Characterization of linoleate dioxygenases in basidiomycetes and the functional role of CcLdo1 in regulating fruiting body development in Coprinopsis cinerea.

Coprinopsis cinerea, a model fungus, is utilized for investigating the developmental mechanisms of basidiomycetes. The development of basidiomycetes is a highly organized process that requires coordination among genetic, environmental, and physiological factors. Oxylipins, a class of widely distributed signaling molecules, play crucial roles in fungal biology. Among oxylipins, the sexual pheromone-inducing factors (psi factors) have been identified as key regulators of the balance between asexual and sexual spore development in Ascomycetes. Linoleate dioxygenases are enzymes involved in the biosynthesis of psi factors, yet their specific physiological functions in basidiomycete development remain unclear. In this study, linoleate dioxygenases in basidiomycetes were identified and characterized. Phylogenetic analysis revealed that linoleate dioxygenases from Basidiomycota formed a distinct clade, with linoleate dioxygenases from Agaricomycetes segregating into three groups and those from Ustilaginomycetes forming a separate group. Both basidiomycete and ascomycete linoleate dioxygenases shared two characteristic domains: the N-terminal of linoleate dioxygenase domain and the C-terminal of cytochrome P450 domain. While the linoleate dioxygenase domains exhibited similarity between basidiomycetes and ascomycetes, the cytochrome P450 domains displayed high diversity in key sites. Furthermore, the gene encoding the linoleate dioxygenase Ccldo1 in C. cinerea was knocked out, resulting in a significant increase in fruiting body formation without affecting asexual conidia production. This observation suggests that secondary metabolites synthesized by CcLdo1 negatively regulate the sexual reproduction process in C. cinerea while not influencing the asexual reproductive process. This study represents the first identification of a gene involved in secondary metabolite synthesis that regulates basidiocarp development in a basidiomycete.

Triglyceride-glucose index as a suitable non-insulin-based insulin resistance marker to predict cardiovascular events in patients undergoing complex coronary artery intervention: a large-scale cohort study.

BACKGROUND: Insulin resistance (IR), a hallmark of proceeding diabetes and cardiovascular (CV) disease, has been shown to predict prognosis in patients undergoing percutaneous coronary intervention (PCI). The triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and metabolic score for insulin resistance (METS-IR) have been shown to be simple and reliable non-insulin-based surrogates for IR. However, limited studies have determined the associations between distinct non-insulin-based IR markers and CV outcomes in patients undergoing complex PCI who are at higher risk of CV events after PCI. Therefore, this study aimed to investigate and compare the prognostic value of these markers in patients undergoing complex PCI. METHODS: This was a descriptive cohort study. From January 2017 to December 2018, a total of 9514 patients undergoing complex PCI at Fuwai Hospital were consecutively enrolled in this study. The 3 IR indices were estimated from the included patients. The primary study endpoint was CV events, defined as a composite of CV death, nonfatal myocardial infarction and nonfatal stroke. RESULTS: During a median follow-up of 3.1 years, 324 (3.5%) CV events occurred. Multivariable Cox regression models showed per-unit increase in the TyG index (hazard ratio [HR], 1.42; 95% confidence interval [CI] 1.13-1.77), rather than per-unit elevation in either Ln(TG/HDL-C ratio) (HR, 1.18; 95%CI 0.96-1.45) or METS-IR (HR, 1.00; 95%CI 0.98-1.02), was associated with increased risk of CV events. Meanwhile, adding the TyG index to the original model led to a significant improvement in C-statistics (0.618 vs. 0.627, P < 0.001), NRI (0.12, P = 0.031) and IDI (0.14%, P = 0.003), whereas no significant improvements were observed when adding Ln (TG/HDL-C ratio) or METS-IR (both P > 0.05) to the original model. CONCLUSIONS: The TyG index, not TG/HDL-C ratio and METS-IR, was positively associated with worse CV outcomes in patients undergoing complex PCI. Our study, for the first time, demonstrated that the TyG index can serve as the suitable non-insulin-based IR marker to help in risk stratification and prognosis in this population.

Glycemic control and cardiovascular outcomes in patients with diabetes and coronary artery disease according to triglyceride-glucose index: a large-scale cohort study.

BACKGROUND: The role of triglyceride-glucose (TyG) index, an insulin resistance indicator, in glycemic management for diabetic patients with coronary artery disease (CAD) was still unknown. Therefore, we aimed to explore the association between glycemic control and cardiovascular (CV) outcomes in patients with diabetes and CAD according to different TyG index levels. METHODS: A total of 9996 diabetic patients with angiograph-proven CAD were consecutively recruited from 2017 to 2018 at Fuwai Hospital. Patients were assigned into 3 groups according to TyG index tertiles (T) (T1: <8.895; T2: 8.895-9.400; T3: ≥9.400). According to American Diabetes Association guidelines, controlled glycemia was defined as targeting glycosylated hemoglobin Alc (HbA1c) < 7%. The primary endpoint was CV events including CV death, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: During a median 3-year follow-up, 381 (3.8%) CV events occurred. Overall, high TyG index (T3) was associated with increased risk of CV events (hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.02-1.94) compared with the lowest TyG index (T1) after multivariable adjustment. Upon stratification by the TyG index, in fully adjusted models, controlled glycemia was associated with reduced risk of CV events in the high TyG index (T3) subgroup (HR: 0.64; 95%CI: 0.42-0.96) but not in the low (T1; HR: 0.79; 95%CI: 0.53-1.16) and moderate (T2; HR: 0.84; 95%CI: 0.56-1.25) TyG index subgroups. CONCLUSIONS: Controlled glycemia was associated with improved CV outcomes in patients with diabetes and established CAD, especially in those with high TyG index levels. Our study, for the first time, provided valuable information that TyG index could help making risk stratification on the glycemic management in diabetic patients with CAD.

High stress hyperglycemia ratio predicts adverse clinical outcome in patients with coronary three-vessel disease: a large-scale cohort study.

BACKGROUND: Coronary three-vessel disease (CTVD) accounts for one-third of the overall incidence of coronary artery disease, with heightened mortality rates compared to single-vessel lesions, including common trunk lesions. Dysregulated glucose metabolism exacerbates atherosclerosis and increases cardiovascular risk. The stress hyperglycemia ratio (SHR) is proposed as an indicator of glucose metabolism status but its association with cardiovascular outcomes in CTVD patients undergoing percutaneous coronary intervention (PCI) remains unclear. METHODS: 10,532 CTVD patients undergoing PCI were consecutively enrolled. SHR was calculated using the formula: admission blood glucose (mmol/L)/[1.59×HbA1c (%)-2.59]. Patients were divided into two groups (SHR Low and SHR High) according to the optimal cutoff value of SHR. Multivariable Cox regression models were used to assess the relationship between SHR and long-term prognosis. The primary endpoint was cardiovascular (CV) events, composing of cardiac death and non-fatal myocardial infarction (MI). RESULTS: During the median follow-up time of 3 years, a total of 279 cases (2.6%) of CV events were recorded. Multivariable Cox analyses showed that high SHR was associated with a significantly higher risk of CV events [Hazard Ratio (HR) 1.99, 95% Confidence interval (CI) 1.58-2.52, P < 0.001). This association remained consistent in patients with (HR 1.50, 95% CI 1.08-2.10, P = 0.016) and without diabetes (HR 1.97, 95% CI 1.42-2.72, P < 0.001). Additionally, adding SHR to the base model of traditional risk factors led to a significant improvement in the C-index, net reclassification and integrated discrimination. CONCLUSIONS: SHR was a significant predictor for adverse CV outcomes in CTVD patients with or without diabetes, which suggested that it could aid in the risk stratification in this particular population regardless of glucose metabolism status.

Hadamard ghost imaging with a small amount of mask plates based on a spread spectrum.

Ghost imaging techniques using low-cost bucket detectors have unrivaled advantages for some wavebands where plane array detectors are not available or where focusing is difficult. In these bands, fine mask plates are the key to implementing high-resolution and quality ghost imaging. However, manufacturing a large number of mask plates is necessary but undoubtedly expensive in traditional Hadamard ghost imaging (HGI). Inspired by the spread spectrum technology, Hadamard ghost imaging based on spread spectrum (HGI-SS) is proposed, in which only two sets of a small number of mask plates are needed to accomplish Nyquist sampling for the object. Their numbers are equal to the lateral pixel resolution and the vertical pixel resolution of the object, respectively. Optical experiments verify the effectiveness of the scheme. For ghost imaging with a resolution requirement of 128 × 128 pixels, HGI-SS needs to prepare only 256 mask plates, while the traditional HGI needs to prepare 16,384 mask plates. HGI-SS may be helpful to expand the pixel resolution of imaging at a relatively low cost of mask plates.

Impact of Relative Improvement in Quantitative Flow Ratio on Clinical Outcomes After Percutaneous Coronary Intervention　- A Subanalysis of the PANDA III Trial.

BACKGROUND: The clinical impact of relative improvements in coronary physiology in patients receiving percutaneous coronary intervention (PCI) for coronary artery disease (CAD) remains undetermined.Methods and Results: The quantitative flow ratio (QFR) recovery ratio (QRR) was calculated in 1,424 vessels in the PANDA III trial as (post-PCI QFR-pre-PCI QFR)/(1-pre-PCI QFR). The primary endpoint was the 2-year vessel-oriented composite endpoint (VOCE; a composite of vessel-related cardiac death, vessel-related non-procedural myocardial infarction, and ischemia-driven target vessel revascularization). Study vessels were dichotomously stratified according to the optimal QRR cut-off value. During the 2-year follow-up, 41 (2.9%) VOCEs occurred. Low (<0.86) QRR was associated with significantly higher rates of 2-year VOCEs than high (≥0.86) QRR (6.6% vs. 1.4%; adjusted hazard ratio [aHR] 5.05; 95% confidence interval [CI] 2.53-10.08; P<0.001). Notably, among vessels with satisfactory post-procedural physiological results (post-PCI QFR >0.89), low QRR also conferred an increased risk of 2-year VOCEs (3.7% vs. 1.4%; aHR 3.01; 95% CI 1.30-6.94; P=0.010). Significantly better discriminant and reclassification performance was observed after integrating risk stratification by QRR and post-PCI QFR to clinical risk factors (area under the curve 0.80 vs. 0.71 [P=0.010]; integrated discrimination improvement 0.05 [P<0.001]; net reclassification index 0.64 [P<0.001]). CONCLUSIONS: Relative improvement of coronary physiology assessed by QRR showed applicability in prognostication. Categorical classification of coronary physiology could provide information for risk stratification of CAD patients.

Association of triglyceride-glucose index with adverse cardiovascular events in patients with established coronary artery disease according to different inflammatory status.

BACKGROUND AND AIMS: This study aimed to investigate the association of the triglyceride-glucose (TyG) index, a simple-but-reliable indicator of insulin resistance, with risk of cardiovascular (CV) events in coronary artery disease (CAD) patients with different inflammation status. METHODS AND RESULTS: We consecutively recruited 20,518 patients with angiograph-proven-CAD from 2017 to 2018 at Fuwai Hospital. Patients were categorized according to baseline TyG index tertiles (T) (tertile 1: ≤8.624; T2: 8.624-9.902 and T3: >9.902) and further assigned into 6 groups by high-sensitivity C-reactive protein (hsCRP) medians. The primary endpoint was CV events including CV death, nonfatal myocardial infarction and nonfatal stroke. During the 3.1-year-follow-up, 618 (3.0%) CV events were recorded. Overall, patients with high TyG index levels (T2 or T3) showed significantly increased risk of CV events (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.01-1.53; HR: 1.33; 95%CI: 1.05-1.68, respectively) compared with those with lowest Tyg index (T1) after adjusting for confounding factors. Upon stratification by hsCRP levels, elevated TyG index was associated with increased risk of CV events only in patients with hsCRP levels > median (per-1-unit-increase HR: 1.39; 95%CI: 1.11-1.74), rather than in those with hsCRP levels ≤ median. Furthermore, adding the TyG index to the predicting model led to a significant improvement in patients with hsCRP > median rather than in those with hsCRP ≤ median. CONCLUSIONS: We firstly found that elevated TyG index levels were associated with increased risk of CV events in CAD patients, especially in those with increased inflammatory status, suggesting that it could help in risk stratification and prognosis in this population.

Global migration and factors influencing retention of Asian internationally educated nurses: a systematic review.

BACKGROUND: Given nurses' increasing international mobility, Asian internationally educated nurses (IENs) represent a critical human resource highly sought after within the global healthcare workforce. Developed countries have grown excessively reliant on them, leading to heightened competition among these countries. Hence, this review aims to uncover factors underlying the retention of Asian IENs in host countries to facilitate the development of more effective staff retention strategies. METHODS: A mixed-methods systematic review was conducted using the Joanna Briggs Institute methodology for mixed-method systematic review. A search was undertaken across the following electronic databases for studies published in English during 2013-2022: CINAHL, Embase, PubMed, Scopus, Web of Science and PsycINFO. Two of the researchers critically appraised included articles independently using the Joanna Briggs Critical Appraisal Tools and Mixed Methods Appraisal Tool (version 2018). A data-based convergent integrated approach was adopted for data synthesis. RESULTS: Of the 27 included articles (19 qualitative and eight quantitative), five each were conducted in Asia (Japan, Taiwan, Singapore and Malaysia), Australia and Europe (Italy, Norway and the United Kingdom); four each in the United States and the Middle East (Saudi Arabia and Kuwait); two in Canada; and one each in New Zealand and South Africa. Five themes emerged from the data synthesis: (1) desire for better career prospects, (2) occupational downward mobility, (3) inequality in career advancement, (4) acculturation and (5) support system. CONCLUSION: This systematic review investigated the factors influencing AMN retention and identified several promising retention strategies: granting them permanent residency, ensuring transparency in credentialing assessment, providing equal opportunities for career advancement, instituting induction programmes for newly employed Asian IENs, enabling families to be with them and building workplace social support. Retention strategies that embrace the Asian IENs' perspectives and experiences are envisioned to ensure a sustainable nursing workforce.

Rapid screening and evaluation of natural antioxidants from leaf, stem, and root of Artemisia argyi by online liquid microextraction combined with HPLC-based antioxidant assay system coupled with calibration quantitative analysis.

To reveal the utilization value of leaf, stem, and root of Artemisia argyi, a rapid online liquid microextraction combined with a high-performance liquid chromatography coupled with 2,2-nitrogen-di (3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt antioxidant assay system was established for analysis of antioxidants in the leaf, stem, and root of A. argyi, and a calibration quantitative method of antioxidant activity with equivalent chlorogenic acid was proposed. Thirty-three positive peaks were identified; among them, 12 compounds were found that possess good antioxidant activity including eleven organic acids (components 2-4, 8, 11-14, 17, 19, and 21) and one flavonoids (component 22). The proposed calibration quantitative method avoided the influence of content of compound and compared the extent of radical scavenging capacity of five antioxidant compounds, which were ranked as follow: 3,5-dicaffeoylquinic acid > 3,4-dicaffeoylquinic acid ≈ 4,5-dicaffeoylquinic acid > 1,4-dicaffeoylquinic acid > chlorogenic acid. In conclusion, this study provided composition and biological potential for the future development of the leaf, stem, and root of A. argyi. It is believed that the online liquid microextraction combined with high-performance liquid chromatography based antioxidant assay system can be widely used for the rapid screening of natural antioxidant components in the different parts of natural products.

An inferior vena cava-priority approach in laparoscopic isolated hepatic caudate lobectomy.

PURPOSE: Laparoscopic isolated caudate lobectomy is still a challenging operation for surgeons. The access route of the operation plays a vital role during laparoscopic caudate lobectomy. There are few references regarding this technique. Here, we introduce a preferred inferior vena cava (IVC) approach in laparoscopic caudate lobectomy. METHODS: Twenty-one consecutive patients with caudate hepatic tumours between June 2016 and December 2021 were included in this study. All of them received laparoscopic caudate lobectomy involving an IVC priority approach. The IVC priority approach refers to prioritizing the dissection of the IVC from the liver parenchyma before proceeding with the conventional left or right approach. It emphasizes the importance of the IVC dissection during process. Clinical data, intraoperative parameters and postoperative results were evaluated. Sixteen patients were performed pure IVC priority approach, while 5 patients underwent a combined approach. We subsequently compared the intraoperative and postoperative between the two groups. RESULTS: All 21 patients were treated with laparoscopic technology. The operative time was 190.95 ± 92.65 min. The average estimated blood loss was 251.43 ± 247.45 ml, and four patients needed blood transfusions during the perioperative period. The average duration of hospital stay was 8.43 ± 2.64 (range from 6.0 to 16.0) days. Patients who underwent the pure inferior vena cava (IVC) approach required a shorter hepatic pedicle clamping time (26 vs. 55 min, respectively; P < 0.001) and operation time (150 vs. 380 min, respectively; P = 0.002) than those who underwent the combined approach. Hospitalization (7.0 vs. 9.0 days, respectively; P = 0.006) was shorter in the pure IVC group than in the combined group. CONCLUSIONS: Laparoscopic caudate lobectomy with an IVC priority approach is safe and feasible for patients with caudate hepatic tumours.

Diagnostic status and epidemiological characteristics of community-acquired bacterial meningitis in children from 2019 to 2020: a multicenter retrospective study.

Community-acquired bacterial meningitis (CABM) is the main cause of morbidity and mortality in children. The epidemiology of CABM is regional and highly dynamic. To clarify the diagnostic status and epidemiological characteristics of children with CABM in this region, and pay attention to the disease burden, so as to provide evidence for the prevention and treatment of CABM. By retrospective case analysis, the clinical data of 918 CABM cases in children aged 0-14 years in Zhejiang Province from January, 2019 to December, 2020 were collected. The etiological diagnosis rate of CABM in children was 23.1%, the annual incidence rate 4.42-6.15/100,000, the annual mortality rate 0.06-0.09/100,000,the cure and improvement rate 94.4%, and the case fatality rate 1.4%. The total incidence of neuroimaging abnormalities was 20.6%. The median length of stay for CABM children was 20(16) days, with an average cost of 21,531(24,835) yuan. In addition, the incidence rate was decreased with age. Escherichia coli(E.coli) and group B Streptococcus agalactiae(GBS) were the principal pathogens in CABM infant<3 months(43.3%, 34.1%), and Streptococcus pneumoniae(S. pneumoniae) was the most common pathogen in children ≥ 3 months(33.9%). In conclusion, the annual incidence and mortality of CABM in children aged 0-14 years in Zhejiang Province are at intermediate and low level. The distribution of CABM incidence and pathogen spectrum are different in age; the incidence of abnormal neuroimaging is high; and the economic burden is heavy.

Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

2024 TSOC/TSPS Joint Consensus: Strategies for Advanced Vascular Wound Management in Arterial and Venous Diseases.

The Taiwan Society of Cardiology (TSOC) and Taiwan Society of Plastic Surgery (TSPS) have collaborated to develop a joint consensus for the management of patients with advanced vascular wounds. The taskforce comprises experts including preventive cardiologists, interventionists, and cardiovascular and plastic surgeons. The consensus focuses on addressing the challenges in diagnosing, treating, and managing complex wounds; incorporates the perfusion evaluation and the advanced vascular wound care team; and highlights the importance of cross-disciplinary teamwork. The aim of this joint consensus is to manage patients with advanced vascular wounds and encourage the adoption of these guidelines by healthcare professionals to improve patient care and outcomes. The guidelines encompass a range of topics, including the definition of advanced vascular wounds, increased awareness, team structure, epidemiology, clinical presentation, medical treatment, endovascular intervention, vascular surgery, infection control, advanced wound management, and evaluation of treatment results. It also outlines a detailed protocol for assessing patients with lower leg wounds, provides guidance on consultation and referral processes, and offers recommendations for various wound care devices, dressings, and products. The 2024 TSOC/TSPS consensus for the management of patients with advanced vascular wounds serves as a catalyst for international collaboration, promoting knowledge exchange and facilitating advancements in the field of advanced vascular wound management. By providing a comprehensive and evidence-based approach, this consensus aims to contribute to improved patient care and outcomes globally.

On-Off Switching of a Photocatalytic Overall Reaction through Dynamic Spin-State Transition in a Hofmann Clathrate System.

Spin-state transition is a vital factor that dominates catalytic processes, but unveiling its mechanism still faces the great challenge of the lack of catalyst model systems. Herein, we propose that the {Fe-Pt} Hofmann clathrates, whose dynamic spin-state transition of metal centers can be chemically manipulated through iodine treatment, can serve as model systems in the spin-related structural-catalytic relationship study. Taking the photocatalytic synthesis of H2O2 as the basic catalytic reaction, when the spin state of Fe(II) in the clathrate is high spin (HS), sacrificial agents are indispensable to the photosynthesis of H2O2 because only the photocatalytic oxygen reduction reaction (ORR) occurs; when it is low spin (LS), both the ORR and water oxidation reaction (WOR) can take place, enabling a high H2O2 photosynthesis rate of 66 000 µM g-1 h-1 under visible-light irradiation. In situ characterizations combined with density functional theory calculations confirmed that, compared with the HS-state counterpart, the LS state can induce strong charge transfer between the LS Fe(II) and the iodide-coordinating Pt(IV) in the polymer and reduce the energy barriers for both the ORR and WOR processes, dominating the on-off switching upon the photosynthesis of H2O2 in O2-saturated water. What's more, the one-pot tandem reactions were conducted to utilize the synthesized H2O2 for transforming the low-value-added sodium alkenesulfonates into value-added bromohydrin products with decent conversion rates. This work provides a pioneering investigation into on-off switching the photocatalytic overall reaction through manipulating the metallic spin-state transition in spin-crossover systems.

Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial.

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.

Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma.

BACKGROUND: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.

High triglyceride-glucose index predicts cardiovascular events in patients with coronary bifurcation lesions: a large-scale cohort study.

BACKGROUND: Coronary bifurcation lesion, as a complex coronary lesion, is associated with higher risk of long-term poor prognosis than non-bifurcation lesions. The triglyceride-glucose (TyG) index has been shown to predict cardiovascular (CV) events in patients with coronary artery disease (CAD). However, the prognostic value of the TyG index in patients with bifurcation lesions who are at high risk of CV events remains undetermined. Therefore, this study aimed to investigate the association between the TyG index and CV events in patients with bifurcation lesions. METHODS: A total of 4530 consecutive patients with angiography-proven CAD and bifurcation lesions were included in this study from January 2017 to December 2018. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Patients were assigned into 3 groups according to TyG tertiles (T) (T1: <8.633; T2: 8.633-9.096 and T3: ≥9.096). The primary endpoint was CV events, including CV death, nonfatal myocardial infarction and nonfatal stroke at 3-year follow-up. Restricted cubic spline (RCS) analysis, Kaplan-Meier curves and Cox proportional hazard models were used to investigate the associations between the TyG index and study endpoints. RESULTS: During a median follow-up of 3.1 years, 141 (3.1%) CV events occurred. RCS analysis demonstrated a linear relationship between the TyG index and events after adjusting for age and male sex (non-linear P = 0.262). After multivariable adjustments, elevated TyG index (both T2 and T3) was significantly associated with the risk of CV events (hazard ratio [HR], 1.68; 95% confidence interval [CI],1.06-2.65; HR, 2.10; 95%CI, 1.28-3.47, respectively). When study patients were further stratified according to glycemic status, higher TyG index was associated with significantly higher risk of CV events in diabetic patients after adjusting for confounding factors (T3 vs. T1; HR, 2.68; 95%CI, 1.17-6.11). In addition, subgroup analysis revealed consistent associations of the TyG index with 3-year CV events across various subgroups. Furthermore, adding the TyG index to the original model significantly improved the predictive performance. CONCLUSIONS: High TyG index was associated with CV events in patients with bifurcation lesions, suggesting the TyG index could help in risk stratification and prognosis in this population.

HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study.

BACKGROUND: Prediabetes is common and associated with poor prognosis in patients with acute coronary syndrome and those undergoing revascularization. However, the impact of prediabetes on prognosis in patients with coronary intermediate lesions remains unclear. The objective of the current study is to explore the impact of prediabetes and compare the prognostic value of the different definitions of prediabetes in patients with coronary intermediate lesions. METHODS: A total of 1532 patients attending Fuwai hospital (Beijing, China), with intermediate angiographic coronary lesions, not undergoing revascularization, were followed-up from 2013 to 2021. Patients were classified as normal glucose tolerance (NGT), prediabetes and diabetes according to various definitions based on HbA1c or admission fasting plasma glucose (FPG). The primary endpoint was defined as major adverse cardiovascular events (MACE), the composite endpoint of all-cause death, non-fatal myocardial infarction and repeated revascularization therapy. Multivariate cox regression model was used to explore the association between categories of abnormal glucose category and MACE risk. RESULTS: The proportion of patients defined as prediabetes ranged from 3.92% to 47.06% depending on the definition used. A total of 197 MACE occurred during a median follow-up time of 6.1 years. Multivariate cox analysis showed that prediabetes according to the International Expert Committee (IEC) guideline (6.0 ≤ HbA1c < 6.5%) was associated with increased risk of MACE compared with NGT (hazard ratio [HR]: 1.705, 95% confidence interval [CI] 1.143-2.543) and after confounding adjustment (HR: 1.513, 95%CI 1.005-2.277). Consistently, the best cut-off point of glycated haemoglobin (HbA1c) identified based on the Youden's index was also 6%. Restricted cubic spline analysis delineated a linear positive relationship between baseline HbA1c and MACE risk. Globally, FPG or FPG-based definition of prediabetes was not associated with patients' outcome. CONCLUSIONS: In this cohort of patients with intermediate coronary lesions not undergoing revascularization therapy, prediabetes based on the IEC-HbA1c definition was associated with increased MACE risk compared with NGT, and may assist in identifying high-risk patients who can benefit from early lifestyle intervention.

Association of sleep quality, its change and sleep duration with the risk of type 2 diabetes mellitus: Findings from the English longitudinal study of ageing.

AIMS: This study aimed to evaluate the association of sleep quality and its long-term change with the risk of type 2 diabetes mellitus (T2DM) and to assess the relationship between sleep duration and the risk of T2DM according to categories of sleep quality. MATERIALS AND METHODS: 5728 participants free of T2DM at wave 4 from the English Longitudinal Study of Ageing were included and received a follow-up with a median time of 8 years. We created a sleep quality score to evaluate sleep quality, which was based on three Jenkins Sleep Problems Scale questions (the frequency of feeling hard to fall asleep, waking up at night, and feeling tired in the morning) and one question for rating overall sleep quality. Participants were allocated into three groups according to their baseline sleep quality scores (groups of good [4-8], intermediate [8-12], and poor quality [12-16]). Sleep duration was assessed by a self-reporting sleep hours from each participant. RESULTS: 411 (7.2%) T2DM cases were documented during the follow-up. Compared with the good quality group, subjects with poor sleep quality showed a significantly higher risk of T2DM (hazard ratio (HR) 1.45, confidence interval (CI) 1.09, 1.92). In participants with good baseline sleep quality, those who experienced worsened sleep quality showed a significantly increased T2DM risk (HR 1.77, 95% CI 1.26, 2.49). Type 2 diabetes mellitus risk was not changed regardless of sleep duration in subjects with good quality. Short sleep duration (≤4h) was associated with an elevated T2DM risk in participants with intermediate sleep quality, and both short (≤4h) and prolonged sleep time (≥9h) were associated with an increased T2DM risk in the poor sleep quality group. CONCLUSIONS: Poor sleep quality is correlated with an increase in T2DM risk, and regulating sleep quality to a good range could potentially be an effective approach for preventing T2DM.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858R/T790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.