Exploring correlations between immune cell phenotypes and the risk of epilepsy: A bidirectional Mendelian randomization study.

BACKGROUND: Neuroinflammation plays an important pathophysiological role in epilepsy; however, the precise connection between immune cells and epilepsy remains unclear. This study used Mendelian randomization (MR) to analyze the causal relationship between 731 immune cell traits and epilepsy. METHODS: Based on data from a genome-wide association study (GWAS), a bidirectional two-sample MR analysis was conducted to investigate the potential influence of immune cell phenotypes on epilepsy. Five MR methods were used to analyze the results, with the inverse variance weighted (IVW) method as the primary method, and the results were corrected using the false discovery rate (FDR) method. Sensitivity analyses were performed to test for heterogeneity and horizontal pleiotropy. RESULTS: After correction for FDR, four immune traits remained significantly associated with epilepsy risk: CD25 expression on memory (OR = 1.04, 95 % CI = 1.02 âˆ¼ 1.06,P = 2.55 × 10-4), IgD+CD38dim (OR = 1.05, 95 % CI = 1.02 âˆ¼ 1.08, P = 4.73 × 10-4), CD24+CD27+ (OR = 1.04, 95 % CI = 1.02 âˆ¼ 1.06, P = 4.82 × 10-4), and IgD-CD38dim (OR = 1.04, 95 % CI = 1.02 âˆ¼ 1.06, P = 1.04 × 10-3) B cells. The risk of generalized epilepsy was significantly associated with two immune cell traits, whereas that of focal epilepsy was significantly associated with seven immune cell traits. Furthermore, immune cell phenotypes are not affected by genetically predicted epilepsy. CONCLUSION: This MR study affirms the causal connection between circulating immune cells and epilepsy, offering guidance for further understanding of the immune mechanisms that underlie epilepsy and the discovery of novel targets for therapy.

Family cohesion and quality of life significantly affecting personality changes in adult epilepsy patients: a case-control study.

OBJECTIVE: The goal of epilepsy treatment is not only to control convulsive seizures but also to improve the quality of life of patients. This study aimed to investigate personality changes and the risk factors for their development in adult epilepsy patients. METHODS: A case-control study in a Class III, Class A hospital. The study comprised 206 adult epilepsy patients admitted to the Neurology Department at the First Hospital of Jilin University between October 2019 and December 2021, while the control group consisted of 154 community volunteers matched with the epilepsy group based on age, sex, and education. No additional treatment interventions were determined to be relevant in the context of this study. RESULTS: There is a significantly higher incidence of personality changes in epilepsy than in the general population, and patients with epilepsy were more likely to become psychoticism, neuroticism, and lie. Epilepsy patient's employment rate and average quality of life score were significantly lower than that of the general population and had strong family intimacy but poor adaptability in this study. There are many factors affecting personality change: sleep disorders, economic status, quality of life, use of anti-seizure drugs, family cohesion and adaptability. The independent risk factors were quality of life and family cohesion.

Reconstruction of the proximal radius with 3D-printed personalized prosthesis after tumor resection: case series.

BACKGROUND: Giant cell tumor of bone (GCTB) (Campanacci III) or malignant tumors extend to the epiphyseal region of the proximal radius, and intra-articular resection of the proximal radius is often needed. In the present study, we present the patients who underwent reconstruction of the proximal radius with 3D-printed personalized prosthesis after tumor resection, aiming to describe the prosthesis design and surgical technique and evaluate the clinical outcomes of this method. METHODS: Between November 2018 and January 2021, 9 patients received radial hemiarthroplasty with 3D-printed personalized prostheses after tumor resection. The pathologic diagnosis was GCTB (Campanacci III) in 7 patients, osteosarcoma (IIB) in 1 patient, and synovial sarcoma (IIB) in 1 patient. The range of motion (ROM) and strength in terms of elbow flexion/extension and forearm supination/pronation were evaluated. Pain was assessed by the visual analog scale (VAS) preoperatively and at each follow-up visit. To evaluate the functional outcome, the Mayo Elbow Performance Score (MEPS) system and the Musculoskeletal Tumor Society (MSTS) scoring system were administered at each follow-up visit. Complications and oncological outcomes were recorded. RESULTS: The patients were followed from 24 to 51 months, with a median follow-up of 35 months. No patients were lost to follow-up. During the follow-up, local recurrence and metastasis were not observed. The VAS score improved from a median of 5 points (range 4-7) preoperatively to 1 point (range 0-2) at the last follow-up visit. The mean MEPS score was 88.5% (83-93), and the mean MSTS score was 25.3 (24-27) at the last follow-up visit. No complications such as infection and aseptic loosening were detected. CONCLUSIONS: The implantation of a 3D-printed personalized prosthesis after proximal radial resection showed excellent oncologic outcomes and postoperative function at short-term follow-up and is a viable alternative method for reconstruction of the proximal radius bone defect after tumor resection.

Autosomal dominant neurodevelopmental disorders associated with KIF1A gene variants in 6 pediatric patients. / å ­ä¾‹KIF1AåŸºå› å˜å¼‚ç›¸å ³å¸¸æŸ“è‰²ä½“æ˜¾æ€§é—ä¼ ç¥žç»å‘è‚²éšœç¢æ‚£å„¿ä¸´åºŠå’Œé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To analyze the clinical and genetic characteristics of children with autosomal dominant neurodevelopmental disorders caused by kinesin family member 1A (KIF1A) gene variation. METHODS: Clinical and genetic testing data of 6 children with KIF1A gene de novo heterozygous variation diagnosed in Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from the year 2018 to 2020 were retrospectively analyzed. Pathogenic variants were identified based on whole exome sequencing, and verified by Sanger sequencing. Moreover, the effect of variants on three-dimensional structure and stability of protein was analyzed by bioinformatics. RESULTS: Among 6 patients there were 4 males and 2 females, and the age of consultation varied from 7 months to 18 years. All cases had varying degrees of motor developmental delay since childhood, and 4 of them had gait abnormalities or fell easily. In addition, 2 children were accompanied by delayed mental development, epilepsy and abnormal eye development. Genetic tests showed that all 6 cases had heterozygous de novo variations of KIF1A gene, including 4 missense mutations c.296C>T (p.T99M), c.761G>A (p.R254Q), c.326G>T (p.G109V), c.745C>G (p.L249V) and one splicing mutation c.798+1G>A, among which the last three variants have not been previously reported. Bioinformatics analysis showed that G109V and L249V may impair their interaction with the neighboring amino acid residues, thereby impacting protein function and reducing protein stability, and were assessed as "likely pathogenic". Meanwhile, c.798+1G>A may damage an alpha helix in the motor domain of the KIF1A protein, and was assessed as "likely pathogenic". CONCLUSIONS: KIF1A-associated neurological diseases are clinically heterogeneous, with motor developmental delay and abnormal gait often being the most common clinical features. The clinical symptoms in T99M carriers are more severe, while those in R254Q carriers are relatively mild.

Hip reconstruction using a customized intercalary prosthesis with the rhino horn-designed uncemented stem for ultrashort proximal femur segments following tumor resection: a combined biomechanical and clinical study.

BACKGROUND: Hip-preserved reconstruction for patients with ultrashort proximal femur segments following extensive femoral diaphyseal tumor resection is a formidable undertaking. A customized intercalary prosthesis with a rhino horn-designed uncemented stem was developed for the reconstruction of these extensive skeletal defects. METHODS: This study was designed to analyze and compare the differences in the biomechanical behavior between the normal femur and the femur with diaphyseal defects reconstructed by an intercalary prosthesis with different stems. The biomechanical behavior under physiological loading conditions is analyzed using the healthy femur as the reference. Five three-dimensional finite element models (healthy, customized intercalary prosthesis with four different stems implemented, respectively) were developed, together with a clinical follow-up of 12 patients who underwent intercalary femoral replacement. RESULTS: The biomechanical results showed that normal-like stress and displacement distribution patterns were observed in the remaining proximal femur segments after reconstructions with the rhino horn-designed uncemented stems, compared with the straight stem. Stem A showed better biomechanical performance, whereas the fixation system with Stem B was relatively unstable. The clinical results were consistent with the FEA results. After a mean follow-up period of 32.33 ± 9.12 months, osteointegration and satisfactory clinical outcomes were observed in all patients. Aseptic loosening (asymptomatic) occurred in one patient reconstructed by Stem B; there were no other postoperative complications in the remaining 11 patients. CONCLUSION: The rhino horn-designed uncemented stem is outstanding in precise shape matching and osseointegration. This novel prosthesis design may be beneficial in decreasing the risk of mechanical failure and aseptic loosening, especially when Stem A is used. Therefore, the customized intercalary prosthesis with this rhino horn-designed uncemented stem might be a reasonable alternative for the reconstruction of SSPF following extensive tumor resection.

Is three-dimensional-printed custom-made ultra-short stem with a porous structure an acceptable reconstructive alternative in peri-knee metaphysis for the tumorous bone defect?

BACKGROUND: Long-lasting reconstruction after extensive resection involving peri-knee metaphysis is a challenging problem in orthopedic oncology. Various reconstruction methods have been proposed, but they are characterized by a high complication rate. The purposes of this study were to (1) assess osseointegration at the bone implant interface and correlated incidence of aseptic loosening; (2) identify complications including infection, endoprosthesis fracture, periprosthetic fracture, leg length discrepancy, and wound healing problem in this case series; and (3) evaluate the short-term function of the patient who received this personalized reconstruction system. METHODS: Between September 2016 and June 2018, our center treated 15 patients with malignancies arising in the femur or tibia shaft using endoprosthesis with a 3D-printed custom-made stem. Osseointegration and aseptic loosening were assessed with digital tomosynthesis. Complications were recorded by reviewing the patients' records. The function was evaluated with the 1993 version of the Musculoskeletal Tumor Society (MSTS-93) score at a median of 42 (range, 34 to 54) months after reconstruction. RESULTS: One patient who experienced early aseptic loosening was managed with immobilization and bisphosphonates infusion. All implants were well osseointegrated at the final follow-up examination. There are two periprosthetic fractures intraoperatively. The wire was applied to assist fixation, and the fracture healed at the latest follow-up. Two patients experienced significant leg length discrepancies. The median MSTS-93 score was 26 (range, 23 to 30). CONCLUSIONS: A 3D-printed custom-made ultra-short stem with a porous structure provides acceptable early outcomes in patients who received peri-knee metaphyseal reconstruction. With detailed preoperative design and precise intraoperative techniques, the reasonable initial stability benefits osseointegration to osteoconductive porous titanium, and therefore ensures short- and possibly long-term durability. Personalized adaptive endoprosthesis, careful intraoperative operation, and strict follow-up management enable effective prevention and treatment of complications. The functional results in our series were acceptable thanks to reliable fixation in the bone-endoprosthesis interface and an individualized rehabilitation program. These positive results indicate this device series can be a feasible alternative for critical bone defect reconstruction. Nevertheless, longer follow-up is required to determine whether this technique is superior to other forms of fixation.

Three-dimensional-printed custom-made hemipelvic endoprosthesis for the revision of the aseptic loosening and fracture of modular hemipelvic endoprosthesis: a pilot study.

BACKGROUND: The aims of this pilot study were (1) to assess the efficacy of 3D-printed custom-made hemipelvic endoprosthesis in restoring the natural location of acetabulum for normal bodyweight transmission; (2) to evaluate the short-term function of the revision with this endoprosthesis and (3) to identify short-term complications associated with the use of this endoprosthesis. METHODS: Between February 2017 and December 2017, seven patients received revision with 3D-printed custom-made hemipelvic endoprosthesis. The body weight moment arm (BWMA) and cup height discrepancy (CHD) after primary and revisional surgery were analyzed to assess acetabulum location with plain radiography. After a median follow-up duration of 29 months (range 24-34), the function was evaluated with the Musculoskeletal Tumor Society (MSTS-93) score and Harris hip score (HHS). Complications were recorded by chart review. RESULTS: The acetabulum locations were deemed reasonable, as evaluated by median BWMA (primary vs. revision, 10 cm vs. 10 cm) and median CHD (primary vs. revision, 10 mm vs. 8 mm). The median MSTS-93 score and HHS score were 21 (range 18-23) and 78 (range 75-82) after the revision. No short or mid-term complication was observed in the follow-up of this series. CONCLUSIONS: Revision with 3D-printed custom-made hemipelvic endoprostheses benefited in reconstructing stable pelvic ring and natural bodyweight transmission for patients encountering the aseptic loosening and fracture of modular hemipelvic endoprosthesis. The revision surgery and appropriate rehabilitation program improved patients' function to a median MSTS score of 22 and pain-free ambulation. The incidence of the complications was low via this individualized workflow.

Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities.

BACKGROUND: Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology. METHODS: Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant. FINDINGS: Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Moreover, loss of CEP295 causes extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts. INTERPRETATION: This study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects. FUNDING: A full list of funding bodies that contributed to this study can be found under "Acknowledgments."

A Nutritional Metabolism Related Prognostic Scoring System for Patients With Newly Diagnosed Osteosarcoma.

Osteosarcoma is a primary malignant bone tumor with high metastatic potential. To date, achieving long-term survival of osteosarcoma patients remains a difficult task. Metabolic reprogramming has emerged as a new hallmark of cancer. However, studies on the prognostic value of hematological markers related to nutritional and metabolism in cancer patients are limited and contradictory. In this retrospective study, we extensively collected 16 hematological markers related to nutritional and metabolism in 223 osteosarcoma patients. A nutritional metabolism related prognostic scoring system (NMRS) in patients with osteosarcoma was constructed by least absolute contraction and selection operator (LASSO) cox regression analysis. Compared with individual hematological indicators, NMRS has stronger predictive power (training set: 0.811 vs. 0.362-2.638; validation set: 0.767 vs. 0.333-0.595). It is an independent prognostic factor for the survival of patients with osteosarcoma [HR: 1.957 (1.375-2.786) training set; HR: 3.146 (1.574-6.266) validation set]. NMRS-based nomograms have good and stable predictive power. NMRS facilitates further risk stratification of patients with the same clinical characteristics.

Hematological Prognostic Scoring System Can Predict Overall Survival and Can Indicate Response to Immunotherapy in Patients With Osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor with a high metastatic potential. Nowadays, there is a lack of new markers to identify prognosis of osteosarcoma patients with response to medical treatment. Recent studies have shown that hematological markers can reflect to some extent the microenvironment of an individual with the potential to predict patient prognosis. However, most of the previous studies have studied the prognostic value of a single hematological index, and it is difficult to comprehensively reflect the tumor microenvironment of patients. Here, we comprehensively collected 16 hematological markers and constructed a hematological prognostic scoring system (HPSS) using LASSO cox regression analysis. HPSS contains many indicators such as immunity, inflammation, coagulation and nutrition. Our results suggest that HPSS is an independent prognostic factor for overall survival in osteosarcoma patients and is an optimal addition to clinical characteristics and well suited to further identify high-risk patients from clinically low-risk patients. HPSS-based nomograms have good predictive ability. Finally, HPSS also has some hints for immunotherapy response in osteosarcoma patients.

A novel mutation in the MYO7A gene is associated with Usher syndrome type 1 in a Chinese family.

OBJECTIVES: We aimed to investigate the genetic causes of hearing loss in a Chinese proband with autosomal recessive congenital deafness. METHODS: The targeted capture of 159 known deafness genes and next-generation sequencing were performed to study the genetic causes of hearing loss in the Chinese family. Sanger sequencing was employed to verify the variant mutations in members of this family. RESULTS: The proband harbored two mutations in the MYO7A gene in the form of compound heterozygosity. She was found to be heterozygous for a novel insertion mutation c.3847_3848 ins TCTG (p.N1285LfsX24) in exon 30 and for the known mutation c.2239_2240delAG (p.R747S fsX16)in exon 19. The novel mutation was absent in the 1000 Genomes Project. These variants were carried in the heterozygous state by the parents and were therefore co-segregated with the genetic disease. Clinical re-assessment, including detailed audiologic and ocular examinations, revealed congenital deafness and retinitis pigmentosa in the proband. Collectively, the combination of audiometric, ophthalmologic and genetic examinations successfully confirmed the phenotype of Usher syndrome type 1 (USH1). CONCLUSION: This study demonstrates that the novel mutation c.3847_3848insTCTG (p. N1285LfsX24) in compound heterozygosity with c.2239_2240delAG in the MYO7A gene is the main cause of USH1 in the proband. Our study expands the mutational spectrum of MYO7A and provides a foundation for further investigations elucidating the MYO7A-related mechanisms of USH1.