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Rei-Chi Hsueh,1 Wan-Jung Wu,1 Chih-Lin Lin,2 Chun-Jen Liu,3 Yi-Wen Huang,4,5 Jui-Ting Hu,6 Chih-Feng Wu,1 Feng-Yu Sung,1 Wen-Jie Liu,1 Ming-Whei Yu1 1Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 2Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan; 3Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; 4Clinical Research Center, Liver Center and Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 5Division of Gastroenterology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 6Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, TaiwanCorrespondence: Ming-Whei Yu, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No. 17, Xuzhou Road Zhongzheng District, Taipei City, 10055, Taiwan, Email yumw@ntu.edu.twBackground: Coexistence of hepatitis B and nonalcoholic fatty liver disease is common; however, little is known about the impact of hepatic steatosis and its major genetic determinants on the natural history of HBV infection. We aimed to study the effects of hepatic steatosis and PNPLA3 variant p.I148M on the risk of hepatocellular carcinoma (HCC) and the lifetime probability of HBsAg seroclearance, which is associated with functional remission and improved long-term outcome of HBV infection.Methods: We conducted a cohort study of 2385 male, HBsAg-positive Taiwanese civil servants recruited in 1989– 1992, and followed up until 2019. Cox regression with competing-risk models was used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs).Results: Of 2385 participants, 628 experienced HBsAg seroclearance and 217 developed HCC. Hepatic steatosis, excess body-mass index, and the PNPLA3-148M variant were significantly associated with higher HBsAg seroclearance rate. However, multivariate analyses accounting for HBsAg seroclearance and various HCC risk factors showed that, while steatosis was associated with decreased HCC risk (sHR [95% CI]: 0.49 [0.36– 0.66]), carriage of the PNPLA3-148M variant allele (vs II homozygotes: 1.64 [1.20– 2.25] for MI heterozygotes; 1.83 [1.20– 2.78] for MM homozygotes) and obesity (1.51 [1.07– 2.13]) were associated with increased risk. The inverse hepatic steatosis-HCC association persisted after additional adjustment for other viral factors or using different follow-up time cut-offs to account for reverse causality. Moreover, the PNPLA3 MM genotype was positively associated with elevations of ALT and AST and liver cirrhosis, while hepatic steatosis was positively associated with ALT but inversely associated with AST and liver cirrhosis.Conclusion: Hepatic steatosis and PNPLA3-148M variant appeared to have distinct impacts on the development of HBV-related progressive liver disease and HCC. PNPLA3 p.I148M, but not a diagnosis of hepatic steatosis, can help to identify HBV carriers with high-risk fatty liver disease in the progression to HCC.Keywords: chronic hepatitis B, HBsAg seroclearance, hepatic steatosis, hepatocellular carcinoma, liver cirrhosis, PNPLA3

Yu-Chan Yang,1 Ke Zeng,2 Wei Wang,2 Zhi-Gang Gong,1 Yi-Lei Chen,1 Jian-Ming Cheng,1 Min Zhang,1 Yan-Wen Huang,1 Xin-Bo Men,2 Jian-Wei Wang,2 Songhua Zhan,1 Wen-Li Tan1 1Department of Radiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Massage, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Songhua Zhan; Wen-Li TanDepartment of Radiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, People’s Republic of China, Email zhansonghua@sina.com; 13764935974@163.comObjective: To investigate the changes of regional homogeneity (Reho) values before and after spinal manipulative therapy (SMT) in patients with chronic low back pain (CLBP) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI).Methods: Patients with CLBP (Group 1, n = 20) and healthy control subjects (Group 2, n = 20) were recruited. The fMRI was performed three times in Group 1 before SMT (time point 1, TP1), after the first SMT (time point 2, TP2), after the sixth SMT (time point 3, TP3), and for one time in Group 2, which received no intervention. The clinical scales were finished in Group 1 every time before fMRI was performed. The Reho values were compared among Group 1 at different time points, and between Group 1 and Group 2. The correlation between Reho values with the statistical differences and the clinical scale scores were calculated.Results: The bilateral precuneus and right mid-frontal gyrus in Group 1 had different Reho values compared with Group 2 at TP1. The Reho values were increased in the left precuneus and decreased in the left superior frontal gyrus in Group 1 at TP2 compared with TP1. The Reho values were increased in the left postcentral gyrus and decreased in the left posterior cingulate cortex and the superior frontal gyrus in Group 1 at TP3 compared with TP1. The ReHo values of the left precuneus in Group 1 at TP1 were negatively correlated with the pain degree at TP1 and TP2 (r = − 0.549, − 0.453; p = 0.012, 0.045). The Reho values of the middle temporal gyrus in Group 1 at TP3 were negatively correlated with the changes of clinical scale scores between TP3 and TP1 (r = 0.454, 0.559; p = 0.044, 0.01).Conclusion: Patients with CLBP showed abnormal brain function activity, which was altered after SMT. The Reho values of the left precuneus could predict the immediate analgesic effect of SMT.Keywords: blood-oxygen-level-dependent functional magnetic resonance imaging, spinal manipulation therapy, chronic low back pain, regional homogeneity

Guannan Yang, Zongjiang Zhao, Xinxue Zhang, Amin Wu, Yawei Huang, Yonghui Miao, Meijuan Yang School of Basic Medical Science, Beijing University of Chinese Medicine, Beijing, People’s Republic of China Abstract: Renal tubular epithelial-to-mesenchymal transition (EMT) and renal tubular interstitial fibrosis are the main pathological changes of diabetic nephropathy (DN), which is a common cause of end-stage renal disease. Previous studies have suggested that berberine (BBR) has antifibrotic effects in the kidney and can reduce apoptosis and inhibit the EMT of podocytes in DN. However, the effect of BBR on the renal tubular EMT in DN and its mechanisms of action are unknown. This study was performed to explore the effects of BBR on the renal tubular EMT and the molecular mechanisms of BBR in DN model KKAy mice and on the high glucose (HG)-induced EMT in mouse renal tubular epithelial cells. Our results showed that, relative to the model mice, the mice in the treatment group had an improved general state and reduced blood glucose and 24-h urinary protein levels. Degradation of renal function was ameliorated by BBR. We also observed the protective effects of BBR on renal structural changes, including normalization of an index of renal interstitial fibrosis and kidney weight/body weight. Moreover, BBR suppressed the activation of the Notch/snail pathway and upregulated the α-SMA and E-cadherin levels in DN model KKAy mice. BBR was further found to prevent HG-induced EMT events and to inhibit the HG-induced expression of Notch pathway members and snail1 in mouse renal tubular epithelial cells. Our findings indicate that BBR has a therapeutic effect on DN, including its inhibition of the renal tubular EMT and renal interstitial fibrosis. Furthermore, the BBR-mediated EMT inhibition occurs through Notch/snail pathway regulation. Keywords: berberine, EMT, renal interstitial fibrosis, diabetic nephropathy, Notch/snail pathway

Yong-Wen Huang,1,* Yun Zhou,1,* Chun-Yan Lan,1 Yin Wang,1 Yan-Ling Feng,1 Rong-Zhen Luo,2 Ji-Hong Liu1 1Department of Gynecology, 2Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status. Methods: Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining. Results: Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P

Chu-Han Gao,1 Lu-Shan Yu,2 Su Zeng,2 Yu-Wen Huang,1 Quan Zhou11Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, 2Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaBackground: Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic–pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary.Methods: Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic–pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed.Results: In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic–pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be associated with sample size and administration route. Children younger than 5 years cleared LVX nearly twice as fast as adults. Patients in intensive care receiving LVX therapy showed significant pharmacokinetic differences compared with healthy subjects. Creatinine clearance explained most of the population variance in the plasma clearance of LVX. Switching from intravenous to oral delivery of LVX had economic benefits. Addition of tamsulosin to the LVX regimen was beneficial for patients with bacterial prostatitis because tamsulosin could increase the maximal concentration of LVX in prostatic tissue. Coadministration of multivalent cation-containing drugs and LVX should be avoided. For patients receiving warfarin and LVX concomitantly, caution is needed regarding potential changes in the international normalized ratio; however, it is unnecessary to seek alternatives to LVX for the sake of avoiding drug interaction with warfarin. It is unnecessary to proactively reduce the dose of cyclosporin or tacrolimus when comedicated with LVX. Transporters such as organic anion-transporting polypeptide 1A2, P-glycoprotein, human organic cation transporter 1, and multidrug and toxin extrusion protein 1 are involved in the pharmacokinetics of LVX.Conclusion: Personalized LVX therapeutics are necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of LVX in special patient populations and active transport mechanisms in vivo are opening up new horizons in clinical practice.Keywords: drug interactions, fluoroquinolone resistance, individual dosing, patient complexity, personalized medicine, pharmacokinetics, pharmacodynamics, therapeutics

Yi-Ting Zhou,1 Lu-Shan Yu,2 Su Zeng,2 Yu-Wen Huang,1 Hui-Min Xu,1 Quan Zhou11Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, 2Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaBackground: Coadministration of 1,4-dihydropyridine calcium channel blockers (DHP-CCBs) with statins (or 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) is common for patients with hypercholesterolemia and hypertension. To reduce the risk of myopathy, in 2011, the US Food and Drug Administration (FDA) Drug Safety Communication set a new dose limitation for simvastatin, for patients taking simvastatin concomitantly with amlodipine. However, there is no such dose limitation for atorvastatin for patients receiving amlodipine. The combination pill formulation of amlodipine/atorvastatin is available on the market. There been no systematic review of the pharmacokinetic drug–drug interaction (DDI) profile of DHP-CCBs with statins, the underlying mechanisms for DDIs of different degree, or the corresponding management of clinical risk.Methods: The relevant literature was identified by performing a PubMed search, covering the period from January 1987 to September 2013. Studies in the field of drug metabolism and pharmacokinetics that described DDIs between DHP-CCB and statin or that directly compared the degree of DDIs associated with cytochrome P450 (CYP)3A4-metabolized statins or DHP-CCBs were included. The full text of each article was critically reviewed, and data interpretation was performed.Results: There were three circumstances related to pharmacokinetic DDIs in the combined use of DHP-CCB and statin: 1) statin is comedicated as the precipitant drug (pravastatin–nimodipine and lovastatin–nicardipine); 2) statin is comedicated as the object drug (isradipine–lovastatin, lacidipine–simvastatin, amlodipine–simvastatin, benidipine-simvastatin, azelnidipine–simvastatin, lercanidipine–simvastatin, and amlodipine–atorvastatin); and 3) mutual interactions (lercanidipine–fluvastatin). Simvastatin has an extensive first-pass effect in the intestinal wall, whereas atorvastatin has a smaller intestinal first-pass effect. The interaction with simvastatin seems mainly driven by CYP3A4 inhibition at the intestinal level, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition. The interaction of CYP3A4 inhibitor with simvastatin has been more pronounced compared with atorvastatin. From the current data, atorvastatin seems to be a safer CYP3A4-statin for comedication with DHP-CCB. There is no convincing evidence that amlodipine is an unusual DHP-CCB, either as a precipitant drug or as an object drug, from the perspective of CYP3A4-mediated drug metabolism. Amlodipine may have interactions with CYP3A5 in addition to CYP3A4, which may explain its particular characteristics in comparison with other DHP-CCBs. The degree of DDIs between the DHP-CCB and statin and the clinical outcome depends on many factors, such as the kind of statin, physicochemical proprieties of the DHP-CCB, the dose of either the precipitant drug or the object drug, the sex of the patient (eg, isradipine–lovastatin), route of drug administration (eg, oral versus intravenous nicardipine–lovastatin), the administration schedule (eg, nonconcurrent dosing method versus concurrent dosing method), and the pharmacogenetic status (eg, CYP3A5-nonexpressers versus CYP3A5-expressers).Conclusion: Clinical professionals should enhance risk management regarding the combination use of two classes of drugs by increasing their awareness of the potential changes in therapeutic efficacy and adverse drug reactions, by rationally prescribing alternatives, by paying attention to dose adjustment and the administration schedule, and by review of the appropriateness of physician orders. Further study is needed – the DDIs between DHP-CCBs and statins have not all been studied in humans, from either a pharmacokinetic or a clinical perspective; also, the strength of the different pharmacokinetic interactions of DHP-CCBs with statins should be addressed by systematic investigations.Keywords: CYP3A4, 1,4-dihydropyridine, drug–drug interactions, HMG-CoA reductase inhibitors, myopathy, polypharmacy, physicochemical phenomena, prescription auditing

Hsin-chung Lee,1,2 Qing-Dong Ling,1,3 Wan-Chun Yu,4 Chunh-Ming Hung,4 Ta-Chun Kao,4 Yi-Wei Huang,4 Akon Higuchi3–51Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taoyuan, 2Department of Surgery, Cathay General Hospital, Da'an District, Taipei, 3Cathay Medical Research Institute, Cathay General Hospital, Hsi-Chi City, Taipei, 4Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan; 5Department of Reproduction, National Research Institute for Child Health and Development, Okura, Tokyo, JapanPurpose: We evaluated the higher levels of carcinoembryonic antigen (CEA) secreted by the LoVo human colon carcinoma cells in a medium containing anticancer drugs. Drug-resistant LoVo cells were analyzed by subcutaneously xenotransplanting them into mice. The aim of this study was to evaluate whether the drug-resistant cells isolated in this study were cancer-initiating cells, known also as cancer stem cells (CSCs).Methods: The production of CEA was investigated in LoVo cells that were cultured with 0–10 mM of anticancer drugs, and we evaluated the increase in CEA production by the LoVo cells that were stimulated by anticancer drug treatment. The expression of several CSC markers in LoVo cells treated with anticancer drugs was also evaluated. Following anticancer drug treatment, LoVo cells were injected subcutaneously into the flanks of severe combined immunodeficiency mice in order to evaluate the CSC fraction.Results: Production of CEA by LoVo cells was stimulated by the addition of anticancer drugs. Drug-resistant LoVo cells expressed lower levels of CSC markers, and LoVo cells treated with any of the anticancer drugs tested did not generate tumors within 8 weeks from when the cells were injected subcutaneously into severe combined immunodeficiency mice. These results suggest that the drug-resistant LoVo cells have a smaller population of CSCs than the untreated LoVo cells.Conclusion: Production of CEA by LoVo cells can be stimulated by the addition of anticancer drugs. The drug-resistant subpopulation of LoVo colon cancer cells could stimulate the production of CEA, but these cells did not act as CSCs in in vivo tumor generation experiments.Keywords: drug treatment, colon cancer cell, 5-fluorouracil, stem cell, CD133

In 2015, ASEAN established a goal of increasing its renewable energy share in its energy portfolio from approximately 13–23% by 2025. Renewable electricity, especially intermittent and variable sources, presents challenges for grid operators due to the uncertain timing and quantity of electricity supply. Grid flexibility, the electric grid's ability to respond to changing demands and supply, now stands a key resource in responding to these uncertainties while maximizing the cost-effective role of clean energy. We develop and apply a grid flexibility assessment tool to assess ASEAN's current grid flexibility using six quantitative indicators: grid reliability, electricity market access; load profile ramp capacity; quality of forecasting tools; proportion of electricity generation from natural gas; and renewable energy diversity. We find that ASEAN nations cluster into three groups: better; moderately; and the least prepared nations. We develop an analytical ramp rate calculator to quantify expected load ramps for ASEAN in an integrated ASEAN Power Grid scenario. The lack of forecasting systems and limited electricity market access represent key weaknesses and areas where dramatic improvements can become cost-effective means to increase regional grid flexibility. As ASEAN pursues renewable energy targets, regional cooperation remains essential to address identified challenges. Member nations need to increase grid flexibility capacity to adequately prepare for higher penetrations of renewable electricity and lower overall system costs.

Background: Endoscopic endonasal approaches (EEAs) are an efficient way to manage skull base lesions; however, studies regarding postoperative rhinosinusitis are limited. This study analyzed the incidence of postoperative rhinosinusitis, the associated risk factors, microbial species, and antibiotic usage in patients who underwent EEA., Methods: Patients who underwent EEAs at a tertiary referral hospital between July 2015 and May 2019 were retrospectively evaluated. Postoperative rhinosinusitis was defined as the presence of a purulent nasal discharge on postoperative endoscopic examination. The mucopus was aspirated and subjected to bacterial culture analysis. The culture results of various groups were analyzed., Results: This study included 300 patients, and the incidence of post-EEA rhinosinusitis was 59.7%. History of endonasal surgery was an independent predictive factor for post-EEA rhinosinusitis [OR 2.547 (1.284-5.052), p= 0.007]. Lesions in the anterior skull base were associated with prolonged use of antibiotics for rhinosinusitis during postoperative care [OR 3.914 (1.329-11.524), p=0.013]. Staphylococcus aureus was the most common causative pathogen, followed by methicillin-resistant Staphylococcus aureus (MRSA) (20.7%), Pantoea dispersa (14.4%), and Pseudomonas aeruginosa (11.7%). P. aeruginosa was more significant in the complex reconstruction group than in the control group. While most patients with post-EEA rhinosinusitis experienced a transient clinical course, one female patient underwent ESS for prolonged rhinosinusitis., Conclusion: Rhinosinusitis is common in the postoperative stage of the EEA. As it usually lasts for a short duration and is treatable with proper medication, aggressive nasal care during the postoperative period is required to prevent related nasal morbidities., Competing Interests: Conflicts of interest: Dr. Ming-Ying Lan, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

The COVID-19 global pandemic exposed healthcare system vulnerabilities, further endangering patient safety. This article explores perspectives on resilience and patient safety among healthcare workers using data from the Taiwan Patient Safety Culture Survey (TPSCS) and implementing Patient Safety Leadership Walkrounds (PSLWs) at E-Da Hospital. In 2021 and 2022, 1340 and 1114 staff members from clinical departments completed TPSCS questionnaires, respectively. 89 leaders from clinical departments participated in PSLWs in 2022. Among the four job categories, scores of Safety Attitude Questionnaire (SAQ) were lower among nurses and medical technicians, while perceptions of resilience and work-life balance were lowest among nurses. Between the two-year surveys, nurses exhibited significant decreases in SAQ in 2022 compared to 2021, while perceptions of work condition and work-life balance significantly declined among pharmacists. Resilience perception significantly decreased among all job categories except physicians during the pandemic. Mediation analyses showed teamwork climate, job satisfaction, management, work condition, and work-life balance were directly associated with safety climate, while resilience acts as a mediator, indirectly potentiating these relationships. Through PSLWs, we identified concerns about patient safety, including workforce, systems, processes, equipment, and work environment. Among these, workforce shortages and unsatisfactory pay emerged as the most pressing challenges. Strong leadership was recognized as a crucial factor in enhancing resilience and patient safety. This study suggests that TPSCS and PSLWs are worth regularly promoting among hospital institutions. Additionally, our findings highlight the urgency of healthcare organizations and governmental agencies to undertake policy reforms to improve healthcare workers' well-being., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the clinical trajectories and identify risk factors linked to post-enucleation urinary incontinence (UI)., Patients and Methods: In this prospective study (April 2020 to March 2022) at a single institution, 316 consecutive patients receiving endoscopic enucleation due to benign prostatic enlargement were included. Patient information and perioperative details were collected. Follow-ups, from 1 to 6 months, assessed postoperative UI using International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and a four-item pad questionnaire, classified per International Continence Society definitions. Logistic regression analysed predictors at 1 week, while generalised estimating equation assessed risk factors from 1 to 3 months postoperatively., Results: Patients with a median prostate volume of 57 mL underwent enucleation, with 22.5% experiencing postoperative UI at 1 week, 5.6% at 3 months, decreasing to 1.9% at 6 months. Multivariable analysis identified age (>80 years), specimen weight (>70 g), en bloc with anteroposterior dissection, and anal tone (Digital Rectal Examination Scoring System score <3) as potential factors influencing UI. Subgroup analysis revealed that specimen weight was associated with both continuous and stress UI. Anal tone was related to both other types and stress UI, while overactive bladder symptoms were associated with urge UI., Conclusion: In summary, our study elucidates transient risk factors contributing to temporary post-enucleation UI after prostatectomy. Informed decisions and personalised interventions can effectively alleviate concerns regarding postoperative UI., (© 2024 BJU International.)

The occurrence and development of cancer involves the participation of many factors, its pathological mechanism is far more complicated than other diseases, and the treatment is also extremely difficult. Although the treatment of cancer adopts diversified methods to improve the survival rate and quality of life of patients, but the drug resistance, metastasis and recurrence of cancer cause most patients to fail in treatment. Therefore, exploring new molecular targets in cancer pathology is of great value for improving and preventing the treatment of cancer. Fortunately, the P2Y2 purinergic receptor (P2Y2 receptor) in the G protein-coupled receptor family has been recognized for regulating cancer progression. Agonist activated P2Y2 receptor has a certain contribution to the growth and metastasis of tumor cells. P2Y2 receptor activation participates in cancer progression by regulating calcium ion channels and classical signaling pathways (such as PLC-PKC and PI3K/AKT). It has the effect of anti-tumor therapy by inhibiting the activation of P2Y2 receptor (the use of antagonist) and reducing its expression. Therefore, in this article, we focus on the expression patterns of P2Y2 receptor in cancer and potential pharmacological targets as anti-cancer treatments., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gaultheria Kalm ex L. (Ericaceae), a type of evergreen shrub, known as a natural source of methyl salicylate, possesses rich germplasm resources, strong habitat adaptability, significant ornamental value, and noteworthy pharmacological activities. However, due to the paucity of whole genomic information, genetically deep research in these areas remains limited. Consequently, we intend to obtain genome data through high-throughput sequencing, gene annotation, flow cytometry, transcription factors prediction and genetic marker analysis for a representative species of this genus, with Gaultheria prostrata selected for our study. In this study, we preliminarily obtained the genome of G. prostrata through next-generation sequencing methods. Utilizing 47.94 Gb of high-quality sequence data (108.95× coverage), assembled into 114,436 scaffolds, with an N50 length of 33,667 bp. The genome size assembled by SOAPdenovo, approximately 417 Mb, corresponded closely to predictions by flow cytometry (440 Mb) and k -mer analysis (447 Mb). The genome integrity was evaluated using BUSCO with 91%. The heterozygosity ratio was 0.159%, the GC content was 38.85%, and the repetitive regions encompassed over 34.6% of the genome. A total of 26,497 protein-coding genes have been predicted and annotated across Nr, Swissprot, GO, KEGG, and Pfam databases. Among these, 14,377 and 2,387 genes received functional annotation in Nr and Swissprot, respectively; 21,895, 24,424, and 22,330 genes were similarly annotated in GO, KEGG, and Pfam. Moreover, A total of 279,785 SSRs were identified and 345,270 primers for these SSRs were designed. Within the various nucleotide types of SSRs, AG/CT and AAG/CTT constituted the predominant dinucleotide and trinucleotide repeat types in G. prostrata . In addition, 1,395 transcription factors (TFs) from 75 TF families, 462 transcription regulators (TRs) from 33 TR families and 840 protein kinase (PKs) from 118 PK families were identified in this genome. We also performed phylogenetic analyses of G. prostrata and related species, including estimation of divergence times and expansion and contraction analyses, followed by positive selection analyses of orthologous gene pairs of G. prostrata and its close relative Vaccinium corymbosum . These results provide a reference for in-depth study of genus Gaultheria , contributing to future functional and comparative genomics analyses and providing supporting data for the development of molecular markers., Competing Interests: The 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 © 2024 Lin, Ding, Huang and Lu.)

Background: The effects of age at HBsAg seroclearance on clinical outcomes and survival in chronic hepatitis B (CHB) have not been adequately assessed. We evaluated the impact of age at HBsAg seroclearance on long-term outcomes, along with how coexisting factors modified risks and life expectancy in CHB patients., Methods: We used multi-state modeling approach to examine transitions through the CHB continuum in a longitudinal cohort study of male civil servants recruited in 1989-1992. Hepatic outcomes and deaths were identified by clinical evaluation and linkage with national health databases. Four sets of risk factors (CHB-related, metabolic, lifestyle, and genetic factors) were assessed., Results: Of 2551 HBsAg carriers, with follow-up until 2021 or death, 695 achieved HBsAg seroclearance, 490 developed cirrhosis (88 decompensated), 252 developed hepatocellular carcinoma (HCC), and 652 died. The cumulative rates for HCC were 1.1% and 1.5% at 10 years after HBsAg seroclearance, respectively, for patients achieving seroclearance at age 50 and 60; correspondingly, the rates for cirrhosis were 2.3% and 3.0%. Developing HBsAg seroclearance was associated with a reduced risk of cirrhosis (HR = 0.37, 95% CI 0.15-0.92) but not HCC. Patients experiencing HBsAg seroclearance lived longer years free of major liver diseases than HBsAg-persistent patients, and achieving seroclearance at age 50 (vs 60) led to a greater increase in the disease-free life expectancy. However, obesity and smoking were associated with adverse hepatic outcomes and loss of the disease-free life expectancy following HBsAg seroclearance., Conclusions: Our findings highlight the benefit of earlier HBsAg seroclearance for gains in disease-free life expectancy and the impact of obesity and smoking on loss of the life years free of major liver diseases following HBsAg seroclearance., (© 2024. Japanese Society of Gastroenterology.)

Background: Bedaquiline, delamanid and fluoroquinolones are associated with increased QTcF. Whether clofazimine is associated with QTcF prolongation is less clear., Methods: All patients with rifampicin-resistant TB enrolled between May 2017 and Dec 2019 were included. ECGs were performed at baseline, month 1, month 3 and month 6 for patients treated with conventional regimens, and at additional timepoint for patients treated with bedaquiline, delamanid and short regimen. We estimated the maximum increase of QTcF and constructed cox proportional hazards models to assess factors associated with QTcF≥501ms., Results: Among 321 patients, 59 (18.4%) patients had QTcF≥501ms during a mean follow-up of 242 days (median 189, range 4-1091). The median maximum increase of QTcF was 43.4 ms (IQR 31.3-65.9) in patients treated with clofazimine. Treatment with clofazimine was significantly associated with QTcF≥501ms as compared to without clofazimine (adjusted hazards ratio (adjHR) 4.35, 95% confidence interval (CI) 2.01-9.44). Among patients not treated with bedaquiline and delamanid, those treated with clofazimine and a fluoroquinolone (adjHR 3.43, 95% CI 1.61-7.34) and those treated with clofazimine and high dose moxifloxacin (adjHR 6.54, 95% CI 2.43-17.60) had a significantly higher risk of QTcF≥501ms as compared to those treated with a fluoroquinolone without other QTcF prolonging agents. Four (1.6%) patients had documented ventricular tachycardia, in which one was Torsade de pointes. One patient was found to have sudden death during hospitalization., Conclusions: Clofazimine was significantly associated with an increased risk of QTcF prolongation. QTcF≥501ms was potentially associated with fatal event and needed to be managed cautiously., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier B.V.)

Accumulation of abnormal chondroitin sulfate (CS) chains in breast cancer tissue is correlated with poor prognosis. However, the biological functions of these CS chains in cancer progression remain largely unknown, impeding the development of targeted treatment focused on CS. Previous studies identified chondroitin polymerizing factor (CHPF; also known as chondroitin sulfate synthase 2) is the critical enzyme regulating CS accumulation in breast cancer tissue. We then assessed the association between CHPF-associated proteoglycans (PGs) and signaling pathways in breast cancer datasets. The regulation between CHPF and syndecan 1 (SDC1) was examined at both the protein and RNA levels. Confocal microscopy and image flow cytometry were employed to quantify macropinocytosis. The effects of the 6-O-sulfated CS-binding peptide (C6S-p) on blocking CS functions were tested in vitro and in vivo. Results indicated that the expression of CHPF and SDC1 was tightly associated within primary breast cancer tissue, and high expression of both genes exacerbated patient prognosis. Transforming growth factor beta (TGF-β) signaling was implicated in the regulation of CHPF and SDC1 in breast cancer cells. CHPF supported CS-SDC1 stabilization on the cell surface, modulating macropinocytotic activity in breast cancer cells under nutrient-deprived conditions. Furthermore, C6S-p demonstrated the ability to bind CS-SDC1, increase SDC1 degradation, suppress macropinocytosis of breast cancer cells, and inhibit tumor growth in vivo. Although other PGs may also be involved in CHPF-regulated breast cancer malignancy, this study provides the first evidence that a CS synthase participates in the regulation of macropinocytosis in cancer cells by supporting SDC1 expression on cancer cells., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Polyurethane foam (PUF) pads are widely used in semiconductor manufacturing, particularly for chemical mechanical polishing (CMP). This study prepares PUF composites with microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC) to improve CMP performance. MCC and NCC were characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD), showing average diameters of 129.7 ± 30.9 nm for MCC and 22.2 ± 6.7 nm for NCC, both with high crystallinity (ca. 89%). Prior to preparing composites, the study on the influence of the postbaked step on the PUF was monitored through Fourier-transform infrared spectroscopy (FTIR). After that, PUF was incorporated with MCC/NCC to afford two catalogs of polyurethane foam composites (i.e., PUFC-M and PUFC-N). These PUFCs were examined for their thermal and surface properties using a differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), dynamic mechanical analyzer (DMA), and water contact angle (WCA) measurements. T g s showed only slight changes but a notable increase in the 10% weight loss temperature ( T d10% ) for PUFCs, rising from 277 °C for PUF to about 298 °C for PUFCs. The value of Tan δ dropped by up to 11%, indicating improved elasticity. Afterward, tensile and abrasion tests were conducted, and we acquired significant enhancements in the abrasion performance (e.g., from 1.04 mm/h for the PUF to 0.76 mm/h for a PUFC-N) of the PUFCs. Eventually, we prepared high-performance PUFCs and demonstrated their capability toward the practical CMP process.

Background and Aim: Currently, hepatitis B virus-related acute liver failure (HBV-ALF) has limited treatment options. Studies have shown that histone lactylation plays a role in the progression of liver-related diseases. Therefore, it is essential to explore lactylation-related gene (LRGs) biomarkers in HBV-ALF to provide new information for the treatment of HBV-ALF., Methods: Two HBV-ALF-related datasets (GSE38941 and GSE14668) and 65 LRGs were used. First, the differentially expressed genes (DEGs) were derived from differential expression analysis, the key module genes from weighted gene co-expression network analysis; and LRGs were used to intersect to obtain the candidate genes. Subsequently, the feature genes obtained from least absolute shrinkage and selection operator regression analysis and support vector machine analysis were intersected to obtain the candidate key genes. Among them, genes with consistent and significant expression trends in both GSE38941 and GSE14668 were used as biomarkers. Subsequently, biomarkers were analyzed for functional enrichment, immune infiltration, and sensitive drug prediction., Results: In this study, five candidate genes (PIGM, PIGA, EGR1, PIGK, and PIGL) were identified by intersecting 6461 DEGs and 2496 key module genes with 65 LRGs. We then screened four candidate key genes from the machine learning algorithm, among which PIGM and PIGA were considered biomarkers in HBV-ALF. Moreover, the results of enrichment analysis showed that the significant enrichment signaling pathways for biomarkers included allograft rejection and valine, leucine, and isoleucine degradation. Thereafter, 11 immune cells differed significantly between groups, with resting memory CD4+ T cells having the strongest positive correlation with biomarkers. Methylphenidate hydrochloride is a potential therapeutic drug for PIGM., Conclusion: Two genes, PIGM and PIGA, were identified as biomarkers related to LRGs in HBV-ALF, providing a basis for understanding HBV-ALF pathogenesis., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: The innate immune response, particularly the reaction of polymorphonuclear neutrophils (PMNs), is crucial in shaping the outcomes of chronic inflammation, fibrosis, or osseointegration following biomaterial implantation. Peri-implantitis or peri-mucositis, inflammatory conditions linked to dental implants, pose a significant threat to implant success. We developed a single-cell analysis approach using a murine model to assess the immune response to implant materials, offering a practical screening tool for potential dental implants., Methods: We performed bioinformatics analysis and established a peri-implant inflammation model by inserting two titanium implants into the maxillary region, to examine the immune response., Results: Bioinformatics analysis revealed that titanium implants triggered a host immune response, primarily mediated by PMNs. In the in vivo experiments, we observed a rapid PMN-mediated response, with increased infiltration around the implants and on the implant surface by day 3. Remarkably, PMN attachment to the implants persisted for 7 days, resembling the immune profiles seen in human implant-mediated inflammation., Conclusions: Our findings indicate that persistent attachment of the short-living PMNs to titanium implants can serve as an indicator or traits of peri-implant inflammation. Therefore, analyzing gingival tissue at the single-cell level could be a useful tool for evaluating the biocompatibility of candidate dental implants.

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases., Competing Interests: Declaration of Competing Interest The authors declare no competing interestsm., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Sarcopenia, characterized by age-related loss of muscle mass and function, poses a significant public health concern, particularly in Asia's rapidly aging population. This systematic review and meta-analysis aimed to evaluate the current epidemiology of sarcopenia in Asia using the 2019 Asian Working Group for Sarcopenia (AWGS) diagnostic criteria., Methods: Databases including PubMed, Embase, Web of Science, and Cochrane were systematically searched for studies published until December 7, 2023, involving older adults aged ≥ 60 years diagnosed with sarcopenia using the 2019 AWGS criteria in Asia. Study quality was assessed, and meta-analyses were conducted to estimate the pooled prevalence of sarcopenia, possible sarcopenia, and severe sarcopenia., Results: A total of 140 studies, collectively involving 156,325 participants (67.1 % community-dwelling older adults with the minimum age for participant inclusion ranging from 60 to 80 years) from various Asian countries, were included. The overall prevalence of sarcopenia among community-dwelling older adults was 16.5 % (95 % CI: 14.7 %-18.4 %). Notably, the prevalence of possible sarcopenia was higher at 28.7 % (95 % CI: 22.0 %-36.5 %), while severe sarcopenia had a lower prevalence of 4.4 % (95 % CI: 3.3 %-5.8 %). Subgroup analyses revealed variations in sarcopenia prevalence based on diagnostic modalities, ranging from 7.5 % (95 % CI: 6.0 %-9.4 %) for assessments using bioelectrical impedance analysis, handgrip strength, gait speed, chair stand and short physical performance battery, to 20.8 % (95 % CI: 18.9 %-23.0 %) when using dual-energy X-ray absorptiometry coupled with muscle strength and physical performance measures., Conclusion: This comprehensive systematic review and meta-analysis highlights the substantial burden of sarcopenia among older adults in Asia, underscoring the need for early identification and intervention strategies to mitigate its adverse consequences on public health., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho -phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f . Compared to LH4f , most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC 50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Aims: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis., Methods: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein., Results: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1., Conclusion: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies., Competing Interests: GenomeFrontier Therapeutics TW Co., Ltd. funded the study and played a crucial role in the study design, data collection and analysis, decision to publish, and preparation of the manuscripts. The coauthors – Peter S. Chang, Yi-Chun Chen, Wei-Kai Hua, Jeff C. Hsu, Jui-Cheng Tsai, Yi-Wun Huang, Yi-Hsin Kao, Pei-Hua Wu, Kuo-Lan Karen Wen, and Sareina Chiung-Yuan Wu – are affiliated with GenomeFrontier Therapeutics TW Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nonlocal metasurfaces, exemplified by resonant waveguide gratings (RWGs), spatially and angularly configure optical wavefronts through narrow-band resonant modes, unlike the broad-band and broad-angle responses of local metasurfaces. However, forward design techniques for RWGs remain constrained at lower efficiency. Here, we present a topology-optimized metasurface resonant waveguide grating (MRWG) composed of titanium dioxide on a glass substrate capable of operating simultaneously at red, yellow, green, and blue wavelengths. Through adjoint-based topology optimization, while considering nonlocal effects, we significantly enhance its diffraction efficiency, achieving numerical efficiencies up to 78% and Q -factors as high as 1362. Experimentally, we demonstrated efficiencies of up to 59% with a Q -factor of 93. Additionally, we applied our topology-optimized metasurface to color selectivity, producing vivid colors at 4 narrow-band wavelengths. Our investigation represents a significant advancement in metasurface technology, with potential applications in see-through optical combiners and augmented reality platforms.

Aim: To examine the dynamic change in hepatic steatosis status during repeated assessments over time, and its potential impact on the risk of developing cardiovascular disease (CVD)., Methods: We assessed trajectories of hepatic steatosis and other metabolic disorders in 3134 middle-aged adults undergoing longitudinal assessment of ultrasonography during a pre-baseline period (1993-2009) in a population-based cohort study of liver health. Subsequently, we determined the association of hepatic steatosis trajectories with the incidence of CVD among 2185 CVD-free individuals, followed until 2021. Metabolic risk factors and cardiovascular events (including coronary heart disease and stroke) were determined through medical examination and linkage with nationwide health databases., Results: We identified three discrete trajectories of hepatic steatosis according to changing pattern over time through group-based trajectory modeling: "stable, non-steatosis" (n = 1298), "intermittent" (n = 921), and "persistent steatosis" (n = 915). During the pre-baseline period, hepatic steatosis trajectories were associated with trajectories of developing diabetes and hypertension, and persistent steatosis (vs. other trajectories) was associated with higher risks and rapidly progressive disease patterns. At a median 13.6 years of follow-up, 629 CVD events occurred. A persistent (vs. non-steatosis: HR 1.44, 95% CI 1.17-1.76), but not intermittent, steatosis pattern predicted the future risk of CVD, after adjustment for age, sex, smoking, and obesity. This association was independent of genetic background, and remained after accounting for pre-baseline body-mass index, other cardiometabolic risk factors, Framingham risk score, medications, and hepatic fibrosis score., Conclusions: The persistence of hepatic steatosis is associated with trajectories of metabolic disorder development and increased risk of CVD. These data have important implications for practice and further research., (© 2024 Japan Society of Hepatology.)

Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro . Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo , with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs. Abbreviations : 3-MA: 3-methyladenine; Baf A1: bafilomycin A 1 ; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID 50 : 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.

Study Objectives: The gold standard for diagnosing obstructive sleep apnea (OSA) is polysomnography (PSG). However, PSG is a time-consuming method with clinical limitations. This study aimed to create a wireless radar framework to screen the likelihood of 2 levels of OSA severity (ie, moderate-to-severe and severe OSA) in accordance with clinical practice standards., Methods: We conducted a prospective, simultaneous study using a wireless radar system and PSG in a Northern Taiwan sleep center, involving 196 patients. The wireless radar sleep monitor, incorporating hybrid models such as deep neural decision trees, estimated the respiratory disturbance index relative to the total sleep time established by PSG (RDI PSG&#95;TST ), by analyzing continuous-wave signals indicative of breathing patterns. Analyses were performed to examine the correlation and agreement between the RDI PSG&#95;TST and apnea-hypopnea index, results obtained through PSG. Cut-off thresholds for RDI PSG&#95;TST were determined using Youden's index, and multiclass classification was performed, after which the results were compared., Results: A strong correlation (ρ = 0.91) and agreement (average difference of 0.59 events/h) between apnea-hypopnea index and RDI PSG&#95;TST were identified. In terms of the agreement between the 2 devices, the average difference between PSG-based apnea-hypopnea index and radar-based RDI PSG&#95;TST was 0.59 events/h, and 187 out of 196 cases (95.41%) fell within the 95% confidence interval of differences. A moderate-to-severe OSA model achieved an accuracy of 90.3% (cut-off threshold for RDI PSG&#95;TST : 19.2 events/h). A severe OSA model achieved an accuracy of 92.4% (cut-off threshold for RDI PSG&#95;TST : 28.86 events/h). The mean accuracy of multiclass classification performance using these cut-off thresholds was 83.7%., Conclusions: The wireless-radar-based sleep monitoring device, with cut-off thresholds, can provide rapid OSA screening with acceptable accuracy and also alleviate the burden on PSG capacity. However, to independently apply this framework, the function of determining the radar-based total sleep time requires further optimizations and verification in future work., Citation: Lin S-Y, Tsai C-Y, Majumdar A, et al. Combining a wireless radar sleep monitoring device with deep machine learning techniques to assess obstructive sleep apnea severity. J Clin Sleep Med . 2024;20(8):1267-1277., (© 2024 American Academy of Sleep Medicine.)

The Short Bowel Syndrome (SBS) Registry (NCT01990040) is a multinational real-world study evaluating the long-term safety of teduglutide in patients with SBS and intestinal failure (SBS-IF) in routine clinical practice. This paper describes the study methodology and baseline characteristics of adult patients who have (ever-treated) or have never (never-treated) received teduglutide. A total of 1411 adult patients (679 ever-treated; 732 never-treated) were enrolled at 124 sites across 17 countries. The mean (standard deviation [SD]) age at enrollment was 55.4 (15.46) years, and 60.2% of patients were women. Crohn's disease was the most common cause of major intestinal resection in both ever-treated (34.1%) and never-treated patients (20.4%). A similar proportion of ever-treated and never-treated patients had a prior history of colorectal polyps (2.7% vs. 3.6%), whereas proportionally fewer ever-treated patients reported a history of colorectal cancer (1.8% vs. 6.2%) or any malignancy (17.7% vs. 30.0%) than never-treated patients. Never-treated patients received a numerically greater mean (SD) volume of parenteral nutrition and/or intravenous fluids than ever-treated patients (12.4 [8.02] vs. 10.1 [6.64] L/week). Ever-treated patients received a mean teduglutide dosage of 0.05 mg/kg/day. This is the first report of patient baseline characteristics from the SBS Registry, and the largest cohort of patients with SBS-IF to date. Overall, ever-treated and never-treated patients had similar baseline characteristics. Differences between treatment groups may reflect variations in patient selection and degree of monitoring.

Background: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB., Methods: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes., Results: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06)., Conclusions: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier B.V.)

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Objectives: To explore the therapeutic effect of acupuncture combined with paroxetine for mild to moderate depression and the regulatory role of brain derived neurotrophic factor (BDNF) in patients based on DNA methylation., Methods: A total of 66 patients with mild to moderate depression who met the inclusion and exclusion criteria were randomly divided into an observation (acupuncture+medication) group and a control (medication) group, with 33 patients in each group, and other 25 healthy volunteers were taken as the healthy group. The patients of the control group were treated by oral administration of paroxetine 20 mg/d for 4 weeks. The patients of the observation group were treated by acupuncture stimulation of Zhongwan (CV12), Qihai (CV6), Zusanli (ST36), Sanyinjiao (SP6), Shangxing (GV23), Shuigou (GV26), Shaoshang (LU11), Yinbai (SP1) and Daling (PC7) (for 20 min, 3 times a week for 4 weeks) on the basis of medication treatment (the same as that of the control group). Before treatment, 2 and 4 weeks of treatment, and 2 weeks of follow-up, the therapeutic effect was assessed using Hamilton Depression Scale 17 (HAMD-17). The SPSS25.0 software was used to form a randomized grouping and to randomly select 25 patients from the observation group and 25 patients from the control group for blood collecting and data analysis. The blood samples were taken for assaying serum BDNF content and the methylation degree of BDNF gene promotor I with ELISA and MassARRAY techniques, respectively., Results: 1) In comparison with those before treatment, the total score of HAMD-17, sleep disorder factor score, and anxiety somatization factor score of both the observation and control groups were significantly decreased after 2 and 4 weeks of treatment, and 2 weeks of follow-up ( P <0.05), except sleep disorder factor score in the control group after 2 weeks of the treatment. Compared with the same time-points of the control group, the HAMD-17 total score and sleep disorder factor score of the observation group were decreased after 2 and 4 weeks of treatment, and 2 weeks of follow-up ( P <0.05), while the anxiety somatization factor score was evidently decreased after 2 weeks of treatment ( P <0.05). 2) Following 2 weeks of treatment, the total effective rate and markedly effective rate of the observation group were 80%(24/30)and 36.67% (11/30), respectively, being significantly higher than those ［(26.67% and 0 %)］ of the control group. After 4 weeks of treatment, the markedly effective rate of the observation group was 70.00% (21/30), being significantly higher than that 40% (12/30) of the control group ( P <0.05), while the total effective rates of the observation and control groups were the same (100%). 3) Before the treatment, comparison among the healthy, observation and control groups showed no statistical significance in the methylation degree of each site (CpG1.2, CpG5.6, CpG8.9, CpG26, CpG27, CpG31, and CpG33.34) of BDNF gene promotor I, while after 4 weeks of the treatment, the methylation degree of CpG31 was considerably lower in the observation group than in the control group ( P <0.05). 4) Before the treatment, the contents of serum BDNF of both observation and control group had no significant difference, but were evidently lower than that of the healthy group ( P <0.05). Compared with that before treatment, the serum BDNF contents in both observation and control groups were significantly increased after the treatment ( P <0.05), and was significantly higher in the observation group than in the control group ( P <0.05). 5) The correlation analysis showed a negative correlation between the BDNF protein content and HAMD-17 score (correlation coefficient ρ=-0.686, P <0.01)., Conclusions: Acupuncture may have an antidepressant role by decreasing CpG31 methylation of BDNF and increasing the serum content of BDNF protein in patients with depression. In addition, acupuncture combined with paroxetine has more advantages in treating mild to moderate depression than oral paroxetine alone, and can improve sleep disorders and anxiety somatization symptoms more quickly.

White Roman goose ( Anser anser domesticus ) feathers, comprised of oriented conical barbules, are coated with gland-secreted preening oils to maintain a long-term nonwetting performance for surface swimming. The geese are accustomed to combing their plumages with flat bills in case they are contaminated with oleophilic substances, during which the amphiphilic saliva spread over the barbules greatly impairs their surface hydrophobicities and allows the trapped contaminants to be anisotropically self-cleaned by water flows. Particularly, the superhydrophobic behaviors of the goose feathers are recovered as well. Bioinspired by the switchable anisotropic self-cleaning functionality of white Roman geese, superhydrophobic unidirectionally inclined conical structures are engineered through the integration of a scalable colloidal self-assembly technology and a colloidal lithographic approach. The dependence of directional sliding properties on the shape, inclination angle, and size of conical structures is systematically investigated in this research. Moreover, their switchable anisotropic self-cleaning functionalities are demonstrated by Sudan blue II/water (0.01%) separation performances. The white Roman goose feather-inspired coatings undoubtedly offer a new concept for developing innovative applications that require directional transportation and the collection of liquids.

Electronic cigarettes (ECs) emit many toxic substances, including metals, that can pose a threat to users and the environment. The toxicity of the emitted metals depends on their oxidation states. Hence, this study examines the oxidation states of metals observed in EC aerosols. X-ray photoelectron spectroscopy analysis of the filters that collected EC aerosols identified the oxidation states of five primary metals (based on surface sample analysis), including chromium(III) (close to 100%) under low power setting while a noticeable amount of chromium(VI) (15%) at higher power settings of the EC, and copper(II) (100%), zinc(II) (100%), nickel(II) (100%), lead(II) (65%), and lead(IV) (35%) regardless of power settings. This observation indicates that the increased temperature due to higher power settings could alter the oxidation states of certain metals. We noted that many metals were in their lesser toxic states; however, inhaling these metals may still pose health risks.

Background: Early retirement is highly prevalent in Taiwan. This study assesses the association between early retirement and all-cause and cause-specific mortality risks while exploring the modifying effect of sociodemographic factors., Methods: Using Taiwan's National Health Insurance Research Database between 2009 and 2019, 1 762 621 early retirees aged 45-64 and an equal number of employed comparators were included. The date and cause of death were identified using the National Death Registry. Cox regression models were used to estimate HRs of early retirement for all-cause mortality and cause-specific mortality. To explore modifying effects, we conducted subgroup analyses based on age groups, sexes, occupation types and general health status (Charlson Comorbid Index score)., Results: The analysis revealed that early retirees, compared with their concurrently employed counterparts, had a higher mortality risk (adjusted HR (aHR) 1.69, 95% CI (1.67 to 1.71)). Specifically, younger individuals (aged 45-54) (aHR 2.74 (95% CI 2.68 to 2.80)), males (aHR 1.78 (95% CI 1.76 to 1.81)), those in farming or fishing occupations (aHR 2.13 (95% CI 2.06 to 2.21)) or the private sector (aHR 1.92 (95% CI 1.89 to 1.96)), and those with the poorest health conditions (aHR 1.79 (95% CI 1.76 to 1.83)) had higher mortality risks of early retirement. Regarding specific causes of death, the top three highest risks were associated with gastrointestinal disorders, followed by suicide and neurological disorders., Conclusions: This study underscores the substantial mortality risk increase linked to early retirement, emphasising the importance of policy considerations, particularly regarding vulnerable populations and specific causes of death potentially linked to unhealthy lifestyles., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Visual assessment, while the primary method for pigmentation and erythema evaluation in clinical practice, is subjective, time-consuming, and may lead to variability in observations among clinicians. Objective and quantitative techniques are required for a precise evaluation of the disease's severity and the treatment's efficacy. This research examines the precision and utility of a newly developed skin imaging system in assessing pigmentation and erythema. Sixty participants were recruited, and their facial images were analyzed with the new OBSERV 520 x skin imaging system, compared to DERMACATCH for regional analysis and VISIA for full-face examination. The degree of skin pigmentation was clinically graded using the MASI scores evaluated by dermatologists. The data revealed positive correlations between the novel skin imaging system and the two conventional instruments in quantifying pigmentation and erythema, whether in regional or full-face analysis. Furthermore, the new skin imaging system positively correlated with the clinical MASI scores (r = 0.4314, P < 0.01). In contrast, our study found no significant correlation between the traditional system and clinical assessment, indicating a more substantial capacity for hyperpigmentation assessment in the new system. Our study validates the innovative skin imaging system's accuracy in evaluating pigmentation and erythema, demonstrating its feasibility for quantitative evaluation in both clinical and research purposes., (© 2024. The Author(s).)

While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads to the absence of iNKT2 and iNKT17 cell subsets, as well as an altered distribution of iNKT1 cells. Thymic iNKT cells lacking GATA-3 exhibited diminished expression of PLZF and T-bet, key transcription factors involved in iNKT cell differentiation, and reduced production of Th2, Th17, and cytotoxic effector molecules. Single-cell transcriptomics revealed a comprehensive absence of iNKT17 cells, a substantial reduction in iNKT2 cells, and an increase in iNKT1 cells in GATA-3-deficient thymi. Differential expression analysis highlighted the regulatory role of GATA-3 in T cell activation signaling and altered expression of genes critical for iNKT cell differentiation, such as Icos , Cd127 , Eomes , and Zbtb16 . Notably, restoration of Icos, but not Cd127, expression could rescue iNKT cell development in GATA-3-deficient mice. In conclusion, our study demonstrates the pivotal role of GATA-3 in orchestrating iNKT cell effector lineage differentiation through the regulation of T cell activation pathways and Icos expression, providing insights into the molecular mechanisms governing iNKT cell development and function.

Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo . Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Parental monitoring is a construct of longstanding interest in multiple fields-but what is it? This paper makes two contributions to the ongoing debate. First, we review how the published literature has defined and operationalized parental monitoring. We show that the monitoring construct has often been defined in an indirect and nonspecific fashion and measured using instruments that vary widely in conceptual content. The result has been a disjointed empirical literature that cannot accurately be described as the unified study of a single construct nor is achieving a cumulative scientific character. Second, we offer a new formulation of the monitoring construct intended to remedy this situation. We define parental monitoring as the set of all behaviors performed by caregivers with the goal of acquiring information about the youth's activities and life. We introduce a taxonomy identifying 5 distinct types of monitoring behaviors (Types 1-5), with each behavior varying along five dimensions (performer, target, frequency, context, style). We distinguish parental monitoring from 16 other parenting constructs it is often conflated with and position monitoring as one element within the broader parent-youth monitoring process: the continuous, dyadic interplay between caregivers and youth as they navigate caregivers attempts' to monitor youth. By offering an explicit and detailed conceptualization of monitoring, we aim to foster more rigorous and impactful research in this area., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)