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.

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.

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.

Objective: To analyze the etiology and clinical characteristics of hypertension in children; to analyze the risk factors for primary hypertension with target organ damage, and to provide evidence for clinical diagnosis of hypertension in children. Methods: Two hundred and thirty-two hospitalized children with hypertension at Children′s Hospital Institute of Pediatrics from April 2013 to December 2017 were retrospectively analyzed, including general situation, clinical manifestation, laboratory examination, auxiliary examination and damage assessment of target organs. Results: (1)There were totally 232 eligible cases, consisting of 184 males(79.3%) and 48 females(20.7%). Among these children: 38 cases(16.4%), 126 cases(54.3%), and 68 cases(29.3%) were diagnosed as prehypertension, hypertension in stage Ⅰ, and hypertension in stage Ⅱ, respectively.(2)The etiological composition of hypertension: there were 181 cases(78%) diagnosed as primary hypertension and 51 cases(22%) diagnosed as secondary hypertension, respectively; the proportion of the primary hypertension children during the period of preschool, school-age, and adolescent was 1.6%(3 cases), 21.0%(38 cases) and 77.4%(140 cases), respectively.The etiology of secondary hypertension was mostly of the renal parenchymal hypertension and renal vascular hypertension(43.1%). (3) The clinical manifestations of primary hypertension were mostly of asymptomatic or mild symptoms, totally 148 cases(64%), and then dizziness, headache, chest pain, chest tightness, palpitation, blurred vision, and other clinical symptoms.(4) The high risk factors for primary hypertension with target-organ damage included cesarean section, glucose metabolism disturbance and body mass index >24 kg/m². Conclusions In recent years, the proportion of primary hypertension among hospitalized children has increased.The changes in the etiology of secondary hypertension are not found.Primary hypertension children are often accompanied with target organ damage.It is of great significance to make blood pressure monitoring as a routine physical examination for primary and middle school students, so as to detect hypertension in children earlier, and make active intervention and improve the prognosis of hypertension in children.

Objective: To compare the difference of efficacy between traditional Hyper-CVAD/MA regimen and the adolescents inspired chemotherapy regimen, CH ALL-01, in treatment of adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) . Methods: In this study we retrospectively analyzed 158 Ph⁺ ALL patients receiving Hyper-CVAD/MA regimen (n=63) or CHALL-01 regimen (n=95) in our center and Changzheng hospital from January 2007 to December 2017, excluding patients with chronic myeloid leukemia in blast crisis. Tyrosine kinase inhibitor (TKI) was administered during induction and consolidation chemotherapy. Patients who underwent hematopoietic stem cell transplantation received TKI as maintenance therapy. Results: Of them, 91.1% (144/158) patients achieved complete remission (CR) after 1-2 courses of induction. CR rate was 90.5% (57/63) for patients in Hyper-CVAD/MA group and 91.6% (87/95) for patients in CHALL-01 group. There was no difference in CR rates between the two groups (χ²=0.057, P=0.811) . The last follow-up was June 2018. A cohort of 134 CR patients could be used for further analysis, among them, 53 patients received Hyper-CVAD/MA regimen and other 81 patients received CHALL-01 regimen. The molecular remission rates were significantly higher in CHALL-01 group (complete molecular response: 44.4%vs 22.6%; major molecular response: 9.9% vs 18.9%) (χ²=7.216, P=0.027) . For the patients in Hyper-CVAD/MA group, the 4-year overall survival (OS) was 44.81% (95%CI: 30.80%-57.86%) and the 4-year disease free survival (DFS) was 37.95% (95%CI: 24.87%-50.93%) . For patients received CHALL-01 regimen, the 4-year OS was 55.63% (95%CI: 39.07%-69.36%) (P=0.037) and 4 year DFS was 49.06% (95%CI: 34.24%-62.29%) (P=0.015) , while there was no significant difference in 4 year cumulative incidence of relapse (CIR) (P=0.328) or cumulative incidence of nonrelapse mortality (CI-NRM) (P=0.138) . The rate of pulmonary infection was lower in patients received CHALL-01 regimen compared with patients received Hyper-CVAD regimen (43.4% vs 67.9%, χ²=7.908, P=0.005) . Conclusions Outcome with CHALL-01 regimen appeared better than that with the Hyper-CVAD/MA regimen in Ph⁺ ALL, which has lower incidence of pulmonary infection, higher molecular remission rate and better OS and DFS.

Objective: To investigate the relationship between donor chimerism and relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The clinical data of 105 patients with acute myeloid leukemia (AML) who underwent allo-HSCT and recurrence-free survival>90 days from January 2010 to January 2019 were retrospectively analyzed. The bone marrow samples were collected at 15, 30, 60, 90, 180, 270, 360 days after transplantation. Donor chimerism was detected by single nucleotide polymorphism (SNP) -PCR. Results: Of the 105 patients, 43 cases were male and 62 cases were female, with a median age of 38 (16-60) years. Till April 2019, the median follow-up was 843 (94-3 261) days. Ninety days after transplantation, 18 cases relapsed, 33 cases died, and 72 cases survived. The 3-year overall survival (OS) rate was (66.8±5.1) %, and the recurrence-free survival (RFS) rate was (65.1±5.0) %. Pre-transplant disease status, pre-transplant minimal residual disease (MRD) , and 90 day post-transplantation chimerism were independent risk factors related to RFS. The risk of recurrence was significantly increased in patients with a donor chimerism rate ≤97.24% at 90 days after transplantation[HR=6.921 (95%CI 2.669-17.950) , P<0.001], which was considered as a sign of early relapse. Conclusion SNP-PCR is an applicable method for detecting donor chimerism in patients after allo-HSCT. Chimerism rate equal or less than 97.24% at 90 days after transplantation predicts a higher risk of relapse.

Objective: To summarize the clinical and genetic features of β-propeller protein-associated neurodegeneration (BPAN). Methods: The clinical data of 17 patients with BPAN with WDR45 gene variants were retrospectively collected at Children’s Hospital of Fudan University, Peking University First Hospital, Capital Institute of Pediatrics, Shengjing Hospital of China Medical University and Shanghai Children's Hospital from June 2016 to December 2018, and their clinical manifestations, electroencephalogram, neuroimaging and genetics were analyzed. Results: Seventeen cases (13 females, 4 males), aged 1.1-8.8 years, were included. The median age of seizure onset was 14.5 months, from 3 months to 24 months of age, manifested with epileptic spasm in 6 cases and focal seizures in 5 cases. Eight patients had only one seizure type and 8 patients had two or more seizure types. Nine patients had complete remission of seizures. All 16 patients with seizures had developmental delay before the seizure onset, of whom 13 patients had moderate to severe seizures. The brain magnetic resonance imaging (MRI) was abnormal in 13 patients, including cerebral atrophy (10 cases) and thinning of the corpus callosum (9 cases). The brain magnetic susceptibility weighted imaging (SWI) in preschool stage showed prominent T2 hypointense signals in bilateral globus pallidus and brainstem ventral in two cases. Five seizure types (spasm, focal, absence, myodonic and generalized tonic clonic seizures)were found on ictal electroencephalogram(EEG) recordings. Compared to female patients(17(6-24) months of ege), male cases had earlier seizure onset (3, 4, 5, 18 months of age) . All patients had de novo variations in WDR45(6 nonsense, 4 frameshift, 3 missense and 4 splicing variations), with hemizygous variants in 3 males, mosaic variants in a male and heterozygous variants in 13 females, within which 5 variations had not been reported (c.977-1C>T,c.976+1G>C,c.10C>T,c.806del and c.110T>C). Conclusions The patients with BPAN have profound developmental delay and are vulnerable to seizures. The male patients with BPAN tend to have more severer clinical phenotype than females. Early brain SWI could facilitate the timely diagnosis of this disease.

Objective: To analyze the clinical characteristics of patients with PCDH19-female limited epilepsy (PCDH19-FE). Methods: The clinical data of 60 female epilepsy patients with PCDH19 gene heterozygous variations at the Department of Pediatrics, Peking University First Hospital from October 2007 to December 2018 were collected and analyzed retrospectively, their clinical manifestations, accessory examination and follow-up treatment were summarized. Results: Data of a total of 60 cases of PCDH19-FE were collected. The seizure onset occurred between 4 and 42 months of age (median: 11 months of age). Focal seizures occurred in 47 patients (78%), generalized tonic-clonic seizures (GTCS) occurred in 30 patients (50%), and other rare types of seizures included atypical absence, myoclonic, clonic, tonic, and atonic seizures. Two or more seizures types existed in 24 patients (40%), and seven patients (12%) had attacks of status epilepticus. Sensitivity to fever was observed in 47 out of them (78%) and clustering of seizures as found in all patients. During the interictal phase, focal discharges were monitored in 22 cases (22/45, 49%), multifocal discharges in 12 cases (12/45, 27%), widely discharging in 2 cases (4%), and both focal and widely discharging in 9 cases (20%). Clinical seizures were detected in 30 patients during the electroencephalogram (EEG) recording, including focal seizures in 22 cases, GTCS seizures in 8 cases, tonic seizure in three cases, myoclonic seizure followed by GTCS in one case, and two types of seizures in four cases. Before seizure onset, 57 patients had normal development and three patients had delayed language development. After seizure onset, varied degrees of intelligence disability were present in 38 cases (63%), language delay in 36 cases (60%), and gait instability in 10 cases (17%). Autistic features occurred in 17 cases (28%); and other behavioral problems like learning difficulties, personality, or emotional disorders existed in 33 cases (55%). Age at last follow-up ranged from one year and 3 months to 22 years and 3 months of age, 17 patients (28%) were seizure-free for more than 2 years (5 to 22 years at the last follow-up). The efficiency of antiepileptic drugs were 65% (33/51) in sodium valproate, 63% (27/43) in levetiracetam and 59% (20/34) in topiramate. Conclusions The clinical features of PCDH19-FE are characterized by clustering of seizures, focal seizures in most cases, sensitivity to fever mostly, focal discharges principally in EEG, varied degrees of intellectual disability or movement disorder, combined with autism spectrum disorders in partial and high efficiency in sodium valproate or levetiracetam treatment.