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Jian Huang,1,&ast; Li Li,2,&ast; Fu-Chen Liu,1 Bi-Bo Tan,3 Yun Yang,1 Bei-Ge Jiang,1 Ze-Ya Pan1 1Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 201805, People’s Republic of China; 2Department of Nephrology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 201805, People’s Republic of China; 3Department of Ultrasonic, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 201805, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ze-Ya Pan; Bei-Ge Jiang, Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, No. 700, MoYu North Road, Jiading, Shanghai, People’s Republic of China, Tel +86-13391236437 ; +86-13764561303, Email hjluffy@126.com; jiang_beige@aliyun.comObjective: To investigate the survival and independent prognostic factors for single large hepatocellular carcinoma (SLHCC) after surgical resection.Methods: Patients with SLHCC who underwent radical resection from January 2013 to December 2017 were retrospectively analyzed. The Kaplan-Meier method was used to analyze the overall survival (OS) rate and recurrence-free survival (RFS) rates. Cox forward stepwise regression was performed to analyze the independent prognostic factors.Results: A total of 485 cases were included. The average age was 51.2± 11.2 years, 88.9% had a history of hepatitis B virus infection, and most patients had normal liver function. The average tumor diameter was 8.8± 3.0 cm. The 1-, 3-, and 5-year OS and RFS rates were 76.8%, 56.7%, and 45.7%, and 61.0%, 46.2%, and 34.7%, respectively. Multivariate analysis showed that liver cirrhosis (HR=1.456, P=0.004), total bilirubin (TB) ≥ 17.1 μmol/L (HR=1.437, P=0.011), glutamyl transferase (GGT) > 60 U/L (HR=1.438, P=0.020), lactate dehydrogenase (LDH) > 225 U/L (HR=1.442, P=0.007), blood loss ≥ 400 mL (HR=1.339, P=0.027), microvascular invasion (MVI) (HR=1.492, P=0.004), satellite lesions (HR=1.859, P< 0.0001) and Edmondson-Steiner grade III+IV (HR=1.740, P=0.018) were independent risk factors for reduced OS in SLHCC patients. Sex (HR=1.763, P=0.003), liver cirrhosis (HR=1.382, P=0.007), GGT > 60 U/L (HR=1.512, P=0.003), LDH > 225 U/L (HR=1.480, P=0.002), MVI (HR=1.545, P=0.001), and satellite lesions (HR=1.564, P=0.001) were independent risk factors for reduced RFS. OS and RFS nomograms were constructed using risk factors with C-index values of 0.692 (95% CI: 0.659– 0.724) and 0.659 (95% CI: 0.623– 0.693), respectively. The Hosmer-Leme test demonstrated the good fit of both nomograms.Conclusion: Surgical resection is the standard and effective treatment for SLHCC patients. Sex, liver cirrhosis, TB≥ 17.1 μmol/L, GGT> 60 U/L, LDH> 225 U/L, blood loss≥ 400 mL, MVI, Edmondson-Steiner grade III+IV, and satellite lesions were found to be independent prognostic factors in SLHCC patients following radical resection. The OS and RFS nomograms accurately predicted the prognosis of SLHCC patients.Keywords: SLHCC, cancer, hepatectomy, prognosis, risk factor

Yu-Hsiang Chiu,1,2 Chen-Chih Chu,1 Chun-Chi Lu,1 Feng-Cheng Liu,1 Shin-En Tang,3 Shi-Jye Chu,1 San-Yuan Kuo,1 Hsiang-Cheng Chen1 1Division of Rheumatology/Immunology/Allergies, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; 3Division of Thoracic Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanCorrespondence: Hsiang-Cheng Chen, Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec, 2, Cheng-Gong Road, Neihu 114, Taipei, Taiwan, R.O.C, Tel +886 2 87927135, Fax +886 2 87927136, Email hccheng@mail.ndmctsgh.edu.twObjective: Krebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays.Methods: Patients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA).Results: Of the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15– 4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937– 2242) and 764.5 U/mL (IQR 503.25– 1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235– 619) and 245 U/mL (IQR 215.25– 291) in the ILD group and the non-ILD group, respectively (p = 0.074).Conclusion: Serum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.Keywords: Sjögren syndrome, interstitial lung disease, KL-6

Jian Huang,1,* Yun Yang,1,* Yong Xia,2,* Fu-Chen Liu,1,* Lei Liu,1 Peng Zhu,1 Sheng-Xian Yuan,1 Fang-Ming Gu,1 Si-Yuan Fu,1 Wei-Ping Zhou,1 Hui Liu,1 Bei-Ge Jiang,1 Ze-Ya Pan1 1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 201805, People’s Republic of China; 2Department of Medical Oncology, Shanghai Mengchao Cancer Hospital, Shanghai, 201805, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ze-Ya Pan; Bei-Ge Jiang No. 700, MoYu North Road, Jiading, Shanghai, People’s Republic of ChinaTel +86-13391236437; +86-13764561303Email hjluffy@126.com; jiang_beige@aliyun.comPurpose: To predict patient survival in early-stage hepatocellular carcinoma (HCC) following hepatic resection. We evaluated the prognostic potential of the aspartate aminotransferase to platelet ratio index (APRI) in order to use it to model a nomogram.Patients and Methods: We randomized 901 early-stage HCC patients treated with hepatic resection at our center into training and validation cohorts that were followed from January 2009 to December 2012. X-tile software was used to establish the APRI cut-off threshold in the training cohort. The validation cohort was subsequently assessed to determine threshold value accuracy. Data generated from the multivariate analysis in the training cohort were used to design a prognostic nomogram. Decision curve analyses (DCA), concordance index values (C-index) and calibration curves were used to determine the performance of the nomogram.Results: X-tile software revealed that the optimal APRI cut-off threshold in the training cohort that distinguished between patients with different prognoses was 0.9. We, therefore, validated its prognostic value. Multivariate analyses showed that poor overall survival was associated with APRI above 0.9, blood loss of more than 400 mL, liver cirrhosis, multiple tumors, tumor size greater than 5 cm, microvascular invasion and satellite lesions. When the independent risk factors were integrated into the prognostic nomogram, it performed well with accurate predictions. Indeed, the performance was better than comparative prognosticators (P< 0.05 for all) with 0.752 as the C-index (95% CI: 0.706– 0.798). These results were verified by the validation cohort.Conclusion: APRI was a noninvasive and accurate predictive indicator for patients with early-stage HCC. Following hepatic resection to treat early-stage HCC, individualized patient survival predictions can be aided by the nomogram based on APRI.Keywords: hepatocellular carcinoma, hepatic resection, survival, nomogram, aspartate aminotransferase to platelet ratio index, APRI

An-Hsun Chou,1–3 Chia-Chih Liao,1,2 Hung-Chen Lee,1,4 Jiin-Tarng Liou,1,2 Fu-Chao Liu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Anesthesiology, Xiamen Chang Gung Hospital, Taoyuan, Taiwan; 4Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, TaiwanCorrespondence: Fu-Chao LiuDepartment of Anesthesiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 5, Fusing Street, Gueishan District, Taoyuan City 33305, TaiwanTel +886-3-3281200 (ext. 3624)Fax +886-3-3281200 (ext. 2787)Email ana5189@cgmh.org.twPurpose: Dexmedetomidine [DEX; (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole] is a selective α2-adrenergic receptor (α2-AR) agonist that attenuates the liver damage associated with local or systemic inflammation. However, it remains unclear whether DEX has protective effects against acetaminophen (Paracetamol, PARA)-induced liver toxicity (PILT).Methods: PILT mice were established by intraperitoneal administration of a hepatotoxic dose of acetaminophen (300 mg/kg). Thirty minutes later, the mice were treated with DEX at a concentration of 0, 5, 25, or 50 μg/kg. Blood and liver samples were obtained for further analysis.Results: DEX treatment significantly attenuated PILT in mice, with the strongest beneficial effects at a dose of 25 μg/kg. The levels of hepatic cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), in addition to myeloperoxidase (MPO) activity, were significantly decreased following DEX treatment. Moreover, DEX treatment reduced macrophage recruitment around the area of hepatotoxicity and the expression levels of hepatic phosphorylated mitogen-activated protein kinase kinase 4 (MAP2K4), c-jun N-terminal kinase (JNK), and c-Jun expression induced by acetaminophen overdose.Conclusion: The data suggest that DEX likely downregulates the JNK signaling pathway and its downstream effectors to promote its hepatoprotective effect, providing a clinical application of DEX for the attenuation of PILT.Keywords: dexmedetomidine, acetaminophen-induced liver toxicity, MAP2K4/JNK/c-Jun

Fu-Chao Liu,1,2,* Shih-Jyun Shen,1,2,* Jr-Rung Lin,1–3 Huang-Ping Yu1,2,4 1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan; 4Department of Anesthesiology, Xiamen Chang Gung Hospital, Xiamen, China *These authors contributed equally to this work Background: Benign prostate hyperplasia, a common disease in elderly men, can be surgically treated with transurethral resection of the prostate (TURP). Postoperative sexual dysfunction is a major issue and is influenced by many factors. The present study aimed to assess whether the intraoperative resected prostate weight influences the probability of postoperative sexual dysfunction.Methods: This population-based study included 41,574 patients from the Nation Health Insurance Research Database who had undergone TURP once between 1997 and 2013. All patients were divided into three groups according to the resected prostate weight (low, medium, and high groups). Perioperative risk factors influencing sexual function were analyzed. The chi-squared test and Fisher’s exact test were used to analyze differences in demographic data. The Cox proportional hazard regression analysis was used to analyze the HRs. All statistical analyses were two-sided, and a P-value

Yung-Fong Tsai,1,2,* Fu-Chao Liu,1,2,* Chang-Fu Kuo,3,4 Ting-Ting Chung,3 Huang-Ping Yu1,2,5 1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Office for Big Data Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5Department of Anesthesiology, Xiamen Chang Gung Hospital, Xiamen, China *These authors contributed equally to this work Background: Immunosuppression plays an essential role to overcome immune-related allograft rejection, but it also causes some nephrotoxicity. This study aimed to investigate how the immunosuppressant combinations affect graft outcomes in kidney transplant recipients. Methods: A nationwide population-based cohort study using the Taiwan National Health Insurance Database was conducted. A total of 3,441 kidney transplant recipients who underwent kidney transplantation during the targeted period were included. The effects on graft outcomes contributed by conventional immunosuppressants, including corticosteroid, calcineurin inhibitors, antimetabolite purine antagonists, and mammalian target of rapamycin inhibitors, were compared. Results: A total of 423 graft failures developed after the index date. Therapy regimens incorporated with purine antagonists had a comparable reduction of graft failure among four main drug groups regardless of whether they were given as monotherapy or in combination (adjusted hazard ratio: 0.52, 95% confidence interval: 0.42–0.63). Corticosteroid was found to have inferior effects among four groups (adjusted hazard ratio: 1.67, 95% confidence interval: 1.28–2.21). Furthermore, all 15 arrangements of mutually exclusive treatment combinations were analyzed by referencing with corticosteroid monotherapy. As referenced with steroid-based treatment, regimens incorporated with purine antagonists all have superior advantage on graft survival regardless of whether given in monotherapy (65% of graft failure reduced), dual therapy (48%–67% reduced), or quadruple therapy (43% reduced). In all triple therapies, only corticosteroid combined with calcineurin inhibitor and purine antagonist demonstrated superior protection on graft survival (52% of graft failure reduced). Conclusion: The results may recommend several superior regimens for contributing to graft survival, and for supporting a steroid-minimizing strategy in immunosuppression maintenance. Keywords: chronic rejection, corticosteroid, graft survival, purine antagonist, steroid-minimizing strategy

Fu-Chao Liu,1,2,* Huan-Tang Lin,1,2,* Chang-Fu Kuo,2–4 Mei-Yun Hsieh,4 Lai-Chu See,3,5,6 Huang-Ping Yu1,2,7 1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Office for Big Data Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 7Department of Anesthesiology, Xiamen Changgung Hospital, Xiamen, China *These authors contributed equally to this work Background: Individuals with a family history of Parkinson’s disease (PD) appear to have a higher risk of developing PD and other neuropsychiatric diseases. However, estimates of the relative risks (RRs) of PD and the roles of genetic and environmental factors in PD susceptibility are unclear. The aim of this study was to examine familial aggregation and genetic contributions to PD and the RRs of other neuropsychiatric diseases in relatives of PD patients. Methods: In this population-based family cohort study, the records of all individuals actively registered in the Taiwan National Health Insurance Research Database in 2015 were queried (N=24,349,599). In total, 149,187 individuals with a PD-affected parent, 3,698 with an affected offspring, 3,495 with an affected sibling, and 15 with an affected twin were identified. Diagnoses of PD were ascertained between January 1, 1999, and December 31, 2015. The prevalence and RRs of PD and other neuropsychiatric diseases in individuals with first-degree relatives with PD, as well as the contributions of heritability and environmental factors to PD susceptibility were investigated. Results: The prevalence of PD was 0.46% in the general population and 0.52% in individuals with first-degree relatives with PD. The RR (95% CI) for PD was 2.20 (1.41–3.45) for siblings, 1.59 (1.47–1.73) for parents, 1.86 (1.63–2.11) for offspring, 63.12 (16.45–242.16) for twins, and 1.46 (1.41–1.52) for spouses. The RR (95% CI) in individuals with first-degree relatives with PD was 1.66 (1.57–1.76) for essential tremor, 1.68 (1.61–1.75) for schizophrenia, and 1.20 (1.12–1.28) for Alzheimer’s disease. The estimated contribution to the phenotypic variance of PD was 11.0% for heritability, 9.1% for shared environmental factors, and 79.9% for non-shared environmental factors. Conclusion: First-degree relatives of PD patients are more likely to develop PD and other neuropsychiatric diseases. Environmental factors account for a high proportion of the phenotypic variance of PD. Keywords: Parkinson’s disease, familial risk, population-based family study

Fu-Chao Liu,1,2 Chang-Fu Kuo,2–5 Lai-Chu See,4,6 Hsin-I Tsai,1,2,7 Huang-Ping Yu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, 2College of Medicine, Chang Gung University, 3Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, 4Department of Public Health, College of Medicine, Chang Gung University, 5Office for Big Data Research, Chang Gung Memorial Hospital, 6Biostatistics Core Laboratory, Molecular Medicine Research Center, 7Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China Introduction: Myasthenia gravis (MG) is clinically heterogeneous and can be life-threatening if bulbar or respiratory muscles are involved. However, relative contributions of genetic, shared, and nonshared environmental factors to MG susceptibility remain unclear. The aim of this study was to examine the familial aggregation and heritability of MG and the relative risks (RRs) of other autoimmune diseases in the relatives of patients with MG.Methods: A population-based family study using the Taiwan National Health Insurance (NHI) Database was conducted. Participants included all individuals (N=23,422,955) who were actively registered in the NHI Database in 2013, 15,066 of whom had at least one first-degree relative with MG. We identified 8,638 parent–child relationships, 3,279 with an affected offspring, 3,134 with affected siblings, and 26 with affected twins. Prevalence and RRs of MG and other autoimmune diseases in the relatives of patients as well as the relative contributions of heritability, shared, and nonshared environmental factors to MG susceptibility were measured.Results: RRs (95% confidence intervals [CIs]) for MG were 17.85 (8.71–36.56) for patients’ siblings, 5.33 (2.79–10.18) for parents, 5.82 (3.03–11.16) for offspring, and 1.42 (0.20–10.10) for spouses without genetic similarities. RRs (95% CIs) in individuals with a first-degree relative with MG were 2.18 (1.53–3.12) for systemic lupus erythematosus, 1.73 (1.09–2.74) for primary Sjögren’s syndrome, 1.90 (1.66–2.18) for autoimmune thyroid disease, and 1.68 (1.22–2.30) for rheumatoid arthritis. Accountability for the phenotypic variance of MG was 82.1% for familial transmission and 17.9% for nonshared environmental factors.Conclusion: Individual risks of MG and other autoimmune diseases are increased in the relatives of patients with MG. Familial transmission of MG was estimated to be 82.1%. Keywords: myasthenia gravis, familial risk, population based family study

Fu-Chao Liu,1,2,* Pei-Chi Ting,1,2,* Jr-Rung Lin,3 Huang-Ping Yu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, 2College of Medicine, Chang Gung University, 3Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China *These authors contributed equally to this work Background: There are very few reports describing the development of gallstone disease after renal transplantation (GSDART) in Asia. The aim of this population-based study was to explore the prevalence, predictive factors, and outcomes of newly developed GSDART. The relationship between immunosuppressant and GSDART was also explored.Patients and methods: Renal transplantation (RT) recipients were identified from the National Health Insurance Research Database of Taiwan during January 1998–December 2012. In total, 2,630 adult patients, who had neither been diagnosed with gallstone disease (GSD) nor undergone cholecystectomy, were included in this study. These patients underwent follow-up till the diagnosis of GSDART was established. Risk factors and post-RT immunosuppressant treatments were investigated and analyzed using Cox regression analysis. The cumulative mortality in patients with and without GSDART was also evaluated.Results: The final dataset comprised 143 patients who developed GSDART and 2,487 patients who had not been diagnosed with GSDART during the follow-up period. The prevalence of GSDART was 5.4%. On performing univariate analysis, age (p=0.0276) and certain immunosuppressant administrations were identified as significant risk factors for GSDART. After adjusting for age, multivariable analysis showed that everolimus (adjusted hazard ratio 0.287, p=0.0013) was independently associated with the development of GSDART. The overall mortality rate (6.99%, p=0.0341) was significantly decreased in the GSDART group.Conclusion: Increased age was the most consistent risk factor for GSD, and everolimus-based immunotherapy indicated a decreased incidence of GSDART in RT recipients. The long-term mortality rate was significantly decreased in patients with GSDART. Keywords: gallstone disease, immunosuppressant, population-based study, renal transplantation

Fu-Chao Liu,1,2,* Huan-Tang Lin,1,2,* Jr-Rung Lin,1–3 Huang-Ping Yu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, 2College of Medicine, 3Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan *These authors contributed equally to this work Abstract: This nationwide, population-based study aimed to clarify the effects of immunosuppressive regimens on new-onset diabetes after liver transplantation (NODALT). The National Health Insurance database of Taiwan was explored for patients who received liver transplantation without pre-transplant diabetes from 1998 to 2012. Information regarding clinical conditions and immunosuppressant utilization among these patients was analyzed statistically. Of the 2,140 patients included in our study, 189 (8.8%) developed NODALT. The pre-transplant risk factors for NODALT were identified as old age, male sex, hepatitis C, alcoholic hepatitis, and immunosuppressant use of tacrolimus (TAC). All patients used corticosteroids as a baseline immunosuppressant. The immunosuppressant regimen of cyclosporine (CsA)+TAC+mycophenolate mofetil (MMF) contributed most to NODALT (adjusted hazard ratio 7.596) in comparison with the regimens of TAC+MMF and CsA+MMF; this regimen also contributed significantly to higher post-transplant bacteremia, urinary tract infection, pneumonia, renal failure, and mortality rate. In conclusion, our analysis confirmed TAC-based immunosuppression contributes to higher NODALT incidence than CsA-based regimen, and TAC-CsA conversion due to any causes might lead to worse clinical outcomes. Clinicians should make better risk stratifications before prescribing immunosuppressants for liver transplant recipients. Keywords: new-onset diabetes, liver transplantation, immunosuppressant, population-based study, clinical outcome

Peter Chi-Ho Chung,1,2 Hsiu-Pin Chen,1,2 Jr-Rung Lin,3,4 Fu-Chao Liu,1,2 Huang-Ping Yu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, 2College of Medicine, 3Clinical Informatics and Medical Statistics Research Center, 4Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan Purpose: The purpose of this study was to assess whether preoperative chronic renal failure (CRF) affects the rates of postoperative complications and survival after liver transplantation. Methods: This population-based retrospective cohort study included 2,931 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. Patients were divided into two groups, based on the presence or absence of preoperative CRF. Results: The overall estimated survival rate of liver transplantation recipients (LTRs) with preoperative CRF was significantly lower than that of patients without preoperative CRF (P=0.0085). There was no significant difference between the groups in terms of duration of intensive care unit stay, total hospital stay, bacteremia, postoperative bleeding, and pneumonia during hospitalization. Long-term adverse effects, including cerebrovascular disease and coronary heart disease, were not different between patients with versus without CRF. Conclusion: These findings suggest that LTRs with preoperative CRF have a higher rate of mortality. Keywords: chronic renal failure, cohort study, survival rate, liver transplantation, population-based study

© 2015 Macmillan Publishers Limited. All rights reserved.Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is bot

BACKGROUND: : Although inflammation induces pain, immune cells also produce mediators that can effectively counteract it. To further elucidate the role of the immune response, we analyzed the relationship of pain behavior, several inflammatory signals, and opioid peptides using partial sciatic nerve ligation in mice at different levels of immunocompromise. METHODS: : Sciatic nerves of C57BL/6C, nonobese diabetic (NOD), or nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice were partially ligated. Responses to mechanical and radiant heat stimuli were observed. Inflammation was detected by immunohistochemistry and flow cytometry. Inflammatory cytokines and opioid peptides were analyzed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay or immunostaining. RESULTS: : Inflammation in immunocompromised mice was subordinate when compared with that seen in C57BL/6C mice. In addition, immunocompromised mice had less pain hypersensitivity at early stages. Whereas proinflammatory tumor necrosis factor-[alpha] (TNF-[alpha]), interleukin 1[beta] (IL-1[beta]), interleukin 6 (IL-6), and interferon-[gamma] (IFN-[gamma]), as well as antiinflammatory interleukin 1 receptor antagonist (IL-1Ra), interleukin 4 (IL-4), interleukin 10 (IL-10), and interleukin 13 (IL-13) cytokine expression and protein were increased in C57BL/6C mice, they were lower in immunocompromised mice. Although enkephalin, dynorphin, and [beta]-endorphin messenger RNA expression also increased in C57BL/6C mice, peaking on day 14, this result was not observed in immunocompromised mice. CONCLUSION: : The contribution of inflammation to nerve injury is complex with biphasic modulation. During the early phase, a wide range of proinflammatory cytokines are released, leading to enhanced pain. In contrast, the analgesic effect of opioid peptides and antiinflammatory cytokines was more predominate in the later phases of injury, leading to attenuated pain responses. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the effects of a human urine preparation on the differentiation of tumor cells. Design: The pheochromocytoma PC12 cells were used to examine the effects of a human urine preparation, CDA-2 on the induction of differentiation markers, neurofilaments, and compared with that induced by nerve growth factor (NGF). The MAPK/ERK kinase (MEK) inhibitor U0126 was used to examine the involvement of mitogen-activated protein kinase (MAPK) signaling pathway in this differentiation inducing effect. Results: We find that CDA-2 could induce differentiation of pheochromocytoma PC12 cells, as evidenced by the markedly increased expression of neurofilaments to a level comparable to those induced by NGF. This phenomenon was accompanied by the phosphorylation of extracellular-signal--regulated kinase (ERK) and could be inhibited by the MEK inhibitor, U0126. Conclusions: Our results demonstrate the presence of active components in the human urine extract that can induce differentiation of PC12 cells and may involve the ERK signaling pathway. This may provide new insights for seeking novel differentiation agents and offer hope for cancer patients. [ABSTRACT FROM AUTHOR]

Background/aim: Hydrogen therapy has demonstrated potential as an antioxidant and anti-inflammatory intervention, particularly in the management of chronic diseases such as chronic kidney disease (CKD) and autoimmune conditions. This case report presents the possible therapeutic benefits of molecular hydrogen capsule treatment in enhancing renal function and alleviating chronic fatigue in an elderly female with coronary artery disease (CAD), type 2 diabetes mellitus (DM) complicated by nephropathy, and systemic lupus erythematosus (SLE). The aim of this study was to investigate the efficacy of adjunctive hydrogen therapy in an elderly patient with multiple chronic comorbidities., Case Report: An 89-year-old female with a history of CAD s/p who had undergone coronary artery bypass grafting (CABG) over 40 years ago, type 2 DM complicated by nephropathy, and SLE was admitted with recurrent cellulitis at the saphenous vein donor site from her previous CABG. Despite antibiotic treatment, wound healing remained limited. In January 2023, the patient initiated adjuvant treatment with molecular hydrogen capsules. Following the introduction of hydrogen therapy, her renal function improved, evidenced by a reduction in serum creatinine levels. Chronic fatigue, assessed using the Taiwan Brief Fatigue Inventory (BFI-T), showed significant improvement. Immunological evaluation revealed a series of changes, suggesting that immune modulation may be the mechanism underlying the observed clinical benefits., Conclusion: Hydrogen therapy was associated with improved renal function and a reduced chronic fatigue in this elderly patient with multiple comorbidities, including CAD, DM, and SLE. The case underscores the potential therapeutic role of hydrogen therapy in immune modulation and the management of chronic conditions, suggesting the need for further investigation in clinical settings., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, though rare, is the most common form of autoimmune encephalitis, predominantly affecting young individuals, particularly females. Standard treatments include corticosteroids, intravenous immunoglobulins (IVIG), and plasmapheresis, with rituximab recommended for those unresponsive to first-line therapies. However, reliable biomarkers for clinical assessment remain elusive. This study investigated the efficacy of adjunctive hydrogen therapy in a patient with anti-NMDAR encephalitis., Case Report: This case report describes a 14-year-old boy with anti-NMDAR encephalitis who exhibited poor response to initial treatment, but showed significant improvement with rituximab and adjunctive hydrogen therapy. Immunophenotyping revealed correlations between treatment outcomes and shifts in B cell subsets, PD-1+ cytotoxic T cells, and regulatory T cell subtypes., Conclusion: This case underscores the importance of integration traditional clinical assessments with advanced diagnostics such as flow cytometry-based immunophenotyping, and suggests a potential role for hydrogen therapy in modulating immune response in this complex autoimmune condition., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Neutrophils that are overactivated can cause inflammatory diseases. Neutrophils possess various surface receptors, including G-protein-coupled chemoattractant receptors, which assist in recognizing pathogen attacks and the inflammatory environment. Therefore, targeting G-protein-coupled chemoattractant receptors and their downstream molecules is important for preventing abnormal neutrophil activation. This study examines the effects and underlying mechanism of myriscagayanone C, a new compound obtained from the fruit of myristica cagayanensis, on neutrophil respiratory burst induced by fMLP. The immunoblotting assay was conducted to assess the mechanisms by which myriscagayanone C inhibits fMLP-induced respiratory burst by disrupting the translocation of Akt to the cellular membrane. Briefly, myriscagayanone C suppressed the production of superoxide anions induced by fMLP on human neutrophils in a concentration-dependent manner (IC 50 : 4.73 ± 0.68 μM). Myriscagayanone C blocked fMLP-induced Akt translocation to the cell membrane, inhibiting Akt T308 and Akt S473 phosphorylation by PDK1 Y373/376 and mTOR S2481 , respectively. Myriscagayanone C inhibited fMLP-induced p47 phox phosphorylation and translocation. Myriscagayanone C did not inhibit the activity of PI3K, the amount of phosphatidylinositol (3, 4, 5)-trisphosphate, or the translocation of phosphorylated-PDK1 Y373/376 and -mTOR S2481 to the membrane. Myriscagayanone C did not inhibit fMLP-induced PKC, Src, ERK1/2, p38 phosphorylation, and intracellular calcium mobilization. Myriscagayanone C did not inhibit the chemotaxis and CD11b expression induced by fMLP. Myriscagayanone C did not inhibit PMA-induced superoxide anion production and neutrophil extracellular trap formation. According to this data, myriscagayanone C inhibits fMLP-induced neutrophil superoxide anion production by interrupting the translocation of Akt to the plasma membrane, which affects the NADPH oxidase activity by preventing p47 phox phosphorylation and translocation., 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. Published by Elsevier B.V.)

Objective: To analyze the relationship between cumulative body mass index (BMI) and cognitive score or cognitive impairment at different age groups among elderly adults aged≥60 years old. Methods: Participants were recruited from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). A total of 27 227 participants aged≥60 years old, who completed at least 2 physical examinations between 1992-1994 and 2018-2021, and completed cognitive function tests from 2018 to 2021, were included in the final analysis. Cognitive score was assessed using the Minimum Mental State Examination (MMSE). Cognitive impairment was defined based on education level: illiterate individuals with MMSE≤17, primary school graduates with MMSE≤20, and secondary school graduates with MMSE≤24. Multivariate linear regression or multivariate logistic regression models were used to analyze the association between 10-year weighted cumulative BMI and cognitive score or cognitive impairment in the general population, as well as in specific age groups (including 60-64 years, 65-69 years, 70-74 years, and≥75 years). Restricted cubic spline was adopted to explore the dose-response relationship. Results: The age of enrolled participants was (72.3±5.8) years, and 10 639 (39.1%) were males. The mean MMSE score was (24.9±6.8), and 4 171 (15.4%) participants had cognitive impairment. In the general population, the MMSE score increased and the risk of cognitive impairment decreased with the increase in cumulative BMI when cumulative BMI was280 kg/m 2 (β=0.095, 95% CI : 0.060-0.130; OR =0.962, 95% CI : 0.946-0.978). When cumulative BMI≥280 kg/m 2 , the associations between cumulative BMI level and MMSE score and cognitive impairment risk were not statistically significant (β=-0.105, 95% CI :-0.212-0.001; OR =1.047, 95% CI : 0.992-1.102). Subgroup analysis according to age groups revealed a potential"U-shaped"correlation between cumulative BMI and MMSE score or cognitive impairment risk in participants aged75 years old. For cumulative BMI levels280 kg/m 2 , the OR and 95% CI for cognitive impairment were 0.983 (0.904-1.069), 0.953 (0.919-0.987), and 0.951 (0.922-0.982) for each 10 kg/m 2 increment in cumulative BMI in the 60-64, 65-69, and 70-74 years old groups, respectively. For cumulative BMI≥280 kg/m 2 , the OR and 95% CI were 1.548 (1.134-2.186), 1.037 (0.938-1.139), and 1.109 (1.014-1.208) in the 60-64, 65-69, and 70-74 age groups. Among those aged≥75 years old, the cumulative BMI level was statistically associated with the increased MMSE score and decreased cognitive impairment (β=0.132, 95% CI : 0.074-0.190; OR =0.961, 95% CI : 0.944-0.979). Conclusions: Overall, when cumulative BMI is280 kg/m 2 , an increase in cumulative BMI is associated with a reduced risk of cognitive impairment in the general population. However, the association varies among individuals aged75 years old and those≥75 years old when cumulative BMI is≥280 kg/m 2 . The findings highlight the necessity of personalized weight management strategies for elderly individuals across different age groups.

Background: Small bowel tumors (SBTs) are a heterogeneous group of difficult-to-diagnose tumors that account for 2%-5% of all gastrointestinal tumors. Single-balloon enteroscopy greatly enhances the diagnosis and treatment of SBTs. However, few epidemiological studies have been conducted in Taiwan to determine the clinical profile of SBTs., Aim: To investigate the clinical characteristics, managements and prognosis of SBTs in a medical center in Taiwan., Methods: The study enrolled 51 patients aged 58.9 ± 8.8 years (range, 22-93) diagnosed with SBTs from November 2009 to July 2021. We retrospectively recorded clinical characteristics, indications, endoscopic findings, pathological results, management, and outcomes for further analysis., Results: A male preponderance was observed (56.8%). The most common indications were suspected small intestinal tumors (52.9%) and obscure gastrointestinal bleeding (39.2%). The most common tumor location was the ileum (41.2%). The performance of imaging studies ( P = 0.004) and the types of findings ( P = 0.005) differed significantly between malignant and benign SBTs. The most frequent imaging finding was a small intestinal mass (43.1%). The top three malignant tumor types were gastrointestinal stromal tumors (GISTs), adenocarcinomas, and lymphomas. Moreover, the proportions of benign and malignant tumors were 27.5% and 72.5%, respectively. The survival rates of patients with malignant tumors in the GIST and non-GIST groups differed significantly ( P = 0.015). Kaplan-Meier survival analysis showed a significant difference in survival between patients in the malignant and benign groups ( P = 0.04). All patients with lymphoma underwent chemotherapy ( n = 7/8, 87.5%), whereas most patients with GISTs underwent surgery ( n = 13/14, 92.8%)., Conclusion: Patients with GISTs have a significantly higher survival rate than those with other malignant SBTs. Therefore, a large-scale nationwide study is warranted to evaluate the population-based epidemiology of SBTs., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The development of multi-cation perovskite quantum dots (PQDs) is limited by the low availability of fitting A-site cations due to the unsuitable radii of a large gamut of amine cations. The impact of oversized or undersized cations on the perovskite structure is detrimental to the structural stabilization and electroluminescence efficiency of the PQDs. Researchers are actively seeking suitable-sized cations to mitigate perovskite defect formation and optimize charge carrier confinement within the PQDs. In contrast to cesium (Cs) or formamidine (FA), which are exposed to degradation pathways, guanidinium (GA)-doping has been to provide a suitable radius and the lack a dipole moment. The triple nitrogen functionality of GA enables it to passivate both the PbBr 6 octahedra and surface defects through vacant A-sites and entropically stabilize the perovskite. Furthermore, the insertion of GA into the PQD lattice is enthalpically facilitated by the presence and arrangement of smaller Cs and Br atoms. Herein, we have synthesized a Cs-FA PQD reference into which GA is doped via two chemical routes. Our triple-cation system exhibits substantially improved optical properties and was applied for the fabrication of a PeLED device. The optimized triple-cation PQDs-based PeLED device exhibited an external quantum efficiency of 5.87% and a luminescence of 13726 cd m -2 .

Alcohol-induced dose dumping (AIDD) remains a serious challenge in the controlled delivery of high potency drugs, such as opioids, which requires extensive investigation and innovative solutions. Current technologies rely on ethanol-insoluble excipients, such as guar gum and sodium alginate, to counteract the increased solubility of hydrophobic polymeric excipients in ethanol. However, these excipients pose several shortcomings, such as high viscosity of coating dispersion, high solution temperature, rapid gelation, and heterogeneity of resulted film. In this work, we explored the application of a cross-linked terpolymer nanoparticle (TPN) as an alcohol-resistant excipient in a water-insoluble controlled release film of ethylcellulose (EC) for the prevention of AIDD. Herein, we optimized the composition of TPN using a central composite design (CCD) to minimize swelling and weight loss of TPN-EC film in the presence of 20% ethanol. The optimized TPN showed a negligible effect on the viscosity of the coating dispersion, while guar gum increased the viscosity by 76-fold. Permeability studies in a pH 1.2 media containing 0% or 40% v/v ethanol revealed that cationic drugs (propranolol HCl, diltiazem HCl, and naloxone HCl (an opioid receptor-binding model drug)) exhibited significantly lower permeability ratios ( P 40% / P 0% ) than un-ionized drugs (theophylline and salicylic acid). FTIR analysis indicated an increase in ionic hydrogen bonding between TPN and the cationic drug in the presence of ethanol. These results suggest that drug-polymer-solvent interactions play an important role in alcohol-independent drug permeability through the TPN-EC film. By leveraging the drug permeability altering capability of the TPN-EC system, the release of cationic drugs in hydroethanolic media appeared to be suppressed, suggesting a promising new mechanism of alcohol resistance.

Background: Local infiltration analgesia (LIA) is a crucial component of multimodal analgesia that enhances recovery after total hip arthroplasty (THA) and knee arthroplasty (TKA). However, LIA can cause fatal local anesthetic systemic toxicity (LAST). The incidences of LIA-induced LAST in different surgeries and anesthetic agents have not been well investigated., Methods: This observational study enrolled 1,267 adult patients who received LIA with bupivacaine for primary THA or TKA under general anesthesia at a single medical center between January 2020 and October 2021. LAST incidence was graded by severity: severe (refractory seizure or arrhythmia requiring lipid rescue), major (seizure or arrhythmia requiring prompt medication), and minor (all other) events. Patient demographics, surgical and anesthesia details, recovery profiles, and LAST incidences were recorded and analyzed., Results: The incidence of severe LAST events was 2.41 per 1000 in unilateral THA, 0 in TKA, and 3.16 per 1000 in the entire cohort. The odds ratio of developing major LAST events was 4.35 in patients undergoing unilateral THA compared with those undergoing unilateral TKA in a matched comparison. Patients who underwent bilateral THA had the highest risk of developing LIA-induced LAST. Additionally, patients using propofol infusion for anesthesia maintenance had a lower risk of seizures and tremors than those using sevoflurane inhalation. The odds ratio of major LAST events was 0.47 in matched comparisons., Conclusions: LIA was associated with a significantly higher risk of LAST in the THA group than in the TKA group. Propofol maintenance reduces the likelihood of seizures and tremors compared with sevoflurane inhalation. Exploring strategies to reduce the incidence of LIA-induced LAST is essential to improve perioperative patient safety., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Ethics Committee of the Chang Gung Medical Foundation (approval number: 202200080B0). The need for informed consent was waived because of the retrospective design of the study and the use of anonymized personal information. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: To compare the prevalence and progression of subclinical atherosclerosis (SA) in populations with different cardiovascular disease (CVD) risks in China, and clarify the relationship between CVD risk stratification and SA. Methods: All participants were from Beijing Community-Based Cohort of Atherosclerosis. A total of 1 462 participants underwent carotid ultrasound and coronary computed tomography scan during 2008-2009 and 2013-2014. After excluding 191 participants with history of CVD and incomplete baseline data, 1 271 participants were included in final analysis. The 10-year CVD risk for participants were calculated based on the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) equation, and risk stratification was performed. The prevalence and progression of SA was determined by carotid intima-media thickness (cIMT), carotid plaque score and coronary artery calcification (CAC) score. Results: In the participants included in this study, 536 (42.2%), 418 (32.9%) and 317 (24.9%) were classified to have low, intermediate and high 10-year risk, respectively. With the rising level of 10-year risk, the proportion of patients with SA and SA progression increased. In low, intermediate and high CVD risk groups, the proportions of participants with CAC were 16.4%, 36.4% and 52.0% (trend P <0.001); and 15.4%, 36.4% and 53.6% had progression of CAC during follow-up, respectively (trend P <0.001); compared with low-risk group, RR s for CAC progression of intermediate and high-risk groups were 2.316 (95% CI : 1.714-3.129) and 3.322 (95% CI : 2.472-4.463), respectively (trend P <0.001). The trend of relationship between CVD risk stratification and cIMT and carotid plaque progression were consistent with CAC. Conclusions: This current study shows CVD risk stratification is closely related to the prevalence and progression of atherosclerosis in Chinese population. However, many people with low CVD risk have atherosclerotic change in their carotid and coronary artery.

Background/aim: Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe complication characterized by elevated pulmonary artery pressure, which can lead to right heart failure and death, if untreated. Standard treatments often fail to adequately manage symptoms, highlighting the need for novel therapeutic approaches. This study investigated the efficacy of molecular hydrogen (H 2 ) therapy in a patient with CTD-PAH., Case Report: We present the case of a 56-year-old female with CTD-PAH, diagnosed in 2013 with Sjogren's syndrome complicated by interstitial lung disease (ILD) and PAH. Despite treatment with sildenafil, bosentan, macitentan, iloprost, and corticosteroids, her condition deteriorated, resulting in severe dyspnea and cardiogenic shock in 2020. In May 2023, molecular hydrogen therapy was initiated as an adjuvant treatment. The patient received daily hydrogen capsules, which led to increased CD127+ Treg cells, reduced anti-Ro antibodies, and decreased B cell subsets. Her clinical symptoms stabilized without adverse effects., Conclusion: This case highlights the potential benefits of molecular hydrogen therapy in CTD-PAH. H 2 therapy exhibiting anti-inflammatory and immunomodulatory effects, leading to improved immune cell profiles and stabilizing clinical symptoms in a patient unresponsive to conventional treatments. Further research is needed to elucidate the mechanisms of H 2 therapy and validate its efficacy in larger cohorts. Molecular hydrogen therapy shows promise as a safe adjunctive treatment for CTD-PAH, offering a new approach for managing this challenging condition., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Most nontraumatic subarachnoid hemorrhages (SAHs) are caused by ruptured saccular aneurysms, often resulting in a devastating clinical event characterized by high mortality and significant morbidity among survivors. Numerous studies have confirmed the neuroprotective effects of the molecular hydrogen due to its unique biological properties., Case Report: We present the case of a 44-year-old female with aneurysmal SAH with rheumatoid arthritis (RA) and newly diagnosed systemic lupus erythematosus (SLE), complicated by acute ischemic infarction. Despite surgical, pharmacological and non-pharmacological interventions, including embolization of the aneurysm, immunosuppressant, non-vitamin K antagonist oral anticoagulant (NOAC), and plasmapheresis, loss of consciousness continued. The patient began daily treatment with hydrogen capsules, resulting in increased in Treg cells, Breg cells, increased TIM3+ expression on Tc cells, and the conversion of anti-dsDNA from positive to negative. Her clinical symptoms stabilized without adverse effects., Conclusion: This case highlights the potential benefits of molecular hydrogen therapy in managing aneurysmal SAH with underlying autoimmune disease, warranting further research., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Epidermal growth factor (EGF) binds with its surface receptor to stimulate gene expression and cancer cell proliferation. EGF stimulates cancer cell growth via phosphoinositide 3‑kinase (PI3K) and programmed cell death ligand 1 (PD‑L1) pathways. As an integrin αvβ3 antagonist, heteronemin exhibits potent cytotoxic effects against cancer cells. It inhibits critical signal transduction pathways promoted by the EGF. In the current study, EGF‑induced signal activation and proliferative effects were investigated in cholangiocarcinoma cells and its molecular targets using qPCR and western blotting analyses. In addition, cell viability assays were performed to assess the growth effects of EGF and heteronemin. Heteronemin reversed the effects of EGF and was further enhanced by blockage of PI3K's activity. In summary, EGF stimulates cholangiocarcinoma cell growth. On the other hand, heteronemin inhibited PI3K activation and PD‑L1 expression to reverse the stimulative effects of EGF‑induced gene expression and proliferation in cholangiocarcinoma cells.

Background: The occurrence of blindness resulting from facial injection is a catastrophic complication that remains a significant safety concern for patients. The aim was to assess public awareness of blindness caused by hyaluronic acid injection., Methods: The Tencent questionnaire platform was used to gather self-reported demographic data, information about injection experience, and factors influencing the understanding of blindness. Additionally, we included an educational section on blindness caused by hyaluronic acid injection and evaluated the respondents' intention to undergo injections., Results: A total of 1000 respondents completed the questionnaire, 15.4% had received filler injections, and 53.7% expressed their consideration of facial filler injections. The majority of respondents (68.3%) reported being aware of the risk of blindness associated with filler injections, with professional health blogs, social media, and news serving as the primary sources of information. Furthermore, 93.4% of the respondents believed that plastic surgeons should discuss the risk of blindness with patients before injection., Conclusions: The majority of the respondents in this study were aware of the possibility of blindness resulting from filler injections. Health blogs, news outlets, and social media platforms are likely the primary channels through which the public obtains information on this topic., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The pursuit of innovative therapeutic strategies in oncology remains imperative, given the persistent global impact of cancer as a leading cause of mortality. Immunotherapy is regarded as one of the most promising techniques for systemic cancer therapies among the several therapeutic options available. Nevertheless, limited immune response rates and immune resistance urge us on an augmentation for therapeutic efficacy rather than sticking to conventional approaches. Ferroptosis, a novel reprogrammed cell death, is tightly correlated with the tumor immune environment and interferes with cancer progression. Highly mutant or metastasis-prone tumor cells are more susceptible to iron-dependent nonapoptotic cell death. Consequently, ferroptosis-induction therapies hold the promise of overcoming resistance to conventional treatments. The most prevalent post-transcriptional modification, RNA m6A modification, regulates the metabolic processes of targeted RNAs and is involved in numerous physiological and pathological processes. Aberrant m6A modification influences cell susceptibility to ferroptosis, as well as the expression of immune checkpoints. Clarifying the regulation of m6A modification on ferroptosis and its significance in tumor cell response will provide a distinct method for finding potential targets to enhance the effectiveness of immunotherapy. In this review, we comprehensively summarized regulatory characteristics of RNA m6A modification on ferroptosis and discussed the role of RNA m6A-mediated ferroptosis on immunotherapy, aiming to enhance the effectiveness of ferroptosis-sensitive immunotherapy as a treatment for immune-resistant malignancies., (© 2024. The Author(s).)

Layer-by-layer deposition has been widely used to prepare heterogeneous nanocomposites with controllable properties, where the controllability of nanocomposite properties can be further enhanced by combining the self-assembly of hard materials, such as nanocrystals, and soft materials, such as polymer matrices. However, the self-assembled structure of nanocrystals in a polymer matrix is limited by thermodynamics. Herein, we introduced the strong interaction between nanocrystals and a substrate to generate a thermodynamically unfavorable one-dimensional nanostructure standing vertically on the substrate. Two different shapes-"wire-like" and "steeple-like" or "antenna-like"-of one-dimensional nanostructures standing vertically on the substrate can be obtained using cube-like nanocrystals as building blocks and carefully controlling their size in each deposited layer. This low-cost and massively parallel scale synthesis method to generate one-dimensional nanostructures standing vertically on a substrate can be used to replace the expensive and time-consuming "lithography" synthesis method. This synthesis method also provides a simple way to design and fabricate one-dimensional nanostructures with desired properties standing vertically on a substrate by controlling nanocrystal properties in each deposited layer.

Investigating the structural heterogeneity of monoclonal antibodies is crucial to achieving optimal therapeutic outcomes. We show that tandem-trapped ion mobility spectrometry enables collision-induced unfolding measurements of subpopulations of a humanised IgGk NIST monoclonal antibody (NISTmAb). Our results indicate that differential glycosylation of NISTmAb does not modulate its conformational heterogeneity.

Background: Persistent inflammation over time can cause gradual harm to the body. Molecular hydrogen has the potential to specifically counteract reactive oxygen species (ROS), reduce disease severity, and enhance overall health. Investigations of the anti-inflammatory and antioxidant properties of oral solid hydrogen capsules (OSHCs) are currently limited, prompting our examination of the beneficial effects of OSHCs. Subsequently, we conducted a clinical study to assess the impact of OSHCs supplementation on individuals with chronic inflammation. Materials and methods: Initially, we evaluated the oxidative reduction potential (ORP) properties of the OSHCs solution by comparing it to hydrogen-rich water (HRW) and calcium hydride (CaH 2 ) treated water. In our outpatient department, stable patients with chronic illnesses who were treated with varying doses of OSHCs were randomized into low-, medium-, and high-dose groups for 4 weeks. Primary outcomes included changes in the serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentrations after four weeks of OSHCs consumption. Secondary outcomes included changes in the Brief Fatigue Inventory-Taiwan (BFI-T) fatigue scale, Control Status Scale for Diabetes (CSSD70) scores, and Disease Activity Score 28 (DAS28). Results: Compared to HRW and CaH 2 , OSHCs demonstrated a prolonged reduction in ORP for 60 minutes in vitro and enabled a regulated release of hydrogen over 24 hours. A total of 30 participants, with 10 in each dosage (low/medium/high) group, completed the study. The average ESR120 significantly decreased from the first week to the fourth week, with a noticeable dose effect (low-dose group, p = 0.494; high-dose group, p = 0.016). Overall, the average CRP concentration showed a distinct decreasing trend after four weeks of OSHCs administration (w0 vs. w4, p = 0.077). The average DAS28 score demonstrated a significant decrease following OSHCs treatment. Furthermore, there were improvements in the BFI-T and CSSD70 scores. Conclusion: OSHCs supplementation may exert anti-inflammatory and antioxidant effects on individuals with chronic inflammation. However, further clinical studies could be investigated to explore the potential therapeutic effects of OSHCs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Young children are susceptible to enterovirus (EV) infections, which cause significant morbidity in this age group., Objective: This study investigated the characteristics of virus strains and the epidemiology of EVs circulating among young children in Taiwan from 2011 to 2020., Methods: Children diagnosed with EV infections from 2011 to 2020 were identified from the routine national health insurance data monitoring disease system, real-time outbreak and disease surveillance system, national laboratory surveillance system, and Statistics of Communicable Diseases and Surveillance Report, a data set (secondary data) of the Taiwan Centers for Disease and Control. Four primary outcomes were identified: epidemic features, characteristics of sporadic and cluster cases of EV infections, and main cluster institutions., Results: From 2011 to 2020, between 10 and 7600 person-times visited the hospitals for EV infections on an outpatient basis daily. Based on 2011 to 2020 emergency department EV infection surveillance data, the permillage of EV visits throughout the year ranged from 0.07‰ and 25.45‰. After typing by immunofluorescence assays, the dominant type was coxsackie A virus (CVA; 8844/12,829, 68.9%), with most constituting types CVA10 (n=2972), CVA2 (n=1404), CVA6 (n=1308), CVA4 (n=1243), CVA16 (n=875), and CVA5 (n=680); coxsackie B virus CVB (n=819); echovirus (n=508); EV-A71 (n=1694); and EV-D68 (n=10). There were statistically significant differences (P<.001) in case numbers of EV infections among EV strains from 2011 to 2020. Cases in 2012 had 15.088 times the odds of being EV-A71, cases in 2014 had 2.103 times the odds of being CVA, cases in 2015 had 1.569 times the odds of being echovirus, and cases in 2018 had 2.274 times the odds of being CVB as cases in other years. From 2011 to 2020, in an epidemic analysis of EV clusters, 57 EV clusters were reported. Clusters that tested positive included 53 (53/57, 93%) CVA cases (the major causes were CVA6, n=32, and CVA10, n=8). Populous institutions had the highest proportion (7 of 10) of EV clusters., Conclusions: This study is the first report of sporadic and cluster cases of EV infections from surveillance data (Taiwan Centers for Disease and Control, 2011-2020). This information will be useful for policy makers and clinical experts to direct prevention and control activities to EV infections that cause the most severe illness and greatest burden to the Taiwanese., (© Fang-Chen Liu, Bao-Chung Chen, Yao-Ching Huang, Shi-Hao Huang, Ren-Jei Chung, Pi-Ching Yu, Chia-Peng Yu. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

COVID-19 may predispose patients to cardiac injuries but whether COVID-19 infection affects the morphological features of coronary plaques to potentially influence the outcome of patients with coronary artery disease (CAD) remains unknown. By using optical coherence tomography (OCT), this study compared the characteristics of coronary plaque in patients with CAD with/without COVID-19 infection. The 206 patients were divided into 2 groups. The COVID-19 group had 113 patients between December 7, 2022, and March 31, 2023, who received OCT assessment after China decided to lift the restriction on COVID-19 and had a history of COVID-19 infection. The non-COVID-19 group had 93 patients without COVID-19 infection who underwent OCT before December 7, 2022. The COVID-19 group demonstrated a higher incidence of plaque ruptures (53.1% vs 38.7%, p = 0.039), erosions (28.3% vs 11.8%, p = 0.004), fibrous (96.5% vs 89.2%, p = 0.041) and diffuse lesions (73.5% vs 50.5%, p <0.001) compared with the non-COVID-19 group, whereas non-COVID-19 group exhibited a higher frequency of cholesterol crystals (83.9% vs 70.8%, p = 0.027), deep calcifications (65.6% vs 51.3%, p = 0.039) and solitary lesions (57.0% vs 34.5%, p = 0.001). Kaplan-Meier survival analysis revealed a significantly lower major adverse cardiac events-free probability in the COVID-19 group (91.6% vs 95.5%, p = 0.006) than in the non-COVID-19 group. In conclusion, OCT demonstrated that COVID-19 infection is associated with coronary pathological changes such as more plaque ruptures, erosions, fibrosis, and diffuse lesions. Further, COVID-19 infection is associated with a higher propensity for acute coronary events and a higher risk of major adverse cardiac events in patients with CAD., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background:  The use of mesh to reinforce the abdominal wall after abdominal flap harvest has been reported to decrease the risk of bulging and herniation. However, the impact of the plane of mesh placement in relation to the anterior rectus sheath (vs. no mesh) on postoperative abdominal complications remains unclear., Methods:  We retrospectively analyzed the length of stay and clinical outcomes in 158 female patients who underwent breast reconstruction with 250 free abdominal flaps. Group 1 consisted of patients who underwent polypropylene sublay-onlay ("sandwich") mesh placement ( N  = 70) versus polypropylene sublay-only mesh (group 2; N  = 54) versus primary fascial repair without mesh (group 3; N  = 34)., Results:  Patient demographics and comorbidities were comparable between study groups, except for rates of neoadjuvant chemotherapy (group 1: 53% vs. group 2: 33% vs. group 3: 24% [ p  < 0.01]), postoperative follow-up in months (group 1: 21.5; group 2: 11.5; group 3: 7.6 [ p  < 0.01]), and length of stay in days (group 1: 4.9 vs. group 2: 4.4 vs. group 3: 3.3 [ p  < 0.01]). No differences were observed in breast flap and donor-site complications between study groups. Patients in group 3 required significantly lower oral morphine equivalent units postoperatively compared with those in groups 1 and 2 (group 1:185.5 vs. group 2: 79.7 vs. group 3: 71.6 [ p  < 0.01])., Conclusion:  Abdominal donor-site closure without mesh was associated with a shorter length of stay and less narcotic intake without an increase in donor-site complications. These findings should be considered when deciding to place mesh for donor-site closure after abdominal flap harvest., Competing Interests: A.M. is a consultant for AxoGen, Gore, and RTI. The remaining authors declare no conflicts of interest. No payment was received for the study., (Thieme. All rights reserved.)

Objective: In recent decades, China has implemented a series of policies to address air pollution. We aimed to assess the health effects of these policies on stroke burden attributable to ambient fine particulate matter (PM 2.5 )., Methods: Joinpoint regression was applied to explore the temporal tendency of stroke burden based on data from the Global Burden of Disease 2019 study., Results: The age-standardized rates of disability-adjusted life year (DALY) for stroke attributable to ambient PM 2.5 in China, increased dramatically during 1990-2012, subsequently decreased at an annual percentage change (APC) of -1.98 [95% confidence interval ( CI ): -2.26, -1.71] during 2012-2019. For ischemic stroke (IS), the age-standardized DALY rates doubled from 1990 to 2014, and decreased at an APC of -0.83 (95% CI : -1.33, -0.33) during 2014-2019. Intracerebral hemorrhage (ICH) showed a substantial increase in age-standardized DALY rates from 1990 to 2003, followed by declining trends, with APCs of -1.46 (95% CI : -2.74, -0.16) during 2003-2007 and -3.33 (95% CI : -3.61, -3.06) during 2011-2019, respectively. Conversely, the age-standardized DALY rates for subarachnoid hemorrhage (SAH) generally declined during 1990-2019., Conclusion: Our results clarified the dynamic changes of the ambient PM 2.5- attributable stroke burden in China during 1990-2019, highlighting the health effects of air quality improvement policies., (Copyright © 2024 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh , is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS).