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Objectives: Guo Min decoction (GMD) is a Chinese traditional medicine that can regulate allergy-related symptoms. Although GMD treatment was reported to treat allergy-associated symptoms by regulating the immune response, the rationale between GMD treatment and angiogenesis has not been reported yet. Our objective is to investigate the angiogenesis-modulating activity of GMD. Materials and Methods: In this study, we used fluorescence recording, alkaline phosphatase (AP) activity staining, and real-time polymerase chain reaction (PCR) experiments to examine the effects of GMD on angiogenesis in a zebrafish model. Results: GMD-treated zebrafish embryos exhibited more intercapillary spaces in the caudal vein plexus (Mock: 11.1 ± 1.8 [n = 20; n: numbers of embryos]; GMD-treated: 16.2 ± 1.9 [n = 20]). AP activity staining showed that treatment with GMD and liquorice (Gan Cao, a component of GMD) induced subintestinal vein outgrowth. However, glycyrrhizin (a component of Gan Cao) had no obvious pro-angiogenic effects on zebrafish. Furthermore, real-time PCR experiments indicated that GMD exposure might be through regulating angiogenesis-related genes (cdh5, nrp1a, and flt1) expressions. Conclusion: Based on these observations, we proposed that GMD had pro-angiogenic activity in a zebrafish model, and it might partially be contributed by one of the components, liquorice.

Summary: Background: Transcatheter arterial embolization (TAE) is an effective alternative to nonoperative management (NOM) to improve the spleen salvage rate for patients with blunt splenic injuries (BSIs), but it is not always available at some institutions. Moreover, laparoscopy has also been used to diagnose and treat trauma, including BSIs. Methods: We present our 11-year experience in performing laparoscopic surgery for spleen salvage in patients with severe BSIs when TAE is infeasible. The outcomes of laparoscopic surgery or TAE for spleen salvage in hemodynamically stable patients with severe BSIs were compared. Results: Fifty-six patients underwent interventions for severe BSIs during this period. Twenty patients underwent laparoscopic surgery, and 36 underwent TAE. There were no significant differences in demographics, preoperative conditions, or clinical characteristics (all p > 0.05). In the laparoscopic surgery group, 15 patients (75 %) underwent laparoscopic splenorrhaphy for spleen salvage surgery, and five (25 %) required splenectomy. No complications requiring intervention were observed in the laparoscopic surgery group, whereas three patients in the TAE group required a late splenectomy for splenic abscess. No significant differences were detected in the splenic preservation rate, complication rate, or length of hospital stay between the groups (all p > 0.05). Conclusion: Laparoscopy is feasible and safe for managing hemodynamically stable patients with severe BSIs, and the outcomes are comparable to those of TAE. When TAE is infeasible, laparoscopy can be considered an alternative to increase the spleen salvage rate.

Abstract Background The prevalence of age-related eye disorders is increasing with the aging of the global population. Community-based visual health education for the elderly has become a crucial intervention. With the advancement of technology, the application of extended reality (XR), such as virtual reality (VR) and augmented reality (AR), in health education has become more popular. This study aims to assess the effectiveness of educating the elderly about common age-related eye disorders through a novel AR-based health education workshop. Methods An AR-based education workshop was designed for the elderly to understand the major visual symptoms of several eye diseases and experience the challenges faced by visually impaired people. The effectiveness of the workshop was assessed by conducting pre- and post-activity surveys to measure the knowledge acquisition of the participants from this workshop. Results The intervention was found to significantly improve knowledge of age-related eye diseases among the elderly, while the participants’ age and education level could influence the effectiveness of their knowledge gained from the workshop. Conclusions Our study revealed the potential of the use of AR technology in facilitating health education on eye diseases in the elderly. The specific backgrounds and characteristics of target participants and the combination of AR with other pedagogical approaches warrant further investigation to maximize the impact of AR-based workshops in health education in broader healthcare contexts.

Conservation of groundwater quality is of paramount importance for sustainable agricultural management. Hydrological factors such as rainfall patterns and water table (WT) management, including drainage practices, play a crucial role in groundwater recharge. This in turn has a significant impact on WT fluctuations, nutrient losses in the soil, and the leaching of fertilizers into groundwater which leads to groundwater pollution. Consequently, this study evaluates the long-term influence of seasonal rainfall and WT fluctuations on groundwater nutrient dynamics in tropical peatlands from an oil palm plantation (OPP). Linear regression analyses and Pearson correlation matrices were adopted to evaluate the relationships between seasonal rainfall, WT, and groundwater chemical parameters. The results showed that there was a significant increase in mean pH, NO3−, Na+, Ca2+, and PO43- values during the wet season compared to the dry season which could be attributed to the leaching of nutrients into groundwater due to rainfall, nutrient runoff from drainage systems and increased nitrification rate. A significant positive correlation (p

Abstract Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies. Graphical Abstract

Osteoarthritis (OA) is a major clinical challenge, and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and scattered treatment targets. Effective early treatments are urgently needed to prevent OA progression. The excessive amount of transforming growth factor β (TGFβ) is one of the major causes of synovial fibrosis and subchondral bone sclerosis, and such pathogenic changes in early OA precede cartilage damage. Herein we report a novel strategy of intra-articular sustained-release of pirfenidone (PFD), a clinically-approved TGFβ inhibitor, to achieve disease-modifying effects on early OA joints. We found that PFD effectively restored the mineralization in the presence of excessive amount of TGFβ1 (as those levels found in patients’ synovial fluid). A monthly injection strategy was then designed of using poly lactic-co-glycolic acid (PLGA) microparticles and hyaluronic acid (HA) solution to enable a sustained release of PFD (the “PLGA-PFD + HA” strategy). This strategy effectively regulated OA progression in destabilization of the medial meniscus (DMM)- induced OA mice model, including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA, and reduced synovitis and pain with cartilage preservation effects. This finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug.

Abstract Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Introduction Pelvic fractures often result in life-threatening bleeding and hemodynamic instability. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a promising strategy for patients with severe pelvic fractures, facilitating subsequent hemostatic interventions. Transcatheter arterial embolization (TAE) is a well-established procedure for managing pelvic fractures accompanied by hemorrhage.Ideally, an angiographic access point distinct from the initial REBOA placement is sought to maintain REBOA deflation without complete removal, thereby preventing hemodynamic instability during the procedure. However, in cases of extreme and severe pelvic trauma, gaining access for REBOA is already challenging, not to mention the additional difficulty posed by subsequent angiographic access.This study aims to assess the challenges associated with gaining access in cases where successful TAE was ultimately performed, particularly in the context of severe pelvic trauma. We investigate the complexities surrounding access management and its implications for patient outcomes.Methods We conducted a retrospective analysis of patients who presented with pelvic fractures and underwent sequential REBOA and TAE procedures at our institution between 2017 and 2023. We excluded patients with Abbreviated Injury Scores (AIS) ≥3 in systems other than the pelvis, those who underwent TAE prior to REBOA, and cases of suboptimal REBOA insertion.We collected demographic data, injury characteristics, details of the REBOA and TAE procedures, information on complications, and data on patient survival. The primary endpoints of our analysis included overall survival and the success of TAE (defined as post TAE mean arterial pressure (MAP) ≥65 mm Hg). Secondary endpoints encompassed the duration details of two interventions.Results Between 2017 and 2023, a total of 17 patients were included in this study. Among this cohort, 12 (70.6%) were male, with a median age of 51 years. Overall survival was 23.5%. Patients were grouped into angiography after REBOA deflation (AAD) or angiography after REBOA removal (AAR). AAR group was younger (39.0 vs 63.0, p=0.030) and had higher Shock Index at triage (2.30 vs 1.10, p=0.015). More patient whose post TAE MAP >=65 mm Hg was found in the AAR group, although no significant difference on overall survival (25.0% vs 22.2%, p=1.000). Angiographic cannulation times, pre-angiographic MAP, and amount of pre-angiographic transfusion of packed red blood cell were similar across groups.Conclusion Our findings provide empirical insights into vascular access selection and suggest that AAR in the management of severe pelvic fractures can be beneficial, particularly when pre-angiographic resuscitation is sufficient. Larger studies are required to validate these observations and assess long-term outcomes.Level of evidence III.

Coreless axial flux permanent magnet machines (C-AFPMMs) offer exceptional efficiency, power, and torque density by eliminating iron losses, making them attractive for applications like electric vehicles, renewable energy systems, and aircraft propulsion. However, the coreless design introduces challenges, including complex mechanical structures, high production costs due to the usage of conventional materials, unstable axial forces leading to mechanical instability, potential cooling difficulties, and higher energy dissipation rates. Recent innovations in winding designs, advanced magnet arrays, and material technologies, combined with novel optimization techniques, have significantly enhanced the electromagnetic performance of these machines. This systematic review synthesizes advancements in AFPMMs with a focus on coreless technology, evaluating research developments, innovations, and applications from 2004 to 2024, based on a comprehensive analysis of 149 articles indexed by major databases such as Web of Science, Scopus, ScienceDirect, Google Scholar, and IEEE. The findings indicate sustained and increasing research activity from 2019 to 2024, with key areas of focus. Of the three coreless designs, single stator double rotors (SSDR) with stator coreless are the most commonly used, followed by double stators single rotor (DSSR) and fully coreless multi-stators multi-rotors (MSMR). There is also growing interest in rotor coreless designs, despite challenges like flux leakage, with Halbach magnet arrays of unconventional shapes being explored to mitigate these effects. These insights highlight the potential for enhancing modular configurations and thermal management in C-AFPMMs through the integration of high-strength materials, 3D printing of parts, and advanced optimization methods.

The current study aims to investigate how Vietnamese high school teachers and students perceive the implementation of mobile learning (M-learning) in classrooms. In this exploratory qualitative study, using a transcendental phenomenology approach, five teachers and six students were invited for semi-structured interviews. The data was then analysed using an analytic tool that was developed from the Framework for the Rational Analysis of Mobile Education (FRAME) model. The findings show that the key prerequisites for M-learning adoption in Vietnamese secondary schools were met, which potentially entail several benefits, including instant feedback, differentiated teaching, increased student involvement and 21st century competencies. Inadequate facilities, negative influences from external variables, instructor incapacity and a lack of student discipline were the barriers to the viability of M-learning in the classroom environment. The suggestions highlighted the responsibilities of the authorities, teachers and the autonomy of the students. Several theoretical and pedagogical implications for policymakers and future research are also discussed.

Introduction: Adipogenesis, the process of white adipose tissue expansion, plays a critical role in the development of obesity. Osteoprotegerin (OPG), known for its role in bone metabolism regulation, emerges as a potential regulator in mediating adipogenesis during obesity onset. Objectives: This study aims to elucidate the involvement of OPG in adipogenesis during the early phases of diet-induced obesity and explore its therapeutic potential in obesity management. Methods: Using a diet-induced obesity model, we investigated OPG expression patterns in adipocytes and explored the mechanisms underlying its involvement in adipogenesis. We also assessed the effects of targeted silencing of OPG and recombinant OPG administration on obesity progression and insulin resistance. Additionally, the impact of electroacupuncture treatment on OPG levels and obesity management was evaluated in both animal models and human participants. Results: OPG expression was prominently activated in adipocytes of white adipose tissues during the early phase of diet-induced obesity. Hyperlipidemia induced Cbfa1-dependent OPG transcription, initiating and promoting adipogenesis, leading to cell-size expansion and lipid storage. Intracellular OPG physically bound to RAR and released the PPARɤ/RXR complex, activating adipogenesis-associated gene expression. Targeted silencing of OPG suppressed obesity development, while recombinant OPG administration promoted disease progression and insulin resistance in obese mice. Electroacupuncture treatment suppressed obesity development in an OPG-dependent manner and improved obesity parameters in obese human participants. Conclusion: OPG emerges as a key regulator in mediating adipogenesis during obesity development. Targeting OPG holds promise for the prevention and treatment of obesity, as evidenced by the efficacy of electroacupuncture treatment in modulating OPG levels and managing obesity-related outcomes.

Study’s Novelty/Excerpt • The study evaluates the gastroprotective properties of the Ex-Maradi variety of Abelmoschus esculentus (okra) against ethanol-induced gastric mucosal damage in Wister rats, specifically comparing fresh okra mucilage (FOM) and dried okra powder (DOP). • The significant ulcer inhibition and antioxidant effects of DOP, particularly at a 500 mg/kg dosage, indicate its potential as a natural therapeutic agent for peptic ulcer disease. • The research highlights the potential for developing green anti-ulcer formulations derived from okra, expanding the scope of nutraceutical applications for this commonly consumed vegetable. Full Abstract Peptic ulcer disease, a notable gastrointestinal disorder, results from an imbalance between gastric acid secretion and the factors maintaining gastric mucosal integrity. Abelmoschus esculentus, commonly known for its mucilaginous and nutraceutical properties, also exhibits an antacid effect. This research aimed to examine the antacid properties of fresh okra fruit mucilage (FOM) and dried okra fruit powder (DOP) of the Ex-Maradi okra fruit variety against ethanol-induced gastric mucosal damage in Wister rats. Rats were randomly assigned to seven groups consisting of six rats each. Rats in the FOM and that of the DOP group were pretreated orally with 250 and 500 mg/kg body weight of the FOM and DOP, respectively; the drug control (DC) group was pretreated orally with 20 mg/kg body weight of Cimetidine while the normal control (NC) group and the ulcer control (UC) group were pretreated orally with normal saline (2 mL/kg body weight). All the treatments were done for seven days before the induction of the ulcer. Ulcer index (UI), percentage inhibition (PI), gastric volume, gastric pH, total acidity, and total antioxidant power (TAP) were evaluated to assess the gastro-protective effect of the FOM and DOP in the rats. Both FOM and DOP groups demonstrated significant (P < 0.05) protection with a low ulcer index (2.41 ± 0.12) and high ulcer inhibition (75.6 %) against the damaging effect of ethanol on the gastric mucosa of the animals. Additionally, DOP also exhibited a strong antioxidant effect with a good percentage inhibition value (56.53 ± 2.1%) compared to the ulcer control group. These results were further supported by the histopathological findings from the rats’ stomachs. In conclusion, the Ex-Maradi okra fruit, especially the DOP500, demonstrated significant (P < 0.05) gastro-protective effects and maintained a relatively intact and continuous epithelial surface of the rats’ stomachs. Overall, its gastroprotective effects may be possibly mediated by its potential to modulate the antioxidant system and gastric acid levels. Hence, the dried okra fruit could be suitable for the development of green anti-ulcer formulations.

In the digital age, social media has a significant impact on consumer perceptions. This business communication study examines the linguistic strategies used to express and repair negative electronic word of mouth (eWOM) in Hong Kong’s luxury hotel sector. The data, which were collected from travel forums, consist of 17,344 words from online hotel reviews (11,647 words) and responses (5,697 words) made by the visitors and senior hotel management of 18 five-star hotels. Using systemic functional linguistics as a framework, this study analyses the logical relations that exist between expectant and concessive conjunctions, as well as the evaluative judgment resources present in an appraisal system. The analysis focuses on the poor service standards framed in the complaints and how the hotel management responds to such situations differently, particularly with respect to repairing customer expectations. This study also examines how loyal fans and frequent travellers present their customer identity when dealing with service-related issues. By developing an understanding of how luxury hotels manage customer complaints, repair customer relationships, and protect their brand reputation through dynamic interactions, this study can provide valuable communication insights for the hotel sector.

Background: Phthalates, ubiquitous in plastics and softening agents, are pervasive in our daily environment. Growing concerns have emerged regarding their potential impact on renal health, particularly due to their propensity to induce oxidative stress. However, the relationship between phthalate exposure and urolithiasis remains poorly understood. This research seeks to explore the connection between phthalate exposure, oxidative stress, and the risk of urolithiasis. Methods: A case-control study involving 285 patients diagnosed with calcium urolithiasis and 594 healthy controls was conducted. Participants completed structured questionnaires and provided urine samples for measuring 10 phthalate metabolites, biomarkers of oxidative stress (malondialdehyde [MDA]) and early renal injury (N-acetyl-beta-D-glucosaminidase [NAG] and albumin/creatinine ratio [ACR]). For subsequent analyses, we utilized distinct categories: the sum of high-molecular-weight phthalate metabolites (∑HMWm), the sum of low-molecular-weight phthalate metabolites (∑LMWm), and the daily intake of di-2-ethylhexyl phthalate (DEHP)(DI_DEHP_5). Results: Stone patients exhibited significantly elevated urinary biomarkers of oxidative stress (MDA) and early renal injury (NAG and ACR), along with higher levels of 9 out of 10 assessed phthalate metabolites compared to normal controls. Within the study population, significant positive associations were found between almost all individual phthalate metabolites and urinary biomarkers of oxidative stress (MDA) as well as early renal injury (NAG and ACR). Logistic regression further confirmed that elevated phthalate levels, including ∑HMWm, ∑LMWm, and DI_DEHP_5, were uniformly associated with an increased risk of oxidative stress, early renal injury, and urolithiasis after adjusting for confounding factors. Conclusions: Our study uncovers a novel association between phthalate exposure and the risk of urolithiasis, underscoring the heightened risk of kidney injury posed by such exposure. Considering the widespread presence of phthalates, regulatory measures and public health interventions are crucial to mitigate phthalate-related nephrotoxicity, while further large-scale longitudinal research is imperative to validate our initial findings and elucidate the underlying mechanisms.

Articular cartilage regeneration is a major challenge in orthopedic medicine. Endothelial progenitor cells (EPCs) are a promising cell source for regenerative medicine applications. However, their roles and functions in cartilage regeneration are not well understood. Additionally, thermosensitive chitosan hydrogels have been widely used in tissue engineering, but further development of these hydrogels incorporating vascular lineage cells for cartilage repair is insufficient. Thus, this study aimed to characterize the ability of EPCs to undergo endothelial–mesenchymal stem cell transdifferentiation and chondrogenic differentiation and investigate the ability of chondrogenic EPC-seeded thermosensitive chitosan-graft-poly (N-isopropylacrylamide) (CEPC-CSPN) scaffolds to improve healing in a rabbit osteochondral defect (OCD) model. EPCs were isolated and endothelial-to-mesenchymal transition (EndMT) was induced by transforming growth factor-β1 (TGF-β1); these EPCs are subsequently termed transdifferentiated EPCs (tEPCs). The stem cell-like properties and chondrogenic potential of tEPCs were evaluated by a series of in vitro assays. Furthermore, the effect of CEPC-CSPN scaffolds on OCD repair was evaluated. Our in vitro results confirmed that treatment of EPC with TGF-β1 induced EndMT and the acquisition of stem cell-like properties, producing tEPCs. Upon inducing chondrogenic differentiation of tEPCs (CEPCs), the cells exhibited significantly enhanced chondrogenesis and chondrocyte surface markers after 25 days. The TGF-β1-induced differentiation of EPCs is mediated by both the TGF-β/Smad and extracellular signal-regulated kinase (Erk) pathways. The CEPC-CSPN scaffold reconstructed well-integrated translucent cartilage and repaired subchondral bone in vivo, exhibiting regenerative capacity. Collectively, our results suggest that the CEPC-CSPN scaffold induces OCD repair, representing a promising approach to articular cartilage regeneration.

BackgroundThe Mendelian randomization approach uses genetic variants as instrumental variables to study the causal association between the risk factors and health outcomes of interest. We aimed to examine the relation between alcohol consumption and cardiovascular risk factors using two genetic variants as instrumental variables: alcohol dehydrogenase 1B (ADH1B) rs1229984 and aldehyde dehydrogenase 2 (ALDH2) rs671.MethodsUsing data collected in the Taiwan Biobank—an ongoing, prospective, population-based cohort study—our analysis included 129,032 individuals (46,547 men and 82,485 women) with complete data on ADH1B rs1229984 and ALDH2 rs671 genotypes and alcohol drinking status. We conducted instrumental variables regression analysis to examine the relationship between alcohol drinking and body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, glycated hemoglobin (HbA1c), triglycerides, high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc).ResultsIn the rs1229984-instrumented analysis, alcohol drinking was only associated with higher levels of SBP in men and lower levels of DBP in women. In the rs671-instrumented analysis, alcohol drinking was associated with higher levels of BMI, SBP, DBP, fasting glucose, triglycerides, HDLc and lower levels of LDLc in men; alcohol drinking was associated with higher levels of HDLc and lower levels of SBP, HbA1c, and triglycerides in women.ConclusionUsing Mendelian randomization analysis, some of our study results among men echoed findings from the previous systematic review, suggesting that alcohol drinking may be causally associated with higher levels of BMI, SBP, DBP, fasting glucose, triglycerides, HDLc, and lower levels of LDLc. Although alcohol drinking is beneficial to a few cardiovascular risk factors, it is detrimental to many others. The assumptions that underlie the Mendelian randomization approach should also be carefully examined when interpreting findings from such studies.

Abstract IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. Materials and methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. Results CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. Conclusion Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Abstract Ancillary service provision and peak shaving (PS) play essential roles in the current day‐to‐day power system operation, which is challenged by the increasing renewable generation penetration. Providing these critical services using classical approaches such as peak load generators has been limited due to high operational costs and environmental impacts. The use of battery energy storage systems (BESS) is another popular method that is limited by high initial investment costs and high degradation rates. In this work, a novel approach to utilize industrial loads and BESS to provide multiple power system services in different stages is proposed. Industrial loads such as aluminium crushers are known for their intensive electricity consumption. Nevertheless, when applied in frequency regulation (FR), they perform poorly due to their discrete nature in operation. This drawback and the aforementioned BESS shortcomings are addressed by combining on‐site BESS with plant machinery to provide FR services and recover BESS related costs. Later, depending on the optimal capacity distribution, BESS usage is extended into the energy arbitrage market to provide PS services. This approach resulted in higher earnings for participating customers and network operators, as well as in less CO2 emissions, and minimal BESS degradations. An Australian case study of the South West Interconnected System, along with Worsley Alumina refinery data of Western Australia has been used to showcase the model performances.

Abstract Peripheral artery disease (PAD) shares common clinical risk factors, for example, endothelial dysfunction, with preserved ejection fraction (LVEF) heart failure (HFpEF). Whether PAD is associated with preclinical systolic dysfunction and higher HF risk among individuals presenting preserved LVEF remains uncertain. We retrospectively included outpatients with at least one known or established cardiovascular (CV) risk factor with LVEF ≥ 50%. Patients were categorized into high risk and low risk of developing PAD (PAD vs Non-PAD) by ankle-brachial index (ABI) (≤ 0.90 or > 1.4) and further stratified based on their history of HFpEF (HFpEF vs. Non-HFpEF), resulting in the formation of four distinct strata. Preclinical systolic dysfunction was defined using dedicated speckle-tracking algorithm. A total of 2130 consecutive patients were enrolled in the study, with a median follow-up of 4.4 years. The analysis revealed a higher prevalence of high risk of developing PAD in patients with HFpEF compared to those without HFpEF (25.1% vs. 9.4%). Both high risk of developing PAD and HFpEF were independently associated with preclinical systolic dysfunction (global longitudinal strain, GLS ≥ − 18%) (odds ratio, OR: 1.38; 95% confidence interval, CI: 1.03–1.86). In comparison to patients at low risk of developing PAD without HFpEF (Non-PAD/Non-HFpEF group), those categorized as having a high risk of developing PAD with HFpEF (PAD/HFpEF group) exhibited the most impaired GLS and a heightened susceptibility to heart failure hospitalization (hazard ratio, HR: 6.51; 95% CI: 4.43–9.55), a twofold increased risk of all-cause mortality (HR: 2.01; 95% CI: 1.17–3.38), cardiovascular mortality (HR: 2.44; 95% CI: 1.08–5.51), and non-cardiovascular mortality (HR: 1.78; 95% CI: 0.82–3.84). A high risk of developing PAD was strongly linked to impaired preclinical systolic function and an increased likelihood for subsequent hospitalization for HF, all-cause mortality, CV mortality and non-CV mortality. There is a clear need for preventive strategies aimed at reducing hospitalizations for HF and mortality in this high-risk population.

Xiaojie Chen,1,2 Jianteng Xie,2 Yifan Zhang,2 Shaogui Zhang,2 Sheng Li,2 Min Lu,2 Danfeng Liu,2 Weiting He,2 Hokhim Yau,2 Runli Jia,2 Yaxi Zhu,2 Wenjian Wang2 1Department of Nephrology, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Department of Nephrology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, People’s Republic of ChinaCorrespondence: Wenjian Wang, Department of Nephrology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106 Zhongshan Er Road, Main Building, Room 1436, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86 (20)83827812-61421, Email wangwenjian@gdph.org.cnObjective: Diabetic kidney disease (DKD) patients with anemia face an elevated risk of glomerular filtration rate decline. However, the association between hemoglobin and estimated Glomerular Filtration Rate (eGFR) progression remains to be elucidated.Methods: A retrospective cohort of 815 subjects with DKD was followed from January 2010 to January 2023. A Cox proportional hazard regression model was utilized to explore the predictive role of hemoglobin in renal outcomes. Renal outcomes were defined as a composite endpoint, including a 50% decline in eGFR from baseline or progression to End-Stage Renal Disease (ESRD). To unveil any nonlinear relationship between hemoglobin and renal outcomes, Cox proportional hazard regression with cubic spline functions and smooth curve fitting was conducted. Additionally, subgroup analyses were performed to identify specific patient populations that might derive greater benefits from higher hemoglobin.Results: Among the 815 DKD subjects, the mean age was 56.482 ± 9.924 years old, and 533 (65.4%) were male. The mean hemoglobin was 121.521± 22.960 g/L. The median follow-up time was 21.103± 18.335 months. A total of 182 (22.33%) individuals reached the renal composite endpoint during the study period. After adjusting for covariates, hemoglobin was found to exert a negative impact on the renal composite endpoint in patients with DKD (HR 0.975, 95% CI [0.966, 0.984]). A nonlinear relationship between hemoglobin and the renal composite endpoint was identified with an inflection point at 109 g/L. Subgroup analysis unveiled a more pronounced association between hemoglobin and renal prognosis in males.Conclusion: Hemoglobin emerges as a predictive indicator for the renal prognosis of diabetic kidney disease in China. This study reveals a negative and non-linear relationship between hemoglobin levels and the renal composite endpoint. A substantial association is noted when hemoglobin surpasses 109 g/L in relation to the renal composite endpoint.Keywords: hemoglobin, eGFR decline, ESRD, diabetic kidney disease, non-linear, Cox proportional-hazards regression

Abstract Background Low-dose computed tomography (LDCT) has been shown useful in early lung cancer detection. This study aimed to develop a novel deep learning model for detecting pulmonary nodules on chest LDCT images. Methods In this secondary analysis, three lung nodule datasets, including Lung Nodule Analysis 2016 (LUNA16), Lung Nodule Received Operation (LNOP), and Lung Nodule in Health Examination (LNHE), were used to train and test deep learning models. The 3D region proposal network (RPN) was modified via a series of pruning experiments for better predictive performance. The performance of each modified deep leaning model was evaluated based on sensitivity and competition performance metric (CPM). Furthermore, the performance of the modified 3D RPN trained on three datasets was evaluated by 10-fold cross validation. Temporal validation was conducted to assess the reliability of the modified 3D RPN for detecting lung nodules. Results The results of pruning experiments indicated that the modified 3D RPN composed of the Cross Stage Partial Network (CSPNet) approach to Residual Network (ResNet) Xt (CSP-ResNeXt) module, feature pyramid network (FPN), nearest anchor method, and post-processing masking, had the optimal predictive performance with a CPM of 92.2%. The modified 3D RPN trained on the LUNA16 dataset had the highest CPM (90.1%), followed by the LNOP dataset (CPM: 74.1%) and the LNHE dataset (CPM: 70.2%). When the modified 3D RPN trained and tested on the same datasets, the sensitivities were 94.6%, 84.8%, and 79.7% for LUNA16, LNOP, and LNHE, respectively. The temporal validation analysis revealed that the modified 3D RPN tested on LNOP test set achieved a CPM of 71.6% and a sensitivity of 85.7%, and the modified 3D RPN tested on LNHE test set had a CPM of 71.7% and a sensitivity of 83.5%. Conclusion A modified 3D RPN for detecting lung nodules on LDCT scans was designed and validated, which may serve as a computer-aided diagnosis system to facilitate lung nodule detection and lung cancer diagnosis.

Abstract Background Amyand’s hernia (AH) is an appendix (with or without acute inflammation) trapped within an inguinal hernia. Most AH with acute appendicitis had a preexisting appendix within the hernia sac. We herein report a variant of AH that has never been described before. An inflamed appendix that was managed conservatively was found to have migrated and trapped in the sac of a previously unrecognized right inguinal hernia 6 weeks after the index admission, resulting in a secondary Amyand’s hernia. Case presentation A 25-year-old healthy Taiwanese woman had persistent right lower abdominal pain for 1 week and was diagnosed with perforated appendicitis with a localized abscess by abdominal computed tomography (CT). No inguinal hernia was noted at that time. Although the inflamed appendix along with the abscess was deeply surrounded by bowel loops so that percutaneous drainage was not feasible, it was treated successfully with antibiotics. However, she was rehospitalized 6 weeks later for having a painful right inguinal bulging mass for a week. Abdominal CT revealed an inflamed appendix with abscess formation in an indirect inguinal hernia raising the question of a Amyand’s hernia with a perforated appendicitis. Via a typical inguinal herniorrhaphy incision, surgical exploration confirmed the diagnosis, and it was managed by opening the hernial sac to drain the abscess and reducing the appendix into the peritoneal cavity, followed by conventional tissue-based herniorrhaphy and a laparoscopic appendectomy. She was then discharged uneventfully and remained well for 11 months. Conclusions Unlike the traditional definition of Amyand’s hernia, where the appendix is initially in the hernia sac, the current case demonstrated that Amyand’s hernia could be a type of delayed presentation following initial medical treatment of acute appendicitis. However, it can still be managed successfully by a conventional tissue-based herniorrhaphy followed by laparoscopic appendectomy.

Abstract Background There is a continuous growth of interest in the development of nano-drug delivery systems that could combine therapy and diagnosis of cancer. Results Novel multifunctional superparamagnetic iron oxide nanoparticles (SPIONs, chemically Fe3O4) conjugated with carboxymethyl sagocellulose (CMSC), and 5-fluorouracil (Fe3O4-CMSC-5FU) were synthesized. The conjugated nanoparticles have the magnetic properties of the SPIONs, which allows the nanoparticles to be localized at the target area by applying an external magnetic field. SPIONs generate heat upon exposure to laser lights, resulting in a photothermic effect. The drug-loading efficiency of 5-FU into the SPIONs-CMSC conjugated nanoparticles was 70 to 84% w/w which could release the drug at intracellular pH (5.4) of cancer cells and resist drug release at pH 7.2. In vivo studies using mice models confirmed the nanoparticles could efficiently deliver 5-FU only to the cancer cells and the anticancer effect was enhanced by laser-induced hyperthermia. Conclusions The combination of targeted delivery of 5-FU with photothermal therapy (PTT) looks promising for selective killing of cancer cells. Furthermore, SPIONs are an excellent contrasting agent for use in computerized tomography (CT) imaging for determining the tumor location and monitoring the progress of the therapy. The focus of this work was the oncological application of multifunctional Fe3O4-CMSC-5FU nanoparticle conjugates, with an emphasis on therapeutic, diagnostic and prognostic purposes.

Summary: Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.

Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

Using a discourse approach, this study examines online news and opinion pieces about calls for the British Museum to return Chinese artefacts. We examine the interpersonal meanings conveyed by the linguistic choices made in these texts. This study uses the appraisal system in the systemic functional linguistic (SFL) framework to examine how news discourse addresses the issue and constructs interpersonal meanings. Graduation resources, as a subcategory of appraisal system, can underpin the degree of meanings and perspectives, allowing writers to adjust the gradability of attitudinal meanings conveyed to readers. This research first examines how the writer’s voice is embedded in graduation resources, and later, how these graduation resources are used in online news articles calling for the return of the artefacts. This study also examines how online newspapers covered a short film by vloggers called “Escape from the British Museum”, which sparked massive social media reactions, offering new perspectives on how social media and traditional news organisations interact to construct meanings through language. The results show that quantification and fulfilment (completion) resources are the two most common subcategories of graduation resources. The findings shed light on the language strategies used in news and social media discourse, as well as the interpersonal meanings behind such requests for cultural heritage repatriation.

Abstract Background The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. Methods Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. Results The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log–alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. Conclusion This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

Abstract Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated to reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) in large trials independent of glycemic control. The mechanisms of this cardioprotective property remain uncertain. Evidence suggests positive hemodynamic changes and favorable cardiac remodeling contributing to the clinical outcomes but results were conflicting. We aim to investigate the potential impact on hemodynamic parameters, cardiac structure and functions. This prospective observational study included T2DM patients receiving canagliflozin 100 mg per day in addition to their antidiabetic treatment. We analyzed hemodynamic parameters assessed by echocardiographic measurements and impedance cardiography (ICG) to evaluate systolic and diastolic functions from baseline to 24 weeks after treatment. A total of 47 patients (25 males and 22 females) averaging 64.6 ± 10.9 years had a significant reduction in HbA1c, body weight, and systolic blood pressure. Hematocrit increased significantly, while NT-proBNP remained unchanged. E/e′, left atrium (LA) volume, and LA stiffness were reduced, while left ventricle (LV) global longitudinal strain (GLS) and LA strain rates increased at 24 weeks by conventional and speckle tracking echocardiography. LV mass and ejection fraction showed no differences. ICG suggested significant improvement in hemodynamic parameters with increased stroke volume index and cardiac output index and decreased systemic vascular resistance index at 12 and 24 weeks. Canagliflozin improved hemodynamic parameters and had a favorable impact on LA and LV reverse remodeling. These changes may explain the beneficial effect on cardiovascular outcomes in large clinical trials.

Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells’ vulnerabilities, potentially marking a significant advancement in managing this deadly disease.

Since November 2022, the use of generative artificial intelligence (GAI) technology has increased in many customer service industries. However, little is known about AI’s language choices and meaning-making resources compared to human responses from a systematic linguistic point of view. The present study is a discourse analysis that explores negative online guest complaints made to four luxury heritage hotels in Hong Kong that are classified as cultural heritage sites with rich interpersonal and historical values. We collected authentic guest complaints and responses from hotel managers from April 2012 to October 2022 in online travel forums, and then had GAI draft response letters on behalf of the hotel managers. Our total dataset was 65,539 words and consisted of three subcorpora: guest complaints (Text a of 115 complaints totaling 26,224 words), hotel manager responses (Text b of 115 response letters totaling 14,975 words), and AI-generated responses (Text c of 115 response letters totaling 24,340 words). This study used systemic functional linguistics to explore interpersonal meanings in texts; for example, appraisal resources, verb processes, and personal pronouns were compared between texts. First, we identified the most frequent words of the common themes across the three subcorpora and found significant differences in lexicogrammatical features between hotel managers and AI-generated responses using the log-likelihood ratio. The results suggest that AI-generated texts are able to provide a tailored and empathetic response to guests, but hotel managers may need to introduce some modifications, such as time indicators, sensory verbs used, and complimentary offers. This study explores the differences in word choices and communication strategies, which have implications and insights for the hospitality industry, especially luxury heritage hotels where caring and personalized customer service are considered important.

Abstract Background For the purpose to examine lower limb melanoma (LLM) and its long-term survival rate, we used data from the Surveillance, Epidemiology and End Results (SEER) database. To estimate the prognosis of LLM patients and assess its efficacy, we used a powerful deep learning and neural network approach called DeepSurv. Methods We gathered data on those who had an LLM diagnosis between 2000 and 2019 from the SEER database. We divided the people into training and testing cohorts at a 7:3 ratio using a random selection technique. To assess the likelihood that LLM patients would survive, we compared the results of the DeepSurv model with those of the Cox proportional-hazards (CoxPH) model. Calibration curves, the time-dependent area under the receiver operating characteristic curve (AUC), and the concordance index (C-index) were all used to assess how accurate the predictions were. Results In this study, a total of 26,243 LLM patients were enrolled, with 7873 serving as the testing cohort and 18,370 as the training cohort. Significant correlations with age, gender, AJCC stage, chemotherapy status, surgery status, regional lymph node removal and the survival outcomes of LLM patients were found by the CoxPH model. The CoxPH model’s C-index was 0.766, which signifies a good degree of predicted accuracy. Additionally, we created the DeepSurv model using the training cohort data, which had a higher C-index of 0.852. In addition to calculating the 3-, 5-, and 8-year AUC values, the predictive performance of both models was evaluated. The equivalent AUC values for the CoxPH model were 0.795, 0.767, and 0.847, respectively. The DeepSurv model, in comparison, had better AUC values of 0.872, 0.858, and 0.847. In comparison to the CoxPH model, the DeepSurv model demonstrated greater prediction performance for LLM patients, as shown by the AUC values and the calibration curve. Conclusion We created the DeepSurv model using LLM patient data from the SEER database, which performed better than the CoxPH model in predicting the survival time of LLM patients.

Background and objective: Multidrug-resistant tuberculosis (MDR-TB) requires extended treatment with regimens with multiple side effects, resulting in high treatment failure rates. Adjunctive lung resection combined with anti-tubercular agents improves outcomes. However, few studies have evaluated the potential harm from surgery and determined the optimal conditions for surgery. We aimed to analyze perioperative conditions to assess risk factors for postoperative complications in a multi-institutional setting. Methods: This retrospective study included 44 patients with MDR-TB who underwent adjunctive lung resection at three management groups of the Taiwan MDR-TB consortium between January 2007 and December 2020. Demographic data, clinical characteristics, radiological findings, sputum culture status before surgery, primary or acquired drug resistance, surgical procedure, complications, and treatment outcomes were collected and analyzed. Multivariate logistic regression was used to identify risk factors for postoperative complications. Results: Twenty-seven patients (61.4%) underwent lung resection using video-assisted thoracic surgery (VATS). The overall surgical complication rate was 20.5%, and the surgical mortality rate was 9.1%. Postsurgical hemothorax was the most common complication (11.4%). According to the univariate analysis, hilum involvement in images, positive preoperative sputum culture, and thoracotomy approach were unfavorable factors. VATS approach [adjusted OR, 0.088 (95% CI, 0.008–0.999)] was the only favorable factor identified by multivariate analysis. Conclusion: The minimally invasive approach is a growing trend, and lobectomies and sublobar resections were the main procedures for MDR-TB. The VATS approach significantly reduced the surgical complication rate. Postsurgical hemothorax was noteworthy, and meticulous hemostasis of the chest wall and residual lung surface is critical for successful resections.

Abstract A pan-sarbecovirus or pan-betacoronavirus vaccine that can prevent current and potential future beta-coronavirus infections is important for fighting possible future pandemics. Here, we report a mucosal vaccine that cross-protects small animal models from sarbecoviruses including SARS-CoV-1, SARS-CoV-2 and its variants. The vaccine comprises a live-but-defective SARS-CoV-2 virus that is envelope deficient and has the orf8 segment replaced by interferon-beta, hence named Interferon Beta Integrated SARS-CoV-2 (IBIS) vaccine. Nasal vaccination with IBIS protected mice from lethal homotypic SARS-CoV-2 infection and hamsters from co-housing-mediated transmission of homotypic virus. Moreover, IBIS provided complete protection against heterotypic sarbecoviruses, including SARS-CoV-2 Delta and Omicron variants, and SARS-CoV-1 in both mice and hamsters. Besides inducing a strong lung CD8 + T cell response, IBIS specifically heightened the activation of mucosal virus-specific CD4 + T cells compared to the interferon-null vaccine. The direct production of interferon by IBIS also suppressed virus co-infection of SARS-CoV-2 in human cells, reducing the risk of genetic recombination when using as live vaccines. Altogether, IBIS is a next-generation pan-sarbecovirus vaccine and warrants further clinical investigations.

Introduction: Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC). Although multiple pharmacological HDAC inhibitors (HDACis) have been developed, none is available in human HCC. Objectives: To investigate the pharmacological effects of a fangchinoline derivative HL23, as a novel HDACi and its molecular mechanisms through TXNIP-mediated potassium deprivation in HCC. Methods: Both in vitro assays and orthotopic HCC mouse models were used to investigate the effects of HL23 in this study. The inhibitory activity of HL23 on HDACs was evaluated by in silico studies and cellular assays. Chromatin immunoprecipitation (ChIP) was conducted to confirm the regulation of HL23 on acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic analysis were conducted to identify the regulatory mechanisms of HL23. The clinical significance of TXNIP and HDACs was evaluated by analysing publicly available database. Results: HL23 exerted compatible HDACs inhibition potency as Vorinostat (SAHA) while had superior anti-HCC effects than SAHA and sorafenib. Both in vitro and in vivo studies showed HL23 significantly suppressed HCC progression and metastasis. HL23 significantly upregulated TXNIP expression via regulating acetylation mark (H3K9ac) at TXNIP promoter. TXNIP was responsible for anti-HCC activity of HL23 through mediating potassium channel activity. HDAC1 was predicted to be the target of HL23 and HDAC1lowTXNIPhigh could jointly predict promising survival outcome of patients with HCC. Combination treatment with HL23 and sorafenib could significantly enhance sorafenib efficacy. Conclusion: Our study identified HL23 as a novel HDACi through enhancing acetylation at TXNIP promoter to trigger TXNIP-dependent potassium deprivation and enhance sorafenib efficacy in HCC treatment.

IntroductionOf all psychiatric disorders, schizophrenia is associated with the highest risk of all-cause mortality. This study aimed to investigate independent risk factors for all-cause mortality in patients with chronic schizophrenia. In addition, the possible causal inter-relationships among these independent risk factors and all-cause mortality were also explored.MethodsWe conducted an analysis of 1,126 patients with chronic schizophrenia from our psychiatric department from April 2003 to August 2022, and retrospectively reviewed their medical records. The study endpoint was all-cause mortality. Baseline clinical characteristics including sociodemographic data, biochemical data, lifestyle factors, comorbidities and antipsychotic treatment were examined with Cox proportional hazards analysis.ResultsThe all-cause mortality rate was 3.9% (44 patients). Multivariate Cox regression analysis revealed that several factors were independently associated with all-cause mortality, including diabetes mellitus (DM), hypertension, heart failure, gastroesophageal reflux disease (GERD), peptic ulcer disease, ileus, underweight, fasting glucose, triglycerides, albumin, and hemoglobin. Structural equation modeling (SEM) analysis revealed that several factors had statistically significant direct effects on all-cause mortality. Heart failure, hypertension, underweight, age at onset, and ileus showed positive direct effects, while albumin and hemoglobin demonstrated negative direct effects. In addition, several factors had indirect effects on all-cause mortality. GERD indirectly affected all-cause mortality through ileus, and peptic ulcer disease had indirect effects through albumin and ileus. Ileus, underweight, DM, and hypertension also exhibited indirect effects through various pathways involving albumin, hemoglobin, and heart failure. Overall, the final model, which included these factors, explained 13% of the variability in all-cause mortality.DiscussionThese results collectively suggest that the presence of DM, hypertension, heart failure, GERD, peptic ulcer disease, ileus, and underweight, along with lower levels of albumin or hemoglobin, were independently associated with all-cause mortality. The SEM analysis further revealed potential causal pathways and inter-relationships among these risk factors contributing to all-cause mortality in patients with chronic schizophrenia.

Alloy nanomaterials exhibit superior plasmonic properties that can exceed traditional single-metal nanomaterials. Hence, they hold great potential for developing highly sensitive sensors capable of detecting small analytes in nanoscale. The self-assembly Au-Pt alloy nanoislands structure is used, for the first time, for localized surface plasmon resonance sensing. Its nanostructure has been studied and characterized by using various microscopy and spectroscopy techniques. It was found that Au0.94-Pt0.06 was the optimum composition with the best sensitivity toward the change of refractive index over various concentrations of NaCl solution and double the sensitivity than that of pure Au nanoislands. The Au-Pt chip with its surface functionalized with nitrotyrosine was successfully developed for highly sensitive detection of antimony (III) ion, the electronic properties of the interaction between nitrotyrosine and Sb during the biosensing was explored using density functional theory simulation to explain their strong adsorption to make nitrotyrosine a successful receptor. The sensor achieved a limit of detection of 0.0504 ppb, which is the best ever value among all those reported for Sb(III) ions sensing. With its high selectivity tested among 14 other common elements, the present Sb(III) ion LSPR sensor also possesses attributes of label-free, easy to fabricate and simple to operate.

Background Patient education (PE) is essential for improving patients’ knowledge, anxiety, and satisfaction, and supporting their postoperative recovery. However, the advantages of video-assisted thoracoscopic surgery (VATS)—smaller incisions and faster recovery—can result in shorter hospital stays, making PE more challenging to implement effectively. Multimedia PE can potentially enhance PE, but its effectiveness for patients undergoing VATS is unclear. Objective This study developed a scenario-based PE web app for lung tumor patients undergoing VATS (SPE-VATS) to facilitate the PE process and evaluated its usability through a clinical trial. Methods The SPE-VATS provided the experimental group (EG: 32 participants) with interactive scenario, query guidance, diagnostic analysis, experience sharing, and active reminder, while the control group (CG: 32 participants) used pamphlets and videos. The usability of SPE-VATS in terms of postoperative anxiety reduction and patient satisfaction with the app was evaluated using self-reported questionnaires based on the state-trait anxiety inventory, technology acceptance model, system usability scale, and task load index. Results There was no statistically significant difference in postoperative anxiety reduction between the EG and CG, possibly because 90% of the participants underwent a low-risk surgical type, and VATS is known to be advantageous in alleviating surgical anxiety. However, females and higher educated EG participants showed a non-significant but favorable reduction than their CG counterparts. Moreover, the EG was highly satisfied with the app (rated 4.2 to 4.4 out of 5.0), with no significant gender and education level difference. They particularly valued the interactive scenario, experience sharing, and diagnostic analysis features of SPE-VATS. Conclusions The SPE-VATS demonstrated its usability and high patient satisfaction, particularly for female and higher educated patients. Low-risk patient predominance and VATS's advantages may explain non-significant postoperative anxiety reduction, warranting further studies on high-risk patients to evaluate the impact of SPE-VATS on clinical practice.

Background Chronic kidney disease (CKD) affects around 10% of the global population and has been estimated to affect around 50% of individuals with type 2 diabetes and 50% of those with heart failure. The guideline-recommended approach is to manage with disease-modifying therapies, but real-world data suggest that prescribing rates do not reflect this in practice.Objective To develop a cross-specialty consensus on optimal management of the patient with CKD using a modified Delphi method.Design An international steering group of experts specialising in internal medicine, endocrinology/diabetology, nephrology and primary care medicine developed 42 statements on aspects of CKD management including identification and screening, risk factors, holistic management, guidelines, cross-specialty alignment and education. Consensus was determined by agreement using an online survey.Participants The survey was distributed to cardiologists, nephrologists, endocrinologists and primary care physicians across 11 countries.Main outcomes and measures The threshold for consensus agreement was established a priori by the steering group at 75%. Stopping criteria were defined as a target of 25 responses from each country (N=275), and a 4-week survey period.Results 274 responses were received in December 2022, 25 responses from Argentina, Australia, Brazil, Guatemala, Mexico, Singapore, South Korea, Taiwan, Thailand, Turkey and 24 responses from Egypt. 53 responses were received from cardiologists, 52 from nephrologists, 55 from endocrinologists and 114 from primary care physicians. 37 statements attained very high agreement (≥90%) and 5 attained high agreement (≥75% and

Abstract Background Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease. Methods MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients. Results We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients’ skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities. Conclusions We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.

Abstract Background Some prospective studies have shown that second‐generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non‐small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second‐line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. Methods Patients with EGFR‐mutated advanced‐stage NSCLC who received first‐line EGFR‐TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second‐line chemotherapy were enrolled. We compared progression‐free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan–Meier and log‐rank tests. Results In total, 209 (54.8%) patients had a negative T790M mutation test and received second‐line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. Conclusion This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.

The cutaneous wound in diabetic patients frequently encounters intractable pathogenic infections due to the hyperglycemia micromilieu which is conducive to bacterial growth and multiplication. Despite the extensive clinical use of antibiotics to treat bacterial infections, the emergence of drug-resistant and super pathogens as well as the potential side effects of antibiotics have elicited alarming challenges to public health. To address this daunting concern, we devise and develop a photo-activated cascade bio-heterojunctions (C-bio-HJs) for rapid sterilization and diabetic cutaneous regeneration. In the designed C-bio-HJs, photo-generated electron-hole pairs of graphite-phase carbon nitride (g-C3N4) are effectively separated with the marriage of molybdenum disulfide (MoS2), which achieves the augmented photodynamic antibacterial effect. Moreover, glucose oxidase (GOx) tethered on the bio-HJs catalyzes glucose into hydrogen peroxide (H2O2) in diabetic wounds for starvation therapy. Furthermore, Mo4+ enables the catalysis of H2O2 into a highly effective hydroxyl radical (·OH) for chemodynamic-photothermal combined antibacterial therapy. Both in vitro and in vivo results authenticate the cascading antibacterial properties and skin regeneration-promoting effects of the C-bio-HJs, which provide a facile strategy to combat diabetic wound healing through the synergistic GOx-primed dynamic therapies.

Meniscus, the cushion in knee joint, is a load-bearing tissue that transfers mechanical forces to extracellular matrix (ECM) and tissue resident cells. The mechanoresponse of human tissue resident stem/progenitor cells in meniscus (hMeSPCs) is significant to tissue homeostasis and regeneration but is not well understood. This study reports that a mild cyclic tensile loading regimen of ∼1800 loads/day on hMeSPCs seeded in 3-dimensional (3D) photocrosslinked gelatin methacryloyl (GelMA) hydrogel is critical in maintaining cellular homeostasis. Experimentally, a “slow walk” biomimetic cyclic loading regimen (10% tensile strain, 0.5 Hz, 1 h/day, up to 15 days) is applied to hMeSPCs encapsulated in GelMA hydrogel with a magnetic force-controlled loading actuator. The loading significantly increases cell differentiation and fibrocartilage-like ECM deposition without affecting cell viability. Transcriptomic analysis reveals 332 mechanoresponsive genes, clustered into cell senescence, mechanical sensitivity, and ECM dynamics, associated with interleukins, integrins, and collagens/matrix metalloproteinase pathways. The cell-GelMA constructs show active ECM remodeling, traced using a green fluorescence tagged (GFT)-GelMA hydrogel. Loading enhances nascent pericellular matrix production by the encapsulated hMeSPCs, which gradually compensates for the hydrogel loss in the cultures. These findings demonstrate the strong tissue-forming ability of hMeSPCs, and the importance of mechanical factors in maintaining meniscus homeostasis.

Objective: Segmentectomy as a parenchymal-sparing surgical approach has been recommended over lobectomy in select patients with early-stage non–small cell lung cancer. This study aimed to address 3 aspects of segmentectomy (“patient indication”; “segmentectomy approaches”; “lymph node assessment”) where there is limited clinical guidance. Methods: A modified Delphi approach comprising 3 anonymous surveys and 2 expert discussions was used to establish consensus on the aforementioned topics among 15 thoracic surgeons (2 Steering Committee; 2 Task Force; 11 Voting Experts) from Asia who have extensive segmentectomy experience. Statements were developed by the Steering Committee and Task Force based on their clinical experience, published literature (rounds 1-3), and comments received from Voting Experts through surveys (rounds 2-3). Voting Experts indicated their agreement with each statement on a 5-point Likert scale. Consensus was defined as ≥70% of Voting Experts selecting either “Agree”/“Strongly Agree” or “Disagree”/“Strongly Disagree.” Results: Consensus from the 11 Voting Experts was reached on 36 statements (11 “patient indication” statements; 19 “segmentation approaches” statements; 6 “lymph node assessment” statements). In rounds 1, 2, and 3, consensus was reached on 48%, 81%, and 100% of drafted statements, respectively. Conclusions: A recent phase 3 trial reported significantly improved 5-year overall survival rates for segmentectomy compared with lobectomy, proposing thoracic surgeons to consider segmentectomy as a surgical option in suitable patients. This consensus serves as a guidance to thoracic surgeons considering segmentectomy in patients with early non–small cell lung cancer, outlining key principles that surgeons should consider in surgical decision-making.