Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Objective: Predicting disease relapse and early intervention could reduce symptom severity. We attempted to identify potential indicators that predict the duration to next admission for an acute affective episode in patients with bipolar I disorder. Methods: We mathematically defined the duration to next psychiatric admission and performed single-variate regressions using historical data of 101 patients with bipolar I disorder to screen for potential variables for further multivariate regressions. Results: Age of onset, total psychiatric admissions, length of lithium use, and carbamazepine use during the psychiatric hospitalization contributed to the next psychiatric admission duration positively. The all-in-one found that hyperlipidemia during the psychiatric hospitalization demonstrated a negative contribution to the duration to next psychiatric admission; the last duration to psychiatric admission, lithium and carbamazepine uses during the psychiatric hospitalization, and heart rate on the discharge day positively contributed to the duration to next admission. Conclusion We identified essential variables that may predict the duration of bipolar I patients’ next psychiatric admission. The correlation of a faster heartbeat and a normal lipid profile in delaying the next onset highlights the importance of managing these parameters when treating bipolar I disorder.

With increasing use, the incidence of adverse events associated with sugammadex, a neuromuscular blockade reverser, is increasing. This study aimed to identify and analyze cases of adverse events caused by sugammadex reported in Korean population. Methods: Out of a total of 12 cases detected using various keywords in the Korean Journal of Anesthesia, Anesthesia and Pain Medicine (Seoul), KoreaMed, PubMed, EMBASE, Web of Science, and The Cochrane Library-CENTRAL from 2013 to December 2020, 10 cases directly associated with sugammadex were selected. Results: Adverse events included five cases of anaphylaxis, one case of cardiac arrest, one case of profound bradycardia, one case of negative pressure pulmonary edema, and two cases of incomplete recovery. Three patients had American Society of Anesthesiologists physical status ≥ 3, two had emergency surgery, and two had a history of allergic reaction. Neuromuscular monitoring was applied in nine cases. The average dose of sugammadex was 2.87 mg/kg, and there were six cases in which one full vial was used, regardless of the state of neuromuscular recovery. Sugammadex was administered immediately after surgery in two cases, at train of four (TOF) 0 in four cases, at TOF 3 in one case, and after evaluation of the clinical signs only with no neuromuscular monitoring in one case. Conclusions: Even with neuromuscular monitoring, an excessive dose of sugammadex was observed. Given that adverse events tend to occur within 10 min of administration, continuous monitoring is important even after administration.

The number of patients requiring intensive care has surged since the outbreak of the SARS-CoV-2 virus. This had rendered the intensive care unit (ICU) a huge challenge not only to provide care for the existing patients but also to support the COVID-19 patients. The ICU was restructured to ensure strict adherence to the infection control guidelines. The aspects of change in the ICU had been ranging from the clinical operation, medication equipment and facilities, medications supply, and staffing. Strategies required upon implementation of change include having contingency plans, being innovative, getting the collaboration from other ICUs, exchanging information, getting support from the health policymakers, and ensuring the safety of the healthcare workers. This article aimed to share the experience of challenges and strategies in managing an ICU for the COVID-19 pandemic in Malaysia.

INTRODUCTION: Nursing home (NH) residents with out-of-hospital cardiac arrests (OHCA) have unique resuscitation priorities. This study aimed to describe OHCA characteristics in NH residents and identify independent predictors of survival. MATERIALS AND METHODS: OHCA cases between 2010-16 in the Pan-Asian Resuscitation Outcomes Study were retrospectively analysed. Patients aged <18 years old and non-emergency cases were excluded. Primary outcome was survival at discharge or 30 days. Good neurological outcome was defined as a cerebral performance score between 1-2. RESULTS: A total of 12,112 cases were included. Of these, 449 (3.7%) were NH residents who were older (median age 79 years, range 69-87 years) and more likely to have a history of stroke, heart and respiratory diseases. Fewer NH OHCA had presumed cardiac aetiology (62% vs 70%, <0.01) and initial shockable rhythm (8.9% vs 18%, <0.01), but had higher incidence of bystander cardiopulmonary resuscitation (74% vs 43%, <0.01) and defibrillator use (8.5% vs 2.8%, <0.01). Non-NH (2.8%) residents had better neurological outcomes than NH (0.9%) residents ( <0.05). Factors associated with survival for cardiac aetiology included age <65 years old, witnessed arrest, bystander defibrillator use and initial shockable rhythm; for non-cardiac aetiology, these included witnessed arrest (adjusted odds ratio [AOR] 3.8, <0.001) and initial shockable rhythm (AOR 5.7, <0.001). CONCLUSION Neurological outcomes were poorer in NH survivors of OHCA. These findings should inform health policies on termination of resuscitation, advance care directives and do-not-resuscitate orders in this population.

BACKGROUND: This study investigated whether xenotransplantation of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism. METHODS: Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies. RESULTS: WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-b1-stimulation in Smad2 phosphorylation and RhoA upregulation. CONCLUSION These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.

BACKGROUND: This study investigated whether xenotransplantation of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism. METHODS: Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies. RESULTS: WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-b1-stimulation in Smad2 phosphorylation and RhoA upregulation. CONCLUSION These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.

This study investigated the regulatory role of nerve growth factor (NGF) in sirtuin 1 (SIRT1) expression in cholestatic livers. We evaluated the expression of NGF and its cognate receptors in human livers with hepatolithiasis and the effects of NGF therapy on liver injury and hepatic SIRT1 expression in a bile duct ligation (BDL) mouse model. Histopathological and molecular analyses showed that the hepatocytes of human diseased livers expressed NGF, proNGF (a precursor of NGF), TrkA and p75NTR, whereas only p75NTR was upregulated in hepatolithiasis, compared with non-hepatolithiasis livers. In the BDL model without NGF therapy, p75NTR, but not TrkA antagonism, significantly deteriorated BDL-induced liver injury. By contrast, the hepatoprotective effect of NGF was abrogated only by TrkA and not by p75NTR antagonism in animals receiving NGF therapy. Intriguingly, a positive correlation between hepatic SIRT1 and NGF expression was found in human livers. In vitro studies demonstrated that NGF upregulated SIRT1 expression in mouse livers and human Huh-7 and rodent hepatocytes. Both NGF and proNGF induced protective effects against hydrogen peroxide-induced cytotoxicity in Huh-7 cells, whereas inhibition of TrkA and p75NTR activity prevented oxidative cell death. Mechanistically, NGF, but not proNGF, upregulated SIRT1 expression in human Huh-7 and rodent hepatocytes via nuclear factor (NF)-κB activity, whereas NGF-induced phosphoinositide-3 kinase/Akt, extracellular signal–regulated kinase and NF-κB signaling and SIRT1 activity were involved in its hepatoprotective effects against oxidative injury. These findings suggest that pharmacological manipulation of the NGF/SIRT1 axis might serve as a novel approach for the treatment of cholestatic disease.
Animals ; Bile Ducts ; Cell Death ; Cholestasis ; Hepatocytes ; Humans ; Hydrogen ; In Vitro Techniques ; Ligation ; Liver ; Mice ; Nerve Growth Factor ; Phosphotransferases ; Rodentia ; Sirtuin 1

BACKGROUND: Early extubation after cardiovascular surgery has some clinical advantages, including reduced hospitalization costs. Herein, we review the results of ultra-fast-track (UFT) extubation, which refers to extubation performed on the operating table just after the operation, or within 1–2 hours after surgery, in patients with congenital cardiac disease. METHODS: We performed UFT extubation in patients (n=72) with a relatively simple congenital cardiac defect or who underwent a simple operation starting in September 2016. To evaluate the feasibility and effectiveness of our recently introduced UFT extubation strategy, we retrospectively reviewed 195 patients who underwent similar operations for similar diseases from September 2015 to September 2017, including the 1-year periods immediately before and after the introduction of the UFT extubation protocol. Propensity scores were used to assess the effects of UFT extubation on length of stay (LOS) in the intensive care unit (ICU), hospital LOS, and medical costs. RESULTS: After propensity-score matching using logistic regression analysis, 47 patients were matched in each group. The mean ICU LOS (16.3±28.6 [UFT] vs. 28.0±16.8 [non-UFT] hours, p=0.018) was significantly shorter in the UFT group. The total medical costs (182.6±3.5 [UFT] vs. 187.1±55.6 [non-UFT] ×100,000 Korean won [KRW], p=0.639) and hospital stay expenses (48.3±13.6 [UFT] vs. 54.8±29.0 [non-UFT] ×100,000 KRW, p=0.164) did not significantly differ between the groups. CONCLUSION: UFT extubation decreased the ICU LOS and mechanical ventilation time, but was not associated with postoperative hospital LOS or medical expenses in patients with simple congenital cardiac disease.
Heart Defects, Congenital* ; Heart Diseases ; Hospitalization ; Humans ; Intensive Care Units ; Length of Stay ; Logistic Models ; Operating Tables ; Propensity Score ; Respiration, Artificial ; Retrospective Studies