High-Area-Capacity Cathode by Ultralong Carbon Nanotubes for Secondary Binder-Assisted Dry Coating Technology.

Thick electrodes with high mass loading and increased content of active materials are critical for achieving higher energy density in contemporary lithium-ion batteries (LIBs). Nonetheless, producing thick electrodes through the commonly used slurry coating technology remains a formidable challenge. In this study, we have addressed this challenge by developing a dry electrode technology by using ultralong multiwalled carbon nanotubes (MWCNT) as a conductive additive and secondary binder. The mixing process of electrode compositions and the fibrillation process of the polytetrafluoroethylene (PTFE) binder were optimized. The resulting LiCoO2 (LCO) electrode exhibited a remarkable mass loading of 48 mg cm-2 and an active material content of 95 wt %. Notably, the thick LCO electrode demonstrated a superior mechanical strength and electrochemical performance. After 100 cycles at a current density of 1/3 C, the electrode still exhibited a capacity retention of 91% of its initial capacity. This dry electrode technology provides a practicable and scalable approach to the powder-to-film LIB electrode manufacturing process.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

Hemorheology and Inflammatory Marker Changes in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis with Mechanical Thrombectomy.

Objective: To investigate hemorheology and inflammatory marker changes after treatment for acute ischemic stroke (AIS) using intravenous thrombolysis (IVT) with mechanical thrombectomy (MT). Methods: We retrospectively reviewed clinical records of patients with AIS (n=83) treated in The First Affiliated Hospital of Bengbu Medical College between January 2021 and December 2022 (n=83). The control group consisted of 38 patients who underwent IVT alone and the observation group consisted of 45 patients who underwent IVT with MT. We compared differences in mean variables related to hemorheology, inflammatory markers, and total efficacy between the two groups. Results: We found that hemorheology values (plasma viscosity [PV], whole blood viscosity [WBV], fibrinogen [FIB], and hematocrit [HCT]), and the levels of inflammatory markers (tumor necrosis factor ɑ [TNF-ɑ] and interleukin-6 [IL-6]) were higher in the control group than in the observation group after treatment (P<0.05). In addition, the total efficacy of the observation group (93.3%) was higher than that in the control group (76.3%; P=0.016). Conclusions: The clinical efficacy of combined IVT and MT in the treatment of AIS is superior to IVT alone, improving levels of hemorheology and inflammatory markers in patients with AIS.

Association between trajectories of maternal depressive symptoms and length of hospital stay, hospitalization costs, and adverse maternal and infantile outcomes: A longitudinal observational study.

This study aimed to determine the trajectories of perinatal depression and their relationship with length of hospital stay (LOS), hospitalization costs, and adverse maternal and infantile outcomes. This longitudinal observational study included 525 participants. Perinatal depressive symptoms were assessed at four waves (from the first trimester to the postpartum period). LOS, hospitalization costs, and adverse maternal (sleep, fatigue, anxiety, perceived stress, and memory problems) and infantile outcomes of participants were obtained from medical records and self-reported questionnaires. Trajectories of perinatal depressive symptoms were explored with latent class growth analysis. Associations between trajectories and adverse maternal and infant outcomes were explored with multiple linear regression and binary logistic regression models. The participants' average age was 29.6 ± 3.9 years. Five heterogeneous developmental trajectories of perinatal depressive symptoms were identified as follows: high-level (7.05%), moderate-increasing (12%), remission (15.05%), moderate-level (37.14%), and low-level (28.76%). The average LOS was 5.78 ± 2.13 days, and the average hospitalization costs were 12,695.27 ± 5457.51 yuan. Compared with the trajectory of low-level depressive symptoms, the LOS, hospitalization costs, and likelihood of adverse outcomes of women with high-level and moderate-increasing depressive symptom trajectories increased. The findings capture the heterogeneity of perinatal depression in Chinese women. Women in the moderate-increasing and high-level trajectory groups had longer LOS, more hospitalization costs, and poor birth outcomes. Elucidating the trajectories of perinatal depression and their relationship with maternal and infant health outcomes provides important insights into the development of person-centred care planning for women during pregnancy and postpartum.

Bronchoalveolar Lavage as Potential Diagnostic Specimens to Genetic Testing in Advanced Nonsmall Cell Lung Cancer.

Background: There is limited knowledge on the yield of performing capture-based targeted ultradeep sequencing on bronchoalveolar lavage (BAL) specimens from advanced nonsmall cell lung cancer (NSCLC) patients. This study aimed to evaluate gene variations and performance characteristics in BAL and tissue specimens using targeted sequencing. Methods: This cohort study retrospectively enrolled 20 patients with advanced NSCLC. The variant detection percentage, correlation of tumor mutation burden (TMB), and allele frequency heterogeneity (AFH) were compared between paired BAL and tissue samples. A three-tiered system was also applied for the interpretation of gene variants according to the guidelines. Results: No statistical difference was observed in variant detection between BAL and tissue samples (P = .591 for variant tier and P = .409 for variant type). In general, BAL achieved higher detection rates in tier I variants (96.2% vs 84.6%) and gene fusions (75% vs 50%) compared with tissue samples; tissue samples had better variants detection rates for other variants, such as tier II (89.6% vs 76.0%), tier III (87.1% vs 72.6%), single nucleotide variant (SNV, 89.6% vs 76.5%), insertion/deletion/duplication (InDel, 74.6% vs 69.8%) and copy number variation (CNV, 93.8% vs 43.8%). Besides, there were significant correlations of TMB (R2 = 0.96, P < .001) and AFH (R2 = 0.87, P < .001) between BALs and paired tissues. Conclusions: The findings demonstrate that BAL may serve as a supplement in liquid biopsy for mutation detection and for routine utilization in clinical settings.

Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer.

BACKGROUND: Some research found that elevated plasma cell-free DNA (cfDNA) concentrations and poor prognosis are associated in non-small cell lung cancer (NSCLC). However, more studies need to be carried out to verify this conclusion. Therefore, this study investigated the relationship between cfDNA concentration and treatment outcomes including prognosis in patients with advanced NSCLC. METHODS: We retrospectively collected medical records and cfDNA data from 160 patients with advanced NSCLC. Progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared between groups using the log rank test. Cox regression analysis was used for estimating the independent predictors of PFS. And we used logistic regression to evaluate the relationship between baseline biomarkers and efficacy. In our study, BT1 cfDNA, BT2 cfDNA, and BT3 cfDNA were defined as cfDNA concentration before the first treatment (baseline cfDNA concentration), cfDNA concentration before the second treatment, and cfDNA concentration before the third treatment, respectively. RESULTS: Patients with low cfDNA (BT1 cfDNA < 15 (ng/mL)) were reported a significantly prolonged median progression-free survival (mPFS) compared with patients with patients with high cfDNA (BT1 cfDNA ≥ 15(ng/mL)) (mPFS: 14.6 vs. 8.3 months, P = 0.002), as well as patients with neutrophil/lymphocyte ratio (NLR)<2.98 (mPFS: 13.1 vs. 7.9 months, P = 0.023). In addition, Cox proportional hazards regression analysis identified independent indicators associated with PFS including BT1 cfDNA ≥ 15 (ng/mL), NLR ≥ 2.98 and extrapulmonary metastasis. The best cut-off value for BT3 cfDNA for predicting disease progression is 41.46 (ng/mL) (Area Under the Curve (AUC): 0.652, 95%CI: 0.516-0.788), achieving 90.7% sensitivity and 37.5% specificity for the prediction of disease progression. BT3 cfDNA (OR = 6.08, 95% CI: 1.94-19.57, P = 0.002) was an independent factor for disease progression in patients with advanced NSCLC. CONCLUSIONS: BT1 cfDNA may be a biomarker to assess the prognosis of advanced NSCLC. Patients with advanced NSCLC with lower cfDNA and NLR before treatment had a better prognosis. Increased BT3 cfDNA concentration was an independent factor of disease progression in advanced NSCLC patients. These findings may assist in identifying high-risk patients and guiding treatment strategies.

Association Between Online Health Information-Seeking Behaviors by Caregivers and Delays in Pediatric Cancer: Mixed Methods Study in China.

BACKGROUND: Pediatric cancer patients in China often present at an advanced stage of disease resulting in lower survival and poorer health outcomes. One factor hypothesized to contribute to delays in pediatric cancer has been the online health information-seeking (OHIS) behaviors by caregivers. OBJECTIVE: This study aims to examine the association between OHIS behaviors by caregivers and delays for Chinese pediatric cancer patients using a mixed methods approach. METHODS: This study used a mixed methods approach, specifically a sequential explanatory design. OHIS behavior by the caregiver was defined as the way caregivers access information relevant to their children's health via the Internet. Delays in pediatric cancer were defined as any one of the following 3 types of delay: patient delay, diagnosis delay, or treatment delay. The quantitative analysis methods included descriptive analyses, Student t tests, Pearson chi-square test, and binary logistic regression analysis, all performed using Stata. The qualitative analysis methods included conceptual content analysis and the Colaizzi method. RESULTS: A total of 303 pediatric cancer patient-caregiver dyads was included in the quantitative survey, and 29 caregivers completed the qualitative interview. Quantitative analysis results revealed that nearly one-half (151/303, 49.8%) of patients experienced delays in pediatric cancer, and the primary type of delay was diagnosis delay (113/303, 37.3%), followed by patient delay (50/303, 16.5%) and treatment delay (24/303, 7.9%). In this study, 232 of the 303 (76.6%) caregiver participants demonstrated OHIS behaviors. When those engaged in OHIS behaviors were compared with their counterparts, the likelihood of patient delay more than doubled (odds ratio=2.21; 95% CI 1.03-4.75). Qualitative analysis results showed that caregivers' OHIS behaviors impacted the cancer care pathway by influencing caregivers' symptom appraisal before the first medical contact and caregivers' acceptance of health care providers' diagnostic and treatment decisions. CONCLUSIONS: Our findings suggest that OHIS among Chinese pediatric caregivers may be a risk factor for increasing the likelihood of patient delay. Our government and society should make a concerted effort to regulate online health information and improve its quality. Specialized freemium consultations provided by health care providers via online health informatic platforms are needed to shorten the time for caregivers' cancer symptom appraisal before the first medical contact.

Glutaredoxin-1 promotes lymphangioleiomyomatosis progression through inhibiting Bim-mediated apoptosis via COX2/PGE2/ERK pathway.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease, characterized by progressive cyst formation and respiratory failure. Clinical treatment with the mTORC1 inhibitor rapamycin could relieve partially the respiratory symptoms, but not curative. It is urgent to illustrate the fundamental mechanisms of TSC2 deficiency to the development of LAM, especially mTORC1-independent mechanisms. Glutaredoxin-1 (Glrx), an essential glutathione (GSH)-dependent thiol-oxidoreductase, maintains redox homeostasis and participates in various processes via controlling protein GSH adducts. Redox signalling through protein GSH adducts in LAM remains largely elusive. Here, we demonstrate the underlying mechanism of Glrx in the pathogenesis of LAM. METHODS: 1. Abnormal Glrx expression in various kinds of human malignancies was identified by the GEPIA tumour database, and the expression of Glrx in LAM-derived cells was detected by real-time quantitative reverse transcription (RT-qPCR) and immunoblot. 2. Stable Glrx knockdown cell line was established to evaluate cellular impact. 3. Cell viability was determined by CCK8 assay. 4. Apoptotic cell number and intracellular reactive oxygen species (ROS) level were quantified by flow cytometry. 5. Cox2 expression and PGE2 production were detected to clarify the mechanism of Bim expression modulated by Glrx. 6. S-glutathionylated p65 was enriched and detected by immunoprecipitation and the direct regulation of Glrx on p65 was determined. 7. The xenograft animal model was established and photon flux was analyzed using IVIS Spectrum. RESULTS: In LAM, TSC2 negatively regulated abnormal Glrx expression and activation in a mTORC1-independent manner. Knockdown of Glrx increased the expression of Bim and the accumulation of ROS, together with elevated S-glutathionylated proteins, contributing to the induction of apoptotic cell death and inhibited cell proliferation. Knockdown of Glrx in TSC2-deficient LAM cells increased GSH adducts on nuclear factor-kappa B p65, which contributed to a decrease in the expression of Cox2 and the biosynthesis of PGE2. Inhibition of PGE2 metabolism attenuated phosphorylation of ERK, which led to the accumulation of Bim, due to the imbalance of its phosphorylation and proteasome degradation. In xenograft tumour models, knockdown of Glrx in TSC2-deficient LAM cells inhibited tumour growth and increased tumour cell apoptosis. CONCLUSIONS: Collectively, we provide a novel redox-dependent mechanism in the pathogenesis of LAM and propose that Glrx may be a beneficial strategy for the treatment of LAM or other TSC-related diseases.

The development and validation of a patient-reported outcome measure to assess financial hardship among older cancer survivors in China: hardship and recovery with distress survey.

Background: Financial hardship has been described as a patient's economic experiencefollowing cancer-related treatment. Standardized patient-reported outcome measures(PROM) to assess this distress has not been well-studied, especially among older cancer survivors. Objective: The aim of this study was to develop and validate PROM for assessing the financial hardship of older cancer survivors in China. Methods: Items were generated using qualitative interviews and literature review. Items were screened based on Delphi expert consultation and patients' opinions. Item response theory (IRT) and classical test theory (CTT) were used to help reduce items. Retained items formed a pilot instrument that was subjected to psychometric testing. A cut-off score for the new instrument for predicting poor quality of life was identified by receiver operating characteristic (ROC) analysis. Results: Qualitative interviews and literature review generated 135 items, which were reduced to 60 items because of redundancy. Following Delphi expert consultation and patients' evaluation, 24 items with high importance were extracted. Sixteen items were selected due to satisfactory statistical analysis based on CTT and IRT. Ten items were retained and comprised 2 domains after loadings in exploratory factor analysis (EFA). Internal consistency was satisfactory (α = 0.838). Test-retest reliability was good (intraclass correlation, 0.909). The ROC analysis suggested that the cut-off of 18.5 yielded an acceptable sensitivity and specificity. Conclusions: The PROM for Hardship and Recovery with Distress Survey (HARDS) consists of 10 items that specifically reflect the experiences of financial hardship among older Chinese cancer survivors, and it also showed good reliability and validity in clinical settings.

The study of bioavailability and endogenous circadian rhythm of menaquinone-7, a form of vitamin K2, in healthy subjects.

Menaquinone-7 (MK-7), a multipotent vitamin K2, possesses a wide range of biological activities, a precise curative effect and excellent safety. A simple and rapid LC-APCI-MS/MS method for the determination of MK-7 in human plasma with single liquid-liquid extraction (LLE) extraction and 4·5-min analysis time has been developed and validated. Four per cent bovine serum albumin (BSA) was used as surrogate matrix for standard curves and endogenous baseline subtraction. This method was reproducible and reliable and was used to analyse of MK-7 in human plasma. The endogenous circadian rhythm and bioavailability of MK-7 were investigated in two randomised single-dose, open, one-way clinical trials (Study I and Study II). A total of five healthy male subjects were enrolled in Study I and 12 healthy male subjects in Study II. Single-dose (1 mg) of MK-7 was given to each subject under fasting condition, and all eligible subjects were given a restricting VK2 diet for 4 d prior to drug administration and during the trial. The experiment results of Study I demonstrated that endogenous MK-7 has no circadian rhythm in individuals. Both studies showed MK-7 are absorbed with peak plasma concentrations at about 6 h after intake and has a very long half-life time.

Homologous recombination deficiency status predicts response to platinum-based chemotherapy in Chinese patients with high-grade serous ovarian carcinoma.

BACKGROUND: Homologous Recombination Deficiency (HRD) is a predictive biomarker for ovarian cancer treated with PARP inhibitors or for breast cancer treated with first-line platinum-based chemotherapy. However, limited research is documented on platinum-based treatment prediction with HRD as a biomarker in ovarian cancer patients, especially in the Chinese population. METHODS: We investigated the association between HRD status and the response of platinum-based chemotherapy in 240 Chinese HGSOC patients. RESULTS: The Pt-sensitive patients showed higher HRD scores than Pt-resistant ones, but this was not significant(median: 42.6 vs. 31.6, p = 0.086). (Pt)-sensitive rate was higher in HRD + BRCAm tumors and in HRD + BRCAwt tumors (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) compared with 74% in the HRD-BRCAwt tumors. We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations or non-BRCA HRR pathway gene mutations (BRCA: 93.6% vs 75.4%, p < 0.001; non-BRCA HRR: 88.6% vs 75.4%, p = 0.062). Patients with HRD status positive had significantly improved PFS compared with those with HRD status negative (median PFS: 30.5 months vs. 16.8 months, Log-rank p = 0.001). Even for BRCAwt patients, positive HRD was also associated with better PFS than the HRD-negative group (median: 27.5 months vs 16.8 months, Log-rank p = 0.010). Further, we found patients with pathogenic mutations located in the DNA-binding domain (DBD) of BRCA1 had improved FPS, compared to those with mutations in other domains. (p = 0.03). CONCLUSIONS: The HRD status can be identified as an independent significance in Chinese HGSOC patients treated with first-line platinum-based chemotherapy.

Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma.

BACKGROUND: Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. Polo-like kinase 1 (PLK1), a member of the serine/threonine kinase PLK family, is the most investigated and essential in the regulation of cell cycle progression, including chromosome segregation, centrosome maturation and cytokinesis. However, the nonmitotic role of PLK1 in CRC is poorly understood. In this study, we explored the tumorigenic effects of PLK1 and its potential as a therapeutic target in CRC. METHODS: GEPIA database and immunohistochemistry analysis were performed to evaluate the abnormal expression of PLK1 in CRC patients. MTT assay, colony formation and transwell assay were performed to assess cell viability, colony formation ability and migration ability after inhibiting PLK1 by RNAi or the small molecule inhibitor BI6727. Cell apoptosis, mitochondrial membrane potential (MMP) and ROS levels were evaluated by flow cytometry. Bioluminescence imaging was performed to evaluate the impact of PLK1 on CRC cell survival in a preclinical model. Finally, xenograft tumor model was established to study the effect of PLK1 inhibition on tumor growth. RESULTS: First, immunohistochemistry analysis revealed the significant accumulation of PLK1 in patient-derived CRC tissues compared with adjacent healthy tissues. Furthermore, PLK1 inhibition genetically or pharmacologically significantly reduced cell viability, migration and colony formation, and triggered apoptosis of CRC cells. Additionally, we found that PLK1 inhibition elevated cellular reactive oxygen species (ROS) accumulation and decreased the Bcl2/Bax ratio, which led to mitochondrial dysfunction and the release of Cytochrome c, a key process in initiating cell apoptosis. CONCLUSION: These data provide new insights into the pathogenesis of CRC and support the potential value of PLK1 as an appealing target for CRC treatment. Overall, the underlying mechanism of inhibiting PLK1-induced apoptosis indicates that the PLK1 inhibitor BI6727 may be a novel potential therapeutic strategy in the treatment of CRC.

3D Intracranial Aneurysm Classification and Segmentation via Unsupervised Dual-Branch Learning.

Intracranial aneurysms are common nowadays and how to detect them intelligently is of great significance in digital health. Whereas most existing deep learning research focused on medical images in a supervised way, we introduce an unsupervised method for the detection of intracranial aneurysms based on 3D point cloud data. In particular, our method consists of two stages: unsupervised pre-training and downstream tasks. As for the former, the main idea is to pair each point cloud with its jittering counterpart and maximise their correspondence. Then we design a dual-branch contrastive network with an encoder for each branch and a subsequent common projection head. As for the latter, we design simple networks for supervised classification and segmentation training. Experiments on the public dataset (IntrA) show that our unsupervised method achieves comparable or even better performance than some state-of-the-art supervised techniques, and it is most prominent in the detection of aneurysmal vessels. Experiments on the ModelNet-40 also show that our method achieves the accuracy of 90.79% which outperforms existing state-of-the-art unsupervised models.

Prenatal stress self-help mindfulness intervention via social media: a randomized controlled trial.

BACKGROUND: Prenatal stress is a pressing issue. However, there is a lack of robust evidence for psychosocial interventions to manage this problem. AIMS: This study aimed to examine the effectiveness of a mindfulness-based intervention on reducing prenatal stress compared to participation in health education groups. METHODS: A randomized controlled trial was conducted in a prenatal clinic of comprehensive tertiary care from April to October 2017. A total of 108 pregnant women were randomly assigned to an intervention or a control group. Participants completed self-report measures of depression, anxiety, perceived stress, fatigue, positive and negative affect, and mindfulness before, immediately after, and 15 weeks after the 4-week intervention period. Generalized estimating equations were used to analyze the intervention outcomes. RESULTS: The results supported greater improvement in terms of perceived stress (Wald χ2=26.94, p<0.001), fatigue (Wald χ2=17.61, p<0.001), positive affect (Wald χ2=9.03, p = 0.011), negative affect (Wald χ2=11.37, p = 0.003), and mindfulness (Wald χ2=24.97, p<0.001) in the intervention group than in the control group. CONCLUSIONS: The self-help mindfulness intervention decreased prenatal stress and negative affect and improved positive affect and mindfulness.

Analysis of the relationship between embryo quality at different developmental stages and secondary sex ratio of single live births / 中华妇产科杂志

Objective: To investigate the effect of embryo quality at different developmental stages on the secondary sex ratio (SSR) of single live birth neonates. Methods: Data for patients with singleton live births after embryo transferred between January 2016 and January 2022 were retrospectively analyzed. The effect of embryo quality at different development stages on the SSR of 11 713 singleton live births were investigated. The association of SSR and embryo quality at different development stages was examined in univariate analysis and in a multivariate logistic regression model, after adjustment for confounders, using two models (Ⅰ and Ⅱ). Results: The age of both male and female, body mass index of both male and female, basal follicle stimulating hormone and estradiol, smoking of male, methods of insemination, methods of sperm extraction, types of transfer cycle and the number of embryo transferred were not related with SSR (all P>0.05). After adjustment for confounders, the probability of a male live birth was higher after transfer of good-quality blastula than after transfer of poorer-quality blastula (model Ⅰ: aOR=0.73, 95%CI: 0.65-0.82, P<0.001; model Ⅱ: aOR=0.73, 95%CI: 0.65-0.82, P<0.001). The quality of cleavage stage embryo was not associated with SSR (model Ⅰ: aOR=0.99, 95%CI: 0.87-1.13, P=0.937; model Ⅱ: aOR=0.99, 95%CI: 0.87-1.13, P=0.899). Conclusions: The SSR of singleton live births after embryo transfer is not correlated with the quality of cleavage stage embryo, but is correlated with the quality of blastula. Good-quality blastula transfer is more likely to result in a male live birth.

The impact of LDL-C/HDL-C ratio on severity of coronary artery disease and 2-year outcome in patients with premature coronary heart disease: results of a prospective, multicenter, observational cohort study / 中华心血管病杂志

Objective: To explore the relationship between low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio with the severity of coronary artery disease and 2-yeat outcome in patients with premature coronary heart disease. Methods: This prospective, multicenter, observational cohort study is originated from the PROMISE study. Eighteen thousand seven hundred and one patients with coronary heart disease (CHD) were screened from January 2015 to May 2019. Three thousand eight hundred and sixty-one patients with premature CHD were enrolled in the current study. According to the median LDL-C/HDL-C ratio (2.4), the patients were divided into two groups: low LDL-C/HDL-C group (LDL-C/HDL-C≤2.4, n=1 867) and high LDL-C/HDL-C group (LDL-C/HDL-C>2.4, n=1 994). Baseline data and 2-year major adverse cardiovascular and cerebrovascular events (MACCE) were collected and analyzed in order to find the differences between premature CHD patients at different LDL-C/HDL-C levels, and explore the correlation between LDL-C/HDL-C ratio with the severity of coronary artery disease and MACCE. Results: The average age of the low LDL-C/HDL-C ratio group was (48.5±6.5) years, 1 154 patients were males (61.8%); the average age of high LDL-C/HDL-C ratio group was (46.5±6.8) years, 1 523 were males (76.4%). The number of target lesions, the number of coronary artery lesions, the preoperative SNYTAX score and the proportion of three-vessel coronary artery disease in the high LDL-C/HDL-C group were significantly higher than those in the low LDL-C/HDL-C group (1.04±0.74 vs. 0.97±0.80, P=0.002; 2.04±0.84 vs. 1.85±0.84, P<0.001; 13.81±8.87 vs. 11.70±8.05, P<0.001; 36.2% vs. 27.4%, respectively, P<0.001). Correlation analysis showed that there was a significant positive correlation between LDL-C/HDL-C ratio and preoperative SYNTAX score, the number of coronary artery lesions, the number of target lesions and whether it was a three-vessel coronary artery disease (all P<0.05). The 2-year follow-up results showed that the incidence of MACCE was significantly higher in the high LDL-C/HDL-C group than that in the low LDL-C/HDL-C group (6.9% vs. 9.1%, P=0.011). There was no significant difference in the incidence of all-cause death, cardiac death, myocardial infarction, stroke, revascularization and bleeding between the two groups. Cox multivariate regression analysis showed that the LDL-C/HDL-C ratio has no correlation with 2-year MACCE, death, myocardial infarction, revascularization, stroke and bleeding events above BARC2 in patients with premature CHD. Conclusion: High LDL-C/HDL-C ratio is positively correlated with the severity of coronary artery disease in patients with premature CHD. The incidence of MACCE of patients with high LDL-C/HDL-C ratio is significantly higher during 2 years follow-up; LDL-C/HDL-C ratio may be an indicator for evaluating the severity of coronary artery disease and long-term prognosis in patients with premature CHD.

Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.

Intratumor heterogeneity of driver mutations and TMB distribution in 30 early-stage LUAD patients with multiple lesions.

Background: Differentiating multiple pulmonary lesions as multiple primary lung cancer (MLC) or intra-pulmonary metastasis (IPM) is critical. Lung cancer also has a high genetic heterogeneity, which influenced the treatment strategy. Genetic information may aid in tracing lineage information on multiple lung lesions. This study applied comprehensive genomic profiling to decipher the intrinsic genetics of multiple lung lesions. Methods: Sixty-six lung adenocarcinomas (LUAD) tumor lesions (FFEP) archived from 30 patients were included in this study. The 508 cancer-related genes were evaluated by targeted next-generation sequencing (MGI-seq 2000). Results: The study included a total of 30 LUADs (66 samples). The majority of tumors demonstrated intra-tumoral heterogeneity. Two hundred twenty-four mutations were detected by sequencing the 66 samples. We investigated the driver gene mutations of NSCLC patients with multiple lesions. EGFR was the most frequently (48/198) mutated driver gene. The codons in EGFR mainly affected by mutations were p.L858R (18/66 [27.3%]) and exon 19del (8/66 [12.1%]). In addition, additional driver genes were found, including TP53, BRAF, ERBB2, MET, and PIK3CA. We also found that the inter-component heterogeneity of different lesions and more than two different mutation types of EGFR were detected in seven patients with two lesions (P3, P10, P24, P25, P28, P29, and P30). The TMB values of different lesions in each patient were different in 26 patients (except P4, P5, P14, and P30). Conclusions: Comprehensive genomic profiling should be applied to distinguishing the nature of multiple lung lesions irrespective of radiologic and histologic diagnoses.

The Relationship between the Unmet Needs of Chinese Family Caregivers and the Quality of Life of Childhood Cancer Patients Undergoing Inpatient Treatment: A Mediation Model through Caregiver Depression.

A large proportion of the global burden of childhood cancer arises in China. These patients have a poor quality of life (QoL) and their family caregivers have high unmet needs. This paper examined the association between the unmet needs of family caregivers and the care recipient's QoL. A total of 286 childhood cancer caregivers were included in this cross-sectional study. Unmet needs and depression among caregivers were assessed by the Comprehensive Needs Assessment Tool for Cancer Caregivers (CNAT-C) and the Patient Health Questionnaire (PHQ-9), respectively. The patient's QoL was proxy-reported by the Pediatric Quality of Life Inventory Measurement Models (PedsQL 3.0 scale Cancer Module). Descriptive analyses, independent Student's t-tests, one-way ANOVA, and mediation analyses were performed. The mean scores (standard deviations) for unmet needs, depression, and QoL were 65.47 (26.24), 9.87 (7.26), and 60.13 (22.12), respectively. A caregiver's unmet needs (r = −0.272, p < 0.001) and depression (r = −0.279, p < 0.001) were negatively related to a care recipient's QoL. Depression among caregivers played a mediating role in the relationship between a caregiver's unmet needs and a care recipient's QoL. As nursing interventions address depression among caregivers, it is important to standardize the programs that offer psychological support to caregivers.

Association Between Long-Term HbA1c Variability and Functional Limitation in Individuals Aged Over 50 Years: A Retrospective Cohort Study.

Background: As mean HbA1c provides incomplete information regarding glycemic variability, there has been considerable interest in the emerging association between glycemic variability and macrovascular events and with microvascular complications and mortality in adults with and without diabetes. However, the association between long-term glycemic variability, represented by visit-to-visit HbA1c variability, and functional limitations has not been clarified in previous literature. The present study aimed to explore the longitudinal association between long-term glycemic variability, represented by visit-to-visit HbA1c variability and functional limitations. Methods: This cohort study included adults aged over 50 years who participated in the 2006 to 2016 waves of the Health and Retirement Study. Physical functions, including mobility, large muscle function, activities of daily living (ADLs), and instrumental ADLs (IADLs), were assessed at baseline and every 2 years, and HbA1c levels were assessed at baseline and every 4 years. Visit-to-visit HbA1c variability was calculated using the HbA1c variability score (HVS) during the follow-up period. Generalized estimating equation models were used to evaluate the longitudinal association between HbA1c variability and functional limitations with adjustment for a series of confounders. Results: A total of 5,544 participants having three HbA1c measurements from 2006 to 2016, having two or more physical function measures (including one at baseline), and age over 50 years were included in this analysis. The mean age at baseline was 66.13 ± 8.39 years. A total of 916 (16.5%) participants had an HVS = 100, and 35.1% had an HVS = 50. The highest HVS category (HVS =100) was associated with increased functional status score (ß = 0.093, 95% CI: 0.021-0.165) in comparison with the lowest HVS category (HVS = 0). Sensitivity analyses using the CV and SD of HbA1c as measures of variability showed similar associations between HbA1c variability and functional limitation. An incremental increase in HbA1c-CV (ß = 0.630, 95% CI: 0.127-1.132) or HbA1c-SD (ß = 0.078, 95% CI: 0.006-0.150) was associated with an increase in functional limitation in the fully adjusted model. Conclusions: HbA1c variability was associated with heightened difficulty in performing functional activities over time after adjusting for mean HbA1c levels and multiple demographics and comorbidities. This study provides further evidence regarding the detrimental effect of HbA1c variability and highlights the significance of steady glycemic control.