XYLEM NAC DOMAIN 1 (EjXND1) relieves cold-induced lignification by negatively regulating the EjHB1-EjPRX12 module in loquat fruit.

INTRODUCTION: Lignin is a principal constituent of the secondary cell wall, which plays a role in both plant growth and defensing against stress, such as low temperature and pest infestation. Additionally, it also accumulates in fleshy fruits and negatively affects fruit quality. Red-fleshed loquat is temperature sensitive and exhibits cold-induced lignification. A number of technologies have been developed, for example, Low Temperature Conditioning (LTC) treatment, which has been applied in order to relieve the symptom of cold injury. OBJECTIVES: The present study seeks to elucidate the regulatory mechanism underlying cold-induced lignification in loquat fruit. METHODS: The target genes were isolated through the analysis of transcriptome. The gene function was analyzed by transient transgenic method in tobacco leaves and loquat fruit, respectively, as well as stable overexpression in liverwort. The regulatory mechanism study was achieved by in vitro protein-protein interaction assays, dual-luciferase assay, and EMSA. RESULTS: In the present study, the Xylem NAC Domain transcription factor EjXND1 was identified as a repressor of loquat fruit lignification. It was demonstrated that EjXND1 could interact with the characterized lignin activator EjHB1, resulting in a diminution of the activation of EjHB1 on EjPRX12 promoter. Furthermore, two highly methylated regions were identified in the promoter of EjXDN1. One of these regions exhibited a negative correlation between methylation level and EjXND1 expression. Additionally, it was shown that hypermethylation of this region weaken the binding affinity of EjXND1 activators to its promoter. CONCLUSION: The EjXND1 plays a role in modified Low Temperature Conditioning (mLTC) treatment that alleviates cold-induced lignification in red-fleshed loquat fruit by targeting the EjHB1-EjPRX12 module and EjXND1 is regulated by the dynamic of DNA methylation level in the promoter.

Methylation of EjNAC5 and its interactions with other transcription factors regulate loquat fruit chilling lignification.

Changes in both lignin biosynthesis and DNA methylation have been reported to be associated with chilling stress in plants. When stored at low temperatures, red-fleshed loquat is prone to lignification, with increased lignin content and fruit firmness, which has deleterious effects on taste and eating quality. Here, we found that 5°C storage mitigated the increasing firmness and lignin content of red-fleshed 'Dahongpao' ('DHP') loquat fruit that occurred during 0°C storage. EjNAC5 was identified by integrating RNA sequencing with whole-genome bisulfite sequencing analysis of 'DHP' loquat fruit. The transcript levels of EjNAC5 were positively correlated with changes in firmness and negatively correlated with changes in DNA methylation level of a differentially methylated region (DMR) in the EjNAC5 promoter. In white-fleshed 'Baisha' ('BS') loquat fruit, which do not undergo chilling-induced lignification at 0°C, the transcripts of EjNAC5 remained low and the methylation levels of the DMR in the EjNAC5 promoter was higher, compared to 'DHP' loquat fruit. Transient overexpression of EjNAC5 in loquat fruit and stable overexpression in Arabidopsis and liverwort led to an increase in lignin content. Furthermore, EjNAC5 interacts with EjERF39 and EjHB1 and activates the transcription of Ej4CL1 and EjPRX12 genes involved in lignin biosynthesis. This regulatory network involves different TFs to those involved in lignification pathway. Our study indicates that EjNAC5 promoter methylation modulates EjNAC5 transcript levels and identifies novel EjNAC5-EjERF39-Ej4CL1 and EjNAC5-EjHB1-EjPRX12 regulatory modules involved in chilling induced-lignification.

The association between Weight-adjusted-Waist Index (WWI) and cognitive function in older adults: a cross-sectional NHANES 2011-2014 study.

BACKGROUND: The impact of obesity on cognitive function has engendered considerable interest. Weight-adjusted waist index (WWI) has emerged as a novel and innovative marker of obesity that reflects weight-independent abdominal obesity. However, the association between WWI and cognitive function remains unclear. To address this gap, the present study aims to explore the relationship between weight-adjusted waist index (WWI) and cognitive performance in older adults. METHODS: We conducted a cross-sectional investigation using datasets from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. The study included 3,472 participants (48.59% male, 51.41% female) of various races (Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black, and Other), with a mean age of 69.95 years (SD = 6.94). Multivariate regression and smoothing curve fitting were used to investigate the linear and nonlinear relationship between WWI and cognitive performance in the following domains: learning and memory, verbal fluency, and processing speed, as measured by Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD-WL), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), respectively. Subgroup analysis and interaction tests were conducted to examine the stability of this relationship across groups. Machine learning models based on random forests were used to analyze the predictive performance of WWI for cognitive function. RESULTS: A total of 3,472 participants were included in the analysis. The results revealed significant negative associations between WWI and low scores on the CERAD-WL [-0.96 (-1.30, -0.62)], AFT [-0.77 (-1.05, -0.49)], and DSST [-3.67 (-4.55, -2.79)]. This relationship remained stable after converting WWI to a categorical variable. In addition, this significant negative association was more pronounced in men than women and diminished with advancing age. Non-linear threshold effects were observed, with correlations intensifying between WWI and CERAD-WL when WWI surpassed 12.25, AFT when WWI surpassed 11.54, and DSST when WWI surpassed 11.66. CONCLUSIONS: A higher WWI, indicating increased abdominal obesity, was associated with deficits in learning, memory, verbal fluency, and processing speed among older adults. These findings suggest that abdominal obesity may play a crucial role in cognitive decline in this population. The stronger relationship observed between WWI and cognition in men highlights the need for gender-specific considerations in interventions targeting abdominal obesity. The results demonstrate the importance of interventions targeting abdominal obesity to preserve cognitive performance in older adults.

Application of circular statistics in temporal distribution of adult mosquitoes in Qingdao, Shandong Province, China, 2021-2023.

BACKGROUND: Analyses of the temporal distribution of mosquitoes are presented in statistical charts, but it is difficult to prove in statistics whether differences in peak periods exist among different years or habitats. This study aimed to investigate the application of circular statistics in determining the peak period and a comparison of differences. METHODS: Surveillance of adult mosquitoes was conducted twice a month by light traps in five different habitats from March to November for 3 years (2021-2023) in Qingdao, Shandong Province, China. The Kruskal-Wallis test was performed to determine the differences in mosquito density among different years and habitats. Circular statistics and line charts were employed to determine the peak period and a comparison of differences. RESULTS: Among a total of 14,834 adult mosquitoes comprising five mosquito species from four genera, Culex pipiens pallens was dominant and accounted for 89.6% of the specimens identified. Aedes albopictus, Armigeres subalbatus, and Anopheles sinensis made up 5.7%, 4.2%, and 0.5%, respectively. Culex tritaeniorhynchus accounted for less than 0.1%. The mean mosquito density (females/trap night) for the trapping period was 10.3 in 2021, 5.6 in 2022, and 3.6 in 2023. Among five habitats, the highest mosquito density was 8.9 in livestock sheds, followed by 6.8 in parks, 5.9 in rural dwellings, 5.5 in urban dwellings, and 5.4 in hospitals. No statistically significant differences were found among different years (H = 1.96, d.f. 2, P = 0.376) and habitats (H = 0.45, d.f. 4, P = 0.978). Overall, the peak period of mosquito activity fell in the months from June to September. The peak period among 3 years differed significantly (F(2,7022) = 119.17, P < 0.01), but there were no statistically significant differences in peak period among different habitats (F(4,7020) = -159.09, P > 0.05). CONCLUSION: Circular statistics could be effectively combined with statistical charts to elucidate the peak period of mosquitoes and determine the differences in statistics among different years and habitats. These findings will provide valuable information for mosquito control and public health management.

Modulating the gut microbiome in non-small cell lung cancer: Challenges and opportunities.

Despite the efficacy of immunotherapy in non-small cell lung cancer (NSCLC), the majority of the patients experience relapse with limited subsequent treatment options. Preclinical studies of various epithelial tumors, such as melanoma and NSCLC, have shown that harnessing the gut microbiome resulted in improvement of therapeutic responses to immunotherapy. Is this review, we summarize the role of microbiome, including lung and gut microbiome in the context of NSCLC, provide overview of the mechanisms of microbiome in efficacy and toxicity of chemotherapies and immunotherapies, and address current ongoing clinical trials for NSCLC including fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs).

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. METHODS: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups. ETHICS AND DISSEMINATION: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION: CRD42022330532.

A Modified Frailty Phenotype Used for Identifying Frailty in Health Care Practice: Validation Among Chinese Older Adults.

OBJECTIVES: The study aimed to evaluate a simplified and practical frailty detection tool derived from the Fried frailty phenotype (FFP). This tool was developed to facilitate the identification of frail individuals in constrained settings, addressing the challenges posed by uncertain cutoffs of FFP indicators in prompt frailty assessment. DESIGN: A longitudinal study and a cross-sectional study. SETTINGS AND PARTICIPANTS: A total of 1978 older adults aged 67.4 ± 6.16 years from the China Health and Retirement Longitudinal Study (CHARLS), and 972 older adults aged 72.8 ± 6.75 years from a pilot cross-sectional study conducted in Shanghai communities. METHODS: Frailty was assessed according to the FFP criterion. A Chinese modified frailty phenotype (CMFP) was developed, incorporating specific cutoffs for grip strength and an alternative test for walk speed. The internal consistency reliability, the criterion, and predictive validity of the CMFP were evaluated. RESULTS: The 5-time chair stand test (5t-CST) was significantly associated with the 2.5-m walk test (r = 0.373 in the CHARLS and 0.423 in the pilot study). Each element of the CMFP showed moderate to strong correlations with the total CMFP score and showed Cronbach's alpha of 0.303 and 0.358 in both populations. The Spearman's r and kappa values between the CMFP and the FFP were 0.795 and 0.663 in the CHARLS, and 0.676 and 0.537 in the pilot study. The areas under the curve (AUC) were 0.936 and 0.928 in the 2 studies, respectively. In addition, frailty assessed by the CMFP significantly predicted future incidence of outcomes, including all-cause mortality, activities of daily living (ADL)/instrumental ADL disability, hospitalization, and depression. CONCLUSIONS AND IMPLICATIONS: The study demonstrated the CMFP as a valid tool, particularly highlighting its excellent predictive ability on outcomes. The 5t-CST may act as a viable alternative test for assessing slowness. The CMFP can be systematically integrated into preclinical practice to identify frail individuals, especially within constrained spaces.

International Cost-Effectiveness Analysis of Durvalumab in Stage III Non-Small Cell Lung Cancer.

Importance: Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems. Objective: To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain). Design, Setting, and Participants: In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023. Main Outcomes and Measures: Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed. Results: The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab. Conclusions and Relevance: In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.

Predictors of quitting support from nonsmoking mothers for smoking fathers: a cross-sectional study from Chinese pupils' families.

BACKGROUND: Quitting support from smokers' partners can predict quit attempts and smoking abstinence but research on factors that predict such support has been limited. To add more evidence for partner support and the improved interventions for smoking cessation, we analyzed some new potential predictors of quitting support from smokers' spouses. METHOD: This cross-sectional study was conducted in in 2022 and 2023, selecting the students' families in which fathers smoked and mothers didn't smoke from grade 1-5 of 13 primary schools in Qingdao, China. Parents who met the criteria completed the online questionnaires and 1018 families were included in the analysis. We measured personal information related to smokers and their spouses such as age, education and nicotine dependence, and variables related to family and marital relationship such as family functioning, perceived responsiveness and power in decision-making of quitting smoking. Quitting support from smokers' spouses was measured by Partner Interaction Questionnaire and generalized linear model was used to explore the potential predictors of partner support. RESULTS: In this study, the mean age of smokers was 39.97(SD = 5.57) and the mean age of smokers' spouses was 38.24(SD = 4.59). The regression analysis showed that for smokers and their spouses, the older age groups showed the lower ratio of positive/negative support(P < 0.05) and smokers with high education showed the less positive and negative partner support(P < 0.05). Nicotine dependence was positively associated with negative support (ß = 0.120, P < 0.01), and perceived responsiveness (ß = 0.124, P < 0.05) as well as family functioning (ß = 0.059, P < 0.05) was positively associated with positive support. These three factors were associated with ratio of positive/negative support(P < 0.05). In addition, power of smoker's spouse in decision-making of quitting smoking was positively associated with the positive (ß = 0.087, P < 0.001) and negative support (ß = 0.084, P < 0.001). CONCLUSIONS: Nicotine dependence, family functioning, power in decision-making of quitting smoking and perceived responsiveness were found to be the predictors of quitting support from smokers' spouses. By incorporating predictors of partner support and integrating some established theories that can improve family functioning and marital relationships, smoking cessation interventions can be further improved.

Construction and Application of a Traditional Chinese Medicine Syndrome Differentiation Model for Dysmenorrhea Based on Machine Learning.

BACKGROUND: Dysmenorrhea is one of the most common ailments affecting young and middle-aged women, significantly impacting their quality of life. Traditional Chinese Medicine (TCM) offers unique advantages in treating dysmenorrhea. However, an accurate diagnosis is essential to ensure correct treatment. This research integrates the age-old wisdom of TCM with modern Machine Learning (ML) techniques to enhance the precision and efficiency of dysmenorrhea syndrome differentiation, a pivotal process in TCM diagnostics and treatment planning. METHODS: A total of 853 effective cases of dysmenorrhea were retrieved from the CNKI database, including patients' syndrome types, symptoms, and features, to establish the TCM information database of dysmenorrhea. Subsequently, 42 critical features were isolated from a potential set of 86 using a selection procedure augmented by Python's Scikit-Learn Library. Various machine learning models were employed, including Logistic Regression, Random Forest Classifier, Support Vector Machine (SVM), K-Nearest Neighbors (KNN), and Artificial Neural Networks (ANN), each chosen for their potential to unearth complex patterns within the data. RESULTS: Based on accuracy, precision, recall, and F1-score metrics, SVM emerged as the most effective model, showcasing an impressive precision of 98.29% and an accuracy of 98.24%. This model's analytical prowess not only highlighted the critical features pivotal to the syndrome differentiation process but also stands to significantly aid clinicians in formulating personalized treatment strategies by pinpointing nuanced symptoms with high precision. CONCLUSION: The study paves the way for a synergistic approach in TCM diagnostics, merging ancient wisdom with computational acuity, potentially innovating the diagnosis and treatment mode of TCM. Despite the promising outcomes, further research is needed to validate these models in real-world settings and extend this approach to other diseases addressed by TCM.

Management of Oncogene Driven Locally Advanced Unresectable Non-small Cell Lung Cancer.

INTRODUCTION: The current standard of care of locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation, followed by consolidation durvalumab. However, there is evidence that the efficacy of chemoradiation and also immunotherapy in many oncogene-positive LA-NSCLC are attenuated, and dependent on the subgroup. AREAS COVERED: We will firstly review the outcomes of standard-of-care therapy in oncogene-driven LA-NSCLC. We looked at various oncogene driven subgroups and the tumor microenvironment that may explain differential response. Finally, we review the role of targeted therapy in the treatment of LA-NSCLC. EXPERT OPINION: Each oncogene-positive subgroup should be treated as its own entity, and continued efforts should be undertaken to incorporate targeted therapy, which is likely to yield superior survival outcomes if trial design can be optimized and toxicities can be managed.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). METHOD: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. RESULTS: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. CONCLUSIONS: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Efficacy and safety of rituximab for primary nephrotic syndrome with acute kidney injury: A two-center prospective cohort study.

The purpose of this study was to investigate the efficacy and safety of a low-dose Rituximab (RTX) regimen driven by peripheral blood B lymphocyte count in the treatment of adult patients with nephrotic syndrome (NS) complicated with acute kidney disease (AKI). We conducted a prospective single-arm study to evaluate the effect of B cells-driven RTX regimen. Patients with NS (MCD, FSGS, MN, IgAN) complicated with AKI fulfilling the inclusion criteria were eligible for this study. Patients were followed up at intervals of 2 months. Student's t-test and Chi-squared test were used to analyze normally distributed continuous variables and non-normally distributed continuous variables, respectively. From August 2018 to January 2022, 23 patients met the inclusion criteria and agreed to participate in the study. 3, 9, and 11 patients were AKI stage 1, 2, and 3, respectively. From baseline to the latest follow-up, 20 patients had complete and partial recovery of renal function. Accompanied by depletion of B cells, significant reduction of urinary protein excretion, serum total cholesterol, and the number of relapses were observed during the 12 months after the first RTX infusion as compared with during the 12 months before RTX injection. The number of patients who maintained steroids and immunosuppressive medications also remarkably decreased. This study indicates that the targets-driven treatment of low-dose RTX can achieve a high remission rate and alleviate the loss of kidney function in treating NS with AKI. The long-term efficacy, side effects, and therapeutic economics of RTX are reasonable.

Real-world assessment of attenuated dosing anti-PD1 therapy as an alternative dosing strategy in a high-income country (as defined by World Bank).

The rising cost of oncological drugs poses a global challenge to patients, insurers, and policy makers, with the leading drugs worldwide by revenue from immune checkpoint inhibitors (ICIs). Despite its cost, ICI is marked as a paradigm shift, offering the potential of a long-term cure. To reduce cost, an attenuated dose of ICI based on pharmacological principles can be used while maintaining efficacy. This real-world study aims to examine the prescribing patterns, the effect of financial constraints, and the outcomes in non-small cell lung cancer (NSCLC). All patients receiving palliative intent ICI treatment for advanced NSCLC between January 2014 and April 2021 in National University Hospital, Singapore were recruited. Demographics, prescription trends, factors affecting the prescription of attenuated dose ICI (AD ICI) versus standard dose ICI (SD ICI), and the effect of dose on survival outcomes, toxicities, and costs were examined. Two hundred seventy-four received ICI. The majority of them were treated in first-line setting. One hundred sixty-two (59%) of patients received AD ICI, whereas 112 (41%) received SD ICI. Patients who did not have a supplemental private as-charged health insurance plan were more likely to have received AD ICI (OR: 4.53 [2.69-7.61] p < 0.001). There was no difference in progression-free survival (PFS) and overall survival (OS)-adjusted HR 1.07 CI [0.76, 1.50] p = 0.697 and HR 0.95 CI [0.67, 1.34] p = 0.773, respectively, between patients who received AD versus SD ICI. A cost minimization analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of USD 7,939,059 over 7 years. Our study provides evidence for AD-ICI as a promising strategy to maximize the number of patients who can be treated with ICI. This has the potential to make significant economic impact and allow more patients to benefit from novel therapies.

PLA2R-IgG4 antibody as a predictive biomarker of treatment effectiveness and prognostic evaluation in patients with idiopathic membranous nephropathy: a retrospective study.

Background: The Kidney Disease Improving Global Outcomes (KDIGO) 2021 guidelines recommend Rituximab (RTX) as the first-line therapy and phospholipase A2 receptor (PLA2R) antibody as a biomarker for remission and prognosis in patients with idiopathic membranous nephropathy (IMN). Methods: This study was a retrospective analysis of 70 patients with IMN treated with either rituximab (RTX) or cyclophosphamide (CTX) and steroid. Quantitative detection of PLA2R-IgG and PLA2R-IgG4 antibodies at sixth month after treatment, determined using time-resolved fluoroimmunoassay (TRFIA), were used for treatment effectiveness analysis and prognostic evaluation in patients with IMN. Results: After 12 months of therapy, the remission rate of proteinuria, including complete remission (CR) and partial remission (PR) in the RTX group and the CTX group, were 74% versus 67.5% (P = 0.114), respectively. Both PLA2R-IgG and PLA2R-IgG4 levels were decreased in patients with remission of proteinuria after 6 months of therapy. Receiver operating characteristic curve (ROC) curve analysis exhibited that the AUC of PLA2R-IgG4 and the PLA2R-IgG as laboratory criteria for proteinuria remission were 0.970 versus 0.886 (P = 0.0516), respectively, after 6 months of treatment. The cut-off value of PLA2R-IgG4 was 7.67 RU/mL and the sensitivity and specificity of remission rate at 6th month were 90.9% and 100%, respectively. Furthermore, the AUC of the PLA2R-IgG4 and PLA2R-IgG to predict the outcome after 12 months of treatment were 0.922 versus 0.897 (P = 0.3270), respectively. With the cut-off value of PLA2R-IgG4 being 22.985 RU/mL, the sensitivity and specificity of remission rate at 12th month were 100% and 87.1%, respectively. Logistic regression analysis revealed that the PLA2R-IgG4 level (P = 0.023), the rate of decrease of PLA2R-IgG4 level (P = 0.034), and eGFR level (P = 0.012) were significantly associated with remission. Conclusions: We found that the patients in the RTX group and CTX group achieved effective remission of proteinuria after 12 months of treatment. PLA2R-IgG4 may be a more effective biomarker for treatment effectiveness analysis and prognostic assessment, compared with anti-PLA2R-IgG for PLA2R associated IMN.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Factors associated with secondhand smoke exposure among non-smoking employees in the workplace: A cross-sectional study in Qingdao, China.

OBJECTIVE: This study was conducted to describe secondhand smoke (SHS) exposure among non-smoking employees in the workplace, and identify factors related to SHS exposure in Qingdao. METHODS: The study participants covered key non-smoking places stipulated in the "Qingdao City Smoking Control Regulations," which included three categories: restaurants, bars, and office buildings. Airborne nicotine concentration in the workplace and saliva cotinine concentration of employees were measured. The questionnaire included employees' demographic factors, smoke-free measures in the workplace, employers' tobacco hazard knowledge, and attitudes towards smoke-free policy. RESULTS: A total of 222 non-smoking employees and 46 non-smoking employers were included in the study. The median concentrations of airborne nicotine and salivary cotinine were 0.389 µg/m3 and 0.575 ng/mL, respectively. Educational status, average number of workplace smokers per day, exposure time to SHS in the workplace, and whether smoking and non-smoking areas were divided significantly related to airborne nicotine concentration. Age, educational status, exposure time to SHS in the workplace, tobacco control training and publicity, and whether the employers support the "Qingdao Tobacco Control Regulation" were significantly related to salivary cotinine concentration. CONCLUSIONS: Despite the implementation of the "Qingdao Smoking Control Regulations" in 2013, the workplace remains an important location for SHS exposure. Interventions such as raising workers' awareness of the risks associated with SHS exposure through health education and developing smoking prevention and cessation programs to reduce SHS exposure in the workplace are urgently needed.

Clinical Evaluation of Antiphospholipase A2 Receptor IgG4 level and Its IgG4-to-IgG Ratio Based on Quantitative Immunoassays in Idiopathic Membranous Nephropathy.

Background: Phospholipase A2 receptor (PLA2R), located at the membrane of glomerular podocyte, is the major autoantigen of idiopathic membranous nephropathy (IMN), and its antibodies with a predominant IgG4 subclass lead to pathological lesions. Further studies could be performed to validate the clinical values of PLA2R-IgG, PLA2R-IgG4, and PLA2R-IgG4-to-IgG ratios, as ultrasensitive and quantitative immunoassays for PLA2R antibodies have been well established in our previous work. Methods: A cohort of 58 IMN patients, 30 of whom were followed from 3 to 42 months, was assessed for serum PLA2R-IgG and -IgG4 levels, and the ratio of PLA2R-IgG4/-IgG combined with relative clinicopathological indicators. Results: Serum PLA2R-IgG4 level was significantly correlated with glomerular PLA2R staining. In addition, it was strongly correlated with PLA2R-IgG and its ratio. PLA2R-IgG and -IgG4 levels were both correlated with high-density lipoprotein and erythrocyte sedimentation rates. The ratio at the first diagnosis can predict the remission, and its efficacy overmatched PLA2R-IgG4. In the survival curves, negative results for the ratio or PLA2R-IgG4 at the first diagnosis demonstrated higher remission rates. Conclusion: Serum PLA2R-IgG4 concentration may replace renal PLA2R immunohistochemistry in IMN diagnosis. We propose that the PLA2R-IgG4-to-IgG ratio and PLA2R-IgG4 could be novel indicators for remission prediction in clinical practice.

Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment.

The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3-15.8 months), 6.8 months (range: 1.5-27.3 months), and 7.8 months (range: 1.4-9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3-570.8, p = 0.02; OR 8.8, 95% CI 1.3-106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy's clinical course. Early screening is imperative given its wide median time to onset.

A Moderated Mediation Model of the Relationship between Family Dynamics and Sleep Quality in College Students: The Role of Big Five Personality and Only-Child Status.

Sleep quality among college students is affected by numerous factors. Previous studies have linked sleep quality to family dynamics as well as personality. However, little is known about the mechanisms underlying this relationship. The aim of this study is to incorporate a moderated mediation model to explore the big five personality traits in mediating the relationship between family dynamics and sleep quality and whether this indirect relationship is modified by only-child status among Chinese undergraduate students. Survey data were collected from a cross-sectional study conducted in Shandong, China and 1022 undergraduate students aged 18-24 were recruited. The mediation and moderated mediation modeling analyses were carried out with the software SPSS PROCESS macro. After controlling for gender and grade, mediation analysis indicated that conscientiousness and agreeableness of the big five personality traits partially mediated the link between family dynamics and sleep quality (ß = -0.0093, CI: -0.0178, -0.0018; ß = -0.0047, CI: -0.0084, -0.0013), and moderation analysis found only-child status acted as a moderator in the relationship between family dynamics and the agreeableness of the big five personality traits (only child, ß = -0.0129, CI: -0.0196, -0.0072; non-only-child, ß = -0.0040, CI: -0.0078, -0.0002). Results showed that family dynamics positively predicted sleep quality both directly and indirectly via the conscientiousness and agreeableness of big five personality traits. Only-child status moderated the indirect association between family dynamics and agreeableness of big five personality traits. The current study advanced our understanding of the mechanism underlying the connection between family dynamics and sleep quality and helped to develop intervention measures to improve sleep quality of college students.