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Wei-Fan Ou,1 Pei-Ya Liao,1 Yu-Wei Hsu,2,3 Yen-Hsiang Huang,1,4– 6 Kuo-Hsuan Hsu,6,7 Jeng-Sen Tseng,1,4– 6,8 Gee-Chen Chang,4,9– 11 Tsung-Ying Yang1,6,12 1Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Cancer Prevention and Control Center, Taichung Veterans General Hospital, Taichung, Taiwan; 3Computer and Communications Center, Taichung Veterans General Hospital, Taichung, Taiwan; 4Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; 5College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 6Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, Taichung, Taiwan; 7Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 8Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 9Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 10School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 11Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 12Department of Life Sciences, National Chung Hsing University, Taichung, TaiwanCorrespondence: Jeng-Sen Tseng, Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, No. 1650, Sect. 4, Taiwan Boulevard, Taichung, 407, Taiwan, Tel +886-4-23592525 ext. 3232, Fax +886-4-23741320, Email tzeng64@gmail.comBackground: Antiangiogenetic therapy and lung cancer, per se, are associated with an increased risk of thromboembolic events (TE). We aim to evaluate the pattern and outcome of TE as well as its influence on survival time of advanced non-small cell lung cancer (NSCLC) patients receiving antiangiogenic therapy.Methods: This was a retrospective cohort study, which included advanced NSCLC patients receiving antiangiogenic therapy. All TE were confirmed by objective image studies. We disclosed the presentation and risk factors of TE and evaluated its influence on outcome.Results: A total of 427 patients were included. TE occurred in 43 patients (10.1%). Deep vein thrombosis (DVT) was the most common TE (n = 20). Up to 46.2% of DVT did not occur in the typical lower extremities. Two patients died of TE. Among patients with continuous use or reuse of antiangiogenetic therapy, 18.2% had recurrent TE events. At the occurrence of TE, 28 patients experienced progressive disease (TE with PD), while tumor status remained stable in another 15 patients (TE without PD). The post-TE survival of patients without and with PD were 8.9 months (95% CI 3.9– 13.9) vs 2.2 months (95% CI 0.1– 4.3), P = 0.012. As compared with patients without TE (31.4 months [95% CI 27.1– 35.7]), TE with PD patients experienced a significantly shorter overall survival (20.1 months [95% CI 15.5– 24.6]), but TE without PD patients had comparable survival time (32.7 months [95% CI 7.4– 28.1]) (P = 0006). The use of hormone analogue and proteinuria predicted the events among TE with PD group (aOR 2.79 [95% CI 1.13=6.92]; P = 0.027) and TE without PD group (aOR 4.30 [95% CI 1.13– 16.42]; P = 0.033), respectively.Conclusion: Owing to the different risk factors and influences on the survival time, TE with and without PD may be two different disease entities.Keywords: non-small cell lung cancer, NSCLC, antiangiogenesis, bevacizumab, ramucirumab, thromboembolism

Ming-Yang Lee,1–3 Ming-Fang Wu,4,5 Shur-Hueih Cherng,6 Ling-Yen Chiu,7 Tsung-Ying Yang,8,9 Gwo-Tarng Sheu5,7,10 1Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Chiayi City, Taiwan; 3Graduate Institute of Natural Healing Science, Nanhua University, Chiayi City, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Divisions of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Department of Biotechnology, Hung Kuang University, Taichung, Taiwan; 7Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 9Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 10Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan Purpose: Tissue transglutaminase 2 (TG2) is a stress-regulated protein and associated with cancer cell survival. However, the effects of TG2 expression in human non-small-cell lung cancer (NSCLC) cells on reactive oxygen species (ROS) production and redox homeostasis have not been fully elucidated.Materials and methods: We investigated the TG2 expression and activity in A549, H1299, H1355, and H460 lung cancer cells by Western blots and quantitative polymerase chain reaction assay. The enzyme-linked immunosorbent assay was used for transglutaminase activity. The epigenetic expression was characterized with histone deacetylase inhibitor trichostatin A and DNA methyltransferase inhibitor 5-Aza treatment. TG2 expression was inhibited by siRNA transfection and the intracellular calcium was measured by Flow-3AM assay, apoptosis was analyzed by Annexin V/propidium iodide assay, and intracellular ROS was detected by fluorescence-activated cell sorting analysis. The ROS scavenger N-acetyl-L-cysteine (NAC) was applied to reduce TG2-knockdown-induced oxidative stress.Results: Only A549 cells expressing high levels of TG2 correlated with high TG2 activity. The expression of TG2 can be regulated by epigenetic regulation in A549, H1299, and H1355 cells. The data also show that TG2 reduction induces apoptosis in A549 and H1299 cells. Furthermore, increased intracellular ROS and calcium levels were both detected in TG2-reduced cells. Moreover, endoplasmic reticulum stress inhibitor (salubrinal) and antioxidant NAC were able to reduce ROS and calcium levels to recover cell viability. Interestingly, the extrinsic and intrinsic apoptosis pathways were activated with a p53 independence upon TG2 reduction. TG2 reduction not only attenuated AKT activation but also reduced superoxide dismutase 2 (SOD2) expression. Exogenous NAC partially recovered SOD2 expression, indicating that mitochondrial-mediated apoptosis accounts for a part of but not all of the TG2-reduction-related death.Conclusion: TG2 plays a protection role in NSCLC cell lines. Regardless of the endogenous level of TG2 and p53 status, reduction of TG2 may result in oxidative stress that induces apoptosis. Therefore, target TG2 expression represents a logical strategy for NSCLC management. Keywords: caspases, oxidative stress, redox homeostasis, NAC, AKT, SOD2

The early microbiota of neonates is crucial for developing the postnatal immune system and establishing normal physiological, metabolic, and neurological functions. This study aimed to investigate the factors influencing the diversity of the neonatal oral microbiome, including mother-to-newborn microbial transmission. The study includes a prospective cohort comprising 73 mothers and 87 neonates and a retrospective cohort comprising 991 mothers and 1,121 neonates. Samples from the maternal cervix and neonatal gastric, bronchial, and oral cavities were analyzed using culture-based methods. Neonatal oral swab samples were also analyzed using 16S rRNA gene sequencing to characterize microbial diversity and composition. Similar genera were detected in the neonatal gastric, bronchial, and oral samples, and the neonatal gastric culture was the most similar to the maternal cervical culture. In addition to mother-to-newborn microbial transmission, various natal factors including birth type, birth weight, delivery mode, maternal chorioamnionitis, maternal diabetes and the presence of microbes in other sites influenced neonatal oral microbiome diversity. Among these factors, the birth type was the most significant, and preterm neonates exhibited decreased oral microbiome diversity, with fewer beneficial bacteria and more pathogens. These findings could serve as a baseline for research on the establishment of the oral microbiota in preterm neonates and its health implications., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Eco-friendly aquaculture technology has become a major global trend in recent years. This study's investigation and analysis revealed that eco-friendly aquaculture management technologies increased the production per unit area of the grouper and the fourfinger threadfin. From an economic perspective, it was estimated that the application of eco-friendly aquaculture management technology might increase grouper production by 18.6 metric tons/ha and the output value by US$7,106.9/ha per year, as well as decrease electricity consumption by 1,510.45 kWh/ha/month. It was estimated that for fourfinger threadfin, the use of eco-friendly aquaculture management technologies might increase the production by 10.1 tons/ha and the output value by US$5,031.8/ha each year, as well as reduce the electricity consumption by 257.18 kWh/ha/month. As such, eco-friendly aquaculture management technologies may increase the output value while reducing energy consumption and costs. Furthermore, regression analysis with dummy variables showed that factors affecting grouper production per unit area included applying eco-friendly aquaculture management technology, stocking density, and harvest specifications. However, no significant relationship was identified between breeding time and production per unit area, and the correlation coefficient was negative. The main factors positively affecting the production per unit area of the fourfinger threadfin were stocking density, the application of eco-friendly aquaculture management technology, and harvest specifications. However, a longer breeding time did not result in better production per unit area. This study showed that eco-friendly aquaculture management technology increased the production per unit area and reduced water consumption, electricity consumption, and operating costs to promote sustainable use of water and land resources and sustainable industrial operation and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High-safety aqueous zinc (Zn) ion batteries are troubled by dendrite growth and hydrogen evolution reaction on Zn anode, which can be well solved via the construction of surface protective layer. The recent researches mainly focus on the bulk property of the protective layer, but its separation from Zn anode is ignored. In this work, high-viscoelasticity alginate-based (HVAA) layer was in-situ constructed on Zn anodes by the cross-linking of sodium alginate with formaldehyde and the plastifying of glycerin. HVAA layer can combine with H 2 O and coordinate with Zn 2+ ions in aqueous electrolyte to achieve viscoelasticity on Zn anode, which can accommodate volume change of Zn anode during plating/stripping processes to continuously protect Zn anodes under the real battery system. Physical block effect of HVAA layer impedes hydrogen evolution corrosion reaction by avoiding the immediate contact of Zn anodes with aqueous electrolyte. Ionic conductive ability of HVAA layer by coordinating oxygen-containing groups with Zn 2+ can uniform ion flux to induce the homogeneous deposition of Zn 2+ on Zn anode. Zn anode with HVAA endows ZnZn symmetric battery with stably cycle of 4000 h and Zn-iodide full batteries with better electrochemical performance of 8000 cycles comparing with bare Zn anode. This work opens a novel route to continuously protect Zn anode through the high-viscoelasticity films to closely fit with Zn surface and implement the high-value application of renewable sources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: CNSLBP accounts for 85% of all LBP cases and impairs physical health, quality of life, and work productivity, posing a significant health and economic burden. Baduanjin (BDJ) exercises are traditional Chinese Qi Gong mind-body exercises that have been practiced for over 1,000 years. However, the standard BDJ protocol established by the State Sports General Administration does not stimulate core muscles, limiting the effectiveness of low back pain rehabilitation. Therefore, it is necessary to improve the original BDJ protocol., Methods: This 24-week single-center, single-blind, parallel-group randomized control superiority trial will allocate 100 patients into two groups (control and intervention) at a 1:1 ratio. The patients in the control group will perform the standard BDJ protocol established by the State Sports General Administration. The patients in the patients in the control group will perform the standard BDJ protocol established by the State Sports General Administration. The intervention group will perform intervention. The primary outcomes will be Quebec back pain disability scale. Secondary outcomes will include visual analog scale pain scores, Surface electromyography. The assessments of the tests will be performed at four time points. Adverse events will be recorded faithfully during the study., Discussion: This randomized control trial is the first to compare a standard BDJ protocol and an optimized protocol in patients with CNSLBP. This study can help guide rehabilitation programs., Trial Registration: Chinese Clinical Trial Registry, ChiCTR2200065618, Registered on 10 Nov. 2022. This protocol is the first version 1, which was approved on 26 Aug 2022., (© 2024. The Author(s).)

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n observed  = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS., (© 2024. The Author(s).)

Objectives: The United States faces an ongoing drug overdose crisis, but accurate information on the prevalence of opioid use disorder (OUD) remains limited. A recent analysis by Keyes et al used a multiplier approach with drug poisoning mortality data to estimate OUD prevalence. Although insightful, this approach made stringent and partly inconsistent assumptions in interpreting mortality data, particularly synthetic opioid (SO)-involved and non-opioid-involved mortality. We revise that approach and resulting estimates to resolve inconsistencies and examine several alternative assumptions., Methods: We examine 4 adjustments to Keyes and colleagues' estimation approach: (A) revising how the equations account for SO effects on mortality, (B) incorporating fentanyl prevalence data to inform estimates of SO lethality, (C) using opioid-involved drug poisoning data to estimate a plausible range for OUD prevalence, and (D) adjusting mortality data to account for underreporting of opioid involvement., Results: Revising the estimation equation and SO lethality effect (adj. A and B) while using Keyes and colleagues' original assumption that people with OUD account for all fatal drug poisonings yields slightly higher estimates, with OUD population reaching 9.3 million in 2016 before declining to 7.6 million by 2019. Using only opioid-involved drug poisoning data (adj. C and D) provides a lower range, peaking at 6.4 million in 2014-2015 and declining to 3.8 million in 2019., Conclusions: The revised estimation equation presented is feasible and addresses limitations of the earlier method and hence should be used in future estimations. Alternative assumptions around drug poisoning data can also provide a plausible range of estimates for OUD population., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

The degradation kinetics, reaction pathways, and disinfection by-products formation of an organic UV filter, benzophenone - 4 (BP4) during UV/persulfate oxidation were investigated. BP4 can hardly be degraded by UV alone, but can be effectively decomposed by UV/persulfate following pseudo-first order kinetics. BP4 degradation rate was enhanced with increasing persulfate dosage and decreasing pH from 8 to 5. However, the degradation rate of BP4 at pH 9 was higher than that at pH 8 because of the presence of phenolic group in BP4 structure. and SO 4 - ⋅ were confirmed as the major contributors to BP4 decomposition in radical scavenging experiments, and the second-order rate constants between HO ⋅ and BP4 as well as those between SO 4 - ⋅ and BP4 were estimated by establishing and solving a kinetic model. The presence of B r - and humic acid inhibited the decomposition of BP4, while N O 3 - promoted it. The mineralisation of BP4 was only 9.1% at the persulfate concentration of 50 μM. Six degradation intermediates were identified for the promulgation of the reaction pathways of BP4 during UV/persulfate oxidation were proposed as a result. In addition, the formation of DBP in the sequential chlorination was evaluated at different persulfate dosages, pH values, and water matrix. The results of this study can provide essential knowledge for the effective control of DBP formation with reducing potential hazard to provide safe drinking water to the public.

Patients with non-small cell lung cancer (NSCLC) and incomplete resection have poor clinical outcomes. The present study aimed to identify risk factors for disease progression and mortality. A total of 65 patients with early-stage NSCLC that underwent operation but had a non-R0 resection between August 2011 and December 2020 were included in the present study, and the clinicopathological features and driver gene mutation status were analyzed. The median follow-up time was 36.2 months; 39 patients (60.0%) experienced disease progression and 3 patients (4.6%) died. In total, 22 patients (33.8%) harbored mutations in driver genes. Multivariate analysis demonstrated that the presence of driver gene mutations was associated with an increased risk of disease progression [adjusted odds ratio, 24.08; 95% confidence interval (CI), 2.77-209.01; P=0.004]. Tumors classed as Eastern Cooperative Oncology Group performance status 2 [adjusted hazard ratio (HR), 3.49; 95% CI, 1.10-11.03; P=0.033], stage II-IIIB tumors (adjusted HR, 2.55; 95% CI, 1.06-6.17; P=0.037) and the presence of a driver gene mutation (adjusted HR, 3.28; 95% CI, 1.55-6.94; P=0.002) were associated with a significantly reduced progression-free survival (PFS). Driver gene-targeted therapy was associated with an increased post-progression survival for patients that were reported to have disease progression (adjusted HR, 0.38; 95% CI, 0.16-0.91; P=0.030). There was no significant impact of driver gene mutation status on the overall survival (OS) of patients. Although the presence of a driver gene mutation was associated with an increased risk of disease progression and a reduced PFS, it was demonstrated that patients with disease progression may benefit from driver gene-targeted therapy, as patients with driver gene-targeted therapy had a similar OS compared with that of patients with a driver gene-negative or unknown status. Therefore, early comprehensive analysis of driver gene mutation status may be recommended for early-stage NSCLC cancer patients experiencing non-R0 resection., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Shen et al.)

Initial studies on the immunogenicity of SARS-CoV-2 (CoV-2) S glycoprotein ("spike") as a protein subunit vaccine suggested sub-optimal efficacy in mammals. Although protein engineering efforts have produced CoV-2 spike protein sequences with greatly improved immunogenicity, additional strategies for improving the immunogenicity of CoV-2 protein subunit vaccines are scaffolding and the use of adjuvants. Comparisons of the effectiveness of engineered protein-only and engineered protein-nanoparticles vaccines have been rare. To explore this knowledge gap, we inoculated mice with two doses of either sequence-optimized trimeric spike protein or one of several sequence-optimized spike nanoparticles. We measured their immune response up to two months after the first dose. We also measured the immune response and protection against live virus in hamsters inoculated with either sequence-optimized trimeric spike protein or a liposome-based sequence-optimized spike nanoparticle. We found that in the presence of adjuvant, the antibody and neutralization titers elicited by spike-nanoparticles were not significantly greater than those elicited by spike-only in mice, even at doses as low as 0.1 µg/animal. Hamsters vaccinated with spike-only or spike-nanoparticles were equally protected from live virus one month after their first inoculation. These results suggest that sequence-optimized protein subunit vaccines in the form of individual prefusion-stabilized trimers can be as effective in improving immunogenicity as scaffolded forms., (© 2024. The Author(s).)

On 6 February 2023, two major earthquakes struck Türkiye, with their epicenters in the Pazarcık (M7.7; focal depth: 8.6 km) and Elbistan (M7.6; focal depth: 7 km) districts of Kahramanmaraş city. Most of the dams in the earthquake region remained structurally safe and stable. However, 17 dams in Türkiye and 1 dam in Syria were damaged during the 2023 Kahramanmaraş earthquakes. The main objective of this study was to better understand the real seismic behaviors of the dams during the two mainshocks and significant aftershocks. An earthfill dam, a concrete-faced rockfill dam (CFRD), and a roller-compacted concrete (RCC) dam constructed in the disaster area were selected to identify the real seismic behaviors of different types of dams during strong earthquakes. Acceleration records measured at the crest, right and left abutments, and foundations of the selected dams during the 2023 Kahramanmaraş earthquakes were taken into account to determine the real seismic behavior of the dams before, during, and after the earthquakes. The results of this investigation provide valuable insights into the real seismic behaviors of different types of dams in the vicinity of fault lines during strong earthquakes.

Objective: This study aimd to assess recent trends in the control of low-density lipoprotein cholesterol (LDL-C) and the utilization of lipid-lowering drugs (LLD) among patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan., Methods: Patients with ASCVD and without a history of hemorrhagic stroke were identified from the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. ASCVD patients were stratified into four categories: those who ever had acute coronary syndrome (ACS), those who underwent percutaneous coronary intervention or coronary artery bypass grafting (PCI/CABG) without ACS, those who ever had an ischemic stroke (IS) without ACS or PCI/CABG, and other ASCVD cases. We assessed their latest recorded LDL-C levels for the periods 2015-16, 2017-18, and 2019-20. LLD therapy patterns were presented as monotherapy, dual therapy, or combination therapy of three or more drugs, with statin use classified by intensity., Results: We identified 3831 ASCVD patients in 2015-16, 3531 in 2017-18, and 1231 in 2019-20. LLD utilization rose from 58.4% in 2015-16 to 73.2% in 2019-20. The proportions of patients achieving LDL-C goals in 2015-16, 2017-18, and 2019-20 were 21.5%, 25.8%, and 33.3% in the ACS cohort (goal <70 mg/dL); 20.4%, 26.1%, and 39.0% in the PCI/CABG cohort (goal <70 mg/dL); 54.4%, 58.5%, and 58.9% in the IS cohort (goal <100 mg/dL); and 60.0%, 65.5%, and 67.0% in the other ASCVD cohort (goal <100 mg/dL), respectively. Over half of the patients were prescribed moderate-intensity statins. Statin use, age, history of diabetes mellitus, and hypertension were important factors for attaining LDL-C goal in ACS patients., Conclusion: Despite improvements in LDL-C management observed over recent years, significant gaps remain in guideline adherence, especially for patients with ACS or PCI/CABG in Taiwan, with over 60% not meeting LDL-C targets. Intensifying efforts to align clinical practice with guidelines are imperative., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg -1 ·d -1 ) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg -1 ·d -1 , i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The fish processing industry generates a significant amount of waste, and the recycling of this waste is an issue of global concern. We sought to utilize the heads of cutlassfish (Trichiurus lepturus), which are typically discarded during processing, to produce peptone, which is an important source of amino acids for microbial growth and recombinant protein production. Cutlassfish head muscle (CHM) were isolated, and the optimal protease and reaction conditions for peptone production were determined. The resulting peptone contained 12.22 % total nitrogen and 3.19 % amino nitrogen, with an average molecular weight of 609 Da, indicating efficient hydrolysis of CHM. Growth assays using Escherichia coli have shown that cutlassfish head peptone (CP) supports similar or superior growth compared to other commercial peptones. In addition, when recombinant chitosanase from Bacillus subtilis and human superoxide dismutase were produced in E. coli, CP gave the highest expression levels among six commercial peptones tested. In addition, the expression levels of chitosanase and superoxide dismutase were 20 % and 32 % higher, respectively, in CP medium compared to the commonly used Luria-Bertani (LB) medium. This study demonstrates the potential of using cuttlassfish waste in the production of microbial media, thereby adding significant value to fish waste. The results contribute to sustainable waste management practices and open avenues for innovative uses of fish processing by-products in biotechnological applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the paper. The authors declared that they don't have competing interests on this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of Interest: Zhang L, None; Liu JW, None; Gao S, None; Yang TY, None; Zhang MX, None.

Background: Bevacizumab is extensively used in the treatment of advanced non-small-cell lung cancer (NSCLC). Numerous clinical trials have proven the clinical efficacies of bevacizumab biosimilars (BB)., Objective: Our study aimed to compare the clinical outcomes between bevacizumab reference product (RP) and BB among advanced NSCLC patients in a real-world setting., Design: We retrospectively analyzed stage IV metastatic NSCLC patients who were treated with bevacizumab as part of a combination therapy. Patients were categorized into chemotherapy (CT) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) groups. We compared the patients' characteristics, treatment efficacy, and adverse events between RP and BB in the two treatment groups., Methods: From January 2020 to July 2022, a total of 171 patients who underwent combination therapy with bevacizumab were screened. Seventy-nine of these patients met the study's inclusion criteria and were enrolled in the final analysis. We utilized the Kaplan-Meier method to estimate progression-free survival (PFS) and the log-rank test to compare PFS between groups. The Cox proportional hazards model was used to identify predictors of PFS., Results: Within the CT cohort, 34 patients were treated with RP in combination with platinum and pemetrexed, and 25 patients received a combination regimen with BB. The median PFS was 6.9 months in the RP group and 8.9 months in the BB group ( p  = 0.255). Within the EGFR-TKI cohort, 20 patients with EGFR -mutant NSCLC received first-line treatment with EGFR-TKI plus bevacizumab. Of these patients, 9 were treated with a combination regimen that included RP, and 11 patients received EGFR-TKI in combination with BB. The median PFS was 18.4 months for the RP group and 13.6 months for the BB group ( p  = 0.363)., Conclusion: In our advanced NSCLC patients, we found no difference in clinical outcomes when receiving treatment with RP or BB. Given a combination regimen, BB was as effective as RP together with either CT or EGFR-TKIs., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Frozen shoulder (FS) is a common shoulder condition accompanied by shoulder pain and a loss of shoulder range of motion (ROM). The typical clinical assessment tools such as questionnaires and ROM measurement are susceptible to subjectivity and individual bias. To provide an objective evaluation for clinical assessment, this study proposes an inertial measurement unit (IMU)-based identification system to automatically identify shoulder tasks whether performed by healthy subjects or FS patients. Two groups of features (time-domain statistical features and kinematic features), seven machine learning (ML) techniques, and two deep learning (DL) models are applied in the proposed identification system. For the experiments, 24 FS patients and 20 healthy subjects were recruited to perform five daily shoulder tasks with two IMUs attached to the arm and the wrist. The results demonstrate that the proposed system using deep learning presented the best identification performance using all features. The convolutional neural network achieved the best identification accuracy of 88.26%, and the multilayer perceptron obtained the best F1 score of 89.23%. Further analysis revealed that the identification performance based on wrist features had a higher accuracy compared to that based on arm features. The system's performance using time-domain statistical features has better discriminability in terms of identifying FS compared to using kinematic features. We demonstrate that the implementation of the IMU-based identification system using ML is feasible for FS assessment in clinical practice.

The human gut microbiota significantly influences various physiological systems, including immune, nervous, and metabolic systems. Recent studies suggest that gut microbiota may affect sleep quality with certain bacteria and metabolites being linked to sleep patterns. However, the underlying chemical signaling pathway remains unclear. In this study, we investigated the effect of four gut bacteria-derived metabolites, tryptamine ( 1 ), indolokine A5 ( 2 ), 2-(1' H -indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 3 ), and phenethylamine (PEA, 4 ), on sleep characteristics in mice and melatonin biosynthesis pathways in zebrafish. Their sleep-promoting effects were evaluated in a pentobarbital-induced sleep mouse model, revealing significant increases in sleep duration and blood melatonin levels, particularly with ITE ( 3 ) and PEA ( 4 ). Further tests in zebrafish embryos showed that ITE ( 3 ) and PEA ( 4 ) increased the expression of genes for melatonin biosynthesis ( Aanat1 , Aanat2 , Tph1a , and Hiomt ) in a concentration-dependent manner, indicating their potential as therapeutic agents for sleep disorders., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Killer meiotic drivers are a class of selfish genetic elements that bias inheritance in their favor by destroying meiotic progeny that do not carry them. How killer meiotic drivers evolve is not well understood. In the fission yeast, Schizosaccharomyces pombe, the largest gene family, known as the wtf genes, is a killer meiotic driver family that causes intraspecific hybrid sterility. Here, we investigate how wtf genes evolve using long-read-based genome assemblies of 31 distinct S. pombe natural isolates, which encompass the known genetic diversity of S. pombe. Our analysis, involving nearly 1,000 wtf genes in these isolates, yields a comprehensive portrayal of the intraspecific diversity of wtf genes. Leveraging single-nucleotide polymorphisms in adjacent unique sequences, we pinpoint wtf gene-containing loci that have recently undergone gene conversion events and infer their ancestral state. These events include the revival of wtf pseudogenes, lending support to the notion that gene conversion plays a role in preserving this gene family from extinction. Moreover, our investigation reveals that solo long terminal repeats of retrotransposons, frequently found near wtf genes, can act as recombination arms, influencing the upstream regulatory sequences of wtf genes. Additionally, our exploration of the outer boundaries of wtf genes uncovers a previously unrecognized type of directly oriented repeats flanking wtf genes. These repeats may have facilitated the early expansion of the wtf gene family in S. pombe. Our findings enhance the understanding of the mechanisms influencing the evolution of this killer meiotic driver gene family., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Theoretical modeling is proposed to predict the maximum spreading of water-based ferrofluid droplets impacting upon dry surfaces influenced by a vertical magnetic field. Constructed on the principle of energy balance, this model demonstrates excellent agreement with numerical findings across various impact velocities, contact angles, and magnetic strengths. Notably, as magnetic field strength escalates, magnetic forces prevail over viscous and capillary forces, exerting a significant influence on spreading dynamics and diminishing the maximum spreading diameter of ferrofluid droplets if the impacting shape is spherical. However, for freely falling droplets, the shape becomes prolate before impacting and the promoted surface energy balances the magnetic inhibitory effect on droplet spreading, thus resulting in an almost unchanged maximum spreading diameter. By postulating complete conversion of initial kinetic energy into magnetic energy, a scaling law is derived for maximum spreading diameter under extremely high magnetic fields. Further interpolation with viscous dissipation and capillary effects enables universal rescaling under diverse impact conditions. Through comparison with numerical outcomes, the validity of our theoretical model is affirmed, establishing a balanced formula between distinct energy components for predicting maximum spreading diameter of ferrofluid droplets accurately.

Taste and odor (T&O) are among the most frequently encountered aesthetic issues in drinking water. While fungi have been reported to produce offensive odors, their contribution to T&O in drinking water remains understudied and often overlooked. In this study, the profiles of fungal community and odorants produced by 10 native fungal isolates were investigated in 36 samples collected from two drinking water treatment plants and a premise plumbing system. A total of 17 odorants were identified with Penicillium , Aspergillus , Paecilomyces , and Alternaria genera exhibiting the highest odorant yields. Significant concentrations of musty/earthy compounds were produced by these fungal isolates, such as 2-methylisoborneol (2-MIB) (26-256 ng/L), geosmin (10-13 ng/L), and 2-isobutyl-3-methoxy-pyrazine (IBMP) (3-13 ng/L). The high odor activity value of the odorants primarily occurred within 4 d, while toxicity continued to increase during the 8 d incubation. UV treatment in premise plumbing significantly ( p < 0.05) reduced the gene read counts of Ascomycota phylum, Aspergillus spp., Fusarium spp., Rhizopus spp., and Trichoderma spp., by 2.3-4.0 times. These findings underscore the previously underestimated role of fungi in contributing to T&O issues in drinking water and corresponding risks to consumers and indicate UV as a promising strategy for fungal control in drinking water.

Background: Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients., Methods: In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1., Findings: Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib., Conclusions: Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC., Funding: This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China., Competing Interests: Declaration of interests Q.Z. declares lecture and presentation fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. S.L. declares grants or contracts from AstraZeneca, Hutchison, BMS, Hengrui, BeiGene, Roche, and Hansoh; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison Medipharma, Simcere, Zai Lab, GenomiCare, Yuhan, prlME Oncology, Menarini, InventisBio, and Roche; lecture and presentation fees from AstraZeneca, Roche, Hansoh, and Hengrui Therapeutics; participation on a data safety monitoring board or advisory board for Roche, Regeneron, AstraZeneca, and Xcovery Holdings; and a leadership or fiduciary role in the Chinese Lung Cancer Associate and CSCO. Z. Wang is an employee of Alpha Biopharma (Jiangsu) and declares no stock ownership in the company. M.-J.A. declares consulting fees from AstraZeneca, Amgen, Merck, Takeda, BMS, ONO, Roche, Daiichi-Sankyo, Janssen, Alpha Pharmaceuticals, Yuhan, Arcus Biosciences, Eutilex, and VORONOI and lecture and presentation fees from AstraZeneca, Amgen, Merck, Takeda, BMS, ONO, Roche, Daiichi-Sankyo, Janssen, and Yuhan. Y.-L.W. declares consulting services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; lecture and presentation fees from AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi; and grants or contracts from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, and Roche., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs., Methods: We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al., Results: We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778., Conclusion: The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.

Multi-informant studies are popular in social and behavioral science. However, their data analyses are challenging because data from different informants carry both shared and unique information and are often incomplete. Using Monte Carlo Simulation, the current study compares three approaches that can be used to analyze incomplete multi-informant data when there is a distinction between reference and nonreference informants. These approaches include a two-method measurement model for planned missing data (2MM-PMD), treating nonreference informants' reports as auxiliary variables with the full-information maximum likelihood method or multiple imputation, and listwise deletion. The result suggests that 2MM-PMD, when correctly specified and data are missing at random, has the best overall performance among the examined approaches regarding point estimates, type I error rates, and statistical power. In addition, it is also more robust to data that are not missing at random., (© 2024. The Psychonomic Society, Inc.)

Purpose: Although the validity of the Epworth Sleepiness Scale (ESS) as an effectiveness measure for sleep apnea treatments such as continuous positive airway pressure (CPAP) has been supported by multiple studies, some researchers continue to challenge it. They suggest that in addition to its impact on relieving patients' daytime sleepiness, CPAP also alters the internal standards patients use to evaluate their sleepiness (i.e., response shift; RS), confounding the meaning of the difference in the ESS scores. We believe an issue yet to be addressed in this debate is that all existing evidence of RS has been obtained through the then-test approach, a retrospective method sensitive to various cognitive mechanisms. Thus, in the current study, we re-examined this issue using the structural equation modeling (SEM) approach, a method that can be directly applied to randomized clinical trial (RCT) data without retrospective measures., Methods: With the ESS data from two independent RCTs, we conducted cross-sectional and longitudinal measure invariance tests in SEM to examine whether CPAP would lead to RS., Results: The ESS demonstrated cross-sectional and longitudinal scalar invariance against CPAP treatments. Its factorial pattern, loadings, and thresholds were invariant between the treatment and control groups and pre- and post-treatment, supporting the comparability of the observed mean ESS scores across time and groups., Conclusion: Our results support the validity of the average difference scores of the ESS for quantifying the effectiveness of CPAP on group-level daytime sleepiness in RCTs with relatively large sample sizes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: This nationwide cohort study evaluated the impact of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on patients with type 2 diabetes mellitus (T2DM) after ischaemic stroke (IS), aiming to compare clinical outcomes between SGLT2i-treated patients and those not receiving SGLT2i., Materials and Methods: Utilizing Taiwan's National Health Insurance Research Database, we identified 707 patients with T2DM treated with SGLT2i and 27 514 patients not treated with SGLT2i after an IS, respectively, from 1 May 2016 to 31 December 2019. Propensity score matching was applied to balance baseline characteristics. The follow-up period extended from the index date (3 months after the index acute IS) until the independent occurrence of the study outcomes, 6 months after discontinuation of the index drug, or the end of the study period (31 December 2020), whichever came first., Results: After propensity score matching, compared with the non-SGLT2i group (n = 2813), the SGLT2i group (n = 707) exhibited significantly lower recurrent IS rates (3.605% per year vs. 5.897% per year; hazard ratio: 0.55; 95% confidence interval: 0.34-0.88; p = 0.0131) and a significant reduction in all-cause mortality (5.396% per year vs. 7.489% per year; hazard ratio: 0.58; 95% confidence interval: 0.39-0.85; p = 0.0058). No significant differences were observed in the rates of acute myocardial infarction, cardiovascular death, heart failure hospitalization, or lower limb amputation., Conclusions: Our findings indicate significantly lower risks of recurrent IS and all-cause mortality among patients with T2DM receiving SGLT2i treatment. Further studies are required to validate these results and investigate the underlying mechanisms behind the observed effects., (© 2024 John Wiley & Sons Ltd.)

Background: In patients with locally advanced esophageal cancer who had undergone chemoradiotherapy (CRT), the limitations of radiological evaluation may necessitate surgical exploration to ascertain disease resectability. Upon intraoperative confirmation of T4b disease (sT4b), the optimal management strategy remains unclear. While some surgeons may opt against resection, others advocate for palliative esophagectomy (PE). Regrettably, the current literature does not provide a consensus on the most effective approach for managing these intricate cases., Methods: The study cohort consisted of 68 patients with esophageal squamous cell carcinoma (ESCC) who presented with sT4b disease following CRT. The perioperative outcomes and overall survival (OS) were compared between patients who underwent PE (n = 56) and those who received an open-close (OC) procedure (n = 12)., Results: Patients who underwent an OC procedure experienced a shorter hospital stay (16.5 vs. 28.8 days; p = 0.052) and showed a non-significant reduction in the rate of major complications (33.9% vs. 25%; p = 0.549) and in-hospital mortality (0% vs. 5.4%; p = 0.412) than those who received PE; however, PE was associated with a superior 2-year OS rate than OC (9.6% vs. 0%; p = 0.009). In multivariable analysis, a pretreatment clinical stage of II/III (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.31-0.87; p = 0.013) and PE with retrosternal reconstruction (HR 0.38, 95% CI 0.15-0.49; p = 0.010) were independently associated with a more favorable OS., Conclusion: PE with retrosternal reconstruction may be a feasible approach for patients with ESCC exhibiting sT4b disease after CRT., (© 2024. Society of Surgical Oncology.)

This study investigated the antioxidative characteristics of Zea mays L. purple corn cob and husk extract (PCHE) and its potential protective effects against blue light (BL)-induced damage in N-retinylidene-N-retinylethanolamine (A2E)-accumulated ARPE-19 retinal pigment epithelial cells. PCHE had a 2,2-diphenyl-1-picrylhydrazyl radical-scavenging capacity and Trolox equivalent antioxidant capacity of 1.28±0.43 mM Trolox equivalents (TE)/g and 2,545.41±34.13 mM TE/g, respectively. Total content of anthocyanins, polyphenols, and flavonoids in the PCHE was 11.13±0.10 mg cyanidin-3-glucoside equivalents/100 g, 227.90±7.38 mg gallic acid equivalents/g, and 117.75±2.46 mg catechin equivalents/g, respectively. PCHE suppressed the accumulation of A2E and the photooxidation caused by BL in a dose-dependent manner. After initial treatment with 25 µM/mL A2E and BL, ARPE-19 cells showed increased cell viability following additional treatment with 15 µg/mL PCHE while the expression of the p62 sequestosome 1 decreased, whereas that of heme oxygenase-1 protein increased compared with that in cells without PCHE treatment. This suggests that PCHE may slow the autophagy induced by BL exposure in A2E-accumulated retinal cells and protect them against oxidative stress., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2024 The Korean Society of Food Science and Nutrition.)

Acute lung injury (ALI), a critical complication of COVID-19, is characterized by widespread inflammation and severe pulmonary damage, necessitating intensive care for those affected. Although glucocorticoids (GCs), such as dexamethasone (Dex), have been employed clinically to lower mortality, their nonspecific systemic distribution has led to significant side effects, limiting their use in ALI treatment. In this study, we explored the conjugation of Dex to hyaluronic acid (HA) to achieve targeted delivery to inflamed lung tissues. We achieved a conjugation efficiency exceeding 98 % using a cosolvent system, with subsequent ester bond cleavage releasing the active Dex, as verified by liquid chromatography. Biodistribution and cellular uptake studies indicated the potential of the HA conjugate for cluster of differentiation 44 (CD44)-mediated targeting and accumulation. In a lipopolysaccharide-induced ALI mouse model, intravenous (IV) HA-Dex administration showed superior anti-inflammatory effects compared to free Dex administration. Flow cytometry analysis suggested that the HA conjugate preferentially accumulated in lung macrophages, suggesting the possibility of reducing clinical Dex dosages through this targeted delivery approach., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. T.-Y.C. is from Holy Stone Healthcare Co., Ltd., The company and funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2024. Published by Elsevier B.V.)

Background: Fentanyl and its analogs contribute substantially to drug overdose deaths in the United States. There is concern that people using drugs are being unknowingly exposed to fentanyl, increasing their risk of overdose death. This study examines temporal trends and spatial variations in the co-occurrence of fentanyl with other seized drugs., Methods: We identified fentanyl co-occurrence (the proportion of samples of non-fentanyl substances that also contain fentanyl) among 9 substances or substance classes of interest: methamphetamine, cannabis, cocaine, heroin, club drugs, hallucinogens, and prescription opioids, stimulants, and benzodiazepines. We used serial cross-sectional data on drug reports across 50 states and the District of Columbia from the National Forensic Laboratory Information System, the largest available database on the U.S. illicit drug supply, from January 2013 to December 2023., Findings: We analyzed data from 11,940,207 samples. Fentanyl co-occurrence with all examined substances increased monotonically over time (Mann-Kendall p  < 0.0001). Nationally, fentanyl co-occurrence was highest among heroin samples (approx. 50%), but relatively low among methamphetamine (≤1%), cocaine (≤4%), and other drug samples. However, co-occurrence rates have grown to over 10% for cocaine and methamphetamine in several Northeast states in 2017-2023., Interpretation: Fentanyl co-occurs most commonly with heroin, but its presence in stimulant supplies is increasing in some areas, where it may pose a disproportionately high risk of overdose., Funding: This work was partly supported by FDA grant U01FD00745501. This article reflects the views of the authors and does not represent the views or policies of the FDA or US Department of Health and Human Services., Competing Interests: TYL previously received an ORISE Fellowship from FDA, and has received consulting fees from the Massachusetts General Hospital Institute for Technology Assessment. JP has received consulting fees from FDA, and is a member of the Editorial Board of the International Journal of Drug Policy. LG and RK are employees of FDA. This article reflects the views of the authors and should not be construed to represent the views or policies of the FDA or the US Department of Health and Human Services. The authors declare no further conflicts of interest., (© 2024 The Author(s).)

Mechanomyography (MMG) may be used to quantify very small motor responses resulting from muscle activation, voluntary or involuntary. The purpose of this study was to investigate the MMG mean peak amplitude (MPA) and area under the curve (AUC) and the corresponding mechanical responses following delivery of transcranial magnetic stimulation (TMS) to the knee extensors. Fourteen adults (23 ± 1 years) received single TMS pulses at intensities from 30-80 % maximum stimulator output to elicit muscle responses in the relaxed knee extensors while seated. An accelerometer-based sensor was placed on the rectus femoris (RF) and vastus lateralis (VL) muscle bellies to measure the MMG signal. Pearson correlation revealed a positive linear relationship between MMG MPA and TMS intensity for RF (r=0.569; p<0.001) and VL (r=0.618; p<0.001). TMS intensity of ≥60 % maximum stimulator output produced significantly higher MPA than at 30 % TMS intensity and evoked measurable movement at the knee joint. MMG MPA was positively correlated to AUC (r=0.957 for RF and r=0.603 for VL; both p<0.001) and knee extension angle (r=0.596 for RF and r=0.675 for VL; both p<0.001). In conclusion, MMG captured knee extensor mechanical responses at all TMS intensities with the response increasing with increasing TMS intensity. These findings suggest that MMG can be an additional tool for assessing muscle activation., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: To investigate the correlation of body composition indices with exercise capacity and nutritional status in male chronic obstructive pulmonary disease (COPD) patients. Methods: The clinical data of 90 male COPD patients admitted to the Department of Respiratory and Critical Care Medicine of China-Japan Friendship Hospital from January 2021 to September 2022 were retrospectively collected, and the patients were subjected to a pulmonary function test, body composition measurement, 6-minute walking test distance (6MWD) test, and dominant handgrip strength measurement (HGS). The patients were categorized into COPD Global Initiative for COPD (GOLD) grade 1, 2, 3 and 4 groups according to the severity of lung function. Based on the fat-free mass index (FFMI), patients were categorized into a low FFMI group (FFMI<17 kg/m 2 ) and a normal FFMI group (FFMI≥17 kg/m 2 ). Based on phase angle (PhA), patients were categorized into the low PhA group (PhA<5°) and the normal PhA group (PhA≥5°). Based on 6MWD, patients were divided into impaired endurance group (6MWD<350 m) and normal endurance group (6MWD≥350 m). Differences in body composition indexes, exercise capacity, and nutritional status of patients in different subgroups were compared. A trend test was used to analyze the trend of GOLD grading and body composition indexes. Correlation analysis was used to analyze the correlation of FFMI, PhA, skeletal muscle mass index (SMI), basal metabolic rate (BMR), and visceral fat index (VFI) with 6MWD, HGS, post-diastolic exertional expiratory volume in the first second as a percentage of exertional lung capacity (FEV 1 %pred), and body mass index (BMI). Results: The age of 90 male COPD patients was 66 (59, 71) years. FFMI, PhA, SMI, BMR, VFI, HGS, and 6MWD tended to decrease with increasing GOLD levels (all P <0.05). In the low FFMI group (31 cases), PhA [5.0° (4.7°, 5.1°) vs 5.8° (5.6°, 6.3°)], SMI [6.3 (5.3, 6.9)vs 8.3 (7.7, 9.1) kg/m 2 ], and BMR [(1 294.5±387.2) vs (1 538.7±207.5) kcal(1 kcal=4.184 kJ)], VFI [(10.0±4.2) grades vs (14.2±3.3) grades], 6MWD [(430.5±90.8) vs (537.2±85.5) m], FEV 1 %pred [(37.8±7.9)% vs (73.7±21.5)%], BMI [(20.2±3.8) vs (25.5±2.9) kg/m 2 ] were lower than those in the normal FFMI group (59 cases, all P <0.05). In the low PhA group (23 cases), FFMI [(16.7±2.2) vs (19.5±1.5) kg/m 2 ], SMI [6.6 (5.9, 7.0) vs 7.3 (7.7, 9.0) kg/m 2 ], BMR [(1 251.8±246.2) vs (1 547.5±206.6) kcal], 6MWD [(451.0±47.1) vs (538.3±87.5) m], HGS [(29.6±4.0) vs (36.4±7.2) kg], FEV 1 %pred [(51.2±15.3)% vs (72.9±22.8)%], BMI [(20.9±3.7) vs (25.5±2.8) kg/m 2 ] were lower than those of the normal PhA group (67 cases, all P <0.05). In the impaired endurance group (21 cases) PhA [5.2° (5.1°, 5.3°) vs 5.8° (5.6°, 6.3°)], FEV 1 %pred [(34.2±15.4)% vs (72.7±22.2)%] were lower than those in the normal endurance group (69 cases, all P< 0.05). Correlation analysis showed that FFMI was positively correlated with HGS, FEV 1 %pred, and BMI ( r values of 0.327, 0.235, and 0.782, all P <0.05); PhA was positively correlated with 6MWD, FEV 1 %pred, and BMI ( r values of 0.341, 0.258, and 0.251, all P <0.05); SMI was positively correlated with HGS and BMI ( r values of 0.411 and 0.710, all P <0.05); BMR was positively correlated with 6MWD, HGS, FEV 1 %pred, and BMI ( r values of 0.338, 0.508, 0.285, and 0.676, all P <0.05); VFI was positively correlated with BMI ( r value of 0.791, P <0.001). Conclusions: FFMI is positively correlated with HGS, FEV 1 %pred, and BMI; PhA is positively correlated with 6MWD, FEV 1 %pred, and BMI; SMI is positively correlated with HGS and BMI; BMR is positively correlated with 6MWD, HGS, FEV 1 %pred, and BMI; VFI is positively correlated with BMI. Body composition indexes may reflect the exercise capacity and nutritional status of male COPD patients.

Recently, the high proportion of methicillin-resistant Staphylococcus aureus infections worldwide has highlighted the urgent need for novel antibiotics to combat this crisis. The recent progress in computational techniques for use in health and medicine, especially artificial intelligence (AI), has created new and potential approaches to combat antibiotic-resistant bacteria, such as repurposing existing drugs, optimizing current agents, and designing novel compounds. Halicin was previously used as a diabetic medication, acting as a c-Jun N-terminal protein kinase (JNK) inhibitor, and has recently demonstrated unexpected antibacterial activity. Although previous efforts have highlighted halicin's potential as a promising antibiotic, evidence regarding its effectiveness against clinical strains remains limited, with insufficient proof of its clinical applicability. In this study, we sought to investigate the antibacterial activity of halicin against MRSA clinical strains to validate its clinical applicability, and a C. elegans model infected by MRSA was employed to evaluate the in vivo effect of halicin against MRSA. Our findings revealed the antibacterial activity of halicin against methicillin-resistant S. aureus clinical strains with MICs ranging from 2 to 4 µg/mL. Our study is also the first work to evaluate the in vivo effect of halicin against S. aureus using a C. elegans model, supporting its further development as an antibiotic.

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

Manganese-based materials have tremendous potential to become the next-generation lithium-ion cathode as they are Earth abundant, low cost and stable. Here we show how the mobility of manganese cations can be used to obtain a unique nanosized microstructure in large-particle-sized cathode materials with enhanced electrochemical properties. By combining atomic-resolution scanning transmission electron microscopy, four-dimensional scanning electron nanodiffraction and in situ X-ray diffraction, we show that when a partially delithiated, high-manganese-content, disordered rocksalt cathode is slightly heated, it forms a nanomosaic of partially ordered spinel domains of 3-7 nm in size, which impinge on each other at antiphase boundaries. The short coherence length of these domains removes the detrimental two-phase lithiation reaction present near 3 V in a regular spinel and turns it into a solid solution. This nanodomain structure enables good rate performance and delivers 200 mAh g -1 discharge capacity in a (partially) disordered material with an average primary particle size of ∼5 µm. The work not only expands the synthesis strategies available for developing high-performance Earth-abundant manganese-based cathodes but also offers structural insights into the ability to nanoengineer spinel-like phases., (© 2024. The Author(s).)

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists., (© 2024 Wiley-VCH GmbH.)

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, and reduce cholesterol synthesis. They also have been demonstrated to improve prognosis in patients with various cancers, suggesting a potential anti-cancer effect of statins. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Docetaxel (DOC) is a microtubule-stabilizing agent currently used as a chemotherapeutic drug in several cancers, including lung cancer. Interestingly, the anti-cancer effects of either drug that are related to abnormal or wild-type TP53 gene have been implied. Therefore, the drug sensitivity of DOC and lovastatin in human lung cancer cells was evaluated. We found that H1355 (mutant TP53-E285K), CL1 (mutant TP53-R248W), and H1299 (TP53-null) human non-small cell lung cancer cells were more sensitive to lovastatin than A549 and H460 cells expressing wild-type TP53. Conversely, A549 and H460 cells showed higher sensitivity to DOC than H1299 and CL1 cells, as demonstrated by the MTT assay. When endogenous TP53 activity was inhibited by pifithrin-α in A549 and H460 cells, lovastatin sensitivities significantly increased, and cancer cell viabilities markedly reduced. These results indicate that TP53 status is associated with the anti-cancer effect of statins in human lung cancer cells. Mutated or null TP53 status is correlated with higher statin sensitivity. Furthermore, DOC-resistant H1299 (H1299/D8) cells showed significant sensitivity to lovastatin treatment compared to DOC-resistant A549 (A549/D16) cells, indicating a potential application of statins/chemotherapy combination therapy to control wild-type and abnormal TP53-containing human lung tumors.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentially delay or cause non-union of fractures by inhibiting prostaglandin synthesis. However, studies have shown conflicting results. This systematic review and meta-analysis aim to synthesize current evidence on the potential influence of NSAIDs on bone healing., Methods: We conducted a comprehensive search of PubMed, Embase, and Cochrane CENTRAL databases for studies published up to 25 July 2023. Specific keywords included "NSAID," "nonsteroidal anti-inflammatory drug," "cyclooxygenase-2 inhibitor," "bone healing," "non-union," "pseudoarthrosis," "delayed union," and "atrophic bone." Eligible studies included prospective, retrospective, and case-controlled studies assessing the correlation between NSAID use and bone healing outcomes. The leave-one-out approach was used to test the robustness of the meta-analysis results., Results: A total of 20 studies with 523,240 patients were included in the analysis. The mean patient age ranged from 6.7 to 77.0 years, with follow-up durations from 3 to 67 months. The meta-analysis revealed no significant difference in non-union or delayed union between NSAID users and non-users [pooled adjusted odds ratio (OR) = 1.11; 95% confidence interval (CI): 0.99-1.23]. Initial analysis identified a significant association between NSAID usage and an increased risk of reoperation, but this association became insignificant upon sensitivity analysis (crude OR = 1.42; 95% CI: 0.88-2.28)., Discussion: NSAIDs may have a minimal impact on non-union or delayed union risks. However, caution is advised due to the limited number of studies and the absence of a specific focus on NSAID types and dosages. Further research is necessary to better understand the implications of NSAID use on bone healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chuang, Yang, Tsai and Huang.)

Background: Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer therapy. This study examines the cardiovascular risks of ICIs compared to non-ICI therapies., Methods: Utilizing the Chang Gung Research Database (CGRD) of Taiwan, this retrospective study analyzed 188,225 cancer patients, with 1,737 undergoing ICI treatment from January 1, 2008, to June 30, 2021. Through 1:1 propensity score matching (PSM), we compared specific outcomes between patients treated with ICIs and those who were not. The analysis also accounted for the competing risk of mortality in assessing the results after PSM. The observation period spanned from this index date to whichever came first: the date of the specific outcomes, the last follow-up recorded, or the end date of the study on June 30, 2022., Results: The study found no significant increase in the risk of cardiac death, non-fatal myocardial infarction, heart failure hospitalization, deep vein thrombosis, or pulmonary embolism in patients treated with ICIs as compared to those receiving non-ICI therapy. Interestingly, ICI treatment was linked to a lower risk of non-fatal stroke (0.27% per year vs. 0.46% per year; subdistribution hazard ratio = 0.59; 95% confidence interval = 0.35-0.98; P = 0.0430). Furthermore, subgroup analysis revealed that the ICI group had a decreased risk of cardiac death in patients with cancers other than head and neck cancer, and a reduced risk of stroke among diabetic patients., Conclusions: ICIs do not significantly elevate the risk of cardiovascular events in cancer patients and may lower the stroke risk, underscoring the need for additional prospective studies to clarify these findings., (© 2024. The Author(s).)

Lead-based halide perovskites have gained significant prominence in recent years in optoelectronics and photovoltaics, owing to their exceptional optoelectronic properties. Nonetheless, the toxicity of lead (Pb) and the stability concern pose obstacles to their potential for future large-scale market development. Herein, stable lead-free Cs 3 Bi 2 I 9 (CBI) films are presented with smooth and compact morphologies synthesized via chemical vapor deposition (CVD), demonstrating their application as an UV photodetector in a self-powered way. The self-powered photodetectors (SPDs) exhibit remarkable characteristics, including a responsivity of 1.57 A W -1 and an impressive specific detectivity of 3.38 × 10 13 Jones under the illumination of 365 nm at zero bias. Furthermore, the SPDs exhibit a nominal decline (≈2.2%) in the photocurrent under constant illumination over 500 h, highlighting its impressive long-term operational stability. Finally, the real-time UV-detection capability of the device is demonstrated by measuring the photocurrent under various conditions, including room light and sunlight at different times. These findings offer a new platform for synthesizing stable and high-quality perovskite films, and SPDs for advancing the development of wearable and portable electronics., (© 2024 Wiley‐VCH GmbH.)

Purpose: Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis., Materials and Methods: We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor ( EGFR ) mutations or anaplastic large-cell lymphoma kinase ( ALK ) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK -negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted., Results: Cohort 1: EGFR TKI-pretreated EGFR -mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK -positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK -negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK -negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients., Conclusion: This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Traditionally, the acquisition of 2D materials involved the exfoliation of layered crystals. However, the anisotropic bonding arrangements within 3D crystals indicate they are mechanically reminiscent of 2D counterparts and could also be exfoliated into nanosheets. This report delineates the preparation of 2D nanosheets from six representative 3D metal-organic frameworks (MOFs) through liquid-phase exfoliation. Notably, the cleavage planes of exfoliated nanosheets align perpendicular to the direction of the minimum elastic modulus (E min ) within the pristine 3D frameworks. The findings suggest that the in-plane and out-of-plane bonding forces of the exfoliated nanosheets can be correlated with the maximum elastic modulus (E max ) and E min of the 3D frameworks, respectively. E max influences the ease of cleaving adjacent layers, while E min governs the ability to resist cracking of layers. Hence, a combination of large E max and small E min indicates an efficient exfoliation process, and vice versa. The ratio of E max /E min , denoted as A max/min , is adopted as a universal index to quantify the ease of mechanical exfoliation for 3D MOFs. This ratio, readily accessible through mechanical experiments and computation, serves as a valuable metric for selecting appropriate exfoliation methods to produce surfactant-free 2D nanosheets from various 3D materials., (© 2024 Wiley‐VCH GmbH.)