Effect of cuff inflation with lidocaine, saline, and air on tracheal tube cuff pressure during laparoscopic resection of colorectal neoplasms: a randomized clinical trial.

BACKGROUND: Tracheal tube cuff pressure will increase after pneumoperitoneum when the cuff is inflated with air, high pressure can cause tracheal mucosal damage. This prospective trial aimed to assess if inflating with normal saline or lidocaine can prevent increase of tracheal tube cuff pressure and tracheal mucosal damage in laparoscopic surgeries with general anesthesia. Whether changes of tracheal tube cuff transverse diameter (CD) can predict changes of tracheal tube cuff pressure. METHODS: Ninety patients scheduled for laparoscopic resection of colorectal neoplasms under general anesthesia were randomly assigned to groups air (A), saline (S) or lidocaine (L). Endotracheal tube cuff was inflated with room-temperature air in group A (n = 30), normal saline in group S (n = 30), 2% lidocaine hydrochloride injection in group L (n = 30). After intubation, tracheal tube cuff pressure was monitored by a calibrated pressure transducers, cuff pressure was adjusted to 25 cmH2O (T0.5). Tracheal tube cuff pressure at 15 min after pneumoperitoneum (T1) and 15 min after exsufflation (T2) were accessed. CD were measured by ultrasound at T0.5 and T1, the ability of ΔCD (T1-0.5) to predict cuff pressure was accessed. Tracheal mucous injury at the end of surgery were also recorded. RESULTS: Tracheal tube cuff pressure had no significant difference among the three groups at T1 and T2. ΔCD had prediction value (AUC: 0.92 [95% CI: 0.81-1.02]; sensitivity: 0.99; specificity: 0.82) for cuff pressure. Tracheal mucous injury at the end of surgery were 0 (0, 1.0) in group A, 0 (0, 1.0) in group S, 0 (0, 0) in group L (p = 0.02, group L was lower than group A and S, p = 0.03 and p = 0.04). CONCLUSIONS: Compared to inflation with air, normal saline and 2% lidocaine cannot ameliorate the increase of tracheal tube cuff pressure during the pneumoperitoneum period under general anesthesia, but lidocaine can decrease postoperative tracheal mucosa injury. ΔCD measured by ultrasound is a predictor for changes of tracheal tube cuff pressure. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

The effect of different endotracheal tube cuff pressure monitoring systems on postoperative sore throat in patients undergoing tracheal intubation: a randomized clinical trial.

BACKGROUND: Postoperative sore throat (POST) is an unpleasant outcome that can occur as a result of tracheal intubation in adults. Increased pressure from the endotracheal tube (ETT) cuff often leads to local mucosal injury, resulting in sore throat. The purpose of this study was to compare the effect of two different ETT cuff pressure monitoring systems vs. no cuff pressure monitoring on the incidence and severity of POST in adults. METHODS: One hundred and fourteen ASA I-III patients of either gender, aged 18-65 years, and undergoing surgery requiring endotracheal intubation were included in this study. Patients were randomized into three groups: control (C), cuff pressure gauge (G), and automated cuff controller (A). The ETT cuff pressure was not monitored intraoperatively in group C but was monitored using a cuff pressure gauge and an automated cuff controller in groups G and A, respectively. Postoperatively, patients were assessed at 2, 24, and 48 h for the presence and severity of POST, hoarseness and cough. RESULTS: One hundred and eleven patients completed the study. POST occurred in 40.5% of the patients in group G (n = 37) (p = 0.013) and 23.7% of the patients in group A (n = 38) (p < 0.001) within 48 h after surgery, compared to 69.4% in group C (n = 36). There were no significant differences in hoarseness, coughing, and dysphagia across the groups at any time. When comparing groups A and C, individuals in group A exhibited a lower occurrence of significant (grade ≥ 2) POST and hoarseness (10.5% vs. 41.7%, p = 0.002; 26.3% vs. 58.3%, p = 0.005). The incidence of significant cough and dysphagia did not differ substantially across the patient groups within 48 h after surgery. POST scores in group A at 2, 24 h postoperatively were both 0 (0-0), which was significantly lower than those in group C (1 (0-2) at 2 h, p < 0.001 ; 1 (0-1) at 24 h, p = 0.001). POST in group G at 2 h postoperatively was graded as 0 (0-1.5) which was milder than group C (P = 0.024). The severity of hoarseness in group A with scores of 0 (0-2) was superior to that in group C (2 (0-2), p = 0.006) at 2 h postoperatively. CONCLUSIONS: In conclusion, the findings of this study indicated that the occurrence of POST can be reduced by using either the cuff pressure gauge approach or the automated cuff controller method. The automated cuff controller monitoring can potentially decrease the severity of POST and hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

Effect of subclavian vein diameter combined with perioperative fluid therapy on preventing post-induction hypotension in patients with ASA status I or II.

BACKGROUND: Perioperative hypotension is frequently observed following the initiation of general anesthesia administration, often associated with adverse outcomes. This study assessed the effect of subclavian vein (SCV) diameter combined with perioperative fluid therapy on preventing post-induction hypotension (PIH) in patients with lower ASA status. METHODS: This two-part study included patients aged 18 to 65 years, classified as ASA physical status I or II, and scheduled for elective surgery. The first part (Part I) included 146 adult patients, where maximum SCV diameter (dSCVmax), minimum SCV diameter (dSCVmin), SCV collapsibility index (SCVCI) and SCV variability (SCVvariability) assessed using ultrasound. PIH was determined by reduction in mean arterial pressure (MAP) exceeding 30% from baseline measurement or any instance of MAP < falling below 65 mmHg for ≥ a duration of at least 1 min during the period from induction to 10 min after intubation. Receiver Operating Characteristic (ROC) curve analysis was employed to determine the predictive values of subclavian vein diameter and other relevant parameters. The second part comprised 124 adult patients, where patients with SCV diameter above the optimal cutoff value, as determined in Part I study, received 6 ml/kg of colloid solution within 20 min before induction. The study evaluated the impact of subclavian vein diameter combined with perioperative fluid therapy by comparing the observed incidence of PIH after induction of anesthesia. RESULTS: The areas under the curves (with 95% confidence intervals) for SCVCI and SCVvariability were both 0.819 (0.744-0.893). The optimal cutoff values were determined to be 45.4% and 14.7% (with sensitivity of 76.1% and specificity of 86.7%), respectively. Logistic regression analysis, after adjusting for confounding factors, demonstrated that both SCVCI and SCVvariability were significant predictors of PIH. A threshold of 45.4% for SCVCI was chosen as the grouping criterion. The incidence of PIH in patients receiving fluid therapy was significantly lower in the SCVCI ≥ 45.4% group compared to the SCVCI < 45.4% group. CONCLUSIONS: Both SCVCI and SCVvariability are noninvasive parameters capable of predicting PIH, and their combination with perioperative fluid therapy can reduce the incidence of PIH.

Effects of continuous and slow tracheal tube cuff deflation on cough reflex during extubation in noncardiac surgery patients: a randomised clinical trial.

BACKGROUND: The incidence of cough reflex during extubation is 76%. Cough reflex causes severe hemodynamic fluctuations and airway complications. This prospective trial investigated the potential effects of tracheal tube cuff deflation on cough reflex during extubation. METHODS: One hundred and twenty-six patients scheduled for operations within 3 h under general anaesthesia with orotracheal intubation were randomly assigned to one of three groups: control (C), experimental (E) or syringe (S) groups. Patients in group C underwent tracheal tube cuff deflation using a 10-ml syringe in 1 s, patients in group E underwent tracheal tube cuff deflation continuously and slowly in 5 s using a cuff pressure gauge until the pressure was zero and patients in group S underwent tracheal tube cuff deflation using a 10-ml syringe at a speed of 1 ml s-1. The incidence and severity of cough reflexs during extubation and the incidence of postoperative airway complications within 48 h were assessed. RESULTS: Compared with group C (60.0%), the incidence of cough reflex in group E was 9.8% (p < 0.001) and in group S was 12.5% (p < 0.001). The severity of cough reflex was graded as 2 (1-2) in group C, 1 (1-1) in group E and 1 (1-1) in group S (p < 0.001 for group comparisons). The incidence of hoarseness in group C was 0.0%, in group E was 19.5% and in group S was 5.0% (p < 0.05 for all groups, p = 0.009 between group C and E). CONCLUSIONS: Compared with deflating a trachal tube cuff with a 10-ml syringe in 1 s, the use of a 10-ml syringe at a speed of 1 ml s-1 or a cuff pressure guage within 5 s can both reduce the incidence of cough reflex, but deflating with a cuff pressure guage can increase the incidence of postoperative hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

Retrospective study of ovarian reaction and fertility in women with discordant antimullerian hormone and follicle-stimulating hormone/luteinizing hormone ratios during in vitro fertilization.

OBJECTIVE: The objective of this study was to examine the predictive ability of follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratio and antimullerian hormone (AMH) levels in the same cohort when both are inconsistent and to identify which has an excellent ability to predict live birth and ovarian response to in vitro fertilization (IVF). METHODS: A retrospective cohort study was performed within 6096 IVF cycles executed between January 2016 and August 2019 at the Center for Assisted Reproduction, The Third Affiliated Hospital of Zhengzhou University, and Jiaozuo Maternity and Child Health Care Hospital. Initially, IVF cycles were classified according to basal FSH/LH ratio and AMH values, and the primary outcome was a comparison of live birth rate per cohort. Secondary outcomes included characteristics of the study individuals such as body mass index (BMI), age, antral follicle count, ovarian sensitivity index, cycle cancellation rate, and cycle outcome data. RESULT(S): Women with FSH/LHhigh ratio and AMHnormal levels had a meaningly higher live birth rate compared with those with FSH/LHnormal ratio and AMHlow levels (46.59% vs. 21.21%, p < 0.001). In addition, women with FSH/LHnormal ratio and AMHlow levels were found to have a higher cancellation rate in their IVF cycles (80.98%). In women with FSH/LHnormal ratio, further multivariate analysis revealed that AMH level, age, number of retrieved oocytes, and FSH dosage were relevant risk factors for live birth. The relative risk of live birth was 0.11 (95% [CI] 0.06-0.20, p < 0.001) in patients with AMHlow compared with patients with AMHnormal . It also suggested that the probability of AMHlow level may be higher as the women's age (≥35 years, odd ratio [OR] 1.94, 95% [CI] 1.44-2.61; p < 0.001) and increasing BMI (≥28 kg/m2 , OR 2.38, 95% [CI] 1.33-4.27; p = 0.004). Receiver operating characteristic curve analysis indicated that AMH had higher sensitivity and specificity to predict live birth compared with FSH/LH (AUC 0.627 vs. 0.539). CONCLUSION(S): AMH levels can be an excellent predictor of the discrepancy between FSH/LH ratio and AMH levels regarding living birth rates in women undergoing IVF.

Causal relationship between genetically predicted depression and cancer risk: a two-sample bi-directional mendelian randomization.

BACKGROUND: Depression has been reported to be associated with some types of cancer in observational studies. However, the direction and magnitude of the causal relationships between depression and different types of cancer remain unclear. METHODS: We performed the two-sample bi-directional mendelian randomization with the publicly available GWAS summary statistics to investigate the causal relationship between the genetically predicted depression and the risk of multiple types of cancers, including ovarian cancer, breast cancer, lung cancer, glioma, pancreatic cancer, lymphoma, colorectal cancer, thyroid cancer, bladder cancer, and kidney cancer. The total sample size varies from 504,034 to 729,150. Causal estimate was calculated by inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the causal relationship. RESULTS: After correction for heterogeneity and horizontal pleiotropy, we only detected suggestive evidence for the causality of genetically predicted depression on breast cancer (OR = 1.09, 95% CI: 1.03-1.15, P = 0.0022). The causal effect of depression on breast cancer was consistent in direction and magnitude in the sensitivity analysis. No evidence of causal effects of depression on other types of cancer and reverse causality was detected. CONCLUSIONS: The result of this study suggests a causative effect of genetically predicted depression on specific type of cancer. Our findings emphasize the importance of depression in the prevention and treatment of breast cancer.

Evolving landscape and academic attitudes toward the controversies of global immuno-oncology trials.

This cross-sectional and longitudinal descriptive analysis aimed to track the evolving landscape of global immuno-oncology (IO) trials and provide insight into the resolution of IO-related controversies. Clinical trials (n = 4510) registered on ClinicalTrials.gov in 2007 to 2019 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), cancer vaccines and immune modulators were included. Most of IO trials are Phase 2 and focus on ICIs and multiple IO therapies. The United States leads global IO research, with stable growth and the best methodological quality. Mainland China ranks first in the number of ACT trials but has the lowest article publication rate (6.2%). A multiple-arm comparative design is often adopted in multiple IO therapies trials (44.0%). Trials studying ICIs and multiple IO therapies are likely to use early registration (80.0% and 86.6%) and stringent corticosteroid-/infection-related criteria. Hospitals have provided the most extensive and strongest support for all IO categories. Big pharma prefers to fund Phase 3-4 ICI trials (6.98%), while small pharma has a wider sponsorship favoring Phase 1-2 trials. The "partial-use-of-corticosteroids" strategy is generally well accepted in ICI trials with a definitive trend (32.5%; P < .001) but is associated with the poor dissemination of results (P ≤ .020), while the complete disclosure and standardization of dose/timing limits are still lacking. Disparities in design features and dissemination of results are widespread in IO trials and are modulated by IO category, cancer type and sponsor. We propose policy reforms to redefine the timely publication of IO trials and standardize the resolution of corticosteroid-/infection-related issues.

Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain.

The chemerin receptor (CMKLR1) is a G protein-coupled receptor found on select immune, epithelial, and dorsal root ganglion/spinal cord neuronal cells. CMKLR1 is primarily coupled to the inhibitory G protein, Gαi, and has been shown to modulate the resolution of inflammation and neuropathic pain. CMKLR1 is activated by both lipid and peptide agonists, resolvin E1 and chemerin, respectively. Notably, these ligands have short half-lives. To expedite the development of long acting, stable chemerin analogs as candidate therapeutics, we used membrane-tethered ligand technology. Membrane-tethered ligands are recombinant proteins comprised of an extracellular peptide ligand, a linker sequence, and an anchoring transmembrane domain. Using this technology, we established that a 9-amino acid-tethered chemerin fragment (amino acids 149-157) activates both mouse and human CMKLR1 with efficacy exceeding that of the full-length peptide (amino acids 21-157). To enable in vivo delivery of a corresponding soluble membrane anchored ligand, we generated lipidated analogs of the 9-amino acid fragment. Pharmacological assessment revealed high potency and wash resistance (an index of membrane anchoring). When tested in vivo, a chemerin SMAL decreased allergic airway inflammation and attenuated neuropathic pain in mice. This compound provides a prototype membrane-anchored peptide for the treatment of inflammatory disease. A parallel approach may be applied to developing therapeutics targeting other peptide hormone G protein-coupled receptors.

[Effect of Kuanxiong aerosol on coronary heart disease angina patients: a multicenter randomized controlled clinical study].

OBJECTIVE: To evaluate the anginal attack-relieving efficacy and safety of Kuanxiong Aerosol (KA) in patients with coronary heart disease (CHD). METHODS: A total of 780 patients confirmatively diagnosed as CHD angina from November 2011 to December 2012 in 13 medical centers in the mainland area were assigned to 2 groups by blocked randomization, the treatment group (376 cases) and the control group (374 cases). When the angina attacked, patients in the treatment group received sublingual spray three times, 0.6 mL each time, while those in the control group sublingually dissolved Nitroglycerin Tablet (NT), 0.5 mg each tablet. The effective rate of angina relief, efficacy of electrocardiogram (ECG), and the incidence of adverse reactions were observed. RESULTS: The 3 min and 5 min remission rates of angina attack were 53.72% (202/376) and 94.41% (355/376) in the treatment group, and 47.86% (179/374) and 90.64% (339/374) in the control group. The 95% confidence interval (CI) of the difference between the 2 groups of 3 min and 5 min remission rates of angina attacks were [(-1.84%, 12.32%) and (-1.33%, 6.85%) respectively, P > 0.05]. The total improvement rates of ST-T changes in the treatment group and the control group after treatment were 74.07% and 73.13% respectively (P > 0.05). The adverse reaction rate was 9.31 (35/376 cases) in the treatment group and 22.46% (84/374 cases) in the control group (P < 0.01). CONCLUSION: KA was not inferior to NT in relieving anginal attacks and improving ischemic ECG changes, and had obviously less adverse reaction.

A perspective of microemulsions in critical metal separation and recovery: Implications for potential application of CO2-responsive microemulsions.

Since the discovery of microemulsions, they have attracted great attention due to its unique properties, such as ultra-low interfacial tension and nanoscale droplets. During the past several decades, microemulsions have shown unparalleled advantages in critical metal separation and recovery, e.g., high separation rate, high recovery efficiency, and good selectivity. Therefore, fundamental understandings of such metal recovery behavior are of great significance for the continuous development of microemulsion-based separation technology in this field. Herein, we first systematically reviewed the application of regular microemulsion in the separation and recovery process of critical metals focusing on their separation mechanisms. Then, we summarized the recent progress of CO2-responsive microemulsions and highlighted their potential application in critical metal separation and recovery, aiming to provide some insights into alleviating the difficulties in demulsification during the stripping stage using regular microemulsions. In this section, the latest development of CO2-responsive microemulsions is introduced, and the relationship between their composition, microstructure and macroscopic properties is discussed. Discussion and future perspectives are provided highlighting the design of new microemulsions and potential application of CO2-responsive microemulsions for metal separation and recovery in the future.

Metastatic patterns of level II-V cervical lymph nodes assessed per vertebral levels in nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: The current cervical lymph nodes classification system is not perfectly reasonable for radiotherapy of nasopharyngeal carcinoma (NPC). This study aimed to determine the metastatic patterns of level II-V lymph nodes in NPC by using vertebrae as anatomical landmarks. MATERIALS AND METHODS: Four hundred and forty node-positive NPC patients were selected. Metastatic lymph nodes were diagnosed using positron emission tomography/computed tomography scan or magnetic resonance imaging. We evaluated univariate and multivariate logistic correlations between the vertebral levels of metastatic level II-V lymph nodes. RESULTS: The metastasis rate of level II-V lymph nodes gradually decreased from C2 (66.5%) and C3 (68.2%) to T1 (4.1%) vertebral levels. When assessed per vertebral level, 98.4% were non-skip metastasis. The interval of vertebral levels and distance between the inferior border of the tumor and the metastatic lymph nodes were similar in N1 and N2 patients. Univariate correlation analysis showed the metastasis of level II-V lymph nodes at each vertebral level was associated with the metastasis at any other vertebral level. In the multivariate analysis, metastasis at any one of the C2-C7 vertebral levels strongly and positively correlated with metastasis at two adjacent vertebral levels, including one level above and one below. CONCLUSION: This is the first study to report the distribution and non-skip metastatic patterns of level II-V lymph nodes assessed per vertebral levels in NPC. The low-risk clinical target volume could be reduced to two vertebral levels below the vertebral level of the metastatic level II-V nodes when both imaging modalities are available.

Disparities in positive results and dissemination of randomized controlled trials in immuno-oncology.

BACKGROUND: This cross-sectional and longitudinal analysis aimed to demonstrate the disparities in positive results and dissemination patterns of randomized controlled trials (RCTs) in global immuno-oncology (IO). METHODS: Phase II-IV RCTs with results reported by article publications registered on ClinicalTrials.gov in 2007-2018 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer, cancer vaccines, and immune modulators were included. RESULTS: Twenty-eight percent of trials were positive (72 of 258), most of which were pharma-sponsored and focused on ICI and multiple IO therapies in lung cancer, melanoma, and multiple cancer types. The recent period of trial start year, upfront registration, large sample size, high strictness score on corticosteroid/infection-related criteria, and survival endpoints were associated with positive results. Trials from Mainland China had a faster publication timeline of positive results but lacked study diversity or full reporting of negative results compared with US and multinational trials. Compared with phase II trials, phase III-IV trials had a higher average proportion of positive results (28.9% vs. 22.2%) and a more stable change over the past decade (23.65% vs. 49.24%). Positive trials yielded more secondary manuscripts (10 vs. 4), a shorter publication process of approximately two years (P < 0.001), and a superiority in the dissemination of journals with an h-index >90 (P < 0.001) compared with negative trials. CONCLUSION: Disparities in positive result dissemination are widespread in IO RCTs and affected by trial features. We proposed improvements in upfront registration, procedural integrity, and adequate inclusion of rival trials reporting negative results within the earlier two years in future reviews.

Immuno-oncology (IO) is a novel treatment modality utilizing the natural ability of body's immune system to fight against cancer. The acknowledged standard method to confer the best medical evidence for showing the efficacy of a new intervention is randomized controlled trials (RCTs), and the publication of trial results via journal articles usually modifies medical decisions. A trial labeled negative means that the pre-specified goal was not met, but it deserves more attention rather than a simple interpretation of scientific failure. Previous studies on oncology trials indicated that negative and positive trials have different patterns of result publication and varied trial features. Although IO-related RCTs obtain a continuously increasing number, the extent and tendencies (positive or negative) of their results have not been assessed. To conduct a timely summary and a comprehensive analysis focusing on the publication details and its relationship with the properties of IO trials, we included phase II­IV IO RCTs with results reported by article publications registered on ClinicalTrials.gov in 2007­2018. We found that disparities in positive results and publication are widespread in IO RCTs and severely affected by IO category, cancer type, sponsorship, trial phase, and geographic origin. Positive trials had a significantly shorter publication timeline of approximately two years, more secondary manuscripts, and a superiority in high-quality publications over negative trials. We propose that investigators should complete registration before trial launch, improve procedural integrity, and allow an adequate inclusion of rival trials reporting negative results within the earlier two years in future IO-related reviews.

Development of a prediction model for radiotherapy response among patients with head and neck squamous cell carcinoma based on the tumor immune microenvironment and hypoxia signature.

INTRODUCTION: The immune system and hypoxia are major factors influencing radiosensitivity in patients with different cancer types. This study aimed at developing a model to predict radiotherapy response in patients with head and neck squamous cell carcinoma (HNSCC) based on the tumor immune microenvironment and hypoxia signature. MATERIALS AND METHODS: We first evaluated the hypoxia status and tumor immune microenvironment in the Cancer Genome Atlas (TCGA) cohort by using transcriptomic data. Differentially expressed genes (DEGs) were identified between the "high immunity and low hypoxia" and "low immunity and high hypoxia" groups and those DEGs significantly associated with disease-specific survival in the univariate Cox regression analysis were selected as the prognostic DEGs. We selected the immune hypoxia-related genes (IHRGs) by intersecting prognostic DEGs with immune and hypoxia gene sets. We used the IHRGs to train a multivariate Cox regression model in the TCGA cohort, based on which we calculated the IHRG prognostic index (IHRGPI) for each patient and validated its efficacy in predicting radiotherapy response in the Gene Expression Omnibus cohorts. Furthermore, we explored potential mechanisms and effective combinational treatment strategies for different IHRGPI groups. RESULTS: Five IHRGs were used to construct the IHRGPI, which was used to dichotomize the cohorts. The patients with lower IHRGPI showed a better radiotherapy response across different cohorts and endpoints, including overall survival, progression-free survival, and recurrence-free survival (p < 0.05). Patients with higher IHRGPI showed greater hypoxia and lesser immune cell infiltration. A lower IHRGPI indicated a better immunotherapy response, while a higher IHRGPI indicated a better chemotherapy response. CONCLUSIONS: IHRGPI is promising for predicting radiotherapy response and guiding combinational treatment strategies in patients with HNSCC.

Development and validation of a joint model for dynamic prediction of overall survival in nasopharyngeal carcinoma based on longitudinal post-treatment plasma cell-free Epstein-Barr virus DNA load.

OBJECTIVES: To develop and validate a joint model for dynamic prediction of overall survival (OS) in nasopharyngeal carcinoma (NPC) based on longitudinal post-treatment plasma cell-free Epstein-Barr virus (cfEBV) DNA load. PATIENTS AND METHODS: We analyzed 695 patients with non-metastatic NPC and detectable post-treatment cfEBV DNA load who did not receive adjuvant therapy. We fitted the trajectories of post-treatment cfEBV DNA load as a function of time into a linear mixed-effect model and fitted a Cox regression model with covariates including age, T and N stages, and lactate dehydrogenase level. Finally, we combined both via joint modeling to develop and validate our dynamic model. RESULTS: A strong positive correlation was found between the individual longitudinal post-treatment cfEBV DNA load and the risk of death from any cause (P < 0.001). We developed a joint model capable of providing subject-specific dynamic prediction of conditional OS based on the evolution of the individual plasma cfEBV DNA load trajectory. The joint model showed reliable performance in both training and validation cohorts, with a large area under the curve (interquartile range [IQR]: training cohort, 0.775-0.850; validation cohort, 0.826-0.900) and low prediction errors (IQR: training cohort, 0.017-0.078; validation cohort, 0.034 -0.071). An increasing amount of data on cfEBV DNA load was associated with better model performance. CONCLUSION: Our model provided reliable subject-specific dynamic prediction of conditional OS, which could help guide individualized post-treatment surveillance, risk stratification, and management of NPC in the future.

Progression-free survival assessed per immune-related or conventional response criteria, which is the better surrogate endpoint for overall survival in trials of immune-checkpoint inhibitors in lung cancer: A systematic review and meta-analysis.

Progression-free survival (PFS) has been used as a surrogate endpoint for overall survival (OS) in lung cancer trials. The pattern of response to immune-checkpoint inhibitors (ICIs) differs from that to conventional chemotherapy, so immune-related response evaluation criteria were proposed. This study aims at determining which PFS measure, PFS assessed per immune-related response evaluation criteria (iPFS), or conventional criteria (cPFS), is the better surrogate endpoint for OS in trials of ICIs in lung cancer. We selected clinical trials in lung cancer that administered ICIs to at least one arm and reported both median OS and median PFS from PubMed, Embase, and The Cochrane Library. We compared the correlation between treatment effect (hazard ratio) on OS and cPFS or iPFS and the correlation between median OS and median cPFS or iPFS using weighted linear regression at trial level. We analyzed 78 ICI arms (13,438 patients) from 54 studies, including 66 arms with cPFS, seven arms with iPFS, and five arms with both kinds of PFS. We demonstrated an excellent correlation between treatment effect (hazard ratio) on OS and iPFS (RWLS2  = 0.91), while the correlation was moderate for cPFS (RWLS2  = 0.38). Similarly, the correlation between median OS and median iPFS was also strong (RWLS2 ranging from 0.86 to 0.96) across different phases of trials and different types of lung cancer, ICI, and treatment modalities, while it was much weaker for median cPFS (RWLS2 ranging from 0.28 to 0.88). In conclusion, iPFS provides better trial-level surrogacy for OS than cPFS in trials of ICIs in lung cancer.

Association Between Body Mass Index and Male Sperm Apoptosis and Apoptosis-Related Factors.

BACKGROUND: Although obesity may affect reproductive functions, the molecular mechanisms of apoptosis-related biomarkers remain uncertain. OBJECTIVE: To examine the effects of body mass index on sperm quality and apoptosis-related factors in seminal plasma of men. METHODS: Data for 54 subfertile men were collected at our reproductive medical center. The men were divided into normal weight, overweight, and obese groups based on their body mass index (BMI). Sperm DNA fragmentation (sperm chromatin structure analysis), sperm apoptosis (annexin V), and sperm apoptosis-related factors (antibody array assay) were assessed and their relationships with BMI were analyzed. RESULTS: BMI was not significantly related to age, duration of infertility, duration of sexual abstinence, semen volume, sperm concentration, or rate of normal sperm morphology (p > 0.05). However, progressive sperm motility was significantly reduced and the rates of sperm DNA fragmentation index (DFI) and sperm apoptosis were significantly increased in overweight and obese men compared with men with normal BMI. Fas/Fasl, Bcl-2/Bax, caspase-3, caspase-8, p53, and p21 were all upregulated in the overweight and obese groups. Protein function annotation by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that apoptosis-related factors were enriched in a network associated with activation of apoptotic signaling pathways, such as apoptosis and p53 signaling. CONCLUSION: These data suggest that increased BMI is associated with increased sperm apoptosis and sperm DNA damage, as well as accelerated expression of apoptosis-related factors via the activation of apoptotic signaling pathways.

Assessment of Modifiable Factors for the Association of Marital Status With Cancer-Specific Survival.

Importance: Married patients with cancer have better cancer-specific survival than unmarried patients. Increasing the early diagnosis and definitive treatment of cancer among unmarried patients may reduce the survival gap. Objectives: To evaluate the extent to which marriage is associated with cancer-specific survival, stage at diagnosis, and treatment among patients with 9 common solid cancers and to recommend methods for reducing the survival gap. Design, Setting, and Participants: This retrospective, population-based cohort study included patients older than 18 years who were diagnosed with 1 of 9 common cancers between January 1, 2007, and December 31, 2016. Patient data were retrieved from the Surveillance, Epidemiology, and End Results Program. Statistical analyses were performed from August 1 to October 1, 2020. Exposures: Marital status, classified as married and unmarried (including single, separated, divorced, widowed, and unmarried patients or domestic partners). Main Outcomes and Measures: The primary outcome was the time ratio (TR) of cancer-specific survival (married vs unmarried). Mediation analyses were conducted to determine the extent to which the association of marriage with cancer-specific survival was mediated by stage at diagnosis and treatment. Results: This study included 1 733 906 patients (894 379 [51.6%] women; 1 067 726 [61.6%] married; mean [SD] age, 63.76 [12.60] years). Multivariate analyses found that those who were married were associated with better cancer-specific survival than unmarried patients (TR, 1.36; 95% CI, 1.35-1.37). Early diagnosis in breast cancer, colorectal cancer, endometrial cancer, and melanoma mediated the association between marital status and cancer-specific survival (breast cancer: proportion mediated [PM], 11.4%; 95% CI, 11.2%-11.6%; colorectal cancer: PM, 10.9%; 95% CI, 10.7%-11.2%; endometrial cancer: PM, 12.9%; 95% CI, 12.5%-13.3%; melanoma: PM, 12.0%; 95% CI, 11.7-12.4%). Surgery mediated the association between marital status and cancer-specific survival in lung (PM, 52.2%; 95% CI, 51.9%-52.4%), pancreatic (PM, 28.9%; 95% CI, 28.6%-29.3%), and prostate (PM, 39.3%; 95% CI, 39.0%-39.6%) cancers. Chemotherapy mediated the association of marital status with cancer-specific survival in lung (PM, 37.7%; 95% CI, 37.6%-37.9%) and pancreatic (PM, 28.6%; 95% CI, 28.4%-28.9%) cancers. Improved cancer-specific survival associated with marriage was greater among men than women (men: TR, 1.27; 95% CI, 1.25-1.28; women: TR, 1.20; 95% CI, 1.19-1.21). The contribution of receiving an early diagnosis and treatment with surgery or chemotherapy to the association between marital status and cancer-specific survival was greater among men than women (early diagnosis: PM, 21.7% [95% CI, 21.5%-21.9%] vs PM, 20.3% [95% CI, 20.2%-20.4%]; surgery: PM, 26.6% [95% CI, 26.4%-26.7%] vs PM, 11.1% [95% CI, 11.0%-11.2%]; chemotherapy: PM, 6.8% [95% CI, 6.7%-6.8%] vs PM, 5.1% [95% CI, 5.0%-5.2%]). Conclusions and Relevance: In this study, survival disparities associated with marital status were attributable to early diagnosis in breast, colorectal, and endometrial cancers as well as melanoma and to treatment-related variables in lung, pancreatic, and prostate cancers. The findings also suggest that marriage may play a greater protective role in the cancer-specific survival of men than of women.

Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro.

BACKGROUND: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. OBJECTIVE: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. METHODS AND RESULTS: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, ß-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. CONCLUSION: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.

Treatment effects of cumulative cisplatin dose during radiotherapy following induction chemotherapy in nasopharyngeal carcinoma: propensity score analyses.

BACKGROUND: The treatment effects of cumulative cisplatin dose (CCD) during radiotherapy (RT) following induction chemotherapy (IC) have not been determined for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 3460 patients with locoregionally advanced NPC who were treated with IC plus cisplatin-based concurrent chemoradiotherapy or RT alone were included in this retrospective study. Three CCD groups (0 mg/m2 ⩽ CCD <100 mg/m2, 100 mg/m2 ⩽ CCD <200 mg/m2, CCD ⩾200 mg/m2) were balanced through the inverse probability of treatment weighting based on propensity scores estimated by a general boosted model. The primary endpoint was overall survival (OS); the secondary endpoints were distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS). RESULTS: CCD ⩾200 mg/m2 and <200 mg/m2 exhibited similar treatment effects for OS and DMFS, and were both superior to CCD <100 mg/m2 for OS and DMFS in patients with stage IVa NPC. The three CCD groups achieved similar treatment effects for patients with stage II-III NPC. After IC, CCD during RT appeared to exert little treatment effect on LRFS. CONCLUSION: The CCD during RT exerts treatment effects and improves OS by reducing the risk of distant metastasis for patients with stage IVa NPC following IC, and CCD <200 mg/m2 (mainly 160 mg/m2 in this group) is recommended. However, RT alone may be sufficient after IC in patients with stage II-III NPC.

Zoonotic parasites carried by invasive alien species in China.

BACKGROUND: The invasive alien species may lead to great environmental and economic crisis due to its strong capability of occupying the biological niche of native species and altering the ecosystem of the invaded area. However, its potential to serve as the vectors of some specific zoonotic pathogens, especially parasites, has been neglected. Thus, the damage that it may cause has been hugely underestimated in this aspect, which is actually an important public health problem. This paper aims to discuss the current status of zoonotic parasites carried by invasive alien species in China. MAIN BODY: This review summarizes the reported zoonotic parasites carried by invasive alien species in China based on the Database of Invasive Alien Species in China. We summarize their prevalence, threat to human health, related reported cases, and the roles of invasive alien species in the life cycle of these parasites, and the invasion history of some invasive alien species. Furthermore, we sum up the current state of prevention and control of invasive alien species in China, and discuss about the urgency and several feasible strategies for the prevention and control of these zoonoses under the background of booming international communications and inevitable globalization. CONCLUSIONS: Information of the zoonotic parasites carried by invasive alien species neither in China or worldwide, especially related case reports, is limited due to a long-time neglection and lack of monitoring. The underestimation of their damage requires more attention to the monitoring and control and compulsory measures should be taken to control the invasive alien species carrying zoonotic parasites.