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Abstract Background Nursing interns encounter numerous professional pressures during clinical practice. Assessing adversity quotient levels and understanding the influencing factors are crucial for supporting students’ seamless transition to professional nurses. Purpose This study examined the adversity quotient subtypes of nursing interns and explored the relationships between adversity quotient and depression, coping styles, positive psychological capital, and professional adaptability. Methods This study employed a cross-sectional research design, involving a survey of 287 nursing interns in five general hospitals in Shanghai, China. Latent profile analysis was conducted to explore the subtypes of adversity quotient with the four domains as input variables. Multinomial logistic regression models and multiple correspondence analysis were used for subsequent data analysis. Results The average adversity quotient score of the nursing interns was 116.63 ± 32.22. A three-profile solution was obtained based on the latent profile analysis results. Three distinct subtypes emerged: a high-adversity quotient subtype (n = 50, 17.4%), a medium-adversity quotient subtype (n = 189, 65.9%), and a relatively low-adversity quotient subtype (n = 48, 16.7%). Multinomial logistic regression revealed that nursing interns in the high-adversity quotient subtype tended to be male, and had higher scores for positive psychological capital, negative coping style, and professional adaptability (p

Abstract. Background:. Non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) have shown similar worsening epidemic patterns globally and shared various overlapping pathophysiological mechanisms. However, evidence on the relationship between NAFLD and IBD risk is lacking. We aimed to investigate the associations between long-term risk of incident IBD and NAFLD in a large prospective cohort. Methods:. Participants from the United Kingdom Biobank cohort (https://biobank.ndph.ox.ac.uk/) who were free of IBD and alcoholic liver disease at baseline were enrolled. Baseline non-alcoholic fatty liver degree was measured by the well-established fatty liver index (FLI). The outcomes of interest included incident IBD, ulcerative colitis (UC), and Crohn's disease (CD). Multivariable Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results:. Among 418,721 participants (mean FLI: 48.11 ± 30.11), 160,807 (38.40%) participants were diagnosed as NAFLD at baseline. During a median of 12.4 years' follow-up, 2346 incident IBD cases (1545 UC, 653 CD, and 148 IBD-unclassified) were identified. Due to limited events, those IBD-unclassified were combined in UC or CD when examining the associated risk of UC or CD, separately. Compared with the lowest quartile of FLI, the highest quartile showed a separately 36.00%, 25.00%, and 58.00% higher risk of incident IBD (HRQ4 vs. Q1 = 1.36, 95% CI: 1.19–1.55, Ptrend

Abstract Background Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent–offspring trios and proband only analysis. Methods We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. Results Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. Conclusion CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.

Abstract Objective Acute ischemic stroke (AIS) is a significant health burden in China, affecting a sizable portion of the population. Conventional pharmacological treatments frequently fall short of desirable outcomes. Therefore, exploring alternative therapies is crucial. Remote ischemic postconditioning (RIPostC) is a noninvasive and cost-effective adjunctive therapy. This study aimed to investigate the efficacy and safety of RIPostC as an adjunctive therapy for AIS to inform clinical practice. Methods A comprehensive search was conducted across the PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, Weipu (VIP), and China Biology Medicine disc (CBM) databases up to October 2023. All included studies underwent bias risk assessment using the Cochrane risk-of-bias assessment tool. The primary outcome measure was the National Institute of Health Stroke Scale (NIHSS), with secondary outcomes including the Barthel index (BI), D-dimer, C-reactive protein (CRP), fibrinogen (FIB), brain-derived neurotrophic factor (BDNF), modified Rankin scale (mRS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels. The data were analyzed using fixed-effects and random-effects models in Review Manager, with mean differences (MDs) and 95% confidence intervals (CIs) calculated for each outcome. The grading of recommendations, assessment, development, and evaluations (GRADE) approach was used to evaluate the level of evidence for each outcome measure. Results This meta-analysis included 38 studies, encompassing 4334 patients. Compared with the control group, the RIPostC group had significantly lower NIHSS scores, serum CRP, D-dimer, IL-6, TNF-α, and FIB levels, and increased BDNF levels. Moreover, it improved the patient’s BI and mRS scores. According to the GRADE approach, the quality of evidence for mRS was deemed “moderate,” while the NIHSS, BI, and CRP were rated as “low” quality. IL-6, TNF-α, FIB, D-dimer, and BDNF received “very low” quality ratings. Conclusion The findings suggest that RIPostC activates endogenous protective mechanisms, providing benefits to patients with AIS.

Abstract Background Marfan syndrome (MFS) is an autosomal dominant connective tissue disease with wide clinical heterogeneity, and mainly caused by pathogenic variants in fibrillin-1 (FBN1). Methods A Chinese 4-generation MFS pedigree with 16 family members was recruited and exome sequencing (ES) was performed in the proband. Transcript analysis (patient RNA and minigene assays) and in silico structural analysis were used to determine the pathogenicity of the variant. In addition, germline mosaicism in family member (Ι:1) was assessed using quantitative fluorescent polymerase chain reaction (QF-PCR) and short tandem repeat PCR (STR) analyses. Results Two cis-compound benign intronic variants of FBN1 (c.3464–4 A > G and c.3464-5G > A) were identified in the proband by ES. As a compound variant, c.3464-5_3464-4delGAinsAG was found to be pathogenic and co-segregated with MFS. RNA studies indicated that aberrant transcripts were found only in patients and mutant-type clones. The variant c.3464-5_3464-4delGAinsAG caused erroneous integration of a 3 bp sequence into intron 28 and resulted in the insertion of one amino acid in the protein sequence (p.Ile1154_Asp1155insAla). Structural analyses suggested that p.Ile1154_Asp1155insAla affected the protein’s secondary structure by interfering with one disulfide bond between Cys1140 and Cys1153 and causing the extension of an anti-parallel β sheet in the calcium-binding epidermal growth factor-like (cbEGF)13 domain. In addition, the asymptomatic family member Ι:1 was deduced to be a gonadal mosaic as assessed by inconsistent results of sequencing and STR analysis. Conclusions To our knowledge, FBN1 c.3464-5_3464-4delGAinsAG is the first identified pathogenic intronic indel variant affecting non-canonical splice sites in this gene. Our study reinforces the importance of assessing the pathogenic role of intronic variants at the mRNA level, with structural analysis, and the occurrence of mosaicism.

Abstract Bladder cancer (BLCA) is a common malignant tumor in urinary system all over the world. However, due to its high recurrence rate and complex causes, clinicians often have limited options for surgical and drug treatments. Recent researchs on the molecular mechanism of BLCA have reveals its biological progress and potential for early diagnosis. Serine hydroxymethyltransferase 1/2 (SHMT1/2) is a crucial enzyme in the one-carbon metabolism of tumor cells, and the expression levels of these isozymes have been found to be associated with the biological progression of various malignant tumors. However, the impact of SHMT1/2 on the biological progression of bladder cancer and its molecular regulation mechanism remain unclear. In this research utilizes BLCA clinical sample data, the TCGA database, and in vitro cell experiments to predict the expression levels of SHMT1/2 in BLCA. The findings indicate that SHMT1 remained unchanged, while SHMT2 expression is increased in BLCA, which was related to poor prognosis. Additionally, SHMT2 affects the growth, migration, and apoptosis of bladder cancer cells in vitro. It also influences the expression levels of E-cadherin and N-cadherin, ultimately impacting the malignant biological progression of bladder tumors. These results establish a correlation between SHMT2 and the malignant biological progression of BLCA, providing a theoretical basis for the early diagnosis and treatment of bladder cancer.

Abstract Objective This study aimed to assess the functions of cell division cycle protein 45 (CDC45) in Non-small cell lung cancer (NSCLC) cancer and its effects on stemness and metastasis. Methods Firstly, differentially expressed genes related to lung cancer metastasis and stemness were screened by differential analysis and lasso regression. Then, in vitro, experiments such as colony formation assay, scratch assay, and transwell assay were conducted to evaluate the impact of CDC45 knockdown on the proliferation and migration abilities of lung cancer cells. Western blotting was used to measure the expression levels of related proteins and investigate the regulation of CDC45 on the cell cycle. Finally, in vivo model with subcutaneous injection of lung cancer cells was performed to verify the effect of CDC45 on tumor growth. Results This study identified CDC45 as a key gene potentially influencing tumor stemness and lymph node metastasis. Knockdown of CDC45 not only suppressed the proliferation and migration abilities of lung cancer cells but also caused cell cycle arrest at the G2/M phase. Further analysis revealed a negative correlation between CDC45 and cell cycle-related proteins, stemness-related markers, and tumor mutations. Mouse experiments confirmed that CDC45 knockdown inhibited tumor growth. Conclusion As a novel regulator of stemness, CDC45 plays a role in regulating lung cancer cell proliferation, migration, and cell cycle. Therefore, CDC45 may serve as a potential target for lung cancer treatment and provide a reference for further mechanistic research and therapeutic development.

Abstract Background The impact of antidepressants on Inflammatory bowel diseases (IBD) has been extensively studied. However, the biological effects and molecular mechanisms of antidepressants in alleviating colitis remain unclear. Methods We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell–cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro. Results We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell–cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes. Conclusions Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.

Abstract Objective To investigate the value of dual-energy dual-source computed tomography (DSCT) in evaluating pulmonary perfusion changes before and after radiotherapy for esophageal cancer, and its clinical use in the early diagnosis of acute radiation pneumonia (ARP). Methods We selected 45 patients with pathologically confirmed esophageal cancer who received radiotherapy (total irradiation dose of 60 Gy). Dual-energy DSCT scans were performed before and after radiotherapy and the normalized iodine concentrations (NIC) in the lung fields of the areas irradiated with doses of > 20 Gy, 10–20 Gy, 5–10 Gy, and 20 Gy groups were 0.780, 0.808, and 0.772, respectively. Sensitivity of diagnosis was 81.3%, 75.0%, and 68.8% and the specificity was 65.5%, 82.8%, and 79.3%, when taking 12.50%, 16.50%, and 26.0% as the diagnostic thresholds, respectively. The difference in NIC values in the lung fields of V 0.05). Conclusion The dual-energy DSCT could effectively evaluate pulmonary perfusion changes after radiotherapy for esophageal cancer, and the NIC reduction rate was useful as a reference index to predict ARP and provide further reference for decisions in clinical practice.

Abstract. Background:. The Global Leadership Initiative on Malnutrition (GLIM) criteria were published to build a global consensus on nutritional diagnosis. Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings. This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition, as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients. Methods:. This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1, 2018, and February 28, 2022, at Beijing You-An Hospital, Capital Medical University. Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography (CT) examination during hospitalization were included in the study. These patients were randomly divided into a modeling group (cohort 1, 667 patients) and a validation group (cohort 2, 335 patients). In cohort 1, optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index (L3-SMI) were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups. Next, patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. Additionally, the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1. Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes. Results:. The optimal cut-off values of L3-SMI were 39.50 cm2/m2 for male patients and 33.06 cm2/m2 for female patients. Based on the cut-off values, 31.63% (68/215) of the male patients and 23.3% (28/120) of the female patients had CT-determined sarcopenia in cohort 2. The prevalence of GLIM-defined malnutrition in cirrhotic patients was 34.3% (115/335) and GLIM-defined malnutrition was an independent risk factor for in-hospital mortality in patients with liver cirrhosis (Wald = 6.347, P = 0.012). Conclusions:. This study provided reference values for skeletal muscle mass index and the prevalence of GLIM-defined malnutrition in hospitalized patients with liver cirrhosis. These reference values will contribute to applying the GLIM criteria in cirrhotic patients.

Abstract The invasive capacity of lung adenocarcinoma (LUAD) is an important factor influencing patients’ metastatic status and survival outcomes. However, there is still a lack of suitable biomarkers to evaluate tumor invasiveness. LUAD molecular subtypes were identified by unsupervised consistent clustering of LUAD. The differences in prognosis, tumor microenvironment (TME), and mutation were assessed among different subtypes. After that, the invasion-related gene score (IRGS) was constructed by genetic differential analysis, WGCNA analysis, and LASSO analysis, then we evaluated the relationship between IRGS and invasive characteristics, TME, and prognosis. The predictive ability of the IRGS was verified by in vitro experiments. Next, the “oncoPredict” R package and CMap were used to assess the potential value of IRGS in drug therapy. The results showed that LUAD was clustered into two molecular subtypes. And the C1 subtype exhibited a worse prognosis, higher stemness enrichment activity, less immune infiltration, and higher mutation frequency. Subsequently, IRGS developed based on molecular subtypes demonstrated a strong association with malignant characteristics such as invasive features, higher stemness scores, less immune infiltration, and worse survival. In vitro experiments showed that the higher IRGS LUAD cell had a stronger invasive capacity than the lower IRGS LUAD cell. Predictive analysis based on the “oncoPredict” R package showed that the high IRGS group was more sensitive to docetaxel, erlotinib, paclitaxel, and gefitinib. Among them, in vitro experiments verified the greater killing effect of paclitaxel on high IRGS cell lines. In addition, CMap showed that purvalanol-a, angiogenesis-inhibitor, and masitinib have potential therapeutic effects in the high IRGS group. In summary we identified and analyzed the molecular subtypes associated with the invasiveness of LUAD and developed IRGS that can efficiently predict the prognosis and invasive ability of the tumor. IRGS may be able to facilitate the precision treatment of LUAD to some extent.

Abstract. Background:. Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. Methods:. In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl4), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. Results:. We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. Conclusion:. We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Background Platycodon grandiflorus belongs to the genus Platycodon and has many pharmacological effects, such as expectorant, antitussive, and anti-tumor properties. Among transcription factor families peculiar to eukaryotes, the basic leucine zipper (bZIP) family is one of the most important, which exists widely in plants and participates in many biological processes, such as plant growth, development, and stress responses. However, genomic analysis of the bZIP gene family and related stress response genes has not yet been reported in P. grandiflorus. Methods P. grandiflorus bZIP (PgbZIP) genes were first identified here, and the phylogenetic relationships and conserved motifs in the PgbZIPs were also performed. Meanwhile, gene structures, conserved domains, and the possible protein subcellular localizations of these PgbZIPs were characterized. Most importantly, the cis-regulatory elements and expression patterns of selected genes exposed to two different stresses were analyzed to provide further information on PgbZIPs potential biological roles in P. grandiflorus upon exposure to environmental stresses. Conclusions Forty-six PgbZIPs were identified in P. grandiflorus and divided into nine groups, as displayed in the phylogenetic tree. The results of the chromosomal location and the collinearity analysis showed that forty-six PgbZIP genes were distributed on eight chromosomes, with one tandem duplication event and eleven segmental duplication events identified. Most PgbZIPs in the same phylogenetic group have similar conserved motifs, domains, and gene structures. There are cis-regulatory elements related to the methyl jasmonate (MeJA) response, low-temperature response, abscisic acid response, auxin response, and gibberellin response. Ten PgbZIP genes were selected to study their expression patterns upon exposure to low-temperature and MeJA treatments, and all ten genes responded to these stresses. The real-time quantitative polymerase chain reaction (RT-qPCR) results suggest that the expression levels of most PgbZIPs decreased significantly within 6 h and then gradually increased to normal or above normal levels over the 90 h following MeJA treatment. The expression levels of all PgbZIPs were significantly reduced after 3 h of the low-temperature treatment. These results reveal the characteristics of the PgbZIP family genes and provide valuable information for improving P. grandiflorus’s ability to cope with environmental stresses during growth and development.

Abstract Background The occurrence of epithelial-mesenchymal transition (EMT) and immune evasion is considered to contribute to poor prognosis in lung adenocarcinoma (LUAD). Therefore, this study aims to explore the key oncogenes that promote EMT and immune evasion and reveal the expression patterns, prognostic value, and potential biological functions. Methods Firstly, we identified gene modules associated with EMT and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Next, we utilized differential analysis and machine learning to identify the key genes and validate them. Moreover, we analyzed the correlation between key genes and tumor microenvironment remodeling, drug sensitivity, as well as mutation frequency. Furthermore, we explored and validated their malignant biological characteristics through in vitro experiments and clinical samples. Finally, potential drugs for LUAD were screened based on CMap and validated through experiments. Results Firstly, WGCNA analysis revealed that red and green modules were highly correlated with EMT and TIDE. Among them, upregulated expression of SPOCK1 was observed in lung adenocarcinoma tissues and was associated with poor prognosis. Additionally, patients in the high SPOCK1 group showed more activation of malignant oncogenic pathways, higher infiltration of immunosuppressive components, and a higher frequency of mutations. The knockdown of SPOCK1 suppressed invasion and metastasis capabilities of lung adenocarcinoma cells, and the high expression of SPOCK1 was associated with low infiltration of CD8+ T cells. Therapeutic aspects, SPOCK1 can be a candidate indicator for drug sensitivity and CMap showed that VER-155008 was the drug candidate with the largest perturbation effect on the SPOCK1 expression profile. In vitro and in vivo experiments validated the cancer-inhibitory effect of VER-155008 in LUAD. Conclusion This study revealed through comprehensive bioinformatics analysis and experimental analysis that SPOCK1 can promote EMT and immune escape in LUAD, and it may serve as a promising candidate prognostic biomarker and therapeutic target for LUAD.

Abstract Bacterial-derived extracellular vesicles (EVs) have emerged as crucial mediators in the cross-talk between hosts and pathogens, playing a significant role in infectious diseases and cancers. Among these pathogens, Helicobacter pylori (H. pylori) is a particularly important bacterium implicated in various gastrointestinal disorders, gastric cancers, and systemic illnesses. H. pylori achieves these effects by stimulating host cells to secrete EVs and generating internal outer membrane vesicles (OMVs). The EVs derived from H. pylori-infected host cells modulate inflammatory signaling pathways, thereby affecting cell proliferation, apoptosis, cytokine release, immune cell modification, and endothelial dysfunction, as well as disrupting cellular junctional structures and inducing cytoskeletal reorganization. In addition, OMVs isolated from H. pylori play a pivotal role in shaping subsequent immunopathological responses. These vesicles incite both inflammatory and immunosuppressive reactions within the host environment, facilitating pathogen evasion of host defenses and invasion of host cells. Despite this growing understanding, research involving H. pylori-derived EVs remains in its early stages across different domains. In this comprehensive review, we present recent advancements elucidating the contributions of EV components, such as non-coding RNAs (ncRNAs) and proteins, to the pathogenesis of gastric and extragastric diseases. Furthermore, we highlight their potential utility as biomarkers, therapeutic targets, and vehicles for targeted delivery.

Abstract Background Different network meta-analyses (NMAs) on the same topic result in differences in findings. In this review, we investigated NMAs comparing aflibercept with ranibizumab for diabetic macular oedema (DME) in the hope of illuminating why the differences in findings occurred. Methods Studies were searched for in English and Chinese electronic databases (PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP; see detailed search strategy in the main body). Two independent reviewers systematically screened to identify target NMAs that included a comparison of aflibercept and ranibizumab in patients with DME. The key outcome of interest in this review is the change in best-corrected visual acuity (BCVA), including various ways of reporting (such as the proportion of participants who gain ≥ 10 ETDRS letters at 12 months; average change in BCVA at 12 months). Results For the binary outcome of BCVA, different NMAs all agreed that there is no clear difference between the two treatments, while continuous outcomes all favour aflibercept over ranibizumab. We discussed four points of particular concern that are illustrated by five similar NMAs, including network differences, PICO (participants, interventions, comparators, outcomes) differences, different data from the same measures of effect, and differences in what is truly significant. Conclusions A closer inspection of each of these trials shows how the methods, including the searches and analyses, all differ, but the findings, although presented differently and sometimes interpreted differently, were similar.

Abstract Background Intestinal lymphangiectasia (IL) is a rare protein-losing enteropathy caused by disorders of the intestinal lymphatics. There are only a few case reports and case series concerning the VCE (video capsule endoscopy) findings of IL. This work aimed to evaluate the VCE characteristics of small intestinal mucosal abnormalities in patients with IL, and to investigate the relationship between clinical and VCE characteristics. Methods Consecutive patients with IL who underwent VCE were enrolled in this retrospective study. The cases were classified into the white villi group and non-white villi group according to mucosal abnormalities detected by VCE. Clinical and endoscopic characteristics were investigated and analyzed. Results A total of 98 patients with IL with a median onset age of 26.3 ± 19.2 years were included. VCE revealed the following small intestinal lesions: (i) white villi type (57/98, 58.2%), i.e.: white-tipped or granular villi, white nodular villi or plaques; (ii) non-white villi type (41/98, 41.8%), i.e.: diffused low and round villi; (iii) complications (46/98, 46.9%), i.e.: bleeding, ulcers, protruding or vesicular-shaped lesions, stenosis and lymphatic leakage. A total of 58.2% (57) and 41.8% (41) of the cases were classified into the white villi and non-white villi groups respectively. The percentage of chylothorax in the white villi group was significantly lower than that in the non-white villi group (12/57 vs. 19/41, p = 0.008). In VCE, there were no significant differences in the involved segments and total detected rate of complications between the white villi and non-white villi groups (p > 0.05), while the detected rate of lymphatic leakage in the white villi group was significantly higher than that in the non-white villi group (31.6% vs. 12.2%, p = 0.026). Conclusions Our study evaluated the entire small intestinal mucosal abnormalities of IL by VCE, especially endoscopic complications. IL has specific VCE abnormalities in addition to classical endoscopic findings.

There are different types of treatment for eye diseases. Although the majority of eye diseases are curable with primary treatments and surgery, some of degenerative eye damages need regeneration that is not gained by conventional procedures. Stem cells, such as mesenchymal stem cells, human embryonic stem cell-derived retinal pigmented epithelium, and inducible pluripotent stem cells, are now considered one of the most important and safe methods for regeneration of various damaged tissues or organs. However, how will stem cell therapy contribute to regeneration and overcome degenerative eye diseases? This review discusses the regenerative mechanisms, clinical applications, and advantages of different types of stem cells for restoring degenerative eye diseases.

Introduction Breast cancer-related lymphedema (BCRL) is a common postoperative complication of breast cancer. It develops in a chronic and vicious cycle. Once lymphedema occurs, it cannot be cured and bring serious physiological, psychological, social and economic burden to patients. Upper limb functional exercises are an effective and convenient intervention for managing lymphedema. However, the optimal exercise sequence remains unclear. Therefore, we aim to compare the effects of exercise sequences under the guidance of commonly used exercise sequences and lymphatic flow theory.Methods An exploratory randomised controlled cross-over trial will be conducted. 32 patients with BCRL are randomly allocated into two groups (group A and group B). Group A patients will perform functional exercise from wrist joint to shoulder joint, and the exercise direction of group B is opposite to that of group A, that is, from shoulder joint to wrist joint end. Exercise time is once a day, each 20–30 min, for 2 weeks. After 2 weeks of washout period, A and B groups of exchange exercise sequences (exercise frequency and duration unchanged). The primary outcome is upper limb circumference, and secondary outcomes are upper limb function and lymphedema symptoms.Ethics and dissemination This study protocol is presented in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines. All participants will sign a written informed consent. The research ethics regional committee of Shanghai Seventh People’s Hospital has approved the study. Regardless of the outcome of this study, the results will be published in open-access journals to ensure public access.Trial registration number ChiCTR2200066463.

Rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) are the most common systemic autoimmune diseases, and they are increasingly being recognized as occurring in the same patient population. These two diseases share several clinical features and laboratory parameters, but the exact mechanism of their co-pathogenesis remains unclear. The intention of this study was to investigate the common molecular mechanisms involved in RA and pSS using integrated bioinformatic analysis. RNA-seq data for RA and pSS were picked up from the Gene Expression Omnibus (GEO) database. Co-expression genes linked with RA and pSS were recognized using weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis. Then, we screened two public disease-gene interaction databases (GeneCards and Comparative Toxicogenomics Database) for common targets associated with RA and pSS. The DGIdb database was used to predict therapeutic drugs for RA and pSS. The Human microRNA Disease Database (HMDD) was used to screen out the common microRNAs associated with RA and pSS. Finally, a common miRNA-gene network was created using Cytoscape. Four hub genes (CXCL10, GZMA, ITGA4, and PSMB9) were obtained from the intersection of common genes from WGCNA, differential gene analysis and public databases. Twenty-four drugs corresponding to hub gene targets were predicted in the DGIdb database. Among the 24 drugs, five drugs had already been reported for the treatment of RA and pSS. Other drugs, such as bortezomib, carfilzomib, oprozomib, cyclosporine and zidovudine, may be ideal drugs for the future treatment of RA patients with pSS. According to the miRNA-gene network, hsa-mir-21 may play a significant role in the mechanisms shared by RA and pSS. In conclusion, we identified commom targets as potential biomarkers in RA and pSS from publicly available databases and predicted potential drugs based on the targets. A new understanding of the molecular mechanisms associated with RA and pSS is provided according to the miRNA-gene network.

Abstract Objective To share our experience on prenatal diagnosis of 7q11.23 microduplication syndrome and to further delineate the fetal phenotypes of the syndrome. Methods A retrospective study was conducted to evaluate seven cases of dup7q11.23 syndrome diagnosed prenatally by chromosomal microarray (CMA). Clinical data were reviewed, including maternal characteristics, indications for prenatal diagnosis, sonographic findings, CMA results, pregnancy outcomes and follow-ups. Results Seven cases, including 2 pairs of MCDA twins, were prenatally identified with dup7q11.23 syndrome. The most common prenatal sonographic features were ventriculomegaly, low-lying conus medullaris, and dilated ascending aorta. All 7 fetuses presented with typical 7q11.23 duplications (1.40–1.55 Mb). Parental chromosome analysis was performed in four pairs of parents, and indicated that the duplications of Case 6 and 7 were inherited from their asymptomatic mother. Conclusion Our case series suggest that prenatal features of dup7q11.23 cases are diversified, with ventriculomegaly and low-lying conus medullaris being the most common intrauterine phenotypes. Additionally, cleft palate, dilated ascending aorta, and renal abnormalities were also observed, and should be taken into consideration in subsequent studies.

Abstract Chromobox protein homolog 4 (CBX4) is a component of the Polycomb group (PcG) multiprotein Polycomb repressive complexes 1 (PRC1), which is participated in several processes including growth, senescence, immunity, and tissue repair. CBX4 has been shown to have diverse, even opposite functions in different types of tissue and malignancy in previous studies. In this study, we found that CBX4 deletion promoted lung adenocarcinoma (LUAD) proliferation and progression in KrasG12D mutated background. In vitro, over 50% Cbx4 L/L , Kras G12D mouse embryonic fibroblasts (MEFs) underwent apoptosis in the initial period after Adeno-Cre virus treatment, while a small portion of survival cells got increased proliferation and transformation abilities, which we called selected Cbx4 −/− , Kras G12D cells. Karyotype analysis and RNA-seq data revealed chromosome instability and genome changes in selected Cbx4 −/− , Kras G12D cells compared with Kras G12D cells. Further study showed that P15, P16 and other apoptosis-related genes were upregulated in the primary Cbx4 −/− , Kras G12D cells due to chromosome instability, which led to the large population of cell apoptosis. In addition, multiple pathways including Hippo pathway and basal cell cancer-related signatures were altered in selected Cbx4 −/− , Kras G12D cells, ultimately leading to cancer. We also found that low expression of CBX4 in LUAD was associated with poorer prognosis under Kras mutation background from the human clinical data. To sum up, CBX4 deletion causes genomic instability to induce tumorigenesis under KrasG12D background. Our study demonstrates that CBX4 plays an emerging role in tumorigenesis, which is of great importance in guiding the clinical treatment of lung adenocarcinoma.

Abstract Design A two-round Delphi survey was conducted to seek opinions from experts about the index system for the evaluation of training courses of clinical nursing staff’s information literacy. Besides, a non-randomized controlled experimental study was adopted to check the application effect of the training courses. Aims This study intended to construct a training course of information literacy for clinical nurses, train nurses in order to improve their information literacy level and provide theoretical reference for the training of information literacy courses for clinical nurses. Methods Two rounds of Delphi study were conducted for the study among 26 clinical medical and nursing experts as well as educational experts from 5 different provinces and cities in China. From July 2022 to October 2022, a total of 84 clinical nurses from two hospitals were selected by the convenience sampling method, of which the nurses in one hospital were the control group and the nurses in the other hospital were the observation group. 42 nurses in the observation group were trained by the constructed information literacy training course. Questionnaire evaluation was used to compare the differences in the level of information literacy of nurses and the training effect between the two groups. Results The results of the Delphi consultation showed that the expert’s judgment coefficient was 0.958, the expert’s familiarity was 0.946, and the expert’s authority coefficient was 0.952. Finally, a training course of information literacy for clinical nurses with 4 course categories and 45 specific course contents was formed. Among them, nursing information awareness included 7 courses, nursing information knowledge 15 courses, nursing information ability 19 courses, and nursing information ethics 4 courses. The results of the empirical study showed that the information literacy level of the nurses in the observation group after the training of the information literacy course was improved, and the scores in nursing information awareness, nursing information knowledge, nursing information ability, and information ethics were significantly higher than those in the control group after training (P

Abstract Background Much less is known about the importance of blood pressure (BP) trajectories concerning the incidence of coronary heart disease (CHD) in people with disabilities. Our aim was to evaluate this association. Methods This cohort study surveyed 5711 adults from the Shanghai Disability Health Survey from June 2012 to June 2019. The latent class growth mixture model was used to examine distinct BP trajectories. We evaluated the association of BP trajectories with the risk of CHD by Cox proportional hazard models. The model for CHD risk fitted to BP trajectories was compared with models fitted to other BP-related indicators by goodness-of-fit, discrimination, and calibration. Results During a median follow-up of 71.74 months, 686 cases (median age was 49.03 (54.49, 58.55) years, 51.90% female) with CHD were identified, with a cumulative incidence of 12.01%. Systolic BP (SBP) and diastolic BP (DBP) were categorized into three classes, respectively. A statistically significant association was only observed between SBP trajectories and CHD. Compared with the normotensive stable SBP group (n = 1956), the prehypertension-stable group (n = 3268) had a higher risk (adjust hazards ratio (aHR) = 1.266, 95% confidence interval (CI) 1.014–1.581), and the stage 1 hypertension-decreasing group (n = 487) had the highest risk (aHR = 1.609, 95%CI 1.157–2.238). Among the BP-related indicators, the SBP trajectory was the strongest predictor of new-onset CHD. Findings were similar when sensitivity analyses were conducted. Conclusions SBP trajectory was a more important risk factor for CHD than other BP-related indicators and stringent BP control strategies may be effective for primary CHD prevention in the disabled population.

Abstract Water inflow is one of the main geohazards that threaten the safety of tunnels and other underground engineering projects. Faulted zone is one of the important geological triggers for such events. Numerical investigations on the evolution of flow behavior in tunnels across fault zones are of significance to the predication and prevention of this type of geohazards. In this work, a numerical investigation model with two overlapped parallel faults is established at a steady stage according to the "Three Zones" fault structure theory. The rapid turbulent flow in the fault zone is simulated by using the improved Darcy-Brinkman seepage model, while the slow laminar flow in ordinary rock zone is described by Darcy equation. The effect of relative position and distance between the tunnel excavation face and overlapped parallel faults to the groundwater pore pressure and flow velocity is studied through several scenarios, and the water inflow rate into the tunnel is calculated. The numerical investigation results reveal that while the tunnel face is excavated into the fault center core, the fractured zone, the ordinary rock zone, and the center of the overlapped faults, the pore pressure value ahead of the excavation face increases while the flow velocity decreases sequentially. The inflow rate is the largest while the tunnel face is excavated to center of the fault center core, which is closely related to the range of the overlapped area. The investigation results offer a practical reference for predicting early warning of water inflow geohazard when a tunnel cross two overlapped parallel faults.

The purpose of this study was to examine the dietary views and practices and to identify associated barriers to and facilitators of healthy eating of rural residents emerging from poverty in the context of rapid socio-economic development. A qualitative design with semi-structured interviews was utilized to collect detailed insights into the dietary behaviors of 22 rural residents from 10 villages in Fengshan town, Dafang county, Guizhou province, China. Thematic analysis was applied to interpret the interview data, guided by the socio-ecological model. Four themes were identified: traditional eating patterns, factors influencing food choice, limited knowledge of healthy diet, and lack of nutritional guidance. Barriers to healthy eating included traditional but unhealthy foods, limited nutritional knowledge, inadequate understanding of nutritional requirements, overwhelming nutritional information, and limited professional guidance. Facilitators encompassed healthy traditional eating patterns, household composition, home gardening, preference for traditional bean and soy products, improved food supply and availability owing to poverty alleviation efforts, and being open to receiving professional dietary guidance. As a preliminary investigation into the dietary views and practices of this population, the study highlights a significant gap in the nutritional knowledge and guidance available to rural residents in China, emphasizing the need for comprehensive strategies that address the complex socio-ecological factors influencing dietary behaviors.

Hand, foot, and mouth disease (HFMD) is a contagious viral infection predominantly affecting infants and young children, caused by multiple enteroviruses, including Enterovirus 71 (EV71), Coxsackievirus A16 (CA16), Coxsackievirus A10 (CA10), and Coxsackievirus A6 (CA6). The high pathogenicity of HFMD has garnered significant attention. Currently, there is no specific treatment or broad-spectrum preventive measure available for HFMD, and existing monovalent vaccines have limited impact on the overall incidence or prevalence of the disease. Consequently, with the emergence of new viral strains driven by vaccine pressure, there is an urgent need to develop strategies for the rapid response and control of new outbreaks. In this study, we demonstrated the broad protective effect of maternal antibodies against three types of HFMD by immunizing mother mice with a trivalent inactivated vaccine targeting EV71, CA16, and CA10, using a neonatal mouse challenge model. Based on the feasibility of maternal antibodies as a form of passive immunization to prevent HFMD, we prepared a multivalent antiviral milk by immunizing dairy cows with the trivalent inactivated vaccine to target multiple HFMD viruses. In the neonatal mouse challenge model, this immunized milk exhibited extensive passive protection against oral infections caused by the three HFMD viruses. Compared to vaccines, this strategy may offer a rapid and broadly applicable approach to providing passive immunity for the prevention of HFMD, particularly in response to the swift emergence and spread of new variants.

AbstractPurpose Few risk-forecasting models of allergic rhinitis (AR) exist that may aid AR pre-exposure prophylaxis (PrEP) in clinical practice. Therefore, this study aimed to develop and validate an effective clinical model for identifying candidates for AR PrEP using a routine medical questionnaire.Methods This study was conducted in 10 Chinese provinces with 13 medical centers (n = 877) between 2019 and 2021. Clinical characteristics and exposure history were collected via face-to-face interviews. Well-trained physicians diagnosed patients with AR based on skin prick test results and clinical performance. The least absolute shrinkage and selection operator model was used to identify potential risk factors for AR, and the logistic regression model was used to construct the risk-forecasting model. Predictive power and model reliability were assessed using area under the receiver operating characteristic curve and calibration curves, respectively.Results This study diagnosed 625 patients with AR who had positive responses to at least one indoor or outdoor allergen and 460 to at least one outdoor pollen allergen. Two nomograms were established to identify two types of AR with various sensitization patterns. Both models had an area under curve of approximately 0.7 in the development and internal validation datasets. Additionally, our findings found good agreement for the calibration curves of both models.Conclusion Early identification of candidates for AR PrEP using routine medical information may improve the deployment of limited resources and effective health management. Our models showed good performance in predicting AR; therefore, they can serve as potential automatic screening tools to identify AR PrEP candidates.

AbstractObjectives To evaluate the clinical utility of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in foetuses with oligohydramnios.Methods In this retrospective study, 126 fetuses with oligohydramnios at our centre from 2018 to 2021 were reviewed. The results of CMA and WES were analysed.Results One hundred and twenty-four cases underwent CMA and 32 cases underwent WES. The detection rate of pathogenic/likely pathogenic (P/LP) copy number variant (CNV) by CMA was 1.6% (2/124). WES revealed P/LP variants in 21.8% (7/32) of the foetuses. Six (85.7%, 6/7) foetuses showed an autosomal recessive inheritance pattern. Three (42.9%, 3/7) variants were involved in the renin–angiotensin–aldosterone system (RAAS), which are the known genetic causes of autosomal recessive renal tubular dysgenesis (ARRTD).Conclusion CMA has low diagnostic utility for oligohydramnios, while WES offers obvious advantages in improving the detection rate. WES should be recommended for fetuses with oligohydramnios.

Abstract The spike protein of SARS‐CoV‐2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS‐CoV‐2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike‐focused vaccines and therapeutics. Compared with the fast‐evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS‐CoV and HCoV‐NL63. Here, we use prime editor (PE) to precisely edit ACE2 at structurally selected sites. We demonstrated that residue changes at Q24/D30/K31 and/or K353 of ACE2 could completely ablate the binding of tested viruses while maintaining its physiological role in host angiotensin II conversion. PE‐mediated ACE2 editing at these sites suppressed the entry of pseudotyped SARS‐CoV‐2 major variants of concern and even SARS‐CoV or HCoV‐NL63. Moreover, it significantly inhibited the replication of the Delta variant live virus. Our work investigated the unexplored application potential of prime editing in high‐risk infectious disease control and demonstrated that such gene editing‐based host factor reshaping strategy can provide broad‐spectrum antiviral activity and a high barrier to viral escape or resistance.

Abstract In lung adenocarcinoma (LUAD), immune heterogeneity of hot and cold tumors has been recognized as one of the major factors affecting immunotherapy and other common treatments. However, there is still a lack of biomarkers that can effectively identify the immunophenotype of cold and hot tumors. First, the immune signatures were obtained based on literature mining, including macrophage/monocyte, IFN-γ response, TGF-β response, IL12 response, lymphocyte activation, and ECM/Dve/immune response. Subsequently, LUAD patients were further clustered into different immune phenotypes based on these immune signatures. Next, the key genes related to the immune phenotypes were screened by WGCNA analysis, univariate analysis, and lasso-cox analysis, and the risk signature was established via the key genes. In additional, we compared the clinicopathological characteristics, drug sensitivity, the abundance of immune infiltration, and the efficacy of immunotherapy and commonly used therapies between patients in the high- and low-risk groups in LUAD. LUAD patients were divided into immune hot phenotype and immune cold phenotype groups. The clinical presentation showed that patients with the immune hot phenotype had higher immunoactivity (including higher MHC, CYT, immune, stromal, ESTIMATE scores, higher abundance of immune cell infiltration, higher abundance of TIL, and enrichment of immune-enriched subtypes) and better survival outcomes than those with the immune cold phenotype. Subsequently, WGCNA analysis, univariate analysis, and lasso-cox analysis identified the genes highly associated with the immune phenotype: BTK and DPEP2. The risk signature, consisting of BTK and DPEP2, is highly correlated with the immune phenotype. High-risk scores were enriched in patients with immune cold phenotype and low-risk scores were enriched in patients with immune hot phenotype. Compared to the high-risk group, the low-risk group had better clinical performance, higher drug sensitivity, and a higher degree of immunoactivity, as well as better efficacy in receiving immunotherapy and common adjuvant therapy. This study developed an immune indicator consisting of BTK and DPEP2 based on the heterogeneity of hot and cold Immunophenotypes of the tumor microenvironment. This indicator has good efficacy in predicting prognosis and assessing the efficacy of immunotherapy, chemotherapy, and radiotherapy. It has the potential to facilitate personalized and precise treatment of LUAD in the future.

Abstract Background Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans. Methods In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta. Results The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22–25). Prenatal social support was significantly associated with methylation level at seven CpGs (P FDR

Summary: Background: Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis. Methods: Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs. Findings: We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44–82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem. Interpretation: This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss. Funding: National Science Foundation, and National Institutes of Health.

Objectives To evaluate the efficiency of chromosomal microarray analysis (CMA) in the prenatal diagnosis of foetuses with isolated absent or hypoplastic nasal bone (NB) in the first and second trimester.Methods From January 2015 to April 2021, foetuses with isolated absent or hypoplastic NB who received invasive prenatal diagnosis were enrolled. The results of CMA were analysedResults There were 221 foetuses, including 166 cases with isolated absent NB and 55 cases with isolated hypoplastic NB. Twenty-four foetuses (10.9%, 24/221) had an ultrasonic diagnosis in the first trimester and 197 (89.1%, 197/221) had a ultrasonic diagnosis in the second trimester. The overall diagnostic yield of CMA was 9.0% (20/221). Aneuploidies were detected in 13 (5.9%, 13/221) foetuses, including 10 Down syndrome, 2 Klinefelter's syndrome and 1 trisomy 18. Pathogenic copy number variations (CNVs) were detected in seven foetuses (3.2%, 7/221). In addition, variants of unknown significance (VOUS) were detected in four foetuses. The foetuses with isolated absent NB had a higher detection rate of chromosome abnormality than the isolated hypoplastic NB, but the difference was not significant in the statistical analysis (10.2% vs. 5.5%, χ2 =0.642, p = .423). No significant difference was observed in the detection rate between the first trimester and the second trimester (16.6% vs. 8.1%, χ2 = 1.002, p = .317, Chi-square test).Conclusion CMA can increase the diagnostic yield of chromosome abnormality, especially pathogenic CNVs for foetuses with isolated absent or hypoplastic NB. CMA should be recommended when isolated absent or hypoplastic NB is suspected antenatally.7

Abstract The development of next-generation sequencing (NGS) enabled a shift from array-based genotyping to directly sequencing genomic libraries for high-throughput genotyping. Even though whole-genome sequencing was initially too costly for routine analysis in large populations such as breeding or genetic studies, continued advancements in genome sequencing and bioinformatics have provided the opportunity to capitalize on whole-genome information. As new sequencing platforms can routinely provide high-quality sequencing data for sufficient genome coverage to genotype various breeding populations, a limitation comes in the time and cost of library construction when multiplexing a large number of samples. Here we describe a high-throughput whole-genome skim-sequencing (skim-seq) approach that can be utilized for a broad range of genotyping and genomic characterization. Using optimized low-volume Illumina Nextera chemistry, we developed a skim-seq method and combined up to 960 samples in one multiplex library using dual index barcoding. With the dual-index barcoding, the number of samples for multiplexing can be adjusted depending on the amount of data required, and could be extended to 3,072 samples or more. Panels of doubled haploid wheat lines (Triticum aestivum, CDC Stanley x CDC Landmark), wheat-barley (T. aestivum x Hordeum vulgare) and wheat-wheatgrass (Triticum durum x Thinopyrum intermedium) introgression lines as well as known monosomic wheat stocks were genotyped using the skim-seq approach. Bioinformatics pipelines were developed for various applications where sequencing coverage ranged from 1 × down to 0.01 × per sample. Using reference genomes, we detected chromosome dosage, identified aneuploidy, and karyotyped introgression lines from the skim-seq data. Leveraging the recent advancements in genome sequencing, skim-seq provides an effective and low-cost tool for routine genotyping and genetic analysis, which can track and identify introgressions and genomic regions of interest in genetics research and applied breeding programs.

Abstract Reactive astrogliosis usually bears some properties of neural progenitors. How injury triggers astrocyte dedifferentiation remains largely unclear. Here, we report that ischemia induces rapid up-regulation of Wnt2 protein in apoptotic neurons and activation of canonical Wnt signaling in reactive astrocytes in mice, primates and human. Local delivery of Wnt2 shRNA abolished the dedifferentiation of astrocytes while over-expressing Wnt2 promoted progenitor marker expression and neurogenesis. Both the activation of Wnt signaling and dedifferentiation of astrocytes was compromised in ischemic caspase-3−/− cortex. Over-expressing stabilized β-catenin not only facilitated neurogenesis but also promoted functional recovery in ischemic caspase-3−/− mice. Further analysis showed that apoptotic neurons up-regulated Wnt2 protein via internal ribosome entry site (IRES)-mediated translation. Knocking down death associated protein 5 (DAP5), a key protein in IRES-mediated protein translation, significantly diminished Wnt activation and astrocyte dedifferentiation. Our data demonstrated an apoptosis-initiated Wnt-activating mechanism which triggers astrocytic dedifferentiation and facilitates neuronal regeneration.

Abstract To understand the association between sodium and potassium consumption levels, hypertension and knowledge, attitudes and behaviors (KAB) toward salt and the commitment to effective sodium reduction and potassium supplementation to achieve the purpose of suppressing hypertension. A stratified multistage random sampling method was used to obtain a representative provincial sample of 7512 residents aged 18–69 years through a cross-sectional survey by the Salt Reduction and Hypertension Prevention Project (SRHPP) in Zhejiang Province of China in 2017–2018. A screening including demographic, anthropometric, salt-related KAB and physical measurements was implemented, and 24-h urine of approximately 1/5 of the participants was collected and tested. The mean age was 44.8 years, 50.1% were women, 44.0% lived in urban areas, and hypertension or prehypertension accounted for approximately 35.0%. The mean 24-h urinary sodium and potassium excretion were 3848.5 (1661.1) mg/d and 1491.1 (710.9) mg/d, respectively. KAB in urban areas was generally more favorable than in rural areas, women were better than men, and the optimal blood pressure group was better than the other two groups (P

Introduction Cancer is the second leading cause of death across the globe with the majority of deaths occurring in low-income and middle-income countries. Evidence has shown that the cancer burden can be substantially reduced by avoiding behavioural risk factors through comprehensive intervention strategies, including workplace health promotion, which has shown to be cost-effective in developed countries while rarely conducted in developing countries. This study aims to explore a feasible and sustainable approach to the prevention and control of cancer in China by developing an evidence-based comprehensive workplace health model equipped with a smartphone application for implementation.Methods and analysis This study is designed as a stepped-wedge, cluster-randomised controlled trial. We will recruit 15 workplaces from three cities in China. A total of 750 employees will be randomly selected for evaluation that includes five rounds of survey conducted every 6 months. After the second evaluation, workplaces will be randomly allocated to start the intervention sequentially every 6 months in three steps with five workplaces per step. A mobile application ‘Healthy Workplace’ will be developed to support the intervention. On-line and off-line health-related activities will be carried out among employees. Employers will provide supportive policies, environment and benefits to facilitate the adoption of healthy behaviours. The primary outcome is the change of Healthy Lifestyle Index Score, which consists of five components including smoking, alcohol drinking, physical activity, diet and body mass index.Ethics and dissemination The study has been approved by Queen Mary University of London Ethics of Research Committee (QMERC22.257) and Chinese Centre for Disease Control and Prevention Institutional Review Board (202210). Written informed consent is required from all participants. Results will be disseminated through presentations, publications and social media.Trial registration number ChiCTR2200058680.

Abstract Background Deregulation of cell-cycle pathway is ubiquitously observed in human papillomavirus negative (HPVneg) head and neck squamous cell carcinoma (HNSCC). Despite being an attractive target, CDK4/6 inhibition using palbociclib showed modest or conflicting results as monotherapy or in combination with platinum-based chemotherapy or cetuximab in HPVneg HNSCC. Thus, innovative agents to augment the efficacy of palbociclib in HPVneg HNSCC would be welcomed. Methods A collection of 162 FDA-approved and investigational agents was screened in combinatorial matrix format, and top combinations were validated in a broader panel of HPVneg HNSCC cell lines. Transcriptional profiling was conducted to explore the molecular mechanisms of drug synergy. Finally, the most potent palbociclib-based drug combination was evaluated and compared with palbociclib plus cetuximab or cisplatin in a panel of genetically diverse HPVneg HNSCC cell lines and patient-derived xenograft models. Results Palbociclib displayed limited efficacy in HPVneg HNSCC as monotherapy. The high-throughput combination drug screening provided a comprehensive palbociclib-based drug-drug interaction dataset, whereas significant synergistic effects were observed when palbociclib was combined with multiple agents, including inhibitors of the PI3K, EGFR, and MEK pathways. PI3K pathway inhibitors significantly reduced cell proliferation and induced cell-cycle arrest in HPVneg HNSCC cell lines when combined with palbociclib, and alpelisib (a PI3Kα inhibitor) was demonstrated to show the most potent synergy with particularly higher efficacy in HNSCCs bearing PIK3CA alterations. Notably, when compared with cisplatin and cetuximab, alpelisib exerted stronger synergism in a broader panel of cell lines. Mechanistically, RRM2-dependent epithelial mesenchymal transition (EMT) induced by palbociclib, was attenuated by alpelisib and cetuximab rather than cisplatin. Subsequently, PDX models with distinct genetic background further validated that palbociclib plus alpelisib had significant synergistic effects in models harboring PIK3CA amplification. Conclusions This study provides insights into the systematic combinatory effect associated with CDK4/6 inhibition and supports further initiation of clinical trials using the palbociclib plus alpelisib combination in HPVneg HNSCC with PIK3CA alterations.

Abstract Lung cancer (LC) is the leading cause of cancer death in China and Australia, the countries with different socioenvironmental contexts in the Western Pacific Region. Comparing the age-period-cohort effect on LC mortality (LCM) between the two countries can help plan interventions and draw lessons for countries in the region. We collected LCM estimates between 1990 and 2019 from the GBD 2019. Age-period-cohort modelling was applied to compute the net drift, local drift, cross-sectional age curve, longitudinal age curve, and the rate ratios (RRs) of period and cohort. China had a higher LC age-standardized mortality rate than Australia in 2019 (men: 58.10 [95% uncertainty interval (UI): 46.53, 70.89] vs. 30.13 [95% UI: 27.88, 32.31]/100,000 population; women: 22.86 [95% UI: 18.52, 27.52] vs. 17.80 [95% UI: 15.93, 19.34]/100,000 population). Period and cohort effects on LCM improved more markedly among Australian men (RR for period effect, from 1.47 [95% confidence interval (CI) 1.41, 1.53] to 0.79 [95% CI 0.75, 0.84]; RR for cohort effect, from 2.56 [95% CI 2.44, 2.68] to 0.36 [95% CI 0.11, 1.18]) and Chinese women (RR for period effect, from 1.06 [95% CI 1.01, 1.11] to 0.85 [95% CI 0.82, 0.89]; RR for cohort effect, from 0.71 [95% CI 0.65, 0.78] to 0.51 [95% CI 0.26, 1.03]) during the study period and birth cohort. The LCM in Chinese population aged 65 to 79 and Australian women aged 75 to 79 increased. Smoking and particulate matter (PM) contributed most to LCM in China, while smoking and occupational carcinogens contributed most in Australia. Decreasing period and cohort risks for LCM attributable to smoking and PM were more remarkable in Australia than in China. The LCM attributable to occupational carcinogens was higher in Australia than in China, particularly for those aged 60 to 79. Vigorous tobacco and PM control, which brought a substantial decline in LCM in Australia, may help reduce LCM in China. Australia should highlight LC prevention among people with occupational exposure. Chinese aged ≥ 65 and Australian women aged ≥ 75 should be the priorities for LC interventions.

Background. The extensive application of hospital information systems in the current information-driven era suggests that nursing education should focus on information education. Methods. The newly developed hospital information system was used and evaluated by 544 students to explore the feasibility and necessity of such applications for teaching. Results. Overall, 97.1% of the students expressed satisfaction, and 96.0% supported simulated information education for nursing. The usability was good, with the system receiving a usability score of 72.625 ± 13.0907. The junior students had a higher score than the sophomores regarding system availability, and the difference was statistically significant. Conclusions. Students generally had a high degree of satisfaction with the simulated information nursing education system and highly approved of the teaching method. However, the system needs to be upgraded.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, has led to the rapid development of Coronavirus disease 2019 (COVID-19) pandemic. COVID-19 represents a fatal disease with a great global public health importance. This study aims to develop a three-parameter Weibull mathematical model using continuous functions to represent discrete COVID-19 data. Subsequently, the model was applied to quantitatively analyze the characteristics for the mortality of COVID-19, including the age, sex, the length of symptom time to hospitalization time (SH), hospitalization date to death time (HD) and symptom time to death time time (SD) and others. A three-parameter mathematical model was developed by combining the reported cases in the Data Repository from the Center for Systems Science and Engineering at Johns Hopkins University and applied to estimate and analyze the characteristics for mortality of COVID-19. We found that the scale parameters of males and females were 5.85 and 5.45, respectively. Probability density functions in both males and females were negative skewness. 5% of male patients died under the age of 43.28 (44.37 for females), 50% died under 69.55 (73.25 for females), and 95% died under 86.59 (92.78 for females). The peak age of male death was 67.45 years, while that of female death was 71.10 years. The peak and median values of SH, HD and SD in male death were correspondingly 1.17, 5.18 and 10.30 days, and 4.29, 11.36 and 16.33 days, while those in female death were 1.19, 5.80 and 12.08 days, and 4.60, 12.44 and 17.67 days, respectively. The peak age of probability density in male and female deaths was 69.55 and 73.25 years, while the high point age of their mortality risk was 77.51 and 81.73 years, respectively. The mathematical model can fit and simulate the impact of various factors on IFR. From the simulation results of the model, we can intuitively find the IFR, peak age, average age and other information of each age. In terms of time factors, the mortality rate of the most susceptible population is not the highest, and the distribution of male patients is different from the distribution of females. This means that Self-protection and self-recovery in females against SARS-CoV-2 virus might be better than those of males. Males were more likely to be infected, more likely to be admitted to the ICU and more likely to die of COVID-19. Moreover, the infection fatality ration (IFR) of COVID-19 population was intrinsically linked to the infection age. Public health measures to protect vulnerable sex and age groups might be a simple and effective way to reduce IFR.

Abstract Objectives To evaluate the effect of prior exposure to simulation-based training on medical students’ performance in simulation-based training in asthma exacerbation. Methods Third-year novice medical students, who had no prior experience in simulation education and completed diagnostics and internal medicine courses, were recruited in this prospective observational study and divided into the pre-exposure and unexposed groups. Each group received a four-hour asthma exacerbation simulation-based training. The pre-exposure group was exposed to a myocardial infarction simulation training two weeks prior to the asthma simulation training. The main outcome was the performance scores in clinical skills and abilities. Performance and task checklist completion were recorded during the training. In addition, the knowledge level was tested before and after the simulation training. Students’ satisfaction was evaluated using a feedback questionnaire. Results In a class of 203 third-year novice medical students, 101 (49.8%) and 102 (50.2%) were assigned to the unexposed and pre-exposure groups, respectively. Scores were higher in the post-simulation test compared with the pre-simulation test. Checklist completion was greater in the pre-exposure group compared with the unexposed group (p 0.001). Totally 73.21% and 26.13% of students strongly agreed and agreed, respectively, that asthma exacerbation simulation-based training was necessary and valuable. Conclusions Prior exposure to simulation training can improve performance in medical students, including communication skills, medical humanistic care and checklist completion in subsequent asthma exacerbation simulation-based training.

Abstract Background The tumor microenvironment (TME) plays an important role in the occurrence and development of gastric cancer (GC) and is widely used to assess the treatment outcomes of GC patients. Immunohistochemistry (IHC) and gene sequencing are the main analysis methods for the TME but are limited due to the subjectivity of observers, the high cost of equipment and the need for professional analysts. Methods The ImmunoScore (IS) was developed in the TCGA cohort and validated in GEO cohorts. The Radiomic ImmunoScore (RIS) was developed in the TCGA cohort and validated in the Nanfang cohort. A nomogram was developed and validated in the Nanfang cohort based on RIS and clinical features. Results For IS, the area under the curves (AUCs) were 0.798 for 2-year overall survival (OS) and 0.873 for 4-year overall survival. For RIS, in the TCGA cohort, the AUCs distinguishing High-IS or Low-IS and predicting prognosis were 0.85 and 0.81, respectively; in the Nanfang cohort, the AUC predicting prognosis was 0.72. The nomogram performed better than the TNM staging system according to the ROC curve (all P

Abstract Background The prevalence of diffuse-type gastric cancer (GC), especially signet ring cell carcinoma (SRCC), has shown an upward trend in the past decades. This study aimed to develop computed tomography (CT) based radiomics nomograms to distinguish diffuse-type and SRCC GC preoperatively. Methods A total of 693 GC patients from two centers were retrospectively analyzed and divided into training, internal validation and external validation cohorts. Radiomics features were extracted from CT images, and the Lauren radiomics model was established with a support vector machine (SVM) classifier to identify diffuse-type GC. The Lauren radiomics nomogram integrating radiomics features score (Rad-score) and clinicopathological characteristics were developed and evaluated regarding prediction ability. Further, the SRCC radiomics nomogram designed to identify SRCC from diffuse-type GC was developed and evaluated following the same procedures. Results Multivariate analysis revealed that Rad-scores was significantly associated with diffuse-type GC and SRCC (p

Abstract Human brucellosis is caused by Brucella species and remains a major burden in both human and domesticated animal populations, especially in Inner Mongolia, China. The aims of this study were to analyze the spatiotemporal trends in human brucellosis in Inner Mongolia during 2010 to 2015, to explore the factors affecting the incidence of brucellosis. The results showed that the annual incidence was 29.68–77.67 per 100,000, and peaked from March to June. The majority of human brucellosis was male farmers and herdsmen, aged 40–59 years. The high-risk areas were mainly Xilin Gol League and Hulunbeier City. The incidence of human brucellosis in Inner Mongolia decreased during 2010 to 2015, although the middle and eastern regions were still high-risk areas. The regions with larger number of sheep and cattle, lower GDP per capita, less number of hospital beds, higher wind speed, lower mean temperature more likely to become high-risk areas of human brucellosis.

Abstract. Background:. Emerging evidence indicates that the sineoculis homeobox homolog 1−eyes absent homolog 1 (SIX1–EYA1) transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes, such as cell-cycle progression and metastasis. However, the roles of the SIX1–EYA1 transcriptional complex and its targets in colorectal cancer (CRC) are still being investigated. This study aimed to investigate the roles of SIX1–EYA1 in the pathogenesis of CRC, to screen inhibitors disrupting the SIX1–EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth. Methods:. Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues (collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, between 2016 and 2018, n = 24). In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1–EYA1 interaction. Cell proliferation, cell survival, and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and Boyden chamber assay, respectively. The Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) method was used to obtain small molecules that specifically disrupted SIX1–EYA1 interaction. CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts, and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth. Results:. Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues (for SIX1, 7.47 ± 3.54 vs.1.88 ± 0.35, t = 4.92, P = 0.008; for EYA1, 7.61 ± 2.03 vs. 2.22 ± 0.45, t = 6.73, P = 0.005). The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1 (CCNA1) and transforming growth factor beta 1 (TGFB1) by binding to the myocyte enhancer factor 3 consensus. Knockdown of both SIX1 and EYA1 could decrease cell proliferation, cell invasion, tumor growth, and in vivo tumor growth (all P

Background Clopidogrel is widely used to prevent and treat cardiovascular atherosclerosis and thrombosis. However, disturbance in the expression and activity of liver cytochrome metabolic enzymes significantly changes clopidogrel efficacy. Therefore, the effect of chronic unpredictable mild stress (CUMS)-induced depression on the expression of liver cytochrome metabolic enzymes and clopidogrel pharmacokinetics in rats were explored. Methods Nine different CUMSs were selected to establish a rat model of depression. Open field experiment and sucrose preference test were applied to explore the depressive behaviors. The concentration of serotonin in the cortex of depressed rats was determined using enzyme linked immunosorbent assay (ELISA). All rats were given 10 mg/kg clopidogrel orally after 12 weeks, and blood samples were collected at different time points. The clopidogrel concentration and CYP2C19/ CYP2C9 activity in rat liver microsomes were assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The rat liver drug enzymes expression was determined by Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). Results Open field experiment and sucrose preference test indicated the successful construction of the CUMS-induced depression model. The concentration of serotonin in the cortex of depressed rats decreased by 42.56% (∗∗p