[Pedigree Analysis and Molecular Mechanism Study of Hereditary Glanzmann Thrombasthenia Caused by Compound Heterozygous Mutation of the ITGA2B Gene].

Objective: The phenotype and genotype of a pedigree with Glanzmann thrombasthenia caused by compound heterozygous mutation in the ITGA2B gene and its molecular pathogenesis were explored. Methods: The platelet aggregation rate of the proband and his family was detected by using a platelet aggregation test with adenosine diphosphate, collagen, epinephrine, arachidonic acid, and ristocetin. The expression levels of CD41 (αⅡb), CD61 (ß3), and CD42b (GPⅠb) on the platelet surface was detected by flow cytometry. Gene sequencing technology was used for the genetic identification of the family. RT-PCR was used in the detection of mRNA splicing, and qRT-PCR was used in detecting the relative mRNA level of the ITGA2B gene. Bioinformatics analysis was used to evaluate the pathogenicity of mutation sites and their effects on protein structure and function. The expressions of total αⅡb and ß3 in platelets were analyzed by Western blot. Results: Except ristocetin, the other four inducers could not induce platelet aggregation in the proband. Flow cytometry showed that the expression levels of αⅡb and ß3 were only 0.25% and 9.76%, respectively, on the platelet surface of the proband, whereas GPⅠb expression was relatively normal. The expression levels of glycoproteins in the other family members were almost normal. c.480C>G and c.2929C>T mutations were detected in the proband through gene sequencing. The c.480C>G mutation was inherited from his mother, and the c.2929C>T mutation was inherited from his father. The RT-PCR and sequencing results showed that the c.480C>G mutation caused mRNA splicing in the proband and his mother, resulting in the deletion of 99 bases in c.476G-574A (p.S160-S192). qRT-PCR showed that the c.2929C>T variant reduced the mRNA level of the ITGA2B gene in the proband and his father. Bioinformatics analysis suggested that the c.480C>G mutation might form a binding sequence with hnRNP A1 protein and generate the 5'SS splice site. The three-dimensional structural model of the αⅡb subunit showed that the ß-propeller domain of the p.S160-S192 deletion lost two ß-strands and one α-helix in blade 2. The c.2929C>T nonsense mutation caused premature translation termination and produced a truncated protein with the deletion of p.R977-E1039, including the cytoplasmic domain, transmembrane domain, and a ß chain of the extracellular Calf-2 domain. The total αⅡb expression of the proband was absent, and the relative expression of ß3 was 11.36% of the normal level. Conclusion: The compound heterozygous mutation c.480C>G in exon 4 and c.2929C>T in exon 28 of the ITGA2B gene probably underlies Glanzmann thrombasthenia in this pedigree.

Changes in primary care visits for respiratory illness during the COVID-19 pandemic: a multinational study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

[Identification of potential biomarkers and immunoregulatory mechanisms of rheumatoid arthritis based on multichip co-analysis of GEO database].

OBJECTIVE: To identify the biomarkers for early rheumatoid arthritis (RA) diagnosis and explore the possible immune regulatory mechanisms. METHODS: The differentially expressed genesin RA were screened and functionally annotated using the limma, RRA, batch correction, and clusterProfiler. The protein-protein interaction network was retrieved from the STRING database, and Cytoscape 3.8.0 and GeneMANIA were used to select the key genes and predicting their interaction mechanisms. ROC curves was used to validate the accuracy of diagnostic models based on the key genes. The disease-specific immune cells were selected via machine learning, and their correlation with the key genes were analyzed using Corrplot package. Biological functions of the key genes were explored using GSEA method. The expression of STAT1 was investigated in the synovial tissue of rats with collagen-induced arthritis (CIA). RESULTS: We identified 9 core key genes in RA (CD3G, CD8A, SYK, LCK, IL2RG, STAT1, CCR5, ITGB2, and ITGAL), which regulate synovial inflammation primarily through cytokines-related pathways. ROC curve analysis showed a high predictive accuracy of the 9 core genes, among which STAT1 had the highest AUC (0.909). Correlation analysis revealed strong correlations of CD3G, ITGAL, LCK, CD8A, and STAT1 with disease-specific immune cells, and STAT1 showed the strongest correlation with M1-type macrophages (R=0.68, P=2.9e-08). The synovial tissues of the ankle joints of CIA rats showed high expressions of STAT1 and p-STAT1 with significant differential expression of STAT1 between the nucleus and the cytoplasm of the synovial fibroblasts. The protein expressions of p-STAT1 and STAT1 in the cell nuclei were significantly reduced after treatment. CONCLUSION: CD3G, CD8A, SYK, LCK, IL2RG, STAT1, CCR5, ITGB2, and ITGAL may serve as biomarkers for early diagnosis of RA. Gene-immune cell pathways such as CD3G/CD8A/LCK-γδ T cells, ITGAL-Tfh cells, and STAT1-M1-type macrophages may be closely related with the development of RA.

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

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

[The effect of glycopyrrolate on intestinal spasm and hemodynamics in painless colonoscopy].

Objective: To investigate the effects of glycopyrrolate on intestinal spasm and hemodynamics in painless colonoscopy. Methods: A total of 100 patients who were scheduled to undergo painless colonoscopy were selected as the study subjects and randomly divided into two groups by a computerized number method. Ten patients in both groups dropped out because of disruption of the study protocol, and 45 patients from each group were included in the final analysis. Before anesthesia induction, patients in group glycopyrrolate (group G) were injected with 0.2 mg glycopyrrolate, while those in congtrol group (group C) were injected with an equal amount of saline. The heart rate, systolic blood pressure, and diastolic blood pressure were recorded at T0 (baseline period), T1 (after anesthesia induction), T2 (colonoscopy over sigmoid colon), T3 (colonoscopy over the liver region), T4 (after the end of examination), and T5 (at the awakening phase), and the degree of intestinal spasm was assessed intraoperatively using the Likert's four-point scale. The numerical rating scale (NRS) was used to assess preoperative and postoperative pain. The incidence of adverse events was recorded. Results: The general data at baseline were not statistically different between the two groups (P>0.05). During the procedure, patients in group G had lower intraoperative intestinal spasm scores than those in group C (P=0.028). Intraoperative hypotension and bradycardia occurrence were lower in group G than in group C (P<0.05), and intraoperative norepinephrine use was also lower than in the group C (P=0.034). Postoperative visual analog scale pain scores were lower in group G (P=0.047), but patients who used glycopyrrolate had a higher proportion of dry mouth (P=0.035). Conclusion: During painless colonoscopy, preoperative administration of glycopyrrolate significantly improved intraoperative hemodynamic fluctuations, reduced the incidence of hypotension and bradycardia, and relieved postoperative pain. However, glycopyrrolate use resulted in the risk of dry mouth.

[Syphilis infection and related factors among HIV-infected patients in Zhejiang Province].

Objective: To investigate syphilis infection and related factors among HIV-infected patients being followed up for more than one year in Zhejiang Province. Methods: Data were collected from the China Disease Control and Prevention Information System, and information such as demographic characteristics, viral load levels, and syphilis serologic test results was collected from HIV-infected persons who were diagnosed with HIV more than 1 year, aged ≥15 years with a current address in Zhejiang Province through December 31, 2022. The logistic regression model analyzed the prevalence of syphilis and the related factors. The SPSS 19.0 software was used for statistical analysis. Results: A total of 33 734 HIV-infected patients, with the prevalence of syphilis was 5.6% (1 879/33 734). Among the syphilis cases, the prevalence of syphilis was 6.4% (1 774/27 934) of males, 7.5% (640/8 543) of 25-34 years old age group, 7.6% (1 025/13 423) of unmarried, 8.3% (1 239/14 862) of homosexual transmission, 6.9% (214/3 080) with a non-local registered residence and 9.6% (602/6 267) with a history of STD before the HIV diagnosis. Multivariate Logistic regression analysis showed that participants who were male (aOR=2.19, 95%CI:1.77-2.72), 25-34 years old age group (aOR=1.80, 95%CI:1.47-2.20), homosexual transmission (aOR=1.67, 95%CI:1.49-1.88), with other provinces registered residence (aOR=1.26, 95%CI:1.09-1.47), and with a history of sexually transmitted disease (STD) before the HIV diagnosis (aOR=1.98, 95%CI:1.78-2.20) were associated with increased risk of syphilis. Being married (aOR=0.79, 95%CI:0.68-0.92) was associated with a decreased risk of syphilis. Conclusions: Syphilis infections were high in HIV-infected patients followed up more than one year in Zhejiang Province. It is recommended that syphilis surveillance and screening frequency should be strengthened among HIV-infected persons with characteristics such as male, homosexual transmission, and STD history.

[Epidemiological characteristic of viral encephalitis in children and adolescents in Henan Province, 2012-2023].

Objective: To understand the epidemiological characteristics and spatiotemporal distribution of viral encephalitis in children and adolescents in Henan Province from 2012 to 2023. Methods: The information about viral encephalitis cases from October 1, 2012 to July 26, 2023 were collected from Zhengzhou Children's Hospital (National Children's Regional Medical Center),Henan Provincial Children's Hospital for the analyses on temporal distribution the cases, the severe illness rate, age distribution, pathogen type and imaging findings of the cases. Results: A total of 6 276 cases of viral encephalitis were included in this study after excluding cases with incomplete information. The cases mainly originated from Zhengzhou (38.96%), followed by Zhoukou (9.93%), Xuchang (8.68%), Zhumadian (7.90%) and Pingdingshan (7.39%). The cases in boys accounted for 62.13% and the cases in girls accounted for 37.87%. Most cases (72.45%) occurred in age group 7-13 years. The overall rate of severe illness cases was 4.51% from 2012 to 2023. There were significant differences in severe illness cases among different areas and years (χ2=5.33,P=0.021; χ2=48.14,P<0.001). Enteroviruses were mainly detected (31.57%), in which Coxsackie virus was predominant (58.37%). Imaging findings showed that cerebral hemisphere damage was most common in children and adolescents with viral encephalitis (54.93%). Conclusions: From 2012 to 2023, more cases of viral encephalitis occurred in boys in Henan. Children and adolescents aged 7-13 years were the main affected group. The prevention of enteroviruses infection, especially Coxsackie virus, needs to be strengthened. Special attention should be paid to the prevention of cerebral hemisphere damage after viral encephalitis diagnosis.

[Multivariate analysis and construction and validation of a nomogram model from data of 1610 patients with non-tumor-related anastomotic stenosis after rectal cancer surgery].

Objective: To assess the risk factors affecting development of non-tumor- related anastomotic stenosis after rectal cancer and to construct a nomogram prediction model. Methods: This was a retrospective study of data of patients who had undergone excision with one-stage intestinal anastomosis for rectal cancer between January 2003 and September 2018 in Nanfang Hospital of Southern Medical University. The exclusion criteria were as follows: (1) pathological examination of the operative specimen revealed residual tumor on the incision margin of the anastomosis; (2) pathological examination of postoperative colonoscopy specimens revealed tumor recurrence at the anastomotic stenosis, or postoperative imaging evaluation and tumor marker monitoring indicated tumor recurrence; (3) follow-up time <3 months; and (4) simultaneous multiple primary cancers. Univariate analysis using the χ2 or Fisher's exact test was performed to assess the study patients' baseline characteristics and variables such as tumor-related factors and surgical approach (P<0.05). Multivariate analysis using binary logistic regression was then performed to identify independent risk factors for development of non-tumor-related anastomotic stenosis after rectal cancer. Finally, a nomogram model for predicting non-tumor-related anastomotic stenosis after rectal cancer surgery was constructed using R software. The reliability and accuracy of this prediction model was evaluated using internal validation and calculation of the area under the curve of the model's receiver characteristic curve (ROC). Results: The study cohort comprised 1,610 patients, including 1,008 men and 602 women of median age 59 (50, 67) years and median body mass index 22.4 (20.2, 24.5) kg/m². Non-tumor-related anastomotic stenosis developed in 121 (7.5%) of these patients. The incidence of non-tumor-related anastomotic stenosis in patients who had undergone neoadjuvant chemotherapy, neoadjuvant radiotherapy, and surgery alone was 11.2% (10/89), 26.4% (47/178), and 4.8% (64/1,343), respectively. Neoadjuvant treatment (neoadjuvant chemotherapy: OR=2.455, 95%CI: 1.148-5.253, P=0.021; neoadjuvant chemoradiotherapy, OR=3.882, 95%CI: 2.425-6.216, P<0.001), anastomotic leakage (OR=7.960, 95%CI: 4.550-13.926, P<0.001), open laparotomy (OR=3.412, 95%CI: 1.772-6.571, P<0.001), and tumor location (distance of tumor from the anal verge 5-10 cm: OR=2.381, 95%CI:1.227-4.691, P<0.001; distance of tumor from the anal verge <5 cm: OR=5.985,95% CI: 3.039-11.787, P<0.001) were identified as independent risk factors for non-tumor-related anastomotic stenosis. Thereafter, a nomogram prediction model incorporating the four identified risk factors for development of anastomotic stenosis after rectal cancer was developed. The area under the curve of the model ROC was 0.815 (0.773-0.857, P<0.001), and the C-index of the predictive model was 0.815, indicating that the model's calibration curve fitted well with the ideal curve. Conclusion: Non-tumor-related anastomotic stenosis after rectal cancer surgery is significantly associated with neoadjuvant treatment, anastomotic leakage, surgical procedure, and tumor location. A nomogram based on these four factors demonstrated good discrimination and calibration, and would therefore be useful for screening individuals at risk of anastomotic stenosis after rectal cancer surgery.

Potent inhibition of human and rat 17ß-hydroxysteroid dehydrogenase 1 by curcuminoids and the metabolites: 3D QSAR and in silico docking analysis.

Curcumin, an extensively utilized natural pigment in the food industry, has attracted considerable attention due to its potential therapeutic effects, such as anti-tumorigenic and anti-inflammatory activities. The enzyme 17ß-Hydroxysteroid dehydrogenase 1 (17ß-HSD1) holds a crucial position in oestradiol production and exhibits significant involvement in oestrogen-responsive breast cancers and endometriosis. This study investigated the inhibitory effects of curcuminoids, metabolites, and analogues on 17ß-HSD1, a key enzyme in oestradiol synthesis. Screening 10 compounds, including demethoxycurcumin (IC50, 3.97 µM) and dihydrocurcumin (IC50, 5.84 µM), against human and rat 17ß-HSD1 revealed varying inhibitory potencies. These compounds suppressed oestradiol secretion in human BeWo cells at ≥ 5-10 µM. 3D-Quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses elucidated the interaction mechanisms. Docking studies and Gromacs simulations suggested competitive or mixed binding to the steroid or NADPH/steroid binding sites of 17ß-HSD1. Predictive 3D-QSAR models highlighted the importance of hydrophobic regions and hydrogen bonding in inhibiting 17ß-HSD1 activity. In conclusion, this study provides valuable insights into the inhibitory effects and mode of action of curcuminoids, metabolites, and analogues on 17ß-HSD1, which may have implications in the field of hormone-related disorders.

Campothecin suppresses cell proliferation and migration in head and neck squamous cell carcinoma by blocking RAB27A-mediated phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway.

Camptothecin (CPT), a naturally occurring alkaloid derived from the Camptotheca acuminate plant, exerts anti-tumor properties. However, its specific impact on head and neck squamous cell carcinoma (HNSCC) remains uncertain. The study was to explore the action and mechanism of CPT on HNSCC cells. First, two HNSCC cell lines (FaDu and TU686) and a normal immortalized keratinocyte (HEK001) cell line, were exposed to a spectrum of CPT concentrations (ranging from 10 to 50 µM) for durations of 24 h and 48 h. Cell viability, proliferation, migration, and invasion were assessed by CCK-8 assay, EdU incorporation assay, wound healing assay and transwell assay. Subsequently, si-RAB27A or negative control (NC) was introduced into FaDu and TU686 cells through transfection, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was manipulated with L740Y-P, an activator of this pathway. The expression of proliferating cell nuclear antigen (PCNA), E-cadherin, PI3K/AKT signaling factors and RAB27A were determined by Western blot analysis. RAB27A was detected by immunofluorescence assay. It was found that CPT significantly hindered the viability, proliferation (p<0.01), migration (p<0.001), and invasion (p<0.001) of FaDu and TU686 cells. At the molecular level, administration of CPT caused a decline in the expression of PCNA, P-PI3K, P-AKT, and RAB27A, alongside an elevation in E-cadherin levels within HNSCC cells (p<0.05, p<0.01 and p<0.001). Reducing RAB27A expression enhanced the suppressive impacts of CPT on HNSCC cell viability (p<0.05 and p<0.01), migration (p<0.001) and invasion (p<0.01), these effects that were reversed upon treatment with L740Y-P in HNSCC cells (p<0.001). In summary, our study highlights the efficacy of CPT in HNSCC, demonstrating its influence on cell processes via the RAB27A-mediated PI3K/AKT pathway.

A nonsolvolytic fluorine/LiNO3-containing electrolyte for stabilizing dynamic interfaces in Li||LiMn2O4 batteries.

Mn-based high voltage cathodes, e.g., spinel LiMn2O4, are considered among the most promising materials for cost-effective, next generation energy storage. When paired with a Li metal anode, secondary batteries based on Li||LiMn2O4 in principle offer a straightforward, scalable approach for achieving cost-effective and high energy density storage demanded in applications. In practice, however, such batteries fail to live up to their promise. Rapid capacity fading caused by irreversible Mn dissolution at the cathode coupled with mossy/dendritic Li deposition at the anode limit their useful life. In this study, we report on the design of electrolytes based on a binary blend of two widely available salts, LiNO3 and LiTFSI, in ethylene carbonate (EC), which simultaneously overcome failure modes at both the cathode and anode of Li||LiMn2O4 batteries. The electrolyte design is motivated by a recent finding that compared with their linear counterparts (e.g., dimethyl carbonate), cyclic carbonates like EC dissolve considerably larger amount of LiNO3, which markedly improves anode reversibility. On the other hand, it is known that nonsolvolytic fluorine-containing Li salts like LiTFSI, lowers the electrolyte's susceptibility to solvolysis, which generates HF species responsible for Mn leaching at the cathode. In particular, we report instead that fluorine groups in the TFSI salt, promote formation of a favorable, fluorine-rich interphase on the Li metal anode. Electrochemical measurements show that the electrolytes enable remarkably improved charge-discharge cycling stability (>1000 charge-discharge cycles) of Li||LiMn2O4 batteries. In-depth atomic-resolution electron microscopy and X-ray/synchrotron diffraction experiments reveal the fundamental source of the improvements. The measurements show that crystallographic degradation of Mn-based cathodes (e.g., surface Mn leaching and bulk defect generation) upon cycling in conventional electrolytes is dramatically lowered in the LiNO3 + LiTFSI/EC electrolyte system. It is shown further that the reduction of Mn dissolution not only improves the cathode stability but improves the reversibility of the Li metal anode via a unique re-deposition mechanism in which Li and Mn co-deposit on the anode. Taken together, our findings show that the LiNO3 + LiTFSI/EC electrolyte system holds promise for accelerating progress towards practical Li||LiMn2O4 batteries because it stabilizes the dynamic interfaces required for long-term stability at both the Li anode and the LiMn2O4 cathode.

Omega-3 fatty acids and major depression: a Mendelian randomization study.

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93-0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88-0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. 'Leave-one-out' analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

Diet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer.

Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa.

Controlling Electrodeposition in Nonplanar High Areal Capacity Battery Anodes via Charge Transport and Chemical Modulation.

Controlling the morphological evolution of electrochemical crystal growth in battery anodes is of fundamental and practical importance, particularly towards realizing practical, high-energy batteries based on metal electrodes. Such batteries require highly reversible plating/stripping reactions at the anode to achieve a long cycle life. While conformal electrodeposition and electrode reversibility have been demonstrated in numerous proof-of-concept experiments featuring moderate to low areal capacity (≤3 mA h/cm2) electrodes, achieving high levels of reversibility is progressively challenging at the higher capacities (e.g., 10 mA h/cm2), required in applications. Nonplanar, "3D" electrodes composed of electrically conductive, porous substrates are conventionally thought to overcome trade-offs between reversibility and capacity because they hypothetically "host" the electrodeposits in an electronically conducting framework, providing redundant pathways for electron flow. Here, we challenge this hypothesis and instead show that a nonplanar substrate with moderate electrical conductivity (ideally, with an electrical conductance similar to the ionic conductance of the electrolyte) and composed of a passivated cathode-facing surface efficiently regulates electro-crystallization. In contrast, an architecture with a high intrinsic electrical conductivity or with a high electrical conductivity coating on the front surface results in dominantly out-of-plane growth, making the 3D architecture in effect function as a 2D substrate. Using Zn as an example, we demonstrate that interconnected carbon fiber substrates coated by SiO2 on the front and Cu on the back successfully ushers electroplated Zn metal into the 3D framework at a macroscopic length scale, maximizing use of the interior space of the framework. The effective integration of electrodeposits into the 3D framework also enables unprecedented plating/stripping reversibility >99.5% at high current density (e.g., 10 mA/cm2) and high areal capacities (e.g., 10 mA h/cm2). Used in full-cell Zn||NaV3O8 batteries with stringent N/P ratios of 3:1, the substrates are also shown to enhance cycle life.

[Theoretical models for influenza vaccination behavior at the individual level].

Influenza imposes a significant disease burden on society and individuals annually, and influenza vaccination is considered a significant public health measure to prevent influenza and reduce influenza-related severe disease and death. The low influenza vaccination rate in China is partly due to certain factors affecting the willingness and behavior of individuals to receive them. Scientific research and targeted interventions on these factors can effectively improve the vaccination situation. Commonly used individual-level theoretical models for influenza vaccination behavior include the health belief model, protection motivation theory, and theory of planned behavior. This study reviews theoretical models commonly employed in researching influenza vaccination willingness and behavior. An overview of these practical applications and challenges models is presented to provide references for relevant research and intervention programs in China.

[Stratified application of gene expression in diagnosis of thyroid nodules].

Objective: To investigate the value of BRAF V600E and multigene detection and stratified application for the diagnosis of thyroid nodules. Methods: A total of 1 117 patients with thyroid nodules resection at Nanjing Gulou Hospital from December 2020 to July 2022 were enrolled in the study. Fine needle aspiration (FNA) and core biopsy samplings were performed for cytopathologic examination and genetic testings; the findings were combined with BSRTC classification. The diagnostic performance of BRAF V600E and multigene detection were compared. Results: Among the 1, 117 patients who underwent thyroid nodules resection, 285 were male and 832 were female, with a median age of 46 years (range: 24-76 years). Postoperative histopathologic examination confirmed 1 040 cases of thyroid cancer and 77 cases of benign nodules. The sensitivity (87.0% vs. 80.8%, P<0.01) and diagnostic accuracy (87.9% vs. 82.1%, P<0.01) of multigene detection were significantly higher than those of BRAF V600E detection. The result of multigene detection showed that BRAF V600E mutation was the most common finding, followed by CCDC6-RET (E1-E12) fusion, ETV6-NTRK3 fusion, and KRAS mutation. Multigene detection had a higher sensitivity (81.9% vs. 72.8%, P<0.01) and lower cancer risk in wild-type (47.6% vs. 57.7%, P=0.069) than BRAF V600E detection in BSRTCⅠ-Ⅴ lesions. Compared with BRAF V600E detection, multigene had no significant difference of sensitivity in BSRTC Ⅰ lesions, but significantly higher sensitivity (86.3% vs 74.0%, P<0.01) in BSRTC Ⅲ lesions. Conclusions: Genetic detection can be used as an effective tool for the diagnosis of thyroid nodules. A stratified application of molecular markers in the diagnosis of thyroid nodules is proposed. Combined with FNA, single gene or multigene detection both can effectively assist in the diagnosis of thyroid nodules. Moreover, multigene detection is superior to single gene detection. For BSRTC Ⅲ lesion with wild-type BRAF, multigene detection can be considered with a repeated FNA.

[A multicenter prospective study on early identification of refractory Mycoplasma pneumoniae pneumonia in children].

Objective: To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods: The prospective multicenter study was conducted in Zhejiang, China from May 1st, 2019 to January 31st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results: A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95%CI 0.593-0.771, P<0.01). Conclusion: In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

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.

[Study on primary screening technique for children with autism spectrum disorder].

To explore screening tools for children with autism spectrum disorder (ASD), which are convenient for primary hospitals, it can provide basic data for formulating ASD prevention policies. This was a cross-sectional study by cluster sampling. Huyi District and Xincheng District were extracted for investigation in Xi'an City. From July 2021 to September 2022, all children aged from 3 months to 36 months who live in the two districts were subjected to primary screening. The child care physician used the routine screening tool "warning signs checklist for screening psychological, behavioral and developmental problems of children" and cartoon pictures of "early high-risk warning signs of autism", the children who were positive in the initial screening were referred to the district level maternal and child health hospital for re-screening, and those who were positive in the re-screening were referred to Xi 'an Children's Hospital for diagnosis. The results showed that a total of 17 905 children aged from 3 months to 36 months were initially screened in the two districts, including 10 588 children aged from 18 months to 36 months, 50 children who were positive in the initial screening and 50 children who were re-screened. 23 children (18 boys and 5 girls) were diagnosed with ASD. The prevalence rate of ASD in children was 2.17‰ (95% confidence interval:1.29‰-3.06‰). 42 children were positive for "warning signs checklist" at the preliminary screening, and 19 were confirmed as ASD. 27 children were positive for "cartoon pictures" in the preliminary screening, and 23 were confirmed with ASD. The "cartoon pictures" in the preliminary screening and diagnosis of consistent rate was higher than the "warning signs checklist", two kinds of screening methods comparison were statistically significant difference in the odds of consistent (χ2=11.01, P=0.001). In conclusion, relying on the three-level network of maternal and child health care, it is conducive to the whole process management of screening and diagnosis of children with ASD, and to guide the formulation of prevention policies. The cartoon pictures of "early high-risk warning signs of autism" can assist the identification of children with ASD based on the "warning signs checklist", which is simple, effective and suitable for promotion in the community health care.