The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

This study explores the effects of enhancing the definitive hematopoiesis(DH)signals during the differentiation of human embryonic stem cells(hESCs)into hematopoietic stem/progenitor cells on the generation efficiency and effector function of natural killer(NK)cells generated from hESCs(also known as hESC-NK cells).The hESC(H1)were transformed into embryoid bodies(Ebs)by centrifugation,and during the induction of K562,were used to analyze the efficiency of hematopoietic differentiation,the efficiency of NK cell generation from hESC,the in vitro effector functions,and the expression of effector function related surface receptors.Compared to the control group,the DH group had a significant increase in the number of arterial hematopoietic endothelial cells(CD34+DLL4+)and a significant decrease in primitive hematopoietic related cells(CD34-CD43+)on day 8 of hematopoietic differentiation(P<0.05).On day 28 of NK cell differentiation,the DH group demonstrated a significant increase in the number of NK cells(CD45+CD56+),while a slight increase in the expression of effector function-related molecules such as IFN-γ,Granzyme B,Perforin and CD107a without statistical significance.Furthermore,the activation receptors CD16a and CD69 were significantly increased,NKP46 was significantly decreased,the inhibitory receptor NKG2A was significantly increased,while CD96 was significantly decreased on hESC-NK cells of DH groups(P<0.05).Conclusively,enhancing the signals for definitive hematopoiesis during hESC differentiation into hematopoietic stem/progenitor cells significantly improves the yield of NK cells and the expression of CD16a without affecting their in vitro effector functions.Our study provides a new approach to improving the efficiency of hESC-NK cell or iPSC-NK cell generation.

Objective To investigate the possible action mechanism of the micro ribonucleic acid-1-3p(miR-1-3p)/Annexin A2(AnxA2)molecular axis in high glucose(HG)-induced neovascularization of human retinal microvascular en-dothelial cells(HRMECs).Methods A cell injury model was established by culturing HRMECs in vitro and treating them with HG.The HRMECs were divided into the Con group(DMEM medium containing fetal bovine serum in volume fraction of 10％),HG group(cultured in 25 mmol·L-1 D-glucose),HG+miR-NC group(transfected with miR-NC),HG+miR-1-3p group(transfected with miR-1-3p mimics),HG+sh-NC group(transfected with sh-NC),HG+sh-AnxA2 group(transfect-ed with sh-AnxA2),HG+miR-1-3p+pcDNA group(transfected with miR-1-3p mimics+pcDNA),and HG+miR-1-3p+pcDNA-AnxA2 group(transfected with miR-1-3p mimics+pcDNA-AnxA2).After 48 h of transfection,cells were collected and cultured in 25 mmol·L-1 D-glucose medium for 24 h.Cell viability and number of migrating cells were detected using MTT and Transwell chamber experiments,respectively.The number of lumen formations was detected by the lumen forma-tion experiment.The dual luciferase reporter assay was adopted to detect the targeting relationship between miR-1-3p and AnxA2.Western blot was used to detect the protein levels of vascular endothelial growth factor(VEGF)and matrix metal-loproteinase-2(MMP-2).Results Compared with the Con group,the expression level of miR-1-3p in the HG group de-creased,while the levels of AnxA2 messenger ribonucleic acid(mRNA)and protein increased,with statistically significant differences(all P＜0.05).Compared with the Con group,the HG group showed an increase in cell viability,number of mi-grating cells,lumen formation and protein levels of VEGF and MMP-2,with statistically significant differences(all P＜0.05).Compared with the HG+miR-NC group,the HG+miR-1-3p group showed a decrease in cell viability,number of migrating cells,lumen formation and protein levels of VEGF and MMP-2,with statistically significant differences(all P＜0.05).Compared with the HG+sh-NC group,the HG+sh-AnxA2 group showed a decrease in cell viability,number of mi-grating cells,lumen formation and protein levels of VEGF and MMP-2,with statistically significant differences(all P＜0.05).Compared with the HG+miR-1-3p+pcDNA group,the HG+miR-1-3p+pcDNA-AnxA2 group showed an increase in cell viability,number of migrating cells,lumen formation and protein levels of VEGF and MMP-2,with statistically signifi-cant differences(all P＜0.05).Conclusion Overexpression of miR-1-3p can inhibit proliferation,migration and neovas-cularization of HRMECs by targetedly regulating AnxA2 expression.

OBJECTIVE: To assess the practical and health economical values of non-invasive prenatal test (NIPT) in Changsha Municipal Public Welfare Program. METHODS: A retrospective analysis was carried out on 149 165 women undergoing NIPT test from April 9, 2018 to December 31, 2019. For pregnant women with high risks, invasive prenatal diagnosis and follow-up of pregnancy outcome were conducted. The cost-benefit of NIPT for Down syndrome was analyzed. RESULTS: NIPT was carried out for 149 165 pregnant women and succeeded in 148 749 cases (99.72%), for which outcome were available in 148 538 (99.86%). 90% of pregnant women from the region accepted the screening with NIPT. 415 (0.27%) were diagnosed as high risk. Among these, 381 (91.81%) accepted amniocentesis, which led to the diagnosis of 212 cases of trisomy 21 (PPV=85.14%), 41 cases with trisomy 18 (PPV=48.81%) and 10 cases with trisomy 13 (PPV=20.83%). The sensitivity and specificity of NIPT for trisomy 21, trisomy 18 and trisomy 13 were (97.70%, 99.98%), (97.62%, 9.97%) and (100%, 99.97%), respectively. In addition, 213 and 30 cases were diagnosed with sex chromosomal aneuploidies (PPV=46.2%) and other autosomal anomalies (PPV=16.57%), respectively. For Down syndrome screening, the cost and benefit of the project was 120.79 million yuan and 1,056.95 million yuan, respectively. The cost-benefit ratio was 1: 8.75, and safety index was 0.0035. CONCLUSION NIPT is a highly accurate screening test for trisomy 21, which was followed by trisomy 18 and sex chromosomal aneuploidies, while it was less accurate for other autosomal aneuploidies. The application of NIPT screening has a high health economical value.
Aneuploidy ; Cost-Benefit Analysis ; Female ; Humans ; Noninvasive Prenatal Testing ; Pregnancy ; Retrospective Studies ; Trisomy 18 Syndrome/genetics*

Objective: To explore the clinical phenotypes and the genetic causes for a 5 years old boy with unexplained growth retardation, developmental delay, special face, and hypothyroidism. Methods: Routine G-banding was performed to analyze the karyotype of the patient and his parents. In addition, whole exome sequencing and low-coverage massively parallel CNV sequencing (CNV-seq) were used to determine the potentially pathogenic variants as well as the copy number variations (CNVs). Results: The child′s karyotype was 46, XY, and his parents′ karyotypes were normal.However, CNV-seq identified a heterozygous deletion of 1.56 Mb on chromosome region 7q11.23 in the patient, including 24 protein-coding genes, which were associated with Williams-Beuren syndrome. His parents′ results of CNV-seq were normal, indicating a de novo CNVs. Conclusion A Williams-Beuren syndrome child presenting with hypothyroidism was diagnosed by CNV-seq, which would contribute to further understanding the clinical phenotypes and pathogenesis of this disease.

Objective:To investigate the relationship between sarcopenia and chronic heart failure(CHF)in the elderly.Methods:In the retrospective study 365 patients aged≥65 years were randomly divided into the CHF group(n=168)and the non-CHF group(n=188). Skeletal muscle mass(ASM) body mass and skeletal muscle mass index(SMI)were measured and compared between the two groups. The correlation between sarcopenia and CHF in the elderly was analyzed.Results:ASM was(15.46±3.02)kg and SMI was(5.12±0.76)kg/m 2in the CHF group which were significantly lower than those in the non-CHF group[(19.87±2.45)kg and(7.23±0.79)kg/m 2 respectively each P<0.01]. The proportion of subjects with sarcopenia in the CHF group was higher than that in the non-CHF group [26.19%(44 cases) vs. 6.38%(12 cases), P<0.01]. Multivariate Logistic regression analysis showed that age( OR=1.87, 95% CI: 1.132 to 2.285 P<0.05) CHF( OR=23.89, 95% CI: 5.394 to 98.842, P<0.01) gender( OR=20.43, 95% CI: 4.294 to 78.324, P<0.01) and body mass index( OR=23.43, 95% CI: 5.328 to 100.786, P<0.01)were risk factors for sarcopenia in elderly patients. Conclusions:CHF is associated with an increased incidence of sarcopenia in elderly patients.

Objective: To compare the carcinogenic abilities of CD133⁺CD44⁺ laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133⁺CD44⁺ laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133⁺CD44⁺ laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133⁺CD44⁺ laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133⁺CD44⁺ laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133⁺CD44⁺ laryngeal cancer stem cells was also higher (80% vs. 50%). What′s more, we identified 15 miRNAs that were significantly upregulated in CD133⁺CD44⁺ laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133⁺CD44⁺ laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions CD133⁺CD44⁺ laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs′ expression is one of the possible causes.

Objective: To understand characteristics of vaginal cervical microbiota in high-risk HPV (hrHPV) infected women and to uncover the relationship between hrHPV infection and vaginal cervical microbiota. Methods: All participants were randomly selected from Peking University First Hospital from September to October of 2017, including 5 subjects of control group, 5 cases of HPV16/18 group, 5 cases of other hrHPV infected group and 3 cases of cervical squamous carcinoma group. All subjects were required to fill in a questionnaire, and cervical and vaginal discharges were separately collected for microscopic examination and new generation sequencing targeting the variable region (V3-V4) of bacterial 16S rRNA gene. Results: Vaginal microbiota analysis: (1) 6 major phylum were found in vaginal microbiota:Firmicutes, Bacteroidetes, Fusobacteria, Actinobacteria, Tenericutes and Proteobacteria. Firmicutes contributed to the majority of normal vaginal flora, Bacteroidetes and Fusobacteria increased in hrHPV infected ones, while Fusobacteria showed significant difference in cervical carcinoma group. (2) Lactobacillus occupied most of normal vaginal flora while genus like Gardnella, Prevotella, Atopobium, Megasphaera and Sneathia increased in hrHPV infected subjects, Sneathia showed significant difference in cervical carcinoma group. (3) No significant difference had been calculated in Alpha diversity of four groups (P=0.073) . Cervical microbiota analysis: (1) Microbial diversity of cervical microbiota was higher than that of vaginal microbiota. (2) Significant difference had been found in Alpha diversity of four groups (P=0.046) . (3) Proteobacteria in normal cervical flora was much more than that in vagina, and Proteobacteria increased significantly in hrHPV infected cervical discharge. (3) Chlamydia increased significantly in cervical carcinoma group. Conclusions The diversity of cervical microbiota is higher than that of vaginal microbiota. Change in cervical microbiota is more obvious than that of vagina in hrHPV infected subjects. Fusobacteria-Sneathia and Chlamydia significantly increase in cervical carcinoma group. Proteobacteria might relate to hrHPV infection.