Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation.

RATIONALE: The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown. OBJECTIVE: This study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM. METHODS AND RESULTS: The expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition. CONCLUSIONS: Sirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.

Carbon Dots-Inked Paper with Single/Two-Photon Excited Dual-Mode Thermochromic Afterglow for Advanced Dynamic Information Encryption.

Achieving thermochromic afterglow (TCAG) in a single material for advanced information encryption remains a significant challenge. Herein, TCAG in carbon dots (CDs)-inked paper (CDs@Paper) was achieved by tuning the temperature-dependent dual-mode afterglow of room-temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF). The CDs were synthesized through thermal treatment of levofloxacin in melting boric acid with post-purification via dialysis. CDs@Paper exhibited TCAG and excitation-dependent afterglow color properties. The TCAG of CDs@Paper exhibited dynamic color changes from blue at high temperatures to yellow at low temperatures by adjusting the proportion of the temperature-dependent TADF and phosphorescence. Notably, two-photon afterglow in CDs-based afterglow materials and time-dependent two-photon afterglow colors were achieved for the first time. Moreover, leveraging the opposite emission responses of phosphorescence and TADF to temperature, CDs@Paper demonstrated TCAG with temperature-sensing capabilities across a wide temperature range. Furthermore, a CDs@Paper-based 3D code containing color and temperature information was successfully developed for advanced dynamic information encryption. This article is protected by copyright. All rights reserved.

Development of a quantum dots based immunochromatographic strip for rapid and on-site detection of African swine fever virus.

African swine fever (ASF) is a lethal disease caused by ASF virus (ASFV), severely impacting the global swine industry. Though nuclear acid-based detection methods are reliable, they are laboratory-dependent. In this study, we developed a device-independent, user friendly and cost-effective quantum dots based immunochromatographic strip (QDs-ICS) with high specificity and sensitivity for the rapid and on-site detection of ASFV antigen. For the preparation of the QDs-ICS, we generated a monoclonal antibody (mAb) mAb-8G8 and polyclonal antibody (pAb) against ASFV-p72 protein. The pAb was labelled with QDs to be used as the detection probe and the mAb-8G8 was coated on the nitrocellulose membrane as the test line. Our results proved that the strip displayed no cross-reactivity with other swine viruses and detection limit of the QDs-ICS was down to 1 ng/mL for the ASFV-p72 protein with great reproducibility. The strip also exhibited high stability with a storage period up to 12 months under room temperature. Twenty blind samples and one hundred clinical samples were examined by the QDs-ICS, conventional PCR and real-time PCR method, respectively. Results showed that the agreement rate between the QDs-ICS and PCR method was 100%, and the agreement rate between the strip and real-time PCR was 94%. The novel QDs-ICS developed here would be an effective tool for on-site detection of ASFV.

Combining KRAS gene status with preoperative D­dimer levels as a predictive marker of venous thromboembolism risk in patients with resectable colorectal cancer: A prospective cohort study.

Colorectal cancer (CRC), one of the most prevalent types of cancer, is accompanied by a notably high incidence of thrombotic complications. The present study aimed to elucidate the association between KRAS mutations and hypercoagulability in operable CRC. The prognostic value of preoperative D-dimer levels was also investigated, thus providing novel insights into the development of therapeutic strategies to enhance patient survival and diminish morbidity. Therefore, a prospective analysis of 333 CRC cases post-surgery at Yan'an Hospital Affiliated to Kunming Medical University, between May 2019 and October 2022 was performed. Data on demographics, tumor characteristics and D-dimer levels were compiled from the electronic health records. Venous thromboembolism (VTE) was diagnosed by doppler or computed tomography angiography, with D-dimer thresholds set at 550 and 1,650 µg/l. KRAS mutations at codons 12 and 13 were assessed in a subset of 56 cases. Subsequently, the factors affecting the hypercoagulable state in these patients were prospectively analyzed, focusing on the pivotal role of KRAS. The results showed that KRAS mutations were associated with elevated preoperative D-dimer levels, with 1,076 µg/l compared with 485 µg/l in the wild-type cohort, indicative of a hypercoagulable state. Increased D-dimer levels were also associated with vascular invasion, distant metastases and a heightened risk of postoperative VTE. Furthermore, multivariate analyses identified KRAS mutations, distant metastases and vascular invasion as independent predictors of elevated D-dimer levels, with relative risk values of 2.912, 1.884 and 1.525, respectively. Conversely, sex, age, tumor location, differentiation grade, Ki67 index and tumor stage could not significantly affect D-dimer levels, thus indicating a complex interplay between tumor genetics and coagulation dysfunction in CRC. The current study suggested that the KRAS mutation status, distant metastasis and vascular invasion could be considered as independent risk factors of blood hypercoagulability in patients with CRC, potentially serving as prognostic factors for VTE risk.

Delayed room temperature phosphorescence enabled by phosphines.

Organic ultralong room-temperature phosphorescence (RTP) usually emerges instantly and immediately decays after excitation removal. Here we report a new delayed RTP that is postponed by dozens of milliseconds after excitation removal and decays in two steps including an initial increase in intensity followed by subsequent decrease in intensity. The delayed RTP is achieved through introduction of phosphines into carbazole emitters. In contrast to the rapid energy transfer from single-molecular triplet states (T1) to stabilized triplet states (Tn*) of instant RTP systems, phosphine groups insert their intermediate states (TM) between carbazole-originated T1 and Tn* of carbazole-phosphine hybrids. In addition to markedly increasing emission lifetimes by ten folds, since TM → Tn* transition require >30 milliseconds, RTP is thereby postponed by dozens of milliseconds. The emission character of carbazole-phosphine hybrids can be used to reveal information through combining instant and delayed RTP, realizing multi-level time resolution for advanced information, biological and optoelectronic applications.

Postovulatory Aging of Mouse Oocytes Impairs Offspring Behavior by Causing Oxidative Stress and Damaging Mitochondria.

Information on long-term effects of postovulatory oocyte aging (POA) on offspring is limited. Whether POA affects offspring by causing oxidative stress (OS) and mitochondrial damage is unknown. Here, in vivo-aged (IVA) mouse oocytes were collected 9 h after ovulation, while in vitro-aged (ITA) oocytes were obtained by culturing freshly ovulated oocytes for 9 h in media with low, moderate, or high antioxidant potential. Oocytes were fertilized in vitro and blastocysts transferred to produce F1 offspring. F1 mice were mated with naturally bred mice to generate F2 offspring. Both IVA and the ITA groups in low antioxidant medium showed significantly increased anxiety-like behavior and impaired spatial and fear learning/memory and hippocampal expression of anxiolytic and learning/memory-beneficial genes in both male and female F1 offspring. Furthermore, the aging in both groups increased OS and impaired mitochondrial function in oocytes, blastocysts, and hippocampus of F1 offspring; however, it did not affect the behavior of F2 offspring. It is concluded that POA caused OS and damaged mitochondria in aged oocytes, leading to defects in anxiety-like behavior and learning/memory of F1 offspring. Thus, POA is a crucial factor that causes psychological problems in offspring, and antioxidant measures may be taken to ameliorate the detrimental effects of POA on offspring.

H2O-Mg2+ Waltz-Like Shuttle Enables High-Capacity and Ultralong-Life Magnesium-Ion Batteries.

Mg-ion batteries (MIBs) are promising next-generation secondary batteries, but suffer from sluggish Mg2+ migration kinetics and structural collapse of the cathode materials. Here, an H2O-Mg2+ waltz-like shuttle mechanism in the lamellar cathode, which is realized by the coordination, adaptive rotation and flipping, and co-migration of lattice H2O molecules with inserted Mg2+, leading to the fast Mg2+ migration kinetics, is reported; after Mg2+ extraction, the lattice H2O molecules rearrange to stabilize the lamellar structure, eliminating structural collapse of the cathode. Consequently, the demo cathode of Mg0.75V10O24·nH2O (MVOH) exhibits a high capacity of 350 mAh g-1 at a current density of 50 mA g-1 and maintains a capacity of 70 mAh g-1 at 4 A g-1. The full aqueous MIB based on MVOH delivers an ultralong lifespan of 5000 cycles The reported waltz-like shuttle mechanism of lattice H2O provides a novel strategy to develop high-performance cathodes for MIBs as well as other multivalent-ion batteries.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Conservative management of a rare case of post thyroidectomy tracheal injury with coagulation abnormalities.

Background: Tracheal injury is a rare but potentially serious acute complication of endotracheal intubation. Very few cases of tracheal injury associated with coagulation abnormalities have been reported in the literature. We present a rare case of a patient presenting with tracheal injury in combination with coagulation abnormalities following thyroidectomy. Case presentation: A 58-year-old woman with a history of postoperative chemotherapy for breast cancer, gastric polyps, multiple colonic polyps, esophageal papillary adenomas, and thyroid adenomas presented with dyspnea following 10 ml hemoptysis on the third day after thyroidectomy; she was admitted to the intensive care unit and underwent tracheal intubation for maintaining the airway. Subsequent bronchoscopy revealed a nodular red neoplasm 5-cm from the carina in the trachea obstructing part of the lumen, with a small amount of fresh hemorrhage on the surface. Tracheal injury was considered the preliminary diagnosis. Fiberoptic bronchoscope guided tracheal intubation helped prevent rupture of the tumor, and the cannula was properly inflated to arrest the bleeding while blocking the lower part of the trachea. An emergency surgical evacuation of the cervical hematoma was performed for managing postoperative bleeding. The patient demonstrated persistent pancytopenia despite frequent transfusions. Laboratory examination results revealed abnormal coagulation parameters, anemia, and hepatic dysfunction. Following a multidisciplinary team discussion, pituitrin for hemostasis, tranexamic acid for strengthening hemostasis treatment, and nutritional support and anti-infection treatment were initiated. Endotracheal tube cuff inflation was performed to compress the bleeding site. Complete resolution of the subcutaneous hematoma was observed nine days after the tracheal injury; bronchoscopy revealed residual ecchymosis in the airway hematoma with no evidence of obstruction. Conclusion: Conservative management of tracheal injury limited to the mucosa or submucosa without significant amount of active bleeding using endotracheal intubation is considered a practical and effective approach. Successful management was ensured by appropriate clinical suspicion, early multidisciplinary team discussion, and prompt diagnosis and interventions.

A population-based cohort of drug exposures and adverse pregnancy outcomes in China (DEEP): rationale, design, and baseline characteristics.

The DEEP cohort is the first population-based cohort of pregnant population in China that longitudinally documented drug uses throughout the pregnancy life course and adverse pregnancy outcomes. The main goal of the study aims to monitor and evaluate the safety of drug use through the pregnancy life course in the Chinese setting. The DEEP cohort is developed primarily based on the population-based data platforms in Xiamen, a municipal city of 5 million population in southeast China. Based on these data platforms, we developed a pregnancy database that documented health care services and outcomes in the maternal and other departments. For identifying drug uses, we developed a drug prescription database using electronic healthcare records documented in the platforms across the primary, secondary and tertiary hospitals. By linking these two databases, we developed the DEEP cohort. All the pregnant women and their offspring in Xiamen are provided with health care and followed up according to standard protocols, and the primary adverse outcomes - congenital malformations - are collected using a standardized Case Report Form. From January 2013 to December 2021, the DEEP cohort included 564,740 pregnancies among 470,137 mothers, and documented 526,276 live births, 14,090 miscarriages and 6,058 fetal deaths/stillbirths and 25,723 continuing pregnancies. In total, 13,284,982 prescriptions were documented, in which 2,096 chemicals drugs, 163 biological products, 847 Chinese patent medicines and 655 herbal medicines were prescribed. The overall incidence rate of congenital malformations was 2.0% (10,444/526,276), while there were 25,526 (4.9%) preterm births and 25,605 (4.9%) live births with low birth weight.

Association between Gut Microbiota Composition and Long-Term Vaccine Immunogenicity following Three Doses of CoronaVac.

BACKGROUND: Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac. METHODS: This was a prospective cohort study recruiting three-dose CoronaVac recipients from two centers in Hong Kong. Blood samples were collected at baseline and one year post-first dose for virus microneutralization (vMN) assays to determine neutralization titers. The primary outcome was high immune response (defined as with vMN titer ≥ 40). Shotgun DNA metagenomic sequencing of baseline fecal samples identified potential bacterial species and metabolic pathways using Linear Discriminant Analysis Effect Size (LEfSe) analysis. Univariate and multivariable logistic regression models were used to identify high response predictors. RESULTS: In total, 36 subjects were recruited (median age: 52.7 years [IQR: 47.9-56.4]; male: 14 [38.9%]), and 18 had low immune response at one year post-first dose vaccination. Eubacterium rectale (log10LDA score = 4.15, p = 0.001; relative abundance of 1.4% vs. 0, p = 0.002), Collinsella aerofaciens (log10LDA score = 3.31, p = 0.037; 0.39% vs. 0.18%, p = 0.038), and Streptococcus salivarius (log10LDA score = 2.79, p = 0.021; 0.05% vs. 0.02%, p = 0.022) were enriched in low responders. The aOR of high immune response with E. rectale, C. aerofaciens, and S. salivarius was 0.03 (95% CI: 9.56 × 10-4-0.32), 0.03 (95% CI: 4.47 × 10-4-0.59), and 10.19 (95% CI: 0.81-323.88), respectively. S. salivarius had a positive correlation with pathways enriched in high responders like incomplete reductive TCA cycle (log10LDA score = 2.23). C. aerofaciens similarly correlated with amino acid biosynthesis-related pathways. These pathways all showed anti-inflammation functions. CONCLUSION: E. rectale,C. aerofaciens, and S. salivarius correlated with poorer long-term immunogenicity following three doses of CoronaVac.

Residential mobility and liver cancer risk: findings from a prospective cohort study in Chinese women.

BACKGROUND: Residential mobility is believed to influence the occurrence and development of cancer; however, the results are inconclusive. Furthermore, limited studies have been conducted on Asian populations. This study aimed to evaluate the relationship between residential mobility and liver cancer risk among Chinese women. METHODS: We enrolled 72,818 women from urban Shanghai between 1996 and 2000, and then followed them until the end of 2016. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association between residential mobility and liver cancer risk. A linear trend test was conducted by ranking variables. A sensitivity analysis was also conducted, excluding participants with follow-up times of less than 2 years, to prevent potential bias. RESULTS: During the 1,269,765 person-years of follow-up, liver cancer was newly diagnosed in 259 patients. Domestic migration (HR = 1.47, 95% CI, 1.44-1.50), especially immigration to Shanghai (HR = 1.47, 95% CI, 1.44-1.50) was associated with an increased risk of liver cancer. In addition, migration frequency, age at initial migration and first immigration to Shanghai had linear trends with an increased liver cancer risk (Ptrend <0.001). The results were similar when excluding participants with less than two years of follow-up. CONCLUSIONS: The possible association between residential mobility and a higher risk of liver cancer in women could suggest the need for effective interventions to reduce adverse environmental exposures and enhance people's health.

FASN-mediated fatty acid biosynthesis remodels immune environment in Clonorchis sinensis infection-related intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA. METHODS: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA. RESULTS: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis. CONCLUSIONS: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs. IMPACT AND IMPLICATIONS: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs.

Down-regulating lncRNA KCNQ1OT1 relieves type II alveolar epithelial cell apoptosis during one-lung ventilation via modulating miR-129-5p/HMGB1 axis induced pulmonary endothelial glycocalyx.

OBJECTIVE: Endothelial glycocalyx (EG) maintains vascular homeostasis and is destroyed after one-lung ventilation (OLV)-induced lung injury. Long noncoding RNAs (lncRNAs) are critically involved in various lung injuries. This study aimed to investigate the role and regulatory mechanism of KCNQ1 overlapping transcript 1 (KCNQ1OT1) in OLV-induced lung injury and LPS-induced type II alveolar epithelial cell (AECII) apoptosis. METHODS: The rat OLV model was established, and the effects of KCNQ1OT1 on OLV-induced ALI in vivo were explored. Bax and Caspase-3 expression in rat lung tissues was measured by immunochemistry (IHC). AECIIs were isolated from rat lungs and treated with LPS or normal saline (control) for in vitro analysis. The expression of KCNQ1OT1, miR-129-5p, and HMGB1 was measured by quantitative real-time PCR (qRT-PCR) or Western blot (WB). Cell proliferation and apoptosis were examined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) and flow cytometry. The downstream targets of KCNQ1OT1 were predicted by bioinformatics, and the binding relationship between KCNQ1OT1 and miR-129-3p was verified by dual-luciferase reporter assays. The potential target of miR-129-5p was further explored on the Targetscan website and revealed to target HMGB1. Enzyme-linked immunosorbent assay (ELISA) or WB was adopted to determine the levels of IL-1ß, TNF-α, MDA, SOD, heparanase (HPA), matrix metalloproteinase 9 (MMP9), heparan sulfate (HS) and syndecan-1 (SDC-1). RESULTS: KCNQ1OT1 and HMGB1 were up-regulated during OLV-induced lung injury, and their expression was positively correlated. KCNQ1OT1 knockdown reduced OLV-induced pulmonary edema and lung epithelial cell apoptosis, increased vascular permeability, reduced IL-1ß, TNF-α, MDA, and SOD levels and glycocalyx markers by targeting miR-129-5p or upregulating HMGB1. Overexpressing KCNQ1OT1 promoted cell apoptosis, reduced cell proliferation, aggravated inflammation and oxidative stress, and up-regulated HMGB1, HPA and MMP9 in LPS-treated AECIIs, while the HMGB1 silencing showed the opposite effects. MiR-129-5p mimics partially eliminated the KCNQ1OT1-induced effects, while recombinant HMGB1 restored the effects of miR-129-5p overexpression on AECIIs. Additionally, KCNQ1OT1 was demonstrated to promote the activation of the p38 MAPK/Akt/ERK signaling pathways in AECIIs via HMGB1. CONCLUSION: KCNQ1OT1 knockdown alleviated AECII apoptosis and EG damage during OLV by targeting miR-129-5p/HMGB1 to inactivate the p38 MAPK/Akt/ERK signaling. The findings of our study might deepen our understanding of the molecular basis in OLV-induced lung injury and provide clues for the targeted disease management.

Role and action mechanisms of miR-149 and miR-31 in regulating function of pig cumulus cells and oocytes.

Understanding the mechanisms for oocyte maturation and optimizing the protocols for in vitro maturation (IVM) are greatly important for improving developmental potential of IVM oocytes. The miRNAs expressed in cumulus cells (CCs) play important roles in oocyte maturation and may be used as markers for selection of competent oocytes/embryos. Although a recent study from our group identified several new CCs-expressed miRNAs that regulate cumulus expansion (CE) and CC apoptosis (CCA) in mouse oocytes, validation of these findings and further investigation of mechanisms of action in other model species was essential before wider applications. By using both in vitro and in vivo pig oocyte models with significant differences in CE, CCA and developmental potential, the present study validated that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes. We demonstrated that miR-149 and miR-31 targeted SMAD family member 6 (SMAD6) and transforming growth factor ß2 (TGFB2), respectively, in the transforming growth factor-ß (TGF-ß) signaling. Furthermore, both miR-149 and miR-31 increased CE and decreased CCA via activating SMAD family member 2 (SMAD2) and increasing the expression of SMAD2 and SMAD family member 4. In conclusion, the present results show that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes by activating the TGF-ß signaling, suggesting that they might be used as markers for pig oocyte quality.

Effects of nonpharmacological interventions on symptom clusters in breast cancer survivors: A systematic review of randomized controlled trials.

Objective: To summarize nonpharmacological interventions and assess their effects on symptom clusters and quality of life (QoL) in breast cancer (BC) survivors. Methods: Seven English and three Chinese electronic databases and three clinical trial registries were searched from January 2001 to August 2023. A narrative approach was applied to summarize the data. The primary outcome was symptom clusters measured by any patient-reported questionnaires, and the secondary outcomes were QoL and intervention-related adverse events. Results: Six published articles, one thesis, and one ongoing trial involving 625 BC survivors were included. The fatigue-sleep disturbance-depression symptom cluster was the most frequently reported symptom cluster among BC survivors. The nonpharmacological interventions were potentially positive on symptom clusters and QoL among the BC survivors. However, some of the included studies exhibited methodological concerns (e.g., inadequate blinding and allocation concealment). The intervention protocols in only two studies were developed following a solid evidence-based approach. Adverse events related to the targeted interventions were reported in six included studies, with none performing a causality analysis. Conclusions: The nonpharmacological interventions could be promising strategies for alleviating symptom clusters in BC survivors. Future studies should adopt rigorously designed, randomized controlled trials to generate robust evidence. Systematic review registration: INPLASY202380028.

Design and statistical analysis reporting among interrupted time series studies in drug utilization research: a cross-sectional survey.

INTRODUCTION: Interrupted time series (ITS) design is a commonly used method for evaluating large-scale interventions in clinical practice or public health. However, improperly using this method can lead to biased results. OBJECTIVE: To investigate design and statistical analysis characteristics of drug utilization studies using ITS design, and give recommendations for improvements. METHODS: A literature search was conducted based on PubMed from January 2021 to December 2021. We included original articles that used ITS design to investigate drug utilization without restriction on study population or outcome types. A structured, pilot-tested questionnaire was developed to extract information regarding study characteristics and details about design and statistical analysis. RESULTS: We included 153 eligible studies. Among those, 28.1% (43/153) clearly explained the rationale for using the ITS design and 13.7% (21/153) clarified the rationale of using the specified ITS model structure. One hundred and forty-nine studies used aggregated data to do ITS analysis, and 20.8% (31/149) clarified the rationale for the number of time points. The consideration of autocorrelation, non-stationary and seasonality was often lacking among those studies, and only 14 studies mentioned all of three methodological issues. Missing data was mentioned in 31 studies. Only 39.22% (60/153) reported the regression models, while 15 studies gave the incorrect interpretation of level change due to time parameterization. Time-varying participant characteristics were considered in 24 studies. In 97 studies containing hierarchical data, 23 studies clarified the heterogeneity among clusters and used statistical methods to address this issue. CONCLUSION: The quality of design and statistical analyses in ITS studies for drug utilization remains unsatisfactory. Three emerging methodological issues warranted particular attention, including incorrect interpretation of level change due to time parameterization, time-varying participant characteristics and hierarchical data analysis. We offered specific recommendations about the design, analysis and reporting of the ITS study.

Placement of bronchial occluder outside the tracheal tube in a patient combined with airway compression undergoing mediastinal tumors resection: a case report.

BACKGROUND: Mediastinal tumors pose a challenging respiratory and circulatory management during anesthesia procedures, there is a risk of circulatory collapse or complete airway obstruction, which in severe cases can lead to cardiac arrest. We reported a case of anesthetic management using a bronchial blocker placed outside the tracheal tube. In this case report, the patient's trachea was so severely compressed that the airway was extremely narrow, only 4 mm at its narrowest point. By reporting the anesthetic management of this patient, we intend to provide an unusual approach for airway management. CASE PRESENTATION: A 52-year-old male patient was admitted to the hospital due to cough and expectoration for one year. Additionally, the patient experienced chest tightness and asthma after physical activity. The enhanced computed tomography revealed there existed an irregular soft tissue mass in the right upper mediastinum, which significantly compressed the trachea and esophagus. The results of the mediastinal puncture pathology showed the presence of mesenchymal tumors. According to the results above, the patient was diagnosed with a mediastinal tumor and scheduled to undergo tumor resection under general anesthesia. We used a bronchial occluder outside the tracheal tube for general anesthesia. After surgery, the patient received thorough treatment and was subsequently discharged from the hospital. CONCLUSION: In patients with severe airway compression from a mediastinal tumor airway compression, positioning a bronchial occluder externally to the tracheal tube is an effective method of airway management. However, we still need more clinical practice to help the process become more standardized.

Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus. APPROACH AND RESULTS: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05). CONCLUSIONS: Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).

Quality appraisal and descriptive analysis of clinical practice guidelines for self-managed non-pharmacological interventions of cardiovascular diseases: a systematic review.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death around the world. Most CVDs-related death can be prevented by the optimal management of risk factors such as unhealthy diet and physical inactivity. Clinical practice guidelines (CPGs) for CVDs, provide some evidence-based recommendations which help healthcare professionals to achieve the best care for patients with CVDs. This systematic review aims to appraise the methodological quality of CPGs systematically and summarize the recommendations of self-managed non-pharmacological interventions for the prevention and management of CVDs provided by the selected guidelines. METHODS: A comprehensive electronic literature search was conducted via six databases (PubMed, Medline, The Cochrane Library, Embase, CINAHL, and Web of Science), seven professional heart association websites, and nine guideline repositories. The Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument was adopted to critically appraise the methodological quality of the selected guidelines. Content analysis was used to summarise recommended self-managed non-pharmacological interventions for CVDs. RESULTS: Twenty-three CPGs regarding different CVDs were included, in which four guidelines of CVDs, three for coronary heart diseases, seven for heart failure, two for atrial fibrillation, three for stroke, three for peripheral arterial disease, and one for hypertrophic cardiomyopathy. Twenty CPGs were appraised as high quality, and three CPGs as moderate quality. All twenty-three CPGs were recommended for use with or without modification. The domain of "Editorial Independence" had the highest standardized percentage (93.47%), whereas the domain of "Applicability" had the lowest mean domain score of 75.41%. The content analysis findings summarised some common self-managed non-pharmacological interventions, which include healthy diet, physical activity, smoking cessation, alcohol control, and weight management. Healthy diet and physical acidity are the most common and agreed on self-managed interventions for patients with CVDs. There are some inconsistencies identified in the details of recommended interventions, the intervention itself, the grade of recommendation, and the supported level of evidence. CONCLUSION: The majority of the summarized non-pharmacological interventions were strongly recommended with moderate to high-quality levels of evidence. Healthcare professionals and researchers can adopt the results of this review to design self-managed non-pharmacological interventions for patients with CVDs.