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Yong-Hong Hu,1,2,* Jia-Wang Wei,1–3,* Hui Chang,1,2,* Wei-Wei Xiao,1,2 Jun-Zhong Lin,1,4 Mu-Yan Cai,1,5 Pei-Qiang Cai,1,6 Ling-Heng Kong,1,4 Gong Chen,1,4 Zhi-Zhong Pan,1,4 Zhi-Fan Zeng,1,2 Pei-Rong Ding,1,4 Yuan-Hong Gao1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Departments of Oncology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China; 4Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 5Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 6Department of Medical Imaging and Interventional Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: In a Phase II clinical trial, we reported the effectiveness and safety of a sandwich neoadjuvant treatment based on a modified oxaliplatin plus capecitabine (XELOX) regimen for locally advanced rectal cancer (LARC). The pathologic complete response (pCR) rate was 42.2%, and no patient presented Grade 4 acute toxicities. This study was performed to evaluate whether the high pCR rate could translate into an improved long-term survival benefit by analyzing the 5-year follow-up results of the trial.Methods: Fifty-one patients with LARC were initially enrolled in the trial. Of these, 2 cases were eliminated due to distant metastasis before treatment. In addition, 4 cases were eliminated for refusing surgery after neoadjuvant chemoradiotherapy (NACRT). Finally, a total of 45 patients were treated with the sandwich NACRT plus total mesorectal excision. We followed up these patients and calculated their overall survival (OS) and disease-free survival (DFS) through a Kaplan–Meier approach. A log-rank test and multivariate survival analysis based on a Cox proportional hazard model were performed to explore the risk factors influencing distant metastasis.Results: The median follow-up time was 60.8 months, and among the 45 patients analyzed, 1 (2.2%) patient suffered local recurrence, and 9 (20.0%) suffered distant metastasis. The 3-year OS and DFS were 95.6% and 84.4%, respectively. In addition, the 5-year OS and DFS were 91.1% and 80.0%, respectively. In the multivariate analysis, postsurgical pathological N stage and carbohydrate antigen 19–9 before treatment maintained statistical significance on distant metastasis.Conclusions: The sandwich NACRT with XELOX regimen might reduce distant metastasis and improve the survival of LARC patients. However, long-term benefits should be verified through further Phase III clinical trials. Keywords: rectal neoplasms, neoadjuvant chemoradiotherapy, locally advanced, neoadjuvant therapy, prognosis

Jiawang Wei,1–3,* Rong Huang,3,* Suping Guo,1,2,* Xuhui Zhang,1,2 Shaoyan Xi,1,4 Qiaoxuan Wang,1,2 Hui Chang,1,2 Xiaohao Wang,1,2 Weiwei Xiao,1,2 Zhifan Zeng,1,2 Yuanhong Gao1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Department of Oncology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China; 4Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: The purpose of this study was to investigate the value of the postsurgical pathological T and N (ypTN) category combined with the American Joint Committee on Cancer-tumor regression grade (AJCC-TRG) in evaluating the prognosis of neoadjuvant chemoradiation therapy (NeoCRT) for locally advanced rectal cancer (LARC) to screen for a subgroup of patients with the worst prognosis. Patients and methods: In total, 265 patients with LARC were enrolled in the trial. All patients received NeoCRT. Total mesorectal excision was performed 6–8 weeks after the completion of radiotherapy. The surgical specimens were re-evaluated based on the AJCC-TRG (seventh edition) and the AJCC-tumor-node-metastasis (TNM; seventh edition) systems. We followed up these patients and calculated their overall survival (OS), disease-free survival (DFS), local recurrence-free survival (RFS), and distant metastasis (DM)-free survival (MFS) rates through the Kaplan–Meier analysis. The logrank test was further applied to evaluate the predictive value of the ypTN stage combined with AJCC-TRG for several survival indexes. Results: The median follow-up period was 65.1 months. The 5-year OS, DFS, RFS, and MFS rates were 79.4%, 68.8%, 94.4%, and 76.5%, respectively. There were significant differences in OS, DFS, and MFS rates among different ypT+AJCC-TRG and ypN+AJCC-TRG subgroups. The 5-year OS, DFS, and MFS rates for ypT3–4+TRG 1 and ypT3–4+TRG2–3 subgroups were 73.9% vs 65.3%, 61.2% vs 52.9%, and 65.0% vs 61.5%, respectively. The 5-year OS, DFS, and MFS rates for ypN1–2+TRG 0–1 and ypN1–2+TRG2–3 subgroups were 64.8% vs 54.1%, 44.9% vs 41.7%, and 61.4% vs 46.3%, respectively. Conclusion: The ypTNM category combined with the AJCC-TRG can more accurately evaluate the prognosis of patients with LARC and identify the subgroup of patients with the worst prognosis and high risk of developing DM, thereby demonstrating clinical significance in guiding individualized postoperative adjuvant therapy and follow-up for LARC. Keywords: ypTNM, NeoCRT, rectal cancer, locally advanced rectal cancer, LARC, AJCC

Objective: This study aimed to analyze the impact of HGF on cardiomyocyte injury, apoptosis, and inflammatory response induced by lipopolysaccharide (LPS)., Methods: Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the levels of HGF, interleukin (IL)-6, IL-10, creatine phosphokinase-isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) in the samples. qPCR and Western blotting (WB) were employed to assess the mRNA and protein expressions of HGF, IL-10, IL-6, PI3K, AKT, p-PI3K, and p-AKT., Results: The outcomes of the in vivo experiment revealed that serum levels of IL-6, IL-10, HGF and SOFA scores in the SC group were elevated in contrast to the non-SC group. The correlation analysis indicated a substantial and positive association among serum HGF, IL-6, and IL-10 levels and SOFA scores. Relative to IL-6, IL-10 levels, and SOFA scores, serum HGF demonstrated the highest diagnostic value for SC. Following LPS administration to stimulate H9c2 cells across various periods (0, 12, 24, 48, and 72 h), the levels of myocardial injury markers (CK-MB and cTnI) in the cell supernatants, intracellular inflammatory factors (mRNA and protein levels of IL-10 and IL-6), apoptosis and ROS levels, exhibited a gradual increase followed by a subsequent decline. Following the overexpression of HGF, there was an increase in cell viability, and a decrease in apoptosis, inflammation, oxidative stress injuries, and the protein phosphorylation expressions of PI3K and AKT. After knockdown of HGF expression, the activity of LPS-induced H9c2 cells was further reduced, leading to increased cell injury, apoptosis, inflammation, oxidative stress,and the expression levels of PI3K and Akt protein phosphorylation were further elevated., Conclusion: HGF was associated with decreased LPS-induced H9c2 apoptosis and inflammation in H9c2 cells, alongside an improvement in cell viability, indicating potential cytoprotective effects. The mechanism underlying these impacts may be ascribed to the suppression of the PI3K/AKT signaling pathway., 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.)

Non-paddy cropping systems play a significant role in food production. However, excessive nitrogen loss from non-paddy soils through nitrate leaching and ammonia volatilization poses a significant challenge to environmental sustainability. In this study, microcosm and field-scale experiments were conducted to explore the potential for using hydrogen peroxide (H 2 O 2 ) to mitigate nitrogen loss and greenhouse gas emissions, aiming at filling gaps in knowledge regarding the underlying biochemical mechanisms. The results show that input of micromolar H 2 O 2 from either artificial addition or natural rainwater into soils in the presence of magnetite (Fe 3 O 4 ) could trigger Fenton-like reaction, which inhibited microbially mediated nitrification of soil-borne ammonium but did not affect the growth of the test crop plant (water spinach). In the absence of Fe 3 O 4 , input of rainwater-borne H 2 O 2 into non-paddy soils caused reduction in the emissions of nitrous oxide (N 2 O) and carbon dioxide (CO 2 ). There was a trend showing that the degree of reduction in N 2 O and CO 2 fluxes increased with increasing concentration of rainwater-borne H 2 O 2 . It was likely that microbially mediated reduction of iron oxides took place during rainfall events, providing Fe(II) that is needed for reaction with rainwater-borne H 2 O 2 , triggering Fenton-like reaction to inhibit the soil microbes that mediate production of N 2 O and CO 2 in the soils. The findings obtained from this study have implications for developing strategies to manage soil‑nitrogen to minimize its environmental impacts., 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: The impact of postoperative sarcopenia on the Textbook Oncological Outcome (TOO) in locally advanced gastric cancer (LAGC) remains uncertain. This study investigates the relationship between sarcopenia and TOO, explores its long-term prognostic value, and develops a prognostic model incorporating sarcopenia and TOO for survival prediction., Methods: We performed a retrospective analysis of clinical and pathological data from patients with LAGC who underwent radical surgery at two Chinese tertiary referral hospitals. Sarcopenia was defined as an SMI < 36.4 cm 2 /m 2 in males and < 28.4 cm 2 /m 2 in females. TOO was defined as the addition of perioperative chemotherapy to the textbook outcomes (TO). A nomogram was developed to predict postoperative overall survival (OS) and recurrence-free survival (RFS) in LAGC patients., Results: The study included 972 patients with LAGC. The overall TOO achievement rate was 67.1%. The TOO achievement rate was significantly higher in patients non-sarcopenia compared to those with sarcopenia (68.9% vs. 61.1%, P = 0.031). Logistic regression revealed that age ≥ 65, high ASA score, and sarcopenia were independent risk factors for TOO failure. Cox regression analysis identified TOO, sarcopenia, tumor size, differentiation, vascular invasion, pT stage, and pN stage as independent predictors of OS and RFS. Nomogram models based on sarcopenia and TOO accurately predicted the 3-year and 5-year OS and RFS., Conclusion: Preoperative sarcopenia was an independent predictor of TOO implementation. A prognostic prediction model that integrates preoperative sarcopenia and TOO, which outperforms the current staging system, can aid clinicians in effectively assessing the prognosis of patients with LAGC., Competing Interests: Declarations Disclosures Qing Zhong, Zi-Fang Zheng, Dong Wu, Zhi-Xin Shang-Guan, Zhi-Yu Liu, Yi-Ming Jiang, Jian-Xian Lin, Jia-Bin Wang, Qi-Yue Chen, Jian-Wei Xie, Wei Lin, Chao-Hui Zheng, Chang-Ming Huang, and Ping Li have no conflicts of interest or financial ties to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intimal hyperplasia (IH) is an innegligible issue for patients undergoing interventional therapy. The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF-BB) are critical events in the development of IH. While the exact mechanism and effective target for IH needs further investigation. Metabolic disorders of arachidonic acid (ARA) are involved in the occurrence and progression of various diseases. In this study, we found that the expressions of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) were significantly increased in the VSMCs during balloon injury-induced IH. Then, we employed a COX-2/sEH dual inhibitor PTUPB to increase the concentration of epoxyeicosatrienoic acids (EETs) while prevent the release of pro-inflammatory prostaglandins. Results showed that PTUPB treatment significantly reduced neointimal thickening induced by balloon injury in rats in vivo and inhibited PDGF-BB-induced proliferation and migration of VSMCs in vitro. Our results showed that PTUPB may reverse the phenotypic transition of VSMCs by inhibiting Pttg1 expression. In conclusion, we found that the dysfunction of ARA metabolism in VSMCs contributes to IH, and the COX-2/sEH dual inhibitor PTUPB attenuates IH progression by reversing the phenotypic switch in VSMC through the Sirt1/Pttg1 pathway., Competing Interests: Declaration of competing interest We would like to submit the enclosed manuscript entitled “Restoration of ARA metabolic disorders in vascular smooth muscle cells alleviates intimal hyperplasia”, which we wish to be considered for publication in “European Journal of Pharmacology”. I would like to declare on behalf of my co-authors that:, (Copyright © 2024 Elsevier B.V. All rights reserved.)

The overuse of pesticides has shown their malpractices. Novel and sustainable formulations have consequently attracted abundant attention but still appear to have drawbacks. Here, we use a maleic anhydride-functionalized cellulose nanocrystals-stabilized Pickering emulsions template to prepare thermo-responsive microcapsules for a pesticide delivery system via radical polymerization with N-isopropyl acrylamide. The microcapsules (MACNCs-g-NIPAM) are characterized by the microscope, SEM, FTIR, XRD, TG-DTG, and DSC techniques. Imidacloprid (IMI) is loaded on MACNCs-g-NIPAM to form smart release systems (IMI@MACNCs-g-NIPAM) with high encapsulation efficiency (~88.49%) and loading capability (~55.02%). The IMI@MACNCs-g-NIPAM present a significant thermo-responsiveness by comparing the release ratios at 35°C and 25°C (76.22% vs 50.78%). It also exhibits advantages in spreadability, retention and flush resistance on the leaf surface compared with the commercial IMI water-dispersible granules (CG). IMI@MACNCs-g-NIPAM also manifest a significant advantage over CG (11.12 mg/L vs 38.90 mg/L for LC 50 ) regarding activity tests of targeted organisms. In addition, IMI@MACNCs-g-NIPAM has shown excellent biocompatibility and low toxicity. All the benefits mentioned above prove the excellent potential of IMI@MACNCs-g-NIPAM as a smart pesticide formulation., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Devising of materials that afforded dual applicability in decontamination and pollutant detection were still a towering challenge owing to the increasing flux of discharge toxic contaminants over the years. Herein, the NiFe 2 O 4 nanoparticles-loaded on cube-like SrTiO 3 (NiFe 2 O 4 /SrTiO 3 ) composite was fabricated by a two-step hydrothermal approach providing remarkable photocatalytic treatment and electrochemical sensing of noxious pollutants in wastewater. The material traits of the fabricated composite were scrutinized by myriad characterization approaches. The NiFe 2 O 4 /SrTiO 3 hybrid material demonstrated high surface area of 19.81 m 2 /g, adequate band gap energy of 2.75 eV, and prominent photoluminescence characteristics. In the presence of visible light, the NiFe 2 O 4 /SrTiO 3 exhibited profound photocatalysis capability to eliminate sewage effluent-bearing chlortetracycline hydrochloride (CTCH) with 88.6% COD removal in 120 min, outperforming other pure materials. Meanwhile, the toxicity examination of effluent, the possible degradation pathway of CTCH and the proposed photocatalysis mechanism were also divulged. More importantly, the glassy carbon electrode was modified with synergized NiFe 2 O 4 /SrTiO 3 (NiFe 2 O 4 /SrTiO 3 -GCE) was adopted for the precise quantification of Hydrazine (Hz). The NiFe 2 O 4 /SrTiO 3 -GCE obeyed first-order response for the Hz detection within the range of 1-10 mM: cyclic voltametric: limit of detection (LOD) of 0.119 μM with sensitivity of 18.9 μA μM -1 cm -2 , and linear sweep voltametric: LOD of 0.222 μM with a sensitivity of 12.05 μA μM -1 cm -2 . The stability and interference of modified electrode were also inspected. This work furnished valuable insights to yield a composite with the prominent S-scheme heterojunction system for quenching of charge carrier recombination and consequently contributing to the future realization into the domains of environmental clean-up and toxic chemical detection., 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 Inc. All rights reserved.)

Background: Insulin resistance is important in hepatocellular carcinoma (HCC) carcinogenesis and progression. The triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio or TyG-body mass index (TyG-BMI) are three non-invasive parameters for insulin resistance. However, their prognostic role in HCC patients undergoing hepatectomy remains unclear., Materials and Methods: HCC patients who underwent hepatectomy at the Meizhou People's Hospital from May 2011 to February 2023 were retrospectively explored. Patients were classified into high and low groups based on different TyG, TG/HDL-c, and TyG-BMI indices. The prognostic role of TyG, TG/HDL-c, and TyG-BMI was evaluated using Kaplan-Meier analysis and Cox regression models. A nomogram incorporating significant prognostic factors was constructed and validated., Results: A lower TyG, lower TG/HDL-c, and lower TyG-BMI were linked to worse overall survival (OS) in HCC patients. Multivariate analysis indicated the TyG index, but not the TG/HDL-c and TyG-BMI index, could independently predict HCC OS. The nomogram incorporating the TNM stage and TyG index demonstrated good calibration, discriminative ability, and clinical benefit for predicting OS in HCC patients., Conclusions: The TyG index could independently predict HCC OS after hepatectomy in this cohort. The nomogram incorporating the TyG index may aid in the prognosis management of HCC., Competing Interests: Declarations Ethics approval and consent to participate The authors are accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted by the Declaration of Helsinki (as revised in 2013). All protocols were approved by the Ethics and Indications Committee of the Meizhou People’s Hospital (2023-C-95). The requirement for informed consent was waived for the retrospective study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The selective photoreduction of CO 2 in aqueous media based on earth-abundant elements only, is today a challenging topic. Here we present the anchoring of discrete molecular catalysts on organic polymeric semiconductors via covalent bonding, generating molecular hybrid materials with well-defined active sites for CO 2 photoreduction, exclusively to CO in purely aqueous media. The molecular catalysts are based on aryl substituted Co phthalocyanines that can be coordinated by dangling pyridyl attached to a polymeric covalent triazine framework that acts as a light absorber. This generates a molecular hybrid material that efficiently and selectively achieves the photoreduction of CO 2 to CO in KHCO 3 aqueous buffer, giving high yields in the range of 22 mmol g -1 (458 μmol g -1 h -1 ) and turnover numbers above 550 in 48 h, with no deactivation and no detectable H 2 . The electron transfer mechanism for the activation of the catalyst is proposed based on the combined results from time-resolved fluorescence spectroscopy, in situ spectroscopies and quantum chemical calculations., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The field of nanomedicine is undergoing a seismic transformations with the rise of nanosimilars, reshaping the pharmaceutical landscape and expanding beyond traditional innovators and generic manufacturers. Nanodrugs are increasingly replacing conventional therapies, offering improved efficacy and safety, while the demand for follow-on products drives market diversification. However, the transition from preclinical to clinical stages presents challenges due to the complex biopharmaceutical behavior of nanodrugs. This review highlights the integration of Quality-by-Design (QbD), in vitro-in vivo correlations (IVIVCs), machine learning, and Model-Informed Drug Development (MIDD) as key strategies to address these complexities. Additionally, it discusses the role of high-throughput processes in the optimization of the nanodrug development pipelines. Covering generations of delivery systems from liposomes to RNA-loaded nanoparticles, this review underscores the evolving market dynamics driven by recent advances in nanomedicine., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The quality of prehospital resuscitation provided by emergency medical technicians (EMTs) is essential to ensure better outcomes following out-of-hospital cardiac arrests (OHCA). We assessed the quality of prehospital resuscitation by recording time to key prehospital interventions using EMT-worn video devices and investigated its association with outcomes of patients with OHCA., Methods: This retrospective, cross-sectional study included cases of non-traumatic OHCA in adults treated by emergency medical services (EMS) in Hsinchu City, Taiwan, during 2022 and 2023. We used data from high-resolution, chest-mounted wearable cameras to define and measure six quality indices (QIs) for prehospital resuscitation interventions (i.e., time spent recognizing OHCA). To evaluate the association between QI performance and sustained return of spontaneous circulation (ROSC), we used multivariable logistic regression., Results: Of 745 patients eligible for this study, 187 (25.1%) achieved sustained ROSC. Six core QIs were analyzed: recognition of OHCA (median time: 9.0 s), time from recognizing OHCA to initiating cardiopulmonary resuscitation (cardiopulmonary resuscitation [CPR]; 9.0 s), automated external defibrillator setup (34.0 s), time from recognizing OHCA to beginning ventilation (160.0 s), advanced airway management (300 s), and deploying a mechanical CPR device (50 s). The performance of the six QIs were not associated with sustained ROSC (Adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.00], 0.99 [0.98-1.00], 1.00 [1.00-1.01], 1.00 [1.00-1.00], 1.00 [1.00-1.00], and 0.99 [0.99-1.00], respectively)., Conclusions: This study describes the rate of sustained ROSC and time to key interventions captured by EMT-worn video devices in non-traumatic OHCA patients. Although we found no direct link between QI performance and improved OHCA outcomes, this study highlights the potential of video-assisted QIs to enhance the documentation and understanding of prehospital resuscitation processes. These findings suggest that further refinement and application of these QIs could support more effective resuscitation strategies and training programs.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity increases risk of cardiovascular disease. This cohort study examines the prognostic value of MASLD, across body weight categories, in a secondary preventative acute myocardial infarction (AMI) cohort., Methods: Patients with AMI were stratified into four phenotypes-obesity MASLD, non-obesity MASLD, obesity non-MASLD, non-obesity non-MASLD. The primary outcome was all-cause mortality. Cox regression analysis was performed to investigate determinants of long-term all-cause mortality., Results: Of 5702 patients, majority were in the non-obesity non-MASLD group (66.7%), followed by obesity MASLD (16.1%), non-obesity MASLD (11.2%) and non-obesity MASLD (6.0%). Across the four phenotypes, obesity MASLD had the highest cardiometabolic burden, followed by non-obesity MASLD. Non-obesity MASLD had the highest risk of heart failure (p = 0.034), cardiogenic shock (p < 0.001), and all-cause long-term mortality (p = 0.019). The non-obesity MASLD (HR 1.400, 95%CI 1.077-1.820, p = 0.012) and obesity MASLD phenotypes (HR 1.222, 95%CI 1.005-1.485, p = 0.044) were independently associated with long-term all-cause mortality., Conclusions: Obesity and non-obesity MASLD phenotypes were predictors of all-cause mortality following AMI, with an even larger magnitude of mortality risk in the non-obesity MASLD group. The recognition of MASLD and its body weight phenotypes will be beneficial in the prognostication following AMI., (© 2024 John Wiley & Sons Ltd.)

Purpose: Three dimensional pulsed continuous arterial spin labeling (3D-pCASL) and incoherent movement within voxels (IVIM) imaging was combined to assess dynamic microscopic structure changes of the hippocampus and temporal lobe white matter (TLWM) of nasopharyngeal carcinoma (NPC) patients post intensity-modulated radiation therapy (IMRT)., Methods: Forty-six patients who were first diagnosed with NPC and underwent IMRT were prospectively enrolled. 3D-CASL and IVIM were performed pre-RT, within 1 week (1 W) post-RT, 3 months (3 M) post-RT, 6 months (6 M) post-RT, and 18 months (18 M) post-RT. Twenty-seven patients completed follow-ups for all time periods, and their data were analyzed. The cerebral flow (CBF) derived from ASL, and apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (F) derived from IVIM of hippocampus and TLWM were analyzed. The quantitative parameters were measured before RT as the baseline, and the corresponding parameter values and change rates at each time point post-RT were compared using the non-parametric Wilcoxon rank sum test., Results: At 1 W post-RT, CBF showed a significant increase and peaked in both the hippocampus and TLWM (p < 0.05) with change rate of 30.3 % and 24.1 %. In the hippocampus, both D and D* were significantly increased from pre-RT to 6 M post-RT with change rate of 6.66 % and 34.7 %, while D*-values remained significantly higher than pre-RT at 12 months post-RT with change rate of 41.2 %. In the TLWM, the F firstly increased and then decreased, and was significantly decreased from pre-RT to 6 M post-RT with change rate of 20.2 %., Conclusion: 3D-PCASL and IVIM can indirectly reflecting the developmental pattern and molecular mechanism of RT induced brain injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: There is limited evidence on the economic burden of depression among the older population in Singapore., Objective: We aim to evaluate the impact of depression on healthcare expenditure and productivity loss among older adults with chronic diseases in Singapore., Methods: Using the data from the Well-being of the Singapore Elderly study (WiSE), a 2011 national representative survey of older adults aged 60 years and above, 2510 respondents were included in this study. The sample comprised 44% male and 56% female respondents with 75% respondents aged between 60 and 74 years old. Healthcare utilisation data was obtained from respondents and healthcare cost was tabulated by multiplying each service unit by the unit cost price. These services include care from polyclinic doctors, private general practitioners (GP), outpatient specialists and inpatient care. We modelled the relationship of healthcare cost and depression using two-part models (probit & generalised linear model - loglink and gamma distribution)., Results: For total healthcare expenditure, older adults with both depression and chronic diseases were associated with an average annual incremental cost of $7940 (95% CI 1490-14400; p = 0.016), compared to those without these conditions. They were also associated with an average incremental cost of $257 (95% CI 38.7-475; p = 0.021) for primary care. Likewise, in the case of specialist outpatient clinics, they had an average incremental cost of $970 (95% CI 163-1780; p = 0.018). However, for inpatient setting, the average incremental cost of $6180 (95% CI 418-12800; p = 0.066) was not significant. Additionally, older adults with depression and chronic diseases contribute to an annual productivity loss of $676 (95% CI 346-1010; p < 0.001)., Discussion: This study provides evidence that there are significant incremental costs associated with depression amongst the older adults with chronic diseases in Singapore's primary healthcare setting. The increased somatic presentations among the depressed older adults and the underdiagnosis of depression in primary care may contribute to higher utilisation of healthcare resources which entail higher expenditure. This is one of the first studies to look at the cost of depression using a representative sample of Singaporean older adults and taking into account the multi-ethnic nature of the population. Analyses were restricted to a cross-sectional design, and data relied heavily on the accuracy of self-report utilisation on health care services which was subjected to recall bias., Conclusion: Depression was found to inflate the total healthcare expenditure among older adults with chronic disease by two-fold. This study provides evidence that there are significant incremental costs associated with depression among the older adults with chronic diseases, demonstrating a need for more resources to improve systematic and clinical care for depressed older adults with chronic diseases., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the National University of Singapore Institutional Review Board (IRB), National Healthcare Group Domain Specific Review Board and Singhealth Centralised IRB. Written informed consent was obtained from respondents in the WiSE study. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Coherent quantum control at high temperatures is important for expanding the quantum world and is useful for applying quantum technologies to realistic environments. Quantum control of spins in diamond has been demonstrated near 1000 K, with the spins polarized and read out at room temperature and controlled at elevated temperatures by rapid heating and cooling. Further increase of the working temperature is challenging due to fast spin relaxation in comparison with the heating and cooling rates. Here we significantly improve the heating and cooling rates by using reduced graphene oxide as the laser absorber and heat drain and hence realize coherent quantum operation at up to 1400 K, which is higher than the Curie temperatures of all known materials. This work facilitates the use of diamond sensors to study a wide range of magnetic effects in the high-temperature regime, such as thermoremanent magnetism and magnetic shape memory effects.

Given the limited head-to-head comparison of cardiovascular and renal outcomes between liraglutide and dulaglutide, our study aimed to investigate the clinical outcomes between dulaglutide and liraglutide in a real-world setting. In this new-user design, comparative and retrospective cohort study, patients with type 2 diabetes mellitus with prescription for GLP-1RAs from January 1, 2016 to December 31, 2022 (n = 8,278) were included. Primary outcome was composite cardiovascular outcomes which was composed of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke. The composite renal outcome was also interested, including new macroalbuminuria, doubling of serum creatinine, worsening of estimated glomerular filtration rate (eGFR), and progression to dialysis. A total of 3,210 subjects receiving liraglutide and 5,068 subjects receiving dulaglutide were identified. In the adjusted cohort by applying inverse probability of treatment weighting, the incidence of composite cardiovascular outcomes was 18.4 and 18.7 events per 1000 person-years in the liraglutide and dulaglutide groups, respectively. The risk of cardiovascular outcomes did not significantly differ between groups (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.85-1.15). Moreover, the risk of composite renal outcomes was also comparable between groups (subdistribution HR 1.07, 95% CI 0.995-1.16). Liraglutide and dulaglutide demonstrated comparable cardiovascular and renal outcomes in a real-world setting., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: This study aimed to explore the risk factors of microvascular obstruction (MVO) after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI)., Materials and Methods: A retrospective analysis was performed on 165 patients with STEMI who successfully underwent emergency PCI and completed cardiac magnetic resonance (CMR) within 1 week after PCI. Total ischemia time (symptom onset to wire, S2W), first medical contact to wire (FMC2W), and door to wire (D2W) were compared with the recommended critical time nodes for STEMI treatment. Left ventricular function was evaluated by CMR cine, and myocardial infarction characteristics and MVO were evaluated by late-gadolinium enhancement (LGE). Binary logistic regression analysis was used to evaluate the effect of delay in treatment of STEMI on the occurrence of MVO after PCI., Results: In this study, 89 (53.9%) patients with STEMI presented with MVO after emergency PCI. The FMC2W time and S2W time in the MVO (+) group were significantly longer than those in the MVO (-) group (P<0.05). Compared with the MVO (-) group, the MVO (+) group had larger myocardial infarction size (IS) and lower left ventricular ejection fraction (LVEF) (P<0.05). Patients with FMC2W time >120min and S2W time >300min had greater myocardial IS and MVO than the FMC2W ≤120min and S2W time ≤300min group, respectively. Logistic regression analysis showed that S2W time >300min (P=0.039, OR=2.756, 95% CI=1.053-7.213) was an independent predictor of MVO after PCI in patients with STEMI., Conclusion: Shortening the total time of myocardial ischemia and increasing the proportion of early reperfusion therapy can prevent or reduce MVO after PCI., (Copyright © 2024 Hellenic Society of Cardiology. Publishing services by Elsevier Inc. All rights reserved.)

Photoelectrochemical devices require solid anodes and cathodes for the easy assembling of the whole cell and thus redox catalysts need to be deposited on the electrodes. Typical catalyst deposition involves drop casting, spin coating, doctor blading or related techniques to generate modified electrodes where the active catalyst in contact with the electrolyte is only a very small fraction of the deposited mass. We have developed a methodology where the redox catalyst is deposited at the electrode based on supramolecular interactions, namely CH-π and π-π between the catalyst and the surface. This generates a very well-defined catalysts-surface structure and electroactivity, together with a very large catalytic response. This approach represents a new anchoring strategy that can be applied to catalytic redox reactions in heterogeneous phase and compared to traditional methods involves about 4-5 orders of magnitude less mass deposition to achieve comparable activity and with very well-behaved electroactivity and stability., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Introduction: Aspartame is a nonnutritive sweetener (NSS), which is widely used in foods and beverages worldwide. The safety of aspartame, a commonly used artificial sweetener, has been debated. Here, we investigated the potential effects and underlying mechanisms of aspartame consumption during pregnancy on placental dysfunction and birth outcomes., Methods: Female Sprague Dawley rats were exposed to a low (30 mg/kg) or high (60 mg/kg) dose of aspartame before and during pregnancy; moreover, we assessed placental histopathological structure, oxidative stress markers, and mitochondrial function. In addition, we explored how aspartame affects birth weight in a human maternal-infant cohort., Results: In animal study revealed that aspartame treatment of female rats for 14 weeks (12 week before pregnancy and 18 days of gestation) causes a significant reduction in the number and weight of fetuses, as well as damage to placental structure. These effects are linked to increased oxidative stress in the placenta, possibly damaging placental trophoblasts, impairing mitochondrial function, and initiating a compensatory mitochondrial biosynthesis mechanism. In the human pregnant cohort revealed that aspartame reduces birth weight considerably., Discussion: These findings suggested the potential risks associated with aspartame consumption during pregnancy. Therefore, the safety of aspartame, particularly in pregnant individuals, should be reconsidered; specifically, tailored, acceptable daily intake guidelines should be developed for aspartame in different populations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yang Ching Chen and Rong Hung Hsieh report financial support was provided by National Science and Technology Council., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BK channels are expressed in mouse cochlear inner hair cells (IHCs) and exhibit Ca 2+ -independent activation at negative potentials. However, the mechanism underlying Ca 2+ -independent activation of the BK channels in mouse IHCs remains unknown. In this study, we found the BK channel expressed in IHCs contains both the STREX-2 (stress axis regulated exon) variant and an alternative splice of exon9 (alt9), which significantly shift the voltage dependence of the BK channels when co-expressed with LRRC52 in 0 [Ca 2+ ] i . Furthermore, we discovered that mechanical force also induces negative shifts in the voltage dependence of IHC-expressed BK channels. Thus, we propose that the additive effects of mechanical force, special isoforms, and LRRC52 co-expression on voltage dependence shifts may account for the Ca 2+ -independent activation of the BK channel in IHC. Additionally, we found that the IHCs-specific deletion of the BK channels causes hearing damage in mice. Our study suggests a mechanism for Ca 2+ -independent activation in IHCs and highlights the crucial role of the BK channel in auditory perception., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pinellia ternata (Thunb.) Makino is a perennial herb of the genus Pinellia in the Araceae family, which is a kind of precious Chinese herbal medicine (Bai et al. 2022). In May 2023, rotting was observed on P. ternata corm in the Tanghe planting base (3.33 ha, 32º46´6˝N, 113º 8´47˝E, 138 m), with an incidence of approximately 10%. To identify the causal agent, five rotten corms were randomly sampled from the Tanghe planting base. Symptomatic corm tissues were cut into small pieces (3 mm3) with asymptomatic tissue margins, disinfected in 75% ethanol for 30s and in 2% sodium hypochlorite for 3 min, rinsed three times with sterile distilled water, and then placed on synthetic nutrient-poor agar (SNA) plates incubated at 20℃ with a 12 h light/dark photoperiod. Hyphal-tips from the growing edge of colonies were transferred to fresh SNA to obtain pure cultures. In total, five pure isolates were obtained with similar colony morphology and white (top view) or grayish white (back view) coloration, with villous surfaces and abundant aerial hyphae. On SNA, the isolates mainly produced microconidia. Microconidia were ellipsoidal to cylindrical, thin-walled, smooth, hyaline and measured 5.40 to 11.98 (av. 7.14) µm long and 1.60 to 5.38 (av. 2.54) µm thick (n=50). Based on these morphological characteristics of colony and conidia, the causal agent was preliminarily identified as Fusarium sp. (Crous et al. 2021). To confirm pathogen identity, the total genomic DNA of 2 isolates (BX-2 and BX-3) was extracted using the 2×T5 Direct PCR kit (Beijing Tsingke Biotech Co., Ltd, Beijing, China). The internal transcribed spacer (ITS), RNA polymerase II second largest subunit (rpb2), translation elongation factor 1-alpha (tef1), and β-tubulin (tub2) gene were PCR-amplified using the universal primers ITS1/ITS4, 5f2/7cr, EF-1/EF-2 and BT2F/BT4R (Crous et al. 2021), respectively. Sequences have been deposited in GenBank (PP125560-PP125561 for ITS, PP782474-PP782475 for rpb2, PP782476-PP782477 for tef1, PP171436-PP171437 for tub2). BLAST search showed that all sequences were 99% to 100% homology with the corresponding sequences of Fusarium proliferatum (CBS 182.32). A phylogenetic tree was constructed based on the Maximum-Likelihood method in MEGA-X (Kumar et al. 2018) and revealed that the two isolates were closest to F. proliferatum. The pathogenicity tests were conducted with the two isolates (BX-2 and BX-3) as described by Liu et al. (2022) with slight modifications. For each treatment, five healthy P. ternata corms were inoculated with 1ml of conidial suspension (1×107 conidia/ml). Control plants (n=5) were inoculated with sterilized water. All samples were covered with plastic bags and maintained at a relative humidity greater than 90% in a greenhouse at 20℃ with a 12 h light/dark photoperiod. After 15 days, inoculated corms showed similar symptoms to those on the original diseased plants, while control plants remained symptomless. F. proliferatum was successfully reisolated from the inoculated plants and identified based on its morphological characteristics. Thus, Koch's postulates were fulfilled. The experiment was repeated thrice with similar results. Morphological characteristics, sequence alignment and Koch's postulates test confirmed that F. proliferatum was the cause of P. ternata corm rot disease. To our knowledge, this is the first report of F. proliferatum causing P. ternata corm rot in Henan province, China. Our findings are important for informed surveillance of the disease.

Precise synthesis of carboxylic acids via catalytic carboxylation with CO2 is highly appealing. Although considerable advancements have been achieved in difunctionalizing carboxylation of unsaturated hydrocarbons, the asymmetric variants are conspicuously underdeveloped, particularly in addressing axially chiral alkenes. Herein, we report the first catalytic atroposelective carboxylation of alkynes with CO2. A variety of valuable axially chiral carboxylic acids are obtained with good yields and high chemo-, regio-, E/Z and enantio-selectivities. Notably, an unexpected anti-selective carbo-carboxylation is observed in the sp2-hybrid carbo-electrophile-initiated reductive carboxylation of alkynes. Mechanistic studies including DFT calculation elucidate the origin of chiral induction and anti-selectivity in vinyl-carboxylation of alkynes., (© 2024 Wiley‐VCH GmbH.)

Non-line-of-sight (NLOS) imaging aims at recovering the shape and albedo of hidden objects. Despite recent advances, real-time video of complex and dynamic scenes remains a major challenge owing to the weak signal of multiply scattered light. Here we propose and demonstrate a framework of spectrum filtering and motion compensation to realize high-quality NLOS video for room-sized scenes. Spectrum filtering leverages a wave-based model for denoising and deblurring in the frequency domain, enabling computational image reconstruction with a small number of sampling points. Motion compensation tailored with an interleaved scanning scheme can compute high-resolution live video during the acquisition of low-quality image sequences. Together, we demonstrate live NLOS videos at 4 fps for a variety of dynamic real-life scenes. The results mark a substantial stride toward real-time, large-scale and low-power NLOS imaging and sensing applications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The carbon-neutral target presents a significant challenge for the sewage sludge treatment and disposal (SSTD) industry, necessitating strategic planning for a low-carbon transition. However, flexible and comprehensive carbon emission analysis tools to support this goal remain lacking. This study presents a carbon emission analysis tool to evaluate the carbon emission characteristics and future mitigation potentials of SSTD. The tool integrates life cycle inventory (LCI) modeling-based analysis, sensitivity analysis, regression analysis, and scenario analysis. Carbon emissions are dynamically calculated based on sludge properties, technological level, and industry external parameters, providing a foundation for adaptable evaluation tailored to local conditions. The framework considers the potential effects of multi-parameter and multi-aspect changes in scene design, both within and outside the industry, to achieve dynamic and comprehensive simulations. A case study conducted in Wuhan, China, demonstrated the usability and application processes of the framework. The results indicated that carbon emissions from SSTD are projected to more than double from 2021 to 2060 without interventions. Among the mitigation measures, energy and chemical savings would yield the largest reduction potential, followed by the technical layout adjustment and the promotion of energy efficiency. Operational optimization in the sludge industry and outside the industry would contribute the least. With all mitigation measures applied, emissions could decrease to -82.91 kt CO 2-eq in 2060, equivalent to 13.03% compensation for emissions from the sewage treatment line. Among all the processes, incineration routes are recommended due to their current and future low carbon emissions. The cooperative resource route of anaerobic digestion and land use also shows promise as it progressively demonstrates superior performance with increasing organic matter and nutrient content of sludge. Critical factors, sub-processes, and emission types for different routes were identified and can be optimized accordingly. The developed method demonstrates sufficient flexibility to be applied to other cities and larger-scale regions, thereby offering technical and strategic support for SSTD towards carbon-neutral operation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In this study, a new lightweight Al-Ti-Ta alloy was developed through a synergistic approach, combining CALPHAD methodology and entropy-driven design. Following compositional optimization, the Al 87.5 Ti 6.25 Ta 6.25 (at.%) alloy was fabricated and isothermally heat-treated at 475 °C for 24 h to attain equilibrium. X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) analyses revealed a dual-phase microstructure comprising a 50 vol.% FCC matrix enriched in Al and 50 vol.% Al 3 (Ti,Ta)-type intermetallic phase (IP). Notably, the FCC phase exhibited a high-melting transition temperature of 660 °C, surpassing conventional Al-Si cast alloys. Phase-specific nanomechanical properties were evaluated using Nanoindentation. Microindentation tests demonstrated exceptional microhardness of approximately 3300 MPa. These results indicate the alloy's superior hardness compared to conventional alloys such as Al-Si (A390), 7075 Al alloy, and CP-Ti, even exceeding Ti-64 alloy at a 15% lower density. The alloy's stability under prolonged heat treatment at 475 °C, reflected by stable phases, microstructure, and mechanical properties, highlights its enhanced thermal stability, which can be attributed to entropy-driven phase stabilization. This study underscores the effectiveness of integrating entropy-driven design strategy with CALPHAD predictions for the accelerated development of advanced Al-based alloys.

Previous studies have shown oviposition deterring properties of 8 coconut free fatty acid (CFFA) compounds on fruit flies with different key deterrent components for different species. Here we evaluated oviposition deterrence of CFFA using laboratory 2-choice bioassays against Zeugodacus cucurbitae, determined key-bioactive deterrent compounds, and evaluated their behavioral mode. Unlike other reported fruit fly species, CFFA mixture increased Z. cucurbitae oviposition when directly applied on an oviposition substrate. When tested individually in subsequent tests, 4 compounds (caprylic, capric, oleic, and linoleic acids) significantly reduced the oviposition ("negative-compounds"), 1 compound (stearic acid) had no effect ("neutral-compound"), and 3 compounds (lauric, myristic, and palmitic acids) stimulated the oviposition ("positive-compounds"). The 4-component negative-compound blend was effective at reducing oviposition. However, adding stearic acid to the 4-component blend (5-component blend, 5c) further reduced oviposition. Adding any of the positive-compounds to the 5c resulted in loss of oviposition deterrence, suggesting the 5c as the key deterrent component blend. The blend was also effective in no-choice assays and when applied on cucumbers, a preferred host of Z. cucurbitae. When given a choice, Z. cucurbitae made 48.5% fewer visits, spent 39% less time, and oviposited 88.2% fewer eggs per min on 5c treated pumpkin agar than on control agar, suggesting that the 5c blend has both spatial repellency and contact deterrence. Given that all compounds are registered food additives and generally regarded as safe, this blend has potential application in behavioral control strategies, such as push-pull, to protect host fruit against Z. cucurbitae., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

Chemical elements support various plant functions, and their reutilization is important for plant ecological adaptation. However, there is a lack of studies comparing the elemental concentration and their reutilization in floral petals and leaves of the same plant. To address this research gap, we conducted a comparative study across 38 plant species with diverse life forms in a common garden. Our investigation focused on the nutrient concentration of 10 elements in both petals and leaves and functional traits, including flower lifespan, dry mass per unit area, water concentration, and vein density. We have found that the elements of nitrogen (N), calcium (Ca), magnesium (Mg), iron (Fe), and manganese (Mn) were more abundant in leaves. In contrast, petals contained higher concentrations of phosphorus (P) and potassium (K). N, P, K, Ca, Mg, and sodium (Na) concentrations of petals were positively related to leaves. In herbaceous plants, their petals showed significant resorption of P and K, while N, P, and K were detected with significant resorption in leaves from all life forms. A positive correlation was found between the resorption of P in leaves and petals. From the perspective of the carbon economic spectrum, N and P showed a negative correlation with dry mass per unit area in leaves. Meanwhile, petal dry mass per area and floral longevity were significantly negatively correlated with P. Our findings elucidate the nutritional basis for the functional differentiation between petals and leaves., (© 2024 Scandinavian Plant Physiology Society.)

Objective: Comparing direct oral anticoagulants (DOACs) and warfarin's efficacy and safety in patients with nonvalvular atrial fibrillation (AF) and liver cirrhosis (LC)., Background: Evidence of the pharmacodynamics of DOACs is limited in patients with AF and LC., Methods: A retrospective cohort study was conducted in the largest hospital system in Taiwan, involving patients with AF and LC for the years 2012 to 2021. Hazards of thromboembolic events (ischemic stroke, transient ischemic attack, and systemic embolism), intracranial hemorrhage, gastrointestinal, major bleeding, and all-cause mortality were investigated with a new-user, active comparator design. Inverse probability of treatment weighting was applied to balance potential confounders between treatment groups., Results: In total, 478 DOAC users and 247 warfarin users were included. DOACs and warfarin demonstrated similar trends in preventing thromboembolic events, namely ischemic stroke [adjusted hazard ratio (aHR), 1.05 (95% CI: 0.42-2.61)], transient ischemic attack [aHR, 1.36 (95% CI: 0.18-10.31)], and systemic embolism [aHR, 0.49 (95% CI: 0.14-1.70)]. DOAC use was associated with a similar risk of intracranial hemorrhage [aHR, 0.65 (95% CI: 0.26-1.59)] and gastrointestinal bleeding [aHR, 0.64 (95% CI: 0.39-1.03)], a decreased risk of major bleeding [aHR, 0.64 (95% CI: 0.42-0.99)], and a reduction in mortality [aHR, 0.73 (95% CI: 0.54-0.99)]. DOAC users exhibited a significant reduction in major bleeding risk in patients with Child-Pugh class A (aHR, 0.48; 95% CI: 0.33-0.70)., Conclusions: DOACs showed potential safety advantages over warfarin for patients with nonvalvular AF and LC, particularly in reducing major bleeding risk in those with Child-Pugh class A., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Osteoporotic bone defects refer to the disruption of bone structural integrity in patients with osteoporosis and pose a substantial challenge to orthopedic surgeons. In this study, we developed a biomimetic hydrogel to improve the osteogenic microenvironment and promote stem cell homing. This hydrogel served as a container for S-nitrosoglutathione and Ca 2+ , promoting the release of bioactive nitric oxide (NO) from bone marrow mesenchymal stem cells (BMSCs) and human vascular endothelial cells and activating the NO/cyclic guanosine monophosphate signaling pathway. These changes promote osteogenic and angiogenic couplings. The hydrogel simultaneously recruited BMSCs by conjugating the stem cell homing peptide SKPPGTSS. Using a rat distal femoral defect model, it was demonstrated that this hydrogel can effectively increase the formation of bone tissue and new blood vessels and has immune-regulating functions. We envision that this hydrogel may be a minimally invasive yet highly effective strategy for expediting the healing of osteoporotic bone defects.

Aim: Bipolar disorder (BD) and major depression have been associated with an increased risk of developing Parkinson's disease (PD); however, few studies have directly compared the risk of PD development between patients with BD and major depression while considering relevant risk factors and psychotropic medications., Methods: Using the Taiwan National Health Insurance Research Database, 21,186 patients with BD, 21,188 patients with major depression, and 42,374 controls were enrolled between 2001 and 2009, and followed until the end of 2011. Individuals who developed PD during the follow-up period were identified. Cox regression models were used to analyze the hazard ratio (HR) of developing PD, adjusting for demographic factors, comorbidities, and psychotropic medication usage., Results: Both patients with BD [HR 8.63, 95% confidence interval (CI) 6.35-11.72] and those with major depression (HR 5.68, 95% CI 4.15-7.78) had an elevated risk of subsequent PD compared to the controls. Patients with BD were associated with a 51% increased risk of subsequent PD compared with patients with major depression. Long-term treatment with antiepileptic mood stabilizers was associated with increased PD risk among patients with late-onset BD and high Charlson comorbidity index scores. Lithium was not associated with an increased PD risk., Conclusions: The study highlights an elevated PD risk in patients with BD and major depression compared to the controls, with BD patients at highest risk. Further research is needed to elucidate the complex interplay between psychotropic medications and neurodegenerative processes in BD, aiming to optimize therapeutic strategies and improve patient outcomes., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Calcineurin is a serine/threonine protein phosphatase that is highly conserved from yeast to human and plays a critical role in many physiological processes. Regulators of calcineurin (RCANs) are a family of endogenous calcineurin regulators, which are capable of inhibiting the catalytic activity of calcineurin in vivo and in vitro. In this study, we first characterized the biochemical properties of yeast calcineurin and its endogenous regulator Rcn1, a yeast homolog of RCAN1. Our data show that Rcn1 inhibits yeast calcineurin toward pNPP substrate with a noncompetitive mode; and Rcn1 binds cooperatively to yeast calcineurin through multiple low-affinity interactions at several docking regions. Next, we reinvestigated the mechanism underlying the inhibition of mammalian calcineurin by RCAN1 using a combination of biochemical, biophysical, and computational methods. In contrast to previous observations, RCAN1 noncompetitively inhibits calcineurin phosphatase activity toward both pNPP and phospho-RII peptide substrates by targeting the enzyme active site in part. Re-analysis of previously reported kinetic data reveals that the RCAN1 concentrations used were too low to distinguish between the inhibition mechanisms [Chan B et al. (2005) Proc Natl Acad Sci USA 102, 13075]. The results presented in this study provide new insights into the interaction between calcineurin and RCAN1/Rcn1., (© 2024 Federation of European Biochemical Societies.)

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

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

Background: While single-incision laparoscopic cholecystectomy (SILC) has gained more popularity in recent years, its application to elderly patients needs further evaluation. Few SILC studies regarded this rapidly growing vulnerable population, and single-incision laparoscopic common bile duct exploration (SILCBDE) was never mentioned. We conducted an observational study of 146 routine SILCBDE to address this issue., Methods: One hundred forty-six consecutive patients underwent SILCBDE with concomitant cholecystectomies during a period of 6 years (July 2012-June 2016 and July 2018-July 2020). Forty patients with an age of 65 years or older were the study target. Characteristics and operative outcomes were compared with the remaining 106 younger patients by retrospective chart review. The primary outcomes include complications and mortality, while the secondary outcomes contain intraoperative blood loss, operative time, procedural conversions, postoperative length of hospital stay, and bile duct stone recurrence., Results: There was no mortality. The bile duct stone clearance rate was 98.6%. The elderly group had higher American Society of Anesthesiologists (ASA) scores, higher comorbidity rate, higher acute cholangitis rate, lower completion intraoperative cholangiography (IOC) rate, longer operative time, more blood loss, longer postoperative hospital stay (p < .001), longer total hospital stay (p < .001), higher procedural conversion rate (p < .05), higher complication rate (p < .001), and the exclusive open conversion (2.5%). The difference in complications derived from Clavien-Dindo grade I., Conclusion: Routine SILCBDE with concomitant cholecystectomy by experienced surgeons is safe and efficacious for elderly patients as for younger patients. Randomized controlled trials are anticipated., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Integrated fixed-film activated sludge (IFAS) system, an improvement of the activated sludge process, combines the advantages of both attached sludge (AS) and suspended sludge (SS). This study aimed to fully decipher the roles of AS and SS in simultaneous N and P removal in an IFAS system through metagenomic analysis. It was found that AS contributed about 84.04%, 97%, and 95.12% to exogenous NO 3 - -N reduction, endogenous NO 3 - -N reduction, and endogenous NO 2 - -N reduction, respectively. Compared with AS, SS exhibited a greater contribution to anaerobic P release (69.06%) and aerobic P uptake (73.48%). Nitrate and nitrite reductase enzymes showed higher activities in AS, while the activities of exopolyphosphatase and alkaline phosphatase D were more active in SS. P content further indicated that in AS, only a small amount of P was stored in EPS, with most presented intracellularly. In SS, the amount of P stored in EPS was found to be higher. Metagenomic analysis revealed genes related to the synthesis and degradation of endogenous carbon were higher in AS, whereas the TCA cycle exhibited higher activity in SS. P removal-related genes (such as ppk2, ppx, and adk) was significantly higher in SS than in AS. The alteration of genes associated with nitrogen metabolism suggested that the microbes in AS had a higher capacity for nitrification and denitrification. In summary, the discrepancy in the roles of AS and SS in N and P removal in IFAS can be attributed to variations in enzyme activity, P storage in EPS, microbial community composition, and functional gene abundance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Ever since their introduction a decade ago, stable introns, a type of noncoding (nc)RNAs, are found to be key players in different important cellular processes acting through regulation of gene expression and feedback loops to maintain cellular homeostasis. Despite being commonly regarded as useless byproducts, recent studies in yeast suggested that stable introns are essential for cell survivability under starvation. In Drosophila, we found that a stable intron, sisR-1, has a direct effect in regulating mitochondrial dynamics during short-term fasting and subsequently improved overall oocyte quality. We speculated that the beneficial effects implicated by sisR-1 is through the activation of mitohormesis, an interesting phenomenon in mitochondrial biology. Mitohormesis is suggested to improve health span and lifespan of cells and organisms, but the involvement of ncRNAs is not well-documented. Here, we discuss the potential role of sisR-1 and other ncRNAs in activating mitohormesis and the possible applications in improving cellular and organismal health., (© 2024 Wiley Periodicals LLC.)

In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion., (© 2024. The Author(s).)

Aim: Evidence suggests an association between maternal hypothyroidism and risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) in offspring. We examined the risk of ASD and ADHD in individuals with congenital hypothyroidism (CHT)., Methods: A nationwide population-based cohort study enrolled a total of 1260 children younger than 12 years with a confirmed diagnosis of CHT and no prior diagnosis of any neurodevelopmental disorders, selected from the National Health Insurance Research Database of Taiwan between 1998 to 2013. In addition, 12,600 controls matched for sex, age, and residence were selected. Cox proportional hazards analysis was used to investigate the association among CHT, ASD, and ADHD., Results: Children with CHT were associated with a higher incidence of ASD (7.1‰ vs 1.3‰, P < 0.001) and ADHD (39.7‰ vs 18.7‰, P < 0.001) than the control group. Cox regression analyses demonstrated that children with CHT were associated with elevated risks of ASD (hazard ratio [HR], 4.72 [95% confidence interval (CI), 2.08-10.70]) and ADHD (HR, 2.03 [95% CI, 1.49-2.77]), after adjusting for demographic data and family history of major psychiatric disorders, compared with the control group., Conclusion: Children with CHT were associated with approximately a two-fold increased risk of ADHD and a four-fold increased risk of ASD than the control group. Our study highlights the need for future research to elucidate the potential pathophysiology among CHD, ASD, and ADHD., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)

Soil nitrogen (N) significantly influences the interaction between plants and pathogens, yet its impact on host defenses and pathogen strategies via alterations in plant metabolism remains unclear. Through metabolic and genetic studies, this research demonstrates that high-N-input exacerbates tomato bacterial wilt by altering γ-aminobutyric acid (GABA) metabolism of host plants. Under high-N conditions, the nitrate sensor NIN-like protein 7 (SlNLP7) promotes the glutamate decarboxylase 2/4 (SlGAD2/4) transcription and GABA synthesis by directly binding to the promoters of SlGAD2/4. The tomato plants with enhanced GABA levels showed stronger immune responses but remained susceptible to Ralstonia solanacearum. This led to the discovery that GABA produced by the host actually heightens the pathogen's virulence. We identified the R. solanacearum LysR-type transcriptional regulator OxyR protein, which senses host-derived GABA and, upon interaction, triggers a response involving protein dimerization that enhances the pathogen's oxidative stress tolerance by activating the expression of catalase (katE/katGa). These findings reveal GABA's dual role in activating host immunity and enhancing pathogen tolerance to oxidative stress, highlighting the complex relationship between tomato plants and R. solanacearum, influenced by soil N status., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)