidence interval [CI]: 2.349-12.364; p < 0.001), but not SS at SVR, significantly predicted the overall risk of post-SVR LREs (n = 49). Furthermore, age and LS (≥ versus <1.46 m/s) at SVR (aHR: 6.759; 95% CI: 2.317-19.723; p < 0.001), but not SS at SVR, independently predicted the risk of post-SVR incident HCC. In contrast, SS (≥ versus <2.87 m/s) at SVR (aHR: 11.212; 95% CI: 1.564-20.132; p = 0.021) and albumin level, but not LS at SVR, significantly predicted the risk of post-SVR non-HCC events., Conclusion: Post-SVR LS better predicts HCC risk. Post-SVR SS helps predict non-HCC risk after antiviral therapy for CHC. LS and SS at SVR provide complementary prognostic information regarding risks of HCC and non-HCC events in the post-SVR setting. Further validation is warranted in larger cohorts., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Biomarkers for predicting the treatment efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with unresectable hepatocellular carcinoma (uHCC) are crucial. Previous studies demonstrated that C-reactive protein and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score at baseline predicted treatment outcomes and that patients with uHCC with AFP response, defined as > 15% decline in AFP level within the initial 3 months of ICI-based therapy, had favorable outcomes when receiving ICI-based therapy. However, whether the combination of CRAFITY score and AFP response could be used to predict treatment efficacy of programmed death-1 (PD-1) blockade-based therapy in uHCC patients remains unclear. We retrospectively enrolled 110 consecutive uHCC patients from May 2017 to March 2022. The median ICI treatment duration was 2.85 (1.67-6.63) months, and 87 patients received combination therapies. The objective response and disease control rates were 21.8% and 46.4%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 2.87 (2.16-3.58) months and 8.20 (4.23-12.17) months, respectively. We categorized patients into three groups based on CRAFITY score (2 vs 0/1) and AFP response: patients with a CRAFITY score of 0/1 and AFP response (Group 1), those with a CRAFITY score of 2 and no AFP response (group 3), and those who did not belong to Group 1 and 3 (i.e., Group 2). The combination of CRAFITY score and AFP response could predict disease control and could predict PFS compared with CRAFITY score or AFP response alone. The combination of CRAFITY score and AFP response was an independent predictor of OS (Group 2 vs Group 1, HR: 4.513, 95% CI 1.990-10.234; Group 3 vs Group 1, HR: 3.551, 95% CI 1.544-8.168). Our findings indicated that the combination of CRAFITY score and AFP response could predict disease control, PFS, and OS in uHCC patients receiving PD-1 blockade-based immunotherapy., Competing Interests: Cheng-Yuan Peng has served as an advisory committee member for AbbVie, Bristol-Myers Squibb, Gilead, and Roche. All other coauthors have no conflicts of interest to declare., (AJCR Copyright © 2023.)

Background: Long head of the biceps tendon (LHBT) instability and biceps reflection pulley (BRP) lesions are common cause of refractory anterior shoulder pain. We described a technique using dynamic arthroscopy to determine associated intraarticular pathologies., Methods: Patients with refractory anterior shoulder pain and arthroscopically-diagnosed LHBT instability were enrolled. LHBT instability and the integrity of BRP and concomitant intra-articular lesions were investigated by ramp test. Demographics and arthroscopic findings were compared between patients with and without BRP tear., Results: Forty patients were enrolled. BRP tear was noted in 25 patients (group A) and superior glenohumeral ligament (SGHL) insufficiency through ramp test in 15 patients (group B). Concomitant intraarticular pathologies were noted in 27 patients, including 19 in group A (76%) and eight in group B (53%), without significant group-wise difference (p = 0.138). The incidence of articular-side subscapularis tear was significantly higher in group A (p = 0.021), and those of the other intraarticular pathologies were similar between groups A and B. Fraying at the articular side of the subscapularis and supraspinatus tendons was frequent in group B, without difference of incidence as compared to group A (p = 0.5 and p = 0.084, respectively)., Conclusions: LHBT instability was a common disorder in patients with refractory shoulder pain. In those patients, dynamic assessment of BRP lesions and SGHL insufficiency and meticulous survey of associated intra-articular pathologies, including subscapularis tear are necessary for making accurate diagnosis and treatment decision., Competing Interests: Conflicts of interest None., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background: Few studies documented incidence rates of different types of stroke among patients with polycystic kidney disease (PKD)., Methods: We conducted a retrospective cohort study based on the National Health Insurance (NHI) Database of Taiwan. The PKD cohort comprised patients aged≥20 years diagnosed with PKD using inpatient claims from 1998 to 2011, excluding prior stroke. The reference cohort was established by inpatients without PKD using 1:4 frequency-matched with age, gender, and baseline comorbidities. The two cohorts were followed-up until stroke hospitalization, death, withdrawal from the NHI program, or the end of 2012. To account for competing risks of death, we used multivariable competing risks regression models to estimate sub-distribution hazard ratio (SHR) adjusted for age, gender, baseline comorbidities and end stage renal disease., Results: 7837 PKD patients and 31,211 reference subjects were followed up through 2012. A total of 955 cases of stroke were identified in the PKD cohort, including 441 ischemic stroke (IS), 289 intracranial hemorrhage (ICH), 73 subarachnoid hemorrhage (SAH) and 232 other stroke. The incidence rates of overall stroke, IS, ICH, and SAH were 21.3, 10.2, 6.8, and 1.7 per 1000 person-years, respectively. The SHR for overall stroke was 1.39 [95% confidence interval (CI) 1.28-1.50]. SAH had the highest SHR, 4.55 [95% CI 3.26-6.37], followed by ICH (1.84), other stroke (1.24), and IS (1.22)., Conclusion: This study illustrated the incidence rates of stroke among inpatient of PKD. The PKD patients had a significantly increased risk of all kinds of stroke after adjusting baseline comorbidities., Competing Interests: Conflicts of interest None declared., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Aims: Long-term risk stratification using combined liver stiffness (LS) and clinically relevant blood tests acquired at the baseline further beyond the sustained virologic response (SVR) visit for chronic hepatitis C (CHC) has not been thoroughly investigated. This study retrospectively investigated the prognostics of liver-related events (LREs) further beyond the SVR visit., Methods: Cox regression and random forest models identified the key factors, including longitudinal LS and noninvasive test results, that could predict LREs, including hepatocellular carcinoma, during prespecified follow-ups from 2010 to 2021. Kaplan-Meier survival analysis estimated the significance of between-group risk stratification., Results: Of the entire eligible cohort ( n  = 520) of CHC patients with SVR to antiviral therapy, 28 (5.4%) patients developed post-SVR LREs over a median follow-up period of 6.1 years (interquartile range = 3.5-8.7). The multivariate Cox regression analysis identified two significant predictors of LREs after the year 3 post-SVR (Y3PSVR) baseline (LRE, n  = 15 of 28, 53.6%, median follow-up = 4.1 [1.6-6.4] years after Y3PSVR): LS at Y3PSVR (adjusted hazard ratio [aHR] = 3.980, 95% confidence interval [CI] = 2.085-7.597, P < 0.001), and α -fetoprotein (AFP) at Y3PSVR (aHR = 1.017, 95% CI = 1.001-1.034, P =0.034). LS ≥1.45 m/s and AFP ≥3.00 ng/mL for Y3PSVR yielded positive likelihood ratios of 4.24 and 2.62, respectively. Kaplan-Meier analysis revealed that among the stratified subgroups, the subgroup with concurrent LS ≥1.45 m/s and AFP ≥3.00 ng/mL at Y3PSVR exhibited the highest risk of LREs after Y3PSVR (log-rank P < 0.001)., Conclusion: We recommend the combined use of concurrent LS and AFP in future prediction models for LREs in CHC. Patients with concurrently high LS and AFP values further beyond the SVR visit may require a recall policy involving intense surveillance., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Sheng-Hung Chen et al.)

Family members of hazardous or harmful alcohol drinkers suffer many consequences of their relative’s alcohol-drinking behaviors and risk developing their own hazardous alcohol drinking behaviors. Studies of alcohol-related healthcare problems have mainly focused on patients, with few studies on their family members. This cross-sectional study explored factors predicting hazardous alcohol drinking behaviors in family members of hazardous alcohol-drinker patients. Participants were recruited from four randomly chosen hospitals in Taiwan. Data were collected using self-report questionnaires on family members’ alcohol use, perceived stress, coping mechanisms, social support, health, quality of life, protective factors against hazardous alcohol drinking, facilitative factors for hazardous alcohol drinking, and demographics. The 318 family members who participated in this study were divided by their Chinese-version Alcohol Use Disorders Identification Test scores into two groups: hazardous alcohol drinkers (score ≥ 8) and non-hazardous alcohol drinkers (score < 8). Significant factors predicting hazardous alcohol drinking behaviors were found by logistic regression to be the frequency of using general coping mechanisms (OR = 1.29, p < 0.01), the frequency of using strategies to cope with patients’ drinking-related behaviors (OR = 0.89, p < 0.01), factors protecting against hazardous alcohol drinking (OR = 0.76, p < 0.01) and factors facilitating hazardous alcohol drinking (OR = 1.52, p < 0.01). Interventions should be designed for family members of hazardous alcohol drinkers to address these four significant predictors.

Objectives: Direct-acting antiviral agents achieve a high cure rate, resulting in early hepatic necroinflammatory resolution and sustained fibrosis regression. This study aimed to obtain longitudinal, concurrent within-subject measurements of liver stiffness (LS) and spleen stiffness (SS) and their correlates over time., Methods: Participants with hepatitis C (n = 592) receiving direct-acting antiviral-based therapy were monitored through point shear-wave elastography from the treatment baseline (TW0) across follow-up visits in terms of LS and SS., Results: Generalized linear mixed modeling indicated that all LS values (2301 visits) were negatively correlated with the follow-up times (all P < .05) from TW0 to 24 weeks (PW24) after the end of treatment (EOT) and positively correlated with baseline LS values (P < .001). The slopes of declines (preceding minus next) differed significantly (P < .001) between TW0-TW4 (treatment week 4) (0.060 [-0.050 to 0.225] meter/second/month [m/s/mo]) and TW4-EOT (0.010 [-0.030 to 0.075] m/s/mo). All SS values (1704 visits) were negatively correlated with time only at PW24 (P < .001) and positively correlated with baseline SS values (P < .001). The slopes of the SS values differed significantly (P < .001) only between EOT-PW12 (-0.010 [-0.110 to 0.083] m/s/mo) and PW12-PW24 (0.043 [-0.063 to 0.160] m/s/mo)., Conclusions: The biphasic fast-to-slow decline in LS occurred early in the on-treatment phase, which is consistent with the resolution of hepatic necroinflammation. The slow-to-fast decline in SS occurred off treatment. Future studies should investigate the association with regressions in liver fibrosis and portal hypertension., (© 2021 American Institute of Ultrasound in Medicine.)

High-resolution ultrasound is preferred as the first-line imaging modality for evaluation of superficial soft tissues, such as the facial muscles. In contrast to magnetic resonance imaging and computed tomography, which require specifically designated planes (axial, coronal and sagittal) for imaging, the ultrasound transducer can be navigated based on the alignment of facial muscles. Botulinum toxin injections are widely used in facial cosmetic procedures in recent times. Ultrasonography is recognized as a useful tool for pre-procedure localization of target muscles. In this pictorial review, we discuss the detailed sonoanatomy of facial muscles and their clinical relevance, particularly with regard to botulinum toxin injections. Furthermore, we have summarized the findings of clinical studies that report ultrasonographic imaging of facial muscles.

Background: For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored., Methods: This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63-7.54)., Results: In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n  = 77), cases achieving sustained virological response (SVR) ( n  = 52) had a significantly lower rate of fibrosis progression than non-SVR cases ( n  = 25) (3.8% versus 24.0%, p  = 0.012). Among the entire cohort ( n  = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases ( n  = 59) was significantly higher than that in non-SVR cases ( n  = 26) (94.9% versus 65.4%, p  = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p  = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p  = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p  = 0.049) and activity response (OR = 17.741, p  = 0.047), respectively., Conclusions: Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: While primary liver cancer (PLC) is one of the most common cancers around the world, few large-scale population-based studies have been reported that evaluated the clinical survival outcomes among peripartum and postmenopausal women with PLC., Aim: To investigate whether peripartum and postmenopausal women with PLC have lower overall survival rates compared with women who were not peripartum and postmenopausal., Methods: The Taiwan National Health Insurance claims data from 2000 to 2012 was used for this propensity-score-matched study. A cohort of 40 peripartum women with PLC and a reference cohort of 160 women without peripartum were enrolled. In the women with PLC with/without menopause study, a study cohort of 10752 menopausal females with PLC and a comparison cohort of 2688 women without menopause were enrolled., Results: Patients with peripartum PLC had a non-significant risk of death compared with the non-peripartum cohort [adjusted hazard ratios (aHR) = 1.40, 95% confidence intervals (CI): 0.89-2.20, P = 0.149]. The survival rate at different follow-up durations between peripartum PLC patients and those in the non-peripartum cohort showed a non-significant difference. Patients who were diagnosed with PLC younger than 50 years old (without menopause) had a significant lower risk of death compared with patients diagnosed with PLC at or older than 50 years (postmenopausal) (aHR = 0.64, 95%CI: 0.61-0.68, P < 0.001). The survival rate of women < 50 years with PLC was significantly higher than older women with PLC when followed for 0.5 (72.44% vs 64.16%), 1 (60.57% vs 51.66%), 3 (42.92% vs 31.28%), and 5 year(s) (37.02% vs 21.83%), respectively ( P < 0.001)., Conclusion: Peripartum females with PLC have no difference in survival rates compared with those patients without peripartum. Menopausal females with PLC have worse survival rates compared with those patients without menopause., Competing Interests: Conflict-of-interest statement: All authors have no conflict of interest related to the manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib-regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2-5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704-5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316-10.88; p = 0.014) and sorafenib-regorafenib sequential (HR: 4.603, 95% CI: 1.386-15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib-regorafenib sequential therapy.

Background & Aims: It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib., Methods: From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups., Results: DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026)., Conclusions: Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib., Competing Interests: The authors have declared that no competing interests exist.

GSK3 are involved in different physical and pathological conditions and inflammatory regulated by macrophages contribute to significant mechanism. Infection stimuli may modulate GSK3 activity and influence host cell adaption, immune cells infiltration or cytokine expressions. To further address the role of GSK3 modulation in macrophages, the signal transduction of three major organs challenged by endotoxin, virus and genetic inherited factors are briefly introduced (lung injury, myocarditis and autosomal dominant polycystic kidney disease). As a result of pro-inflammatory and anti-inflammatory functions of GSK3 in different microenvironments and stages of macrophages (M1/M2), the rational resolution should be considered by adequately GSK3., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest and no financial support for this publication., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale & Objective: Outcomes reported in trials involving patients with autosomal dominant polycystic kidney disease (ADPKD) are heterogeneous and rarely include patient-reported outcomes. We aimed to identify critically important consensus-based core outcome domains to be reported in trials in ADPKD., Study Design: An international 2-round online Delphi survey was conducted in English, French, and Korean languages., Setting & Participants: Patients/caregivers and health professionals completed a 9-point Likert scale (7-9 indicating critical importance) and a Best-Worst Scale., Analytical Approach: The absolute and relative importance of outcomes were assessed. Comments were analyzed thematically., Results: 1,014 participants (603 [60%] patients/caregivers, 411 [40%] health professionals) from 56 countries completed round 1, and 713 (70%) completed round 2. The prioritized outcomes were kidney function (importance score, 8.6), end-stage kidney disease (8.6), death (7.9), blood pressure (7.9), kidney cyst size/growth (7.8), and cerebral aneurysm (7.7). Kidney cyst-related pain was the highest rated patient-reported outcome by both stakeholder groups. Seven themes explained the prioritization of outcomes: protecting life and health, directly encountering life-threatening and debilitating consequences, specificity to ADPKD, optimizing and extending quality of life, hidden suffering, destroying self-confidence, and lost opportunities., Limitations: Study design precluded involvement from those without access to internet or limited computer literacy., Conclusions: Kidney function, end-stage kidney disease, and death were the most important outcomes to patients, caregivers, and health professionals. Kidney cyst-related pain was the highest rated patient-reported outcome. Consistent reporting of these top prioritized outcomes may strengthen the value of trials in ADPKD for decision making., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Data on noninvasive liver fibrosis staging after viral eradication are unclear. This histology-based study validated the performance of liver stiffness (LS) measurements after viral eradication., Methods: Consecutive participants with chronic hepatitis C (CHC) who received concomitant LS measurements through acoustic radiation force impulse (ARFI) elastography and percutaneous liver biopsy were prospectively screened and analyzed., Results: Of the 644 patients, 521 (80.9%) underwent a biopsy at treatment baseline, and the remaining 123 (19.1%) underwent a biopsy at 3 years (median; interquartile range, 0.1) after the sustained virological response (SVR) to pegylated interferon-based and direct-acting antiviral treatments. The proportions of histological fibrosis stages did not differ significantly between the pretreatment and post-SVR groups (P = .0615). However, the LS values differed significantly (P < .0001). The median LS values (presented as shear wave velocities in meters per second) were 1.51 (0.92) for the pretreatment group and 1.22 (0.77) for the post-SVR group. The cutoffs (areas under the receiver operating characteristic curve, obtained using the bootstrap method) to dichotomize between METAVIR fibrosis stage F1 versus stages F2-F4, F1-F2 versus F3-F4, and F1-F3 versus F4 were 1.47 (0.8333, 95% confidence interval [CI] 0.7981-0.8663), 1.81 (0.8763, 95% CI 0.8376-0.9107), and 1.86 (0.8811, 95% CI 0.8378-0.9179) in the pretreatment group, respectively, and 1.22 (0.7872, 95% CI 0.7001-0.8624), 1.59 (0.8808, 95% CI 0.8034-0.9422), and 1.75 (0.9018, 95% CI 0.8201-0.9644) in the post-SVR group, respectively., Conclusions: The performance of LS measurements through ARFI elastography is promising to determine the liver fibrosis stage on necroinflammation-resolved histology in CHC after viral eradication., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Aim: Patients with autosomal dominant polycystic kidney disease (ADPKD) are at increased risk of premature mortality, morbidities and complications, which severely impair quality of life. However, patient-centered outcomes are not consistently reported in trials in ADPKD, which can limit shared decision-making. We aimed to identify outcomes important to patients and caregivers and the reasons for their priorities., Methods: Nominal group technique was adopted involving patients with ADPKD and caregivers who were purposively selected from eight centres across Australia, France and the Republic of Korea. Participants identified, ranked and discussed outcomes for trials in ADPKD. We calculated an importance score (0-1) for each outcome and conducted thematic analyses., Results: Across 17 groups, 154 participants (121 patients, 33 caregivers) aged 19 to 78 (mean 54.5 years) identified 55 outcomes. The 10 highest ranked outcomes were: kidney function (importance score 0.36), end-stage kidney disease (0.32), survival (0.21), cyst size/growth (0.20), cyst pain/bleeding (0.18), blood pressure (0.17), ability to work (0.16), cerebral aneurysm/stroke (0.14), mobility/physical function (0.12), and fatigue (0.12). Three themes were identified: threatening semblance of normality, inability to control and making sense of diverse risks., Conclusion: For patients with ADPKD and their caregivers, kidney function, delayed progression to end-stage kidney disease and survival were the highest priorities, and were focused on achieving normality, and maintaining control over health and lifestyle. Implementing these patient-important outcomes may improve the meaning and relevance of trials to inform clinical care in ADPKD., (© 2019 Asian Pacific Society of Nephrology.)

Little is known about how the initial infection and diagnosis of hepatitis C virus (HCV) impacts a patient's experience of living with and adjusting to the disease. In the present qualitative, descriptive study, we explored the initial experiences of patients in Taiwan diagnosed with HCV. Eighteen participants were recruited from hepatology clinics of a teaching hospital in Taichung, Taiwan by purposive sampling. Data were collected via in-depth face-to-face interviews and analyzed by conventional content analysis. The core theme describing the illness trajectory was "Oasis in the desert". Two main themes described the participants' experiences and adjustment to the diagnosis of hepatitis C: "Getting lost in the journey" and "The calm after the storm". Our findings highlight the need for health-care providers to coordinate interactions between patients and multi-disciplinary teams to manage the integration of different treatment options. There is a demand for educational interventions and online information for patients and the general population, which could improve knowledge of HCV., (© 2018 John Wiley & Sons Australia, Ltd.)

Helicobacter pylori (H. pylori) infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. Increased T-cell infiltration is found at sites of H. pylori infection. The CCR6 + subset of CD4 + regulatory T cells (Tregs), a newly characterized subset of Tregs, has been reported to contribute to local immune inhibition. However, whether CCR6 + Tregs are present in H. pylori gastritis, and what their relationship is to disease prognosis, remains to be elucidated. In this study, gastric infiltrating lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed. We found that in gastric infiltrating lymphocytes, CCR6 +  CD4 +  CD25 high Tregs, which express high levels of CD45RO, are positively associated with more severe inflammation in gastric mucosa during H. pylori infection. Furthermore, the frequency of CCR6 + Tregs in gastric infiltrating lymphocytes, but not CCR6 - Tregs, is significantly increased in inflamed gastric tissues, which is inversely correlated with significantly lower expression of IFN-γ +  CD8 + T cells. We also found that the frequency of CCR6 + Tregs is positively correlated with the frequency of CD4 +  IFN-γ + T cells. In addition, the frequency of CCR6 + Tregs, but not that of CCR6 - Tregs, is significantly correlated with increased inflammation in H. pylori gastritis. This study demonstrates that immunosuppression in H. pylori gastritis might be related to the activity of CCR6 + Tregs, which could influence disease prognosis., (© 2018 John Wiley & Sons Ltd.)

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells. Reducing this resistance might shed light on the treatment of human gastric adenocarcinoma. In this study, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors can restore TRAIL responsiveness in gastric adenocarcinoma cells. The effect of two GSK-3 inhibitors, SB-415286, and LiCl, on apoptosis signaling of TRAIL in human gastric adenocarcinoma cell lines and primary gastric epithelial cells was analyzed. Both inhibitors can sensitize gastric adenocarcinoma cells, but not primary gastric epithelial cells, to TRAIL-induced apoptosis by increasing caspase-8 activity and its downstream signal transmission. Adding p53 siRNA can downregulate GSK-3 inhibitor-related sensitization to TRAIL-induced apoptosis and caspase-3 activity. GSK-3 inhibitors strongly activate the phosphorylation of JNK. Inhibition of JNK leads to earlier and more intense apoptosis, showing that the activation of JNK may provide anti-apoptotic equilibrium of pro-apoptotic cells. Our observations indicate that GSK-3 inhibitors can sentize AGS gastric adenocarcinoma cells to TRAIL-induced apoptosis. Therefore, in certain types of gastric adenocarcinoma, GSK-3 inhibitor might enhance the antitumor activity of TRAIL and mightbe a promising candidate for the treatment of certain types of gastric adenocarcinoma., Competing Interests: The authors have declared that no competing interests exist.

Background: The reported incidence of shoulder redislocation varies among different reports. This was a nationwide study to investigate the recurrence rate of shoulder dislocation after closed reduction., Methods: We performed a cohort study to analyze the incidence of first dislocation as well as second and third repeated dislocations in a nationwide dataset from the National Health Insurance Research Database of Taiwan. Patients who had any shoulder dislocation event and received closed reduction from 2000 to 2013 were included., Results: From this dataset of 1 million persons, we identified 1074 patients who had a shoulder dislocation. Of these, 210 had a second shoulder dislocation and 93 had a third shoulder dislocation. The shoulder redislocation rates were 9.4%, 12.7%, and 17.0% at 1 year, 2 years, and 5 years, respectively, after the first shoulder dislocation and 19.6% at overall follow-up. Patients in the youngest age group and male patients had higher risks of redislocation (adjusted hazard ratios, 3.28 and 1.41, respectively). The mean time to recurrence was 13.1 months. However, the patients who had a second shoulder dislocation had a shorter time to recurrence and a higher risk of redislocation (44%), with no statistical differences in risk among any age or sex groups., Conclusions: After the first shoulder dislocation, male patients and younger patients had higher shoulder redislocation rates. However, after the second shoulder dislocation, all groups shared a similar high shoulder redislocation rate regardless of age or sex. Surgical treatment should be considered for patients with multiple episodes of shoulder dislocation., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background/aim: The programmed death 1 (PD-1) receptor and its ligand (PD-L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of tumor infiltrating T lymphocytes in gastric adenocarcinoma patients are not well-defined., Materials and Methods: We characterized the expression of PD-1 and PD-L1 in peripheral blood and tumor infiltrating cells and analyzed the association between PD-1/PD-L1 expression and disease progression in a cohort of 60 patients with Helicobacter pylori infection, including 18 with gastric adenocarcinoma, 23 with gastritis, and 19 asymptomatic controls., Results: Relative to controls, the expression of PD-1 on peripheral blood and tumor infiltrating T cells increased with disease progression. In vitro, T cells induced PD-L1 expression on primary gastric adenocarcinoma epithelial cells in an IFN-γ-dependent manner, which in turn promoted T cells apoptosis. Blocking of PD-L1 reversed this effect., Conclusion: This study provides evidence for a new therapeutic target in gastric adenocarcinoma patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hyperlipidemia is a risk factor of arteriosclerosis, stroke, and other coronary heart disease, which has been shown to correlate with single nucleotide polymorphisms of genes essential for lipid metabolism, such as lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5). In this study, the effect of magnolol, the main active component extracted from Magnolia officinalis, on LPL activity was investigated. A dose-dependent up-regulation of LPL activity, possibly through increasing LPL mRNA transcription, was observed in mouse 3T3-L1 pre-adipocytes cultured in the presence of magnolol for 6 days. Subsequently, a transgenic knock-in mice carrying APOA5 c.553G>T variant was established and then fed with corn oil with or without magnolol for four days. The baseline plasma triglyceride levels in transgenic knock-in mice were higher than those in wild-type mice, with the highest increase occurred in homozygous transgenic mice (106 mg/dL vs 51 mg/dL, p<0.01). After the induction of hyperglyceridemia along with the administration of magnolol, the plasma triglyceride level in heterozygous transgenic mice was significantly reduced by half. In summary, magnolol could effectively lower the plasma triglyceride levels in APOA5 c.553G>T variant carrier mice and facilitate the triglyceride metabolism in postprandial hypertriglyceridemia.

Background: To compare on-treatment and off-treatment parameters acquired using acoustic radiation force impulse elastography, the Fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI) in patients with chronic hepatitis C (CHC)., Methods: Patients received therapies based on pegylated interferon or direct-acting antiviral agents. The changes in paired patient parameters, including liver stiffness (LS) values, the FIB-4 index, and APRI, from baseline to sustained virologic response (SVR) visit (24 weeks after the end of treatment) were compared. Multiple regression models were used to identify significant factors that explained the correlations with LS, FIB-4, and APRI values and SVR., Results: A total of 256 patients were included, of which 219 (85.5%) achieved SVR. The paired LS values declined significantly from baseline to SVR visit in all groups and subgroups except the nonresponder subgroup (n = 10). Body mass index (P = 0.0062) and baseline LS (P < 0.0001) were identified as independent factors that explained the LS declines. Likewise, the baseline FIB-4 (P < 0.0001) and APRI (P < 0.0001) values independently explained the declines in the FIB-4 index and APRI, respectively. Moreover, interleukin-28B polymorphisms, baseline LS, and rapid virologic response were identified as independent correlates with SVR., Conclusions: Paired LS measurements in patients treated for CHC exhibited significant declines comparable to those in FIB-4 and APRI values. These declines may have correlated with the resolution of necroinflammation. Baseline LS values predicted SVR.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life threatening inherited kidney disease and is responsible for 5-10% of cases of end-stage kidney disease (ESKD). Cystic kidneys may enlarge up to 20 times the weight of a normal kidney due to the growth of renal cysts, and patients with ADPKD have an increased risk of morbidity, premature mortality, and other life-time complications including renal and hepatic cyst and urinary tract infection, intracranial aneurysm, diverticulosis, and kidney pain which impair quality of life. Despite some therapeutic advances and the growing number of clinical trials in ADPKD, the outcomes that are relevant to patients and clinicians, such as symptoms and quality of life, are infrequently and inconsistently reported. This potentially limits the contribution of trials to inform evidence-based decision-making. The Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) project aims to establish a consensus-based set of core outcomes for trials in PKD (with an initial focus on ADPKD but inclusive of all stages) that patients and health professionals identify as critically important., Methods: The five phases of SONG-PKD are: a systematic review to identify outcomes that have been reported in existing PKD trials; focus groups with nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with health professionals to elicit individual values and perspectives on outcomes for trials involving patients with PKD; an international three-round Delphi survey with all stakeholder groups (including patients, caregivers, healthcare providers, policy makers, researchers, and industry) to gain consensus on critically important core outcome domains; and a consensus workshop to review and establish a set of core outcome domains and measures for trials in PKD., Discussion: The SONG-PKD core outcome set is aimed at improving the consistency and completeness of outcome reporting across ADPKD trials, leading to improvements in the reliability and relevance of trial-based evidence to inform decisions about treatment and ultimately improve the care and outcomes for people with ADPKD.

This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004-2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22-0.63) for those without cirrhosis and 0.54 (0.31-0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored.

Background/purpose: Effective mediators activate downstream transducers regulating inflammation and angiogenesis. Correlation among mediators IL-6, IL-27, TNF-α, and VEGF with STAT proteins at diverse clinical-pathologic stages of cirrhotic patients remains limited., Methods: Plasma mediators were assayed from 158 naïve liver cirrhosis (LC-total group) and 144 non-LC individuals. The LC-total group included 69 hepatitis B virus-infected (LC-HBV) patients, 40 hepatitis C virus-infected (LC-HCV) patients, and 49 patients without HBV-/HCV- infection (LC-NBNC). Another 144 non-LC individuals comprised 54 healthy persons (HG) and 90 chronic hepatitis patients (CH-total) as the control group. To correlate with plasma mediators, 52 paired liver tissues (CH: 41 and LC: 11 cases) served for p-STAT1 and p-STAT3 immunostaining., Results: Although IL-6, IL-27, TNF-α, and VEGF were expressed significantly in CH-total versus HG (p = 0.011, p < 0.001, p = 0.007, p = 0.004, respectively) and overall viral hepatitis patients versus HG (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively), only IL-6 presented the strongest correlation in cirrhotic patients than noncirrhotic patients (LC-HBV vs. HG, p < 0.001, vs. CH-HBV, p = 0.001; LC-HCV vs. HG, p = 0.001, vs. CH-HCV, p = 0.031; LC-NBNC vs. HG, p < 0.001). Over-expressed IL-6 linked with poorer liver function (albumin: r = -0.346, p < 0.001; bilirubin: r = 0.271, p = 0.001; INR: r = 0.308, p < 0.001; Child-Turcotte-Pugh Classification C vs. A or B, p = 0.001, p = 0.007, respectively), variceal severity (p = 0.045), and bleeding (p = 0.047), as well as patients' mortality (p = 0.005). Furthermore, plasma IL-6 significantly correlated with tissues p-STAT3 expression (r = 0.737, p = 0.010) (IL-27: r = 0.078, p = 0.820; TNF-α: r = -0.145, p = 0.670; VEGF: r = 0.142, p = 0.678) in cirrhotic patients than noncirrhotic patients., Conclusion: Over-expression of IL-6 reflects hepatic dysfunction and varices bleeding with mortality, as well as correlates p-STAT3 expression in cirrhotic patients., (Copyright © 2015. Published by Elsevier B.V.)

Background: Excessive alcohol use has been associated with health, social and legal problems. Alcohol-related problems have been studied primarily in problem-drinker patients, with few studies on their family members, particularly about their own hazardous or harmful alcohol-drinking behaviours., Method: In this qualitative descriptive study, participants were recruited from three hospitals randomly selected from northern and central Taiwan (2:1). Hazardous-drinker patients and their family members were screened using the Chinese version Alcohol Use Disorders Identification Test (scores ≥8 indicate harmful or hazardous drinkers). Data were collected in individual, audiotaped, in-depth interviews using an interview guide. Verbatim interview transcripts were analysed using ATLAS.ti, version WIN 7.0., Results: The sample of 35 family members with hazardous or harmful drinking behaviours perceived that their own alcohol-drinking behaviours were related to six major patterns: family habits, leisure activities with friends, work pressures, personal taste, a way to forget one's problems and to express happiness., Conclusion: We recommend that programmes targeting harmful or hazardous drinking among problem-drinker patients' family members should educate participants about the standard amounts of alcohol in alcoholic beverages, recommended amounts of alcohol consumption for males and females, the long-term effects of excessive alcohol consumption; address sources of risk factors at work; offer strategies to resist social pressures to drink; and build positive strategies for coping with stress.

Background: Medial knee osteoarthritis (OA) typically occurs with excessive mechanical load within the medial compartment, resulting in degeneration of the articular cartilage., Purpose: A novel extracapsular implant (Latella Knee Implant) has been developed to unload the medial compartment of the knee. The implant displaces the iliotibial band (ITB) over the lateral femoral condyle, thereby increasing its effective moment arm, resulting in a transfer of load from the medial compartment to the lateral compartment of the knee. A cadaveric study was performed to evaluate the effect of altering the moment arm of the ITB on knee biomechanics., Study Design: Controlled laboratory study., Methods: A 6-degrees-of-freedom robotic testing system was utilized to measure medial and lateral compartment loads in 8 fresh-frozen cadaveric knees at various ITB loads and knee flexion angles. Measurements were made with and without the implant in place. The system measured the compartment forces at flexion angles between 0° and 30° under 3 simulated loading conditions (300 N quadriceps, 100 N hamstrings, and [1] 0 N ITB, [2] 50 N ITB, [3] 100 N ITB)., Results: Lateral displacement of the ITB between 15 and 20 mm resulted in medial compartment unloading between 34% and 65%., Conclusion: Unloading the medial compartment with this novel implant has the potential to address the treatment gap for patients with medial knee OA., Clinical Relevance: Currently, there exists a treatment gap for patients with medial compartment OA who have exhausted conservative management but whose disease and symptoms do not warrant more invasive surgical procedures. An extracapsular implant to unload the medial compartment could fill this treatment gap by providing patients and surgeons with a less invasive option for early to mid-stage OA. Unloading the medial compartment may alleviate pain and improve function, allowing patients with early-stage medial OA to remain active longer prior to considering more invasive options such as arthroplasty., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: V.N.S. has received consulting fees from, is employed by, owns stock in, is a board member of, is a patent holder of patents owned by, and receives royalties from Cotera, Inc. V.N.S.’s spouse owns stock in Cotera, Inc. H.S.G. receives consulting fees from, owns stock in, is a board member of, is a patent holder of patents owned by, and receives royalties from Cotera, Inc. H.S.G.’s parents, children, and siblings own stock in Cotera, Inc. J.T.K. receives consulting fees from and owns stock options in Cotera, Inc.

Molecular diagnostics in cancer pharmacogenomics is indispensable for making targeted therapy decisions especially in lung cancer. For routine clinical practice, the flexible testing platform and implemented quality system are important for failure rate and turnaround time (TAT) reduction. We established and validated the multiplex EGFR testing by MALDI-TOF MS according to ISO15189 regulation and CLIA recommendation in Taiwan. Totally 8,147 cases from Aug-2011 to Jul-2015 were assayed and statistical characteristics were reported. The intra-run precision of EGFR mutation frequency was CV 2.15% (L858R) and 2.77% (T790M); the inter-run precision was CV 3.50% (L858R) and 2.84% (T790M). Accuracy tests by consensus reference biomaterials showed 100% consistence with datasheet (public database). Both analytical sensitivity and specificity were 100% while taking Sanger sequencing as the gold-standard method for comparison. EGFR mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002 ± 0.016% (95% CI: 0.000-0.036) (L858R) and 0.292 ± 0.289% (95% CI: 0.000-0.871) (T790M). The average TAT was 4.5 working days and the failure rate was less than 0.1%. In conclusion, this study provides a comprehensive report of lung cancer EGFR mutation detection from platform establishment, method validation to clinical routine practice. It may be a reference model for molecular diagnostics in cancer pharmacogenomics.

Few studies have compared the distinct hepatic collagen morphometrics of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study compared the discrepancies between CHB and CHC in liver fibrosis (F) quantification by using the collagen proportionate area (CPA) and liver stiffness (LS) measured with shear wave velocity (SWV).This study enrolled 274 eligible consecutive patients diagnosed with CHB (n = 137) or CHC (n = 137). Their ages ranged from 20 to 80 years (median = 50). In total, 154 patients (56.2%) were male. Participant LS was measured by using acoustic radiation force impulse elastography preceding an immediate percutaneous liver biopsy. The total proportion of the collagen stained with picrosirius red to the total tissue area was expressed as the CPA percentage, which was stratified into portal-bridging (PB) and perisinusoidal (PS) proportionate areas (PAs).Based on the METAVIR F staging system, 36 (26.3%), 36 (26.3%), 28 (20.4%), and 37 (27.0%) participants in the CHB group and 34 (24.8%), 45 (32.9%), 34 (24.8%), and 24 (17.5%) participants in the CHC group were staged as F1, F2, F3, and F4, respectively. Both the total CPAs and PBPAs were significantly (P < 0.05) higher in the CHC group than in the CHB group within all F-stratified subgroups. The SWVs were significantly (P < 0.05) higher in the CHC group than in the CHB group only within the F2, F3, and F4 subgroups. However, the PSPAs did not differ significantly between the CHC and CHB groups within all subgroups. Multiple regression analysis revealed that viral hepatitis etiology (P < 0.001), METAVIR F stages (P < 0.001), and platelet count (P = 0.007) were independent factors correlated with the CPA (R = 0.543, P < 0.001).In conclusion, both the F stage-stratified CPAs and SWVs tended to be higher in cases of CHC than in those of CHB. The type of viral hepatitis significantly affected both the CPA and SWV values. The PBPAs were more closely correlated with F stages and SWV than were the PSPAs., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Hepatitis C virus (HCV) infection is a global public health issue. Adequate treatment for hepatitis C patients is important, but anticipated side effects make patients fearful of receiving treatment. Little is known about the experiences of hepatitis C patients who have completed treatment with pegylated interferon and ribavirin. The purpose of this study was to explore the experiences of hepatitis C patients who had undergone therapy with pegylated interferon and ribavirin and gain an understanding of what factors contributed to completion of treatment., Method: This was a qualitative study with 21 adult hepatitis C patients purposively sampled from outpatient liver clinics of a medical university hospital in Taichung City, Taiwan. Participants had completed 6-12 months of therapy with pegylated interferon and ribavirin. Data were collected through individual, face-to-face, in-depth interviews conducted in the participants' homes from June-October 2013. Data were analysed using conventional content analysis., Results: Data analysis revealed three themes that described the strategies employed to alleviate and ease symptoms and manage the processes involved: restructuring their lifestyle, adopting a positive attitude, and seeking support., Conclusion: Hepatitis C patients face many challenges during treatment with pegylated interferon and ribavirin. These findings provide knowledge that can be used in designing effective programs to help other Hepatitis C patients manage the side effects of pegylated interferon and ribavirin therapy, complete treatment and improve quality of life.

Humor plays an essential role in human interactions. Precisely what makes something funny, however, remains elusive. While research on natural language understanding has made significant advancements in recent years, there has been little direct integration of humor research with computational models of language understanding. In this paper, we propose two information-theoretic measures-ambiguity and distinctiveness-derived from a simple model of sentence processing. We test these measures on a set of puns and regular sentences and show that they correlate significantly with human judgments of funniness. Moreover, within a set of puns, the distinctiveness measure distinguishes exceptionally funny puns from mediocre ones. Our work is the first, to our knowledge, to integrate a computational model of general language understanding and humor theory to quantitatively predict humor at a fine-grained level. We present it as an example of a framework for applying models of language processing to understand higher level linguistic and cognitive phenomena., (© 2015 The Authors. Cognitive Science published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.)

Background: Transarterial chemoembolization (TACE) and sorafenib are the therapeutic standard for intermediate and advanced stage hepatocellular carcinoma (HCC) patients respectively. High costs with adverse events (AE) of sorafenib might limit sorafenib dosage, further affecting therapeutic response. To attain greatest benefit, we evaluated the efficacy of different doses and effect of TACE during and after sorafenib discontinuation in patients representing Child-Pugh Classification Class A with venous or extra-hepatic invasion., Methods: A total 156 patients met the criteria and were divided into Groups I (n = 52) accepting 800 mg/day; II (n = 58) accepting 800 mg/day and reduced to 400 mg/day owing to AE; and III (n = 46) accepting 400 mg/day. TACE was performed during and after sorafenib discontinuation and therapeutic response bimonthly to four-monthly was rated thereafter., Results: Median duration of sorafenib treatment and patients' survival were 4.00 ± 0.45 and 7.50 ± 1.44 months in all cases; 2.50 ± 0.90 and 5.00 ± 1.10 months in Group I; 5.50 ± 1.27 and 16.50 ± 1.86 months in Group II; 4.00 ± 0.94 and 6.50 ± 2.49 months in Group III. Group II presented the best response and survival benefit (p = 0.010 and p = 0.011 respectively). Child-Pugh Classification score 5 (Hazard Ratio = 0.492, p = 0.049), absent AE (3.423, p = 0.015), tumor numbers ≤ 3 (0.313, p = 0.009), sorafenib duration ≤ 1 cycle (3.694, p = 0.004), and absent TACE (3.197, p = 0.008) significantly correlated with patient survival. TACE benefit appeared in separate and total cases during (p = 0.002, p = 0.595, p = 0.074, p = 0.002 respectively) and after discontinuation of sorafenib administration (p = 0.001, p = 0.034, p = 0.647, p = 0.001 respectively)., Conclusions: Low-dosage sorafenib not only appeared tolerable and lowered economic pressure but also provided satisfactory results. TACE benefited patient's survival during and after sorafenib discontinuation.

Background: The aim of this study was to compare the diagnostic performances of the collagen proportionate area (CPA) and liver stiffness measurement (LSM) for liver fibrosis quantification in chronic hepatitis C (CHC)., Methods: A total of 137 eligible consecutive Taiwanese patients (74 women and 63 men; age 21-80 years; median age 54 years), with CHC underwent LSM by using acoustic radiation force impulse (ARFI) elastography and an immediate percutaneous liver biopsy for METAVIR scoring. Liver tissue sections were stained using picrosirius red. Areas of the stained collagen and the tissue parenchyma were calculated in pixels. The ratio between the two areas was expressed as a CPA percentage. The result of LSM was presented as shear wave velocity (SWV)., Results: METAVIR fibrosis (F) stages were dichotomized using the CPA (%) and SWV (m/s), and the optimal cut-off values were 7.47 and 1.59 for F1 versus F2-4; 12.56 and 1.73 for F1, 2 versus F3, 4; 15.32 and 1.96 for F1-3 versus F4. To dichotomize F1 versus F2-4, the areas under receiver operating characteristic curves for the CPA was 0.9349 (95% confidence interval: 0.8943-0.9755) and for SWV was 0.8434 (0.7762-0.9105) (CPA versus SWV, P = 0.0063). For F1, 2 versus F3, 4, the CPA was 0.9436 (0.9091-0.9781); SWV was 0.8997 (0.8444-0.9551) (P = 0.1587). For F1-3 versus F4, the CPA was 0.8647 (0.7944-0.9349); SWV was 0.9036 (0.8499-0.9573) (P = 0.2585). The CPA could be predicted in a linear regression formula by using SWV and platelet count (R2 = 0.524)., Conclusions: The CPA and ARFI elastography are promising tools for liver fibrosis evaluation. The CPA was superior to ARFI elastography in the diagnosis of significant fibrosis (≥ F2). The CPA may be independent of severe necroinflammation, which may augment liver stiffness.

Background: Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited., Methods: Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain., Results: Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1., Conclusions: Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.

One of the most puzzling and important facts about communication is that people do not always mean what they say; speakers often use imprecise, exaggerated, or otherwise literally false descriptions to communicate experiences and attitudes. Here, we focus on the nonliteral interpretation of number words, in particular hyperbole (interpreting unlikely numbers as exaggerated and conveying affect) and pragmatic halo (interpreting round numbers imprecisely). We provide a computational model of number interpretation as social inference regarding the communicative goal, meaning, and affective subtext of an utterance. We show that our model predicts humans' interpretation of number words with high accuracy. Our model is the first to our knowledge to incorporate principles of communication and empirically measured background knowledge to quantitatively predict hyperbolic and pragmatic halo effects in number interpretation. This modeling framework provides a unified approach to nonliteral language understanding more generally.

Background & Aims: The relationship between pyogenic liver abscess (PLA) and gastrointestinal (GI) cancer was first reported more than 20 years ago, yet little is known about this connection. We evaluated this association in a population-based, retrospective, cohort study., Methods: Using Taiwan National Health Insurance claims data, we collected data on a cohort of 14,690 patients with PLA diagnosed from 2000 to 2007. A reference cohort of 58,760 persons without PLA (controls) was selected from the same database, frequency matched by age, sex, and index year. Both cohorts were followed up until the end of 2009, and incidences of GI cancer were calculated., Results: The incidence of GI cancer was 4.30-fold higher among patients with PLA compared with controls (10.8 vs 2.51/1000 person-years). Site-specific analysis showed that the highest incidence of colorectal cancer was among patients with PLA and diabetes mellitus, followed by patients with PLA without diabetes and controls with diabetes (9.58, 5.76, and 1.49/10,000 person-years, respectively). The PLA cohort also had a high risk of small intestine cancer (adjusted hazard ratio [aHR], 12.7; 95% confidence interval [CI], 5.79-27.7) and biliary tract cancer (aHR, 9.56; 95% CI, 6.68-13.7). Their risk of pancreatic cancer (aHR, 2.51; 95% CI, 1.68-3.76) was also significant. However, patients with PLA did not have an increased risk of gastric cancer compared with controls., Conclusions: In a population-based study, we found that the incidence of GI cancer is increased more than 4-fold among patients with PLA compared with controls. PLA might therefore be an indicator of GI cancer. Patients with PLA had the highest incidence of colorectal cancer, followed by cancers of the biliary tract, pancreas, and small intestine., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Portal hypertension and splenomegaly are common in patients with cirrhosis. However, there is limited previous in vivo research on the correlation between spleen stiffness and stages of liver fibrosis. This study aimed to evaluate the diagnostic value of spleen stiffness measurement (SSM), using acoustic radiation force impulse (ARFI) technology, for liver fibrosis assessment. Eligible patients with chronic hepatitis B or C (n = 163) underwent concurrent liver stiffness measurement (LSM), SSM and percutaneous liver biopsy. Receiver operating characteristic curves estimated the diagnostic performance of SSM, with multiple linear regression models for LSM and SSM determining the significance of explanatory factors. Results indicated significant correlation between LSM and SSM (R(2) = 0.574, P < 0.0001). Using SSM to classify METAVIR fibrosis (METAVIR F) scores, the areas under curves were 0.839 (95% CI: 0.780-0.898) for METAVIR F1 vs F2-4, 0.936 (95% CI: 0.898-0.975) for F1-2 vs F3-4 and 0.932 (95% CI: 0.893-0.971) for F1-3 vs F4, all P < 0.001. Multiple linear regression models identified BMI, spleen stiffness, METAVIR F3 and F4, serum alanine aminotransferase, international normalized ratio of prothrombin time, sodium and platelet count as significant independent explanatory factors for liver stiffness (adjusted R(2) = 0.724, P < 0.001). Male gender, liver stiffness, METAVIR F2, F3 and F4 also significantly and independently explained spleen stiffness (adjusted R(2) = 0.647, P < 0.001). ARFI SSM is potentially useful as a single or adjunct predictor of stages of liver fibrosis., (© 2012 Blackwell Publishing Ltd.)

Background: Previous research has shown variation in the effects of patient factors, including hepatic necroinflammatory activity, on liver stiffness measurement (LSM). This prospective study attempts to identify explanatory factors for LSM in patients with chronic hepatitis C (CHC) using acoustic radiation force impulse (ARFI) technology., Methods: A cohort of 127 Taiwanese patients with CHC underwent ARFI LSM and immediate percutaneous liver biopsy. This study compares the concurrent diagnostic performances of LSM and FibroTest using receiver operating characteristic (ROC) curves. Three multiple linear regression models were used to evaluate the significance of concurrent patient factors in explaining LSM., Results: To classify METAVIR fibrosis (F) stages, the areas under ROC curves (AUCs) were ARFI LSM, 0.847 (95% confidence interval (CI), 0.779-0.914) and FibroTest, 0.823 (95% CI, 0.748-0.898), for F1 versus F2-4; ARFI LSM, 0.902 (95% CI, 0.835-0.970) and FibroTest, 0.812 (95% CI, 0.735-0.888), for F1-2 versus F3-4; ARFI LSM, 0.831 (95% CI, 0.723-0.939) and FibroTest, 0.757 (95% CI, 0.648-0.865), for F1-3 versus F4. After adjusting for other demographic and biological covariates, biochemical and histological necroinflammatory factors consistently explained LSM. Factors included serum alanine aminotransferase (ALT)/upper limit of normal (ULN) categories (model R(2) = 0.661, adjusted R(2) = 0.629), ActiTest A scores (R(2) = 0.662, adjusted R(2) = 0.636), and METAVIR activity (A) grades (R(2) = 0.651, adjusted R(2) = 0.620). METAVIR F stages, body mass index, and platelet count were also independently associated with LSM. Necroinflammatory degrees, including ALT/ULN, ActiTest A scores, and METAVIR A grades, explained the false positivity of liver fibrosis staging using ARFI LSM., Conclusions: The degree of hepatic necroinflammatory activity independently and significantly exaggerated liver fibrosis evaluation using ARFI LSM. However, comparisons with concurrent FibroTest indicate that ARFI LSM may be a promising alternative, or adjunctive single indicator, for liver fibrosis evaluation in patients with CHC.

Aims: Effective cytokines can drive the commitment of naive T cells to regulate immune response after antigen-mediated activation. Aims are to elucidate the clinical role of serum IL-27 and IL-6 in the different stages of naïve hepatitis B virus (HBV)-infected patients., Methods: Samples with well-characterized clinical profiles were assessed from 395 HBV-infected patients including chronic hepatitis B (CHB) group in 291 patients, liver cirrhosis (LC) group in 57 patients, hepatocellular carcinoma (HCC) group in 47 patients. Another 139 non-HBV infected individuals were enrolled as control group (CG) including 104 with normal liver function (NF) and 35 with liver dysfunction (LD)., Results: The HBV-infected group and separated groups presented significantly higher IL-27 and IL-6 expression than the CG or subgroups of CG. In contrast to IL-27, IL-6 showed significant differences with deteriorating liver condition compared with LC or HCC with CHB groups. Furthermore, IL-6, rather than IL-27, showed significant statistical differences in patients with advanced liver disease compared with those of mild or moderate to severe liver disease and in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. The data associated with liver function, including Albumin, Bilirubin, INR, Platelet and AFP levels, were significantly correlated to IL-6 expression, but had weak correlation to IL-27 expression in HBV patients., Conclusion: Serum IL-27 can trigger immune response to prevent hepatic injury in different clinical-pathologic stages of HBV-infected patients earlier, but IL-6 may play an extremely important role to determine the liver progression., (© 2012 John Wiley & Sons A/S.)

Background: The roles remain unclear of early on-treatment quantitative serum HBsAg and hepatitis B virus (HBV) DNA levels in the prediction of a sustained response (SR) to peginterferon alfa-2a therapy in HBeAg-negative chronic hepatitis B (CHB) patients infected with genotype B or C., Aims: To determine their roles in HBeAg-negative CHB patients infected with genotype B or C., Methods: Sixty-one patients were treated with peginterferon alfa-2a for 48 weeks. Serum HBsAg levels were quantified using the Abbott Architect HBsAg QT assay throughout treatment. Multiple regression analyses were performed to identify independent predictors of SR., Results: Nineteen patients (31%) achieved SR with serum HBV DNA levels <312 copies/mL at 24 weeks post-treatment. Serum HBsAg levels at 12 (OR 31.9; 95% CI 4.8-209.6; P = 0.0003) and 24 weeks of therapy (OR 8.8; 95% CI 2.0-38.0; P = 0.0035), and HBV DNA levels at baseline (OR 7.0; 95% CI 1.3-36.2; P = 0.0203), 12 (OR 7.9; 95% CI 1.2-48.4; P = 0.0249) and 24 weeks of therapy (OR 22.3; 95% CI 2.2-224.0; P = 0.0083) were early independent predictors of SR. A serum HBsAg cut-off of 150 IU/mL at week 12 had an AUC, sensitivity, specificity and positive and negative predictive values of 0.75, 63%, 95%, 86% and 85% with respect to predicting SR respectively., Conclusions: A quantitative serum HBsAg level at 12 weeks of therapy can be used for the early prediction of SR to peginterferon therapy in HBeAg-negative CHB patients infected with genotype B or C., (© 2012 Blackwell Publishing Ltd.)

Background: Apolipoprotein A5 (APOA5) over-expression enhances lipolysis of triglyceride (TG) through stimulation of lipoprotein lipase (LPL) activity; however, an APOA5 G185C variant was found associated with hypertriglyceridemia. The aim of this study was, therefore, to explore the importance of APOA5 185GG in the activation of LPL., Methods: A fragment containing mature human APOA5 cDNA was obtained by RT-PCR and subcloned into pET-15b vector. Site-directed mutagenesis was performed to generate 19 variants. Recombinant human APOA5 wild type and variants were produced in Escherichia coli, and then activation of LPL was measured., Results: Activity of APOA5 variants on LPL-mediated 1,2-dimyristoyl-sn-glycero-3-phosphocholine hydrolysis was reduced by 17 to 74% in comparison to wild type APOA5 (P<0.0001). All variants also showed reduced activation (P<0.0001) of LPL-mediated hydrolysis of very low-density lipoprotein (VLDL); activation abilities of APOA5 variants ranged from 31 to 81% of wild-type APOA5., Conclusions: APOA5 residue 185G is very important in LPL-mediated VLDL hydrolysis, and any mutation at this residue will decrease LPL activation and concomitant TG modulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This research explores the social factors influencing hospital physicians' initial adoption of duloxetine hydrochloride, with a focus on colleague interactions. The study analyzes archival data compiled by the National Health Insurance Research Database of Taiwan to examine how the prescribing decisions made by psychiatrists' colleagues influence the likelihood of the psychiatrists' initial prescription. The results show that the adoption ratio of a physician's colleagues in a medical center is positively associated with the likelihood of a physician's adoption of the new drug. Specifically, colleague groups with similar and longer tenure as well as similar and older age have significantly positive effects. Colleague groups with the same and different gender also have positive effects. In summary, tenure and age, rather than gender, are vital sources of heterogeneous colleague interactions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)