Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

BACKGROUND: Alpha-glucosidase inhibitors or dipeptidyl peptidase-4 inhibitors are both hypoglycemia agents that specifically impact on postprandial hyperglycemia. We compared the effects of acarbose and sitagliptin add on to metformin on time in range (TIR) and glycemic variability (GV) in Chinese patients with type 2 diabetes mellitus through continuous glucose monitoring (CGM). METHODS: This study was a randomized, open-label, active-con-trolled, parallel-group trial conducted at 15 centers in China from January 2020 to August 2022. We recruited patients with type 2 diabetes aged 18-65 years with body mass index (BMI) within 19-40 kg/m 2 and hemoglobin A1c (HbA1c) between 6.5% and 9.0%. Eligible patients were randomized to receive either metformin combined with acarbose 100 mg three times daily or metformin combined with sitagliptin 100 mg once daily for 28 days. After the first 14-day treatment period, patients wore CGM and entered another 14-day treatment period. The primary outcome was the level of TIR after treatment between groups. We also performed time series decomposition, dimensionality reduction, and clustering using the CGM data. RESULTS: A total of 701 participants received either acarbose or sitagliptin treatment in combination with metformin. There was no statistically significant difference in TIR between the two groups. Time below range (TBR) and coefficient of variation (CV) levels in acarbose users were significantly lower than those in sitagliptin users. Median (25th percentile, 75th percentile) of TBR below target level <3.9 mmol/L (TBR 3.9 ): Acarbose: 0.45% (0, 2.13%) vs . Sitagliptin: 0.78% (0, 3.12%), P = 0.042; Median (25th percentile, 75th percentile) of TBR below target level <3.0 mmol/L (TBR 3.0 ): Acarbose: 0 (0, 0.22%) vs . Sitagliptin: 0 (0, 0.63%), P = 0.033; CV: Acarbose: 22.44 ± 5.08% vs . Sitagliptin: 23.96 ± 5.19%, P <0.001. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV (group with small wave, moderate wave and big wave). No significant difference was found in the complexity of glucose time series index (CGI) between acarbose users and sitagliptin users. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV. CONCLUSIONS: Acarbose had slight advantages over sitagliptin in improving GV and reducing the risk of hypoglycemia. Time series analysis of CGM data may predict GV and the risk of hypoglycemia. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR2000039424.
Humans ; Metformin/therapeutic use* ; Sitagliptin Phosphate/therapeutic use* ; Acarbose/therapeutic use* ; Diabetes Mellitus, Type 2/blood* ; Middle Aged ; Male ; Female ; Adult ; Blood Glucose/drug effects* ; Hypoglycemic Agents/therapeutic use* ; Aged ; Glycated Hemoglobin/metabolism* ; Adolescent ; Young Adult ; China ; East Asian People

Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
Organoids/physiology* ; NAV1.2 Voltage-Gated Sodium Channel/genetics* ; Humans ; Anticonvulsants/pharmacology* ; Epilepsy/drug therapy* ; Mutation ; Cerebral Cortex/drug effects* ; Action Potentials/drug effects* ; Carbamazepine/pharmacology*

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity. Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixed-effects model. Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed. Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Objective:To understand the epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023.Methods:The data of this study were collected from the ARI surveillance data from 16 provinces in China from 2009 to 2023, with a total of 28 278 ARI cases included in the study. The clinical specimens from ARI cases were screened for HRSV nucleic acid from 2009 to 2023, and differences in virus detection rates among cases of different age groups, regions, and months were analyzed.Results:A total of 28 278 ARI cases were enrolled from January 2009 to September 2023. The age of the cases ranged from<1 month to 112 years, and the age M ( Q1, Q3) was 3 years (1 year, 9 years). Among them, 3 062 cases were positive for HRSV nucleic acid, with a total detection rate of 10.83%. From 2009 to 2019, the detection rate of HRSV was 9.33%, and the virus was mainly prevalent in winter and spring. During the Corona Virus Disease 2019 (COVID-19) pandemic, the detection rate of HRSV fluctuated between 6.32% and 18.67%. There was no traditional winter epidemic peak of HRSV from the end of 2022 to the beginning of 2023, and an anti-seasonal epidemic of HRSV occurred from April to May 2023. About 87.95% (2 693/3 062) of positive cases were children under 5 years old, and the difference in the detection rate of HRSV among different age groups was statistically significant ( P<0.001), showing a decreasing trend of HRSV detection rate with the increase of age ( P<0.001). Among them, the HRSV detection rate (25.69%) was highest in children under 6 months. Compared with 2009-2019, the ranking of HRSV detection rates in different age groups changed from high to low between 2020 and 2023, with the age M (Q1, Q3) of HRSV positive cases increasing from 1 year (6 months, 3 years) to 2 years (11 months, 3 years). Conclusion:Through 15 years of continuous HRSV surveillance analysis, children under 5 years old, especially infants under 6 months old, are the main high-risk population for HRSV infection. During the COVID-19 pandemic, the prevalence and patterns of HRSV in China have changed.

Noncarious lesions,a multifactorial condition encompassing tooth attrition,abrasion,and erosion,have a surge in prevalence and required increased attention in clinical practice.These nonbacterial-associated tooth de-fects can compromise aesthetics,phonetics,and mastica-tory functions.When providing full-arch fixed occlusal rehabilitation for such cases,the treatment strategy should extend beyond by restoring dentition morphology and aesthetics.This report details a complex case of erosive dental wear addressed through a fully digital,full-arch fixed occlusal rehabilitation.A 4D virtual patient was created using multiple digital data sources,including intraoral scanning,3D facial scanning,digital facebow registration,and mandibular movement tracing.With a comprehensive understanding of the masticatory system,various types of microinvasive prostheses were customized for each tooth,including labial ve-neers,buccal-occlusal veneers,occlusal veneers,overlays,inlays,and full crowns,were customized for each tooth.The reported digital workflow offered a predictable diagnostic and treatment strategy,which was facilitated by virtual visual-ization and comprehensive quality control throughout the process.