Objective:To summarize the clinical phenotype and genetic features of patients with relapsing encephalopathy with cerebellar ataxia (RECA) caused by ATP1A3 gene R756 variants. Methods:A retrospective analysis was performed on patients carrying the ATP1A3 gene R756 variants, identified by whole-exome sequencing of family members, at Capital Center for Children′s Health, Capital Medical University and Children's Medical Center, Peking University First Hospital from August 2005 to February 2024. Their clinical, laboratory, neuroimaging, electrophysiological and genetic characteristics were summarized. Results:A total of 13 RECA patients were enrolled in this study, including 8 males and 5 females. The age of onset was 8 months to 5 years, with a median age of onset of 18 months. All of 13 patients presented paroxysmal episodes of neurological decompensations triggered by fever and residual symptoms following the acute phase. During acute attack stage, ataxia was observed in all 13 cases, muscle weakness in 12 cases, dysarthria in 12 cases, altered consciousness in 10 cases, dysphagia in 10 cases, dystonic episodes in 4 cases, abnormal eye movement in 2 cases, choreoathetosis in 2 cases, and epileptic seizures in 1 case. All 13 patients had residual symptoms during the nonparoxysmal period, of whom 9 patients had ataxia, 9 patients had dysarthria, 4 patients had dystonia, 3 patients had cognitive disorders, and 1 patient had epileptic seizures. All 13 cases had ATP1A3 missense variants, and variant c.2266C>T/p.R756C was found in 6 cases, c.2267G>A/p.R756H in 5 cases, and c.2267G>T/p.R756L in 2 cases. Nine cases carried de novo variants, 4 with inherited variants. Conclusions:RECA caused by variants of ATP1A3 in residue 756 typically presents with an acute onset during infancy or early childhood, precipitated by febrile episodes and characterized by recurrent episodes of ataxia, with bulbar paralysis, muscle weakness and altered consciousness. Recurrence is common, and the most common persistent symptoms are cerebellar ataxia and dysarthria. A few patients have cognitive impairment. Three types of ATP1A3 gene variants R756C, R756H and R756L are related with RECA, and R756C is the most common variant.

Objective:To summarize the clinical phenotype and genetic features of patients with relapsing encephalopathy with cerebellar ataxia (RECA) caused by ATP1A3 gene R756 variants. Methods:A retrospective analysis was performed on patients carrying the ATP1A3 gene R756 variants, identified by whole-exome sequencing of family members, at Capital Center for Children′s Health, Capital Medical University and Children's Medical Center, Peking University First Hospital from August 2005 to February 2024. Their clinical, laboratory, neuroimaging, electrophysiological and genetic characteristics were summarized. Results:A total of 13 RECA patients were enrolled in this study, including 8 males and 5 females. The age of onset was 8 months to 5 years, with a median age of onset of 18 months. All of 13 patients presented paroxysmal episodes of neurological decompensations triggered by fever and residual symptoms following the acute phase. During acute attack stage, ataxia was observed in all 13 cases, muscle weakness in 12 cases, dysarthria in 12 cases, altered consciousness in 10 cases, dysphagia in 10 cases, dystonic episodes in 4 cases, abnormal eye movement in 2 cases, choreoathetosis in 2 cases, and epileptic seizures in 1 case. All 13 patients had residual symptoms during the nonparoxysmal period, of whom 9 patients had ataxia, 9 patients had dysarthria, 4 patients had dystonia, 3 patients had cognitive disorders, and 1 patient had epileptic seizures. All 13 cases had ATP1A3 missense variants, and variant c.2266C>T/p.R756C was found in 6 cases, c.2267G>A/p.R756H in 5 cases, and c.2267G>T/p.R756L in 2 cases. Nine cases carried de novo variants, 4 with inherited variants. Conclusions:RECA caused by variants of ATP1A3 in residue 756 typically presents with an acute onset during infancy or early childhood, precipitated by febrile episodes and characterized by recurrent episodes of ataxia, with bulbar paralysis, muscle weakness and altered consciousness. Recurrence is common, and the most common persistent symptoms are cerebellar ataxia and dysarthria. A few patients have cognitive impairment. Three types of ATP1A3 gene variants R756C, R756H and R756L are related with RECA, and R756C is the most common variant.

Objective:To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID.Methods:In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis.Results:Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased ( P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency ( P<0.05) . Conclusion:The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

Background::Understanding the trends of the prevalence and incidence rate of chronic obstructive pulmonary disease (COPD) is vital for improving the control and prevention of COPD. We aimed to examine the trends in the prevalence and incidence rate of COPD among adults aged 50 years or older in the United States during 2000-2020.Methods::Utilizing data from the Health and Retirement Study, we analyzed COPD prevalence across survey waves and calculated COPD incidence rates between consecutive interview waves, stratified by gender and race. We employed joinpoint regression models to investigate trends in COPD prevalence and incidence.Results::The individuals reporting COPD are more likely to be women and Caucasians. The age-adjusted prevalence of COPD among adults aged 50 years and over showed an increasing trend throughout the study period, spanning from 9.02% in 2000 to 9.88% in 2020 (average biennial percent change [ABPC] = 0.41, 95% confidence interval [CI]: 0.10, 0.71; p = 0.01). The age-adjusted incidence rate of COPD among adults aged 50 and over showed a decreasing trend throughout the study period 1031.1 per 100,000 person-years in 2000 to 700.5 per 100,000 person-years in 2020 (ABPC = -1.63, 95% CI: -2.88, -0.36; p = 0.02). Conclusion::Our findings indicate a rising prevalence of COPD among older adults in the United States since 2000, while the incidence rate of COPD has shown a declining trend.

Objective:To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID.Methods:In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis.Results:Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased ( P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency ( P<0.05) . Conclusion:The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

Abstract: Objective　To evaluate the application of variable number tandem repeats (VNTR) and whole genome sequencing (WGS) in tracing the transmission of Mycobacterium tuberculosis in a tuberculosis outbreak in school, and explore the roles of these genetic methodologies in addressing tuberculosis transmission in school environments. Methods Identification of mycobacterial strains, spacer oligonucleotide typing (Spoligotyping), VNTR, and WGS were performed on six Mycobacterium tuberculosis strains obtained from TB cases in the first multidrug-resistant tuberculosis outbreak happened in a school in Beijing. Genotyping characteristics were analyzed to identify the transmission chain. Results The 6 culture-positive strains involved 6 students from 4 classes across 2 grades. One of them was the first case, three were close contacts of the first case, and the other two were general contacts. All 6 strains were identified as Mycobacterium tuberculosis. Spoligotyping results indicated that 5 of the strains were of the Beijing genotype; the other one had no result. VNTR genotyping divided the 6 strains into 3 clusters with a clustering rate of 66.7%. The largest one of the 3 clusters contained 4 strains with the same genotype, indicating a significant level of recent transmission. The remaining two strains, differing by 1.0-1.6 copies at 1-2 loci from the other four strains, were identified as individual strains. The results of WGS showed that the genomic SNP differences among the 6 strains were greater than 12 SNPs. According to the molecular biology identification criteria of this study, the strains exhibited significant heterogeneity with no homology. Conclusions WGS offers higher accuracy and advantages over VNTR genotyping in evaluating the recent transmission of tuberculosis. WGS can more accurately characterize recent TB transmission in the case of TB outbreaks in schools, especially when there are drug-resistant TB cases, and should be used as a supplement to traditional epidemiology.

Background::Understanding the trends of the prevalence and incidence rate of chronic obstructive pulmonary disease (COPD) is vital for improving the control and prevention of COPD. We aimed to examine the trends in the prevalence and incidence rate of COPD among adults aged 50 years or older in the United States during 2000-2020.Methods::Utilizing data from the Health and Retirement Study, we analyzed COPD prevalence across survey waves and calculated COPD incidence rates between consecutive interview waves, stratified by gender and race. We employed joinpoint regression models to investigate trends in COPD prevalence and incidence.Results::The individuals reporting COPD are more likely to be women and Caucasians. The age-adjusted prevalence of COPD among adults aged 50 years and over showed an increasing trend throughout the study period, spanning from 9.02% in 2000 to 9.88% in 2020 (average biennial percent change [ABPC] = 0.41, 95% confidence interval [CI]: 0.10, 0.71; p = 0.01). The age-adjusted incidence rate of COPD among adults aged 50 and over showed a decreasing trend throughout the study period 1031.1 per 100,000 person-years in 2000 to 700.5 per 100,000 person-years in 2020 (ABPC = -1.63, 95% CI: -2.88, -0.36; p = 0.02). Conclusion::Our findings indicate a rising prevalence of COPD among older adults in the United States since 2000, while the incidence rate of COPD has shown a declining trend.

Objective:To summarize the clinical phenotype and gene mutation characteristics of male patients with epilepsy caused by mosaic PCDH19 mutation. Methods:The clinical data of 3 male patients with epilepsy caused by mosaic PCDH19 mutation were analyzed.Microdroplet digital polymerase chain reaction (mDDPCR) was used for the detection of mosaicism in the three probands and their family members.Relevant literatures were reviewed. Results:The seizure onset age were 5 months, 9 months and 6 months of life respectively.Focal seizures occurred in 2 cases and multiple seizure types occurred in 1 case.Three patients presented with clusters of seizures.Fever sensitivity was observed in 2 cases out of the 3 cases.Two patients had intellectual disability and 1 patient had autistic manifestation.The clinical phenotype in 2 patient fulfilled the diagnosis of Dravet syndrome. PCDH19 mosaic mutations c. 317T>A(p.M106K), c.158dupT(p.D54Gfs*35) and c. 1639G>C(p.A547P) were detected respectively, and were identified as de novo after parental validation.Mutant allele fractions (MAF) in the blood samples were identified as 81.18%, 37.08%, 77.64%, respectively.The MAF of multiple tissues in 1 patient varied from 78.67% to 98.46%.Review of literature revealed that a total of 11 cases with mosaic PCDH19 mutation were reported.Among them, seizure onset occurred between 5 and 31 months of age.Focal seizures occurred in 9 cases, 3 cases of the 9 cases had only focal seizures.Generalized tonic clonic seizures occurred in 4 cases.Two or more seizures were observed in 6 cases.Clustering of seizures was found in all patient and sensitivity to fever was observed in 9 patients.Seven patients had mild to severe intellectual disability and 5 patients had autistic features. Conclusions:The clinical phenotypes of male patients with epilepsy caused by PCDH19 mosaic mutation are characterized by clustering of seizures, sensitivity to fever, focal seizures in most cases, varied degree of intellectual disability and autistic features in partial.

Objective:To follow up and clarify the prognosis of 670 pediatric patients with Dravet syndrome (DS).Methods:The clinical data of DS pediatric patients treated in the Department of Pediatrics, Peking University First Hospital from February 2005 to August 2016 were recorded, and genetic testing was carried out.DS pediatric patients were followed up via subsequent visits at the outpatient and telephone interview.Results:Among 670 cases with DS, 556 cases (556/670 cases, 83.0%) carried SCN1A mutations.In the follow-up, 608 cases were contacted (608/670 cases, 90.7%) and 62 cases (62/670 cases, 9.3%) were lost.The last follow-up median age was 8 years 5 months.Eighty-two cases (82/608 cases, 13.5%) were seizure-free for more than 1 year, with a median age of 9 years and 2 months.Thirty-eight cases relapsed (38/82 cases, 46.3%), mainly induced by fever (34 cases) or mi-ssing antiepileptic drugs (2 cases). Analysis of the relative factors of patients that were seizure-free for more than 1 year showed that children with missense SCN1A mutations, inherited mutations and an older age had a relatively good outcome for seizure control.Twenty-five cases (25/608 cases, 4.1%) were deceased, with a median age of 4 years.The mortality factors included multiple organ dysfunction syndromes after prolonged status epilepticus (12 cases), possible sudden unexpected death in epilepsy (7 cases), asphyxiation after vomiting with or without a seizure (2 cases), and an accidental injury (1 case). The fatal causes in the remaining 3 cases were unknown. Conclusions:DS is an intractable epileptic syndrome, but few patients may have a seizure remission (seizure free for more than 1 year). Patients with mi-ssense SCN1A mutations, inherited mutations and an older age have a relatively good outcome for seizure control.The mortality rate is high in DS patients.The causes of mortality include multiple organ dysfunction syndromes after prolonged status epilepticus, possible sudden unexpected death in epilepsy, and so on.

Objective:To evaluate the clinicopathologic characteristics and outcomes of HIV-negative plasmablastic lymphoma (PBL) .Methods:Medical records of 15 patients diagnosed with HIV-negative PBL in Changhai Hospital between January 2013 and August 2019 were reviewed, and clinicopathologic characteristics and outcomes were analyzed.Results:Median age was 59 years (range: 17-69) . All patients had extranodal involvement. According to the Cotswolds-modified Ann Arbor staging system, 1 (6.7%) , 2 (13.3%) , 3 (20.0%) , and 9 (60.0%) patients were classified as at Ⅰ,Ⅱ,Ⅲ and Ⅳ, respectively. Plasmablast and immunoblast proliferations were typical manifestations of PBL. Immunohistochemical staining showed tumor cells were diffusely positive for plasma cell markers CD38, CD138, and Mum-1, while negative for B cell markers CD20, CD10, PAX-5, and BCL-6. Median Ki-67 index was 80% (70%-90%) . Epstein-Barr virus-encoded RNA (EBER) expression was detected in 3 patients, and 1 of them was positive. All patients received chemotherapy, 80% combined with bortezomib as the first line, and responses were observed in 8 patients (6 complete and 2 partial responses) . Median progression-free survival (PFS) and overall survival (OS) were 6.8 (95% CI 2.5-11.1) months and 17.9 (95% CI 5.6-30.2) months, the 3-year PFS and OS rates were 21.2% (95% CI 1.4%-56.8%) and 38.5% (95% CI 12.0%-65.0%) , respectively. Conclusion:HIV-negative PBL with high invasiveness is extremely prone to extranodal involvement and most patients were at the advanced stage. Patients receiving an intensive therapy combined with bortezomib and bridged autologous stem cell transplantation may improve long-time survival.