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Background and Aim Chronic hepatitis C virus (HCV) infection, long‐term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene–environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome‐wide association study (GWAS). Methods Two case‐control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results In this GWAS, we found that two SNPs were associated with HCC at P, Genome‐wide association study (GWAS) showed that five SNPs in 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and 4823173) and two in SAMM50 (rs3761472 and rs3827385), were associated with HCC in the United States.

Background: Host immune response and chronic inflammation associated with chronic hepatitis B virus (HBV) infection play a key role in the pathogenesis of liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Methods: We sampled 175 HCC, 117 cirrhotic and 165 non-cirrhotic controls from a prospective cohort study of chronically HBV-infected individuals. Multivariable polytomous logistic regression and canonical discriminant analysis (CDA) were used to compare baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to generate receiver operating characteristic curves to compare the predictive ability of marker groups. Results: After multivariable adjustment, HGF (Q4v1OR:3.74;p-trend=0.0001), SLAMF1 (Q4v1OR:4.07;p-trend=0.0001), CSF1 (Q4v1OR:3.00;p-trend=0.002), uPA (Q4v1OR:3.36;p-trend=0.002), IL-8 (Q4v1OR:2.83;p-trend=0.004), and OPG (Q4v1OR:2.44;p-trend=0.005) were all found to be associated with cirrhosis development compared to controls; these markers predicted cirrhosis with 69% accuracy. CDA analysis identified a nine marker model capable of predicting cirrhosis development with 79% accuracy. No markers were significantly different between HCC and cirrhotic participants. Conclusion: This is the first prospective study to assess immunologic markers in relation to liver disease in chronically-HBV infected individuals. While validation in required, these findings highlight the importance of immunologic processes in HBV-related cirrhosis.

Rationale: Exposure to humidifier disinfectants (HDs) can increase the risk of asthma, but the characteristics of HD-related asthma are currently unclear. Polyhexamethylene guanidine (PHMG)–contain...

Background Clinical and experimental studies suggest immunologic proteins contribute to hepatocellular carcinoma (HCC) development. Aim To evaluate circulating immunologic markers and HCC risk. Methods From a Taiwanese cohort of chronically hepatitis B virus (HBV)-infected individuals followed over time (REVEAL-HBV), we sampled 175 who developed HCC, 117 cirrhosis only, and 165 non-cirrhotic controls. From a similar Taiwanese cohort of chronically hepatitis C virus (HCV)-infected individuals (REVEAL-HCV), we included 94 individuals who developed HCC, 68 cirrhosis only and 100 non-cirrhotic controls. We compared pre-diagnostic plasma levels of 102 markers in HCC cases to non-cirrhotic and cirrhotic controls using polytomous logistic regression. A priori markers included insulin-like growth factor binding protein-3 (IGFBP-3), intercellular adhesion molecule 1 (ICAM-1) and interleukin 6 (IL-6). P-values for other markers were corrected for multiple testing (false discovery rate = 10%). Results In both REVEAL-HBV and REVEAL-HCV, increasing levels of ICAM-1 were associated with increased risk of HCC compared to non-cirrhotic controls (P-trend 0.02 and 0.001, respectively). In both REVEAL-HBV and REVEAL-HCV, two novel markers [C-X-C motif chemokine 11 (CXCL11) and hepatocyte growth factor (HGF)] were positively associated [strongest odds ratioquartile 4 versus 1 (OR) 4.55 for HGF in HCV], while two [complement factor H related 5 (CFHR5) and stem cell factor (SCF)] were negatively associated (strongest ORQ4vQ1 0.14 for SCF in HCV) with development of HCC compared to non-cirrhotic controls. Conclusions We confirmed the association for ICAM-1 and identified 4 additional proteins associated with HBV- and HCV-related HCC. These findings highlight the importance of immunologic processes in HBV- and HCV-related HCC.

Background: Exposure to traffic-related pollution is positively associated with cardiovascular diseases (CVD), but little is known about how different sources of traffic pollution (eg, gasoline-powered cars, diesel-engine vehicles) contribute to CVD. Therefore, we evaluated the association between exposure to different types of engine exhaust and CVD mortality. Methods: We recruited 12,098 participants from REVEAL-HBV cohort in Taiwan. The CVD mortality in 2000–2014 was ascertained by the Taiwan Death Certificates. Traffic pollution sources (2005–2013) were based on information provided by the Directorate General of Highway in 2005. Exposure to PM2.5 was based on a land-use regression model. We applied Cox proportional hazard models to assess the association of traffic vehicle exposure and CVD mortality. A causal mediation analysis was applied to evaluate the mediation effect of PM2.5 on the relationship between traffic and CVD mortality. Results: A total of 382 CVD mortalities were identified from 2000 to 2014. We found participants exposed to higher volumes of small car and truck exhausts had an increased CVD mortality. The adjusted hazard ratio (HR) was 1.10 for small cars (95% confidence interval [CI], 0.94–1.27; P-value = 0.23) and 1.24 for truck (95% CI, 1.03–1.51; P-value = 0.03) per one unit increment of the logarithm scale. The findings were still robust with further adjustment for different types of vehicles. A causal mediation analysis revealed PM2.5 had an over 60% mediation effect on traffic-CVD association. Conclusions: Exposure to exhaust from trucks or gasoline-powered cars is positively associated with CVD mortality, and air pollution may play a role in this association.

Background Diversity in the HLA genes might be associated with disease outcomes—the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Methods We utilized DNA from > 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus. Results Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend = 1.18 × 10–7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend = .031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio = 1.40; 95% confidence interval, 1.06–1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control. Conclusions Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.

Few studies have demonstrated an association of sarcopenia-associated body measurements with chronic diseases through a comprehensive methodology. This study aims to examine the relationship between sarcopenia-associated body measurements and chronic diseases. This is a cohort study. We recruited 316 community dwellers, including 76 patients with sarcopenia and 240 controls, and obtained their body measurements associated with sarcopenia. We collected three-dimensional anthropometric body-surface measurements from 11,158 participants during 2000–2008 and followed up this cohort for 15 years to examine the association of these measurements with the risk of chronic diseases such as hypertension, type 2 diabetes mellitus (T2DM), heart disease, and nephrotic syndrome. Univariate analysis, canonical correlation, and Cox regression analysis were performed to explore the associations. Decreased waist width, upper left arm circumference, and left thigh circumference were significantly associated with sarcopenia. The adverse body measure score (ABMS) was derived by combining significant measurements, namely left upper arm circumference, waist width, and left thigh circumference, and used to predict the risk of hypertension, T2DM, heart diseases, and nephrotic syndrome. A positive association was observed between the ABMS and chronic diseases. Considering the first quartile of the ABMS as a reference, we determined hazard ratios of 2.259, 2.495, 1.332, and 1.595 for hypertension, T2DM, heart disease, and nephrotic syndrome, respectively, in the fourth quartile. Chronic diseases were more strongly associated with the ABMS than with sarcopenia-related body measurements alone. A high ABMS, which includes higher upper arm circumference, higher waist width, and lower thigh circumference, can significantly predict chronic diseases.

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization’s goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan–Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03–1.57% among noncirrhotic males and 2.57–6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

The presented paper discusses the summary of the special issue consisting of 13 peer-reviewed papers regarding Redefinition of SI Units and Its Implications. The papers discuss state-of-the-art reviews and progress made as of now and ongoing progress regarding the redefinition of SI units at different National Metrology Institutes (NMIs) and academic/research institutes across the globe. Different methodologies adopted while investigating redefinition of SI units have been discussed and summarized by the researchers, which will serve as a pivotal point in guiding the researchers in upcoming time.

Hepatitis B virus (HBV) genotype E (HBV‐E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV‐E‐induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC−) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC− and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC− group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC− with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06‐1.10 per 1‐year increase in age), male sex (OR, 2.03; 95% CI, 1.11‐3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31‐1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. Conclusion: HBV‐E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.

Background: Clostridium difficile infection (CDI) is increasing in children. We aimed to compare the clinical characteristics between CDI and colonization and to identify the risk factors for severe diseases of CDI in children. Method: We retrospectively reviewed 124 children (1–18 years old) from 2011 to 2018. CDI was defined as diarrhea (≥3 loose stool in the past 24 h) with confirmed toxigenic strain. Colonization was defined as presence of C. difficile without clinical symptoms. Severe diseases included ileus, acute kidney injury, gastrointestinal bleeding or mortality. Patients younger than 1 year old and coinfections with other enteric pathogens were excluded. Results: Among 124 patients with C. difficile identified, 49 of them fulfilled CDI definition and 75 had C. difficile colonization. Children with CDI were more likely to present with watery (74% vs. 1%, p

Objectives The microRNAs (miRNAs) are known to be commonly expressed in papillary thyroid carcinoma. The BRAFV600E mutation is the most common genetic mutation in thyroid cancer. The main aim of this study was to determine the possible association between expression of the three miRNAs and that of BRAFV600E mutation and the clinicopathological features in papillary thyroid carcinoma. Methods This study was conducted on 51 paraffin-embedded tissues (42 thyroid cancer, 9 benign tumor) obtained from patients undergoing thyroidectomy at the Endocrine Center of OOO University Hospital. Results miRNAs expression was significantly high in patients with cervical lymph node metastasis and advanced TNM stage. In addition, miR-146b expression levels were significantly higher in papillary thyroid carcinoma patients with BRAFV600E mutation. The relative quantification (2-ΔΔCt) of miR-146b was also high among the miRNAs. Individually, the AUCs for miRNA-146b was 0.923 (cutoff value −1.97, sensitivity 88.9%, specificity 85.7%). Conclusions Especially, expression of miR-146b increased higher in PTC patients with BRAFV600E mutation. These findings showed a role of miR-146b as potential biomarkers in differentiating PTC from benign tumor and as a prognostic indicator of PTCs. Further investigation will need for the roles of miRNAs in the pathogenesis of papillary thyroid carcinomas.

Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA.Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and HE images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence.In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence.Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections.NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240draw=2rank=1 ).

AimsTo study the clinical characteristics of 2000 patients with uveitis admitted to the ophthalmology centre of the Second Hospital of Jilin University.MethodsWe retrospectively analysed 2000 patients with uveitis who were admitted to the uveitis clinic of the Second Hospital of Jilin University from July 2010 to June 2019 and analysed data on sex, onset age, onset season, anatomical classification, visual acuity and compared the results with those of other investigation studies.ResultsAmong 2000 uveitis patients, the mean age of onset was 39.9±14.9 years. There were 946 male patients (47.3%) and 1054 female patients (52.7%). By anatomical classification, panuveitis was the most common (986 cases, 49.3%), followed by anterior uveitis (786 cases, 39.3%), posterior uveitis (119 cases, 6.0%) and intermediate uveitis (109 cases, 5.5%). Among anterior uveitis cases, ankylose spondylitis (207 cases, 26.34%), Fuchs syndrome (74 cases, 9.41%) and viral uveitis (71 cases, 9.03%) were the most common. Among panuveitis cases, Vogt-Koyanagi-Harada syndrome (372 cases, 37.73%), Behcet’s disease (142 cases, 14.40%) and sympathetic ophthalmitis (33 cases, 3.35%) were the most common. Uveitis often occurs during the autumn–winter transition period. The prevalence of anterior uveitis is highest in November, and statistical analysis shows that the incidence of uveitis has a significant correlation with the month. Panuveitis has the most significant effect on vision.ConclusionPanuveitis and anterior uveitis are the most common anatomical classifications of uveitis, which has a significant impact on vision, and their incidence is related to seasonal changes.

Summary Background Spinal cord stimulation has been an established treatment for chronic back and leg pain for more than 50 years; however, outcomes are variable and unpredictable, and objective evidence of the mechanism of action is needed. A novel spinal cord stimulation system provides the first in vivo, real-time, continuous objective measure of spinal cord activation in response to therapy via recorded evoked compound action potentials (ECAPs) in patients during daily use. These ECAPs are also used to optimise programming and deliver closed-loop spinal cord stimulation by adjusting the stimulation current to maintain activation within patients' therapeutic window. We aimed to examine pain relief and the extent of spinal cord activation with ECAP-controlled closed-loop versus fixed-output, open-loop spinal cord stimulation for the treatment of chronic back and leg pain. Methods This multicentre, double-blind, parallel-arm, randomised controlled trial was done at 13 specialist clinics, academic centres, and hospitals in the USA. Patients with chronic, intractable pain of the back and legs (Visual Analog Scale [VAS] pain score ≥60 mm; Oswestry Disability Index [ODI] score 41–80) who were refractory to conservative therapy, on stable pain medications, had no previous experience with spinal cord stimulation, and were appropriate candidates for a spinal cord stimulation trial were screened. Eligible patients were randomly assigned (1:1) to receive ECAP-controlled closed-loop spinal cord stimulation (investigational group) or fixed-output, open-loop spinal cord stimulation (control group). The randomisation sequence was computer generated with permuted blocks of size 4 and 6 and stratified by site. Patients, investigators, and site staff were masked to the treatment assignment. The primary outcome was the proportion of patients with a reduction of 50% or more in overall back and leg pain with no increase in pain medications. Non-inferiority (δ=10%) followed by superiority were tested in the intention-to-treat population at 3 months (primary analysis) and 12 months (additional prespecified analysis) after the permanent implant. This study is registered with ClinicalTrials.gov , NCT02924129 , and is ongoing. Findings Between Feb 21, 2017, and Feb 20, 2018, 134 patients were enrolled and randomly assigned (67 to each treatment group). The intention-to-treat analysis comprised 125 patients at 3 months (62 in the closed-loop group and 63 in the open-loop group) and 118 patients at 12 months (59 in the closed-loop group and 59 in the open-loop group). The primary outcome was achieved in a greater proportion of patients in the closed-loop group than in the open-loop group at 3 months (51 [82·3%] of 62 patients vs 38 [60·3%] of 63 patients; difference 21·9%, 95% CI 6·6–37·3; p=0·0052) and at 12 months (49 [83·1%] of 59 patients vs 36 [61·0%] of 59 patients; difference 22·0%, 6·3–37·7; p=0·0060). We observed no differences in safety profiles between the two groups. The most frequently reported study-related adverse events in both groups were lead migration (nine [7%] patients), implantable pulse generator pocket pain (five [4%]), and muscle spasm or cramp (three [2%]). Interpretation ECAP-controlled closed-loop stimulation provided significantly greater and more clinically meaningful pain relief up to 12 months than open-loop spinal cord stimulation. Greater spinal cord activation seen in the closed-loop group suggests a mechanistic explanation for the superior results, which aligns with the putative mechanism of action for spinal cord stimulation and warrants further investigation. Funding Saluda Medical.

Magnetic resonance image-guided high-intensity focused ultrasound (MRgFUS)-based thermal ablation of the ventral intermediate nucleus of the thalamus (VIM) is a minimally invasive treatment modality for essential tremor (ET). Dentato-rubro-thalamic tractography (DRTT) is becoming increasingly popular for direct targeting of the presumed VIM ablation focus. It is currently unclear if patients with implanted pulse generators (IPGs) can safely undergo MRgFUS ablation and reliably acquire DRTT suitable for direct targeting. We present an 80-year-old male with a spinal cord stimulator (SCS) and an 88-year-old male with a cardiac pacemaker who both underwent MRgFUS for medically refractory ET. Clinical outcomes were measured using the Clinical Rating Scale for Tremor (CRST). DRTT was successfully created and imaging parameter adjustments did not result in any delay in procedural time in either case. In the first case, 7 therapeutic sonications were delivered. The patient improved immediately and durably with a 90% CRST-disability improvement at 6-week follow-up. In our second case, 6 therapeutic sonications were delivered with durable, 75% CRST-disability improvement at 6 weeks. These are the first cases of MRgFUS thalamotomy in patients with IPGs. DRTT targeting and MRgFUS-based thermal ablation can be safely performed in these patients using a 1.5-T MRI.

BackgroundUse of humidifier disinfectants (HD) at home leads to chemical airborne exposure, causing HD associated lung injury (HDLI) with high mortality. However, the lung function in children diagnosed with HDLI is not well studied. We investigated the effect of HD exposure on lung function, prognosis, and exposure characteristics associated with the lung function phenotype in children.MethodsEighty-one children diagnosed with HDLI in a nationwide cohort were tested for spirometry and diffusing capacity of the lung for carbon monoxide (DLco) from July 2013 and followed up with at five time points over 2 years. The results were compared with 122 children without HD exposure as controls. Home investigation and questionnaire analysis were conducted to assess HD inhalation exposure.ResultsHDLI survivor’s mean percent of predicted forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and corrected DLco were significantly lower compared with the control group. On longitudinal assessment, FVC was within the normal range, but flattened, and spirometry showed a predominantly restrictive pattern. Corrected DLco did not normalize above 80% despite increasing age. The persistently low phenotype of lung function was associated with initial exposure age, especially less than 12 months of age. Higher density HD exposure during sleep and close distance between the bed and the humidifier were significantly associated with persistently low corrected DLco.ConclusionsHD exposure affects prolonged decrement in lung function, especially DLco, particularly among children who are exposed within the first year of life. These results suggested that early-life HD exposure determines long-term prognosis of lung function in children.

Objective: Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD) that has shown variable efficacy. This report describes long-term outcomes of DBS for TRD. Methods: A consecutive series of 8 patients with TRD were implanted with ventral capsule/ventral striatum (VC/VS) DBS systems as part of the Reclaim clinical trial. Outcomes from 2009 to 2020 were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Demographic information, MADRS scores, and data on adverse events were collected via retrospective chart review. MADRS scores were integrated over time using an area-under-the-curve technique. Results: This cohort of patients had severe TRD-all had failed trials of ECT, and all had failed a minimum of 4 adequate medication trials. Mean ± SD follow-up for patients who continued to receive stimulation was 11.0 ± 0.4 years (7.8 ± 4.3 years for the entire cohort). At last follow-up, mean improvement in MADRS scores was 44.9% ± 42.7%. Response (≥ 50% improvement) and remission (MADRS score ≤ 10) rates at last follow-up were 50% and 25%, respectively. Two patients discontinued stimulation due to lack of efficacy, and another patient committed suicide after stimulation was discontinued due to recurrent mania. The majority of the cohort (63%) continued to receive stimulation through the end of the study. Conclusions: While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this small open-label study demonstrates that some patients achieve meaningful and sustained clinical benefit. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including patient selection, integrative outcome measures, and long-term observation is essential for future trial design. Trial Registration: ClinicalTrials.gov identifier: NCT00837486.

Background The prevalence of atopic dermatitis (AD) is increasing worldwide. Prenatal particulate matter with an aerodynamic diameter

Background Atrial fibrillation/atrial flutter (AF/AFL) hospitalisations are common, however, little is known about the long-term outcomes of these episodes. Objective To examine the incidence of mortality, all-cause and cause-specific re-hospitalisations at up to 8 years after a hospitalisation for AF/AFL. Methods Unique patients hospitalised with a primary diagnosis of AF/AFL from 2008–2015 were identified using nation-wide hospitalisation data from Australia and New Zealand. All-cause mortality was the primary outcome. Secondary endpoints included all-cause and cause-specific re-hospitalisations. Results were reported as incident rate per 100 patient-years. Results We included 265,737 patients (mean age 69.9±13.9y, female 45.2%, elective 28.7%). The median length of stay was 1 day (Interquartile range [IQR] 0–4 days) and the median CHA2DS2-VASc score was 2 (IQR 1–2). During the index hospitalisation, 9,837 (3.7%) patients underwent catheter or surgical ablation and 52,634 (19.8%) underwent cardioversion. During the median follow-up time of 3.4 years (range 0–8.0 years), 53,669 patients died (incident rate of 5.7/100 patient-years) with a survival probability gradually decreasing from 92.8% (95% CI 92.7–92.9%) at 1-year to 65.4% (95% CI 64.9–65.8%) at 8-years post-discharge (Table 1 and Figure 1). All-cause re-hospitalisations occurred in 210,118 patients (incident rate of 22.2/100 patient-years) with a rehospitalisation-free survival probability of 7.1% (95% CI 6.9—7.3%) at the end of follow-up. Unplanned re-hospitalisations occurred more frequently than planned episodes (incident rate of 17.2 vs. 16.6/100 patient-years respectively). AF/AFL accounted for 25.1% of all-cause re-hospitalisations (incident rate of 8.9/100 patient-years) and the probability of freedom from re-hospitalisations for AF/AFL was 55.4% (95% CI 55.0–55.8%) at 8-years. Incident rates of re-hospitalisations for catheter ablation (1.5/100 patient-years), stroke (1.6/100 patient-years), heart failure (2.7/100 patient-years), and acute myocardial infarction (1.0/100 patient-years) were low. In subgroup analyses, worse survival was observed in female patients, older age groups, patients with comorbid heart failure, hypertension, diabetes, and those who did not undergo ablation during the index hospitalisation. Conclusion Nearly two-thirds of patients were surviving by 8-years following an AF/AFL hospitalisation with a low rate of re-hospitalisations for stroke, heart failure, and myocardial infarction. However, re-hospitalisations for recurrent atrial arrhythmia were common. Efforts to reduce re-hospitalisations, especially unplanned encounters, are required to improve patient outcomes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of Australia

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.

PURPOSE During magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for refractory tremor, high temperatures must be achieved and sustained for tissue necrosis. We assessed the impact of both patient-specific as well as procedure-related factors on the efficiency of acoustic energy transfer, or heating efficiency (HE). METHODS Retrospective analysis of 92 consecutive patients (857 sonications) with essential tremor or tremor-dominant Parkinson's disease treated at a single institution. Temperature elevations at the target were measured for each sonication with MR thermometry. HE of each sonication was defined as the ratio of peak temperature elevation and the delivered energy. HE was analyzed with respect to patient skull features (area, thickness, skull density ratio [SDR]), computed from CT scans, as well as demographic and clinical variables (age, sex, diagnosis, and duration of symptoms). RESULTS Across the full range of sonication energies that can be delivered with current devices (up to 36 kJ), average sonication HE was diminished in patients with lower SDR. In individual subjects, there was a progressive loss in HE as sonication energy was titrated up throughout the course of treatment, with a more rapid decline in patients with higher SDR. This energy-dependent loss in HE was not related to procedural factors, namely, the number of previous sonications, or the cumulative energy deposited during previous sonications. In contrast to SDR, neither skull area nor thickness was an independent predictor of average HE or the rate of its decline with increasing energies. In 11% of patients, all of whom with SDR

Multilevel lateral interbody fusion is an acceptable surgical technique in patients with severe degenerative adult spinal deformity (ASD). The current standard-of-care in spine surgery includes the use of patient reported outcome measures (PROMs) to assess post-operative improvement. Objective activity data during the peri-operative period may provide supplementary information for patients recovering from ASD surgery. In this report, we use smartphone-based activity data as an objective outcome measure for a patient who underwent a two-stage operation for ASD corrective surgery: lateral osteotomy and lumbar interbody fusion with posterior column release. An 82-year-old male presented with intractable back pain secondary to severe thoracolumbar scoliotic deformity (Lenke 5BN). Pre-operative images demonstrated the presence of bridging osteophytes over the left lateral aspect of L2-5 disc spaces and over the apex of the lumbar curvature, with significant neuroforaminal stenosis. Surgical correction was completed in two stages: (1) left-sided lateral osteotomy using anterior-to-psoas approach (ATP) in a right lateral decubitus position, and (2) multilevel Ponte osteotomies and instrumented fusion from T10-pelvis. Post-operative radiography showed correction to scoliotic deformity and sagittal misalignment. The patient had developed seroma and wound dehiscence, which was evacuated on post-operative day 11. At 14-month follow-up, the patient reported significant improvement in pain symptoms, corroborated by patient reported outcome measures. To further quantify and assess patient recovery, smartphone-based patient activity data was collected and analyzed to serve as a proxy for the patient's functional improvement. The patient's walking steps-per-day was compared pre- and post-operatively. The patient's pre-operative baseline was 223 steps/day; the patient's activity during immediate post-operative recovery dropped to 179 steps/day; the patient returned to baseline activity levels approximately 3 months after surgery, reaching an average of 216 steps/day. In conclusion, we found that lateral osteotomy through an ATP approach is a powerful tool to restore normal spine alignment and can be successfully performed using anatomic landmarks. Additionally, smartphone-based mobility data can assess pre-operative activity level and allow for remote patient monitoring beyond routine follow-up schedule.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD.

Background: Hepatitis C virus (HCV) in diffuse large B-cell lymphoma (DLBCL) is associated with a higher prevalence and distinctive clinical characteristics and outcomes. Methods: A retrospective analysis of adult DLBCL patients from 2011 to 2015 was studied. Results: A total of 206 adult DLBCL were enrolled with 22 (10.7%) HCV-positive patients. Compared to HCV-negative patients, the HCV-positive group had a poor performance status (p = 0.011), lower platelet count (p = 0.029), and higher spleen and liver involvement incidences (liver involvement, p = 0.027, spleen involvement, p = 0.026), and they received fewer cycles of chemotherapy significantly due to morbidity and mortality (p = 0.048). Overall survival was shorter in HCV-positive DLBCL (25.3 months in HCV-positive vs. not reached (NR), p = 0.049). With multivariate analysis, poor performance status (p &lt, 0.001), advanced stage (p &lt, 0.001), less chemotherapy cycles (p &lt, 0.001), and the presence of liver toxicity (p = 0.001) contributed to poor OS in DLBCL. Among HCV-positive DLBCL, the severity of liver fibrosis was the main risk factor related to death. Conclusion: Inferior survival of HCV-positive DLBCL was observed and associated with poor performance status, higher numbers of complications, and intolerance of treatment, leading to fewer therapy. Therefore, anti-HCV therapy, such as direct-acting antiviral agents, might benefit these patients in the future.

ALT ≥ 80 U/L and HBV DNA ≥ 2000 IU/ml are treatment criteria of APASL guidelines for chronic hepatitis B (CHB) patients. The need of antiviral therapy for patients in gray zone (ALT

Breast cancer (BC) incidence is increasing around the globe, including in Taiwan, though the cause of the increasing incidence is less clear. We followed up 11,296 Taiwanese females who did not have BC at baseline, and ascertained new invasive BC (N = 351) through data linkage to the National Cancer Registry from 1991 to 2018 to examine whether reproductive, lifestyle and environmental risk factors including polycyclic aromatic hydrocarbons (PAH) were associated with BC risk. We conducted a nested case–control study using baseline blood available from a total of 305 women with BC and 598 women without BC matched on time in cohort. We examined the association of PAH-albumin adducts and BC risk using conditional logistic regression models. Age at menarche (HR 0.6 (95% CI 0.5–0.9) for ≥ 15 vs.

Aim: This case–control study aimed to investigate the interrelations of body measurements and selected biomarkers in type 2 diabetes mellitus (T2DM).Methods: We recruited 98 patients with T2DM and 98 controls from 2016 to 2018 in Taiwan. Body measurements were obtained using a three-dimensional body surface scanning system. Four biomarkers related to insulin resistance, adipokines, and inflammation were assayed. A multiple logistic regression model was used to perform multivariable analyses.Results: Four body measurements, namely waist circumference (odds ratio, OR = 1.073; 95% confidence interval, CI = 1.017–1.133), forearm circumference (OR = 1.227; 95% CI = 1.002–1.501), thigh circumference (OR = 0.841; 95% CI = 0.73–0.969), and calf circumference (OR = 1.25; 95% CI = 1.076–1.451), were significantly associated with T2DM. Leptin (OR = 1.09; 95% CI = 1.036–1.146) and adiponectin (OR = 0.982; 95% CI = 0.967–0.997) were significantly associated with T2DM. Six body measurement combinations, namely body mass index, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, forearm-to-thigh ratio, and calf-to-thigh ratio (CTR), were significantly associated with T2DM. CTR had the strongest linear association with T2DM. Moderating effects of significant biomarkers, namely leptin and adiponectin, were observed. Participants with high leptin-to-adiponectin ratios and in the fourth CTR quartile were 162.2 times more prone to develop T2DM.Conclusions: We concluded that a combination of leptin and adiponectin modulated the strength of the association between body measurements and T2DM while providing clues for high-risk group identification and mechanistic conjectures of preventing T2DM.

Accurate risk prediction for hepatocellular carcinoma (HCC) among patients with chronic hepatitis B (CHB) may guide treatment strategies including initiation of antiviral therapy and also inform implementation of HCC surveillance. There have been 26 risk scores developed to predict HCC in CHB patients with (n = 14) or without (n = 12) receiving antiviral treatment; all of them invariably include age in the scoring formula. Virological biomarkers of replicative activities (i.e., hepatitis B virus DNA level or hepatitis B envelope antigen status) are frequently included in the scores derived from patients with untreated CHB, whereas measurements that gauge severity of liver fibrosis and/or reserve of hepatic function (i.e., cirrhosis diagnosis, liver stiffness measurement, platelet count, or albumin) are essential components in the scores developed from treated patients. External validation is a prerequisite for clinical application but not yet performed for all scores. For the future, higher predictive accuracy may be achieved with machine learning based on more comprehensive data.

Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant [KD]: 1.95 × 10(–10) ± 0.21 × 10(–10) M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti–SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti–SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14(+) cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027–1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.

Background Cure rates of hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) for patients with active and inactive hepatocellular carcinoma (HCC) may differ, but well-controlled studies are limited. We aimed to evaluate DAA outcomes in a large East Asian HCV/HCC population compared with HCV/non-HCC patients. Methods Using data from the Real-World Evidence from the Asia Liver Consortium (REAL-C) registry (Hong Kong, Japan, South Korea, and Taiwan), we used propensity score matching (PSM) to match HCC and non-HCC (1:1) groups for age, sex, cirrhosis, prior treatment, HCV genotype, treatment regimen, baseline platelet count, HCV RNA, total bilirubin, alanine aminotransferase, and albumin levels to evaluate DAA treatment outcomes in a large population of HCV/HCC compared with HCV/non-HCC patients. Results We included 6081 patients (HCC, n = 465; non-HCC, n = 5 616) treated with interferon-free DAAs. PSM of the entire study population yielded 436 matched pairs with similar baseline characteristics. There was no statistically significant difference in the overall SVR rate of HCC (92.7%) and non-HCC (95.0%) groups. Rates of treatment discontinuation, adverse effects, and death were also similar between HCC and non-HCC groups. Among patients with HCC, those with active HCC had a lower SVR than inactive HCC cases (85.5% vs 93.7%; P = .03). On multivariable analysis, active HCC, but not inactive HCC, was significantly associated with lower SVR (OR, 0.28; P = .01) when compared with non-HCC. Conclusions Active HCC but not inactive HCC was independently associated with lower SVR compared with non-HCC patients undergoing DAA therapy, although cure rate was still relatively high (85%) in active HCC patients.

INTRODUCTION:It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).METHODS:This retrospective cohort study analyzed an international consortium that encompas

In a circular economy, an enterprise should pursue long-term business and economic opportunities for environmental and societal benefits. One of the critical issues in industries with a circular economy is the development of the reverse logistics system for semi-finished product packaging and shipping. There are several challenges while designing this system; for example, the use of reusable semi-finished product shipping boxes and a logistics system for shipping the products and returning these boxes. In this research, under the context of global manufacturing, a logistics system for reusable semi-finished product packaging in LCD panel industry is studied. The cost models of semi-finished product packaging in a traditional logistics mode and a green logistics mode are introduced. In the green logistics mode, the shipping boxes are redesigned to be reusable and capable of accommodating multiple various-sized panels simultaneously. The cost models involve material cost, shipping, and recycling cost. The economic performances of the traditional and green logistics modes at different package recycling levels are analyzed. The results show that the total cost of the green logistics mode is beneficial, always lower than that of the traditional logistics mode, even at a low recycling rate (30%). In addition, in the green mode, the material cost of shipping boxes is the most influential sector of the total cost.

BackgroundTo compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin.MethodsWe conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications.ResultsWe identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95).ConclusionThe risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

One-third of the global hepatitis C virus (HCV) burden is found in Asia. Real-world data from diverse East Asian cohorts remain limited. This study addressed the real-world status of direct-acting antiviral (DAA) therapy among patients from East Asia. Chronic hepatitis C (CHC) patients from clinical sites in Japan, Taiwan, South Korea, and Hong Kong were recruited in the REAL-C registry, an observational chart review registry. The primary outcome was sustained virologic response (SVR12, HCV RNA PCR

Background: Mycoplasma pneumoniae is a common pathogen for pneumonia in children, especially in the post-pneumococcal conjugate vaccination era. Though self-limited disease was found in the majority of the patients, severe diseases occurred occasionally. The emergence of macrolide resistance was reported worldwide. It is important to delineate whether macrolide resistance or delayed treatment affects outcome. Methods: We retrospectively collected pediatric patients with M. pneumoniae infection confirmed by positive PCR in a tertiary medical center in Taiwan from 2010 to 2017. Patients’ clinical characteristics, bacterial load, macrolide resistance and treatment outcome were analyzed. Results: Among 471 children with positive M. pneumoniae PCR, 95% were diagnosed with pneumonia. Seventeen percent of patients had extrapulmonary complications, and 1.5% had respiratory failure. Delayed treatment was associated with prolonged fever after appropriate treatment, fulminant disease, and extrapulmonary manifestations (p

Although bronchial responsiveness (BR) is usually categorized as normal or hyperresponsive to aid the diagnosis of asthma, it exists on a continuous spectrum, not in a dichotomous manner. We aimed to evaluate the distribution profile of BR in a general population of 7-year-olds.In 2015, 7-year-old Korean children from a nationwide birth cohort study visited regional study hospitals for skin prick test, standard spirometry, and bronchial provocation to establish reference values for the general population. Their BR degrees were categorized into five ordered groups: hyperresponsive BRs were classified into group 1 (provocative concentration (PC) of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1], PC20 of4 mg/mL) and group 2 (PC20 of ≥4 mg/mL and16 mg/mL), and nonresponsive BRs were categorized into group 3 (final FEV1 percentage fall after inhaling 16 mg/mL of methacholine [FEV1%fall] of15% and ≤20%), group 4 (FEV1%fall of10% and ≤15%), and group 5 (FEV1%fall of ≤10%).In total, 559 subjects finished all tests reliably. Groups 1 and 2 comprised 10.0% and 15.7% of the total population, respectively. Groups 3, 4, and 5 comprised 14.7%, 18.4%, and 41.1%, respectively. As the group number increased, the proportion of those with recent wheezing and those with indoor allergen sensitization decreased (P for trend = 0.001 and P for trend 0.001, respectively), and the baseline FEV1/FVC increased (P for trend 0.001) CONCLUSION: BR of the 7-year-olds in the general population, while showing a wide distribution across phenotypes, is associated with allergic symptoms, negatively correlated with baseline lung function and positively correlated with indoor allergen sensitization.

Subaxial cervical spine injuries may be treated with either nonoperative stabilization or surgical fixation. The subaxial injury classification (SLIC) provides 1 method for suggesting the degree of necessity for surgery. In the current study, we examined if the SLIC score, or other preoperative metrics, can predict failure of nonoperative management.We performed a retrospective chart review to identify patients who presented with acute, nonpenetrating, subaxial cervical spine injury within our health system between 2007 and 2016. Patient demographics, medical comorbidities, injuries, and treatments were collected. Logistic regression analysis was used to determine potential predictors of failure of nonoperative management.During the study period, 40 patients met the inclusion criteria. A small subset of patients failed nonoperative management (n = 5, 12.5%). The mean SLIC score was 3.9 ± 1.9; however, 14 (35%) patients had scores4. Neither total SLIC score (P = 0.68) nor SLIC subscores (morphology [P = 0.96], discoligamentous complex [P = 0.83], neurologic status [P = 0.60]) predicted failure of nonoperative treatment. Time to evaluation/treatment did predict failure of nonoperative management. Evaluation within 8 hours of injury was a negative predictor of failure (odds ratio = 0.03, P = 0.001) and evaluation 24 hours or more after injury was a positive predictor of failure (odds ratio = 66.00, P0.001). We created a modified SLIC score on the basis of these findings, which significantly predicted failure of nonoperative management (P = 0.044).Management of subaxial spine injuries is complex. In our cohort, SLIC scoring did not adequately predict odds of failure of nonoperative management. Time to evaluation, however, did. We created a modified SLIC score that significantly predicted failure of nonoperative management.

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included. Keywords: Chronic hepatitis B, Pegylated interferon alfa, Entecavir, Tenofovir disoproxil fumarate, Tenofovir alafenamide

Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk.This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance.At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P.0001) and adjusted hazard ratio for HCC of 14.1 (P = .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P = .005) was associated independently with HCC development.Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Neuromorphic computing with intelligent power-efficient data processing has become an innovative technology to overcome the performance bottleneck of traditional von Neumann-type computing architecture. As an essential element to construct a neuromorphic system, a kind of artificial synapse with high technology maturity, rich functionality, and homeostatic regulation based on simple and robust mechanism is in urgent demand. Here, we propose the dual-gate low-temperature polycrystalline silicon thin film transistor to be a prospective candidate for scalable biomimetic synapse. Fundamental bilingual homosynaptic behaviors, including excitatory postsynaptic current, inhibitory postsynaptic current, and paired pulse facilitation, have been successfully emulated based on the charge trapping mechanism under electric pulse stimulation at either top or bottom gates. The strength of the top-gated induced excitatory and inhibitory responses can be dynamically modulated by the electrical biases at the modulatory bot...

Background Tarlov cysts (TC) are commonly found spinal perineural cysts. Symptomatic TCs are rare, however, and there is no consensus on their pathogenesis and optimal management. Objective To characterize cyst growth in patients with symptomatic TCs. Methods This is a retrospective cohort study of 28 subjects, evaluated for symptomatic TCs (2011-2017). Each of the subjects had multiple magnetic resonance imaging (MRIs) across time and was included in a natural history analysis. Results A total of 42 TCs were identified across the 28 subjects, of which 7 cysts (17%) across 5 subjects demonstrated growth. Across a mean follow-up of 4.7 ± 1.8 years, TCs grew at a relative rate of 2.9 ± 2.6% in the anteroposterior, 4.3 ± 3.8% in the craniocaudal, and 1.4 ± 1.4% in the transverse dimensions per year. None of the cysts decreased in size between successive MRIs. Symptoms of cerebrospinal fluid (CSF) hypotension (positional headaches) were positive predictors of prior cyst growth on logistic regression (P = 0.02, odds ratio = 10). A total of 2 of the 5 subjects were initially asymptomatic from their TCs, and developed symptoms during the period of cyst growth, whereas 2 others experienced worsening of their symptoms during cyst growth. Conclusion We report on the growth of TCs, which is consistent with a widely-held theory that hydrostatic and pulsatile forces of CSF along with a ball-valve phenomenon allow for continuous dilation of TCs.

Background: Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroi...

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs 15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p 15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.