A constraint on historic growth in global photosynthesis due to increasing CO2.

The global terrestrial carbon sink is increasing1-3, offsetting roughly a third of anthropogenic CO2 released into the atmosphere each decade1, and thus serving to slow4 the growth of atmospheric CO2. It has been suggested that a CO2-induced long-term increase in global photosynthesis, a process known as CO2 fertilization, is responsible for a large proportion of the current terrestrial carbon sink4-7. The estimated magnitude of the historic increase in photosynthesis as result of increasing atmospheric CO2 concentrations, however, differs by an order of magnitude between long-term proxies and terrestrial biosphere models7-13. Here we quantify the historic effect of CO2 on global photosynthesis by identifying an emergent constraint14-16 that combines terrestrial biosphere models with global carbon budget estimates. Our analysis suggests that CO2 fertilization increased global annual photosynthesis by 11.85 ± 1.4%, or 13.98 ± 1.63 petagrams carbon (mean ± 95% confidence interval) between 1981 and 2020. Our results help resolve conflicting estimates of the historic sensitivity of global photosynthesis to CO2, and highlight the large impact anthropogenic emissions have had on ecosystems worldwide.

Discovery of New Isotopes

Using the fusion-evaporation reaction ^{106}Cd(^{58}Ni,4n)^{160}Os and the gas-filled recoil separator SHANS, two new isotopes _{76}^{160}Os and _{74}^{156}W have been identified. The α decay of ^{160}Os, measured with an α-particle energy of 7080(26) keV and a half-life of 201_{-37}^{+58} µs, is assigned to originate from the ground state. The daughter nucleus ^{156}W is a ß^{+} emitter with a half-life of 291_{-61}^{+86} ms. The newly measured α-decay data allow us to derive α-decay reduced widths (δ^{2}) for the N=84 isotones up to osmium (Z=76), which are found to decrease with increasing atomic number above Z=68. The reduction of δ^{2} is interpreted as evidence for the strengthening of the N=82 shell closure toward the proton drip line, supported by the increase of the neutron-shell gaps predicted in theoretical models.

Isolated non-immune mediated second-degree atrioventricular block in fetus: natural history and predictive factors for spontaneous recovery.

OBJECTIVES: To uncover the clinical course of fetal isolated non-immune mediated second-degree AVB and determine the factors associated with the spontaneous recovery for fetal non-immune second-degree atrioventricular block (AVB). METHODS: A total of 20 fetuses with isolated, non-immune mediated second-degree AVB were prospectively recruited between 2014 and 2022. These fetuses were divided into the spontaneous recovery group (n=12) and the non-spontaneous recovery group (n=8). Maternal and fetal basic characteristics, intrauterine and postnatal outcomes were compared between groups. RESULTS: Twelve fetuses restored 1:1 atrioventricular conduction in utero and did not recur during the postnatal follow-up period. The residual eight fetuses maintained as second-degree AVB and six of them were aborted due to parental request in utero. Of the two live children with second-degree AVB, one of them progressed to complete AVB at the latest follow up at the age of 34 months, but without any symptoms, heart enlargement or dysfunction. The residual one progressed to complete AVB and was finally diagnosed with type 2 long-QT syndrome. Fetuses in the spontaneous recovery group presented with earlier gestational age at diagnosis (20.0[17.0-26.0] vs. 24.5[18.0-35.0] weeks, p=0.004) and higher atrial rate (147[130-160] vs 138.00[125.00-149.00] bpm, p=0.006) in comparison with the non-spontaneous recovery group. A cut-off value of 22.5 weeks of gestational age and 144 bpm of atrial rate at diagnosis could predict the failure of spontaneous recovery, with sensitivities of 87.5%, 75%, and specificities of 92.0%, 87.5%, respectively. CONCLUSIONS: The outcome of fetal non-immune second-degree AVB was favorable. Earlier gestational age at diagnosis and higher atrial rate were related to spontaneous reversion for isolated non-immune-mediated second-degree AVB. However, prenatal gene test should be performed for those with persistent AVB to exclude the heritable disorders including LQTS. These findings may provide important references for clinical management and prenatal counseling. This article is protected by copyright. All rights reserved.

Analysis of postoperative recurrence-free survival in non-small cell lung cancer patients based on consensus clustering.

AIMS: This study aims to assess whether consensus clustering, based on computed tomography (CT) radiomics from both intratumoral and peritumoral regions, can effectively stratify the risk of non-small cell lung cancer (NSCLC) patients and predict their postoperative recurrence-free survival (RFS). MATERIALS AND METHODS: A retrospective analysis was conducted on the data of surgical patients diagnosed with NSCLC between December 2014 and April 2020. After preprocessing CT images, radiomic features were extracted from a 9-mm region encompassing both the tumor and its peritumoral area. Consensus clustering was utilized to analyze the radiomics features and categorize patients into distinct clusters. A comparison of the differences in clinical pathological characteristics was conducted among the clusters. Kaplan-Meier survival analysis was employed to investigate differences in survival among the clusters. RESULTS: A total of 266 patients were included in this study, and consensus clustering identified three clusters (Cluster 1: n=111, Cluster 2: n=61, Cluster 3: n=94). Multiple clinical risk factors, including pathological TNM staging, programmed cell death ligand 1 (PD-L1), and epidermal growth factor receptor (EGFR) expression status exhibit significant differences among the three clusters. Kaplan-Meier survival analysis demonstrated significant variations in RFS across the clusters (P<0.001). The 3-year cumulative recurrence-free survival rates were 76.5% (95% CI: 68.6-84.4) for Cluster 1, 45.9% (95% CI: 33.4-58.4) for Cluster 2, and 41.5% (95% CI: 31.6-51.5) for Cluster 3. CONCLUSIONS: Consensus clustering of CT radiomics based on intratumoral and peritumoral regions can stratify the risk of postoperative recurrence in patients with NSCLC.

Prediction of programmed death-1 expression status in non-small cell lung cancer based on intratumoural and peritumoral computed tomography (CT) radiomics nomogram.

AIMS: This study aimed to predict the expression of programmed death-1 (PD-1) in non-small cell lung cancer (NSCLC) using intratumoral and peritumoral computed tomography (CT) radiomics nomogram. MATERIALS AND METHODS: Two hundred patients pathologically diagnosed with NSCLC from two hospitals were retrospectively analyzed. Of these, 159 NSCLC patients from our hospital were randomly divided into a training cohort (n=96) and an internal validation cohort (n=63) at a ratio of 6:4, while 41 NSCLC patients from another medical institution served as the external validation cohort. The radiomic features of the gross tumor volume (GTV) and peritumoral volume (PTV) were extracted from the CT images. Optimal radiomics features were selected using least absolute shrinkage and selection operator regression analysis. Finally, a CT radiomics nomogram of clinically independent predictors combined with the best rad-score was constructed. RESULTS: Compared with the 'GTV' and 'PTV' radiomics models, the combined 'GTV + PTV' radiomics model showed better predictive performance, and its area under the curve (AUC) values in the training, internal validation, and external validation cohorts were 0.90 (95% confidence interval [CI]: 0.83-0.97), 0.85 (95% CI: 0.74-0.96) and 0.78 (95% CI: 0.63-0.92). The nomogram constructed by the rad-score of the 'GTV + PTV' radiomics model combined with clinical independent predictors (prealbumin and monocyte) had the best performance, with AUC values in each cohort being 0.92 (95% CI: 0.85-0.98), 0.88 (95% CI: 0.78-0.97), and 0.80 (95% CI: 0.66-0.94), respectively. CONCLUSION: The intratumoral and peritumoral CT radiomics nomogram may facilitate individualized prediction of PD-1 expression status in patients with NSCLC.

Association of serum 25-hydroxyvitamin D with cardiovascular mortality and kidney outcome in patients with early stages of CKD.

PURPOSE: While serum 25-hydroxyvitamin D (25[OH]D) deficiency is prevalent in chronic kidney disease (CKD), the effects of 25(OH)D deficiency on cardiovascular mortality and kidney outcomes in patients with early-stage CKD remain incompletely understood. METHODS: This multicenter retrospective cohort study included adult patients with stages 1-3 CKD from 19 medical centers across China between January 2000 and May 2021. The primary outcome was cardiovascular mortality. The secondary study outcome included CKD progression (defined as a sustained > 40% eGFR decrease from baseline or progress to end-stage kidney disease), and annual percentage change of eGFR. RESULTS: Of 9229 adults with stages 1-3 CKD, 27.0% and 38.9% had severe (< 10 ng/mL) and moderate (10 to < 20 ng/mL) serum 25(OH)D deficiency, respectively. Compared with patients having 25(OH)D ≥ 20 ng/mL, a significantly higher risk of cardiovascular mortality (hazard ratio [HR] 1.90, 95% CI 1.37-2.63), CKD progression (HR 2.20, 95% CI 1.68-2.88), and a steeper annual decline in eGFR (estimate - 7.87%; 95% CI - 10.24% to - 5.51% per year) was found in those with serum 25(OH)D < 10 ng/mL. Similar results were obtained in subgroups and by sensitivity analyses. CONCLUSIONS: 25(OH)D deficiency is associated with increased risks of cardiovascular mortality and CKD progression in patients with early-stage CKD. Studies are needed to determine whether early intervention for 25(OH)D deficiency could improve the prognosis of patients with early-stage CKD.

Individual and area-level socioeconomic status, Life's Simple 7, and comorbid cardiovascular disease and cancer: a prospective analysis of the UK Biobank cohort.

OBJECTIVES: We aimed to investigate the associations of individual and area-level socioeconomic status (SES) with incident cardiovascular diseases (CVD) alone, cancer alone, and comorbid CVD and cancer, and the mediation role of cardiovascular health score in these associations. STUDY DESIGN: This was a population-based prospective cohort study. METHODS: We used data from the UK Biobank, a population-based prospective cohort study. Latent class analysis was used to create an individual-level SES index based on three indicators (household income, education level, and employment status), and the Townsend Index was defined as the area-level socioeconomic status. We used the American Heart Association's (AHA) Life's Simple 7 (smoking, body weight, physical activity, diet, blood pressure, blood glucose, and total cholesterol) to calculate the cardiovascular health score. We used Cox proportional hazard regression models to estimate the hazard ratio (HR) and 95% confidence interval (CI) adjusted for demographic, environmental, and genetic factors. RESULTS: Compared with high SES, the HRs in participants with low individual and area-level SES were 1.33 (95% confidence interval [CI] 1.29 to 1.38) and 1.24 (95% CI 1.20 to 1.29) for incident CVD, 0.96 (95% CI 0.93 to 0.99) and 0.95 (95%CI 0.92 to 0.98) for incident cancer, 1.32 (95%CI 1.24 to 1.40) and 1.15 (95%CI 1.08 to 1.22) for incident comorbid CVD and cancer, respectively. Additionally, the mediation proportion of CVD score for individual and area-level SES was 47.93% and 48.87% for incident CVD, 44.83% and 59.93% for incident comorbid CVD and cancer. The interactions between individual-level SES and CVD scores were significant on incident CVD, and comorbid CVD and cancer, and the protective associations were stronger in participants with high individual-level SES. CONCLUSIONS: Life's Simple 7 significantly mediated the associations between SES and comorbid CVD and cancer, while almost half of the associations remained unclear.

[Analysis of tumor regression after concurrent radiochemotherapy for locally advanced hypopharyngeal carcinoma].

Objective: To investigate the pathological characteristics of tumor regression and the expression level of chemoradiotherapy resistance-related molecular markers after preoperative concurrent radiochemotherapy in patients with locally advanced hypopharyngeal carcinoma. Methods: The clinical data of 44 patients with locally advanced hypopharyngeal carcinoma who underwent preoperative concurrent radiochemotherapy in the Department of Head and Neck Surgery of Shandong Otolaryngology Hospital from August 2016 to August 2020 were retrospectively analyzed. All patients received preoperative concurrent chemotherapy and radiotherapy. After radiochemotherapy, electronic laryngoscopy and imaging examination were performed to assess the tumor regression status. After 4 weeks, surgical resection was performed, and the specimens of the primary focus were processed as continuous pathological sections. After operation, HE staining and TdT-mediated dUTP nick-end labeling (TUNEL) method were used to detect the distribution characteristics and apoptosis of the remaining cancer focus, and immunohistochemistry was performed to determine the proliferation of the remaining cancer focus and the expression of radiation resistance-related molecular markers [signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1alpha (HIF-1α), sex determining region Y-box 2 (SOX2), and P53]. Results: A total of 44 patients were included, all of whom were male, with a mean age of (58.3±3.5) years. There were 40 cases of pyriform sinus carcinoma and 4 cases of posterior pharyngeal wall carcinoma. Twenty-nine cases were in stage T3 and 15 cases were in stage T4. There were 6 stage Ⅲ cases and 38 stage Ⅳ cases. According to the response evaluation criteria in solid tumors (RECIST), 13 patients achieved complete response (CR), 22 patients had partial response (PR), and 9 patients achieved stable disease (SD) after concurrent radiochemotherapy. The primary lesion resection methods included 19 cases of hypopharyngeal circumferential resection and 2 cases of total laryngectomy and partial hypopharyngeal resection. Twenty-three cases underwent supracricoid cartilage subtotal laryngectomy cricoid tongue fixation (CHP). Among 22 patients with PR, 10 had large PR (remission rate ≥70%) and 12 had small PR (remission rate <70%). The residual tumor was found in 30 patients (68.2%) after resection of all primary lesions by HE staining of pathological sections, of which 3 patients (3/13) with CR had residual cancer, all of which were focal residues. In large PR patients, residual cancer was detected in 6 cases (6/10), scattered in 4 cases, and focal residual in 2 cases, respectively. Large residual tumors were detected in small PR and SD patients. TUNEL method did not show any sign of apoptosis in 30 specimens with residual cancer focus, and the positive expression rate of Ki-67 was less than 10%. The expression of STAT3 (3.40±2.49 vs 5.23±3.02, t=-2.932, P=0.007) in 19 cases (63.3%) and HIF-1α (3.73±2.66 vs 6.97±3.05, t=-4.45, P<0.001) in 22 cases (73.3%) of residual cancer were significantly higher than those before radiochemotherapy. Other molecular markers showed no significant changes. All patients were followed up for 3 years. The 2-year survival rate was 59.3%, and the 3-year survival rate was 54.1%. Conclusions: Preoperative radiochemotherapy can make some patients with locally advanced hypopharyngeal carcinoma achieve complete or significant remission in clinical evaluation, but pathological detection still shows some residual cancer lesions with enhanced anti-apoptosis ability and decreased proliferation activity.

XAI-enabled neural network analysis of metabolite spatial distributions.

We used deep neural networks to process the mass spectrometry imaging (MSI) data of mouse muscle (young vs aged) and human cancer (tumor vs normal adjacent) tissues, with the aim of using explainable artificial intelligence (XAI) methods to rapidly identify biomarkers that can distinguish different classes of tissues, from several thousands of metabolite features. We also modified classic neural network architectures to construct a deep convolutional neural network that is more suitable for processing high-dimensional MSI data directly, instead of using dimension reduction techniques, and compared it to seven other machine learning analysis methods' performance in classification accuracy. After ascertaining the superiority of Channel-ResNet10, we used a novel channel selection-based XAI method to identify the key metabolite features that were responsible for its learning accuracy. These key metabolite biomarkers were then processed using MetaboAnalyst for pathway enrichment mapping. We found that Channel-ResNet10 was superior to seven other machine learning methods for MSI analysis, reaching > 98% accuracy in muscle aging and colorectal cancer datasets. We also used a novel channel selection-based XAI method to find that in young and aged muscle tissues, the differentially distributed metabolite biomarkers were especially enriched in the propanoate metabolism pathway, suggesting it as a novel target pathway for anti-aging therapy.

Development and validation of risk prediction models for stroke and mortality among patients with type 2 diabetes in northern China.

BACKGROUND: Stroke is one of the leading causes of disability and mortality in patients with type 2 diabetes mellitus (T2DM). Risk models have been developed for predicting stroke and stroke-associated mortality among patients with T2DM. Here, we evaluated risk factors of stroke for individualized prevention measures in patients with T2DM in northern China. METHODS: In the community-based Tianjin Chronic Disease Cohort study, 58,042 patients were enrolled between January 2014 and December 2019. We used multiple imputation (MI) to impute missing variables and univariate and multivariate Cox's proportional hazard regression to screen risk factors of stroke. Furthermore, we established and validated first-ever prediction models for stroke (Model 1 and Model 2) and death from stroke (Model 3) and evaluated their performance. RESULTS: In the derivation and validation groups, the area under the curves (AUCs) of Models 1-3 was better at 5 years than at 8 years. The Harrell's C-index for all models was above 0.7. All models had good calibration, discrimination, and clinical net benefit. Sensitivity analysis using the MI dataset indicated that all models had good and stable prediction performance. CONCLUSION: In this study, we developed and validated first-ever risk prediction models for stroke and death from stroke in patients with T2DM, with good discrimination and calibration observed in all models. Based on lifestyle, demographic characteristics, and laboratory examination, these models could provide multidimensional management and individualized risk assessment. However, the models developed here may only be applicable to Han Chinese.

[Predictive value of plasma exosomal miR-124-3p for the risk of chronic cerebral hypoperfusion].

Objective: To investigate the predictive value of plasma exosomal microRNA (miR)-124-3p in the risk of chronic cerebral hypoperfusion (CCH). Methods: A case-control study. Thirty patients who were diagnosed with CCH (CCH group) based on cranial artery spin labeling (ASL) in the neurology outpatient clinic of Sichuan Provincial People's Hospital from March 2022 to June 2022 and 30 healthy volunteers (control group) were included. Age, gender, smoking history, alcohol consumption history, diabetes history, hypertension, hyperlipidemia history, uric acid, fasting blood glucose, homocysteine and plasma exosomal miR-124-3p expression level were compared between the two groups. Comparisons of categorical variables were analyzed by either χ2 test or Fisher's exact test. If the data of continuous variables followed a normal distribution, they were expressed as mean±standard deviation (SD) and compared by t-test for two independent samples; otherwise, the data were expressed as M(Q1, Q3), and analyzed by Mann-Whitney U test for comparison between two groups. The correlation between cerebral blood flow and exosomal miR-124-3p levels was analyzed by Pearson's correlation. Binary multifactorial logistic regression analysis was used to determine the risk factors associated with CCH, and corresponding odds ratios (OR) and 95% confidence intervals (CI) were calculated. P<0.05 was considered significant. Results: There was no significant difference in age (64±8 vs. 60±8 years old), gender (33.3% vs. 30.0%), history of smoking (20.0% vs. 3.3%), alcohol consumption (20.0% vs. 6.7%), diabetes mellitus (13.3% vs. 13.3%), hypertension (53.3% vs. 30.0%), history of hyperlipidemia (46.7% vs. 36.7%), uric acid (288±60 vs.319±67 µmol/L), and fasting glucose [4.99(4.63, 5.91) vs. 5.28(5.09, 6.05) mmol/L] and homocysteine [11.35(10.18, 13.08) vs.11.00(9.78, 13.03) µmol/L] between the CCH and control groups (P>0.05). Plasma exosomal miR-124-3p expression was significantly higher in the CCH group than in the control group [13.08 (8.59, 21.55) vs. 2.85 (1.44, 5.10), respectively; U=169.50, P<0.001]. Pearson's correlation test showed that the level of exosomal miR-124-3p was negatively correlated with cerebral blood flow in the hypoperfused region in patients with CCH (r=-0.932, P<0.001). Multi-factor logistic regression analysis showed that plasma exosomal miR-124-3p was independently associated with the risk of CCH (OR=1.169,95%CI 1.063-1.286,P=0.001). Conclusions: The expression of plasma exosomal miR-124-3p is negatively correlated with cerebral blood flow in areas of low perfusion and is an independent risk factor for CCH. Plasma exosomal miR-124-3p may thus serve as a valid biomarker for CCH risk prediction.

[The role of intravoxel incoherent motion diffusion-weighted imaging in distinguishing diabetic nephropathy from non-diabetic renal disease in diabetic patients].

Objective: To investigate the intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the differential diagnosis of diabetic nephropathy (DN) and non-diabetic renal disease (NDRD) among patients with type 2 diabetes mellitus (T2DM). Methods: A diagnostic test. In this prospective study, patients with T2DM who underwent both IVIM-DWI and renal biopsy at the First Medical Center of Chinese PLA General Hospital between October 2017 and September 2021 were consecutively enrolled. IVIM-DWI parameters including perfusion fraction (f), pure diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were measured in the renal cortex, medulla, and parenchyma. Patients were divided into the DN group and NDRD group based on the renal biopsy results. IVIM-DWI parameters, clinical information, and diabetes-related biochemical indicators between the two groups were compared using Student's t-test or Mann-Whitney U test. The correlation of IVIM-DWI parameters with diabetic nephropathy histological scores were analyzed using Spearman's correlation analyzes. The diagnostic efficiency of IVIM-DWI parameters for distinguishing between DN and NDRD were assessed using the receiver operating characteristic (ROC) curves. Results: A total of 27 DN patients and 23 NDRD patients were included in this study. The DN group comprised 19 male and 8 female patients, with an average age of 52±9 years. The NDRD group comprised 16 male and 7 female patients, with an average age of 49±10 years. The DN group had a higher D* value in the renal cortex and a lower f value in the renal medulla than the NDRD group (9.84×10-3 mm2/s vs. 7.35×10-3 mm2/s, Z=-3.65; 41.01% vs. 46.74%, Z=-2.29; all P<0.05). The renal medulla D* value was negatively correlated with DN grades, interstitial lesion score, and interstitial fibrosis and tubular atrophy (IFTA) score (r=-0.571, -0.409, -0.409; all P<0.05) while the renal cortex f value was positively correlated with vascular sclerosis score (r=0.413, P=0.032). The renal cortex D* value had the highest area under the curve (AUC) for discriminating between the DN and NDRD groups (AUC=0.802, sensitivity 91.3%, specificity 55.6%). Conclusion: IVIM-derived renal cortex D* value can be used non-invasively to differentiate DN from NDRD in patients with T2DM that can potentially facilitate individualized treatment planning for diabetic patients.

[Clinical characteristics and their influences on the survival of leptomeningeal metastasis derived from lung adenocarcinoma harboring epithelial growth factor receptor mutation].

Objective: To analyze the clinical characteristics of leptomeningeal metastasis (LM) patients from epithelial growth factor receptor (EGFR)-mutated lung adenocarcinoma, and their impacts on the survival of the patients. Methods: From July 2018 to July 2022, the clinicopathological data of 81 patients diagnosed as EGFR-mutated lung adenocarcinoma LM by cytopathology who admitted to the Department of Oncology of Xiangya Hospital of Central South University were retrospectively analyzed, including 33 males and 48 females. The age ranged from 31 to 76 years, with a median age of 54 years. All the 81 patients were followed up, with a median follow-up of 21.0 months (95%CI: 12.5 to 29.5 months). The Kaplan Meier method was used to draw survival curve. Cox proportional hazards regression model was used to analyze the impact of the factors on the survival of patients. Results: Among the 81 patients, the interval between the initial diagnosis of lung cancer and the pathological diagnosis of LM in cerebrospinal fluid (CSF) was 0-108 months, with a median interval of 14 months. Fifty-two patients (64.2%) used the third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), while 17 patients (21.0%) used EGFR-TKIs in combination with other drugs, and 12 patients (14.8%) were treated with best supportive care (BSC). Sixty patients (74.1%) had a Kanofsky performance status (KPS) score of less than 60 points, and 71 patients (87.7%) had brain parenchymal metastasis and/or spinal metastasis. Twenty-two patients (27.2%) used pemetrexed through intrathecal CSF, and 17 patients (21.0%) used pemetrexed through the Ommaya sac to the CSF of the ventricle. The incidence of adverse event related to the administration of pemetrexed through CSF was 64.1% (25/39), mainly manifested as myelosuppression, including 22 patients of leukocyte reduction, 25 patients of hemoglobin reduction, and 14 patients of platelet reduction. The median post-leptomeningeal metastasis overall survival (pLM-OS) in 81 patients was 11.0 (95%CI: 7.7-14.3) months. KPS score≥60 points (HR=0.407, 95%CI: 0.170-0.973, P=0.043), CSF cytology negative after treatment (vs persistent positive, HR=0.351, 95%CI: 0.155-0.792, P=0.012), intraventricular administration of pemetrexed (vs non intraventricular administration of pemetrexed, HR=0.319, 95%CI: 0.137-0.745, P=0.008) and the treatment with third-generation EGFR-TKIs after LM (vs EGFR-TKIs in combination with other drugs, HR=0.486, 95%CI: 0.237-0.998, P=0.049) were a factor affecting pLM-OS of patients. Conclusions: Brain parenchyma, or/and spine are the most sites where the LM patients concurrently metastasize. KPS score≥60 points and CSF cytology negative after treatment, intraventricular administration of pemetrexed and the treatment with third-generation EGFR-TKIs are indictors affecting pLM-OS of the patients.

[Establishment and preliminary application of organoids in ovarian cancer].

Objective: To explore the establishment and application of ovarian cancer organoids. Methods: Fresh ovarian tumor tissues, obtaining from patients underwent surgery in the First Affiliated Hospital of Nanjing Medical University between October 2021 and March 2022, were collected, enzymatic degraded, digested, and embedded into matrigel to establish organoids. A total of 32 ovarian cancer samples were collected. Hematoxylin eosin (HE) staining and immunofluorescence (IF) procedure were used to verify the morphological structure of organoids and their expression of molecular markers. 3D cyto-live or dead assay was used to detecte the live or dead cells in organoids. Carboplatin with a concentration ranging from 5 to 80 µmol/L (5, 10, 20, 40, 80 µmol/L) was added to organoids to calculate the 50% inhibitory concentration (IC50) in different organoids. Results: (1) Organoids from a total of 32 patients were established, of which 18 cases could be passaged stably in the long term in vitro, while 14 could be passaged in the short time. The average amplification time of long-term passage in vitro was over 3 months, and the longest reached 9 months. (2) In HE staining, significant nuclei atypia and local micropapillary structures were observed in organoids. IF staining revealed that ovarian cancer organoids expressed molecular markers similar to primary tumor tissues, such as Pan cytokeratin (Pan-CK), p53, paired box gene 8 (PAX8), and Wilms tumor gene 1 (WT1). (3) In 3D cyto-live or dead assay, a large number of apoptotic cells were observed inside and around the organoids after added carboplatin. The sensitivity to carboplatin varied in 18 organoids could amplify in the long term, with an average IC50 of (29.5±15.8) µmol/L. Moreover, IC50 values of 4 organoids derived from patients received neoadjuvant chemotherapy were much higher than the 14 organoids which did not received neoadjuvant chemotherapy [(48.7±11.3) µmol/L vs (24.0±12.1) µmol/L; t=3.429, P=0.022]. Conclusions: Organoids recapitulate ovarian cancers in vitro and could be stably passaged. Organoids derived from patients received neoadjuvant chemotherapy have higher resistance to carboplatin.

[Comparison of the effects and safety of dydrogesterone and medroxyprogesterone acetate on endometrial hyperplasia without atypia: a randomized controlled non-inferior phase â ¢ clinical study].

Objective: To compare the effects and safety of dydrogesterone (DG) and medroxyprogesterone acetate (MPA) on the treatment in patients with endometrial hyperplasia without atypia (EH). Methods: This was a single-center, open-label, prospective non-inferior randomized controlled phase Ⅲ trial. From February 2019 to November 2021, patients with EH admitted to the Obstetrics and Gynecology Hospital of Fudan University were recruited. Enrolled patients were stratified according to the pathological types of simple hyperplasia (SH) or complex hyperplasia (CH), and were randomised to receive MPA or DG. Untill May 14, 2022, the median follow-up time after complete response (CR) was 9.3 months (1.1-17.2 months). The primary endpoint was the 6-month CR rate (6m-CR rate). The secondary endpoints included the 3-month CR rate (3m-CR rate), adverse events rate, recurrence rate, and pregnancy rate in one year after CR. Results: (1) A total of 292 patients with EH were enrolled in the study with the median age of 39 years (31-45 years). A total of 135 SH patients were randomly assigned to MPA group (n=67) and DG group (n=68), and 157 CH patients were randomly assigned to MPA group (n=79) and DG group (n=78). (2) Among 292 patients, 205 patients enrolled into the primary endpoint analysis, including 92 SH patients and 113 CH patients, with 100 patients in MPA group and 105 in DG group, respectively. The 6m-CR rate of MPA group and DG group were 90.0% (90/100) and 88.6% (93/105) respectively, and there were no statistical significance (χ2=0.11, P=0.741), with the rate difference (RD) was -1.4% (95%CI:-9.9%-7.0%). Stratified by the pathology types, the 6m-CR rate of SH patients was 93.5% (86/92), and MPA group and DG group were respectively 91.1% (41/45) and 95.7% (45/47); and the 6m-CR rate of CH patients was 85.8% (97/113), and MPA group and DG group were 89.1% (49/55) and 82.8% (48/58) respectively. The 6m-CR rates of the two treatments had no statistical significance either (all P>0.05). A total of 194 EH patients enrolled into the secondary endpoint analysis, including 88 SH patients and 106 CH patients, and 96 patients in MPA group and 98 in DG group, respectively. The 3m-CR rate of SH patients were 87.5% (77/88), while the 3m-CR rates of MPA group and DG group were 90.7% (39/43) and 84.4% (38/45), respectively; the 3m-CR rate of CH patients was 66.0% (70/106), and MPA group and DG group had the same 3m-CR rate of 66.0% (35/53). No statistical significance was found between the two treatments both in SH and CH patients (all P>0.05). (3) The incidence of adverse events between MPA group and DG group had no statistical significance (P>0.05). (4) A total of 93 SH patients achieved CR, and the cumulative recurrence rate in one year after CR were 5.9% and 0 in MPA group and DG group, respectively. While 112 CH patients achieved CR, and the cumulative recurrence rate in one year after CR were 8.8% and 6.5% in MPA group and DG group, respectively. There were no statistical significance between two treatment groups (all P>0.05). Among the 93 SH patients, 10 patients had family planning but no pregnancy happened during the follow-up period. Among the 112 CH patients, 21 were actively preparing for pregnancy, and the pregnancy rate and live-birth rate in one year after CR in MPA group were 7/9 and 2/7, while in DG group were respectively 4/12 and 2/4, and there were no statistical significance in pregnancy rate and live-birth rate between the two treatment groups (all P>0.05). Conclusions: Compared with MPA, DG is of good efficacy and safety in treating EH. DG is a favorable alternative treatment for EH patients.

[Research and reflection on the diversified method system of multi-stages and multi-scenarios surveillance and early warning of infectious diseases].

With the outbreak of infectious diseases, more and more attention has been paid to surveillance and early warning work. Timely and accurate monitoring data is the basis of infectious diseases prevention and control. Effective early warning methods for infectious diseases can improve the timeliness and sensitivity of early warning work. This paper briefly introduces the intelligent early warning model of infectious diseases, summarizes the emerging surveillance and early warning methods of infectious diseases, and seeks the possibility of diversified surveillance and early warning in different epidemic stages and different outbreak scenarios of infectious diseases. This paper puts forward the idea of constructing a diversified method system of infectious diseases surveillance and early warning based on multi-stages and multi-scenarios and discusses the future development trend of infectious diseases surveillance and early warning, in order to provide reference for improving the construction level of infectious diseases surveillance and early warning system in China.

[Primary adrenal NK/T cell lymphoma: a clinicopathologic analysis of six cases].

Objective: To investigate the clinicopathologic features of primary adrenal NK/T cell lymphoma (PANKL). Methods: Six cases of PANKL were collected at Henan Provincial People's Hospital from January 2000 to December 2021. The clinicopathologic features including morphology, immunophenotype, treatment and prognosis were retrospectively analyzed, and relevant literature was reviewed. Results: There were two males and four females. The median age was 63 years (ranged from 57 to 68 years). The tumors involved bilateral adrenal glands in 4 cases and unilateral adrenal gland in 2 cases. The main clinical symptom was low back pain without obvious cause. Serum lactate dehydrogenase (LDH) is elevated in five cases. The imaging feature was rapidly enlarging mass initially confined to unilateral/bilateral adrenal glands. Morphologically, the lymphoid cells were mainly medium-sized with a diffuse growth pattern. Coagulative necrosis and nuclear fragmentation were common. Angioinvasion was seen. Immunophenotypically, the neoplastic cells were positive for CD3, CD56 and TIA-1 while CD5 was negative in 5 cases. All cases were positive for EBER by in situ hybridization with more than 80% proliferative activity by Ki-67. Four cases received chemotherapy, one case underwent surgery, and one case underwent surgery with chemotherapy. Follow-up was done in 5 cases; one case was lost to follow-up. Three patients died with a median survival of 11.6 months (3-42 months). Conclusions: PANKL is rare with highly aggressive clinical presentation and poor prognosis. Accurate diagnosis entails correlation of histomorphology, immunohistochemistry, EBER in situ hybridization and clinical history.

[A preliminary study on the tear matrix metalloproteinase 9 point-of-care assay using a domestic kit].

Objective: To compare the point-of-care assays for tear matrix metalloproteinase 9 (MMP-9) using domestic and InflammaDry kits, and to evaluate the feasibility of diagnosing dry eye with the domestic kit. Methods: It was a cross-sectional study. Thirty dry eye patients and 30 age-and sex-matched normal volunteers were continuously enrolled in this cross-sectional study from June 2022 to July 2022. Both domestic and InflammaDry kits were used to detect the tear MMP-9 levels. The positive rates were recorded for qualitative analysis, and the gray ratios of bands (the gray value of detection bands to that of control bands) were collected for quantitative analysis. The correlations of MMP-9 levels with age, ocular surface disease index, fluorescence tear break-up time, tear meniscus height, Schirmer's Ⅰ test score, corneal fluorescein staining score, and meibomian gland dropout were analyzed. The Mann-Whitney U test, paired Chi-square test, Kappa test, and Spearman's correlation coefficient were used for statistical analysis. Results: There were 14 males and 16 females (30 eyes) in the control group, and their age was (39.37±19.55) years. In the dry eye group, 11 males and 19 females (30 eyes), aged (46.87±17.85) years, had moderate to severe dry eye. The positive rates of MMP-9 in tear fluid were significantly different between dry eye patients (InflammaDry: 86.67%; domestic kit: 70.00%) and controls (InflammaDry: 16.67%, P<0.001; domestic kit: 6.67%, P<0.001). Although the sensitivity of the domestic kit was lower than that of the InflammaDry kit (70.0% vs. 86.7%, P=0.001), the specificity was higher (93.3% vs. 83.3%, P=0.001). In dry eye patients, the positive coincidence rate was 80.7% (21/26), the negative coincidence rate was 100% (4/4), and the total coincidence rate was 83.3% (25/30), with no significant difference between the two kits (McNemar test: χ2=3.20, P>0.05), and the results of both kits were consistent (Kappa=0.53, P=0.001). The Spearman's correlation coefficient showed the gray ratios using both kits were positively correlated with the corneal fluorescein staining score (InflammaDry: ρ=0.48, P<0.05; domestic kit: ρ=0.52, P=0.003). Conclusion: The performances of the domestic and InflammaDry kits are consistent in the point-of-care assay for tear MMP-9, and the domestic kit has lower sensitivity but higher specificity.

[Expression profile of circular RNA in inflammatory response in human bronchial epithelial cells induced by carbon black nanoparticles].

Objective: To explore the toxic effect of carbon black nanoparticles on human bronchial epithelial cells, and identify the differentially expressed circular RNA based on the full transcriptome high-throughput sequencing, so as to provide evidence for the development of biomarkers exposed to carbon black nanoparticles and their application on epigenetic toxicology. Methods: In June 2020, 16 HBE cells were treated with carbon black nanoparticles at concentrations of 20, 40 and 80 µg/ml, and 16 HBE cells without any intervention were used as the control group. The cytotoxicity of carbon black nanoparticles was detected by CCK8 and LDH experiments. Real-time quantitative fluorescent PCR (qRT-PCR) and ELISA were used to detect the changes of interleukin-6 (IL-6) and interleukin-8 (IL-6, IL-8) mRNA and protein levels of carbon black nanoparticles with concentration gradient after 72 h exposure. Western blot analysis was conducted to detect the expression levels of toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (P-NF-κB), apoptosis-related speckled protein (ASC) and Caspase-1 associated with nuclear factor-κB. According to high-throughput sequencing results, differentially expressed Circrnas were screened and identified by qRT-PCR, and those with stable differentially expressed circrnas and the strongest association with the NF-κB pathway were selected for ring performance identification. Results: After being exposed to carbon black nanoparticles for 72 h, the activity of 16HBE cells decreased significantly (P<0.05), and the release of lactate dehydrogenase increased significantly (P<0.05). Compared with control group, mRNA expression levels of IL-6 and IL-8, protein levels of IL-6 and IL-8 were increased, and protein levels of TLR4, p-NF-κB, ASC and Caspase-1 were significantly up-regulated in 16 HBE cells of different concentrations, with statistical significance (P<0.05). Compared with the control group, a total of 492 differentially expressed circular Rnas (|log2 FC|>1) were detected. Among the 5 differentially expressed (P<0.05) circular Rnas, circ_002642 was selected as the object of subsequent research on circular Rnas, affter 72 hours of exposure to 80 µg/ml CBNPs, 16HBE cells showed signlficantly higher expression of circ_002642 (P<0.05) . Conclusion: Carbon black nanoparticles can induce differentially expressed circular RNAs associated with inflammatory response in human bronchial epithelial cells.