Endoscopic variceal ligation versus propranolol for the primary prevention of oesophageal variceal bleeding in patients with hepatocellular carcinoma: an open-label, two-centre, randomised controlled trial.

OBJECTIVE: This randomised trial aimed to address whether endoscopic variceal ligation (EVL) or propranolol (PPL) is more effective at preventing initial oesophageal variceal bleeding (EVB) in patients with hepatocellular carcinoma (HCC). DESIGN: Patients with HCC and medium-to-large oesophageal varices (EVs) but without previous EVB were randomised to receive EVL (every 3-4 weeks until variceal eradication) or PPL (up to 320 mg daily) at a 1:1 ratio. Long-term follow-up data on EVB, other upper gastrointestinal bleeding (UGIB), non-bleeding liver decompensation, overall survival (OS) and adverse events (AEs) were analysed using competing risk regression. RESULTS: Between June 2011 and April 2021, 144 patients were randomised to receive EVL (n=72) or PPL (n=72). In the EVL group, 7 patients experienced EVB, and 30 died; in the PPL group, 19 patients had EVB, and 40 died. The EVL group had a lower cumulative incidence of EVB (Gray's test, p=0.009) than its counterpart, with no mortality difference (Gray's test, p=0.085). For patients with Barcelona Clinic Liver Cancer (BCLC) stage A/B, EVL was better than PPL in reducing EVB (p<0.001) and mortality (p=0.003). For patients beyond BCLC stage B, between-group outcomes were similar. Other UGIB, non-bleeding liver decompensation and AEs did not differ between groups. A competing risk regression model confirmed the prognostic value of EVL. CONCLUSION: EVL is superior to PPL in preventing initial EVB in patients with HCC. The benefits of EVL on EVB and OS may be limited to patients with BCLC stage A/B and not to those with BCLC stage C/D. TRIAL REGISTRATION NUMBER: NCT01970748.

Mac-2-Binding Protein Glycosylation Isomer to Albumin Ratio Predicts Bacterial Infections in Cirrhotic Patients.

INTRODUCTION: Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel biomarker for liver fibrosis, but little is known about its role in cirrhosis-associated clinical outcomes. This study aimed to investigate the predictive role of M2BPGi in cirrhosis-associated complications. METHODS: One hundred and forty-nine cirrhotic patients were retrospectively enrolled. Patients were followed up for 1 year, and cirrhosis-associated clinical events were recorded. Receiver operating characteristic curve (ROC) analysis was used to establish the values of the predictive models for cirrhotic outcomes, and Cox proportional hazards regression models were used to identify predictors of clinical outcomes. RESULTS: Sixty (40.3%) patients experienced cirrhosis-associated clinical events and had higher M2BPGi levels compared to those without events (8.7 vs. 5.1 cutoff index, p < 0.001). The most common cirrhosis-associated complications were bacterial infections (24.2%). On ROC analysis, M2BPGi to albumin ratio (M2BPGi/albumin) had comparable discriminant abilities for all cirrhosis-associated events (area under the ROC curve [AUC] = 0.74) compared with M2BPGi, Child-Pugh, model for end-stage liver disease, albumin-bilirubin scores, and neutrophil-to-lymphocyte ratio and was superior to M2BPGi alone for all bacterial infectious events (AUC = 0.80). Cox regression analysis revealed that the M2BPGi/albumin, but not M2BPGi alone, independently predicted all cirrhosis-associated events (hazard ratio [HR] = 1.34, p = 0.038) and all bacterial infectious events (HR = 1.51, p = 0.011) within 1 year. However, M2BPGi/albumin did not predict other cirrhotic complications and transplant-free survival. DISCUSSION/CONCLUSION: M2BPGi/albumin might serve as a potential prognostic indicator for patients with cirrhosis, particularly for predicting bacterial infections.

Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy.

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.

Minimal Fluoroscopic Catheter Ablation for Adult Patients with Paroxysmal Supraventricular Tachycardia without the Assistance of Intracardiac Echocardiography.

Background: Radiation exposure during fluoroscopic procedures increases the risk of cancer for both patients and operators. Objectives: The aim of this study was to investigate the safety and efficacy of adopting a three-dimensional electroanatomical mapping (3D EAM) system during ablation for paroxysmal supraventricular tachycardia (PSVT), without the assistance of intracardiac echocardiography (ICE), for both right- and left-chamber cardiac procedures. Methods: We retrospectively enrolled all patients with PSVT from September 2018 to December 2020. The patients were grouped according to the use of the 3D EAM system (3D-guided group, n = 102 vs. conventional group, n = 226). Results: The acute success rates were high in both groups (100% vs. 99.1%). The fluoroscopy time was significantly lower in the 3D-guided group than in the conventional group (2.4 ± 4.4 vs. 19.0 ± 10.8 min); the procedure time was significantly increased in the 3D-guided group (104.5 ± 29.9 vs. 94.0 ± 31.9 min), and this was associated with the post-electrophysiology test diagnosis after adjustment for multiple variables [standardized B coefficient (ß) 0.188]. There was no learning curve for each electrophysiologist in terms of fluoroscopy and procedure times. Conclusions: The 3D EAM system, without the assistance of ICE, was safe and effective in guiding PSVT ablation in both left- and right-chamber ablation.

Sodium-Glucose Cotransporter-2 Inhibition Exacerbates Hepatic Encephalopathy in Biliary Cirrhotic Rats.

In liver cirrhosis, hepatic inflammation and abundant portal-systemic collaterals are indicated for the development of hepatic encephalopathy. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a type of anti-diabetic agent which exert pleiotropic and anti-inflammatory effects. Diabetes and chronic liver disease often coexist, but the influence of SGLT-2 inhibition on liver cirrhosis and hepatic encephalopathy remains unknown. This study investigated the effect of SGLT-2 inhibition on cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats via common bile duct ligation. A total of two weeks of treatment with the SGLT-2 inhibitor, empagliflozin 30 mg/kg/d, was applied. The motor activities, hemodynamics, biochemistry parameters, plasma levels of vascular endothelial growth factor (VEGF), and the severity of portal-systemic collateral shunts were measured. The hepatic histopathology and protein expressions were examined. We found that empagliflozin treatment did not affect hemodynamics, liver biochemistry, or blood glucose levels in cirrhotic rats. Empagliflozin did not affect hepatic inflammation and fibrosis. The protein expression of factors related to liver injury were not influenced by empagliflozin. However, empagliflozin decreased motor activities in cirrhotic rats and increased portal-systemic collateral shunts and VEGF plasma levels. In summary, SGLT-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy, which was evidenced by a decrease in motor activity. A possible mechanism could be an increase of portal-systemic shunts related to VEGF upregulation. Therefore, empagliflozin use should be cautious in cirrhotic patients regarding the development of hepatic encephalopathy. SIGNIFICANCE STATEMENT: Sodium-glucose cotransporter-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy through increased portal-systemic shunts related to VEGF up-regulation.

α-Adrenergic blockade prevented environmental temperature reduction-induced transient portal pressure surge in cirrhotic and portal hypertensive rats.

Exposure to low temperatures has been associated with increased gastroesophageal variceal bleeding in patients with cirrhosis and portal hypertension; however, the mechanism remains unclear. Therefore, the aim of the present study was to evaluate the impact of environmental temperature reduction on portal hypertension and the role of adrenergic signaling pathways in this phenomenon. Male Sprague-Dawley rats underwent common bile duct ligation or partial portal vein ligation to induce liver cirrhosis and/or portal hypertension. The impacts of acute or chronic changes in environmental temperature were surveyed. The results showed that acute cooling from 25 to 15°C and 5°C increased the portal pressure by 10.6% and 15.5% in cirrhotic rats, and by 22.2% and 36.1% in portal hypertensive rats, respectively. The transient portal pressure surge started shortly after cooling, reached a peak within 5 min and returned to baseline after 10 min. Systemic vascular resistance, mean arterial pressure and splanchnic blood flow increased significantly at the same time. Plasma epinephrine and norepinephrine concentrations, phospholipase C, protein kinase C activity and myosin phosphorylation of peripheral arteries increased significantly in response to cooling. Phentolamine (an α-blocker) but not propranolol (a non-selective ß-blocker) dose-dependently inhibited the transient portal pressure surge and aforementioned molecular changes. In conclusion, environmental temperature reduction induced peripheral vasoconstriction via α-adrenergic pathways, and redistribution of blood flow to the splanchnic system led to a surge in transient portal pressure. Treatment with α-adrenergic receptor antagonists may exert additional benefits in controlling portal hypertension, especially on exposure to low temperatures.

Improved diffusion and storage of lithium ions via recrystallization induced conducting pathways in a Li:Ta2O5-based electrolyte for all-solid-state electrochromic devices with enhanced performance.

In this study, we have investigated the improvements in the performance of an all-solid-state complementary electrochromic device (ECD) by using the proposed high pressure treatment (HPT). The Li:Ta2O5electrolyte layer was recrystallized by the HPT utilizing pressurized CO2gas (∼200 atm) and at low temperature (<60 °C), which enhanced the coloration performance of the WO3/Li:Ta2O5/NiO complementary ECD by ∼20%. The reliability and durability of the ECD were confirmed by long term transmittance retention measurements, which indicated an improvement in the coloration performance by ∼14% upon the release of the bias voltages. The ability of the devices that were fabricated with and without the HPT process to withstand high temperature environments was also verified. In addition, photoluminescence (PL) and transmittance measurements were carried out to examine the effects of the bonding between WO3and NiO. To determine the differences in lithium-ion (Li+) injection, electrical measurements were performed by utilizing varying pulse rising speeds to confirm device characteristics. The materials were characterized in terms of their composition and structure using high-resolution transmission electron microscopy along with energy-dispersive x-ray spectroscopy. Finally, a mechanistic model has been proposed to explain the improved EC characteristics based on the amorphous to crystalline transition accompanying the HPT process.

Alteration of gut microbial composition associated with the therapeutic efficacy of fecal microbiota transplantation in Clostridium difficile infection.

BACKGROUND/PURPOSE: Clostridium difficile infection (CDI) leads to a significant cause of hospital-acquired morbidity and mortality. Fecal microbiota transplantation (FMT) is effective to treat recurrent or refractory CDI (rCDI). However, the change of microbial composition contributed by FMT and its association with treatment outcomes is not well determined in Taiwan. We aimed to investigate the efficacy of FMT and the association with microbial alteration endemically. METHODS: Twelve patients who received FMT for rCDI in Taipei Veterans General Hospital were prospectively enrolled from April 2019 to July 2020. The clinical assessments and fecal microbial analyses in comparison with fecal materials of unrelated donors were conducted before and after FMT. RESULTS: The overall success rate of FMT for rCDI was 91.7%. A prominence of Proteobacteria, Gammaproteobacteria and Enterobacteriales were observed in the feces of patients with rCDI. Increased fecal phylogenetic diversities and a significant microbial dissimilarity were provided by successful FMT compared to patients before treatment. However, the distinctness was not obvious between patients' feces at baseline and after unsuccessful FMT. Moreover, dynamic change of fecal microbial composition after FMT was observed during follow-up but did not interrupt the treatment effects of FMT. CONCLUSION: Gut dysbiosis commonly co-exists in patients with rCDI. Restoration of gut microbial communities by FMT provides a promising strategy to treat antibiotic-failed CDI, and the extent of microbial change would be related to the treatment outcomes of FMT. Besides, the effectiveness of FMT for CDI could be maintained even the gut microbiota has diverged over time.

Effects of PCSK-9 Inhibition by Alirocumab Treatments on Biliary Cirrhotic Rats.

Hyperlipidemia and oxidative stress with elevated oxidized low-density lipoprotein (ox-LDL) exacerbate hepatic inflammation and fibrosis. The plasma level of low-density lipoprotein (LDL) is controlled by proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab is a monoclonal antibody that decreases LDL via inhibiting PCSK9 function. Apart from lipid-lowering effects, alirocumab exerts anti-inflammation, anti-angiogenesis and anti-oxidant effects. This study aims to investigate the impact of alirocumab treatment on common bile duct ligation (BDL)-induced biliary cirrhotic rats. After a 4-week treatment of alirocumab, the hemodynamic data, blood biochemistry, ox-LDL level, oxidative stress markers, severity of hepatic encephalopathy and abnormal angiogenesis of BDL rats were measured and compared to the control group. BDL rats presented cirrhotic pictures and elevated ammonia, total cholesterol, LDL and ox-LDL levels compared to the control group. Alirocumab decreased plasma levels of total cholesterol, LDL, and oxidative stress markers; however, it did not affect the hemodynamics, liver and renal biochemistry, and the plasma levels of ammonia and ox-LDL. The motor activities, portal-systemic collaterals and mesenteric vascular density were not significantly different between alirocumab-treated and control groups. In addition, it did not affect hepatic inflammation, intrahepatic angiogenesis, liver fibrosis and free cholesterol accumulation in the liver of BDL rats. In conclusion, PCSK9 inhibition by alirocumab treatment ameliorates hyperlipidemia and systemic oxidative stress in biliary cirrhotic rats. However, it does not affect the plasma level of ox-LDL, intrahepatic inflammation and fibrosis. In addition, PCSK9 inhibition has a neutral effect on abnormal angiogenesis and hepatic encephalopathy in biliary cirrhotic rats.

Efficacy and safety of cervicothoracic epidural blood patch for patients with spontaneous intracranial hypotension.

BACKGROUND: Epidural blood patch (EBP) is a generally effective treatment for spontaneous intracranial hypotension (SIH) caused by cerebrospinal fluid (CSF) leakage through the spinal dura mater. It is still unclear; however, whether application near the leakage site (targeted EBP) is more effective than distal application (untargeted EBP). Further, EBP targeted to high thoracic or cervical spine levels is infrequent due to greater technical requirements and potential complications. Here, we examined the safety and efficacy of EBP applied to high thoracic or cervical spine levels. METHODS: We retrospectively reviewed the clinical and outcome data of 13 patients receiving cervical or high thoracic EBP for SIH. All patients were referred by neurologists following poor response to conservative treatment and presented with persistent headache aggravated by orthostatic changes. RESULTS: Neuroimaging confirmed CSF leakage and targeted EBP resulted in immediate pain improvement. Repeated injections provided additional improvement for patients with recurrent headache. No serious adverse events were documented during follow-up. CONCLUSION: Based on recent studies and our clinical experience, we conclude that EBP targeted to the high thoracic and cervical spine is safe and effective for early-stage SIH.

Matrix metalloproteinase-9 inhibition or deletion attenuates portal hypertension in rodents.

Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB-3CT (MMP-2 and -9 inhibitor) for 28 days in the first and second series, respectively. MMP-9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB-3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α-SMA and mesenteric eNOS protein expressions compared to wild-type BDL mice. Liver SMAD2 phosphorylation was down-regulated in all series with MMP inhibition or knock-out. In conclusion, MMP-9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP-9 may be targeted in the treatment of liver cirrhosis.

Functional dyspepsia in depression: A population-based cohort study.

BACKGROUND: Patients with functional dyspepsia (FD) are more likely to have persistent depression, yet whether depression and antidepressant treatments are associated with subsequent risk of FD remain unclear. METHODS: Using population-based insurance administrative data of Taiwan, an 11-year historic cohort study was assembled, comparing cases aged 18 and above with the diagnosis of depressive disorder, to a propensity score-matched sample of adults without depression. Incident FD as a primary diagnosis was ascertained. Hazard ratios of FD were calculated using Cox regression models by age, gender, other comorbidities, nonsteroidal anti-inflammatory medications, antidepressants and antidiabetic agents. RESULTS: A total of 20,197 people with depressive disorder and 20,197 propensity score-matched comparisons without depression were followed up. The incidence of FD was 1.7-fold greater in the depressive cohort than in comparisons (12.9 versus 7.57 per 1000 person-years), with an adjusted hazard ratio (aHR) of 2.16 (95% confidence interval (CI) 1.93~2.41). Increased risks were significant regardless of comorbidities or medication uses, the highest in the untreated depression group compared to the group without depression, with an aHR of 2.51(95% CI 2.15~2.93). CONCLUSIONS: This population-based study showed that patients with depressive disorder are at elevated risk of FD. Antidepressant treatment could reduce the risk of FD.

Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats.

Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis-related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation (BDL) in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P=0.010, 0.044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated endothelial nitric-oxide synthase (eNOS) was down-regulated. Portosystemic shunts determined by splenorenal shunt (SRS) flow decreased in both transplantation groups (P=0.037, 0.032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared with sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.

Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats.

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.

Prediction of Repeated Self-Harm in Six Months: Comparison of Traditional Psychometrics With Random Forest Algorithm.

Suicidal risk has been a significant mental health problem. However, the predictive ability for repeated self-harm (SH) has not improved over the past decades. This study thus aimed to explore a potential tool with theoretical accommodation and clinical application by employing traditional logistic regression (LR) and newly developed machine learning, random forest algorithm (RF). Starting with 89 items from six commonly used scales (i.e., proximal suicide risk factors) as preliminary predictors, both LR and RF resulted in a better solution with much fewer items in two phases of item selections and analyses, with prediction accuracy 88.6% and 79.8%, respectively. A combination with 12 selected items, named LR-12, well predicted repeated self-harm in 6-month follow-up with satisfactory performance (AUC = 0.84, 95% CI: 0.76-0.92; cut-off point by 1/2 with sensitivity 81.1% and specificity 74.0%). The psychometrically appealing LR-12 could be used as a screening scale for suicide risk assessment.

Adaptive Synaptic Memory via Lithium Ion Modulation in RRAM Devices.

Biologically plausible computing systems require fine-grain tuning of analog synaptic characteristics. In this study, lithium-doped silicate resistive random access memory with a titanium nitride (TiN) electrode mimicking biological synapses is demonstrated. Biological plausibility of this RRAM device is thought to occur due to the low ionization energy of lithium ions, which enables controllable forming and filamentary retraction spontaneously or under an applied voltage. The TiN electrode can effectively store lithium ions, a principle widely adopted from battery construction, and allows state-dependent decay to be reliably achieved. As a result, this device offers multi-bit functionality and synaptic plasticity for simulating various strengths in neuronal connections. Both short-term memory and long-term memory are emulated across dynamical timescales. Spike-timing-dependent plasticity and paired-pulse facilitation are also demonstrated. These mechanisms are capable of self-pruning to generate efficient neural networks. Time-dependent resistance decay is observed for different conductance values, which mimics both biological and artificial memory pruning and conforms to the trend of the biological brain that prunes weak synaptic connections. By faithfully emulating learning rules that exist in human's higher cortical areas from STDP to synaptic pruning, the device has the capacity to drive forward the development of highly efficient neuromorphic computing systems.

Increases in repolarization heterogeneity predict left ventricular systolic dysfunction and response to cardiac resynchronization therapy in patients with left bundle branch block.

INTRODUCTION: This study aimed to investigate the association between T-wave morphology and impaired left ventricular ejection fraction (LVEF) in patients with complete left bundle branch block (cLBBB), and the predictive value of T-wave morphology for response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: We enrolled 189 patients with cLBBB on electrocardiogram performed between January 2007 and December 2011 who underwent standard echocardiography. Repolarization parameters, including the QRS-to-T angle (TCRT), T-wave morphology dispersion (TMD), T-wave loop area (PL), and T-wave residuum (TWR), were reconstructed from digital standard 12-lead electrocardiograms by T-wave morphology analysis. CRT response was defined as ≥15% reduction in left ventricular end-systolic volume at 12 months after CRT implantation. The clinical outcome endpoint was a composite of heart failure hospitalization, heart transplantation, or death during follow up (mean, 5.8 years). On logistic regression, a higher heart rate, longer QRS duration, increased TMD, and larger TWR were all independently associated with LVEF < 40%. Among 40 patients who underwent CRT, those with a larger TMD (P = .007), larger PL (P = .025), and more negative TCRT (P = .015) had better response to CRT. A large TMD (P = .018) and large PL (P = .003) were also independent predictors of the clinical outcome endpoint. CONCLUSIONS: Increases in repolarization heterogeneity in patients with cLBBB are associated with impaired LVEF. A large TMD and large PL may be useful as additional predictors of response to CRT, improving patient selection for CRT.

A prospective, multicenter, noninterventional study in Taiwan to evaluate the safety and tolerability of lacosamide as adjunctive therapy for epilepsy in clinical practice.

RATIONALE: Lacosamide (LCM) was initially approved in Taiwan in March 2014 for use as adjunctive therapy for focal impaired awareness seizures and secondarily generalized seizures (SGS) in patients with epilepsy ≥16 years of age. The efficacy and tolerability of adjunctive LCM for the treatment of patients with focal seizures have been demonstrated in randomized, placebo-controlled trials. However, the trials do not reflect a flexible dose setting. This study (EP0063) was conducted to assess the safety and tolerability of LCM in real-world clinical practice in Taiwan. Effectiveness of LCM was also assessed as an exploratory objective. METHODS: EP0063 was a multicenter, prospective, noninterventional study with an expected observation period of 12 months ±â€¯60 days. Eligible patients were ≥16 years of age, had focal impaired awareness seizures and/or SGS (in line with approved indication in Taiwan at the time of the study), were taking at least one concomitant antiseizure medication (ASM), and had at least one seizure in the 3 months before baseline. Patients were prescribed LCM by their treating physician in the course of routine clinical practice. The primary safety variable was treatment-emergent adverse events (TEAEs) spontaneously reported to, or observed by, the treating physician. Based on safety data from previous studies of LCM and known side effects of other ASMs, certain TEAEs (including but not limited to cardiac and electrocardiogram, suicidality, and rash related terms) were analyzed separately. Effectiveness variables included Clinical Global Impression of Change (CGIC) and change in 28-day seizure frequency from baseline to 12 months (or final visit), and freedom from focal seizures. RESULTS: A total of 171 patients were treated with LCM, of whom 139 (81.3%) completed the study. The Kaplan-Meier estimated 12-month retention was 82.9%. Patients had a mean (standard deviation [SD], range) age of 38.5 (14.0, 16-77) years, and 96 (56.1%) were male. Patients were taking a mean (SD, range) of 2.8 (1.1, 1-6) ASMs at baseline. Mean (SD, range) duration of LCM treatment was 288.7 (111.9, 2-414) days, and the mean (SD, range) daily dosage of LCM was 205.0 (82.7, 50.0-505.2) mg/day. Overall, 95 (55.6%) patients reported at least one TEAE, most commonly dizziness (33 [19.3%] patients). Drug-related TEAEs were reported in 74 (43.3%) patients, and drug-related TEAEs leading to discontinuation of LCM were reported in 14 (8.2%) patients. Two (1.2%) patients died during LCM treatment, which were considered not related to LCM. Two (1.2%) patients had suicidality-related TEAEs; these TEAEs were considered either not related to LCM or the relationship was not recorded. Rash-related TEAEs were reported in five (2.9%) patients (considered LCM-related in two patients). Based on the CGIC, at 12 months (or final visit), 109 (63.7%) patients were considered to have improved, 54 (31.6%) had no change, and the remaining eight (4.7%) were minimally worse. At 12 months (or final visit), the median percentage change in focal seizure frequency was -50.0. During the first 6 months of the study, 21 (12.3%) patients were free from focal seizures; 37 (21.6%) patients were free from focal seizures in the last 6 months of the study; and 14 (8.2%) were free from focal seizures for the full 12 months of the study. CONCLUSIONS: Results of this prospective, noninterventional study suggest that adjunctive LCM was generally safe and well tolerated in this patient group in real-world practice in Taiwan. Effectiveness was also favorable, with more than 60% of patients considered to be improved by their physician at 12 months (or final visit).

Sustained effects of faculty leadership development modules for clinical instructors of core competences education in Taiwan: a four-year explanatory case study.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) core competencies (CC) in general medicine-based primary care are essential for junior medical trainees. In this country, a regular faculty development (FD) program aimed at training faculty in instructing (teaching and assessing) these CC had operated. However, leadership was not emphasized. In a new intervention module, the roles and associated responsibilities of clinical instructors to conduct, design, and lead CC-based education were emphasis. AIMS: This follow-up explanatory case study compares the effectiveness of intervention module with that of the previous regular module. METHODS: The regular group (n = 28) comprised clinical instructors who participated in the FD module during the 2013-2014 year while the intervention group (n = 28) was composed of 2015-2016 participants. Prior to the formal (hands-on) training, participants in the intervention group were asked to study the online materials of the regular module. These participants then received a 30-h hands-on training in conducting, designing, and leading skills. Finally, they prepared a 10-h reflective end-of-module presentation of their real-world practices. RESULTS: Following the training, a higher degree improvement in participants self-reported familiarity with CC education, self-confidence in their ability to deliver CC education and sustained involve CC education were noted among the intervention FD group, compared with the regular FD group. In the intervention group, senior academicians (associate and full professor) are more substantially involved in designing and leading CC-based courses than junior academicians (lecturers and assistant professors). Among non-teaching award winners of in the intervention FD group, the follow-up degree of sustained involvement in delivering, designing and leading CC-based courses was significantly higher than that of the regular group. CONCLUSIONS: Our study demonstrated that leadership training in the intervention FD modules substantially motivated clinical instructors to become leaders in CC education.

Clinical Outcomes of Complete Left Bundle Branch Block According to Strict or Conventional Definition Criteria in Patients with Normal Left Ventricular Function.

BACKGROUND: Complete left bundle branch block (cLBBB) is associated with poor outcomes in patients with heart failure (HF) but appears to have minimal effects on cardiovascular (CV) mortality in relatively healthy adults. New criteria to define strict cLBBB have been proposed. OBJECTIVES: The aim of this study was to stratify the potential risk of cLBBB according to conventional or strict criteria in patients with normal ejection fraction (EF). METHODS: Patients with cLBBB from 2010 to 2013 who underwent baseline echocardiography within 1 year and had a left ventricular ejection fraction (LVEF) > 50% were enrolled. A control group of patients without intraventricular conduction abnormalities matched for age and sex was included. Primary outcomes including CV mortality, HF admission, EF reduction of 40%, and total mortality were compared. RESULTS: A total of 137 patients with cLBBB were included, of whom 118 had strict cLBBB. The mean age was 72 ± 15 years and 56.2% were men. With a median follow-up of 4.3 years, normal LVEF patients with cLBBB but without a history of atrial fibrillation had a significantly higher risk of CV mortality (p < 0.001), EF reduction to 40% (p < 0.001), and admission for HF (p < 0.001). A similar risk of CV events was noted for the patients with conventional and strict cLBBB. CONCLUSIONS: In patients with normal EF and without a history of atrial fibrillation, the presence of cLBBB led to a greater risk of CV mortality, HF admission and EF reduction to < 40%. Strict cLBBB carries a similar risk of CV events to conventional cLBBB.