[Related factors of acute symptomatic seizures and epilepsy in children with myelin oligodendrocyte glycoprotein antibody-associated disease].

Objective: To investigate the risk factors of acute symptomatic seizures (ASS) and epilepsy in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods: A ambispective cohort study was used including 74 children with MOGAD who were admitted to the Department of Pediatrics of Peking University First Hospital from January 2013 to June 2023 and were followed up. Demographic information, clinical information, treatment status, ASS and epilepsy status were collected. The clinical phenotypes were classified. According to the presence or absence of ASS in the course of disease, the children and the course of disease were divided into groups with and without ASS. Chi-square test, Fisher exact test and Mann Whitney U test were used to analyze the correlation between symptoms and auxiliary examination characteristics and the occurrence of ASS in the two groups of children. Multivariate Logistic regression analysis was used for multivariate analysis. Results: The onset age of the 74 children with MOGAD was 6.58 (3.80, 9.67) years, including 38 females (51.4%) and 36 males (48.6%). The duration of the final follow-up was 2.67 (1.10, 4.12) years, with a total of 239 times acute clinical episodes. ASS occurred in 39.2% (29/74) children during the course of disease and in 29.3% (70/239) of attacks. The common phenotypes were ADEM (67 times (28.0%)), optic neuritis (37 times (15.4%)) and cerebral cortical encephalitis (31 times (13.0%)) in 239 times acute clinical episodes. The incidence of ASS in ADEM and cerebral cortical encephalitis phenotype was 28.4%(19/67) and 100.0% (31/31), respectively. Multivariate analysis showed that cortical involvement on magnetic resonance imaging during clinical attacks was an independent risk factor for ASS (ß=-1.49, OR=0.23) after excluding attacks involving only optic nerve or spinal cord (49 episodes). During the follow-up, 5 children (6.8%) had epilepsy, and all children with epilepsy had multiple clinical attacks of MOGAD and previous ASS. Conclusions: Cortical involvement on magnetic resonance imaging during clinical episodes is an independent risk factor for ASS in children with MOGAD. All MOGAD children with epilepsy had ASS and multiple MOGAD clinical episodes in the past.

[Clinicopathological features of breast cancer with HER2 low expression: a real-world retrospective study].

Objective: To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. Methods: The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. Results: The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (P<0.001), Ki-67 index below 35% (P<0.001), well or moderate differentiation (P<0.001) and over the age of 50 (P=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. Conclusions: The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.

Effect of Multicomponent Intervention on Functional Decline in Chinese Older Adults: A Multicenter Randomized Clinical Trial.

OBJECTIVES: To confirm whether multicomponent exercise following vivifrail recommendations was an effective method for improving physical ability, cognitive function, gait, balance, and muscle strength in Chinese older adults. METHODS: This was a multicenter and randomized clinical trial conducted in Jiangsu, China, from April 2021 to April 2022. Intervention lasted for 12 weeks and 104 older adults with functional declines were enrolled. All participants were randomly assigned to a control (usual care plus health education) or exercise group (usual care plus health education plus exercise). Primary outcomes were the change score of Short Physical Performance Battery (SPPB) and activities of daily living (ADL). The secondary outcomes included instrumental activities of daily living, Tinetti scores, Frailty score, short-form Mini Nutritional Assessment, Mini-Mental State Examination, Geriatric Depression Scale-15, the 12-item Short Form Survey, 4-meter gait speed test, 6-min walking distance, grip strength, and body composition analysis. RESULTS: Among the participants, the average age was 85 (82, 88) years. After 12 weeks of follow-up, the exercise group showed a significant improvement in SPPB, with a change of 2 points (95% confidence interval [0, 3.5], P<0.001) compared to control. In contrast, SPPB remained stable in the control group. Compared to the control group, ADL improved in the exercise group, as did instrumental activities of daily living, Tinetti, Frailty, Short Form Survey, 4-meter gait speed test, and 6-min walking distance. Although there was no significant difference between groups in body composition analysis after post-intervention, the exercise group still improved in soft lean mass (P=0.002), fat-free mass (P=0.002), skeletal muscle mass index (P<0.001), fat-free mass index (P=0.004), appendicular skeletal muscle mass (P<0.001), and leg muscle mass (P<0.001), while the control group had no significant increase. No difference was observed in adverse events during trial period. CONCLUSIONS: The multicomponent exercise intervention following vivifrail recommendations is an effective method for older adults with functional decline and can reverse the functional decline and improve gait, balance, and muscle strength. Additionally, the 12-week multicomponent exercise method provides guidance for Chinese medical professionals working in the field of geriatrics and is a promising method to improve physical function in the general population.

[Clinicopathological features of fibrin-associated diffuse large B-cell lymphoma: a report of six cases].

Objective: To investigate the clinical, pathological and immunophenotypic features, molecular biology and prognosis of fibrin-associated large B-cell lymphoma (LBCL-FA) in various sites. Methods: Six cases of LBCL-FA diagnosed from April 2016 to November 2021 at the Beijing Friendship Hospital, Capital Medical University, Beijing, China and the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China were collected. The cases were divided into atrial myxoma and cyst-related groups. Clinical characteristics, pathological morphology, immunophenotype, Epstein Barr virus infection status, B-cell gene rearrangement and fluorescence in situ hybridization of MYC, bcl-2, bcl-6 were summarized. Results: The patients' mean age was 60 years. All of them were male. Three cases occurred in atrial myxoma background, while the others were in cyst-related background, including adrenal gland, abdominal cavity and subdura. All cases showed tumor cells located in pink fibrin clot. However, three cyst-related cases showed the cyst wall with obviously fibrosis and inflammatory cells. All cases tested were non germinal center B cell origin, positive for PD-L1, EBER and EBNA2, and were negative for MYC, bcl-2 and bcl-6 rearrangements, except one case with MYC, bcl-2 and bcl-6 amplification. All of the 5 cases showed monoclonal rearrangement of the Ig gene using PCR based analysis. The patients had detailed follow-ups of 9-120 months, were treated surgically without radiotherapy or chemotherapy, and had long-term disease-free survivals. Conclusions: LBCL-FA is a group of rare diseases occurring in various sites, with predilection in the context of atrial myxoma and cyst-related lesions. Cyst-related lesions with obvious chronic inflammatory background show more scarcity of lymphoid cells and obvious degeneration, which are easy to be missed or misdiagnosed. LBCL-FA overall has a good prognosis with the potential for cure by surgery alone and postoperative chemotherapy may not be necessary.

[CK7+/CD117- low grade oncocytic tumor of the kidney: a clinicopathological analysis].

Objective: To investigate the clinicopathological, immunohistochemical and molecular characteristics of low grade oncocytic tumors (LOT) of the kidney with CK7+/CD117- staining pattern for enhancing the understanding of renal LOT. Methods: The clinical data, histological morphology and immunophenotypes of seven renal LOT cases diagnosed at the Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine from January 2017 to April 2021 were analyzed. The patients were followed up. Among the seven patients, five underwent high-throughput DNA targeted sequencing, and their molecular characteristics were analyzed. Results: The patients' age ranged 59-82 years, with an average of 70 years. There were 2 males and 5 females. The boundary of the tumor was clear. The tumor cells had homogeneous eosinophilic cytoplasm and round or oval nuclei, with a perinuclear halo. Small basophilic nucleoli were conspicuous (WHO/International Society of Urological Pathology grade 2). In the hypercellular areas, the tumor cells were mainly arranged in dense solid or nest. In the stroma, there were dilated veins, thick-walled arterioles and thick collagen fiber bundles that divided the cells into pseudonodules. In the sparsely cellular area, the tumor cells were arranged in the so-called "tissue culture" fashion. In addition, the stroma contained fresh hemorrhagic foci and lymphoid aggregates. High-throughput sequencing of 5 cases revealed that one case harbored mTOR gene missense mutation and another case harbored TSC1 frameshift mutation. Conclusions: LOT of the kidney is an indolent tumor with an overall good prognosis. Pathologists should not misdiagnose it as renal oncocytoma and chromophobe renal cell carcinoma.

[Effectiveness, safety and cost of urinary follicle stimulating hormone in controlled ovarian stimulation in China: multi-center retrospective cohort study of 102 061 in vitro fertilization cycles].

Objective: To explore the effectiveness, safety and cost between urinary follicle stimulating hormone (uFSH) and recombinant follicle stimulating hormone (rFSH) in controlled ovarian stimulation (COS) in China. Methods: Data were collected from 16 reproductive centers in China covering oocytes collection time from May 1, 2015 to June 30, 2018. Eligible patients were over 18 years old, adopting COS with uFSH (uFSH group) or rFSH (rFSH group) as start gonadotropins (Gn), and using in vitro fertilization (IVF) and (or) intracytoplasmic sperm injection for fertilisation, excluding frozen embryo recovery cycle. Generalised estimating equation was used to address the violation of independency assumption between cycles due to multiple IVF cycles for one person and clustering nature of cycles carried out within one center. Controlling variables included age, body mass index, anti-Müllerian hormone level, cause of infertility, ovulation protocol, type of fertilisation, number of embryos transferred, number of days of Gn use. Results: Totally 102 061 cycles met eligibility criteria and were included in the analyses. In terms of effectiveness, after controlling relevant unbalanced baseline characteristics, compared with rFSH group, the high oocyte retrieval (>15 oocytes was considered high retrieval) rate of uFSH group significantly decreased in gonadotropin-releasing hormone agonist protocol (OR=0.642, P<0.01) and in gonadotropin-releasing hormone antagonist protocol (OR=0.556, P=0.001), but the clinical pregnancy rate per transfer cycle and the live birth rate per transfer cycle significantly increased (OR=1.179, OR=1.169, both P<0.01) in both agonist and antagonist protocols. For safety, multiple analysis result demonstrated that in the agonist protocol, compared with rFSH group, the incidence of moderate to severe ovarian hyperstimulation syndrome of uFSH group significantly decreased (OR=0.644, P=0.002). The differences in ectopic pregnancy rate and multiple pregnancy rate between the uFSH and rFSH groups were not significant (P=0.890, P=0.470) in all patients. In terms of cost, compared with rFSH group, the uFSH group had lower total Gn costs for each patient (P<0.01). Conclusion: For patients who underwent COS, uFSH has better safety, and economic profiles over rFSH in China.

Pharmacological inhibition of eIF2alpha phosphorylation by integrated stress response inhibitor (ISRIB) ameliorates vascular calcification in rats.

Vascular calcification (VC) is an independent risk factor for cardiovascular events and all-cause mortality with the absence of current treatment. This study aimed to investigate whether eIF2alpha phosphorylation inhibition could ameliorate VC. VC in rats was induced by administration of vitamin D3 (3×10(5) IU/kg, intramuscularly) plus nicotine (25 mg/kg, intragastrically). ISRIB (0.25 mg/kg·week), an inhibitor of eIF2alpha phosphorylation, ameliorated the elevation of calcium deposition and ALP activity in calcified rat aortas, accompanied by amelioration of increased SBP, PP, and PWV. The decreased protein levels of calponin and SM22alpha, and the increased levels of RUNX2 and BMP2 in calcified aorta were all rescued by ISRIB, while the increased levels of the GRP78, GRP94, and C/EBP homologous proteins in rats with VC were also attenuated. Moreover, ISRIB could prevent the elevation of eIF2alpha phosphorylation and ATF4, and partially inhibit PERK phosphorylation in the calcified aorta. These results suggested that an eIF2alpha phosphorylation inhibitor could ameliorate VC pathogenesis by blocking eIF2alpha/ATF4 signaling, which may provide a new target for VC prevention and treatment.

THE INCREASED PLASMA LEVELS OF INTERMEDIN IN PATIENTS WITH TYPE 2 DIABETES MELLITUS.

Context: Intermedin (IMD) is the member of calcitonin gene-related peptide family, and tightly associated with type 2 diabetes mellitus (T2DM). The change of plasma IMD levels in T2DM is still unknown. Objective: We aimed to investigate the plasma levels of IMD in patients with T2DM. Design: Fortyone patients with T2DM who were hospitalized in the endocrinology department of Civil Aviation General Hospital from January 2012 to June 2015 were enrolled, and 44 volunteers were selected as the control group. Subjects and Methods: Plasma level of IMD was detected by ELISA. Diagnostic value of IMD was analyzed by area under the receiver operating characteristic (ROC) curve (AUC). Results: The plasma level of IMD in T2DM group was higher than that in the healthy control group, whereas smoking or cardiovascular complications did no influence the IMD levels. IMD levels were correlated with BMI, DBP, triglyceride, uric acid, urea nitrogen, fasting and 2 hours postprandial blood glucose, and HbA1C. The greatest value of AUC for IMD was only 58.73%. Conclusions: Although plasma levels of IMD were increased in patients with T2DM, the very low diagnostic value of IMD for T2DM might not be used for the disease diagnosis.

[Clinical follow-up study of myelin oligodendrocyte glycoprotein antibody-associated disease in children].

Objective: To summarize the clinical characteristics of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and compare the differences in efficacy of different disease-modifying drugs. Methods: An ambispective cohort study was conducted in 42 children diagnosed with MOGAD at Department of Pediatrics, Peking University First Hospital from January 2012 to March 2021 and conducted long-term follow-up to analyze clinical phenotypes and compare the efficacy of different disease-modifying drugs such as rituximab, mycophenolate mofetil and azathioprine. Kruskal-Wallis H test was used to compare the annual relapse rate of disease-modifying drugs at different times, expanded disability status scale (EDSS) score at the last follow-up, and Wilcoxon rank test was used to compare the annual relapse rate before and after modified disease therapy. The Log-rank (Mantel-Cox) survival curve was used to compare the relapse rate of different disease-modifying drugs. Results: Of the 42 cases, 22 were male and 20 were female, with the age at disease onset of 5.96 (2.33-12.90) years. The disease duration was 4.46 (1.25-13.00) years at the last follow-up with 161 clinical acute attacks. Acute disseminated encephalomyelitis (ADEM) was the most common phenotype of first attack and all attacks during disease course ((60% (25/42) for first attack, 38% (61/161) for all attacks). The most common clinical syndrome was neuromyelitis optica spectrum disorders (NMOSD) (50%, 21/42). Of the 42 children, 5 (12%) showed encephalitis and 6 (14%) combined with anti-N-methyl-D-aspartate receptor (NMDAR) antibody overlap syndrome. The most commonly involved areas of brain magnetic resonance imaging (MRI) were subcortical white matter (71%, 88/124), cortex (26%, 32/124) and periventricular white matter (25%, 32/124). Spinal cord MRI was most frequently involved in cervical (70%, 16/23) and thoracic (61%, 14/23) medulla, and 43% (10/23) longitudinally extensive transeverse myelitis. Disease-modifying drugs were used in 34 patients. The annual relapse rate after treatment with rituximab, mycophenolate mofetil and azathioprine decreased (all P<0.05) and there was no statistically significant difference in the annual relapse proportion among the groups (P=0.307). Conclusions: The most common clinical attack of first and all of MOGAD in children is ADEM, and the most common clinical syndrome is NMOSD. Rituximab, mycophenolate mofetil and azathioprine can reduce the annual relapse rate, but it is not clear effect of which treatment is better.

[Translocations of MYC, bcl-2 and bcl-6 genes and Epstein-Barr virus infection in primary cardiac large B-cell lymphoma].

Objective: To investigate the translocations of MYC, bcl-2 and bcl-6 genes, the Epstein-Barr virus (EBV) status and the clinicopathological features of primary cardiac large B cell lymphoma (LBCL). Methods: Seven cases of primary cardiac LBCL were collected at Beijing Friendship Hospital, Capital Medical University, China from February 2013 to May 2019. The clinical feature, pathological morphology and immunophenotype were analyzed. The detections of EBV and gene rearrangements of MYC, bcl-2 and bcl-6 were conducted. The 2017 WHO classification of tumors of haematopoietic and lymphoid tissues was used to classify the tumors. Results: Four patients with right atrial lesions showed diffuse infiltration of medium size lymphoid cells with small vascular hyperplasia, without evidence of EBV infection. Without detectable gene rearrangements of MYC and bcl-2, 2 of the patients showed bcl-6 gene break-apart. The diagnosis was revised from diffuse LBCL to high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). There was a case of CD5+ diffuse LBCL involving the right atrium and ventricle and 2 cases of fibrin-associated diffuse LBCL located at left atrium without gene rearrangements of MYC, bcl-2 and bcl-6. However, EBER and EBNA2 were highly expressed in fibrin-associated diffuse LBCL. The patients were followed up for 10-71 months. Four cases of HGBL-NOS and a case of CD5+ diffuse LBCL received R-CHOP with/without autologous stem cell transplantation. All but two patients survived. Two cases of fibrin-associated diffuse LBCL were disease free without adjuvant chemotherapy and radiotherapy. Conclusions: Primary cardiac LBCL is heterogeneous, including at least HGBL-NOS. Primary cardiac HGBL-NOS most frequently occurs in the right atrium. Tumor cells of primary cardiac LBCL have the morphological characteristics similar to Burkitt lymphoma, lacking MYC and bcl-2 gene rearrangements, but usually show bcl-6 gene disruption. Fibrin-associated diffuse LBCL has a good prognosis and postoperative chemotherapy seems unnecessary.