The Ehlers-Danlos syndromes(EDS)are a group of rare hereditary connective tissue disorders characterized by joint hypermobility,skin hyperextensibility,and tissue fragility.The clinical and genetic hetero-geneity of EDS frequently leads to underdiagnosis and misdiagnosis.Genetic testing is an essential approach to clarify the underlying diagnosis.Recent research has preliminarily established genotype-phenotype correlations and introduced the novel concept of"disease spectrum"in some subtypes.These studies deepen our under-standing of EDS etiology and provide important insights into clinical management.Published in 2023,the Chinese Guidelines for Diagnosis and Treatment of the Ehlers-Danlos Syndromes(the Guidelines)recommend performing genetic testing with deep phenotyping for patients who meet the clinical diagnostic criteria or are sus-pected of having EDS.However,it should be noted that the clinical diagnosis might differ from the molecular diagnosis.Furthermore,cutting-edge approaches such as periodic data reanalysis,integration of RNA sequen-cing into family-based whole-genome sequencing,and third-generation sequencing may facilitate the reclassifi-cation of variants of uncertain significance or resolve undiagnosed cases.This article summarizes recent progress in the genetics research of EDS,with the hope of offering a valuable resource for clinical diagnosis,treatment and scientific research to optimize the quality of life of patients with EDS.

Objective To investigate the role of the renin-angiotensin system(RAS)in the pathogenesis of acute kidney injury(AKI)after laparoscopic radical nephrectomy(LRN)and the predictive value of RAS activation status for AKI.Methods Eighty-two patients undergoing LRN at the Third Medical Center of General Hospital of PLA from December,2023 to March,2024 were enrolled,including 57 with postoperative AKI and 25 without AKI according to KDIGO criteria.Blood and urine samples were collected from the patients before and at 24 h after the operation for analyzing the correlation of urinary aldosterone,plasma ACE2,Ang1-7,Nrf-2,and IL-10 levels with postoperative AKI.Univariate and multivariate logistic regression analyses and ROC curve were employed to identify the risk factors for postoperative AKI and their predictive value for AKI.Results Compared with those without postoperative AKI,the patients with AKI had significantly higher postoperative urinary aldosterone levels and lower plasma ACE 2,Ang 1-7,Nrf-2,and IL-10 levels(P<0.05).Postoperative urinary aldosterone level was positively correlated with AKI and negatively with estimated glomerular filtration rate(eGFR)(P<0.05);plasma levels of ACE 2,Nrf-2,and IL-10 were all negatively correlated with AKI and positively with eGFR.Urinary aldosterone was a risk factor and plasma ACE 2,Ang 1-7,Nrf-2 and IL-10 were protective factors for AKI,and among them urinary aldosterone was an independent risk factor(AUC=0.651)and plasma Nrf-2 was an independent protective factor(AUC=0.679).The unconventional RAS pathway indices had an AUC of 0.758,and aldosterone combined with the unconventional pathway indices had an AUC of 0.788 for predicting postoperative AKI.Conclusion Activation of the conventional RAS pathway and suppression of the unconventional pathway contribute to AKI following LRA possibly by affecting eGFR.Aldosterone combined with the unconventional pathway indicators can predict the occurrence of AKI after LRN.

Objective To investigate the role of the renin-angiotensin system(RAS)in the pathogenesis of acute kidney injury(AKI)after laparoscopic radical nephrectomy(LRN)and the predictive value of RAS activation status for AKI.Methods Eighty-two patients undergoing LRN at the Third Medical Center of General Hospital of PLA from December,2023 to March,2024 were enrolled,including 57 with postoperative AKI and 25 without AKI according to KDIGO criteria.Blood and urine samples were collected from the patients before and at 24 h after the operation for analyzing the correlation of urinary aldosterone,plasma ACE2,Ang1-7,Nrf-2,and IL-10 levels with postoperative AKI.Univariate and multivariate logistic regression analyses and ROC curve were employed to identify the risk factors for postoperative AKI and their predictive value for AKI.Results Compared with those without postoperative AKI,the patients with AKI had significantly higher postoperative urinary aldosterone levels and lower plasma ACE 2,Ang 1-7,Nrf-2,and IL-10 levels(P<0.05).Postoperative urinary aldosterone level was positively correlated with AKI and negatively with estimated glomerular filtration rate(eGFR)(P<0.05);plasma levels of ACE 2,Nrf-2,and IL-10 were all negatively correlated with AKI and positively with eGFR.Urinary aldosterone was a risk factor and plasma ACE 2,Ang 1-7,Nrf-2 and IL-10 were protective factors for AKI,and among them urinary aldosterone was an independent risk factor(AUC=0.651)and plasma Nrf-2 was an independent protective factor(AUC=0.679).The unconventional RAS pathway indices had an AUC of 0.758,and aldosterone combined with the unconventional pathway indices had an AUC of 0.788 for predicting postoperative AKI.Conclusion Activation of the conventional RAS pathway and suppression of the unconventional pathway contribute to AKI following LRA possibly by affecting eGFR.Aldosterone combined with the unconventional pathway indicators can predict the occurrence of AKI after LRN.

Objective:Given the high incidence and mortality rate of sepsis,early identification of high-risk patients and timely intervention are crucial.However,existing mortality risk prediction models still have shortcomings in terms of operation,applicability,and evaluation on long-term prognosis.This study aims to investigate the risk factors for death in patients with sepsis,and to construct the prediction model of short-term and long-term mortality risk. Methods:Patients meeting sepsis 3.0 diagnostic criteria were selected from the Medical Information Mart for Intensive Care-IV(MIMIC-IV)database and randomly divided into a modeling group and a validation group at a ratio of 7?3.Baseline data of patients were analyzed.Univariate Cox regression analysis and full subset regression were used to determine the risk factors of death in patients with sepsis and to screen out the variables to construct the prediction model.The time-dependent area under the curve(AUC),calibration curve,and decision curve were used to evaluate the differentiation,calibration,and clinical practicability of the model. Results:A total of 14 240 patients with sepsis were included in our study.The 28-day and 1-year mortality were 21.45%(3 054 cases)and 36.50%(5 198 cases),respectively.Advanced age,female,high sepsis-related organ failure assessment(SOFA)score,high simplified acute physiology score II(SAPS II),rapid heart rate,rapid respiratory rate,septic shock,congestive heart failure,chronic obstructive pulmonary disease,liver disease,kidney disease,diabetes,malignant tumor,high white blood cell count(WBC),long prothrombin time(PT),and high serum creatinine(SCr)levels were all risk factors for sepsis death(all P<0.05).Eight variables,including PT,respiratory rate,body temperature,malignant tumor,liver disease,septic shock,SAPS II,and age were used to construct the model.The AUCs for 28-day and 1-year survival were 0.717(95%CI 0.710 to 0.724)and 0.716(95%CI 0.707 to 0.725),respectively.The calibration curve and decision curve showed that the model had good calibration degree and clinical application value. Conclusion:The short-term and long-term mortality risk prediction models of patients with sepsis based on the MIMIC-IV database have good recognition ability and certain clinical reference significance for prognostic risk assessment and intervention treatment of patients.

Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.
Animals ; Disease Models, Animal ; Hydrocephalus/genetics* ; Mice ; Mice, Knockout ; Neurons ; beta Catenin/genetics*

Objective: To analyze the characteristics of changes in serum cholesterol level in sepsis patients, and to explore its correlation with prognosis. Methods: A retrospective analysis was conducted. Two hundred and six patients with sepsis admitted in the Third People′s Hospital of Dalian from February 2015 to February 2019 were enrolled (observation group), and 206 patients without sepsis hospitalized in the same period were served as control group. The basic clinical data of the two groups were collected, and the results of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and biochemical parameters were compared. The patients with sepsis were divided into death group and survival group, and risk factors influencing the prognosis of patients with sepsis were analyzed with Logistic regression analysis. Results: Compared with control group, the levels of serum TC [(2.49 ± 1.14) mmol/L vs. (3.40 ± 1.26) mmol/L, t=6.240] and HDL-C [(1.66 ± 0.89) mmol/L vs. (2.49 ± 0.81) mmol/L, t=5.532] in observation group were significantly lower (P<0.05), and that of LDL-C showed no statistically significant difference [(1.96 ± 0.91) mmol/L vs. (2.10 ± 0.72) mmo/L, t=0.940, P>0.05]. In observation group, the patients in death group (85 cases) were older than those of the survival group (121 cases)[(75.6 ± 8.6) years vs. (62.5 ± 6.0) years, t=4.565], serum creatinine (SCr) was higher than that of survival group [(246.2 ± 34.6) μmol/L vs. (165.4 ± 35.6) μmol/L, t=5.420], and the levels of serum TC [(2.15 ± 0.59) mmol/L vs. (2.89 ± 1.02) mmol/L, t= 5.475], HDL-C [(1.40 ± 0.42) mmol/L vs. (1.94 ± 0.52) mmol/L, t=4.856] and LDL-C [(1.73 ± 0.56) mmol/L vs. (1.97 ± 0.72) mmol/L, t=4.261] were significantly lower than those of survival group (P<0.05). Logistic regression analysis showed that age was the risk factor of death in sepsis patients (OR=1.256, 95% CI 1.006 -1.056, P=0.012), and TC was the protective factor for the prognosis of sepsispatients (OR=-0.758, 95%CI 0.579-0.867, P=0.014). Conclusions The levels of TC, HDL-C in sepsis patients are significantly lowered, and the levels of TC, HDL-C, LDL-C in death group are significantly lower than those in survival group. TC may be used as a clinical indicator to assess the outcome of sepsis patients.

Objective To analyze the genetic characteristics of VP1-VP4 genes carried by cox-sackievirus A6 (CVA6) strains isolated from severe cases of hand, foot, and mouth disease (HFMD) in Shenzhen during 2012 to 2015. -ethods The VP1-VP4 genes of CVA6 strains isolated from severe HFMD cases in Shenzhen during 2012 to 2015 were amplified and sequenced. Phylogenetic analysis was performed to analyze the VP1-VP4 genes of CVA6 isolates and sequences downloaded from GenBank by using DNASTAR6. 0 and MEGA6. 02 software packages. Results Four cases of severe HFMD were caused by CVA6 in Shenzhen during 2012 to 2015. All of the patients had the symptom of fever, skin rash and aseptic encephalitis. The CVA6 strain causing severe HFMD in 2013 shared 98. 8％-98. 9％ homology in nucleotide sequences and 99. 3％-99. 8％ in amino acid sequences with the strains isolated in 2012. Two amino acid mutations were found in the CVA6 strain isolated in 2013, which were G73E in VP2 region and S13G in VP1 region. However, the CVA6 strain isolated in 2015 only shared 95. 0％ homology in nucleotide sequences and 99. 3％ homology in amino acid sequences with the strain isolated in 2013. Six amino acid mutations were identified including E73G in VP2 region and T5A, S27N, A30V, N137S and V242I in VP1 region. The phylogenetic analysis revealed that the four CVA6 strains belong to D3 sub-genotype. The CVA6 strains causing severe cases in 2012 had the nearest genetic relationship with the strain isolated in Changsha in 2012 (KJ156349). The CVA6 strain isolated in Shenzhen in 2013 had the nearest genetic relationship with the strain isolated in Shanghai in 2013 (KJ612513). The Shenzhen CVA6 isolate in 2015 showed high similarity to Weifang CVA6 isolate in 2014 (KX752785). Conclusions All CVA6 strains causing severe HFMD ca-ses in Shenzhen during 2012 to 2015 belongs to D3 sub-genotype. Mutations of S27N and A30V in the VP1 region of the CVA6 isolate in 2015 are located in the B cell epitopes. In addition, the VP1-V242I mutation in the CVA6 strain isolated in 2015 is located in the binding site of PSGL-1 receptor. These mutations may affect the binding of CVA6 strains to the cellular receptors and their infectivity to people.

Objective To evaluate the effect of short-term training of objective structured clinical examination (OSCE) examiner in general practice residency training final examination.Methods Sixty examiners from Xinjiang Uygur Autonomous Region participated in half-day workshop of OSCE.The participants were interviewed with questionnaire before and after the training program and the effect of training was evaluated.Results The study showed that 78.3％ (47/60) examiners knew OSCE and understood the concept and implementation steps before the training;21.7％ (13/60)had used it before;95.0％ (57/60) examiners intended to learn the performance of OSCE.After training most participants completely or basically understood the 6 test stands and implementation methods of OSCE;the participants were highly satisfied with the training duration,contents and methods,and the satisfaction rates were all over 70％.Conclusion The examiners recognize the advantages of OSCE in assessment of clinical skills and have strong intention of application.Short-term training has a certain effect and feasibility.

Objective To analysis the implementation of the objective structured clinical examination (OSCE) for completion of general practice residency training in Xinjiang Uygur autonomous region.Methods Ninety eight general practice residents took training-completion examination applying OSCE in Xinjiang Uygur Autonomous Region.The examiners (including SP examiners) and examinees were interviewed with questionnaire after the OSCE.Results All 60 examiners and 98 examinees were generally in favor of using OSCE in general practice residency training completion examination;100.0％ (60/60) examiners and 86.7％ (85/98) examinees thought that it was necessary;98.3％ (59/60) examiners and 89.8％ (88/98) examinees thought that the OSCE was able to evaluate the clinical competence of general practice;95.0％ (57/60) examiners and 78.6％ (77/98) examinees thought the OSCE examination stations reasonable;40.8 ％ (40/98) examinees thought that the difficulty degree of the exam was moderate,35.7％ (35/98) and 20.4％ (20/98) examinees thought that it was difficult or very difficult,particularly for history writing and case analysis.Conclusions The examiners and examinees recognize the advantages of OSCE in assessment of clinical competence.This study provides useful information for application of OSCE in general practice residency training completion assessment.

Objective: To investigate androgen receptor(AR)expression in invasive breast carcinoma and the correlation with surrogate molecular breast carcinoma subtypes. Methods: Immunohistochemical staining of AR and other biomarkers was performed in a cohort of 870 cases of primary invasive breast carcinomas collected from August to December, 2016. The association of AR expression with different histological and surrogate molecular subtypes was analyzed. Results: The positive expression rate of AR in the immunohistochemistry-based surrogate subtypes was 96.3%(207/215) for Luminal A, 89.8%(378/421) for Luminal B, 82.4%(75/91) for HER2 overexpression and 37.1%(53/143) for triple negative breast carcinoma, with significant differences among the four groups (P<0.01). AR correlated positively with the expression of ER(P<0.01), PR(P<0.01), HER2(P=0.007), GATA3(P<0.01), GCDFP15(P<0.01)and mammaglobin(P<0.01), while negatively with the expression of Ki-67(P<0.01), CK5/6(P<0.01)and CK14(P<0.01). Conclusions AR exhibits a high expression in invasive breast carcinoma, which is mainly correlated with ER-positive breast carcinoma. Regardless of the relatively low expression rate, AR is a potential therapeutic target in triple negative breast carcinoma.