Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Serum fibroblast growth factor-2 levels complement vital biomarkers for diagnosing heart failure.

BACKGROUND: Early diagnosis of atrial fibrillation is important as it is crucial for improving patient outcomes. Fibroblast growth factor-2 (FGF2) may serve as a diagnostic biomarker for heart failure due to its ability to promote cardiac fibrosis and hypertrophy; however, the relationship between FGF2 concentration and heart failure is unclear. Therefore, this study aimed to explore whether FGF2 could aid in distinguishing patients with heart failure from healthy controls and those with dyspnea without heart failure. Additionally, to evaluate the possible correlation between serum FGF2 levels and its diagnostic parameters in patients with heart failure. METHODS: Plasma FGF2 concentration was measured in 114 patients with a complaint of dyspnea (enrolled in the study between January 2022 and August 2022). Based on heart failure diagnosis, the patients were assigned to three groups, as follows: heart failure (n = 80), non-heart-failure dyspnea (n = 34), and healthy controls (n = 36), following physical examination. Possible correlations between serum FGF2 levels and other prognostic parameters in patients with heart failure were analyzed. RESULTS: Serum FGF2 levels were higher in patients with heart failure (125.60 [88.95, 183.40] pg/mL) than in those with non-heart-failure dyspnea (65.30 [28.85, 78.95] pg/mL) and healthy controls (78.90 [60.80, 87.20] pg/mL) (p < 0.001). Receiver operating characteristic curve analysis identified FGF2 concentration as a significant predictor in heart failure diagnosis, with an area under the curve of 0.8693 (p < 0.0001). Importantly, in the heart failure group, serum FGF2 concentrations correlated with key prognostic parameters for heart failure, such as reduced left ventricular ejection fraction and elevated serum levels of N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Elevated serum FGF2 level is strongly associated with an increased risk of heart failure and could serve as a useful biomarker to complement vital diagnostic parameters for heart failure.

Single-cell and bulk RNA sequencing reveal heterogeneity and diagnostic markers in papillary thyroid carcinoma lymph-node metastasis.

PURPOSE: Papillary thyroid carcinoma (PTC) is characterized by lymph-node metastasis (LNM), which affects recurrence and prognosis. This study analyzed PTC LNM by single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing (RNA-seq) to find diagnostic markers and therapeutic targets. METHODS: ScRNA-seq data were clustered and malignant cells were identified. Differentially expressed genes (DEGs) were identified in malignant cells of scRNA-seq and bulk RNA-seq, respectively. PTC LNM diagnostic model was constructed based on intersecting DEGs using glmnet package. Next, PTC samples from 66 patients were used to validate the two most significant genes in the diagnostic model, S100A2 and type 2 deiodinase (DIO2) by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC). Further, the inhibitory effect of DIO2 on PTC cells was verified by cell biology behavior, western blot, cell cycle analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, and xenograft tumors. RESULTS: Heterogeneity of PTC LNM was demonstrated by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. A total of 19 differential genes were used to construct the diagnostic model. S100A2 and DIO2 differ significantly at the RNA (p < 0.01) and protein level in LNM patient tissues (p < 0.001). And differed in PTC tissues with different pathologic typing (p < 0.001). Further, EdU (p < 0.001) and cell biology behavior revealed that PTC cells overexpressed DIO2 had reduced proliferative capacity. Cell cycle proteins were reduced and cells are more likely to be stuck in G2/M phase (p < 0.001). CONCLUSIONS: This study explored the heterogeneity of PTC LNM using scRNA-seq. By combining with bulk RNA-seq data, diagnostic markers were explored and the model was established. Clinical diagnostic efficacy of S100A2 and DIO2 was validated and the treatment potential of DIO2 was discovered.

Deep learning-based facial analysis for predicting difficult videolaryngoscopy: a feasibility study.

While videolaryngoscopy has resulted in better overall success rates of tracheal intubation, airway assessment is still an important prerequisite for safe airway management. This study aimed to create an artificial intelligence model to identify difficult videolaryngoscopy using a neural network. Baseline characteristics, medical history, bedside examination and seven facial images were included as predictor variables. ResNet-18 was introduced to recognise images and extract features. Different machine learning algorithms were utilised to develop predictive models. A videolaryngoscopy view of Cormack-Lehane grade of 1 or 2 was classified as 'non-difficult', while grade 3 or 4 was classified as 'difficult'. A total of 5849 patients were included, of whom 5335 had non-difficult and 514 had difficult videolaryngoscopy. The facial model (only including facial images) using the Light Gradient Boosting Machine algorithm showed the highest area under the curve (95%CI) of 0.779 (0.733-0.825) with a sensitivity (95%CI) of 0.757 (0.650-0.845) and specificity (95%CI) of 0.721 (0.626-0.794) in the test set. Compared with bedside examination and multivariate scores (El-Ganzouri and Wilson), the facial model had significantly higher predictive performance (p < 0.001). Artificial intelligence-based facial analysis is a feasible technique for predicting difficulty during videolaryngoscopy, and the model developed using neural networks has higher predictive performance than traditional methods.

Regulation of the expression of casein alpha S1 and S2 genes in the bovine mammary epithelial cells by STAT5A.

Cow milk is rich in protein. Major cow milk proteins include casein α S1 (CSN1S1), casein α S2 (CSN1S2), casein ß (CSN2), casein kappa (CSN3), lactalbumin α (LALBA), and ß-lactoglobulin (LGB). These milk proteins are produced through gene expression in the mammary epithelial cells. Little is known about the molecular mechanism that mediates the expression of milk protein genes in cows. In this study, we tested the hypothesis that the expression of milk protein genes in cows is mediated by STAT5A, a transcription factor that is induced to bind and activate the transcription of target genes by extracellular signals such as prolactin. To circumvent the need of prolactin-responsive bovine mammary epithelial cells, we generated a plasmid that expresses a constitutively active bovine STAT5A variant, bSTAT5ACA. Transfection of the bovine mammary epithelial cell line MAC-T cells with the bSTAT5ACA expression plasmid caused a more than 100,000-fold and 600-fold increase in the expression of CSN1S1 and CSN1S2 mRNAs, respectively, compared with transfection of the wild-type bovine STAT5A (bSTAT5A) expression plasmid. Transfection of bSTAT5ACA, however, had no significant effect on the expression of CSN2, CSN3, LALBA, or LGB mRNA in MAC-T cells. Transfection of bSTAT5ACA caused a more than 260-fold and 120-fold increase in the expression of a luciferase reporter gene linked to the bovine CSN1S1 and CSN1S2 promoters in MAC-T cells, respectively, compared with that of bSTAT5A. The bovine CSN1S1 and CSN1S2 promoters each contain a putative STAT5 binding site, and gel-shift and super-shift assays confirmed bSTAT5ACA binding to both sites. These results together suggest that STAT5A plays a major role in regulating the expression of CSN1S1 and CSN1S2 genes in the bovine mammary epithelial cells and that STAT5A regulates the expression of these genes at least in part by binding to the STAT5 binding sites in their promoter regions. These results also suggest that STAT5A does not play a major role in regulating the expression of other major milk protein genes.

Comparison of milk protein concentrate, micellar casein, and whey protein isolate in loading astaxanthin after the treatment of ultrasound-assisted pH shifting.

Milk proteins can be used as encapsulation walls to increase the bioavailability of active compounds because they can bind hydrophobic, hydrophilic, and charged compounds. The objective of this study was to investigate the effects of astaxanthin (ASTA) encapsulation and the functional properties of milk protein and ASTA nanocomposites by an ultrasound-assisted pH-shifting treatment of different milk proteins, including milk protein concentrate (MPC), micellar casein (MCC), and whey protein isolate (WPI). The ultrasound-assisted pH-shifting treatment of milk protein helped to improve the encapsulation rate of ASTA. Therein, MCC showed great improvement of encapsulating ASTA after co-treatment with the raised encapsulated rate of 5.11%, followed by WPI and MPC. Furthermore, the nanocomposites of ASTA with milk protein exhibit improved bioavailability, antioxidant capacity, and storage stability. By comparison, MCC-encapsulated ASTA has the best storage stability, followed by MPC, and WPI-encapsulated ASTA has the least stability over a 28-d storage period. The results of intrinsic fluorescence and surface hydrophobicity showed that milk protein underwent fluorescence quenching after binding to ASTA, which was due to the hydrophobic sites of the protein being occupied by ASTA. In general, the nanocomposites of milk protein and ASTA fabricated by using an ultrasound-assisted pH-shifting treatment have the potential to be better nano-delivery systems for ASTA in functional foods, especially MCC, which showed excellent performance in encapsulation after treatment technique.

[Analyses of the risk factors for the progression of primary antiphospholipid syndrome to systemic lupus erythematosus].

Objectives: Analyze the clinical characteristics of patients with primary antiphospholipid syndrome (PAPS) progressing to systemic lupus erythematosus (SLE).Explore the risk factors for the progression from PAPS to SLE. Methods: The clinical data of 262 patients with PAPS enrolled in Peking Union Medical College Hospital from February 2005 to September 2021 were evaluated. Assessments included demographic data, clinical manifestations, laboratory tests (serum levels of complement, anti-nuclear antibodies, anti-double-stranded DNA antibodies), treatment, and outcomes. Kaplan-Meier analysis was used to calculate the prevalence of SLE in patients with PAPS. Univariate Cox regression analysis was employed to identify the risk factors for PAPS progressing to SLE. Results: Among 262 patients with PAPS, 249 had PAPS (PAPS group) and 13 progressed to SLE (5.0%) (PAPS-SLE group). Univariate Cox regression analysis indicated that cardiac valve disease (HR=6.360), positive anti-double-stranded DNA antibodies (HR=7.203), low level of complement C3 (HR=25.715), and low level of complement C4 (HR=10.466) were risk factors for the progression of PAPS to SLE, whereas arterial thrombotic events (HR=0.109) were protective factors (P<0.05 for all). Kaplan-Meier analysis showed that the prevalence of SLE in patients suffering from PAPS with a disease course>10 years was 9%-15%. Hydroxychloroquine treatment had no effect on the occurrence of SLE in patients with PAPS (HR=0.753, 95%CI 0.231-2.450, P=0.638). Patients with≥2 risk factors had a significantly higher prevalence of SLE compared with those with no or one risk factor (13-year cumulative prevalence of SLE 48.7% vs. 0 vs. 6.2%, P<0.001 for both). Conclusions: PAPS may progress to SLE in some patients. Early onset, cardiac-valve disease, positive anti-dsDNA antibody, and low levels of complement are risk factors for the progression of PAPS to SLE (especially in patients with≥2 risk factors). Whether application of hydroxychloroquine can delay this transition has yet to be demonstrated.

[Efficacy and safety of first-line treatment with anti-CD38 monoclonal antibody-based regimen for primary plasma cell leukemia].

Objective: To analyze the efficacy and safety of first-line treatment with an anti-CD38 monoclonal antibody regimen for primary plasma cell leukemia (pPCL). Methods: Patients diagnosed with pPCL from December 1st, 2018 to July 26th, 2023, receiving first-line treatment of anti-CD38 monoclonal antibody-based regimens across multiple centers including Peking University People's Hospital, Fuxing Hospital of Capital Medical University, Qingdao Municipal Hospital, Shengjing Hospital of China Medical University, Handan Central Hospital, the First Affiliated Hospital of Harbin Medical University, the Fourth Hospital of Hebei Medical University and General Hospital of Ningxia Medical University were consecutively included. A total of 24 pPCL patients were included with thirteen being male and eleven being female. The median age [M(Q1, Q3)] was 60 (57, 70) years. Patients were grouped according to peripheral blood plasma cell (PBPC) percentage [5%-19% (n=14) vs ≥20% (n=10)]. Last follow-up date was September 26th, 2023. The median follow-up period was 9.1 (4.2, 15.5) months. Patients' data related with clinical baseline characteristics, efficacy, survival and safety were retrospectively collected. Cox proportional hazards regression model was used to analyze risk factors associated with survival. Results: Among 24 pPCL patients, 16 (66.7%) patients had anemia at diagnosis, 13(54.2%) patients had thrombocytopenia, 8 (33.3%) patients had a baseline estimated glomerular filtration rate (eGFR)<40 ml·min-1·(1.73m2)-1, 13 (54.2%) patients had elevated lactate dehydrogenase (LDH) levels. The median PBPC percentage was 16% (8%, 26%) . Fluorescence in situ hybridization testing indicated that patients harboring 17p deletion, t(4;14) or t(14;16) were 6 (25.0%), 4 (16.7%) and 4 (16.7%), respectively. The overall response rate was 83.3% (20/24). The median progression-free survival (PFS) was 20.5 (95%CI: 15.8-25.2) months, and the median overall survival (OS) was not reached. Estimated 1-year and 2-year PFS and OS rates were 75.0% and 89.1%, 37.5% and 53.4%, respectively. The median PFS and OS for patients with PBPC percentages 5%-19% and≥20% were not reached and 20.5 (95%CI:15.7-25.3) months, 17.8 months and not reached, respectively. There was no significant statistical difference of PFS and OS between two groups (all P>0.05). Multivariate Cox regression analysis showed that 1p32 deletion was the risk factor associated with PFS (HR=7.7, 95%CI: 1.1-54.9, P=0.043). Seventeen patients (70.8%) developed grade 3-4 hematologic toxicities. Twelve patients (50.0%) developed grade 3-4 thrombocytopenia. Sixteen patients (66.7%) developed infection. All hematologic toxicities and infections were improved after supportive treatment. Conclusion: First-line treatment with anti-CD38 monoclonal antibody-based therapy for pPCL is effective and safe.

Two-Stage Treatment Protocol of Fungal Periprosthetic Hip and Knee Joint Infections: the Clinical Experience from a Single Center Experience.

PURPOSE OF THE STUDY: To evaluate the clinical results and safety of fungal periprosthetic joint Infections (fPJIs) using two-stage treatment protocol. MATERIAL AND METHODS: 8 patients with fPJIs (3 hips and 5 knees) using two-stage revision were reviewed retrospectively and followed up at least 2 years. The preoperative demographic data, two-stage treatment protocol, results of microbiology and histologic workup and postoperative follow-up results (reimplantation success rate and infection free time) were recorded. RESULTS: 7 patients got successful reimplantation, with a 75% reimplantation success rate. Two patients got knee arthrodesis eventually. All patients were infection free with a median follow-up of 4.0 ± 2.0 years (range, 2-7 years). Of them, Candida species were found in 7 patients, while non-Candida specimen was only isolated in 1 patient with Aspergillus. Only 2 patients had coexisting bacterial infection (Methicillin-resistant coagulase-negative Staphylococci and Proteus mirabilis respectively). The average interval between the initial surgery and diagnosis of fPJIs was 21.50±34.79 months (range, 4-104 months). The mean time of spacer implantation was 7.75±2.77 months (range, 6-14 months). None serious complication or above knee amputation was found. DISCUSSION: fPJIs are very rare and considerable challenge after total hip or knee arthroplasty. The goal of therapy is to eradicate local infection and maintain function. Candida species were the most common pathogen. The duration between spacer placement and staged reimplantation was highly variable, and generally dependent upon the results of joint aspirates and infl ammatory markers. The current study shows that the two-stage treatment protocol is recommended for fungal periprosthetic hip and knee joint infections. CONCLUSIONS: The two-stage treatment protocol is recommended for fungal periprosthetic hip and knee joint infections. The safety and effi cacy of biantibiotical impregnated (antifungal + antibiotics) cement spacer is confi rmed. Further evidence-based work is needed to determine the optimal drug dose and reimplantation time. KEY WORDS: two-stage treatment protocol, fungal periprosthetic infections, hip spacer, knee spacer.

[Ultrasonic convex array probe applied to increase success rate of external cephalic version without anesthesia].

Objective: To explore the feasibility of using ultrasonic convex array probe compressing abdominal wall to increase success rate of external cephalic version (ECV) without anesthesia in full-term and near-term pregnancy. Methods: Totally 190 singleton and non-cephalic presentation pregnant women in 36-39+4 weeks of gestation performed ECV from April 2019 to August 2023 in the First Affiliated Hospital of Nanjing Medical University were analyzed. According to whether use the ultrasound probe compressing fetal breech or not, the pregnant women were divided into two groups: 81 cases in the probe-compressing group (including primipara 61 cases and multipara 20 cases) and 109 cases in the non-probe-compressing group(including primipara 72 cases and multipara 37 cases). Clinical data, ECV related factors and complications were analyzed and compared between the two groups. Results: (1) The overall success rate of ECV was 64.2% (122/190). There was no significant difference in the success rate of ECV between probe-compressing group and non-probe-compressing group [69.1% (56/81) vs 60.6% (66/109), χ2=1.490, P=0.222]. The total vaginal delivery rate after successful ECV was 81.1% (99/122), while 71.1% (54/76) in primipara and 97.8% (45/46) in multipara, respectively. (2) Compare to the non-probe-compressing group, the success rate of ECV in primipara was significantly higher in the probe-compressing group [45.8% (33/72) vs 70.5% (43/61)], but the gestational age was shorter and the height was higher in the probe-compressing group (all P<0.05). The success rate of ECV of multipara in the probe-compressing group (65.0%, 13/20) was lower than that in the non-probe-compressing group (89.2%, 33/37), but there was no significant difference between the two groups (P>0.05). (3) Multivariate logistic regression analysis showed that abdominal wall compressed by ultrasound probe (OR=2.601, 95%CI: 1.113-6.075; P=0.027) and amniotic fluid index (AFI; OR=1.010, 95%CI: 1.001-1.020; P=0.028) were positive factors for the successful rate of ECV in primipara pregnant women. (4) The main complication of ECV was transient fetal heart rate reduction (8.9%,17/190), the incidence in the probe-compressing group was significantly higher than that in the non-probe-compressing group [14.8% (12/81) vs 4.6% (5/109); χ2=5.967, P=0.015]. No statistical differences were found in rates of complications between the ECV successful and unsuccessful pregnant women, and between probe-compressing and non-probe-compressing groups (all P>0.05). No adverse maternal and neonatal outcomes related to ECV were observed. Conclusions: The ultrasonic convex array probe compressing could significantly improve the success rate of ECV in primipara without increasing the incidence of adverse maternal and fetal outcomes. The success rate of ECV in primipara is influenced by AFI and operation mode.

[Annual progress in pulmonary rehabilitation 2023].

Pulmonary rehabilitation is a key component of long-term management strategies for chronic respiratory diseases (CRD). This comprehensive intervention, carefully tailored to individual patients based on thorough assessments, has undergone significant expansion and refinement toward personalization and precision in recent years. This review consolidates findings from studies published between October 2022 and September 2023, covering advances in CRD rehabilitation, assessment criteria, mechanisms, and innovative equipments. The primary objective is to enhance the knowledge base of healthcare professionals and pave the way for future research efforts in this important area.

[Genetic and clinical characteristics of single and compound types of patients with long QT syndrome type 3].

Objective: To explore the genetic background and clinical features of patients with long QT syndrome type 3 (LQT3). Methods: This retrospective cohort included patients diagnosed with LQT3 at the Department of Cardiology, Renmin Hospital of Wuhan University from January 1998 to December 2022. Patients were categorized into compound type group and single type group based on the presence of a single SCN5A mutation. The two groups were followed up and the differences in baseline characteristics, electrocardiograms, and clinical events between the two groups and probands were compared. Kaplan-Meier curves were used for survival analysis, and the log-rank test was employed to compare the event-free survival rates of first cardiac events between the groups and probands. Results: A total of 97 LQT3 patients were enrolled, including 59 probands. The age at diagnosis was (23.45±19.86) years, with 46 patients (47.4%) being male. Among them, 89 patients were classified as single type group, while 8 patients were classified as compound type group. Genetic testing identified 49 SCN5A mutations, with missense mutations being the majority (91.8%), primarily located in transmembrane regions (40.8%, n=20), interdomain linker regions (28.6%, n=14), and C-terminus (22.4%, n=11). The first cardiac event occurred in 44 patients (45.4%), with an onset age of (13.82±12.50) years. The main trigger was identified as rest or sleep (54.5%, n=24). Compared with patients in single type group, patients in compound type group were younger at diagnosis ((10.35±10.28) years vs. (24.63±20.13) years, P=0.040), had a significantly higher proportion of syncope (87.5% (7/8) vs. 33.7% (30/89), P=0.009), aborted cardiac arrest (62.5% (5/8) vs. 11.2% (10/89), P=0.001), and a lower incidence of event-free survival rates of first cardiac events (12.5% (1/8) vs.58.4% (52/89), log-rank P=0.001). The probands in compound type group had a significantly higher proportion of aborted cardiac arrest comparing to probands in single type group (62.5% (5/8) vs. 17.6% (9/51), P=0.020), while the difference in the incidence rate of event-free survival rates of first cardiac events between the probands in two groups was not statistically significant (12.5% (1/8) vs. 39.2% (20/51), log-rank P=0.08). Conclusion: Compound type LQT3 patients are not uncommon. Such patients are diagnosed at a younger age and exhibit more severe phenotypes, requiring close follow-up and proactive intervention strategies.

[Preliminary study on the role and mechanism of IL-6 receptor antagonists in improving post-infarction ventricular arrhythmia].

Objective: To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. Methods: The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Results: Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP (P all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower (P all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group (P all<0.05). Conclusions: TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial.

BACKGROUND: Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596). RESULTS: A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28], with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802). CONCLUSIONS: NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.

Development and validation of a nomogram to predict poor short-term response to recombinant human growth hormone treatment in children with growth disorders.

PURPOSE: The purpose of this study was to develop and validate a clinical predictive model for predicting the likelihood of a poor therapeutic response during the first year of recombinant human growth hormone (rhGH) treatment in children with growth disorders. METHODS: A total of 627 pediatric patients with growth disorders (GHD, ISS, TS, SGA) from The LG Growth Study cohort were evaluated. Restricted cubic splines (RCS) were utilized to investigate the association between predictors and the risk of poor rhGH response. Variables were selected using LASSO regression, and multivariate logistics regression models were established. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC) were used to assess the predictive model's accuracy and clinical value. The predictive accuracy of the model was validated on the testing set. RESULTS: Two predictive models containing 8 baseline predictors (diagnosis, age, height SDS, bone age minus chronological age, rhGH dosage, distance from mid-parental height in SDS, weight SDS, IGF-1 SDS) and 1 post-treatment predictor (height SDS gain at 6 months) were constructed by multivariate logistic regression analyses. The nomogram was built based on the multivariate predictive model and showed good discrimination and model fit effects in both the training set and the testing set. DCA and CIC analyses presented good clinical usability. CONCLUSION: The clinical predictive model for predicting the probability of poor short-term response of rhGH treatment in pediatric patients with growth disorders is useful and can assist physicians in making clinical decisions.

Association of residential greenness with the risk of metabolic syndrome in Chinese older adults: a longitudinal cohort study.

AIMS: We aimed to investigate the association between residential greenness and MetS in older Chinese adults. METHODS: Longitudinal data on sociodemographic characteristics and lifestyle were collected from the Shenzhen Healthy Ageing Research (SHARE) cohort. Greenness exposure was assessed through satellite-derived Normalized Difference Vegetation Index (NDVI) values in the 250-m, 500-m, and 1250-m radius around the residential address for each participant. MetS was defined by standard guidelines for the Chinese population. RESULTS: A total of 49,893 older Chinese adults with a mean age of 70.96 (SD = 5.26) years were included in the study. In the fully adjusted models, participants who lived in the highest quartile of NDVI250-m, NDVI500-m, and NDVI1250-m had a 15% (odds ratio, OR = 0.85, 95% confidence interval, CI: 0.80-0.90), 12% (OR = 0.88, 95% CI: 0.83-0.93), and 11% (OR = 0.89, 95% CI: 0.85-0.95) lower incidence of MetS, respectively, than those living in the lowest quartile (all p-trend < 0.01). Interactions and subgroup analyses showed that age, sex, smoking status, and drinking status were significant effect modifiers (p-interaction for all NDVI < 0.05). CONCLUSIONS: Residential greenness is associated with a lower risk of MetS in Chinese older adults, especially for young older adults, females, non-smokers, and non-drinkers.

COVID-19 pandemic and neonatal birth weight: a systematic review and meta-analysis.

OBJECTIVES: Lockdown was implemented in many countries during the pandemic, which led to myriad changes in pregnant women's lives. However, the potential impacts of the COVID-19 pandemic on neonatal outcomes remain unclear. We aimed to evaluate the association between the pandemic and neonatal birth weight. STUDY DESIGN: This was a systematic review and meta-analysis of the previous literature. METHODS: We searched the MEDLINE and Embase databases up to May 2022 and extracted 36 eligible studies that compared neonatal birth weight between the pandemic and the prepandemic period. The following outcomes were included: mean birth weight, low birth weight (LBW), very low birth weight (VLBW), macrosomia, small for gestational age (SGA), very small for gestational age (VSGA), and large for gestational age (LGA). Statistical heterogeneity among studies was assessed to determine whether a random effects model or fixed effects model was conducted. RESULTS: Of the 4514 studies identified, 36 articles were eligible for inclusion. A total of 1,883,936 neonates during the pandemic and 4,667,133 neonates during the prepandemic were reported. We identified a significant increase in mean birth weight (pooled mean difference [95% confidence interval (CI)] = 15.06 [10.36, 19.76], I2 = 0.0%, 12 studies) and a reduction in VLBW (pooled OR [95% CI] = 0.86 [0.77, 0.97], I2 = 55.4%, 12 studies). No overall effect was identified for other outcomes: LBW, macrosomia, SGA, VSGA, and LGA. There was publication bias for mean birth weight with a borderline significance (Egger's P = 0.050). CONCLUSION: Pooled results showed the pandemic was significantly associated with an increase in mean birth weight and a reduction in VLBW, but not for other outcomes. This review provided clues about the indirect effects of the pandemic on neonatal birth weight and more healthcare measures needed to improve neonatal long-term health.

Assessing hydrological connectivity for natural-artificial catchment with a new framework integrating graph theory and network analysis.

Anthropogenic activities alter the underlying surface conditions and arrangements of landscape features in a drainage basin, interfering with the pollutant (e.g., dissolved nitrogen, phosphorus) transport network configuration and altering the hydrological response. Assessing the impact of anthropogenic activities on hydrological connectivity for natural-artificial catchment is critical to understand the hydrological-driven ecosystem processes, services and biodiversity. However, quantifying this impact at catchment scale remains challenging. In this study, a new framework was proposed to quantify the impact of anthropogenic activities on hydrological connectivity combined with graph theory and network analysis. This framework was exemplified in a natural-artificial catchment of the Yangtze River basin of China. Based on remote sensing and field-investigated data, three transport networks were constructed, including natural transport network (N1), ditch-road transport network (N2), and terrace-dominated transport network (N3), which reflected the different human intervention. The results showed that human intervention improved the connectivity of the nodes and enhanced the complexity of the catchment transport network structure. Anthropogenic activities significantly decreased the hydrological structural connectivity of the catchment. In particular, compared with the N1 network, the critical nodes for hydrological connectivity which were judged by connectivity indexes were reduced by 92.94% and 95.29% in the N2 and N3 network, respectively. Furthermore, the ditch-road construction had a greater impact than terraces in decreasing hydrological structural connectivity at catchment scale. This framework has proven effective in quantifying the hydrological connectivity analysis under different human intervention at the catchment scale and facilitates the improvement of catchment management strategies.

[Relationship between chronic radiation enteritis of cervical cancer and gut microbiota].

OBJECTIVE: To explore the relationship between gut microbiota and chronic radiation enteritis of cervical cancer patients. METHODS: Fecal samples were collected from 34 patients with cervical cancer who had received radiotherapy for at least 6 months but less than 2 years. The patients were divi-ded into mild toxicity group (mild, M) with no symptoms or mild symptoms and severe toxicity group (severe, S) with severe symptoms by clinical diagnosis of radiation enteritis, modified inflammatory bo-wel disease questionnaire (IBDQ) and Vaizey questionnaire. DNA extracted from fecal samples was sequenced and analyzed by 16S rRNA sequencing method. The analysis indexes included α-diversity, ß-diversity, taxonomic composition analysis, taxonomic hierarchy tree and linear discriminant analysis (LDA) effect size (LEfSe). RESULTS: From the perspective of species diversity, most indices of α diversity in group M were higher than those in group S. Although there was no significant difference, it also indicated a correlation between low species diversity and severity of intestinal symptoms to some extent. There was also a significant difference in the distribution of ß diversity between the two groups, indicating that the microbial characteristics were different between the two groups. From the perspective of species composition, the M group had higher Firmicutes [66.5% (M) vs. 56.0% (S)] and lower Proteobacteria [4.1% (M) vs. 13.9% (S)] than the S group at the level of phyla. At the level of genus, there were also significant differences between the two groups: Shigella [2.7% (M) vs. 8.5% (S)], Faeca-libacterium [7.0% (M) vs. 2.7% (S)], Lachnospiraceae_Clostridium [1.3% (M) vs. 4.7% (S)]. Through LEfSe also found some species with statistically significant differences between the two groups. The abundance of Peptoniphilus, Azospirillum and Actinomyces in group M was significantly higher, while the abundance of Veillonellaceae, Rhodobacteraceae, and Rhodobacterales in group S was significantly higher. The taxonomic hierarchy tree also intuitively showed the difference in species composition between the two groups at each taxonomic level in space. CONCLUSION: The severity of chronic radiation enteritis of cervical cancer is closely related to the characteristics and composition of gut microbiota.

[Reliability and validity of the Chinese version of adverse childhood experiences international questionnaire in parents of preschool children].

OBJECTIVE: To test the reliability and validity of the Chinese version of adverse childhood experiences international questionnaire (ACE-IQ) in Chinese parents of preschool children. METHODS: The parents of preschool children in 6 kindergartens in Tongzhou District of Beijing were selected by stratified random cluster sampling, and the Chinese version of ACE-IQ after translation and adaptation was used for survey online. The collected data were randomly divided into two parts. One part of the data (n=602) was used for exploratory factor analysis (EFA), to screen items and evaluate structural validity, and then form the final Chinese version of ACE-IQ. The other part of the data (n=700) was used for confirmatory factor analysis (CFA), criterion validity analysis and reliability analysis. At the same time, experts investigation method was used to evaluate the content validity of the final Chinese version of ACE-IQ. RESULTS: After deleting four items of collective violence, the Chinese version of ACE-IQ with twenty-five items indicated good structural, criterion and content validity. Analysis results showed that the Chinese version of ACE-IQ presented a seven-factor model dimension, namely emotional neglect, physical neglect, family dysfunction, family violence, emotional and physical abuse, sexual abuse and violence outside the home, and the total score of the binary version of ACE-IQ Chinese version was positively correlated with the total score of childhood trauma questionaire-28 item short form (CTQ-SF, r=0.354, P < 0.001) and the center for epidemiological studies depression scale (CES-D, r=0.313, P < 0.001) respectively. Results from five experts showed that the item-level content validity index (I-CVI) of 25 items was between 0.80 and 1.00, and the average of all I-CVIs on the scale (S-CVI/Ave) of the scale was 0.984. At the same time, the internal consistency (Cronbach's α coefficient) of the whole scale was 0.818, and the split-half reliability (Spearman-Brown coefficient) was 0.621, which demonstrated good reliability. CONCLUSION: This study has formed a Chinese version of ACE-IQ with 25 items and 7 dimensions, which has good reliability and validity among the parents of preschool children in China. It can be used as an evaluation instrument for measuring the minimum threshold of the adverse childhood experiences in the parents of preschool children in the cultural background of China.