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Meng-Chin Ho,1 Ying-Shan Chung,2,3 Yu-Ching Lin,1,4 Ming-Szu Hung,1,4,5 Yu-Hung Fang1,3 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Puzi City, Chiayi County, Taiwan, Republic of China; 2Department of Pharmacy, Chang Gung Memorial Hospital, Puzi City, Chiayi County, Taiwan, Republic of China; 3Department of Nursing, Chang Gung University of Science and Technology, Puzi City, Chiayi County, Taiwan, Republic of China; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City, Chiayi County, Taiwan, Republic of China; 5School of Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, Republic of ChinaCorrespondence: Yu-Hung Fang, Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County, 61363, Taiwan, Republic of China, Tel +886-5-362-1000 ext. 2762, Fax +886-5-362-3005, Email 8902062@gmail.comPurpose: Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib.Patients and Methods: This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes.Results: A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS: 33.2 and 25.1 months, p < 0.01) and multivariate analyses (Combination use: hazard ratio: 1.29; 1.05– 1.59, p = 0.01). The percentages of patients who were able to receive 2nd line therapy also significantly decreased in afatinib with PPI cohort.Conclusion: The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF.Keywords: proton-pump inhibitor, epidermal growth factor receptor tyrosine kinase inhibitor, non-small cell lung cancer, afatinib, Chang Gung Research Database

Ying-Shan Chung,1,2 Yu-Ching Lin,3,4 Ming-Szu Hung,3– 5 Meng-Chin Ho,3 Yu-Hung Fang2,3 1Department of Pharmacy, Chang Gung Memorial Hospital, Puzi City, Taiwan, Republic of China; 2Department of Nursing, Chang Gung University of Science and Technology, Puzi City, Taiwan, Republic of China; 3Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Puzi City, Taiwan, Republic of China; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City, Taiwan, Republic of China; 5School of Medicine, College of Medicine, Chang Gung University; Guishan Township, Taoyuan, Taiwan, Republic of ChinaCorrespondence: Yu-Hung Fang, Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County, 61363, Taiwan, Republic of China, Tel +886-5-362-1000 ext. 2762, Fax +886-5-362-3005, Email 8902062@gmail.comAim: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated Clostridioides difficile infection (CDI) among lung cancer patients have been reported in case reports and adverse events reporting system databases in the United States and Japan, but clinical data remained insufficient. This study aims to evaluate CDI in lung cancer patients receiving EGFR-TKIs.Methods: We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12/31/2019.Results: We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio [HR], 3.30; 95% CI, 1.67– 6.5) and systemic steroids (HR, 4.9; 95% CI, 2.65– 9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94– 3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, 1.98– 5.91) and mortality rate (HR, 2.34, 95% CI, 1.67– 3.28) than diarrhea without CDI.Conclusion: Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs.Keywords: Clostridioides difficile infection, CDI, epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs, lung cancer

Ta-Hsiang Wong,1,2 Cheng-Maw Ho,3,4 Hsao-Hsun Hsu,3,4 Yao-Ming Wu,3,4 Ming-Chih Ho,3,4 Po-Huang Lee,3,4 Rey-Heng Hu3,4 1Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan; 2School of Medicine, National Taiwan University, Taipei, Taiwan; 3Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; 4College of Medicine, National Taiwan University, Taipei, TaiwanCorrespondence: Cheng-Maw Ho, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan, Tel +886-223123456-265914, Email miningho@ntu.edu.twPurpose: Liver transplantation (LT) is the definite curative treatment for hepatocellular carcinoma (HCC), but recurrence can occur even under stringent criteria. “Delayed” HCC recurrence (> 3 years after LT) is not common. Here, we present the clinical features of patients who developed delayed HCC recurrence after LT.Patients and Methods: We reviewed the data of eligible patients from February 1999 to December 2020 from medical records.Results: From among 195 (17%) HCC patients who received LT, 34 experienced HCC recurrence, with 5 (15%) delayed recurrence. These five explant tumors were staged T1b–T2, graded II–III, with two vascular invasion and four beyond the Milan criteria. The median time to recurrence was 6.1 years, with the longest interval being nearly 18 years. Recurrence patterns included two extrahepatic, one intrahepatic, and two mixed extrahepatic and intrahepatic recurrences. A drastic increase in serum alpha-fetoprotein levels was observed in four cases 1 year before recurrence. Management of recurrence included locoregional (surgssical resection in three, radiotherapy in three, transarterial chemoembolization in one, radiofrequency ablation in one) and systemic sorafenib use in three. Two patients died within 12– 18 months, one died within 18– 24 months, and two are still alive until the end of the study, with respective 13.5- and 16.5-month survival.Conclusion: Delayed HCC recurrence could occur over 10 years. Therefore, continual surveillance for recurrence is justified, but biomarkers and intervals or intensities specific for delayed recurrence are not validated, which warrants further validation to facilitate personalized medical care.Keywords: liver transplantation, hepatocellular carcinoma, recurrence, survival, case series

Background and Objectives: The use of conduction anesthesia and induced hypotension are traditionally contraindicated in patients with aortic stenosis. This hypothesis-generating observational pilot study details the clinical outcomes in patients with aortic stenosis undergoing hypotensive epidural anesthesia for total hip replacement.Methods: From a database of 1,947 consecutive patients undergoing total hip replacement under hypotensive epidural anesthesia performed from 1994 to 2005, 22 patients were identified with aortic stenosis. Chart review was performed. All patients were monitored with central venous pressure and radial arterial catheters. Cardiovascular and renal outcomes, thromboembolic events, and blood loss and transfusion were assessed.Results: Twenty-two patients were identified: 19 patients (86%) were American Society of Anesthesiologists classification III, and 3 patients (14%) were American Society of Anesthesiologists classification IV. The mean age was 75 years (range: 58-92). No patient suffered from preoperative angina, syncope, or resting dyspnea. Valve areas ranged from 0.9 to 1.8 cm(2) and peak gradient from 12 to 64 mm Hg. Systolic blood pressure was maintained at 60 to 100 mm Hg. The mean duration of hypotension was 91 minutes (range: 50-200). Heart rate was maintained at a mean (+/-SD) of 70 +/- 11. Central venous pressure was maintained at baseline value. Mean intraoperative crystalloid administered was 1,695 mL (range: 900-4,000), and mean estimated blood loss was 234 mL (range: 100-1,500). There were no deaths, myocardial infarctions, cerebrovascular accidents, or pulmonary embolic events. No patient developed renal dysfunction.Conclusions: We report the absence of complications (with calculated upper limit 95% confidence interval of approximately 13.6%) when hypotensive epidural anesthesia was performed in 22 patients with noncritical asymptomatic aortic stenosis. [ABSTRACT FROM AUTHOR]

Here, we present a protocol for the in vitro phosphorylation of Src kinase domain (SrcKD), preparation of phospho-SrcKD in complex with the D1 domain of rPTP epsilon (rPTPεD1), and binding assays using biolayer interferometry (BLI). We describe steps for the in vitro phosphorylation of SrcKD and preparation of the phospho-SrcKD: rPTPεD1 complex for small-angle X-ray scattering (SAXS) experiments. We then detail instructions for the BLI binding assay to determine the binding affinity between phospho-SrcKD and rPTPεD1. For complete details on the use and execution of this protocol, please refer to EswarKumar et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The association between influenza infection and thromboembolism (TE) events, including cardiovascular events, cerebrovascular events, pulmonary embolism, and deep vein thrombosis, is supported by compelling evidence. However, there is a disparity in the risk factors that impact the outcomes of severe influenza-complicated TE in intensive care unit (ICU) patients. The objective of this study was to evaluate the outcomes of severe influenza-complicated TE in ICU patients and identify any associated risk factors., Methods: A retrospective cohort study was conducted, recruiting consecutive patients with TE events admitted to the ICU between December 2015 through December 2018 at our institution in Taiwan. The study included a group of 108 patients with severe influenza and a control group of 192 patients with severe community-acquired pneumonia. Associations between complicated TE, length of ICU stay, and 90-day mortality were evaluated using logistic regression analysis, and risk factors were identified using univariate and multivariate generalized linear regression analyses., Results: TE event prevalence was significantly higher in ICU patients with severe influenza than in ICU patients with severe CAP (21.3% vs. 5.7%, respectively; p < 0.05). Patients with severe influenza who developed TE experienced a significant increase in the ratio of mechanical ventilation use, length of mechanical ventilation use, ICU stay, and 90-day mortality when compared to patients without TE (all p < 0.05). The comparison of severe CAP patients with and without TE revealed no significant differences (p > 0.05). The development of thromboembolic events in patients with severe influenza or severe noninfluenza CAP is linked to influenza infection and hypertension (p < 0.05). Furthermore, complicated TE and the severity of the APACHE II score are risk factors for 90-day mortality in ICU patients with severe influenza (p < 0.05)., Conclusions: Patients with severe influenza and complicated TE are more likely to have an extended ICU stay and 90-day mortality than patients with severe CAP. The risk is significantly higher for patients with a higher APACHE II score. The results of this study may aid in defining better strategies for early recognition and prevention of severe influenza-complicated TE., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Liver cirrhosis compromises immunity against cryptococcosis, and liver transplant recipients tend to develop the disease earlier after transplantation, possibly due to unrecognized pretransplant infection. We assessed the prevalence and characteristics of cryptococcosis among liver transplant candidates and whether pre-transplant cryptococcal antigen (CrAg) can detect the disease before transplantation., Methods: We retrospectively included liver transplant candidates in a tertiary hospital during 2017-2022. Serum CrAg and pulmonary computed tomography were incorporated in routine transplant evaluation. Other investigations were done if indicated. Cryptococcosis was diagnosed by positive culture or CrAg. Risk factors for cryptococcosis were also assessed., Results: Of the 377 candidates with a median MELD-Na score of 18, 84.4% had hepatitis B virus (HBV) infection. Cryptococcosis was diagnosed in 10 (2.6%) candidates, by CrAg in 6, culture in 2, or both in 2. Only 3 had fever, and 3 were asymptomatic; 7 had pulmonary cryptococcosis. Of the 10 candidates with cryptococcosis, one underwent transplantation after 143-day antifungals. Of the 87 candidates undergoing liver transplantation, one (1.2%) recipient developed cryptococcosis 14 days post-transplant with negative CrAg three weeks before transplantation. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis (odds ratio 4.4, 95% confidence interval 1.2-16.5, p = 0.03) after the adjustment of MELD-Na score., Conclusions: The prevalence of cryptococcosis was 2.6% among our liver transplant candidates and CrAg detected 80% of the cases. Disease presentation was mild and pulmonary disease predominated. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Eukaryotic ribosomal proteins contain extended regions essential for translation coordination. Dedicated chaperones stabilize the associated ribosomal proteins. We identified Bcp1 as the chaperone of uL14 in Saccharomyces cerevisiae. Rkm1, the lysine methyltransferase of uL14, forms a ternary complex with Bcp1 and uL14 to protect uL14. Rkm1 is transported with uL14 by importins to the nucleus, and Bcp1 disassembles Rkm1 and importin from uL14 simultaneously in a RanGTP-independent manner. Molecular docking, guided by crosslinking mass spectrometry and validated by a low-resolution cryo-EM map, reveals the correlation between Bcp1, Rkm1, and uL14, demonstrating the protection model. In addition, the ternary complex also serves as a surveillance point, whereas incorrect uL14 is retained on Rkm1 and prevented from loading to the pre-60S ribosomal subunits. This study reveals the molecular mechanism of how uL14 is protected and quality checked by serial steps to ensure its safe delivery from the cytoplasm until its incorporation into the 60S ribosomal subunit., (© 2024 Yeh et al.)

Diagnosis of early hepatic steatosis would allow timely intervention. B-mode ultrasound imaging was in question for detecting early steatosis, especially with a variety of concomitant parenchymal disease. This study aimed to use the surgical specimen as a reference standard to elucidate the clinical performance of ultrasonic echogenicity and backscatter parametric and nonparametric statistics in real-world scenarios. Ultrasound radio-frequency (RF) signals of right liver lobe and patient data were collected preoperatively. Surgical specimen was then used to histologically determine staging of steatosis. A backscatter nonparametric statistic (h), a known backscatter parametric statistic, i.e., the Nakagami parameter (m), and a quantitative echo intensity (env) were calculated. Among the 236 patients included in the study, 93 were grade 0 (<5% fat) and 143 were with steatosis. All the env, m and h statistics had shown significant discriminatory power of steatosis grades (AUC = 0.643-0.907 with p-value < 0.001). Mann-Whitney U tests, however, revealed that only the backscatter statistics m and h were significantly different between the groups of grades 0 and 1 steatosis. The two-way ANOVA showed a significant confounding effect of the elevated ALT on env (p-value = 0.028), but no effect on m or h. Additionally, the severe fibrosis was found to be a significant covariate for m and h. Ultrasonic signals acquired from different scanners were found linearly comparable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Attentional bias (AB) for addictive substances is a feature of attention found in individuals with substance misuse or diagnosed with substance use disorders. When AB exists, the attention of the addicted individual may be quickly oriented to cues related to the addictive substance or be maintained on these cues for a longer time. AB toward opioids was found in Western samples of smokers with chronic noncancer pain. The level of AB was dose-responsive. However, similar studies in the Taiwanese population are lacking. This study compared the patterns of AB for opioid analgesics in Taiwanese participants with chronic noncancer pain to that of individuals without pain. This study aimed to investigate if AB toward opioids is presented in Taiwanese heavy smokers who are on long-term opioid therapy for pain control. Materials and Methods: Participants were grouped into chronic noncancer pain smokers, chronic pain nonsmokers, and smokers without pain, according to smoking habits and whether or not on long-term opioid therapy for pain control. Each participant completed demographic questionnaires, mood scales, and the opioid-related visual probe task. Differences in AB among the groups were compared using a three-way analysis of covariance controlling for daily cigarette consumption. Results: Chronic noncancer pain smokers ( n = 17) and chronic pain nonsmokers ( n = 16) displayed more severe levels of depression, anxiety, and pain, compared to smokers without pain ( n = 28). Only did chronic pain nonsmokers show significant AB for opioid cues that were displayed for a short time. Analysis on reaction time found that smokers without pain consistently responded faster to the tasks. No difference in reaction time was found between the pain groups. Conclusions: The current study did not fully replicate findings from studies that were based in Western countries. Formulary availability and regulatory limitations might have affected patient's perception of prescription opioids in Taiwan. However, chronic pain nonsmokers exhibited initial orientation toward opioid-related cues when daily cigarette consumption was accounted for. According to previous research, this AB for shortly displayed opioid cues can be associated with the expectation of pain relief. The current finding also indicated general psychomotor retardation in individuals who were on long-term use of opioids.

The study's objective is to validate the Malay version of the Patient Health Questionnaire-4 (PHQ-4) among Malaysian undergraduates. A cross-sectional survey was distributed at three universities in Malaysia (N = 500; mean age = 21.66 ± 1.57). The internal consistency of the Malay PHQ-4 was acceptable (α = .78, 95 % CI [.74, .81]), while the test-retest reliability was good (ICC = .77, 95 % CI [.34, .91], p < .001). The one-factor structure showed the best fit in confirmatory factor analysis and was similar across sexes. The Malay PHQ-4 has acceptable psychometric properties and can be used for pre-clinical screening purposes among Malaysian undergraduate students., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Late recurrence of hepatocellular carcinoma after curative resection significantly influences long-term patient survival outcomes, and yet it remains understudied. This study aims to explore the risk factors and patterns of late recurrence and predictors of subsequent outcome., Methods: This single-center retrospective study analyzed 1,701 consecutive patients who achieved a disease-free survival period exceeding 2 years after curative resection for hepatocellular carcinoma between 2001 and 2018. Univariate and multivariate analyses of factors associated with late recurrence and death after recurrence were conducted using Cox's models., Results: The mean age of patients was 60.2 years, with 76.8% being male. During a median follow-up of 8.1 years, 653 patients (38.4%) experienced late recurrence, with median time to recurrence being 4.0 years (interquartile range, 2.7-6.0). Factors such as age >60, chronic hepatitis C, cirrhosis, high albumin-bilirubin grade, absence of family history, multiple tumors, satellite nodules, alpha-fetoprotein levels <400 ng/mL, and minor hepatic resection were identified as risk factors for late recurrence. Among patients with late recurrence, 131 (20.1%) underwent surgical treatment, 272 (41.7%) received radiofrequency ablation, and 27 (4.1%) exhibited extrahepatic lesions. A higher-high albumin-bilirubin grade, recurrent tumor >3 cm, and nonsurgical treatment emerged as predictors of death after late recurrence., Conclusion: Over one-third of patients who remain disease-free for more than 2 years postresection will experience late recurrence during subsequent follow-up. For 2-year disease-free survivors, risk factors for late recurrence differ from early recurrence. Treating underlying hepatitis is of paramount importance, given its association with both the risk of late recurrence and survival outcomes post-recurrence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aim: The REgistry of Selective Internal radiation therapy in AsiaNs (RESIN) was a multicenter, single-arm, prospective, observational study of 90 Y resin microspheres in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) from Taiwan. RESIN is the first real-life clinical study of this therapy in an Asian cohort. Study objectives were to evaluate the safety and efficacy of 90 Y resin microspheres., Methods: Adults with HCC or mCRC scheduled to receive SIRT with 90 Y resin microspheres were included. Primary endpoints were best overall response rate (ORR), adverse events, and changes from baseline in liver function. Secondary efficacy endpoints included overall survival (OS)., Results: Of 107 enrolled patients, 83 had HCC, and 24 had mCRC. ORR was 55.41% (HCC) and 33.33% (mCRC). Of 58 HCC patients with 6-month post-SIRT data, 13.79% (n = 8) had resection, transplantation, transarterial chemoembolization, or radiofrequency ablation as the result of down-staging or down-sizing of their lesions. One hundred and ten treatment emergent adverse events (TEAEs) were reported in 51 patients, and five serious adverse events (SAEs) were reported in five patients. The most frequent TEAEs were abdominal pain, nausea and decreased appetite (HCC), and abdominal pain, decreased appetite, fatigue, and vomiting (mCRC). Two deaths due to SAEs (probably related to SIRT) were reported, both in patients with extensive HCC, active hepatitis infection, and other comorbidities. Median OS was 24.07 (HCC) and 12.66 (mCRC) months., Conclusions: Safety and efficacy outcomes with the routine use of SIRT with 90 Y resin microspheres in Taiwan are consistent with published data., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The attachment to mobile devices during the COVID-19 pandemic has led to the possibility of increased nomophobia, which is the intense fear of losing access to one's mobile device. Therefore, this study aimed to determine if nomophobia was independently associated with suicidality before and during the COVID-19 pandemic among university students in Malaysia. This cross-sectional study had two-time points in data collection: one year before and one year into the COVID-19 pandemic. N  = 806 university students aged ≥ 18 years completed an online questionnaire comprising the Nomophobia Questionnaire, Multidimensional Scale of Perceived Social Support, and the Suicidal Behaviors Questionnaire-Revised. A multiple logistic regression (controlling for gender, age, and social support) was conducted to determine the association between nomophobia and suicidality before and during the COVID-19 pandemic. The prevalence of severe nomophobia before and during the COVID-19 pandemic was 15.7% and 35.6% respectively. The level of nomophobia was significantly higher during the COVID-19 pandemic compared to pre-pandemic. Pre-pandemic, there were no significant associations. During the pandemic, participants with moderate (a OR 3.09, 95% CI [1.14-8.40], p  = .027) and severe (a OR 3.57, 95% CI [1.25-10.20], p  = .018) nomophobia had higher odds of suicide plan. During the pandemic, moderate and severe nomophobia were independently associated with more than three times higher odds for a lifetime suicide plan. Our study findings carry implications for the well-being of university students.

Rationale: The prevalence, clinical characteristics, and outcomes of invasive pulmonary aspergillosis in patients with severe community-acquired pneumonia (CAP) in intensive care units remain underestimated because of the lack of a disease-recognition scheme and the inadequacy of diagnostic tests., Objectives: To identify the prevalence, risk factors, and outcomes of severe CAP complicated with invasive pulmonary aspergillosis (IPA) in intensive care units (ICUs)., Methods: We conducted a retrospective cohort study including recruited 311 ICU-hospitalized patients with severe CAP without influenza or with influenza. Bronchoalveolar lavage fluid (BALF) samples were from all patients and subjected to mycological testing. Patients were categorized as having proven or probable Aspergillus infection using a modified form of the AspICU algorithm comprising clinical, radiological, and mycological criteria., Measurements and Main Results: Of the 252 patients with severe CAP and 59 influenza patients evaluated, 24 met the diagnostic criteria for proven or probable Aspergillus infection in the CAP group and 9 patients in the influenza group, giving estimated prevalence values of 9.5% and 15.3%, respectively. COPD and the use of inhaled corticosteroids were independent risk factors for IPA. IPA in patients with severe CAP was significantly associated with the duration of mechanical support, the length of ICU stay, and the 28-day mortality., Conclusions: An aggressive diagnostic approach for IPA patients with severe CAP and not only influenza or COVID-19 should be pursued. Further randomized controlled trials need to evaluate the timing, safety, and efficacy of antifungal therapy in reducing IPA incidence and improving clinical outcomes., (© 2024. The Author(s).)

The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence., (© 2024. The Author(s).)

Objectives: The experience of thermal ablation of lung lesions is limited, especially performing the procedure under localisation by cone-beam CT in the hybrid operation room (HOR). Here, we present the experience of microwave ablation (MWA) of lung nodules in the HOR., Methods: We reviewed patients who underwent image-guide percutaneous MWA for lung nodules in the HOR under general anaesthesia between July 2020 and July 2022. The workflow in the HOR including the pre-procedure preparation, anaesthesia consideration, operation methods, and postoperative care was clearly described., Results: Forty lesions in 33 patients who underwent MWA under general anaesthesia (GA) in the HOR were analysed. Twenty-seven patients had a single pulmonary nodule, and the remaining six patients had multiple nodules. The median procedure time was 41.0 min, and the median ablation time per lesion was 6.75 min. The median global operation room time was 115.0 min. The median total dose area product was 14881 μGym 2 . The median ablation volume was 111.6 cm 3 . All patients were discharged from the hospital with a median postoperative stay of 1 day. Four patients had pneumothorax, two patients had pleural effusion during the first month of outpatient follow-up, and one patient reported intercostal neuralgia during the 3-month follow-up., Conclusions: Thermal ablation of pulmonary nodules under GA in the HOR can be performed safely and efficiently if we follow the workflow provided. The procedure provides an alternative to managing pulmonary nodules in patients., Clinical Relevance Statement: Thermal ablation of pulmonary nodules under GA in the HOR can be performed safely and efficiently if the provided workflow is followed., Key Points: • We tested the feasibility of microwave ablation of lung lesions performed in a hybrid operating room. • To this end, we provide a description of microwave ablation of the lung under cone-beam CT localisation. • We describe a workflow by which ablation of the pulmonary nodule can be performed safely under general anaesthesia., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC)., Methods: Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child-Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors., Results: Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child-Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2 years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18-2.41) for cirrhotic stage B or C, 1.07 (1.04-1.10) for MELD scores, and 1.14 (1.04-1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14-0.33)., Conclusion: Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Preoperative imaging evaluation of liver volume and hepatic steatosis for the donor affects transplantation outcomes. However, computed tomography (CT) for liver volumetry and magnetic resonance spectroscopy (MRS) for hepatic steatosis are time consuming. Therefore, we investigated the correlation of automated 3D-multi-echo-Dixon sequence magnetic resonance imaging (ME-Dixon MRI) and its derived proton density fat fraction (MRI-PDFF) with CT liver volumetry and MRS hepatic steatosis measurements in living liver donors., Methods: This retrospective cross-sectional study was conducted from December 2017 to November 2022. We enrolled donors who received a dynamic CT scan and an MRI exam within 2 days. First, the CT volumetry was processed semiautomatically using commercial software, and ME-Dixon MRI volumetry was automatically measured using an embedded sequence. Next, the signal intensity of MRI-PDFF volumetric data was correlated with MRS as the gold standard., Results: We included the 165 living donors. The total liver volume of ME-Dixon MRI was significantly correlated with CT (r = 0.913, p < 0.001). The fat percentage measured using MRI-PDFF revealed a strong correlation between automatic segmental volume and MRS (r = 0.705, p < 0.001). Furthermore, the hepatic steatosis group (MRS ≥5%) had a strong correlation than the non-hepatic steatosis group (MRS <5%) in both volumetric (r = 0.906 vs. r = 0.887) and fat fraction analysis (r = 0.779 vs. r = 0.338)., Conclusion: Automated ME-Dixon MRI liver volumetry and MRI-PDFF were strongly correlated with CT liver volumetry and MRS hepatic steatosis measurements, especially in donors with hepatic steatosis., Competing Interests: Declaration of competing interest The Authors declare no potential financial or nonfinancial conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/purpose: Hepatocellular carcinoma (HCC) can be noninvasively diagnosed through dynamic computed tomography (CT) and magnetic resonance imaging (MRI). We compared the diagnostic performance of CT and gadoxetic acid-enhanced MRI (EOB-MRI) in categorizing tumors by using the 2018 version of the Liver Imaging Reporting And Data System (LI-RADS v2018) and assessing liver tumors before resection., Methods: Data from a prospective cohort from October 2011 to March 2019 on 106 hepatic tumors in 96 patients with suspected malignancy were included in this study. We performed preoperative CT and EOB-MRI, and reviewed these images retrospectively. Ninety-seven tumors from 87 patients were pathologically diagnosed as HCC, and nine tumors were non-HCC. The clinical data, imaging characteristics, diagnostic performance, and outcomes of CT and EOB-MRI were analyzed and compared., Results: EOB-MRI had more favorable diagnostic performance (area under curve: 0.920 vs. 0.868) and significantly higher sensitivity (86.87% vs. 69.70%, p = 0.005) than did CT. However, the specificity of EOB-MRI did not differ from that of CT (88.89% vs. 88.89%, p > 0.999). Fourteen (14.5%) patients with pathologically verified HCC had lesions categorized as LI-RADS 4 through CT and as LI-RADS 5 through EOB-MRI. Patients with EOB-MRI-categorized but not CT-categorized LI-RADS 5 lesions had significantly longer overall survival than did those with LI-RADS 4 lesions (p < 0.001)., Conclusion: EOB-MRI had higher sensitivity than did CT in diagnosing HCC. Patients with EOB-MRI-categorized LI-RADS 5 lesions had more favorable outcomes than did those with LI-RADS 4 lesions after liver resection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP + varicosities in the PGP9.5 + nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1 ) condensed TH + sympathetic nerves in the portal space, 2 ) extension of sympathetic nerves from the portal to the intralobular space, in which the TH + nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3 ) the TH + nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology. NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1 ) sensory nerves in the hepatoportal space; 2 ) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3 ) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Depression and anxiety are prevalent mental health issues worldwide, especially among parental caregivers. By expanding the family stress model, this cross-sectional study investigated the relevant factors associated with depressive symptoms, anxiety symptoms, and satisfaction with life among Malaysian parental caregivers of adolescent psychiatric patients. Data were collected through questionnaires ( N = 207) across five major public hospitals through convenience sampling. Participants answered questionnaires measuring financial strain, caregiver burden, relationship quality, belief in mental illness, perceived COVID-19 stress, satisfaction with health services, depressive symptoms, anxiety symptoms and life satisfaction. Findings revealed that relationship quality among spouses, COVID-19 stress and caregiver burden were significantly correlated with anxiety symptoms, depressive symptoms and satisfaction with life. The multiple regression model also suggested that depressive symptoms ( β = .613, p < .001), anxiety symptoms ( β = .657, p < .001) and relationship quality among spouses ( β = .264, p < .001) were the most influential predictors of anxiety symptoms, depressive symptoms and satisfaction with life respectively. By addressing the mental health needs of parental caregivers, this study can contribute to improving the overall quality of care and support provided to adolescent patients and their caregivers in Malaysia and beyond., Competing Interests: The authors declare none., (© The Author(s) 2024.)

Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC.

The structure determination of protein tyrosine phosphatase (PTP): phospho-protein complexes, which is essential to understand how specificity is achieved at the amino acid level, remains a significant challenge for protein crystallography and cryoEM due to the transient nature of binding interactions. Using rPTPεD1 and phospho-SrcKD as a model system, we have established an integrative workflow to address this problem, by means of which we generate a protein:phospho-protein complex model using predetermined protein structures, SAXS and pTyr-tailored MD simulations. Our model reveals transient protein-protein interactions between rPTPεD1 and phospho-SrcKD and is supported by three independent experimental validations. Measurements of the association rate between rPTPεD1 and phospho-SrcKD showed that mutations on the rPTPεD1: SrcKD complex interface disrupts these transient interactions, resulting in a reduction in protein-protein association rate and, eventually, phosphatase activity. This integrative approach is applicable to other PTP: phospho-protein complexes and the characterization of transient protein-protein interface interactions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Phycobilisomes (PBS) are antenna megacomplexes that transfer energy to photosystems II and I in thylakoids. PBS likely evolved from a basic, inefficient form into the predominant hemidiscoidal shape with radiating peripheral rods. However, it has been challenging to test this hypothesis because ancestral species are generally inaccessible. Here we use spectroscopy and cryo-electron microscopy to reveal a structure of a "paddle-shaped" PBS from a thylakoid-free cyanobacterium that likely retains ancestral traits. This PBS lacks rods and specialized ApcD and ApcF subunits, indicating relict characteristics. Other features include linkers connecting two chains of five phycocyanin hexamers (CpcN) and two core subdomains (ApcH), resulting in a paddle-shaped configuration. Energy transfer calculations demonstrate that chains are less efficient than rods. These features may nevertheless have increased light absorption by elongating PBS before multilayered thylakoids with hemidiscoidal PBS evolved. Our results provide insights into the evolution and diversification of light-harvesting strategies before the origin of thylakoids., (© 2023. The Author(s).)

Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Perioperative fresh frozen plasma (FFP) is commonly transfused to patients undergoing liver resection for hepatocellular carcinoma (HCC), but its impacts in this population remain unknown. This study aimed to investigate the association of perioperative FFP transfusion with short-term and long-term outcomes in these patients., Methods: We retrospectively identified and retrieved clinical data for HCC patients undergoing liver resection between March, 2007 and December, 2016. Study outcomes included postoperative bacterial infection, extended length of stay (LOS) and survival. Propensity score (PS) matching was used to determine the association of FFP transfusion with each outcome., Results: A total of 1427 patients were included, and 245 of them received perioperative FFP transfusions (17.2%). Patients received perioperative FFP transfusions were older, underwent liver resection in the earlier time period, and had more extensive resection, poorer clinical conditions, and higher proportions of receiving other blood components. Perioperative FFP transfusion was associated with higher odds of both postoperative bacterial infection (OR = 1.77, p = 0.020) and extended LOS (OR = 1.93, p=<0.001), and the results remained similar after PS-matching. However, perioperative FFP transfusion did not significantly affect survival in these patients (HR = 1.17, p = 0.185). A potential association of postoperative FFP transfusions and poorer 5-year but not overall survival was observed in a subgroup of patients with low postoperative albumin levels after PS-matching., Conclusion: Perioperative FFP transfusions were associated with poorer short-term postoperative outcomes in HCC patients undergoing liver resection, including postoperative bacterial infection and extended LOS. Reducing perioperative FFP transfusions has the potential to improve their postoperative outcomes., Competing Interests: Declarations of interest The authors declare no conflicts of interest relevant to this manuscript submitted to the Journal of the Formosan Medical Association., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

This cross-sectional study aimed to validate the Life Events Checklist for DSM-5 (LEC-5) among Malaysian undergraduates (N = 500; mean age = 21.66 ± 1.57), of which 90.4% had ever experienced a lifetime traumatic event. Cronbach's alpha of .87 (95% CI [.86, .89]) and McDonald's omega of .89 (95% CI [.89, .93]) indicated good reliability. Confirmatory factor analysis based on a six-factor structure showed the best fit. The measurement invariance showed that the six-factor structure was similar across sexes. Therefore, the Malay LEC-5 is a valid and reliable instrument to screen for traumatic events among Malaysian undergraduates., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Vibrio α-hemolysins (αHLs) are β-pore-forming toxins secreted by Vibrio pathogens, crucial for the facilitation of bacterial infections through host cell lysis. These toxins are produced as inactive precursors, requiring proteolytic maturation and membrane association for activation within host tissues. Here, we investigate Vibrio campbellii αHL (VcαHL), and establish that its hemolytic activity is significantly stimulated by calcium ions, with an EC 50 that aligns with physiological calcium concentrations. Furthermore, we illustrate the vital contribution of calcium ions to the oligomerization of VcαHL on membranes. Using X-ray crystallography and cryo-electron microscopy, we decipher both the immature and assembled structures of VcαHL and elucidate the conformational changes corresponding to toxin assembly. We also identify a calcium-binding module that is integral for VcαHL's calcium-dependent activation. These findings provide insights into the regulatory mechanisms of VcαHL and have the potential to inform the development of targeted therapeutic strategies against Vibrio infections., (© 2023. Springer Nature Limited.)

The abuse of antibiotics has led to the emergence of multidrug-resistant microbial pathogens, presenting a pressing challenge in global healthcare. Membrane-disrupting antimicrobial peptides (AMPs) combat so-called superbugs via mechanisms different than conventional antibiotics and have good application prospects in medicine, agriculture, and the food industry. However, the mechanism-of-action of AMPs has not been fully characterized at the cellular level due to a lack of high-resolution imaging technologies that can capture cellular-membrane disruption events in the hydrated state. Previously, we reported PepD2M, a de novo-designed AMP with potent and wide-spectrum bactericidal and fungicidal activity. In this study, we use cryo-electron tomography (cryo-ET) and high-speed atomic force microscopy (HS-AFM) to directly visualize the pepD2M-induced disruption of the outer and inner membranes of the Gram-negative bacterium Escherichia coli, and compared with a well-known pore-forming peptide, melittin. Our high-resolution cryo-ET images reveal how pepD2M disrupts the E. coli membrane using a carpet/detergent-like mechanism. Our studies reveal the direct membrane-disrupting consequence of AMPs on the bacterial membrane by cryo-ET, and this information provides critical insights into the mechanisms of this class of antimicrobial agents., (© 2023. Springer Nature Limited.)

Background and Aim: This study aimed to investigate the survival outcomes of antiviral agents (direct-acting antivirals [DAAs] or interferon [IFN]) in patients with hepatitis C virus who underwent liver resection for primary hepatocellular carcinoma., Methods: This retrospective single-center study included 247 patients, between 2013 and 2020, being treated with DAAs (n = 93), IFN (n = 73), or no treatment (n = 81). Overall survival (OS), recurrence-free survival (RFS), and risk factors were analyzed., Results: After a median follow-up time of 50.4 months, the rates of 5-year OS and RFS in the IFN, DAA, and no treatment groups were 91.5% and 55.4%, 87.2% and 39.8%, and 60.9% and 26.7%, respectively. One hundred and twenty-eight (51.6%) patients developed recurrence; recurrence was mostly (86.7%) intrahepatic, and 58 (23.4%) developed early recurrence, most of which received no antiviral treatment. The OS and RFS were similar between patients who received antiviral treatment before (50.0%) and after surgery, but longer survival was observed in patients achieving sustained virologic response. In multivariate analysis, antiviral treatment was protective for OS (hazard ratio [HR] 0.475, 95% confidence interval [CI]: 0.242-0.933) with significance but not RFS, in contrast to microvascular invasion (OS HR 3.389, 95% CI: 1.637-7.017; RFS HR 2.594, 95% CI: 1.520-4.008). In competing risk analysis, DAAs (subdistribution HR 0.086, 95% CI: 0.007-0.991) were protective against hepatic decompensation events but not recurrence events., Conclusion: In patients with hepatitis C virus, antiviral treatment suggested OS benefit for primary hepatocellular carcinoma after resection, and DAAs might be protective against hepatic decompensation. Following adjustment for oncological factors, IFN and DAA treatment was not significantly advantageous relative to the other., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

ATP-dependent RAD51 recombinases play an essential role in eukaryotic homologous recombination by catalyzing a four-step process: 1) formation of a RAD51 single-filament assembly on ssDNA in the presence of ATP, 2) complementary DNA strand-exchange, 3) ATP hydrolysis transforming the RAD51 filament into an ADP-bound disassembly-competent state, and 4) RAD51 disassembly to provide access for DNA repairing enzymes. Of these steps, filament dynamics between the ATP- and ADP-bound states, and the RAD51 disassembly mechanism, are poorly understood due to the lack of near-atomic-resolution information of the ADP-bound RAD51-DNA filament structure. We report the cryo-EM structure of ADP-bound RAD51-DNA filaments at 3.1 Å resolution, revealing a unique RAD51 double-filament that wraps around ssDNA. Structural analysis, supported by ATP-chase and time-resolved cryo-EM experiments, reveals a collapsing mechanism involving two four-protomer movements along ssDNA for mechanical transition between RAD51 single- and double-filament without RAD51 dissociation. This mechanism enables elastic change of RAD51 filament length during structural transitions between ATP- and ADP-states., (© 2023. Springer Nature Limited.)

Background: Sarcopenia is a common finding in patients with decompensated cirrhosis without effective therapy. We aimed to examine whether a transjugular portosystemic shunt (TIPS) could improve the abdominal muscle mass assessed by cross-sectional images in patients with decompensated cirrhosis and to investigate the association of imaging-defined sarcopenia with the prognosis of such patients., Methods: In this retrospective observational study, we enrolled 25 Decompensated cirrhosis patients aged >20 who received TIPS for the control of variceal bleeding or refractory ascites between April 2008 and April 2021. All of them underwent preoperative computed tomography or magnetic resonance imaging, which was used to determine psoas muscle (PM) and paraspinal muscle (PS) indices at the third lumbar vertebra. First, we compared baseline muscle mass with muscle mass at 6 and 12 months after TIPS placement and analyzed PM- and PS-defined sarcopenia to predict mortality., Results: Among 25 patients, 20 (80.0%) and 12 (48.0%) had PM- and PS-defined sarcopenia, respectively, at baseline. In total, 16 and 8 patients were followed up for 6 and 12 months, respectively. All imaging-based muscle measurements performed 12 months after TIPS placement were significantly greater than the baseline measurements (all p < 0.05). Unlike patients with PS-defined sarcopenia (p = 0.529), patients with PM-defined sarcopenia had poorer survival than did patients without (p = 0.036)., Conclusion: PM mass in patients with decompensated cirrhosis may increase by 6 or 12 months after TIPS placement and imply a better prognosis. Patients with preoperative PM-defined sarcopenia may suggest poorer survival., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: The impact of viral background on long-term effectiveness of different treatment modalities for recurrent hepatocellular carcinoma (HCC) was not fully analyzed., Method: Consecutive 726 patients who developed intrahepatic recurrence after primary hepatectomy for HCC between 2008 and 2015 were retrospectively studied. Post-recurrence survival (PRS) and rerecurrence-free survival (R-RFS) and risk factors were analyzed., Results: After a median follow-up period of 56 months, the 5-year PRS rates of the patients who underwent rehepatectomy, radiofrequency ablation (RFA), and transarterial chemoembolization (TACE) were 79.4%, 83.0%, and 54.6%, respectively. The treatment benefit for PRS was consistently observed in patients with hepatitis B virus (HBV) and non-B, non-C subgroups, but not hepatitis C virus (HCV). For patients with late recurrence of HCC, R-RFS was superior in HBV subgroup and HCV subgroup which received antiviral treatment (compared to naïve HCV subgroup). Survival difference triaged by viral status was lost in the counterpart with early recurrence. Overall, RFA improved PRS and R-RFS in patients receiving antiviral treatment., Conclusion: To achieve long-term survival after HCC recurrence, rehepatectomy and RFA were comparably effective, particularly among those with HBV. Antiviral treatment complemented survivals of patients with HCV after RFA, particularly in late first recurrence., (© 2023. The Society for Surgery of the Alimentary Tract.)

Most rice ( Oryza sativa ) cultivars cannot survive under prolonged submergence. However, some O. sativa ssp. indica cultivars, such as FR13A, are highly tolerant owing to the SUBMERGENCE 1A-1 ( SUB1A-1 ) allele, which encodes a Group VII ethylene-responsive factor (ERFVII) protein; other submergence-intolerant cultivars contain a SUB1A-2 allele. The two alleles differ only by a single substitution at the 186 th amino acid position from serine in SUB1A-1 to proline in SUB1A-2 resulting in only SUB1A-1 being able to be phosphorylated. Two other ERFVIIs, ERF66 and ERF67 , function downstream of SUB1A-1 to form a regulatory cascade in response to submergence stress. Here, we show that SUB1A-1, but not SUB1A-2, interacts with ADA2b of the ADA2b-GCN5 acetyltransferase complex, in which GCN5 functions as a histone acetyltransferase. Phosphorylation of SUB1A-1 at serine 186 enhances the interaction of SUB1A-1 with ADA2b. ADA2b and GCN5 expression was induced under submergence, suggesting that these two genes might play roles in response to submergence stress. In transient assays, binding of SUB1A-1 to the ERF67 promoter and ERF67 transcription were highly induced when SUB1A-1 was expressed together with the ADA2b-GCN5 acetyltransferase complex. Taken together, these results suggest that phospho-SUB1A-1 recruits the ADA2-GCN5 acetyltransferase complex to modify the chromatin structure of the ERF66/ERF67 promoter regions and activate gene expression, which in turn enhances rice submergence tolerance., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Regulation of CO 2 fixation in cyanobacteria is important both for the organism and global carbon balance. Here we show that phosphoketolase in Synechococcus elongatus PCC7942 (SeXPK) possesses a distinct ATP-sensing mechanism, where a drop in ATP level allows SeXPK to divert precursors of the RuBisCO substrate away from the Calvin-Benson-Bassham cycle. Deleting the SeXPK gene increased CO 2 fixation particularly during light-dark transitions. In high-density cultures, the Δxpk strain showed a 60% increase in carbon fixation and unexpectedly resulted in sucrose secretion without any pathway engineering. Using cryo-EM analysis, we discovered that these functions were enabled by a unique allosteric regulatory site involving two subunits jointly binding two ATP, which constantly suppresses the activity of SeXPK until the ATP level drops. This magnesium-independent ATP allosteric site is present in many species across all three domains of life, where it may also play important regulatory functions., (© 2023. The Author(s).)

Acetaminophen (Apap) is widely used and is known to form toxic haloacetamides (HAcAms) during chlorination. Metformin (Met) is a typical medication with usage much higher than that of Apap and its ubiquitous presence in the environment is known. The objective of this study was to investigate the effects of Met which contains multiple amino groups potentially joining reactions and different chlorination methods on HAcAm formation from Apap. In addition, a major drinking water treatment plant (DWTP) using the largest river in southern Taiwan was sampled to study the influence of Apap in a DWTP on the HAcAm formation. Results showed increasing dichloroacetamide (DCAcAm) molar yields of Apap at a Cl/Apap molar ratio of 5 during chlorination (0.15%) and two-step chlorination (0.03%). HAcAms were formed by the chlorine substitution of hydrogen on the methyl group in Apap followed by the cleavage of the bonding between nitrogen and aromatic. While a high Cl/Apap ratio during chlorination led to reactions between chlorine and HAcAms formed decreasing the HAcAm yields, the two-step chlorination further reduced the HAcAm formation during chlorination by a factor of 1.8-8.2. However, Met which limitedly formed HAcAms increased the DCAcAm yields of Apap by 228% at high chlorine dosages during chlorination and by 244% during two-step chlorination. In the DWTP, trichloroacetamide (TCAcAm) formation was important. The formation was positively correlated with NH 4 + , dissolved organic carbon (DOC), and specific ultraviolet absorbance (SUVA). DCAcAm dominated in the presence of Apap. The DCAcAm molar yields were 0.17%-0.27% and 0.08%-0.21% in the wet and dry seasons, respectively. The HAcAm yields of Apap in the DWTP were limitedly changed between different locations and seasons. Apap could be one important cause for HAcAm formation in a DWTP, as the presence of other pharmaceuticals such as Met possibly worsens the situation in chlorine applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Human mitochondrial NAD(P) + -dependent malic enzyme (ME2) is well-known for its role in cell metabolism, which may be involved in cancer or epilepsy. We present potent ME2 inhibitors based on cyro-EM structures that target ME2 enzyme activity. Two structures of ME2-inhibitor complexes demonstrate that 5,5'-Methylenedisalicylic acid (MDSA) and embonic acid (EA) bind allosterically to ME2's fumarate-binding site. Mutagenesis studies demonstrate that Asn35 and the Gln64-Tyr562 network are required for both inhibitors' binding. ME2 overexpression increases pyruvate and NADH production while decreasing the cell's NAD + /NADH ratio; however, ME2 knockdown has the opposite effect. MDSA and EA inhibit pyruvate synthesis and thus increase the NAD + /NADH ratio, implying that these two inhibitors interfere with metabolic changes by inhibiting cellular ME2 activity. ME2 silence or inhibiting ME2 activity with MDSA or EA decreases cellular respiration and ATP synthesis. Our findings suggest that ME2 is crucial for mitochondrial pyruvate and energy metabolism, as well as cellular respiration, and that ME2 inhibitors could be useful in the treatment of cancer or other diseases that involve these processes., (© 2023. The Author(s).)

Background: Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H 2 O) levels to investigate their relationship with serum VEGF levels., Material and Methods: New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb ([HbO 2 ]), deoxy-Hb ([HbR]), total Hb ([HbT]), and H 2 O ([H 2 O]) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed., Results: Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median [IQR], 1926.00 [1348.50-3092.00] mL/day vs. 1069.00 [722.00-1486.75] mL/day, p < 0.001) and had more positive daily net intake and output (mean [SD], 1,235.06 [1303.14] mL/day vs. 313.17 [744.75] mL/day, p = 0.012), lower [HbO 2 ] and [HbT] over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher [H 2 O] on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with [HbO 2 ] and [HbT] (rho = - 0.246 and - 0.266, p = 0.042 and 0.027, respectively) but positively correlated with [H 2 O] (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and [H2O] in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on [H 2 O] (standardized coefficient = 0.281, p = 0.038)., Conclusions: In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation., (© 2023. The Author(s).)

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform., Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC., Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort., Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies., Competing Interests: P.J.C. is the consultant and received a grant from TCM Biotech. S.T.T., C.F.H., and Y.C.W. are employees of TCM Biotech., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Primary sclerosing cholangitis (PSC) is a rare disease in Asia, and few studies have investigated the disease in this ethnicity, particularly in wait-listed patients for liver transplantation (LT). We aimed to investigate the prognostic factors and outcomes of wait-listed patients with PSC in an Asian transplant center., Methods: Survival was retrospectively analyzed., Results: Eighteen (10 male and 8 female) wait-listed patients with PSC, with a median age at diagnosis of 44.5 years, were included. Compared with men, women had significantly higher aspartate aminotransferase to platelet ratio index scores (3.28 vs. 1.13; P  = 0.012) and bilirubin levels (7.68 vs. 4.03 mg/dl; P  = 0.043) and more often presented with decompensating events, including ascites [5 (63%) vs. 1 (10%); P  = 0.043] and splenomegaly [8 (100%) vs. 4 (40%); P  = 0.013]. Compared with the non-LT group, the LT group exhibited a superior survival rate for women ( P  = 0.004) but not for men. In the univariable analysis, significant risk factors associated with overall survival included malignancies with a hazard ratio (95% confidence interval) of 5.53 (1.00-30.51) and esophageal varices (EV) [4.18 (1.05-16.61)], whereas female gender [25.00 (1.49-500.00)], LT [0.09 (0.01-0.80)] and EV [39.03 (2.92-521.96)] were indicated in the multivariable analysis., Conclusions: For Asian wait-listed patients with PSC, EV and female gender were the risk factors related to overall survival, and LT was the protective factor. Our experiences suggested that LT brings more benefits in female patients. Strategies are needed to provide equivalent transplant benefits., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Sarcopenia is an adverse prognostic factor in patients with liver cirrhosis and hepatocellular carcinoma (HCC). Image-based sarcopenia assessment allows a standardized method to assess abdominal skeletal muscle. However, which is an index muscle for sarcopenia remains unclear. Therefore, we investigated whether sarcopenia defined according to different muscle groups with computed tomography (CT) scans can predict the prognosis of HCC after radioembolization., Methods: In this retrospective study, we analyzed patients who underwent radioembolization for unresectable HCC between January 2010 and December 2019. Before treatment, the total abdominal muscle (TAM), psoas muscle (PM), and paraspinal muscle (PS) areas were evaluated using a single CT slice at the third lumbar vertebra. In previous studies, sarcopenia was determined using the TAM, PM, and PS after stratifying by sex. Finally, we investigated each muscle-defined sarcopenia to decide whether or not it can serve as a prognostic factor for overall survival (OS)., Results: We included 92 patients (74 men and 18 women). TAM, PM, and PS areas were significantly higher in the men than in the women (all p < 0.05). The patients with sarcopenia defined using PM, but not TAM and PS, exhibited significantly poorer OS than those without sarcopenia (median 15.3 vs. 23.8 months, p = 0.034, 0.821, and 0.341, respectively). After adjustment for clinical variables, such as body mass index, liver function, alpha-fetoprotein level, clinical staging, treatment response, and posttreatment curative therapy, PM-defined sarcopenia (hazard ratio: 1.899, 95% confidence interval: 1.087-3.315) remained an independent predictor for the poor OS., Conclusion: CT-assessed sarcopenia defined using PM was an independent prognostic factor for the poorer prognosis of unresectable HCC after radioembolization., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Bipolar Disorder (BD) is known to be equally distributed among males and females. The well-documented increased risk of medical comorbidities in patients with BD, in comparison to BD patients without medical comorbidities, shows a negative impact on the course of illness. There is some evidence suggesting that women with BD have higher psychiatric and medical comorbidities in comparison to men with BD, however there is no evidence in comparison to women without BD or other major psychiatric illness. These comorbidities, along with various psychosocial factors, are known to affect the course of BD., Methods: We aimed to systematically review the literature on cardiovascular, metabolic and endocrine comorbidities in women with BD in comparison to men with BD and control women. A comprehensive search of electronic databases including PubMed, PsycINFO, Embase, and SCOPUS was conducted, and a total of 61 identified studies were included in this review., Results: Women with BD had higher rates of cardiovascular risk factors/mortality, diabetes mellitus II and thyroid disorders compared to women in the general population. In comparison to men with BD, women with BD had comparable cardiovascular risk but higher prevalence of metabolic and thyroid disorders., Limitations: Gender specific data was limited in multiple studies., Conclusions: Results present a need for gender-specific screening and interventions for various medical comorbidities in patients with BD., Competing Interests: Conflict of interest M.F. receives commercial funding from Merck. All other authors report no financial relationships with commercial interests. All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Medication adherence, especially among children and adolescents with psychiatric disorders, is often seen as a major treatment challenge. The purpose of this study is to systematically review studies addressing specific aspects of parental factors that are positively or negatively associated with medication adherence among children and adolescents with psychiatric disorders. A systematic literature search of English language publications, from inception through December 2021, was conducted from PubMed, Scopus, and MEDLINE databases. This review has complied with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. A total of 23 studies (77,188 participants) met inclusion criteria. Nonadherence rates ranged between 8% to 69%. Parents' socioeconomic background, family living status and functioning, parents' perception and attitude towards the importance of medication taking in treating psychiatric disorders, and parents' mental health status are significant parental characteristics associated with medication adherence in children and adolescents with psychiatric disorders. In conclusion, by identifying specific parental characteristics related to the medication adherence of children and adolescents with psychiatric disorders, targeted interventions on parents could be developed to guide parents in improving their child's medication adherence.

Bed is often the personal care unit in hospitals, nursing homes, and individuals' homes. Rich care-related information can be derived from the sensing data from bed. Patient fall is a significant issue in hospitals, many of which are related to getting in and/or out of bed. To prevent bed falls, a motion-sensing mattress was developed for bed-exit detection. A machine learning algorithm deployed on the chip in the control box of the mattress identified the in-bed postures based on the on/off pressure pattern of 30 sensing areas to capture the users' bed-exit intention. This study aimed to explore how sleep-related data derived from the on/off status of 30 sensing areas of this motion-sensing mattress can be used for multiple layers of precision care information, including wellbeing status on the dashboard and big data analysis for living pattern clustering. This study describes how multiple layers of personalized care-related information are further derived from the motion-sensing mattress, including real-time in-bed/off-bed status, daily records, sleep quality, prolonged pressure areas, and long-term living patterns. Twenty-four mattresses and the smart mattress care system (SMCS) were installed in a dementia nursing home in Taiwan for a field trial. Residents' on-bed/off-bed data were collected for 12 weeks from August to October 2021. The SMCS was developed to display care-related information via an integrated dashboard as well as sending reminders to caregivers when detecting events such as bed exits and changes in patients' sleep and living patterns. The ultimate goal is to support caregivers with precision care, reduce their care burden, and increase the quality of care. At the end of the field trial, we interviewed four caregivers for their subjective opinions about whether and how the SMCS helped their work. The caregivers' main responses included that the SMCS helped caregivers notice the abnormal situation for people with dementia, communicate with family members of the residents, confirm medication adjustments, and whether the standard care procedure was appropriately conducted. Future studies are suggested to focus on integrated care strategy recommendations based on users' personalized sleep-related data.