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An-An Li,1,2 Yu Zhang,1,2 Wei-Lai Tong,1,2 Jiang-Wei Chen,1 Shan-Hu Huang,1 Jia-Ming Liu,1 Zhi-Li Liu1,2 1Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of ChinaCorrespondence: Zhi-Li Liu; Jia-Ming Liu, Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Donghu District, Nanchang, 330006, People’s Republic of China, Tel/Fax +86-791-88693201, Email liuzhiliyfy@163.com; zgm7977@ncu.edu.cn; liujiamingdr@hotmail.comPurpose: Pyroptosis plays an important role in the occurrence and progression of many tumors; however, the specific mechanisms involved remain unknown. Here, we construct a pyroptosis-related gene signature that can be used to predict survival prognosis of skin cutaneous melanoma (SKCM) and provide guidance for clinical treatment.Methods: By integrating data from the two databases from the GTEx and TCGA, differentially expressed genes (DEGs) from normal tissues and skin cutaneous tumor tissues were identified. The main signaling pathways and function enrichment of these differential genes were determined. Univariate and multivariate COX regression analysis, and risk score analysis were used to construct a signature to assess its predictive value for overall survival. The mRNA expression of these five genes in melanoma cells was determined by quantitative polymerase chain reaction (qPCR). The pRRophetic algorithm was used to estimate the half-maximal inhibitory concentration (IC50) of chemotherapy drugs in SKCM patients. The expression of multiple immune checkpoint genes also was evaluated.Results: Sixteen DEGs associated with pyroptosis in SKCM and normal skin tissues were identified. Of these, 12 pyroptosis-related DEGs were associated with the prognosis of SKCM. A five-gene signature (GSDMA, GSDMC, IL-18, NLRP6, and AIM2) model was constructed. Patients were divided into high-risk and low-risk groups using the risk scores. Of these, the high-risk group had a worse survival prognosis. There are significant differences in the predicted sensitivity of the high-risk and low-risk groups to chemotherapeutic drugs. In addition, compared with the high-risk group, the low-risk group showed higher expression of PD-1, PDL-1, CTLA-4, LAG-3, and VSIR.Conclusion: In this study, we constructed a novel prognostic pyroptosis-related gene-signature for SKCM. These genes showed good predictive value for patient prognosis and could provide guidance for better treatment of SKCM patients.Keywords: skin cutaneous melanoma, pyroptosis, prognosis, signature, risk model

This review is intended to provide risk assessors and risk managers with a better understanding of issues associated with total exposures of human populations to ethylene oxide from endogenous and exogenous pathways. Biomonitoring of human populations and lab animals exposed to ethylene oxide has relied upon the detection of hemoglobin adducts such as 2-hydroxyethylvaline (HEV), which provides a useful measure of total exposure to ethylene oxide from all pathways. Recent biomonitoring data from CDC provide an excellent characterization of total exposure to ethylene oxide to the general U.S. population by demographic factors such as age, gender, and race as well as smoking habit, which might be comparable to previous measurements reported for humans and lab animals. The biochemical pathways including gastrointestinal (production by bacteria) and systemic (enzymatic production) pathways by which endogenous ethylene is generated and converted to ethylene oxide are described. The relative importance of endogenous pathways and exogenous pathways via ambient air or tobacco smoke was quantified based upon available data to characterize their relative importance to total exposure. Considerable variation was noted for HEV measurements in human populations, and important sources of variation for all pathways are discussed. Issues related to risk assessment and risk management of human populations exposed to ethylene oxide are provided within the context of characterizing total exposure, and data needs for supporting future risk assessment identified. [ABSTRACT FROM AUTHOR]

Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID., (Copyright © 2024. Published by Elsevier Inc.)

This study investigates the potential of antimicrobial peptides (AMPs) as alternatives to combat antibiotic resistance, with a focus on two AMPs containing unnatural amino acids (UAAs), E2-53R (16 AAs) and LE-54R (14 AAs). In both peptides, valine is replaced by norvaline (Nva), and tryptophan is replaced by 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Microbiological studies reveal their potent activity against both Gram-negative (G(-)) and Gram-positive (G(+)) bacteria without any toxicity to eukaryotic cells at test concentrations up to 32 μM. Circular dichroism (CD) spectroscopy indicates that these peptides maintain α-helical structures when interacting with G(-) and G(+) lipid model membranes (LMMs), a feature linked to their efficacy. X-ray diffuse scattering (XDS) demonstrates a softening of G(-), G(+) and eukaryotic (Euk33) LMMs and a nonmonotonic decrease in chain order as a potential determinant for bacterial membrane destabilization. Additionally, XDS finds a significant link between both peptides' interfacial location in G(-) and G(+) LMMs and their efficacy. Neutron reflectometry (NR) confirms the AMP locations determined using XDS. Lack of toxicity in eukaryotic cells may be related to their loss of α-helicity and their hydrocarbon location in Euk33 LMMs. Both AMPs with UAAs offer a novel strategy to wipe out antibiotic-resistant strains while maintaining human cells. These findings are compared with previously published data on E2-35, which consists of the natural amino acids arginine, tryptophan, and valine.

We previously reported an ability of low-intensity vibration (LIV) to improve selected biomarkers of bone turnover and gene expression and reduce osteoclastogenesis but lacking of evident bone accrual. In this study, we demonstrate that a prolonged course of LIV that initiated at 2 weeks post-injury and continued for 8 weeks can protect against bone loss after SCI in rats. LIV stimulates bone formation and improves osteoblast differentiation potential of bone marrow stromal stem cells while inhibiting osteoclast differentiation potential of marrow hematopoietic progenitors to reduce bone resorption. We further demonstrate that the combination of LIV and RANKL antibody reduces SCI-related bone loss more than each intervention alone. Our findings that LIV is efficacious in maintaining sublesional bone mass suggests that such physical-based intervention approach would be a noninvasive, simple, inexpensive and practical intervention to treat bone loss after SCI. Because the combined administration of LIV and RANKL inhibition better preserved sublesional bone after SCI than either intervention alone, this work provides the impetus for the development of future clinical protocols based on the potential greater therapeutic efficacy of combining non-pharmacological (e.g., LIV) and pharmacological (e.g., RANKL inhibitor or other agents) approaches to treat osteoporosis after SCI or other conditions associated with severe immobilization., Competing Interests: YP, AM, OFA, JSM, JC, JH, AL, JQF, WAB, WQ have nothing to disclose. HMB and WDD are co-founders and managing members of InflamaCORE, LLC and have licensed patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. HMB and WDD are Scientific Advisory Board Members for ZyVersa Therapeutics., (© 2024 Published by Elsevier Inc.)

Background and Aims: Opioid-induced esophageal dysfunction (OIED) often presents as spastic esophageal disorders (SEDs) and esophagogastric junction outflow obstruction (EGJOO). The aim of this study was to evaluate and compare clinical outcomes of peroral endoscopic myotomy (POEM) for SEDs and EGJOO among opioid users and nonusers., Methods: This propensity score (PS) matching study included consecutive opioid users and nonusers who underwent POEM for SEDs and EGJOO between January 2018 and September 2022. The following covariates were used for the PS calculation: age, sex, duration of symptoms, Eckardt score, type of motility disorder, and length of myotomy during POEM. Clinical response was defined as a post-POEM Eckardt score ≤3., Results: A total of 277 consecutive patients underwent POEM during the study period. PS matching resulted in the selection of 64 pairs of patients strictly matched 1:1 (n = 128) with no statistically significant differences in demographic, baseline, or procedural characteristics or in the parameters considered for the PS between the 2 groups. Clinical response to POEM was significantly lower among opioid users (51 of 64 [79.7%]) versus nonusers (60 of 64 [93.8%]) (P = .03) at a median follow-up of 18 months. Among opioid users, higher opioid dose (>60 morphine milligram equivalents per day) was associated with a higher likelihood of failure to respond to POEM (odds ratio, 4.59; 95% confidence interval, 1.31-3.98; P = .02)., Conclusions: Clinical response to POEM for SEDs and EGJOO is significantly lower among opioid users versus nonusers. There was a dose-relationship between opioids and response to POEM, with higher daily opioid usage associated with a higher likelihood of treatment failure., Competing Interests: Disclosure The following authors disclosed financial relationships: D. Yang: consultant for Olympus, Fujifilm, Apollo Endosurgery, Medtronic, and Microtech; and research support from Microtech and 3D-Matrix. M.K. Hasan: consultant for Boston Scientific and Olympus. P. V. Draganov: consultant for Olympus, Boston Scientific, Fujifilm, Cook Medical, and Medtronic. N. Sharma: consultant for Boston Scientific, Medtronic, Steris, and Olympus. J. H. Hwang: consultant for Boston Scientific, Olympus, Medtronic, Fujifilm, and Microtech. A. Sethi: consultant for Boston Scientific, Interscope, Medtronic, and Olympus; and research support from Boston Scientific and Fujifilm. P. Benias: consultant for Boston Scientific, Apollo Endosurgery, and Fujifilm. P. Kedia: consultant for Boston Scientific, Olympus, and Medtronic. S. Jawaid: consultant for Lumendi, Creo Medical, and ConMed. M. B. Ujiki: member of the advisory board for Boston Scientific and Apollo Endosurgery; and speaker for Gore and Medtronic. R. Kim: consultant for Medtronic, Cook Medical, and Apollo Endosurgery. M. Othman: consultant for Olympus, Boston Scientific, Creo Medical, Apollo Endosurgery, Lumendi, AbbVie, and Nestle; and research support from Boston Scientific, ConMed, Lucid Diagnostic, AbbVie, and Nestle. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Cardiovascular diseases represent a significant threat to the overall well-being of the global population. Continuous monitoring of vital signs related to cardiovascular health is essential for improving daily health management. Currently, there has been remarkable proliferation of technology focused on collecting data related to cardiovascular diseases through daily electronic skin monitoring. However, concerns have arisen regarding potential skin irritation and inflammation due to the necessity for prolonged wear of wearable devices. To ensure comfortable and uninterrupted cardiovascular health monitoring, the concept of biocompatible electronic skin has gained substantial attention. In this review, biocompatible electronic skins for cardiovascular health monitoring are comprehensively summarized and discussed. The recent achievements of biocompatible electronic skin in cardiovascular health monitoring are introduced. Their working principles, fabrication processes, and performances in sensing technologies, materials, and integration systems are highlighted, and comparisons are made with other electronic skins used for cardiovascular monitoring. In addition, the significance of integrating sensing systems and the updating wireless communication for the development of the smart medical field is explored. Finally, the opportunities and challenges for wearable electronic skin are also examined., (© 2024 Wiley‐VCH GmbH.)

Coronary artery disease (CAD) is the most common type of heart disease and represents the leading cause of death in both men and women worldwide. Early detection of CAD is crucial for decreasing mortality, prolonging survival, and improving patient quality of life. Herein, a non-invasive is described, nanoparticle-based diagnostic technology which takes advantages of proteomic changes in the nano-bio interface for CAD detection. Nanoparticles (NPs) exposed to biological fluids adsorb on their surface a layer of proteins, the "protein corona" (PC). Pathological changes that alter the plasma proteome can directly result in changes in the PC. By forming disease-specific PCs on six NPs with varying physicochemical properties, a PC-based sensor array is developed for detection of CAD using specific PC pattern recognition. While the PC of a single NP may not provide the required specificity, it is reasoned that multivariate PCs across NPs with different surface chemistries, can provide the desirable information to selectively discriminate the condition under investigation. The results suggest that such an approach can detect CAD with an accuracy of 92.84%, a sensitivity of 87.5%, and a specificity of 82.5%. These new findings demonstrate the potential of PC-based sensor array detection systems for clinical use., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare form of plasma cell dyscrasia often treated with high-dose chemotherapy and autologous stem cell transplantation (ASCT). ASCT has resulted in satisfactory and sustained therapeutic outcomes. However, a substantial number of patients eventually experience disease progression, requiring second-line treatment. Therefore, it would be of further benefit to identify patients who will acquire the best long-term survival after ASCT. The aim of this study was to fully reveal the outcomes of patients undergoing ASCT in a large series with long-term follow-up. Long-term outcomes of 239 patients with newly diagnosed POEMS syndrome undergoing ASCT at a single center were evaluated retrospectively. Rates of hematologic complete response (CR H ) and vascular endothelial growth factor (VEGF) complete response (CR V ) were 57.3% and 68.6%, respectively, with 90.5% of patients achieving an overall clinical response. At a median follow-up of 94 months, the 5-year overall survival (OS) rate was 92.8%, and the 5-year time to next-line treatment (TTNT) rate was 72.2% (median TTNT, 96 months). Patients achieving CR H (5-year TTNT rate, 82.5% versus 60.7%; P < .0001) or CR V (5-year TTNT rate 83.7% versus 54.2%; P < .0001) had better survival outcomes compared to non-CR group patients. Dual hematologic and VEGF complete responses carry further benefit for survival (median TTNT, 129 months versus 68 months; P < .0001). Seven cases of second primary malignancy were recorded, all of which were solid tumors. Front-line ASCT resulted in excellent long-term survival in patients with POEMS syndrome, with the best survival observed in those achieving dual hematologic and VEGF CRs., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: While colon endoscopic mucosal resection (EMR) is an effective technique, removal of larger polyps often requires piecemeal resection, which can increase recurrence rates. Endoscopic submucosal dissection (ESD) in the colon offers the ability for en bloc resection and is well-described in Asia, but there are limited studies comparing ESD vs EMR in the West., Aim: To evaluate different techniques in endoscopic resection of large polyps in the colon and to identify factors for recurrence., Methods: The study is a retrospective comparison of ESD, EMR and knife-assisted endoscopic resection performed at Stanford University Medical Center and Veterans Affairs Palo Alto Health Care System between 2016 and 2020. Knife-assisted endoscopic resection was defined as use of electrosurgical knife to facilitate snare resection, such as for circumferential incision. Patients ≥ 18 years of age undergoing colonoscopy with removal of polyp(s) ≥ 20 mm were included. The primary outcome was recurrence on follow-up., Results: A total of 376 patients and 428 polyps were included. Mean polyp size was greatest in the ESD group (35.8 mm), followed by knife-assisted endoscopic resection (33.3 mm) and EMR (30.5 mm) ( P < 0.001) . ESD achieved highest en bloc resection (90.4%) followed by knife-assisted endoscopic resection (31.1%) and EMR (20.2%) ( P < 0.001). A total of 287 polyps had follow-up (67.1%). On follow-up analysis, recurrence rate was lowest in knife-assisted endoscopic resection (0.0%) and ESD (1.3%) and highest in EMR (12.9%) ( P = 0.0017). En bloc polyp resection had significantly lower rate of recurrence (1.9%) compared to non- en bloc (12.0%, P = 0.003). On multivariate analysis, ESD (in comparison to EMR) adjusted for polyp size was found to significantly reduce risk of recurrence [adjusted hazard ratio 0.06 (95%CI: 0.01-0.57, P = 0.014)]., Conclusion: In our study, EMR had significantly higher recurrence compared to ESD and knife-assisted endoscopic resection. We found factors including resection by ESD, en bloc removal, and use of circumferential incision were associated with significantly decreased recurrence. While further studies are needed, we have demonstrated the efficacy of ESD in a Western population., Competing Interests: Conflict-of-interest statement: Mike T. Wei: Consultant for Neptune Medical, AgilTx, Capsovision; Margaret Zhou and Andrew Ofosu: No conflicts; Andrew Li: Consultant for Neptune Medical; Joo Ha Hwang: Consultant for Olympus, Medtronic, Boston Scientific, Lumendi, Fujifilm, Noah Medical, Neptune Medical, and Micro-Tech; Shai Friedland: Consultant for Intuitive Surgical and Capsovision., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Skin cancer is the most common secondary malignancy among young adult childhood cancer survivors (YA-CCS). Skin examination to detect skin cancer early (including melanoma as well as basal or squamous cell skin cancers), both physician-based (PSE) and self-skin exam (SSE), is recommended, particularly for radiotherapy-exposed YA-CCS who are at high risk of developing skin cancer., Methods: Awareness and prevalence of skin examination and demographic, clinical, and healthcare correlates were examined in a population-based sample of YA-CCS with diverse cancer types excluding melanoma. Descriptive frequencies and logistic regression models were conducted using sample weights to correct for non-response bias with PSE, SSE and adherence to both as outcomes., Results: The sample comprised 1064 participants with 53% Latino. Eight percent of participants were aware of the need for skin examination; 9% reported receipt of PSE within past 2 years; 35% reported regular SSE; and 6% were adherent to both. Among the radiotherapy-treated, 10% were aware of the need for skin examination, 10% reported recent PSE; 38% reported regular SSE; and 8% were adherent to both. Healthcare and clinical factors including healthcare self-efficacy, engagement in cancer-related follow-up care, greater treatment intensity and greater number of treatment-related late effects were positively associated with PSE and SSE. Latino YA-CCS were less likely to engage in PSE and SSE., Conclusion(s): Adherence to recommended screening for skin cancer was low in this at-risk population, notably for YA-CCS exposed to radiotherapy. The development of effective strategies to expand skin cancer screening is needed in this at-risk population., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Study of the molecular mechanisms of metastasis is still the research focus for osteosarcoma (OS) prevention. This study investigates the mechanism of valosin-containing protein (VCP) promoting OS metastasis in vitro through autophagy and epithelial-mesenchymal transition (EMT)., Methods: Different cell lines of osteosarcoma (143B and MG63) were adopted in this study. The level of VCP expression in osteosarcoma cells was changed, and the level of autophagy and the progression of the epithelial-mesenchymal transition (EMT) were observed. Then autophagy and EMT in OS cells were changed artificially, and proliferation and migration ability were observed., Results: The expression of LC3II/I was decreased, but the insolubilized P62 protein expression was increased in the VCP inhibiting group and the autophagy inhibitor treatment group. Simultaneously, E-cadherin protein expression increased while N-cadherin protein expression decreased in the VCP inhibiting group but increased in the TGF-β1 treatment group. In addition, suppressing VCP can cause a decrease in Transforming Growth Factor β1 (TGF-β1), smad2, smad3, phosphorylated smad2 (p-smad2), and phosphorylated smad3 (p-smad3). Autophagy inhibitors and agonists have no significant effect on the migration and invasion of OS cells but can significantly affect the ability of cells to resist anoikis. EMT inhibitors and agonists have a proportional effect on the migration and invasion of OS cells., Conclusion: VCP is likely to promote the migration and invasion of OS cells by inducing EMT, possibly via TGF-β1/smad2/3 signaling pathway. In this process, VCP-mediated autophagy may contribute to successful distant metastasis of tumor cells indirectly., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. MSA patients have a prodromal phase subsequent to the insidious onset of neuropathology. Therefore, understanding the early pathological events is important in determining the pathogenesis, which will assist with developing disease-modifying therapy. Although the definite diagnosis of MSA relies on the positive post-mortem finding of oligodendroglial inclusions composed of α-synuclein, only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. We review up-to-date knowledge of human oligodendrocyte lineage cells and their association with α-synuclein, and discuss the postulated mechanisms of how oligodendrogliopathy develops, oligodendrocyte progenitor cells as the potential origins of the toxic seeds of α-synuclein, and the possible networks through which oligodendrogliopathy induces neuronal loss. Our insights will shed new light on the research directions for future MSA studies.

Electrosurgery is the application of high-frequency electrical alternating current to biologic tissue to cut, coagulate, desiccate, and/or fulgurate. Electrosurgery is commonly used in gastrointestinal endoscopy, with applications including biliary sphincterotomy, polypectomy, hemostasis, the ablation of lesions, and endoscopic surgery. Understanding electrosurgical principles is important in endoscopic surgery to achieve the desired therapeutic effect, optimize procedural outcomes, and minimize risks or adverse events. This article describes fundamental principles that apply to electrosurgical units, operator technique, and practical considerations for achieving desired tissue effects in endoscopic surgery; and provides practical guidance and safety considerations when using electrosurgical units in endoscopic surgery., Competing Interests: Disclosure A. Li: No relevant disclosures. M.J. Zhou: No relevant disclosures. J.H. Hwang: Consultant for Olympus, Medtronic, Boston Scientific, Micro-Tech, and Lumendi., (Copyright © 2022 Elsevier Inc. All rights reserved.)

HELQ plays a key role in DNA damage response and cell-cycle checkpoint regulation. It has been implicated in ovarian and pituitary tumors and may play a role in germ cell maintenance. This study investigated the role of HELQ in lung cancer. The expression of HELQ in patients with non-small-cell lung cancer (NSCLC) was downregulated compared with normal human lungs. Clinical prognostic analysis of Kaplan-Meier plots revealed that patients with NSCLC with low HELQ levels had a reduced overall survival. Further, we found that HELQ depletion enhanced lung cancer cell malignancy. Furthermore, overexpression of HELQ in lung cancer cells reduced cell migration in vitro, while DNA damage repair was inhibited. Both in vitro and in vivo studies have shown that HELQ induces cell death. Mechanistically, we found that cells overexpressing HELQ showed a tendency to induce necrosis. After analyzing the database of HELQ interactors. we found that RIPK3 may interact with it and proved this conclusion by immunoprecipitation. Our findings identified the tumor suppressive role of HELQ in malignant human lung cancer and unraveled a potential therapeutic strategy for cancer treatment through HELQ activation. Moreover, HELQ may also be a predictive biomarker for the clinical predisposition, progression, and prognosis of lung cancer., (© 2022 International Federation for Cell Biology.)

Background: The presence of screw tunnels in the femoral neck is a problem for patients with proximal femoral fractures after removal of internal fixation. The question of how much does the existence of the screw tunnels affect the strength of the femur and whether the patient needs to be protected with an adjunctive device has been controversial. The objective of this finite element analysis was to determine (1) whether the screw tunnels affects normal weight bearing after removal of internal fixation of a proximal femur fracture, (2) which screw tunnels parameters affect the weight bearing capacity of the entire femur., Hypothesis: The presence of the screw tunnels reduces the load-bearing capacity of the femur, and the arrangement, diameter and wall thickness of the screw tunnels affect the load-bearing capacity of the femur., Materials and Methods: Twenty patients who underwent surgical treatment for proximal femur fracture at our hospital were included in the study. Computed tomography (CT) values of the screw tunnel wall in the femur after removal of internal fixations were analysed. Mimics v16.0 and Hypermesh v13.0 software programs were used to generate 3-dimensional (3D) tetrahedral finite element models of the proximal femur with different screw tunnel numbers, diameters, thicknesses, and arrangements. An acetabulum exerting a vertical pressure load of 600N on the femoral head was simulated and the force on various parts of the femur in each model was calculated., Results: There was no difference in the Hounsfield Units of the tunnel walls and cortical bone of the proximal femur (893.48±61.28 vs. 926.34±58.43; p=0.091). In each of the 3D models, the cancellous bone was the first structure to reach maximal stress. The compressive strength of the femur decreased with increasing thickness of the screw tunnel wall and decreased with increasing tunnel diameter. The femoral neck model with the inverted triangle screw tunnel arrangement had the highest compressive strength., Discussion: The femoral neck with screw tunnels can withstand day-to-day stress without special intervention. For femoral neck fractures fixed with cannulated screws, inverted triangle screws are recommended; For a single screw tunnel in the femoral neck, the larger the diameter of the femoral neck internal screw channel, the weaker the load-bearing capacity of the femur., Level of Evidence: III; well-designed computational non-experimental study., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: Endoplasmic reticulum stress (ERS) and long non-coding RNAs (lncRNAs) are important in melanoma development and progression. This study aimed to explore the prognostic value of ERS-associated lncRNA profiles in cutaneous melanoma (CM)., Methods: The Cancer Genome Atlas (TCGA) provides the raw data of CM. GSEA website was used to obtain ERS-related genes, and mRNA and LncRNA co-expression network were used to obtain ERS-related lncRNAs. A Lasso regression analysis was used to identify a prognostic risk model for the composition of ERS-related lncRNAs. Patients were divided into high- and low-risk groups based on the model's risk score. The researchers then compared the two groups' survival rates, immune infiltration, chemotherapeutic drug sensitivity, and immune checkpoint gene expression., Results: Thirty-nine ERS-related lncRNAs were discovered to be prognostic. A prognostic risk model made up of ten ERS-related lncRNAs was discovered. Patients in the low-risk group had a better prognosis than those in the high-risk group. An examination of tumor microenvironment revealed that risk scores correlated with immune cell infiltration in eight cases. Dacarbazine, paclitaxel, and cisplatin, three chemotherapy drugs, were more sensitive in the low-risk group than in the high-risk group., Conclusion: This study identified a risk model of ten ERS-related lncRNAs that have significant prognostic value in CM and could help guide clinical treatment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

In the modern world, with so much inherent stress, mental health disorders (MHDs) are becoming more common in every country around the globe, causing a significant burden on society and patients' families. MHDs come in many forms with various severities of symptoms and differing periods of suffering, and as a result it is difficult to differentiate between them and simple to confuse them with each other. Therefore, we propose a support system that employs deep learning (DL) with wearable device data to provide physicians with an objective reference resource by which to make differential diagnoses and plan treatment. We conducted experiments on open datasets containing activity motion signal data from wearable devices to identify schizophrenia and mood disorders (bipolar and unipolar), the datasets being named Psykose and Depresjon. The results showed that, in both workflow approaches, the proposed framework performed well in comparison with the traditional machine learning (ML) and DL methods. We concluded that applying DL models using activity motion signal data from wearable devices represents a prospective objective support system for MHD differentiation with a good performance.

Background: Spinal cord injury (SCI) has devastating physical and social consequences for patients. Systemic administration of methylprednisolone (MP) at a higher dosage though can reduce neurological deficits following acute SCI. Still, this treatment regimen is controversial, owing to the apparent dose-related side effects and relatively minor improvement in neurological function. Therefore, this study aimed at the bibliometric analysis of published literature related to SCI treatment, which may lead to future research trends., Methods: The literature published relating to SCI and using glucocorticoids for its treatment between 1982 and 2022 was collected and scanned in the Web of Science collection database using the keywords glucocorticoid, dexamethasone, MP, corticosteroids, and SCI, followed by using VOSviewer for bibliometric analysis of these articles., Results: A total of 1,848 published articles and 7,448 authors on SCI and glucocorticoid usage were identified. The SCI total link strength accounts for 1,341, and MP for 762 has a strong link to neuroprotection and inflammation. The mean citation count for the top 20 most-cited articles was 682 (range: 358-1,828), where most of these were descriptive studies having focused on clinical features. The Journal of Neurotrauma was the highest-ranked journal with 6,010 citations. A total of 69 articles were published by Michael G Fehlings from the University of Toronto with 6,092 citations. The University of Toronto has published 90-related manuscripts with 7,632 citations. In contrast, 800 articles were published in the United States, with 39,633 citations and total link strength of 5,714. The second-ranked country was China, with 241 published articles and 3,403 citations., Conclusions: The research published on applying MP in treating SCI has increased with time. Although the United States has made a significant global contribution to this important field of research, it requires rigorous clinical trials designed to verify the therapeutic role of MP in SCI and its appropriate dosage to find solutions for neurological recovery., 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 © 2022 Zhang, Li, Xiao, Zhong, Tong, Wang, Liu and Liu.)

Breast cancer (BC) was the most common malignant tumor in women, and breast infiltrating ductal carcinoma (IDC) accounted for about 80% of all BC cases. BC patients who had bone metastases (BM) were more likely to have poor prognosis and bad quality of life, and earlier attention to patients at a high risk of BM was important. This study aimed to develop a predictive model based on machine learning to predict risk of BM in patients with IDC. Six different machine learning algorithms, including Logistic regression (LR), Naive Bayes classifiers (NBC), Decision tree (DT), Random Forest (RF), Gradient Boosting Machine (GBM), and Extreme gradient boosting (XGB), were used to build prediction models. The XGB model offered the best predictive performance among these 6 models in internal and external validation sets (AUC: 0.888, accuracy: 0.803, sensitivity: 0.801, and specificity: 0.837). Finally, an XGB model-based web predictor was developed to predict risk of BM in IDC patients, which may help physicians make personalized clinical decisions and treatment plans for IDC patients., 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 © 2022 Liu, Li, Wu, Tong, Li, Sun, Liu and Liu.)

Background and study aims  Gastroparesis post-lung transplant (LTx) can lead to increased risk of gastroesophageal reflux (GER) and accelerated graft dysfunction. We aimed to evaluate the efficacy and safety of gastric per-oral endoscopic myotomy (G-POEM), a promising tool in patients with refractory gastroparesis, for managing refractory gastroparesis and GER in post-LTx patients. Patents and methods  This was a multicenter retrospective study on post-LTx patients who underwent G-POEM for management of gastroparesis and GER that were refractory to standard medical therapy. The primary outcome was clinical success post-G-POEM. Secondary outcomes included the rate of post-G-POEM objective esophageal pH exam normalization, rate of gastric emptying scintigraphy (GES) normalization, technical success, and adverse events. Results  A total of 20 patients (mean age 54.7 ± 14.1 years, Female 50 %) underwent G-POEM at a median time of 13 months (interquartile range 6.5-13.5) post-LTx. All G-POEM procedures were technically successful. Clinical success was achieved in 17 (85 %) patients during a median follow-up time of 8.9 (IQR: 3-17) months post-G-POEM. Overall GCSI and two of its subscales (bloating and postprandial fullness/early satiety) improved significantly following G-POEM. Two patients (10 %) developed post-procedural AEs (delayed bleeding 1, pyloric stenosis 1, both moderate in severity). Post-G-POEM GES improvement was achieved in 12 of 16 patients (75 %). All 20 patients were on proton pump inhibitors pre-G-POEM, as opposed to five post-G-POEM. Post-G-POEM PH study normalization was noted in nine of 10 patients (90 %) who underwent both pre- and post-G-poem pH testing. Conclusions  G-POEM is a promising noninvasive therapeutic tool for management of refractory gastroparesis and GER post-LTx., Competing Interests: Competing interests Dr. Hwang is a consultant for Boston Scientific, Olympus, and Medtronic, Dr. Draganov is a consultant for Olympus, Boston Scientific, Cook, Lumendi, Microtech. Dr. Zuchelli is a consultant for Boston Scientific, Dr. Piraka is a recipient of study funding from Aries and US Endoscopy, Dr. Khashab is a consultant for Boston Scientific, Olympus, and Medtronic., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Recent studies suggest that routine laboratory tests are not required within 1 day after partial knee arthroplasty. In this study, we evaluated the utility of routine postoperative laboratory tests after initial unilateral total knee arthroplasty (TKA) in an Asian population. In addition, we explored risk factors associated with abnormal test results., Methods: Clinical data of patients who underwent original unilateral TKA between 2015 and 2020 were retrospectively analyzed. Patient characteristics and laboratory test results were recorded. Multivariate binary logistic regression analysis was performed to identify risk factors associated with 3 abnormal laboratory results., Results: A total of 713 patients, who underwent relevant laboratory tests within 3 days of TKA surgery, were enrolled. Among them, 8.1%, 9.9%, and 3.4% patients with anemia, hypoalbuminemia, and abnormal serum potassium levels required clinical intervention after surgery. Binary logistic regression analysis revealed that preoperative hemoglobin levels, estimated blood loss, and age were independent risk factors of postoperative blood transfusion in TKA patients. On the other hand, preoperative albumin levels, intraoperative blood loss, and operation time were risk factors associated with postoperative albumin supplementation. In addition, lower body mass index (BMI) and preoperative hypokalemia were potential risk factors of postoperative potassium supplementation., Conclusion: Considering that more than 90% of abnormal postoperative laboratory tests do not require clinical intervention, we believe that routine laboratory tests after surgery have little significance in patients with primary unilateral TKA. However, postoperative laboratory testing is necessary for patients with established risk factors., (© 2022. The Author(s).)

Objective: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been engendering enormous hazards to the world. We obtained the complete genome sequences of SARS-CoV-2 from imported cases admitted to the Guangzhou Eighth People's Hospital, which was appointed by the Guangdong provincial government to treat coronavirus disease 2019 (COVID-19). The SARS-CoV-2 diversity was analyzed, and the mutation characteristics, time, and regional trend of variant emergence were evaluated., Methods: In total, 177 throat swab samples were obtained from COVID-19 patients (from October 2020 to May 2021). High-throughput sequencing technology was used to detect the viral sequences of patients infected with SARS-CoV-2. Phylogenetic and molecular evolutionary analyses were used to evaluate the mutation characteristics and the time and regional trends of variants., Results: We observed that the imported cases mainly occurred after January 2021, peaking in May 2021, with the highest proportion observed from cases originating from the United States. The main lineages were found in Europe, Africa, and North America, and B.1.1.7 and B.1.351 were the two major sublineages. Sublineage B.1.618 was the Asian lineage (Indian) found in this study, and B.1.1.228 was not included in the lineage list of the Pangolin web. A reasonably high homology was observed among all samples. The total frequency of mutations showed that the open reading frame 1a (ORF1a) protein had the highest mutation density at the nucleotide level, and the D614G mutation in the spike protein was the commonest at the amino acid level. Most importantly, we identified some amino acid mutations in positions S, ORF7b, and ORF9b, and they have neither been reported on the Global Initiative of Sharing All Influenza Data nor published in PubMed among all missense mutations., Conclusion: These results suggested the diversity of lineages and sublineages and the high homology at the amino acid level among imported cases infected with SARS-CoV-2 in Guangdong Province, China., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Studies of nervous system effects of glyphosate, a widely used herbicide, have not been critically examined. The aim of this paper was to systematically review glyphosate-induced neurotoxicity literature to determine its usefulness in regulatory decision-making. The review was restricted to mammalian studies of behavior, neuropathology, and neuropharmacology; in vitro and other biochemical studies were considered supplementary information. Glyphosate formulation studies were also considered, despite uncertainties regarding toxicities of the formulated products; no studies used a formulation vehicle as the control. Inclusion criteria were developed a priori to ensure consistent evaluation of studies, and in vivo investigations were also ranked using ToxRTool software to determine reliability. There were 27 in vivo studies (open literature and available regulatory reports), but 11 studies were considered unreliable (mostly due to critical methodological deficiencies). There were only seven acceptable investigations on glyphosate alone. Studies differed in terms of dosing scenarios, experimental designs, test species, and commercial product. Limitations included using only one dose and/or one test time, small sample sizes, limited data presentation, and/or overtly toxic doses. While motor activity was the most consistently affected endpoint (10 of 12 studies), there were considerable differences in outcomes. In six investigations, there were no marked neuropathological changes in the central or peripheral nervous system. Other neurological effects were less consistent, and some outcomes were less convincing due to influences including high variability and small effect sizes. Taken together, these studies do not demonstrate a consistent impact of glyphosate on the structure or function of the mammalian nervous system.

The nigrostriatal dopaminergic (DA) system, which includes DA neurons in the ventral and dorsal tiers of the substantia nigra pars compacta (vSNc, dSNc) and DA terminals in the dorsal striatum, is critically implicated in motor control. Accumulating studies demonstrate that both the nigrostriatal DA system and motor function are impaired in aged subjects. However, it is unknown whether dSNc and vSNc DA neurons and striatal DA terminals age in similar patterns, and whether these changes parallel motor deficits. To address this, we performed ex vivo patch-clamp recordings in dSNc and vSNc DA neurons, measured striatal dopamine release, and analyzed motor behaviors in rodents. Spontaneous firing in dSNc and vSNc DA neurons and depolarization-evoked firing in dSNc DA neurons showed inverse V-shaped changes with age. But depolarization-evoked firing in vSNc DA neurons increased with age. In the dorsal striatum, dopamine release declined with age. In locomotor tests, 12-month-old rodents showed hyperactive exploration, relative to 6- and 24-month-old rodents. Additionally, aged rodents showed significant deficits in coordination. Elevating dopamine levels with a dopamine transporter inhibitor improved both locomotion and coordination. Therefore, key components in the nigrostriatal DA system exhibit distinct aging patterns and may contribute to age-related alterations in locomotion and coordination., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

During the early development of the mammalian visual system, the distribution of neuronal preferred orientations in the primary visual cortex (V1) gradually shifts to match major orientation features of the environment, achieving its optimal representation. By combining computational modeling and electrophysiological recording, we provide a circuit plasticity mechanism that underlies the developmental emergence of such matched representation in the visual cortical network. Specifically, in a canonical circuit of densely-interconnected pyramidal cells and inhibitory parvalbumin-expressing (PV+) fast-spiking interneurons in V1 layer 2/3, our model successfully simulates the experimental observations and further reveals that the nonuniform inhibition plays a key role in shaping the network representation through spike timing-dependent plasticity. The experimental results suggest that PV + interneurons in V1 are capable of providing nonuniform inhibition shortly after vision onset. Our study elucidates a circuit mechanism for acquisition of prior knowledge of environment for optimal inference in sensory neural systems., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

The increasing prevalence of SARS-CoV-2 variants with spike mutations has raised concerns owing to higher transmission rates, disease severity, and escape from neutralizing antibodies. Rapid and accurate detection of SARS-CoV-2 variants provides crucial information concerning the outbreaks of SARS-CoV-2 variants and possible lines of transmission. This information is vital for infection prevention and control. We used a Cas12a-based RT-PCR combined with CRISPR on-site rapid detection system (RT-CORDS) platform to detect the key mutations in SARS-CoV-2 variants, such as 69/70 deletion, N501Y, and D614G. We used type-specific CRISPR RNAs (crRNAs) to identify wild-type (crRNA-W) and mutant (crRNA-M) sequences of SARS-CoV-2. We successfully differentiated mutant variants from wild-type SARS-CoV-2 with a sensitivity of 10 -17  M (approximately 6 copies/μL). The assay took just 10 min with the Cas12a/crRNA reaction after a simple RT-PCR using a fluorescence reporting system. In addition, a sensitivity of 10 -16  M could be achieved when lateral flow strips were used as readouts. The accuracy of RT-CORDS for SARS-CoV-2 variant detection was 100% consistent with the sequencing data. In conclusion, using the RT-CORDS platform, we accurately, sensitively, specifically, and rapidly detected SARS-CoV-2 variants. This method may be used in clinical diagnosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)-mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull-down assays to assess the interaction between RAGE and mitogen-activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3-MKK3-p38 signaling module. Mechanistically, we found that activation of p38 mitogen-activated protein kinase (MAPK)/NF-κB signaling depends on mediation of the RAGE-MKK3 interaction by C-terminal RAGE (ctRAGE) amino acids (AAs) 2-5. We found that ctRAGE R2A-K3A-R4A-Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE-MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2-5, which leads to assembly of the MEKK3-MKK3-p38 signaling module and subsequent activation of the p38MAPK/NF-κB pathway, and ultimately results in diabetic encephalopathy (DE)., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objective: The coronavirus disease 2019 (COVID-19) pandemic continues to present a major challenge to public health. Vaccine development requires an understanding of the kinetics of neutralizing antibody (NAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: In total, 605 serum samples from 125 COVID-19 patients (from January 1 to March 14, 2020) varying in age, sex, severity of symptoms, and presence of underlying diseases were collected, and antibody titers were measured using a micro-neutralization assay with wild-type SARS-CoV-2., Results: NAbs were detectable approximately 10 days post-onset (dpo) of symptoms and peaked at approximately 20 dpo. The NAb levels were slightly higher in young males and severe cases, while no significant difference was observed for the other classifications. In follow-up cases, the NAb titer had increased or stabilized in 18 cases, whereas it had decreased in 26 cases, and in one case NAbs were undetectable at the end of our observation. Although a decreasing trend in NAb titer was observed in many cases, the NAb level was generally still protective., Conclusion: We demonstrated that NAb levels vary among all categories of COVID-19 patients. Long-term studies are needed to determine the longevity and protective efficiency of NAbs induced by SARS-CoV-2., (Copyright © 2021 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Video 1EUS-guided cholecystoduodenostomy and ERCP in a patient with surgically altered anatomy with a double-balloon endoluminal interventional platform., (© 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Background: Data on the current estimates of the disease burden of Clostridioides difficile (C. difficile) infection in the setting of end-stage liver disease (ESLD) are emerging., Aims: We examined the recent trends and predictors of hospitalizations and in-hospital mortality from C. difficile infection among hospitalizations with ESLD in the USA., Methods: We performed a retrospective analysis using the National Inpatient Sample, 2005-2014. We defined ESLD and C. difficile infection using the International Classification of Diseases, Ninth Revision, Clinical Modification. Multivariable logistic regression was used to determine the risk factors that impacted hospitalization and mortality., Results: The prevalence of coding for C. difficile infection in decompensated cirrhosis increased from 1.3% in 2005 to 2.7% in 2014, with an annual rate of 7.8%. In hospitalizations with hepatocellular carcinoma, C. difficile infection increased steadily from 1.0 to 1.7% with an annual incremental rate of 6.4%. Among hospitalizations with ESLD, each passing 2-year period, increasing age, female, higher Charlson index, accompanying infection, hepatorenal syndrome, and ascites were associated with C. difficile infection. Although C. difficile infection was an independent predictor of in-hospital mortality during hospitalization with decompensated cirrhosis (odds ratio 1.53, 95% confidence interval 1.44-1.63), the proportion of in-hospital mortality during hospitalization with C. difficile infection and decompensated cirrhosis decreased from 15.4% in 2005 to 11.1% in 2014, with an annual rate of - 3.1% (95% CI - 5.7% to - 0.3%)., Conclusions: While the prevalence of C. difficile infection in hospitalized patients with ESLD increased approximately twofold, the in-hospital mortality decreased significantly during the past decade.

As the population affected by Alzheimer's disease (AD) grows, so does the need for a noninvasive and accurate diagnostic tool. Current research reveals that AD pathogenesis begins as early as decades before clinical symptoms. The unique properties of nanoparticles (NPs) may be exploited to develop noninvasive diagnostics for early detection of AD. After exposure of NPs to biological fluids, the NP surface is altered by an unbiased but selective and reproducible adsorption of biomolecules commonly referred to as the biomolecular corona or protein corona (PC). The discovery that the plasma proteome may be differentially altered during health and disease leads to the concept of disease-specific PCs. Herein, the disease-specific PCs formed around NPs in a multi-NPs platform are employed to successfully identify subtle changes in plasma protein patterns and detect AD (>92% specificity and ≈100% sensitivity). Similar discrimination power is achieved using banked plasma samples from a cohort of patients several years prior to their diagnosis with AD. With the nanoplatform's analytic ability to analyze pathological proteomic changes into a disease-specific identifier, this promising, noninvasive technology with implications for early detection and intervention could benefit not only patients with AD but other diseases as well., (© 2020 Wiley-VCH GmbH.)

Reducing preventable hospital re-admissions in Sickle Cell Disease (SCD) could potentially improve outcomes and decrease healthcare costs. In a retrospective study of electronic health records, we hypothesized Machine-Learning (ML) algorithms may outperform standard re-admission scoring systems (LACE and HOSPITAL indices). Participants (n = 446) included patients with SCD with at least one unplanned inpatient encounter between January 1, 2013, and November 1, 2018. Patients were randomly partitioned into training and testing groups. Unplanned hospital admissions (n = 3299) were stratified to training and testing samples. Potential predictors (n = 486), measured from the last unplanned inpatient discharge to the current unplanned inpatient visit, were obtained via both data-driven methods and clinical knowledge. Three standard ML algorithms, Logistic Regression (LR), Support-Vector Machine (SVM), and Random Forest (RF) were applied. Prediction performance was assessed using the C-statistic, sensitivity, and specificity. In addition, we reported the most important predictors in our best models. In this dataset, ML algorithms outperformed LACE [C-statistic 0·6, 95% Confidence Interval (CI) 0·57-0·64] and HOSPITAL (C-statistic 0·69, 95% CI 0·66-0·72), with the RF (C-statistic 0·77, 95% CI 0·73-0·79) and LR (C-statistic 0·77, 95% CI 0·73-0·8) performing the best. ML algorithms can be powerful tools in predicting re-admission in high-risk patient groups., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Viral hepatitis is the primary cause of liver diseases, among which liver cancer is the leading cause of death from cancer. However, this cancer is often diagnosed in the later stages, which makes treatment difficult or even impossible. This study applied deep learning (DL) models for the early prediction of liver cancer in a hepatitis cohort. In this study, we surveyed 1 million random samples from the National Health Insurance Research Database (NHIRD) to analyze viral hepatitis patients from 2002 to 2010. Then, we used DL models to predict liver cancer cases based on the history of diseases of the hepatitis cohort. Our results revealed the annual prevalence of hepatitis in Taiwan increased from 2002 to 2010, with an average annual percentage change (AAPC) of 5.8% (95% CI: 4.2-7.4). However, young people (aged 16-30 years) exhibited a decreasing trend, with an AAPC of -5.6 (95% CI: -8.1 to -2.9). The results of applying DL models showed that the convolution neural network (CNN) model yielded the best performance in terms of predicting liver cancer cases, with an accuracy of 0.980 (AUC: 0.886). In conclusion, this study showed an increasing trend in the annual prevalence of hepatitis, but a decreasing trend in young people from 2002 to 2010 in Taiwan. The CNN model may be applied to predict liver cancer in a hepatitis cohort with high accuracy., (© 2020 UICC.)

Background and Aims: In general, physical activity (PA) and nonalcoholic fatty liver disease (NAFLD) have an inverse association. However, studies assessing the impact of the widely accepted Physical Activity Guidelines for Americans (PA Guidelines) on NAFLD are lacking., Approach and Results: We performed a serial, cross-sectional analysis among adults by using the 2007-2016 US National Health and Nutrition Examination Survey. NAFLD and advanced fibrosis were defined by using various noninvasive panels. A PA questionnaire assessed the leisure-time PA, occupation-related PA, transportation-related PA, and total sitting time as sedentary behavior. PA was categorized according to the PA Guidelines. Of the 24,588 individuals (mean age, 47.4 years; 47.9% males), leisure-time PA (≥150 minutes per week) demonstrated 40% lower odds of NAFLD, whereas transportation-related PA was associated with a 33% risk reduction in NAFLD. Analysis of total PA and sitting times simultaneously showed a dose-response association between sitting time and NAFLD (P for trend < 0.001). Compliance with the PA Guidelines was lower in individuals with NAFLD versus those without NAFLD. The trends in compliance with the PA Guidelines for any type of PA remained stable in individuals with NAFLD except for a downtrend in transportation-related PA. In contrast, an improvement in compliance with the PA Guidelines for leisure time was noted in the cohort without NAFLD. Although PA demonstrated a 10% stronger association with risk reduction of NAFLD in women, women showed a lower tendency of meeting the PA Guidelines. Trends in total sitting time increased significantly regardless of NAFLD status., Conclusions: Sedentary behavior emerged as an independent predictor of NAFLD. Overall compliance with the PA Guidelines was lower in the cohort with NAFLD, with sex- and ethnicity-based differences. Implementation of these observations in clinical practice may improve our understanding as well as clinical outcomes., (© 2020 by the American Association for the Study of Liver Diseases.)

The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are likely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data-derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48 weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175 ppt for heritable translocations in mice following 8.5 weeks of EO exposure. The lowest PDE for chromosomal aberrations was 238 ppt in the mouse peripheral blood lymphocytes following 48 weeks of inhalation exposure. The diverse dose-response data for EO-induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238 ppt as the lowest PDE in this retrospective analysis., (© 2020 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society.)

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique., 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 © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: Healthy diet has been recommended for nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent mortality. We aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD., Methods: We performed cohort study using the Third National Health and Nutrition Examination Survey from 1988 to 1994 and linked mortality data through 2015. We used the Healthy Eating Index (HEI) scores to define diet quality, with higher HEI scores (Q4) indicating better adherence to dietary recommendations. NAFLD was defined as ultrasonographic hepatic steatosis., Results: Multivariate analysis showed that subjects with higher diet quality were inversely associated with NAFLD in a dose-dependent manner. During the median follow-up of 23 years, having a higher diet quality was associated with reduction in risk of all-cause mortality in the age, sex, Race/ethnicity-adjusted hazard ratio (HR) (Q4, HR: 0.60, 95% CI: 0.52-0.68) and the multivariate model (Q4, HR: 0.81, 95% CI: 0.71-0.92). Higher diet quality was associated with a lower risk for all-cause mortality in subjects without NAFLD; however, this protective association with diet quality was not noted in those with NAFLD. Furthermore, a high diet quality was associated with a lower risk for cancer-related mortality in the total population and among those without NAFLD. This association was not noted in those with NAFLD., Conclusions: High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer-related and all-cause mortality in those without NAFLD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recurrence of paroxysmal supraventricular tachycardia (PSVT) has been reported to be lower in patients treated with radiofrequency catheter ablation (RFCA) than in those who are not. Few population-based surveys have stated the cost-effectiveness related to this treatment. We, therefore, performed a nationwide retrospective study using National Health Insurance Research Database (NHIRD) data from 2001-2012 in Taiwan. The incidence of PSVT-related admissions was computed from patients' first admission for a primary PSVT diagnosis. There were 21,086 patients hospitalized due to first-time PSVT, of whom 13,075 underwent RFCA, with 374 recurrences (2.86%). In contrast, 1751 (21.86%) of the remaining 8011 patients who did not receive RFCA, most of whom had financial concerns, experienced PSVT recurrence. The relative PSVT recurrence risk in those who did not receive RFCA was 7.6 times (95%CI: 6.67-8.33) that of those who did undergo RFCA. In conclusion, the PSVT recurrence rate was much higher in patients who did not receive RFCA at their first admission. Furthermore, RFCA proved cost-effective, with the ratio of the incremental cost-effectiveness ratio (ICER) and gross domestic product (GDP) being only 1.15. To prevent readmission and avoid incremental cost, the authority could provide a financial supplement for every patient so that the procedure is performed, reducing the PSVT-recurrence life-years (disease-specific DALY)., Competing Interests: The authors declare no conflicts of interest.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and encompasses a spectrum of pathology from simple steatosis to inflammation and significant fibrosis that leads to cirrhosis. NAFLD and its comorbid conditions extend well beyond the liver. It is a multisystemic clinical disease entity with extrahepatic manifestations such as cardiovascular disease, type 2 diabetes, chronic kidney disease, hypothyroidism, polycystic ovarian syndrome, and psoriasis. Indeed, the most common causes of mortality in subjects with NAFLD are cardiovascular disease, followed by malignancies and then liver-related complications as a distant third. This review focuses on several of the key extrahepatic manifestations of NAFLD and areas for future investigation. Clinicians should learn to screen and initiate treatment for these extrahepatic manifestations in a prompt and timely fashion before they progress to end-organ damage.

Background & Aims: Trends of mortality associated with extrahepatic complications of chronic liver disease might be changing. We studied trends in mortality from extrahepatic complications of viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease in the United States., Methods: We performed a population-based study using US Census and the National Center for Health Statistics mortality records from 2007 through 2017. We identified trends in age-standardized mortality using Joinpoint trend analysis with estimates of annual percent change., Results: The liver-related mortality among patients with hepatitis C virus (HCV) infection increased from 2007 through 2013 and then decreased once patients began receiving treatment with direct-acting antiviral (DAA) agents, from 2014 through 2017. Among patients with HCV infection, the age-standardized mortality for extrahepatic cancers was 2.6%, for cardiovascular disease was 1.9%, and for diabetes was 3.3%. Among individuals with hepatitis B virus infection, liver-related mortality decreased steadily from 2007 through 2017. During the study, age-standardized mortality from hepatitis B virus-related extrahepatic complications increased by an average of 2.0% each year. Although liver-related mortality from ALD continued to increase, mortality from extrahepatic complications of ALD did not change significantly during the 11-year study. Among patients with nonalcoholic fatty liver disease, the cause of death was most frequently cardiovascular disease, which increased gradually over the study period, whereas liver-related mortality increased rapidly., Conclusions: In an analysis of US Census and the National Center for Health Statistics mortality records, we found that after widespread use of DAA agents for treatment of viral hepatitis, cause-specific mortality from extrahepatic cancers increased, whereas mortality from cardiovascular disease or diabetes increased only among patients with HCV infection. These findings indicate the need to reassess risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals successfully treated for HCV infection with DAA agents., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The pathogenetic pathways leading to increasing prevalence of advanced fibrosis in the setting of nonalcoholic fatty liver disease (NAFLD) and resulting in higher rates of liver-related and cardiovascular morbidity and mortality in the United States are multifactorial. 1 The negative health impact of "low-normal" thyroid function, which is defined as a higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range, may be comparable with overt and subclinical hypothyroidism. 2-4 We reported a strong association between biopsy-proven advanced fibrosis in NAFLD with increasing TSH levels in a dose-dependent manner even within the euthyroid reference range. 5 To generalize our findings across all ethnicities, we examined the association of both low-normal thyroid function and subclinical hypothyroidism with advanced fibrosis in the US general population., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)