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To understand the adaptation of water use strategy of plant community to habitat heterogeneity, we measured the δD and δ18O values of xylem water of shrubs and potential water sources (soil water in different layers or groundwater) of Ammopiptanthus mongolicus communities on sand dune and Gobi from April to September in 2021 in the Ulan Buh Desert. Employing the MixSIAR model, we examined the seasonal dynamics of water source of each shrub by quantifying the contribution of different potential water sources. The results showed that A. mongolicus and Artemisia xerophytica on sand dune mainly used soil water of 10-25 cm in April and May after heavy rain in early spring, whereas Artemisia ordosica mainly used soil water of 10-200 cm. During the drought event within summer from June to August, A. mongolicus increasingly used soil water of 100-200 cm and groundwater, but A. xerophytica and A. ordosica increased the usage of 50-200 cm soil water. After the moderate rain in September, A. mongolicus evenly used soil water in all layers and groundwater, whereas two Artemisia shrubs preferred soil water of 10-50 cm. On Gobi, A. mongolicus and Nitraria sphaerocarpa evenly used soil water in all layers in April and May, mainly used 50-150 cm soil water from June to August and used 10-50 cm soil water in September. Convolvulus tragacanthoides mainly used soil water of 10-50 cm (from April to May), 25-150 cm (from June to August), and 10-25 cm (in September), separately. There were seasonal differences in water use of three shrubs on sand dune and Gobi A. mongolicus communities. During drought, A. mongolicus on sand dune could use deep soil water and groundwater, and that on Gobi relied only on deep soil water, which was more sensitive to rainfall.

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Functional near-infrared spectroscopy was used to record spontaneous hemodynamic fluctuations form the bilateral temporal lobes in 25 children with autism spectrum disorder (ASD) and 22 typically developing (TD) children. The coupling between oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb) was calculated by Pearson correlation coefficient, showing significant difference between ASD and TD, thus the coupling could be a characteristic feature for ASD. To evaluate the discrimination ability of the feature obtained in different acquisition times, the receiver operating characteristic curve (ROC) was constructed and the area under curve (AUC) was calculated. The results showed AUC > 0.8 when the time duration was longer than 1.5 min, but longer than 4 min, AUC value (~0.87) hardly varied, implying the maximal discrimination ability reached. This study demonstrated the coupling could be one of characteristic features for ASD even acquired in a short measurement time.

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Immunotherapy targeting immune checkpoints (ICPs), such as programmed death-ligand-1 (PD-L1), is used as a treatment option for advanced or metastatic non-small cell lung cancer (NSCLC). However, overall response rate to anti-PD-L1 treatment is limited due to antigen heterogeneity and the immune-suppressive tumor microenvironment. Human leukocyte antigen-G (HLA-G), an ICP as well as a neoexpressed tumor-associated antigen, is previously demonstrated to be a beneficial target in combination with anti-PD-L1. In this study, a nanobody-based trispecific T cell engager (Nb-TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD-L1- and/or HLA-G. Nb-TriTE shows broad spectrum anti-tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb-TriTE exhibits superior anti-cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb-TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb-TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP-targeting Nb-TriTE.

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Pharyngeal endoderm cells undergo convergence and extension (C&E), which is essential for endoderm pouch formation and craniofacial development. Our prior work implicates Gα13/RhoA-mediated signaling in regulating this process, but underlying mechanisms remain unclear. Here, we used endoderm-specific transgenic and Gα13 mutant zebrafish to demonstrate that Gα13 plays a crucial role in pharyngeal endoderm C&E by regulating RhoA activation and E-cadherin expression. We showed that during C&E, endodermal cells gradually establish stable cell-cell contacts, acquire apical-basal polarity, and undergo actomyosin-driven apical constriction, processes that require Gα13. Additionally, we found Gα13-deficient embryos exhibit reduced E-cadherin expression, partially contributing to endoderm C&E defects. Notably, interfering with RhoA function disrupts spatial actomyosin activation without affecting E-cadherin expression. Collectively, our findings identify critical cellular processes for pharyngeal endoderm C&E and reveal that Gα13 controls this through two independent pathways: modulating RhoA activation and regulating E-cadherin expression, thus unveiling intricate mechanisms governing pharyngeal endoderm morphogenesis.

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Purpose: This study aimed to identify the occurrence of excessive daytime sleepiness (EDS) in epilepsy patients with interictal epileptiform discharges and to explore the impact of interictal sleep architecture and sleep-related events on EDS. Methods: This study included 101 epilepsy patients with interictal epileptiform discharges (IED) and 100 control patients who underwent simultaneous polysomnography and video ambulatory electroencephalography for >7 h throughout a single night. Multiple sleep latency tests were used to assess EDS. Comorbid EDS was present in 25 and 11 patients in the IED epilepsy and control groups, respectively. In addition, univariate and multivariate logistic regression analyses were performed to explore the factors influencing EDS. Results: The epilepsy group had a higher prevalence of comorbid EDS and shorter R sleep duration. Univariate logistic regression analysis indicated that an increased risk of EDS may be associated with prolonged N1 sleep duration, higher arousal index, lower mean saturation (mSaO2), higher oxygen desaturation index (ODI), and duration of wake after sleep onset (WASO). Multivariate logistic regression analysis revealed that N1 sleep duration was significantly correlated with EDS. Conclusion: In epilepsy patients with IED, the arousal index, mSaO2, ODI, and duration of WASO were weakly correlated with EDS, and the duration of N1 sleep demonstrated a significant positive correlation with EDS, which requires further research.

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BACKGROUND: There have been concerns about the potential cardiovascular (CV) adverse effects associated with methylphenidate (MTH) use. However, only limited evidence exists on the long-term safety of MTH. OBJECTIVE: To evaluate whether MTH use is associated with long-term CV risk. METHODS: This was a retrospective cohort study using 2003-2017 data from the Health and Welfare Database in Taiwan. Patients newly diagnosed with attention deficit and hyperactivity disorder (ADHD) and between 3 and 18 years of age were included. Two treatment statuses were assessed: initial treatment ≥7 days and ≥180 days. Patients treated with MTH were compared with those receiving non-medication therapy. One-to-one propensity score matching was used to balance between-group differences. Study outcomes included major CV events, chronic CV disease, cardiogenic shock and all-cause mortality. Cox proportional hazard models were used to estimate HRs between the two groups. RESULTS: We began with 307 459 patients with ADHD. After exclusion, 224 732 patients were included in the final cohort. The results showed that compared with non-ADHD medication users, patients who were treated with MTH for more than 7 days had a similar risk of major CV events (HR 0.85, 95% CI 0.72 to 0.99; p=0.040). Identical trends were found in groups who were treated for more than 180 days (HR 0.83, 95% CI 0.69 to 1.00; p=0.050). The results of the sensitivity analyses were consistent with the main analyses across all groups and individual outcomes. CONCLUSION: Short-term MTH use did not increase CV risk among patients with ADHD. More evidence on long-term MTH use and risk of cardiogenic shock and death is warranted.

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Purpose: The Rho-associated protein kinase and myosin light chain kinase (ROCK/MYLK) pathway undeniably plays a pivotal role in the pathophysiology of primary open-angle glaucoma (POAG). In our study, we utilized both ocular hypertension (OHT) rabbit models and clinical investigations to gain invaluable insights that propel the development of novel treatments targeting proteins and genes associated with the trabecular meshwork (TM), thereby offering promising avenues for the management of POAG. Methods: Following microbead injections into the anterior chamber of the ocular cavity of rabbits, we observed elevated histiocyte numbers and immune scores for MYLK-4/ pMLC-2, alongside a reduction in the void space within the TM. Notably, treatment was performed with 0.1% ITRI-E-(S)-4046, a compound with dual kinase inhibitor (highly specific inhibitor of ROCK1/2 and MYLK4), significantly reduced intraocular pressure (IOP; P < 0.05) and expanded the void space within the TM (P < 0.0001) compared with OHT rabbits. In clinical investigations, we utilized whole transcriptome sequencing to analyze gene expression specifically related to the TM, obtained from patients (5 early-onset and 5 late-onset) undergoing trabeculectomy. Results: Our findings revealed 103 differential expression genes (DEGs) out of 265 molecules associated with the Rho family GTPase pathway, exhibiting a P value of 1.25E-10 and a z-score of -2.524. These results underscore significant differences between the early-onset and late-onset POAG and highlight the involvement of the ROCK/MYLK pathway. Conclusions: These findings underscore the critical involvement of the ROCK/MYLK pathway in both OHT-related and different onsets of POAG, providing valuable insights into the TM-related molecular mechanisms underlying the disease.

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Ferroptosis is a specific form of cell death characterized by excessive accumulation of cellular lipid peroxides. Ferroptosis is closely associated with various diseases, inhibition of which may help alleviate multi-organ injury caused by ischemia-reperfusion and enhance the anti-tumor effect by promoting the immunity of T cells. However, clinical approved drugs targeting ferroptosis process remain rare. In this study, we unexpectedly found that (R)-crizotinib, the first-generation ALK inhibitor, has potent inhibitory activity against ferroptosis across various cell lines. Moreover, its chiral molecule (S)-crizotinib, which was considered to share no common targets with (R)-crizotinib, also suppresses ferroptosis with an efficacy similar to that of (R)-crizotinib. We further demonstrated that both crizotinib enantiomers inhibit ferroptosis independently of their known targets, but through a common mechanism involving the targeting of AGPAT3-mediated synthesis of ether-linked polyunsaturated fatty acids (PE-O-PUFA), which are known to promote lipid-ROS generation and ferroptosis. In line with their activity in cell lines, (R)-crizotinib and (S)-crizotinib effectively mitigate renal ischemia-reperfusion injury in mice. Furthermore, the two compounds also inhibit lipid-ROS accumulation in CD8+ T cells in draining lymph nodes of B16-F10 subcutaneous xenograft mice, thereby promoting anti-tumor effects. Collectively, our study firstly reports a common activity shared by (R)-crizotinib and (S)-crizotinib in ferroptosis regulation. As a clinically approved drug, (R)-crizotinib has well-established pharmacokinetics and safety, which makes it a promising candidate for repurposing. Given the current lack of FDA-approved ferroptosis inhibitors, our findings suggest therapeutically repurposing (R)-crizotinib as well as its enantiomer (S)-crizotinib for treating ferroptosis-related diseases.

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Hernandia nymphaeifolia (C. Presl) Kubitzki, a native tree of Taiwan, is a sea drift plant (Yang and Lu 1996). It is a salt- and wind-tolerant tree (Bezona et al. 2009) and was selected for the afforestation of badlands in coastal areas of Taiwan. In December 2022, all H. nymphaeifolia seedlings at a nursery in Wu-Lai, Taiwan were diseased and wilted with a similar progression. The initial symptom was small zonate white or gray lesions with water-soaked periphery on leaves. Then, expansion and fusion of leaf spots which caused leaf blight and defoliation were observed. Seedlings eventually wilted. Sporophores found on the host were generally hypophyllous, solitary, erect, and easily detachable. The upper portion of the sporophore was considered an individual conidium and consisted of a pyramidal head that was fusiform to ventricose, 206.3 to 501.8 µm (average: 378.0 ± 75.3 µm) long, and 63.6 to 104.5 µm (average: 85.0 ± 16.2 µm) wide at the broadest point (n=30). Branches within the pyramidal head were short, compact, and di- or trichotomously branched. The central stipe was hyaline, broad, septate, tapering toward an acute apex, and sometimes constricted at the basal septum. Sclerotia were gray or black, spherical, and 1.0 to 2.5 mm (n=10) in diameter and observed on older lesions. The fungus was isolated from infected tissue and sporophores and maintained on potato dextrose agar (PDA) at 20°C in darkness. Sclerotia were produced on PDA after 4 to 5 weeks and were irregular or spherical, but no sporophore was developed. The fungus was identified as Grovesinia moricola (I. Hino) Redhead based on morphological characteristics (Tomoko et al. 2006). Three DNA samples was obtained from the cultures isolated from the diseased leaf, sporophores and sclerotia. They were then amplified by PCR with primers for the internal transcribed spacer region (ITS; primers ITS5/ITS4) and the large subunit nuclear ribosomal RNA gene (LSU; primers LR0R/LR5) (Cho et al. 2017), and then sequenced respectively. The sequences were deposited into GenBank with accession nos. PP727191 to PP727193 and PP748518 to PP748520. BLAST analysis of the three isolates showed 100% identity to the sequences of G. moricola from Taiwan (OP550202, OP550203) for the ITS region and 99.9% identity to the sequence of G. moricola from the USA (MW013804) for the LSU rRNA gene. The specimens (FS2022-140) and the culture (Asco-0109) in this study were deposited into the herbarium of Taiwan Forestry Research Institute in Taiwan. Koch's postulates were performed by inoculating four 8-month-old, asymptomatic, potted H. nymphaeifolia plants; every plant was inoculated with sporophores from infected leaves on the upper surface of each of five leaves. Four uninoculated plants were kept in separate pots and served as controls. All plants were covered with transparent plastic bags individually and incubated in a growth chamber at 18 to 20°C with 8 h of light. Similar leaf spots and sporophores were observed after 2 to 4 days and 10 days on every inoculated plant but not on uninoculated plants. The pathogen with a similar colony on PDA was reisolated from the leaf spots of the inoculated plants. Molecular identification of the reisolated pathogen by the above method was carried out. The sequences showed 99.9% identity to the sequence of G. moricola, and were deposited into GenBank with accession nos. PQ157896 to PQ157897 (ITS region) and PQ157701 to PQ157702 (LSU rRNA gene). The pathogenicity test was repeated once. G. moricola is known to cause severe defoliation on woody and annual plants, including at least 73 host species and 36 families distributed in the eastern United States and Japan (Trolinger et al. 1978). This is the first report of G. moricola on H. nymphaeifolia in the world. Control of the disease would play an important role in maintaining healthy seedlings for the afforestation in Taiwan.

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A study on DPC and iDPC images of crystals is achieved with simulation. It highlights the use of electron wave intensity distribution to visualize the dynamic effect on DPC and iDPC contrasts. Electron waves near heavy atoms exhibit significant oscillations and rapid intensity decay. This oscillation causes DPC and iDPC signal inversion. Bloch wave theory is used to derive DPC and iDPC intensity distributions, elucidating the impact of dynamic effect on the contrast.

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Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. Although significant progress has been made in elucidating the underlying mechanisms, further investigation is required for clarifying molecular diagnostic and therapeutic targets. In this study, we found that the mRNA level of protein phosphatase 2 regulatory subunit B' delta (Ppp2r5d) was altered in the peripheral blood plasma of DCM patients. Knockdown of Ppp2r5d in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of Ppp2r5d in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, Ppp2r5d-deficient cardiomyocytes showed an increase in phosphorylation of STAT3 at Y705 and a decrease in phosphorylation of STAT3 at S727. The elevated levels of phosphorylation at Y705 in STAT3 triggered the upregulation of interleukin 6 (IL6) expression. Moreover, the decreased phosphorylation at S727 in STAT3 disrupted mitochondrial electron transport chain function and dysregulated ATP synthesis and ROS levels. These results hereby reveal a novel role for Ppp2r5d in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease.

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BACKGROUND/PURPOSE: The National Medicines Policy (NMP) is crucial as it sets the framework for ensuring access to affordable, high-quality medicines and promoting their rational use, which is essential for public health and the efficiency of the healthcare system. This study aims to evaluate the current state of Taiwan's NMP, identify pressing issues for improvement, and establish actionable suggestions through expert consensus to ensure the sustainable provision and use of medications. METHODS: A modified two-round Delphi technique was employed. The first-round survey identified key issues and suggestions for policy improvement, while the second-round survey evaluated the feasibility and effectiveness of these suggestions. The expert panel, consisting of 50 specialists from pharmacy, medicine, public health, and the pharmaceutical industry, evaluated key issues related to the NMP's efficacy using a 4-point Likert scale. RESULTS: The first-round survey identified 13 key issues in Taiwan's NMP, primarily focusing on the rational use and accessibility of medications. The second-round survey proposed 54 policy improvement suggestions for these issues, of which 20 were considered strong suggestions and 23 were moderate suggestions. The policy recommendations cover medication reimbursement, pharmacy professional services, administration, legislation, and education. CONCLUSION: The study highlights the urgent need for reforms in Taiwan's NMP, providing specific policy improvement suggestions to ensure high-quality medications and pharmaceutical services while supporting the sustainable operation of Taiwan's NHI system. The study underscores the significance of proactive measures to fortify healthcare sustainability in the face of evolving healthcare landscapes.

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BACKGROUND: BK polyomavirus (BKV) infection is a critical complication hindering graft survival after kidney transplantation. We aimed to investigate the risk factors and outcome of BKV infection in pediatric kidney transplantation. METHODS: The clinical and follow-up data of pediatric kidney transplant recipients at the Children's Hospital of Fudan University from Jan 2015 to June 2023 were retrospectively analyzed. RESULTS: A total of 217 patients were included in the study with mean follow-up time of 24.3 ± 19.9 months. The mean age at transplantation was 9.7 ± 4.2 years. The patient survival rate and graft survival rate were 98.2% and 96.8%, respectively. Twenty-nine patients (13.4%) developed BKV infection, which was detected at 5.8 ± 3.2 months after transplantation. Among these 29 patients with BKV infection, 8 patients (3.6%) developed BKV nephropathy (BKVN), which was diagnosed at 8.3 ± 2.9 months after transplantation, and 2 patients developed graft failure eventually. Compared with the non-BKV infection group (eGFR 76.7 ± 26.1 mL/min/1.73 m2) and BKV infection without BKVN group (eGFR 85.2 ± 23.8 mL/min/1.73 m2), BKVN group had lowest eGFR during follow-up (33.5 ± 11.0 ml/min/1.73 m2, P < 0.001). Younger age at transplant (OR 0.850, 95%CI 0.762-0.948, P = 0.005), CAKUT disease of primary etiology (OR 2.890, 95%CI 1.200-6.961, P = 0.018), and CMV negative recipient serostatus before transplantation (OR 3.698, 95%CI 1.583-8.640, P = 0.003) were independent risk factors for BKV infection. CONCLUSIONS: Incidence of BKV infection is quite high within 12 months after pediatric kidney transplantation and children with BKVN have poor graft function. Younger age at transplant, CAKUT disease, and CMV negative recipient serostatus before transplantation increase the risk of BKV infection after kidney transplantation.

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INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and severe psoriasis subtype characterized by the rapid onset of coalescing sterile pustules over broad body areas and systemic inflammation. Data on its clinical course and outcomes in Taiwan are limited. We evaluated the clinical profile and outcomes of patients with GPP flares in Taiwan. METHODS: This retrospective analysis included adult patients with moderate-to-severe GPP flares occurring in January 2008-December 2021. Data were extracted from medical charts and electronic health records in the Chang Gung Research Database. Statistical analyses were performed using SAS for Windows (version 9.4). Multivariate Poisson regression models were built to investigate different predictors of GPP flare rate. RESULTS: Thirty-four patients with 81 moderate-to-severe GPP flares were identified. Of the 14 patients undergoing genetic analysis, 10 (71.4%) had an IL36RN mutation. Patients' mean age at the index GPP flare was 47.1 ± 16.5 years; 58.0% of the flares were severe, while 42.0% were moderate. Overall, 96.3% of GPP flares were treated with at least one systemic therapy, acitretin being the most prescribed (85.2%), followed by cyclosporine (45.7%) and methotrexate (18.5%). After treatment, the proportion of flares responding positively increased from 0% on day 2 to 6.2% by week 12. Patients were newly diagnosed with psoriasis (23.5%), hypertension (20.6%), diabetes mellitus (14.7%), psoriatic arthritis (2.9%), malignant tumor (8.8%), and depression/anxiety (2.9%) after enrollment. Complications occurring within 12 weeks of GPP flares included arthritis (25.9% of the flares), skin infection (8.6%), and other infections (2.5%). No fatalities were reported. In the multivariate model, former smokers, patients with hepatic disease, and patients with psoriatic arthritis had an increased GPP rate ratio (RR) of 13.33 (95% confidence interval, CI, 2.87-61.78), 14.08 (95% CI 3.04-65.29), and 34.84 (95% CI 4.77- 254.42), respectively. Contrarily, obese and rheumatoid arthritis patients had a lower GPP rate ratio of 0.21 (95% CI 0.08-0.54) and 0.07 (95% CI 0.006-0.78), respectively. CONCLUSIONS: Our findings highlight the complexity of GPP flare presentations and the need for individualized, patient-centered management approaches and continued research to improve affected individuals' care and outcomes.

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Hemorrhagic stroke is a global health problem owing to its high morbidity and mortality rates. Nicotinamide riboside is an important precursor of nicotinamide adenine dinucleotide characterized by a high bioavailability, safety profile, and robust effects on many cellular signaling processes. This study aimed to investigate the protective effects of nicotinamide riboside against collagenase-induced hemorrhagic stroke and its underlying mechanisms of action. An intracerebral hemorrhage model was constructed by stereotactically injecting collagenase into the right striatum of adult male Institute for Cancer Research mice. After 30 minutes, nicotinamide riboside was administered via the tail vein. The mice were sacrificed at different time points for assessments. Nicotinamide riboside reduced collagenase-induced hemorrhagic area, significantly reduced cerebral water content and histopathological damage, promoted neurological function recovery, and suppressed reactive oxygen species production and neuroinflammation. Nicotinamide riboside exerts neuroprotective effects against collagenase-induced intracerebral hemorrhage by inhibiting neuroinflammation and oxidative stress.

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0D organic-inorganic metal halides (OIMHs) provide unprecedented versatility in structures and photoluminescence properties. Here, a series of bluish-white emissive 0D OIMHs, (TPE-TPP)2Sb2BrxCl8-x (x = 1.16 to 8), are prepared by assembling the 1-triphenylphosphonium-4-(1,2,2-triphenylethenyl)benzene cation (TPE-TPP)+ with antimony halides anions. Based on experimental characterizations and theoretical calculations, the emission of the 0D OIMHs are attributed to the fluorescence of the organic cations with aggregation-induced emission (AIE) properties. The 0D structure minimized the molecular motion and intermolecular interactions between (TPE-TPP)+ cations, effectively suppressing the non-radiative recombination processes. Consequently, the photoluminescence quantum efficiency (PLQE) of (TPE-TPP)2Sb2Br1.16Cl6.84 is significantly enhanced to 55.4% as compared to the organic salt (TPE-TPP)Br (20.5%). The PLQE of (TPE-TPP)2Sb2BrxCl8-x can also be readily manipulated by halide substitution, due to the competitive processes between non-radiative recombination on the inorganic moiety and the energy transfer from inorganic to organic. In addition, electrically driven light-emitting diodes (LEDs) are fabricated based on (TPE-TPP)2Sb2Br1.16Cl6.84 emitter, which exhibited bluish-white emission with a maximum external quantum efficiency (EQE) of 1.1% and luminance of 335 cd m-2. This is the first report of electrically driven LED based on 0D OIMH with bluish-white emission.

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Introduction: There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes. Methods: SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases. Results: After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions. Conclusion: Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes.

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BACKGROUND: Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. RESULTS: Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. CONCLUSIONS: These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.

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Background: While hyperuricemia has been correlated with cardiovascular (CV) diseases, further evidence is required to evaluate the implications of stable serum uric acid (sUA) levels, especially concerning low sUA. This study aimed to investigate prolonged stable sUA levels and CV events/mortality. Methods: We conducted a retrospective cohort study at a medical center using electronic medical records linked with the national claims database. Patients with at least two sUA measurements, with intervals ranging from 6 months to 4 years, were included. The mean of the first two eligible sUA measurements were analyzed, stratified by sex. Outcomes of interest comprised major adverse cardiovascular events (MACE), heart failure hospitalization, CV and all-cause mortality. Results: This study included 33,096 patients (follow-up: men 6.6 years, women 6.4 years). After multivariable adjustment, cubic spline models showed that long-term high sUA levels were consistently associated with a higher risk of MACE, heart failure hospitalization, CV and all-cause mortality. A U-shaped association was observed between sUA levels and all-cause mortality in both sexes and between sUA levels and CV mortality in women. The impact of sUA, especially lower levels, on CV events and mortality was more pronounced in women than in men. Conclusion: Long-term high sUA levels are consistently associated with increased risk of CV events and mortality. A U-shaped association between sUA levels and all-cause mortality was observed in both men and women and was pronounced in women. The findings underscore the importance of considering sUA levels, especially in women, when assessing CV risk.