Objective:To explore the clinical phenotypes and genetic characteristics of a pedigree with Distal arthrogryposis type 5D (DA5D) caused by compound heterozygous variants in the ECEL1 gene. Methods:A child (proband) diagnosed with DA5D and his family members (proband′s parents and sister) who was admitted to the Department of Rehabilitation Medicine of Henan Children′s Hospital in July 2022 due to " multiplex distal arthrogryposis" were enrolled into this study. Clinical data of the proband were collected and peripheral blood samples were obtained from the proband and members of his family about 3 mL. Trio-whole genome sequencing (trio-WGS) was carried out to detected the genetic variations of the proband and his family members. The candidate′s pathogenic gene variants were screened and analyzed by Genome Aggregation Database (gnomAD) and other databases. The screened variants wer annotated for clinical phenotypes using databases like the Online Mendelian Inheritance in Man (OMIM). The pathogenicity of the candidate variants was predicted by bioinformatics tools such as Provean. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), pathogenicity ratings were conducted for variant sites. The protein conservation and mutation structure prediction of ECEL1 protein among species were carried out though MEGA-X and PyMOL. The research protocol of this study was reviewed by the Ethics Committee of Henan Provincial Children′s Hospital (Approval No. 2023-H-H01), and informed consent for clinical research was obtained from the guardians of the probands.Results:The proband had multiplex distal arthrogryposis involving hands, feet, knees, and ankles, and had right ptosis, micrognathia, low auricular position, and upturned nose. The parents and sister both had normal phenotypes. Trio-WGS and Sanger sequencing revealed that the child had compound heterozygous variants of paternal c. 1742_c.1743insT and maternal c. 2314T>G, for which the father and sister were carriers of the c. 1742_c.1743insT heterozygous variant and the mother was carrier of c. 2314T>A. Neither mutation site has been reported. According to guidelines of ACMG, the c. 1742_c.1743insT variant was classified as likely pathogenic (PSV1+ PM2_Supporting), and c. 2314T>G was classified as uncertain (PM2_Supporting+ PM3+ PP3). The results of conserved analysis of amino acid residue sequences of ECEL1 protein showed that the missense mutation of the maternal c. 2314T>G(p.Cys772Gly) was highly conserved among humans and other seven species. The protein structure prediction revealed that the c.1742_c.1743insT frameshift mutation led to the protein truncation, and the c. 2314T>G missense mutation resulted in the failure of forming 1 disulfide bond.Conclusion:The compound heterozygous variants of ECEL1 gene were considered to be pathogenic for this DA5D patient, which have expanded the mutational spectrum of the ECEL1 gene and provided a reference for clinical diagnosis as well as genetic counseling for this family.

OBJECTIVE: To explore the clinical phenotypes and genetic characteristics of a pedigree with Distal arthrogryposis type 5D (DA5D) caused by compound heterozygous variants in the ECEL1 gene. METHODS: A child (proband) diagnosed with DA5D and his family members (proband's parents and sister) who was admitted to the Department of Rehabilitation Medicine of Henan Children's Hospital in July 2022 due to "multiplex distal arthrogryposis" were enrolled into this study. Clinical data of the proband were collected and peripheral blood samples were obtained from the proband and members of his family about 3 mL. Trio-whole genome sequencing (trio-WGS) was carried out to detected the genetic variations of the proband and his family members. The candidate's pathogenic gene variants were screened and analyzed by Genome Aggregation Database (gnomAD) and other databases. The screened variants were annotated for clinical phenotypes using databases like the Online Mendelian Inheritance in Man (OMIM). The pathogenicity of the candidate variants was predicted by bioinformatics tools such as Provean. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), pathogenicity ratings were conducted for variant sites. The protein conservation and mutation structure prediction of ECEL1 protein among species were carried out though MEGA-X and PyMOL. The research protocol of this study was reviewed by the Ethics Committee of Henan Provincial Children's Hospital (Approval No. 2023-H-H01), and informed consent for clinical research was obtained from the guardians of the probands. RESULTS: The proband had multiplex distal arthrogryposis involving hands, feet, knees, and ankles, and had right ptosis, micrognathia, low auricular position, and upturned nose. The parents and sister both had normal phenotypes. Trio-WGS and Sanger sequencing revealed that the child had compound heterozygous variants of paternal c.1742_c.1743insT and maternal c.2314T>G, for which the father and sister were carriers of the c.1742_c.1743insT heterozygous variant and the mother was carrier of c.2314T>A. Neither mutation site has been reported. According to guidelines of ACMG, the c.1742_c.1743insT variant was classified as likely pathogenic (PSV1+PM2_Supporting), and c.2314T>G was classified as uncertain (PM2_Supporting+PM3+PP3). The results of conserved analysis of amino acid residue sequences of ECEL1 protein showed that the missense mutation of the maternal c.2314T>G (p.Cys772Gly) was highly conserved among humans and other seven species. The protein structure prediction revealed that the c.1742_c.1743insT frameshift mutation led to the protein truncation, and the c.2314T>G missense mutation resulted in the failure of forming 1 disulfide bond. CONCLUSION The compound heterozygous variants of ECEL1 gene were considered to be pathogenic for this DA5D patient, which have expanded the mutational spectrum of the ECEL1 gene and provided a reference for clinical diagnosis as well as genetic counseling for this family.
Humans ; Pedigree ; Arthrogryposis/genetics* ; Male ; Female ; Heterozygote ; Phenotype ; Mutation ; Child ; Metalloendopeptidases

Objective:To explore the clinical phenotypes and genetic characteristics of a pedigree with Distal arthrogryposis type 5D (DA5D) caused by compound heterozygous variants in the ECEL1 gene. Methods:A child (proband) diagnosed with DA5D and his family members (proband′s parents and sister) who was admitted to the Department of Rehabilitation Medicine of Henan Children′s Hospital in July 2022 due to " multiplex distal arthrogryposis" were enrolled into this study. Clinical data of the proband were collected and peripheral blood samples were obtained from the proband and members of his family about 3 mL. Trio-whole genome sequencing (trio-WGS) was carried out to detected the genetic variations of the proband and his family members. The candidate′s pathogenic gene variants were screened and analyzed by Genome Aggregation Database (gnomAD) and other databases. The screened variants wer annotated for clinical phenotypes using databases like the Online Mendelian Inheritance in Man (OMIM). The pathogenicity of the candidate variants was predicted by bioinformatics tools such as Provean. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), pathogenicity ratings were conducted for variant sites. The protein conservation and mutation structure prediction of ECEL1 protein among species were carried out though MEGA-X and PyMOL. The research protocol of this study was reviewed by the Ethics Committee of Henan Provincial Children′s Hospital (Approval No. 2023-H-H01), and informed consent for clinical research was obtained from the guardians of the probands.Results:The proband had multiplex distal arthrogryposis involving hands, feet, knees, and ankles, and had right ptosis, micrognathia, low auricular position, and upturned nose. The parents and sister both had normal phenotypes. Trio-WGS and Sanger sequencing revealed that the child had compound heterozygous variants of paternal c. 1742_c.1743insT and maternal c. 2314T>G, for which the father and sister were carriers of the c. 1742_c.1743insT heterozygous variant and the mother was carrier of c. 2314T>A. Neither mutation site has been reported. According to guidelines of ACMG, the c. 1742_c.1743insT variant was classified as likely pathogenic (PSV1+ PM2_Supporting), and c. 2314T>G was classified as uncertain (PM2_Supporting+ PM3+ PP3). The results of conserved analysis of amino acid residue sequences of ECEL1 protein showed that the missense mutation of the maternal c. 2314T>G(p.Cys772Gly) was highly conserved among humans and other seven species. The protein structure prediction revealed that the c.1742_c.1743insT frameshift mutation led to the protein truncation, and the c. 2314T>G missense mutation resulted in the failure of forming 1 disulfide bond.Conclusion:The compound heterozygous variants of ECEL1 gene were considered to be pathogenic for this DA5D patient, which have expanded the mutational spectrum of the ECEL1 gene and provided a reference for clinical diagnosis as well as genetic counseling for this family.

Centralized monitoring is a risk-based remote monitoring mode that can effectively improve monitoring efficiency and quality. From July to September 2023, this study developed a centralized monitoring scheme for investigator initiated trials(IIT). This scheme utilized electronic data collection system and clinical research document management system, using programming techniques to compare the consistency of key project processes and data, monitor data filling, distribution trends, logical relationships, as well as documents such as informed consent forms, protocol violation records, and adverse event reports. It could timely identify problems in clinical trials and develop targeted response measures. From October to December 2023, 6 experts conducted centralized monitoring for 153 IIT projects using this scheme and found common issues in program execution(86 projects), ethical approvals(68 projects), and informed consent forms(67 projects), and so on. At the scome time, corresponding measures were developed. The process took a total of 20 days, with an average time of 6.27 hours per project. Compared with traditional on-site monitoring, the centralized monitoring scheme developed in this study had shown certain advantages in terms of timeliness, which could help guide the efficient implementation of on-site monitoring work and provide references for tertiary public hospitals to improve the quality of clinical trials.

Background::Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China.Methods::Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher’s exact test was used for comparison of categorical variables. Results::A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk.Conclusions::PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

Objective:To explore the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Spastic paraplegia type 5A (SPG5A).Methods:A pedigree suspected for Hereditary spastic paraplegia (HSP) at Henan Children′s Hospital on August 15 2022 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples were collected from members of the pedigree. Following extraction of genomic DNA, trio-WGS was carried out, and candidate variant was verified by Sanger sequencing.Results:The child, a 1-year-old boy, had presented with microcephaly, hairy face and dorsal side of distal extremities and trunk, intellectual and motor development delay, increased muscle tone of lower limbs, hyperreflexes of bilateral knee tendons, and positive pathological signs. His parents and sister both had normal phenotypes. Trio-WGS revealed that the child has harbored a homozygous c. 1250G>A (p.Arg417His) variant of the CYP7B1 gene, for which his mother was heterozygous, the father and sister were of the wild type. The variant was determined to have originated from maternal uniparental disomy (UPD). The result of Sanger sequencing was in keeping with the that of trio-WGS. SPG5A due to maternal UPD of chromosome 8 was unreported previously. Conclusion:The child was diagnosed with SPG5A, a complex type of HSP, for which the homozygous c. 1250G>A variant of the CYP7B1 gene derived from maternal UPD may be accountable.

Centralized monitoring is a risk-based remote monitoring mode that can effectively improve monitoring efficiency and quality. From July to September 2023, this study developed a centralized monitoring scheme for investigator initiated trials(IIT). This scheme utilized electronic data collection system and clinical research document management system, using programming techniques to compare the consistency of key project processes and data, monitor data filling, distribution trends, logical relationships, as well as documents such as informed consent forms, protocol violation records, and adverse event reports. It could timely identify problems in clinical trials and develop targeted response measures. From October to December 2023, 6 experts conducted centralized monitoring for 153 IIT projects using this scheme and found common issues in program execution(86 projects), ethical approvals(68 projects), and informed consent forms(67 projects), and so on. At the scome time, corresponding measures were developed. The process took a total of 20 days, with an average time of 6.27 hours per project. Compared with traditional on-site monitoring, the centralized monitoring scheme developed in this study had shown certain advantages in terms of timeliness, which could help guide the efficient implementation of on-site monitoring work and provide references for tertiary public hospitals to improve the quality of clinical trials.

OBJECTIVE: To explore lung ultrasound radiomics features which related to extravascular lung water index (EVLWI), and to predict EVLWI in critically ill patients based on lung ultrasound radiomics combined with machine learning and validate its effectiveness. METHODS: A retrospective case-control study was conducted. The lung ultrasound videos and pulse indicated continuous cardiac output (PiCCO) monitoring results of critically ill patients admitted to the department of critical care medicine of the First Affiliated Hospital of Guangxi Medical University from November 2021 to October 2022 were collected, and randomly divided into training set and validation set at 8:2. The corresponding images from lung ultrasound videos were obtained to extract radiomics features. The EVLWI measured by PiCCO was regarded as the "gold standard", and the radiomics features of training set was filtered through statistical analysis and LASSO algorithm. Eight machine learning models were trained using filtered radiomics features including random forest (RF), extreme gradient boost (XGBoost), decision tree (DT), Naive Bayes (NB), multi-layer perceptron (MLP), K-nearest neighbor (KNN), support vector machine (SVM), and Logistic regression (LR). Receiver operator characteristic curve (ROC curve) was plotted to evaluate the predictive performance of models on EVLWI in the validation set. RESULTS: A total of 151 samples from 30 patients were enrolled (including 906 lung ultrasound videos and 151 PiCCO monitoring results), 120 in the training set, and 31 in the validation set. There were no statistically significant differences in main baseline data including gender, age, body mass index (BMI), mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), cardiac index (CI), cardiac function index (CFI), stroke volume index (SVI), global end diastolic volume index (GEDVI), systemic vascular resistance index (SVRI), pulmonary vascular permeability index (PVPI) and EVLWI. The overall EVLWI range in 151 PiCCO monitoring results was 3.7-25.6 mL/kg. Layered analysis showed that both datasets had EVLWI in the 7-15 mL/kg interval, and there was no statistically significant difference in EVLWI distribution. Two radiomics features were selected by using LASSO algorithm, namely grayscale non-uniformity (weight was -0.006 464) and complexity (weight was -0.167 583), and they were used for modeling. ROC curve analysis showed that the MLP model had better predictive performance. The area under the ROC curve (AUC) of the prediction validation set EVLWI was higher than that of RF, XGBoost, DT, KNN, LR, SVM, NB models (0.682 vs. 0.658, 0.657, 0.614, 0.608, 0.596, 0.557, 0.472). CONCLUSIONS The gray level non-uniformity and complexity of lung ultrasound were the most correlated radiomics features with EVLWI monitored by PiCCO. The MLP model based on gray level non-uniformity and complexity of lung ultrasound can be used for semi-quantitative prediction of EVLWI in critically ill patients.
Humans ; Extravascular Lung Water/diagnostic imaging* ; Retrospective Studies ; Critical Illness ; Case-Control Studies ; Bayes Theorem ; China ; Lung/diagnostic imaging*

Objective:To investigate the clinical significance of a new classification system for atlas fractures based on pre- and post-treatment CT features, with a focus on diagnosis and treatment.Methods:A retrospective analysis was conducted on 75 cases of cervical vertebra fractures treated at the Sixth Hospital of Ningbo City between January 2015 and December 2020. The study included 44 males and 31 females, with an average age of 53.3±13.0 years (range: 27-81 years). The fractures were classified according to the Landells classification, resulting in 12 cases of type I, 13 cases of type II, 33 cases of type III, 9 cases that were difficult to classify due to fracture lines located at anatomical junctions, and 8 cases that could not be classified using the Landells classification due to diverse injury mechanisms. To establish a new preliminary classification for cervical vertebra fractures, the researchers considered whether the fracture line in the CT images involved the facet joint surface of the atlas, the impact on bilateral half-rings, and the displacement distance of the fracture ends. Five spinal surgeons were randomly selected to classify the CT images of the 75 patients using the new classification method. After one month, the imaging data of the 75 cases of cervical vertebra fractures were randomized and reclassified to assess the reliability and repeatability of the classification.Results:The new cervical vertebra fracture classification method comprised three types based on whether the fracture line involved the facet joint surface of the atlas: type A (no involvement of the facet joint surface of the atlas), type B (involvement of one side of the facet joint surface with intact contralateral half-ring), and type C (involvement of one side of the facet joint surface with fractured contralateral half-ring). Additionally, based on the maximum displacement distance between the fracture ends (>4 mm), six subtypes were identified: subtype 1 (≤4 mm displacement) and subtype 2 (>4 mm displacement). Consequently, the subtypes were classified as A1, A2, B1, B2, C1, and C2. According to the new classification method, the 75 patients included 17 cases of A1, 12 cases of A2, 7 cases of B1, 13 cases of B2, 12 cases of C1, and 14 cases of C2. The classification demonstrated excellent consistency, as assessed by the five doctors, with Kappa values of 0.85 and 0.91 for reliability and repeatability, respectively. At the final follow-up, all conservatively treated patients achieved bone healing, while four surgically treated patients experienced non-union of the fracture ends but exhibited good fusion between the atlas and axis. The remaining surgically treated patients achieved bony union without complications such as loosening or fracture of internal fixation.Conclusion:The new cervical vertebra fracture classification method, based on CT imaging features, comprehensively covers common clinical cases of cervical vertebra fractures and demonstrates excellent consistency. It provides valuable clinical guidance for the diagnosis and treatment of cervical vertebra fractures.

Objective:To evaluate the long-term efficacy of AdVance sling bulbar urethral suspension and artificial urethral sphincter (AUS) implantation in the treatment of moderate to severe male stress urinary incontinence.Methods:The clinical data of 12 male patients with urinary incontinence who underwent surgical treatment in Peking University People's Hospital from June 2011 to June 2017 were retrospectively analyzed. The median age was 75(64-80) years. There were 9 cases after radical prostatectomy and 3 cases after transurethral prostatectomy. Patients had a median history of urinary incontinence of 3(1-9) years, and needed an average of 8(5-10) pads per day. Among them, 5 patients had moderate urinary incontinence and 7 patients had severe urinary incontinence. All patients underwent urinary incontinence surgery for the first time. Among the 12 patients, 6 received AdVance sling ball urethral suspension (AdVance group), and 6 received AUS implantation (AUS group). The median age of the AdVance group was 72 (64-73) years. The median number of pads used daily was 6 (5-8) tablets. Urinary incontinence Quality of Life questionnaire (I-QOL) score was (15.0±5.4). Five patients had moderate urinary incontinence and one patient had severe urinary incontinence. In the AUS group, the median age was 78(76-80) years old, the median daily pad use was 8(6-10) tablets, and the I-QOL score was (16.7±5.1), all of which were severe urinary incontinence. The daily pad usage, I-QOL and postoperative complications were recorded at 1 and 5 years after operation.Results:All patients completed the operation successfully. The postoperative follow-up was 5-7 years (mean 5.5 years). In AdVance group, 1 patient with severe urinary incontinence had no significant improvement in postoperative symptoms at 1 year after operation. The other 5 patients showed significant improvement in urinary incontinence symptoms. In the AdVance group, the median number of pads used per day was 2.5 (1-10), and the I-QOL score was (75.0±28.1), which were all significantly improved compared with that before operation ( P<0.05). The median number of pads used per day in the AdVance group 5 years after operation was 2.5(1-10), and the I-QOL score was (78.3±29.3), which were significantly improved compared with those before operation (all P<0.01). In the AUS group, no pad was needed at 1 year after operation, which was significantly improved compared with that before operation ( P<0.01). Urethral erosion occurred in 2 cases 3 years after operation, and the AUS was removed. Urinary incontinence recurred and returned to the preoperative state without reoperation. The other 4 cases did not need to use the pad 5 years after operation. In AdVance group, 3 patients had perineal pain within 3 months after operation, which was related to activity and relieved spontaneously. No wound infection, urethral erosion and other complications occurred. Urethral erosion occurred in 3 cases in AUS group. Conclusions:AdVance sling ball urethral suspension is effective for patients with moderate stress urinary incontinence and has fewer complications. AUS implantation is effective for patients with severe male stress urinary incontinence. However, the long-term complications of this operation may affect the postoperative efficacy.