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Tumor-infiltrating B and plasma cells (TIB) are prevalent in lung adenocarcinoma (LUAD); however, they are poorly characterized. We performed paired single-cell RNA and B-cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multiregion normal tissues. By integrative analysis of ∼50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PC) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and PCs with distinct differentiation trajectories. BCR clonotype diversity increased but clonality decreased in LUADs, smokers, and with increasing pathologic stage. TIBs were mostly localized within CXCL13+ lymphoid aggregates, and immune cell sources of CXCL13 production evolved with LUAD progression and included elevated fractions of CD4 regulatory T cells. This study provides a spatial landscape of TIBs in early-stage LUAD.Significance:While TIBs are highly enriched in LUADs, they are poorly characterized. This study provides a much-needed understanding of the transcriptional, clonotypic states and phenotypes of TIBs, unraveling their potential roles in the immunopathology of early-stage LUADs and constituting a road map for the development of TIB-targeted immunotherapies for the treatment of this morbid malignancy.This article is highlighted in the In This Issue feature, p. 2483

With the development of chronic kidney disease (CKD), the patients showed a gradual decline in renal function, which eventually progressed to end-stage renal disease (ESRD), accompanied by various cardiovascular and cerebrovascular events. Maintenance hemodialysis (MHD) is one of the effective methods to treat ESRD, but some patients still die from cardiovascular and cerebrovascular complications. The purpose of this study was to investigate the relationship between troponin T (TnT), n-terminal brain natriuretic peptide (NT-proBNP), cardiac structure and function and cardiovascular disease in maintenance hemodialysis patients. In this experimental study, 100 patients with MHD were randomly selected as research objects. According to the level of NT-proBNP before dialysis, they were divided into two groups, namely the low NT-proBNP group and the high NT-proBNP group. The clinical and biological indicators and the average value of echocardiography were detected in the two groups. The degree of CKD disease was divided into six stages according to GFR, and the influence of different stages on the cardiac function of CKD patients was detected. The experimental results showed that the levels of TnT and NT-proBNP in MHD patients were significantly increased, and the levels of TnT and NT-proBNP and cardiac function were correlated with the patients with cardiovascular diseases. Cardiac ultrasound confirmed that the NT-proBNP level of patients with left ventricular hypertrophy was significantly higher than that of patients without left ventricular hypertrophy, and the difference between the two was statistically significant (P0.005).

Background Video-assisted thoracic surgery (VATS) has been widely used in the surgical treatment of thoracic diseases, and it suggested surgical and oncological advantages compared with open surgery. However, reports on the application of VATS in surgery of small cell lung cancer (SCLC) are scarce. This study aimed to explore the advantages and disadvantages of different surgical approaches in the treatment of pathological stage T1(pT1) SCLC in terms of safety, clinical outcomes, and lymph node dissection. Patients and Methods Patients who underwent lobectomy for pT1 SCLC between January 2014 and September 2017 were identified from the National Collaborative Lung Cancer Database (LinkDoc Database). The patients were stratified based on the surgery approach (VATS or open lobectomy). Perioperative outcomes and long-term survival were analyzed using SPSS software. Results A total of 169 patients with pT1 SCLC met the criteria and were enrolled for this study, including 110 cases of VATS lobectomies and 59 cases of open lobectomies. VATS lobectomy was associated with less blood loss than open surgery (168.1 ± 237.4 vs. 340.0 ± 509.8 mL, P = .002). Open lobectomy harvested more N2 LNs (11.8 ± 8.2 vs. 8.4 ± 5.8, P = .048) and identified more metastasis positive LNs (3.1 ± 6.0 vs. 1.4 ± 3.0, P = .050). Open lobectomy associated with longer overall survival (OS) but has no statistical difference (23.4 ± 13.2 vs. 20.2 ± 10.9, P = .070). Conclusion Open lobectomy had better lymph node dissection results, and comparable postoperative complications, postoperative hospital stay, and OS to VATS lobectomy. Further studies may still be needed to confirm the recommendation of thoracoscopic approach as a routine surgical procedure for operable SCLC, and until then, open surgery should still be considered.

Alcohol use disorder (AUD) is one of the most serious public health problems worldwide. AUD is a complex disorder, and there is ample evidence that genetic predisposition is critical to its development. Recent studies have shown that genetic predisposition leads to the onset of AUD, and alcohol metabolism can affect epigenetic inheritance, which in turn affects synaptic plasticity, alters brain function, and leads to more severe addictive behaviors. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play an important role in alcohol addiction. This paper reviews the regulatory role of ncRNAs. ncRNAs are involved in enzyme and neurotransmitter reaction systems during alcohol use disorder. Alcohol consumption regulates the expression of ncRNAs that mediate epigenetic modification and synaptic plasticity, which play an important role in the development of chronic AUD. ncRNAs may be used not only as predictors of therapeutic responses but also as therapeutic targets of AUD. Chronic alcoholism is more likely to lead to neuroimmune disorders, including permanent brain dysfunction. AUD induced by long-term alcoholism greatly alters the expression of genes in the human genome, especially the expression of ncRNAs. Alcohol can cause a series of pathological changes by interfering with gene expression, such as through disordered miRNA-mRNA expression networks, epigenetic modifications, disordered metabolism, and even synaptic remodeling. ncRNAs are involved in the transition from moderate drinking to alcohol dependence.

Cofactors are essential components of numerous enzymes, therefore their characterization by structural, biophysical, and biochemical approaches is crucial for understanding the resulting catalytic and regulatory mechanisms. In this chapter, we present a case study of a recently discovered cofactor, the nickel-pincer nucleotide (NPN), by demonstrating how we identified and thoroughly characterized this unprecedented nickel-containing coenzyme that is tethered to lactase racemase from Lactiplantibacillus plantarum. In addition, we describe how the NPN cofactor is biosynthesized by a panel of proteins encoded in the lar operon and describe the properties of these novel enzymes. Comprehensive protocols for conducting functional and mechanistic studies of NPN-containing lactate racemase (LarA) and the carboxylase/hydrolase (LarB), sulfur transferase (LarE), and metal insertase (LarC) used for NPN biosynthesis are provided for potential applications towards characterizing enzymes in the same or homologous families.

Disseminated fusariosis is a rare and fatal infection in immunocompromised patients.We report a case of disseminated amphotericin-resistant fusariosis in a paediatric patient with acute lymphoblastic leukaemia and review the features of reported disseminated fusariosis in China.Case reports of disseminated fusariosis were searched from the Chinese literature over the last two decades.The presented case is a 15-year-old female who developed fever and multiple painful purple plaques with black necrotic centres and blood blisters. Fusarium was detected in blood and skin lesions with a high minimum inhibitory concentration (MIC) of amphotericin B (AMB) (32 μg/mL) and a low MIC of voriconazole (VRC) (0.25 μg/mL). The Fusarium fujikuroi species complex was finally identified by rRNA gene analysis. Combination therapy of VRC and terbinafine (TRF) successfully resolved the disease after more than four months of treatment. Based on the review, the most common manifestations of disseminated fusariosis were fever, skin lesions and positive blood cultures, comprising nine cases (64.3%). Other sites of infection, including the lungs, eyes, sinuses or bone marrow, occurred in eight cases (57.1%). Seven patients (50%) were cured after monotherapy or combination therapy with AMB and VRC.In view of this case and the review of the literature, early identification of Fusarium infection and the appropriate antifungal drugs are critical for successful treatment. Primary therapy should consist of VRC or liposomal amphotericin B (L-AMB), with salvage therapy consisting of posaconazole (PSC). The combination of antifungals is probably necessary and more effective.

This study aimed to explore the efficacy of two unique combinations of nerve blocks on postoperative pain and functional outcome after total knee arthroplasty (TKA).Patients scheduled for TKA were randomized to receive a combination of adductor canal block (ACB) + infiltration between the popliteal artery and capsule of the posterior knee block (IPACK) + sham obturator nerve block (ONB) + sham lateral femoral cutaneous nerve block (LFCNB) (control group), or a combination of ACB + IPACK + ONB + sham LFCNB (triple nerve block group), or a combination of ACB + IPACK + ONB + LFCNB (quadruple nerve block group). All patients received local infiltration analgesia. Primary outcome was postoperative morphine consumption. Secondary outcomes were the time until first rescue analgesia, postoperative pain assessed on the visual analog scale (VAS), QoR-15 score, functional recovery of knee, and postoperative complications.Compared with the control group, the triple and quadruple nerve block groups showed significantly lower postoperative morphine consumption (17.2 ± 9.7 mg vs. 11.2 ± 7.0 mg vs. 11.4 ± 6.4 mg, P = .001). These two groups also showed significantly longer time until first rescue analgesia (P = .007 and .010, respectively, analyzed with Kaplan-Meier method), significantly lower VAS scores on postoperative day 1 (P.01), significantly better QoR-15 scores on postoperative days 1 and 2 (P.001), and significantly better functional recovery of knee including range of motion (P = .002 and .001 on postoperative days 1 and 2), and daily ambulation distance (P.001 and P = .004 on postoperative days 1 and 2). However, the absolute change in morphine consumption, VAS scores, and QoR-15 scores did not exceed the reported minimal clinically important differences (MCIDs) (morphine consumption: 10 mg; VAS scores: 1.5 at rest and 1.8 during movement; QoR-15 scores: 8.0). The MCIDs of other outcomes have not been reported in literature. The triple and quadruple nerve block groups showed no significant differences in these outcomes between each other. The three groups did not show a significant difference in complication rates.Adding ONB or ONB + LFCNB to ACB + IPACK can statistically reduce morphine consumption, improve early pain relief, and functional recovery. However, the absolute change in morphine consumption, VAS scores, and QoR-15 scores did not exceed the MCIDs. Based on our findings and considering the sample size of this study, there is not enough clinical evidence to support the triple or quadruple nerve block use within a multimodal analgesic pathway after TKA.

Summary Background Icotinib has provided survival benefits for patients with advanced, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). We aimed to compare icotinib with chemotherapy in patients with EGFR-mutant stage II–IIIA NSCLC after complete tumour resection. Here, we report the results from the preplanned interim analysis of the study. Methods In this multicentre, randomised, open-label, phase 3 trial done at 29 hospitals in China, eligible patients were aged 18–70 years, had histopathogically confirmed stage II–IIIA NSCLC, had complete resection up to 8 weeks before random assignment, were treatment-naive, and had confirmed activation mutation in exon 19 or exon 21 of the EGFR gene. Participants were randomly assigned (1:1) with an interactive web-based response system to receive either oral icotinib 125 mg thrice daily for 2 years or four 21-day cycles of intravenous chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 of each cycle plus cisplatin 75 mg/m2 on day 1 of each cycle for adenocarcinoma or squamous carcinoma; or pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every 3 weeks for non-squamous carcinoma). The primary endpoint was disease-free survival assessed in the full analysis set. Secondary endpoints were overall survival assessed in the full analysis set and safety assessed in all participants who received study drug. This trial is registered with ClinicalTrials.gov , NCT02448797 . Findings Between June 8, 2015, and August 2, 2019, 322 patients were randomly assigned to icotinib (n=161) or chemotherapy (n=161); the full analysis set included 151 patients in the icotinib group and 132 in the chemotherapy group. Median follow-up in the full analysis set was 24·9 months (IQR 16·6–36·4). 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median disease-free survival was 47·0 months (95% CI 36·4–not reached) in the icotinib group and 22·1 months (16·8–30·4) in the chemotherapy group (stratified hazard ratio [HR] 0·36 [95% CI 0·24–0·55]; p Interpretation Our results suggest that compared with chemotherapy, icotinib significantly improves disease-free survival and has a better tolerability profile in patients with EGFR-mutant stage II–IIIA NSCLC after complete tumour resection. Funding Betta Pharmaceuticals Translation For the Chinese translation of the abstract see Supplementary Materials section.

ObjectivesThis work aims to examining the latest early childhood caries situation in children aged 3 and 5 and its related risk factors in Zhejiang Province during the COVID-19 pandemic.MethodThere are 3,537 children and their main caregivers participate in this study. We used chi square test or U-test to analyze whether there were differences in the prevalence of dental caries under different variables. The risk factors on ECC were determined by multivariate logistic analysis.ResultsThe ECC rate of children in this study was 57.51%. The mean decayed missing filled teeth (dmft) scores were 3.01. The result of multivariate logistic analysis showed higher ECC prevalence was found in children as age increasing, with lower district economic level, with high frequency of confectionary consumption, having oral medical treatment behavior and bad evaluation of children's oral health by parents.ConclusionIn general, the prevalence rate of ECC in this study was lower than five years ago, but still higher than those developed countries. And it was associated with age, district economic level, frequency of confectionary consumption, oral medical treatment behavior and evaluation of children's oral health by parents.

OBJECTIVE This study aimed to examine the association of subjective and objective sleep quality with subsequent peptic ulcer rebleeding among older patients. METHODS Of 1196 older patients with peptic ulcer bleeding (PUB) recruited from 12 grade A hospitals in the People's Republic of China, 1106 achieved full recovery from PUB, and they were followed up for up to 30 days. Using multiple measures at 1-week intervals, patients who presented PUB symptoms were invited to have an esophagogastroduodenoscopy examination. Subjective sleep quality was measured using the Pittsburgh Sleep Quality Index. Objective sleep quality domains were measured using an accelerometer, including sleep onset latency, sleep efficiency, total sleep time, and the number of awakenings. RESULTS This study documented a 30-day cumulative ulcer rebleeding rate of 15.3%. Multivariate analyses showed that longer sleep onset latency (hazard ratio [HR] = 2.136 [1.336-2.558]) and more nighttime awakenings (HR = 1.698 [1.169-2.666]) increased the risk of ulcer rebleeding. However, a longer total sleep time (HR = 0.768 [0.698-0.887]) and better sleep efficiency (HR = 0.795 [0.682-0.975]) protected against ulcer rebleeding. Older patients who perceived poorer sleep quality were also more likely to experience ulcer rebleeding (HR = 2.295 [1.352-3.925]). CONCLUSIONS The present results highlight the importance of proper treatment and prevention of sleep problems in older adults after successful PUB treatment. Our results, if replicable in future studies with more rigorous design and representative samples, might shed light on the etiology of ulcer rebleeding and suggest new pathways for preventing this disease.

Background Esophageal cancer (EC) is a malignant tumor with high mortality. Nomogram is an important tool used in clinical prognostic assessment. We aimed to establish a novel nomogram to predict the overall survival (OS) of EC patients after radical esophagectomy. Methods Data pertaining to the survival, demography, and clinicopathology of 311 EC patients who underwent radical esophagectomy were retrospectively investigated. The nomogram was established based on Cox hazard regression analysis. The calibration curves and Harrell's concordance index (C‐index) were used to verify the predictive accuracy and ROC curves were used to assess the efficacy of the nomogram. Kaplan–Meier curves showed the prognostic value of the related risk classification system. Pearson correlation test was performed to determine the correlation between the risk classification system and TNM staging. Results The median OS and 5‐year survival rates in the primary and validation cohorts were 44 months and 29.8%, and 52 months and 27.1%, respectively. We used six independent prognostic factors—age, Sex, AGR, PRL, N stage, and PNI—in the nomogram. The C‐index of nomogram was 0.75 and 0.70 in the primary and validation cohorts, respectively. Calibration curves indicated high consistency between actual and predicted OS. ROC curves showed that nomogram has a better efficacy compared with TNM staging in both cohorts. Patients were divided into three risk groups according to the total nomogram score, the median OS in each group was significantly different in both cohorts. Furthermore, the risk classification system was strongly correlated with the T and N staging system and exhibited a better OS prediction capability. Conclusions We established a novel and practical nomogram with a subordinate risk classification system to predict the OS of patients after radical esophagectomy. Compared with AJCC staging, this nomogram had preferable clinical capability in terms of individual prognosis assessment., We built and validated a novel nomogram to predict OS in radical esophageal cancer resection patients, the nomogram showed considerable prognostic capability especially compared with AJCC staging. Furthermore, a related risk classification system was generated for clinical evaluation.

Purpose To compare the morphological and biomechanical properties of normal cornea and keratoconus at different stages. Methods A total of 408 patients (517 eyes) with keratoconus were included in this study. According to the Topographic Keratoconus (TKC) grading method, keratoconus was divided into stage I (TKC = 1, 130 eyes), stage II (TKC = 1–2, 2, 164 eyes), stage III (TKC = 2–3, 3, 125 eyes) and stage IV (TKC = 3–4, 4, 98 eyes). A total of 158 normal subjects (158 eyes) were recruited as the normal group. The corneal morphological parameters and biomechanical parameters were obtained with Scheimpflug tomography (Pentacam) and corneal visualization Scheimpflug technology (Corvis ST), and the receiver operating characteristic (ROC) curves were drawn. Results Each corneal morphological and most biomechanical parameters of the keratoconic eyes were significantly different from those of the normal eyes in this study (p 0.9), with the Belin-Ambrósio deviation (BAD-D) and Tomographic and Biomechanical Index (TBI) showing higher efficiency. The efficiency of BAD-D and TBI was high in differentiating keratoconus at different stages (AUC > 0.963). The comparison of ROC curves of keratoconus at different stages did not reveal statistically significant differences for TBI. Conclusion BAD-D and TBI can effectively diagnose stage I keratoconus. Moreover, the efficiency of TBI is the same in diagnosing keratoconus at all stages, while the diagnostic efficiency of other parameters increases with the increase in keratoconus stages.

BackgroundThe outbreak of coronavirus disease 2019 (COVID-19) has brought indelible harms to the world and aroused great concern worldwide. This paper aims to analyze the impact of COVID-19 on sexual function using bibliometrics, and summarize research hotspots in this field.MethodsRelevant publications concerning the impact of COVID-19 on sexual function in the Web of Science collection database (WoSCC) between January 1, 2020 and March 12, 2022 were screened and analyzed by bibliometric analysis using the visualization software CiteSpace and VOSviewer.ResultsOf the 1,054 publications screened, the United States (US) contributed the most (398/37.8%), followed by the United Kingdom (UK) (119/11.3%). Among all institutions, the University of Toronto in Canada enjoyed the largest number of publications (30), and Johns Hopkins University in the US enjoyed the highest frequency of citation (235). The journal INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH published the largest number of studies in this field (31), and the most-cited journal was LANCET. “Chow, Eric,” “Ong, Jason J,” and “Stephenson, Rob” tied for first place in publications (8), and “Fish, Jessica N.” enjoyed the highest number of citations (99). Burstness analysis of references and keywords showed that the developing research trends in this field mainly focused on “sexual transmission” and “angiotensin converting-enzyme 2 (ACE2)” during the COVID-19 pandemic.ConclusionThe impact of COVID-19 on sexual function remains an urgent concern at present, and the management of sexual health during the pandemic needs to be further improved. More frequent and deeper cooperation between countries and institutions is required in future. Meanwhile, searching for more evidence on whether COVID-19 can achieve sexual transmission and the pathophysiological mechanisms underlying the impact of COVID-19 on sexual function remains a focus of research in the coming years.

The ubiquity of polycyclic aromatic hydrocarbons (PAHs) in soils in petroleum refining areas is an important problem affecting human and ecological safety. In this study, 103 topsoil (0-0.50 m) samples were collected from a retired petroleum refinery area in Guangdong province, south China. The PAHs concentrations were determined by ultrasonic extraction and gas chromatography-mass spectrometry detection methods. Twelve PAHs controlled priority listed by the US Environmental Protection Agency (USEPA) were investigated. The results revealed that the concentration of Ʃ

Objective This study aims to establish the predictive model of carotid plaque formation and carotid plaque location by retrospectively analyzing the clinical data of subjects with carotid plaque formation and normal people, and to provide technical support for screening patients with carotid plaque. Methods There were 4300 subjects in the ultrasound department of Maanshan People's Hospital collected from December 2013 to December 2018. We used demographic and biochemical data from 3700 subjects to establish predictive models for carotid plaque and its location. The leave-one-out cross-validated classification, 600 external data validation, and area under the receiver operating characteristic curve (AUC) were used to verify the accuracy, sensitivity, specificity, and application value of the model. Results There were significant difference of age (F = − 34.049, p χ2 = 191.067, p χ2 = 4.762, p χ2 = 8.306, p F = 15.322, p F = 13.840, p F = 52.074, p (F = 2.679, p p p p p Conclusion Demographic characteristics and blood biochemical indexes were used to establish the carotid plaque and its location discriminant models based on Fisher discriminant analysis (FDA), which has high application value in community screening.

The aim of this study is to evaluate the value of the triglyceride-glucose (TyG) index and the risk of large artery atherosclerotic (LAA) stroke. Information on general demographic and clinical characteristics, magnetic resonance angiography (MRA) examination, and blood biochemical index determination were obtained. Based on age stratification, three models to evaluate the odds ratio (OR) and the 95% confidence interval (95% CI) were employed to determine the correlation between the TyG index and the risk of LAA stroke. The most effective TyG index threshold in predicting a high risk of LAA stroke was identified using receiver operating characteristic (ROC) curve analysis. Logistic regression verified the association between the risk of LAA stroke and the TyG index. Both with and without age stratification, logistic regression analysis showed that the TyG index was a significant predictor of the occurrence of LAA stroke ( P < 0.05 ). The maximum Youden index for determining a high risk of LAA stroke was found at a TyG index of 4.60. The area under the ROC curve was 0.69 (95% CI: 0.646–0.742, P < 0.05 ), sensitivity was 78.0%, and specificity was 63.4%. An elevated TyG index was remarkably associated with a high risk of LAA stroke.

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.

Demyelination results from the pathological loss of myelin and is a hallmark of many neurodegenerative diseases. Despite the prevalence of demyelinating diseases, there are no disease modifying therapies that prevent the loss of myelin or promote remyelination. This review aims to summarize studies in the field that highlight the importance of nuclear hormone receptors in the promotion and maintenance of myelination and the relevance of nuclear hormone receptors as potential therapeutic targets for demyelinating diseases. These nuclear hormone receptors include the estrogen receptor, progesterone receptor, androgen receptor, vitamin D receptor, thyroid hormone receptor, peroxisome proliferator-activated receptor, liver X receptor, and retinoid X receptor. Pre-clinical studies in well-established animal models of demyelination have shown a prominent role of these nuclear hormone receptors in myelination through their promotion of oligodendrocyte maturation and development. The activation of the nuclear hormone receptors by their ligands also promotes the synthesis of myelin proteins and lipids in mouse models of demyelination. There are limited clinical studies that focus on how the activation of these nuclear hormone receptors could alleviate demyelination in patients with diseases such as multiple sclerosis (MS). However, the completed clinical trials have reported improved clinical outcome in MS patients treated with the ligands of some of these nuclear hormone receptors. Together, the positive results from both clinical and pre-clinical studies point to nuclear hormone receptors as promising therapeutic targets to counter demyelination.

Summary Immune checkpoint inhibitors (ICIs) have shown a powerful benefit in the neoadjuvant therapy for esophageal cancer, but evidence for its safety and efficacy is limited and may not reflect real-world practice. We retrospectively reviewed the database of treatment-naive patients from 15 esophageal cancer centers in China who received ICIs as neoadjuvant treatment for locally advanced esophageal cancer from May 2019 to December 2020. The primary endpoints were rate and severity of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs). Secondary endpoints included pathologically complete response (pCR) rate, R0 resection rate, mortality and morbidity. Among the 370 patients, 311 (84.1%) were male with a median age of 63 (range: 30–81) years and stage III or IVa disease accounted for 84.1% of these patients. A total of 299 (80.8%) patients were treated with ICIs and chemotherapy. TRAEs were observed in 199 (53.8%) patients with low severity (grade 1-2, 39.2%; grade 3-4, 13.2%; grade 5, 1.4%), and irAEs occurred in 24.3% of patients and were mostly of grade 1-2 severity (21.1%). A total of 341 (92.2%) patients had received surgery and R0 resection was achieved in 333 (97.7%) patients. The local pCR rate in primary tumor was 34.6%, including 25.8% of ypT0N0 and 8.8% of ypT0N+. The rate of postoperative complications was 41.4% and grade 3 or higher complications occurred in 35 (10.3%) patients. No death was observed within 30 days after surgery, and three patients (0.9%) died within 90 days postoperatively. This study shows acceptable toxicity of neoadjuvant immunotherapy for locally advanced esophageal cancer in real-world data. Long-term survival results are pending for further investigations.

Background The optimal strategy of percutaneous coronary intervention (PCI) for isolated left anterior descending (LAD) ostial lesions remains debatable. This study aimed to compare clinical outcomes of patients with isolated LAD ostial stenosis treated by single-stent crossover versus accurate ostial stenting. Methods A total of 216 eligible consecutive patients with isolated de novo LAD ostial stenosis were enrolled, and were stratified according to the stenting techniques. Clinical follow-up was performed by review of medical charts or telephone contact with the patients, and repeat angiography was made at 9-12 months after the procedure. Major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, non-fatal stroke and target vessel revascularization (TVR) were recorded. Results Single-stent crossover and accurate ostial stenting were applied to 78 (36%) and 138 (64%) patients, respectively. During a mean of 13 ± 4.1 months of follow-up, the rate of composite MACE (19.6 vs. 8.9%; P = 0.040) was higher in LAD ostial stenosis patients treated with accurate ostial stenting than those treated with single-stent crossover technique, mainly driven by more frequent TVR (17.4 vs. 7.7%; P = 0.048). PCI strategy was an independent predictor of MACE (hazard ratio 2.561; 95% CI, 1.041-6.299; P = 0.021) in the multivariable Cox regression analysis. Conclusions Our retrospective study suggests that the single-stent crossover technique is associated with a better 1-year clinical outcome compared with accurate ostial stenting in patients with isolated LAD ostial stenosis.

Defective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2–mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development., Eye lens cells are highly enriched in cholesterol that sustains lens transparency, and disruption of cholesterol biosynthesis leads to cataracts. The authors show that cholesterol biosynthesis regulated by Qki is essential for maintenance of membrane integrity of lens cells and proper protein folding.

Objective To determine whether machine learning techniques would enhance our ability to incorporate key variables into a parsimonious model with optimized prediction performance for electroencephalographic seizure (ES) prediction in critically ill children. Methods We analyzed data from a prospective observational cohort study of 719 consecutive critically ill children with encephalopathy who underwent clinically-indicated continuous EEG monitoring (CEEG). We implemented and compared three state-of-the-art machine learning methods for ES prediction: (1) random forest; (2) Least Absolute Shrinkage and Selection Operator (LASSO); and (3) Deep Learning Important FeaTures (DeepLIFT). We developed a ranking algorithm based on the relative importance of each variable derived from the machine learning methods. Results Based on our ranking algorithm, the top five variables for ES prediction were: (1) epileptiform discharges in the initial 30 minutes, (2) clinical seizures prior to CEEG initiation, (3) sex, (4) age dichotomized at 1 year, and (5) epileptic encephalopathy. Compared to the stepwise selection-based approach in logistic regression, the top variables selected by our ranking algorithm were more informative as models utilizing the top variables achieved better prediction performance evaluated by prediction accuracy, AUROC and F1 score. Adding additional variables did not improve and sometimes worsened model performance. Conclusion The ranking algorithm was helpful in deriving a parsimonious model for ES prediction with optimal performance. However, application of state-of-the-art machine learning models did not substantially improve model performance compared to prior logistic regression models. Thus, to further improve the ES prediction, we may need to collect more samples and variables that provide additional information.

We analyzed the prognostic value of N6-methyladenosine (m6A) regulatory genes in lung adenocarcinoma (LADC) and their association with tumor immunity and immunotherapy response. Seventeen of 20 m6A regulatory genes were differentially expressed in LDAC tissue samples from the TCGA and GEO databases. We developed a five-m6A regulatory gene prognostic signature based on univariate and Lasso Cox regression analysis. Western blot analysis confirmed that the five prognostic m6A regulatory proteins were highly expressed in LADC tissues. We constructed a nomogram with five-m6A regulatory gene prognostic risk signature and AJCC stages. ROC curves and calibration curves showed that the nomogram was well calibrated and accurately distinguished high-risk and low-risk LADC patients. Weighted gene co-expression analysis showed significant correlation between prognostic risk signature genes and the turquoise module enriched with cell cycle genes. The high-risk LADC patients showed significantly higher PD-L1 levels, increased tumor mutational burden, and a lower proportion of CD8+ T cells in the tumor tissues and improved response to immune checkpoint blockade therapy. These findings show that this five-m6A regulatory gene signature is a prognostic biomarker in LADC and that immune checkpoint blockade is a potential therapeutic option for high-risk LADC patients.

Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE).This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE.This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively.Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.【中文题目：非小细胞肺癌围手术期免疫治疗 相关不良反应管理的临床诊疗建议】 【中文摘要：背景与目的 肺癌围手术期治疗（术前新辅助治疗及术后辅助治疗）作为手术的重要辅助手段，已成为非小细胞肺癌（non-small cell lung cancer, NSCLC）全程管理中越来越重要的环节。近年来，小规模临床研究发现免疫新辅助治疗主要病理缓解率明显提升，甚至达到完全病理缓解，有望成为NSCLC治疗的重要组成部分。然而，免疫新辅助治疗带来疗效和生存获益，同时，其相关严重不良反应（延误手术、丧失手术机会、死亡等）备受关注。本诊疗建议目的是针对免疫检查点抑制剂相关不良反应（immune-related adverse event, irAE）形成适合国内医疗现状的诊疗方案。方法 本文由胸外科专家、肿瘤学专家、胸内科专家以及irAE相关科室专家（消化内科、呼吸内科、心血管内科、感染内科、血液内科、内分泌科、风湿免疫科、神经内科、皮肤科和急诊科）共同完成本诊疗意见的制定工作。专家充分参考irAE指南、胸外科公开发表的大型临床研究数据以及国内医生的临床实战经验和公开发表个案，多学科反复讨论，形成针对围手术期免疫治疗相关不良反应的诊疗建议。结果 本诊疗意见涵盖irAE相关的预防、评估、检查、治疗和监测全过程，以便全面、有效的指导临床工作。结论 围手术期irAE管理是肺癌免疫围手术期治疗的重要组成部分，随着免疫围手术期治疗的不断发展，未来需要更多的研究，以优化围手术irAE的诊疗。 】 【中文关键词：肺肿瘤；围手术期免疫治疗；免疫相关不良事件；诊疗建议】.

To investigate the effect of overnight orthokeratology (OOK) on the ocular surface and dry eye-related cytokines in children.A non-randomized, prospective pilot study was conducted including sixty myopes treated with OOK and sixty age-matched spectacle wearing participants. The following tests were performed before and after 1, 3, 6 and 12 months: ocular surface disease index (OSDI), noninvasive tear breakup time (NITBUT), tear meniscus height (TMH), corneal fluorescein staining (CFS), meiboscore using noncontact meibography. Then the concentrations of interleukin-17A (IL-17A), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in tear samples were detected with a multiplex immunobead assay at different time points.All parameters had no statistical differences between the two groups prior to treatment. No adverse events were observed except trace to moderate corneal staining and allergic conjunctivitis in the treatment group. NITBUT significantly decreased after 6 and 12 months OOK wearing (P = 0.003 and P = 0.001, respectively). After wearing OOK there was a significant increase in CFS at each follow-up time point compared with baseline (P = 0.023, P = 0.016, P = 0.001, and P 0.001at 1, 3, 6, and 12 months, respectively). The upper meiboscore and the total meiboscore increased gradually and peaked at 12 months of OOK (both P 0.001). The concentration of the three cytokines in the treatment group significantly increased after OOK wearing. These increases occurred at different time points: IL-17A increased significantly 3 months after OOK, IL-6 at 6 months, and PGE2 at 12 months (all P 0.001). However, there were no significant changes in the above parameters in the control group. There were no significant differences in the OSDI or TMH at any follow-up time point compared to baseline in both groups (both P 0.05).Short-term OOK may reduce the stability of the tear film and increase damage to the corneal epithelium. Long-term OOK could induce ocular inflammation through the disruption of meibomian glands.

Severe acute ischaemic stroke early after wedge resection is very rare in healthy middle-aged patients. Here, we reviewed the data and characteristics of 9 cases. The infarction resulted from embolism in intracranial arteries, severely impacting the quality of life. In the first 2 patients, the onset symptom was confused with residual anaesthetic effects early after surgery. Drawing from the initial 2 cases, the following 7 patients received accurate diagnosis and emergent endovascular thrombus aspiration with good outcome due to immediate reperfusion. Furthermore, we discuss the principal causes of severe acute stroke in healthy middle-aged patients and the efficacy of endovascular thrombus aspiration.

OBJECTIVE: To study the clinical features of children with colorectal polyps and the efficacy of endoscopic treatment. METHODS: A retrospective analysis was performed on the medical data of 1 351 children with colorectal polyps who were admitted and received colonoscopy and treatment in the past 8 years, including clinical features and the pattern and outcomes of endoscopic treatment. RESULTS: Among the 1 351 children, 893 (66.10%) were boys and 981 (72.61%) had an age of 2

Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction.

The aim of this research was to examine the effects of biochar addition (B0:0 t·hm

Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. Methods: We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. Results: We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction–induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

Background Treatment of coronary in-stent restenosis (ISR) remains challenging in contemporary clinical applications. Drug-coated balloon (DCB) angioplasty offers an effective treatment for ISR. Shenqi is a novel iopromide-based paclitaxel-coated balloon and its clinical safety, effectiveness and angiographic efficacy in patients with ISR have not been investigated. Methods A total of 216 subjects with the first occurrence of ISR at 11 investigational sites in China were randomly allocated in a 1:1 fashion to treatment with DCB SeQuent Please or Shenqi. Clinical follow-up was planned at 1, 6, 9 and 12 months, and angiographic follow-up was planned at 9 months. The study was powered for the primary endpoint of 9-month in-segment late loss. Results At 9-month follow-up, the in-segment late loss was 0.29 ± 0.43 mm with Shenqi versus 0.30 ± 0.46 mm with SeQuent Please, and the one-sided 97.5% upper confidence limit of the difference was 0.14 mm, achieving noninferiority of Shenqi compared with SeQuent Please (P = 0.002). In total, 12 patients developed target lesion failure (TLF) in the Shenqi group compared with 16 patients in the SeQuent Please group (10.91% versus 15.09%; P = 0.42) within 1 year. TLF was mainly driven by target lesion revascularization (9.09%) followed by target vessel-related myocardial infarction (1.82%) and cardiovascular death (0.91%) in the Shenqi group. Conclusions Shenqi DCB was noninferior to SeQuent Please DCB for the primary endpoint of 9-month in-segment late loss. Shenqi DCB may become an attractive alternative treatment for patients with coronary ISR, withholding the need for additional stent implantation.

Background The majority of previous studies of the clinical outcome of video‐assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non‐small cell lung cancer (pN2 NSCLC) have been single‐center experiences with small patient numbers. The aim of this study was therefore to investigate these procedures but in a large cohort of Chinese patients with pathological N2 NSCLC in real‐world conditions. Methods Patients who underwent lobectomy for pN2 NSCLC by either VATS or thoracotomy were retrospectively reviewed from 10 tertiary hospitals between January 2014 and September 2017. Perioperative outcomes and overall survival of the patients were analyzed. Cox regression analysis was performed to identify potential prognostic factors. Propensity‐score analysis was performed to reduce cofounding biases and compare the clinical outcomes between both groups. Results Among 2144 pN2 NSCLC, 1244 patients were managed by VATS and 900 by open procedure. A total of 305 (24.5%) and 344 patients died during VATS and the thoracotomy group during a median follow‐up of 16.7 and 15.6 months, respectively. VATS lobectomy patients had better overall survival when compared with those undergoing the open procedure (P, The present study aimed to investigate the clinical outcome of video‐assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non‐small cell lung cancer (pN2 NSCLC) using a large cohort of Chinese patients in real world conditions. VATS lobectomy might be a feasible alternative for pN2 NSCLC.

N2 non-small cell lung cancer (NSCLC) without N1 involvement, also known as skip metastases (pN0N2), has been suggested as a subgroup of heterogeneous N2 disease with better survival. This real-world observational study aimed to elucidate the prognostic impacts of skip N2 metastases using a large number of pathologic N2 NSCLC from 10 participating centers in China.Medical records of pN2 NSCLC patients after surgical resection at 10 thoracic surgery centers between January 2014 and September 2017 were retrospectively reviewed based on the LinkDoc database. Clinical data on patient demographics, tumor characteristics, treatments and clinical outcomes were collected. Overall survival of patients with and without skip metastases was evaluated and compared by Kaplan-Meier method and Log-rank test. Cox proportional hazard model was established to identify potential prognostic predictors. Subgroup analysis was carried out to further explore the prognostic significance of skip metastases.Among 2653 surgically resected N2 patients, 881 (33.2%) had skip metastases. Patients with skip N2 had a significant better overall survival (P = 0.0019). Multivariate COX regression analysis showed borderline significance of skip metastases (HR = 0.81, 95%CI: 0.645-1.017, P = 0.0698) after adjustment for other covariates. Other independent prognostic predictors included smoking history, tumor location, stage and N2 station involved (P 0.05). Subgroup analysis demonstrated significant survival benefits of skip N2 in most subpopulations.This study suggested a prognostic benefit of skip N2 metastases in real world practice. Further subdivision of N2 disease is warranted for better patient management and prognostic prediction (NCT03429192).

LOTUS domains are helix-turn-helix protein folds identified in essential germline proteins and are conserved in prokaryotes and eukaryotes. Despite originally predicted as an RNA binding domain, its molecular binding activity towards RNA and protein is controversial. In particular, the most conserved binding property for the LOTUS domain family remains unknown. Here, we uncovered an unexpected specific interaction of LOTUS domains with G-rich RNA sequences. Intriguingly, LOTUS domains exhibit high affinity to RNA G-quadruplex tertiary structures implicated in diverse cellular processes including piRNA biogenesis. This novel LOTUS domain-RNA interaction is conserved in bacteria, plants and animals, comprising the most ancient binding feature of the LOTUS domain family. By contrast, LOTUS domains do not preferentially interact with DNA G-quadruplexes. We further show that a subset of LOTUS domains display both RNA and protein binding activities. These findings identify the LOTUS domain as a specialized RNA binding domain across phyla and underscore the molecular mechanism underlying the function of LOTUS domain-containing proteins in RNA metabolism and regulation.

Long noncoding RNAs (lncRNAs) participate in organ fibrosis and various pulmonary diseases, but its role in idiopathic pulmonary fibrosis (IPF) is not fully understood. In this study, we found lncRNA Hoxaas3 (Hoxaas3) was up-regulated in the mice model of BLM-induced PF and TGF-β1-induced fibrogenesis in lung fibroblasts (LF). Overexpression of Hoxaas3 promoted fibrogenesis, whereas Hoxaas3 inhibition attenuated lung fibrosis both in vitro and in vivo, through regulation of miR-450b-5p. Furthermore, miR-450b-5p inhibition stimulated fibrogenesis by regulating runt-related transcription factor 1 (Runx1), whereas up-regulation of miR-450b-5p alleviated fibrogenesis in LF. Mechanistically, our study showed that Hoxaas3 regulated lung fibroblast activation and fibrogenesis by acting as a competing endogenous RNA for miR-450b-5p: Hoxaas3 decreased the expression of miR-450b-5p to stimulate level and activity of Runx1 and induced fibrotic LF, whereas Runx1 inhibition alleviated the pro-fibrotic effect of Hoxaas3. In addition, Hoxaas3 was regulated by TGF-β1/Smad4 pathway as its transcriptional target. In conclusion, our study showed the role and mechanism of the TGF-β1/Smad4- Hoxaas3–miR-450b-5p–Runx1 axis for a better understanding of PF, demonstrated Hoxaas3 maybe a new diagnostic biomarker or potential therapeutic target for IPF.

Peri-articular infiltration analgesia (PIA) is a widely used method to control post-operative pain in total knee arthroplasty (TKA) patients. However, there are limited data that support the use of morphine in PIA. This study aims to evaluate the efficacy of peri-articular morphine infiltration for pain management in TKA patients. Based on a double-blind, randomized approach, patients were allocated to the morphine or control group. Patients in the morphine group received a peri-articular infiltration of an analgesic cocktail consisting of ropivacaine, epinephrine, and morphine. Morphine was omitted from the cocktail in the control group. Primary outcomes were post-operative consumption of morphine hydrochloride used for rescue analgesia and post-operative pain as assessed by visual analog scale (VAS) score. Secondary outcomes were functional recovery as assessed by a range of knee motion, quadriceps strength, and daily ambulation distance. The duration of hospital stay was also recorded. Tertiary outcomes included the occurrence of post-operative adverse effects and the consumption of antiemetics. Patients in the morphine group had significantly lower post-operative morphine consumption in the first 24 h and total morphine consumption. There was no significant difference between the two groups in post-operative VAS pain scores at rest or during motion. There was no significant difference between the two groups in the post-operative knee range of motion, quadriceps strength, daily ambulation distance, or duration of post-operative hospital stay. The two groups were similar in the incidence of adverse effects and the consumption of antiemetics. Adding morphine into the analgesic cocktail of PIA could reduce postoperative morphine consumption in TKA patients, but does not improve early pain relief or accelerate functional recovery or provide clinical benefits for TKA patients. In addition, the complications and safety of peri-articular morphine infiltration need to be further investigated in larger sample studies.

Background Observational studies suggest that regular physical activity may reduce cardiovascular morbidity and cancer recurrence in survivors of breast cancer. The association between physical activity and cardiac function with breast cancer therapy is unknown. Methods Self‐reported physical activity was assessed using the Godin Leisure‐Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Multivariable regression models estimated associations between clinical variables and physical activity. Generalized estimating equations adjusted for prespecified variables estimated associations between baseline physical activity and longitudinal echocardiographic measures of systolic and diastolic function. Results Physical activity was low at baseline, prior to cancer therapy initiation. More than half of participants reported no moderate‐strenuous physical activity, and only 12.1% met guideline recommended levels of physical activity. Physical activity increased after chemotherapy completion; however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Body mass index, hyperlipidemia and higher cancer stage were significantly associated with lower total physical activity at baseline. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time (β 0.4%, 95% CI 0.1, 0.7, P = .02 for each 10‐unit increase in total activity). There tended to be a cardioprotective association with cardiotoxicity risk, although this was not statistically significant (HR 0.83, 95% CI 0.66, 1.04, P = .097). Conclusions A small proportion of breast cancer patients and survivors are engaged in regular moderate‐strenuous physical activity. While only modest associations between self‐reported physical activity and left ventricular systolic function were observed, our findings do not exclude a cardioprotective benefit of exercise., Self‐reported physical activity was assessed using the Godin Leisure‐Time Exercise Questionnaire at repeated intervals in a longitudinal cohort study of 603 breast cancer participants treated with doxorubicin and/or trastuzumab. Physical activity was low at baseline and increased somewhat after chemotherapy completion however, only 26.0% of individuals were sufficiently active 3 years after cancer diagnosis. Higher baseline physical activity was very modestly associated with an attenuation in the absolute decline in left ventricular ejection fraction over time.

Although significant progress has been made in the treatment of lung cancer, it remains the leading cause of cancer‑associated mortality. Liriopesides B (LPB) is a natural product isolated from the tuber of Liriope platyphylla, whose effective substances have exhibited antitumor activity in several types of cancer. However, the functions of LPB in non‑small cell lung cancer (NSCLC) require further investigation. Therefore, the present study aimed to investigate whether LPB influences the pathogenic effects of NSCLC. In the present study, it was demonstrated that LPB reduced proliferation, and induced apoptosis and cell cycle arrest in non‑small cell lung cancer cells. CCK‑8 and colony formation assays demonstrated that LPB decreased cell viability and proliferation of H460 and H1975 cells in a dose‑dependent manner. Flow cytometry revealed that LPB significantly induced apoptosis of NSCLC cells, along with changes in the expression of apoptosis‑associated proteins, including an increase in Bax, caspase‑3, and caspase‑8 expression, and a decrease in Bcl‑2 and Bcl‑xl expression. LPB inhibited the progression of the cell cycle from the G1 to the S phase. Furthermore, autophagy was increased in cells treated with LPB. Finally, the expression of programmed death‑ligand 1 was significantly decreased by LPB. In conclusion, the results of the present study highlight a potential novel strategy for the clinical treatment of NSCLC.

Background Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ASC patients, and construct a corresponding competing risk nomogram for LC-SM. Methods Data on 2705 patients with first primary lung ASC histologically diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) was utilized to calculate the 3-year and 5-year probabilities of LC-SM and OCSM, and a competing risk model was built. Based on the model, we developed a competing risk nomogram to predict the 3-year and 5-year cumulative probabilities of LC-SM and the corresponding concordance indexes (C-indexes) and calibration curves were derived to assess the model performance. To evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was conducted. Furthermore, patients were categorized into three groups according to the tertile values of the nomogram-based scores, and their survival differences were assessed using CIF curves. Results The 3-year and 5-year cumulative mortalities were 49.6 and 55.8% for LC-SM and 8.2 and 11.8% for OCSM, respectively. In multivariate analysis, increasing age, male sex, no surgery, and advanced T, N and M stages were related to a significantly higher likelihood of LC-SM. The nomogram showed good calibration, and the 3-year and 5-year C-indexes for predicting the probabilities of LC-SM in the validation cohort were both 0.79, which were almost equal to those of the ten-fold cross validation. DCA demonstrated that using the nomogram gained more benefit when the threshold probabilities were set within the ranges of 0.24–0.89 and 0.25–0.91 for 3-year and 5-year LCSM, respectively. In both the training and validation cohorts, the high-risk group had the highest probabilities of LC-SM, followed by the medium-risk and low-risk groups (both P Conclusions The competing risk nomogram displayed excellent discrimination and calibration for predicting LC-SM. With the aid of this individualized predictive tool, clinicians can more expediently devise appropriate treatment protocols and follow-up schedules.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

The difference of the patients bearing hepatocellular carcinoma (HCC) with and without cirrhosis at clinical level has not been completely determined. This study compared their differences in clinicopathological traits and prognostic factors for relapse-free survival (RFS) and overall survival (OS). Animal model was established to validate the result of clinical observation. As a result, 82 patients bearing HCC with no cirrhosis (HCC-NC) and 146 patients bearing HCC with cirrhosis (HCC-C) were included. HCC-NC exhibited shorter prothrombin time and higher plasma albumin than HCC-C. In HCC-NC, satellite nodule was an independent risk factor for OS, and high γ-glutamyl transpeptidase was an independent risk factor for RFS. In HCC-C, female sex was an independent risk factor for OS. Stratified analysis showed the OS and RFS of HCC-NC were better than HCC-C in conditions like without cancer embolus (in the portal vein or bile duct), without lymphadenopathy in hepatic portal, without satellite nodule and with small or high-differentiated tumor. Animal model analysis showed HCC-NC had a higher liver/body weight ratio, less tumor count and smaller max tumor volume than HCC-C. In conclusion, clinicopathological traits and risk factors influencing postoperative OS and RFS differed between patients with HCC-C and HCC-NC.

The early detection of non–small‐cell lung cancer (NSCLC) remains a common concern. The aim of our study was to validate the diagnostic value of a seven‐autoantibody (7‐AAB) panel compared with radiological diagnosis for NSCLC. We constructed a nomogram and a scoring table based on the 7‐AAB panel’s result to predict the risk of NSCLC. We prospectively enrolled 268 patients who presented with radiological lesions and underwent both the 7‐AAB panel test and pathological diagnosis by surgical resection. A comparison between the 7‐AAB panel and radiological diagnosis was performed. A nomogram and a scoring table based on the 7‐AAB panel’s result to predict the risk of NSCLC were constructed and internally validated. The 7‐AAB panel test had a specificity of 90.2% and a positive predictive value (PPV) of 92.7%, which were significantly higher than those of the radiological diagnosis. The 7‐AAB panel also showed a preferable sensitivity in patients with early‐stage disease. Seven factors, including the 7‐AAB panel results, were integrated into the nomogram. For more convenient application, we formulated a scoring table based on the nomogram. The area under the receiver operating characteristic curve was 0.840 and 0.860 in the training group and validation group, respectively, which was higher than that using the 7‐AAB panel or radiological diagnosis alone. This study reveals that our 7‐AAB panel has clinical value in the diagnosis of NSCLC. The utility of our nomogram and the scoring table indicated that they have the potential to assist clinicians in avoiding unnecessary treatment or needless follow‐up., Our study was conducted to validate the diagnostic value of a 7‐autoantibody (7‐AAB) panel compared with radiological diagnosis for NSCLC. We constructed a nomogram and a scoring table based on the 7‐AAB panel’s result to predict the risk of NSCLC.

Diabetes mellitus (DM) plays an important role in restenosis and late in-stent thrombosis (ST). The current study using optical coherence tomography (OCT) aims to compare target lesion neointima in patients with or without diabetes after zotarolimus-eluting stent (ZES) treatment. OCT images of 90,212 struts and quantitative coronary angiography (QCA) in 62 patients (32 with DM and 30 without DM) with 69 de novo coronary lesions (34 DM and 35 non-DM) both after ZES implantation and 12 ± 1 month angiographic follow-up were recorded. Patient characteristics, lesion characteristics, clinical outcomes, and OCT findings including neointimal thickness, coverage, malapposition, and intimal morphology were analyzed. Baseline patient characteristics and lesion characteristics data were similar between the two groups. Higher neointimal thickness (0.14 ± 0.09 mm vs. 0.09 ± 0.04 mm, p = 0.021), more neovascularization (3.03 ± 6.24 vs. 0.52 ± 1.87, p = 0.017) and higher incidence of layered signal pattern (12.19 ± 19.91% vs. 4.28 ± 9.02%, p = 0.049) were observed in diabetic lesions comparing with non-diabetic lesions. No differences were found in malapposition, uncovered percentage, and thrombus between the two groups (all p > 0.05). Occurrence of clinical adverse events was also similar during the follow-up period (p > 0.05). Although more neointimal proliferation and more neovascularization were found in diabetic coronary lesions when compared with non-diabetic lesions, treatment with ZES showed similar stent malapposition rate at 1-year follow-up. The data indicated that ZES treatment could possibly be effective in treating diabetic coronary lesions. ClinicalTrials.gov identifier, NCT01747356.

Notch refers to a set of genes encoding a family of transmembrane receptors in mammalian cells. Previous evidence indicated that Notch receptors were implicated in the onset of gastric cancer. However, there is little evidence on the different genetic expression patterns of the four Notch receptors and their values for patient prognosis. Most recently, we investigated the transcriptional data of Notch receptors and related patient survival in patients with GC based on several databases, including ONCOMINE, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER. According to our findings, gastric cancer tissues, compared with adjacent normal tissues presented a higher level of expression of Notch1/2/3. We also performed a survival analysis and noted that gastric cancer patients with high transcription levels of Notch1/2/3/4 had a low relapse-free survival. In gastric cancer patients, higher levels of infiltration in their CD4+ T cells, macrophages, neutrophils, and dendritic cells were positive associated with the expression of Notch receptors. Notch expression had significant association with diverse immune marker sets in gastric cancer. Overall, this study provides evidence that Notch1/2/3/4 could become the potential targets for precision treatment and new biomarkers in the prognosis of gastric cancer.

Objective This study aimed to investigate the minimum effective concentration (MEC90, defined as effective in 90% of patients) of ropivacaine during the combined procedure of adductor canal block (ACB) and infiltration between the popliteal artery and capsule of the posterior knee (IPACK) block for patients undergoing total knee arthroplasty. Methods This double-blind, randomized dose-finding trial was based on a biased coin up-and-down sequential design, where the concentration of ropivacaine administered to a given patient depended on the previous patient’s response. Before surgery, the first patient received 20 mL of 0.2% ropivacaine for ACB and again for IPACK. If the block failed, the next subject received a 0.025% higher ropivacaine concentration; otherwise, the next subject received either a 0.025% smaller dose (probability of 0.11) or the same dose (probability of 0.89). The primary outcome was whether the block was successful. Block success was defined as the patient did not suffer significant pain and did not receive rescue analgesia within 6 h after surgery. MEC90 was estimated by isotonic regression, and the 95% confidence interval (CI) was calculated by bootstrapping. Secondary outcomes were numerical rating scale (NRS) pain scores at postoperative 24 h and 48 h, postoperative morphine consumption, and time to hospital discharge. Secondary outcomes were compared between patients whose blocks succeeded with those which failed. Results Based on analysis of 52 patients, the MEC90 was 0.247% (95% CI 0.227–0.271%), MEC95 was 0.260% (95% CI 0.244–0.282%) and MEC99 was 0.272% (95% CI 0.260–0.291%). In contrast, four of nine trials in a recent systematic review reported ropivacaine concentrations below 0.247%. Patients whose blocks succeeded ( n = 45) had significantly lower NRS pain scores, lower morphine consumption, and shorter hospitalization than patients whose blocks failed ( n = 7). Conclusions Our small trial suggests that 0.247% ropivacaine in 20 mL respectively can provide successful ACB + IPACK block in 90% of patients. However, given that many published trials have used lower concentrations, our findings should be verified in larger studies.

The prevention of the COVID-19 pandemic is highly complicated by the prevalence of asymptomatic and recurrent infection. Many previous immunological studies have focused on symptomatic and convalescent patients, while the immune responses in asymptomatic patients and re-detectable positive cases remain unclear. Here we comprehensively analyzed the peripheral T-cell receptor (TCR) repertoire of 54 COVID-19 patients in different courses, including asymptomatic, symptomatic, convalescent, and re-detectable positive cases. We identified a set of V–J gene combinations characterizing the upward immune responses through asymptomatic and symptomatic courses. Furthermore, some of these V–J combinations could be awakened in the re-detectable positive cases, which may help predict the risk of recurrent infection. Therefore, TCR repertoire examination has the potential to strengthen the clinical surveillance and the immunotherapy development for COVID-19.