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.

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.

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.

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.

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

BACKGROUND AND AIMS: We investigated whether empagliflozin reduces hepatic steatosis in metabolic-dysfunction associated steatotic liver disease (MASLD) patients without diabetes mellitus (DM). APPROACH AND RESULTS: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without DM (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. Primary outcome was difference in change of MRI-PDFF between two groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF <5%), ALT drop≥17U/L, MRI-PDFF decline≥30%, 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. Empagliflozin group had greater reduction in median MRI-PDFF compared to placebo group (-2.49% vs -1.43%;p=0.025), with a non-significant trend of resolution of hepatic steatosis (44.9% vs 28.6%;p=0.094). There was no significant difference in ALT drop≥17U/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 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 non-diabetic MASLD subjects. (ClinicalTrials.gov Identifier: NCT04642261).

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

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with high lethality. Clonorchis sinensis (C. sinensis) infection is an important risk factor for ICC. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis-infected ICC. METHODS: We performed single-cell RNA sequencing, whole exome sequencing, RNA-sequencing, metabolomics and spatial transcriptomics in 251 ICC patients from three medical centers. The alterations of metabolic and immune microenvironment of C. sinensis-infected ICCs were validated through in vitro co-culture system and hydrodynamic injection ICC mouse model. RESULTS: We revealed that C. sinensis infection was significantly associated with ICC patients' overall survival and immunotherapy response. Fatty acid biosynthesis and the expression of FASN, a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-infected ICCs. ICC cell lines treated with C. sinensis-produced excretory/secretory products (ESPs) displayed an elevation of FASN and free fatty acid. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage-like (TAM-like) macrophages and the impairment function of T cells, which led to the immunosuppressive microenvironment formation and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-infected ICCs than non-C. sinensis-infected ICCs. Importantly, FASN inhibitor significantly reversed immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in ICC mouse models treated with ESPs from C. sinensis. CONCLUSIONS: We uncover the metabolic signature and immune microenvironment of C. sinensis-infected ICCs and highlight the combination of FASN inhibitors with immunotherapy as a promising strategy for treating C. sinensis-infected ICCs. IMPACT AND IMPLICATIONS: C. sinensis-infected ICC patients have a poorer prognosis and worse response to immunotherapy than non-C. sinensis-infected ICCs. The underlying molecular characteristics of C. sinensis-infected ICCs remains unclear. Herein, we demonstrate that up-regulation of FASN and free fatty acids in C. sinensis-infected ICCs leads to immunosuppressive microenvironment formation and tumor progression. Thus, administration of FASN inhibitors could significantly reverse immunosuppressive environment and further enhance anti-PD-1 efficacy in combating C. sinensis-infected ICCs.

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.

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 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.

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.

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.

Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches.

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

A New Isolated Fungus and Its Pathogenicity for Apis mellifera Brood in China.

In this article, we report the pathogenicity of a new strain of fungus, Rhizopus oryzae to honeybee larvae, isolated from the chalkbrood-diseased mummies of honeybee larvae and pupae collected from apiaries in China. Based on morphological observation and internal transcribed spacer (ITS) region analyses, the isolated pathogenic fungus was identified as R. oryzae. Koch's postulates were performed to determine the cause-and-effect pathogenicity of this isolate fungus. The in vitro pathogenicity of this virulent fungus in honeybees was tested by artificially inoculating worker larvae in the lab. The pathogenicity of this new fungus for honeybee larvae was both conidial-concentration and exposure-time dependent; its highly infectious and virulent effect against the larvae was observed at 1 × 105 conidia/larva in vitro after 96 h of challenge. Using probit regression analysis, the LT50 value against the larvae was 26.8 h at a conidial concentration of 1 × 105 conidia/larva, and the LC50 was 6.2 × 103 conidia/larva. These results indicate that the new isolate of R. oryzae has considerable pathogenicity in honeybee larvae. Additionally, this report suggests that pathogenic phytofungi may harm their associated pollinators. We recommend further research to quantify the levels, mechanisms, and pathways of the pathogenicity of this novel isolated pathogen for honeybee larvae at the colony level.

Left ventricular global longitudinal strain using a novel fully automated method: A head-to-head comparison with a manual layer-specific strain and establishment of normal reference ranges.

BACKGROUND: A novel automated method for measuring left ventricular (LV) global longitudinal strain (GLS) along the endocardium has advantages in terms of its rapid application and excellent reproducibility. However, it remains unclear whether the available normal range for conventional GLS using the manual method is applicable to the automated GLS method. This study aimed to compare automated GLS head-to-head with manual layer-specific GLS, and to identify whether a specialized normal reference range for automated GLS is needed and explore the main determinants. METHODS: In total, 1683 healthy volunteers (men, 43%; age, 18-80 years) were prospectively enrolled from 55 collaborating laboratories. LV GLS was measured using both manual layer-specific and automated methods. RESULTS: Automated GLS was higher than endocardial, mid-myocardial, and epicardial GLS. Women had a higher automated GLS than men. GLS had no significant age dependency in men, but first increased and then decreased with age in women. Accordingly, sex- and age-specific normal ranges for automated GLS were proposed. Moreover, GLS appeared to have different burdens in relation to dominant determinants between the sexes. GLS in men showed no dominant determinants; however, GLS in women correlated with age, body mass index, and heart rate. CONCLUSIONS: Using the novel automated method, was LV GLS higher than when using the manual GLS method. The normal ranges of automated GLS stratified according to sex and age were provided, with dominant determinants showing sex disparities that require full consideration in clinical practice.

The gut microbiota regulates the depressive-type behaviors and inflammatory processes after severe burn injuries in mice.

An emerging number of studies have recently revealed the correlation between burn injuries and psychological disorders. Gut microbiota and inflammatory factors may play a vital role in this process. Nevertheless, there are few studies conducted to disclose the potential mechanism of the gut microbiota between depression and burn injuries. In this study, we constructed a burn model of C57BL/6 mice, which showed that the symptom of depression became more and more severe with the burn of mice lasted longer. Meanwhile, there are significant differences of composition of gut microbiota among mice before and after burn. Then, we tested the inflammatory factors in the brain and peripheral blood, which showed an increased expression of Iba1, VWF, TNF-α and IL-6, and a decreased expression of IL-10 in burn mice. In addition, the expression of zonula occludens-1 (ZO-1) in cecum showed a down-regulation in burn mice, which indicated impaired intestinal barrier function. Lastly, the crossing fecal microbiota transplantation (FMT) and cohousing experiment were conducted to determine the functions of cross-transplantation of fecal microbiota on the depressive-type behaviours in burned mice. According to the score of Tail suspension test (TST), the burn mice were divided into two groups: Resilient mice (no-depressed mice) and Abnormal mice (depressed mice). After abnormal mice were transplanted with fecal microbiota of resilient mice, the symptom of depression was improved, and the expression of TNF-α, IL-6 and IL-10 return to normal levels (P < 0.05). On the contrary, after resilient mice were transplanted with fecal microbiota of abnormal mice both the TST scores and inflammatory factor developed depressive-type changes. In conclusion, our study demonstrated the changes of gut microbiota and inflammatory factors in depressed burn mice and non-depressed burn mice. The gut microbiota dysbiosis could impaired intestinal barrier function and lead to neuroinflammation, and this phenomenon could be significantly mitigated by FMT.

KRAS-mutant colorectal cancer cell lines cause a prothrombotic state through the upregulation of thrombin: experimental study.

Background: The KRAS genotype status is strongly associated with a prothrombotic state in colorectal cancer, and hypercoagulability and cancer-related thrombosis are among the significant events leading to poor prognosis. However, this correlation has not been confirmed at the cellular level. This study aimed to assess the maximum platelet aggregation rate and thrombin expression induced by colorectal cancer cells under different KRAS genotypes. Materials and methods: Platelet aggregation rate assay and western blotting analysis were used to detect platelet aggregation and thrombin expression induced by four colorectal cancer cells with different KRAS genotypes, including RKO, HCT116, SW480, and SW620. FVIIa/tissue factor and thrombin inhibitors were added to explore changes in platelet aggregation rates induced by colorectal cancer cells and the association between KRAS genotype status and hypercoagulable state. Results: KRAS-mutant cells were more likely to increase maximal platelet aggregation, with RKO, HCT116, SW480, and SW620 inducing 34.7%, 55.4%, 44.4%, and 63.8% of platelet aggregation, respectively. The maximum platelet aggregation rate was higher in the metastatic rectal cancer tumour strain SW620 than in the primary rectal cancer strain SW480. RKO cells had lower thrombin expression than the other three cells. Furthermore, the addition of thrombin inhibitors caused a more significant decrease in the platelet aggregation rate in KRAS-mutant cell lines compared to KRAS wild-type cell lines. Conclusion: Compared to KRAS wild-type colorectal cancer cells, KRAS-mutant colorectal cancer cell lines were more likely to be hypercoagulable through the upregulation of thrombin expression, which was mainly achieved through the TF-thrombin pathway.

Whole-Genome Sequencing of an Escherichia coli ST69 Strain Harboring blaCTX-M-27 on a Hybrid Plasmid.

Objective: Escherichia coli is a common Gram-negative human pathogen. The emergence of E. coli with multiple-antibiotic-resistant phenotypes has become a serious health concern. This study reports the whole-genome sequences of third-generation cephalosporin-resistant (3GC-R) and multidrug-resistant (MDR) E. coli EC6868 and explores the acquired antibiotic-resistance genes (ARGs) as well as their genetic contexts. Methods: E. coli EC6868 was isolated from a vaginal secretion sample of a pregnant patient in China. The antimicrobial susceptibility was assessed, and whole-genome sequencing was conducted. The acquired ARGs, insertion sequence (IS) elements, and integrons within the genome of E. coli EC6868 were identified, and the genetic contexts associated with the ARGs were analyzed systematically. Results: E. coli EC6868 was determined to belong to ST69 and harbored a 144.9-kb IncF plasmid (pEC6868-1) with three replicons (Col156, IncFIBAP001918, and IncFII). The ESBL gene blaCTX-M-27 was located on the structure "∆ISEcp1-blaCTX-M-27-IS903B", which was widely present in the species of Enterobacteriales. Other ARGs carried by plasmid pEC6868-1 were mainly located on the 18.9-kb IS26-composite transposon (five copies of intact IS26 and one copy of truncated IS26) composing of IS26-mphA-mrx(A)-mphR(A)-IS6100, ∆TnAs3-eamA-tet(A)-tetR(A)-aph(6)-Id-aph(3")-Ib-sul2-IS26, and a class 1 integron, which was widely present on IncF plasmids of E. coli, mainly distributed in ST131, ST38, and ST405. Notably, pEC6868 in our study was the first report on a plasmid harboring the 18.9-kb structure in E. coli ST69 in China. Conclusion: The 3GC-R E. coli ST69 strain with an MDR IncF plasmid carrying blaCTX-M-27 and other ARGs, conferring resistance to aminoglycosides, macrolides, sulfonamides, tetracycline, and trimethoprim, was identified in a hospital in China. Mobile genetic elements including ISEcp1, IS903B, IS26, Tn3, IS6100 and class 1 integron were found within the MDR region, which could play important roles in the global dissemination of these resistance genes.

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.

Global fungal-host interactome mapping identifies host targets of candidalysin.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.

Direct in Situ Fabrication of Multicolor Afterglow Carbon Dot Patterns with Transparent and Traceless Features via Laser Direct Writing.

Multicolor afterglow patterns with transparent and traceless features are important for the exploration of new functionalities and applications. Herein, we report a direct in situ patterning technique for fabricating afterglow carbon dots (CDs) based on laser direct writing (LDW) for the first time. We explore a facile step-scanning method that reduces the heat-affected zone and avoids uneven heating, thus producing a fine-resolution afterglow CD pattern with a minimum line width of 80 µm. Unlike previous LDW-induced luminescence patterns, the patterned CD films are traceless and transparent, which is mainly attributed to a uniform heat distribution and gentle temperature rise process. Interestingly, by regulating the laser parameters and CD precursors, an increased carbonization and oxidation degree of CDs could be obtained, thus enabling time-dependent, tunable afterglow colors from blue to red. In addition, we demonstrate their potential applications in the in situ fabrication of flexible and stretchable optoelectronics.