Shorter telomere length increases the risk of lymphocyte immunodeficiency: A Mendelian randomization study.

BACKGROUND: For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear. METHODS: The two-sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome-Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results. RESULTS: The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014-1.472, p = .035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281-1.935, p < .001). Analysis of B cell subsets revealed that shorter TL may be associated with a higher percentage of Naive-mature B cells, and a lower percentage of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings. CONCLUSION: In summary, our findings suggest that shorter TL may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. The relevant mechanisms and potential therapeutic avenues still need further investigation.

Systemic immune-inflammation index is associated with cardiac complications following acute ischemic stroke: A retrospective single-center study.

BACKGROUND: Stroke-induced heart syndrome is a feared complication of ischemic stroke, that is commonly encountered and has a strong association with unfavorable prognosis. More research is needed to explore underlying mechanisms and inform clinical decision making. This study aims to explore the relationship between the early systemic immune-inflammation (SII) index and the cardiac complications after acute ischemic stroke. METHODS: Consecutive patients with acute ischemic stroke were prospectively collected from January 2020 to August 2022 and retrospectively analyzed. We included subjects who presented within 24 hours after symptom onset and were free of detectable infections or cancer on admission. SII index [(neutrophils × platelets/ lymphocytes)/1000] was calculated from laboratory data at admission. RESULTS: A total of 121 patients were included in our study, of which 24 (19.8 %) developed cardiac complications within 14 days following acute ischemic stroke. The SII level was found higher in patients with stroke-heart syndrome (p<.001), which was an independent predictor of stroke-heart syndrome (adjusted odds ratio 5.089, p=.002). CONCLUSION: New-onset cardiovascular complications diagnosed following a stroke are very common and are associated with early SII index.

Age-Related Effects on MSC Immunomodulation, Macrophage Polarization, Apoptosis, and Bone Regeneration Correlate with IL-38 Expression.

Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs' endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site.

Single-cell RNA sequencing reveals cell type-specific immune regulation associated with human neuromyelitis optica spectrum disorder.

Introduction: One rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear. Methods: Here, single-cell RNA sequencing (scRNA-seq) is used to characterize peripheral blood mononuclear cells from individuals with NMOSD. Results: The differentiation and activation of lymphocytes, expansion of myeloid cells, and an excessive inflammatory response in innate immunity are observed. Flow cytometry analyses confirm a significant increase in the percentage of plasma cells among B cells in NMOSD. NMOSD patients exhibit an elevated percentage of CD8+ T cells within the T cell population. Oligoclonal expansions of B cell receptors are observed after therapy. Additionally, individuals with NMOSD exhibit elevated expression of CXCL8, IL7, IL18, TNFSF13, IFNG, and NLRP3. Discussion: Peripheral immune response high-dimensional single-cell profiling identifies immune cell subsets specific to a certain disease and identifies possible new targets for NMOSD.

Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aß protein deposition. The cerebrospinal fluid amyloid protein test showed Aß42/Aß40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

C-kit controls blood-brain barrier permeability by regulating caveolae-mediated transcytosis after chronic cerebral hypoperfusion.

Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA sequencing. After identified the key EC dysfunction factor, C-kit, we used the C-kit inhibition drug (imatinib) and C-kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of C-kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated C-kit with stem cell factor (SCF) to observe the effects of C-kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase C-kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of C-kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit C-kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that C-kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH.

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease, and approximately 10% of AD cases are early-onset familial AD (EOFAD), which is mainly linked to point mutations in genes encoding presenilins (PS1 and PS2). Mutations in PS2 are extremely rare and have not received enough attention. Recently, studies have found that Rho GTPase activity is closely related to the pathogenesis of AD. In this study, we used transcriptome sequencing in PS2 siRNA-transfected SH-SY5Y cells and found a group of differentially expressed genes (DEGs) related to the regulation of GTPase activity. Among those DEGs, the most significantly downregulated was Rho guanine nucleotide exchange factor 5 (ARHGEF5). GTPase activity in PS2 siRNA-transfected cells was significantly decreased. Then, we found that the expression of ARHGEF5 and the GTPase activity of Mitochondrial Rho GTPase 2 (Miro2) in PS2 D439A mutant SH-SY5Y cells were significantly decreased. We found for the first time that PS2 can bind to Miro2, and the PS2 D439A mutation reduced the binding between PS2 and Miro2, reduced the expression of Miro2, and resulted in an imbalance in mitochondrial fusion/fission dynamics. In conclusion, PS2 gene knockdown may participate in the pathogenesis of AD through the regulation of GTPase activity. The imbalance in mitochondrial dynamics mediated by the PS2 D439A mutation through regulation of the expression and GTPase activity of Miro2 may be a potential pathogenic mechanism of AD.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.

Bibliometric analysis and visualized study of research on autophagy in ischemic stroke.

Aims: To summarize and clarify the current research status and indicate possible future directions in the field of autophagy in ischemic stroke, we performed a comprehensive and multidimensional bibliometric analysis of the literature in this field published from 2011 to 2022. Methods: We retrieved articles on the field of autophagy in ischemic stroke published between 2011 and 2022 from Web of Science Core Collection (WOSCC). VOSviewer (version 1.6.19) and CiteSpace (version 6.2.R2 Basic) were used to identify the leading topics as well as generate visual maps of Countries/regions, organizations, authors, journals, and keyword networks in the related field. Results: A total of 568 publications were contained in this research. The journal with the most publications were Front Pharmacol, Mol Neurobiol, and Neuroscience. China was the most productive country with respect to co-authorship, with the Capital Med Univ being the organization with the most. co-authorships. In terms of authorship analysis, eight of the top 10 most contributive authors were from China. The co-occurring author keywords can be divided into three main clusters, including "protective effect of autophagy in ischemic stroke," "autophagy-targeted therapy for ischemic stroke," and "mitochondrial function in cerebral ischemia-reperfusion injury". Conclusion: This bibliometric analysis helps us reveal the current research hotspots in the research field of autophagy in ischemic stroke and guide future research directions. Subsequent trends in this special field are likely to identify and develop novel autophagy-targeted therapy strategies to effectively prevent and treat ischemic stroke.

[Melatonin promotes osteogenesis of bone marrow mesenchymal stem cells by improving the inflammatory state in ovariectomized rats].

Objective: To investigate the effects of melatonin (MT) on bone mass and serum inflammatory factors in rats received ovariectomy (OVX) and to investigate the effects of MT on the levels of inflammatory factors in culture medium and osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) stimulated by lipopolysaccharide. Methods: Fifteen 12-week-old Sprague Dawley (SD) rats were randomly divided into 3 groups. The rats in Sham group only received bilateral lateral abdominal incision and suture, the rats in OVX group received bilateral OVX, and the rats in OVX+MT group received 100 mg/(kg·d) MT oral intervention after bilateral OVX. After 8 weeks, the levels of serum inflammatory factors [interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α)] were detected using ELISA assay. Besides, the distal femurs were detected by Micro-CT to observe changes in bone mass and microstructure, and quantitatively measured bone volume fraction, trabecular thickness, and trabecular number. The BMSCs were extracted from the femurs of three 3-week-old SD rats using whole bone marrow culture method and passaged. The 3rd-5th passage BMSCs were cultured with different concentrations of MT (0, 1, 10, 100, 1 000 µmol/L), and the cell viability was then detected using cell counting kit 8 (CCK-8) to select the optimal concentration of MT for subsequent experiments. Cells were devided into osteogenic induction group (group A) and osteogenic induction+1/5/10 µg/mL lipopolysaccharide group (group B-D). The levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) in cell culture medium were detected using ELISA assay after corresponding intervention. According to the results of CCK-8 method and ELISA detection, the cells were intervened with the most significant concentration of lipopolysaccharide for stimulating inflammation and the optimal concentration of MT with osteogenic induction, defining as group E, and the cell culture medium was collected to detect the levels of inflammatory factors by ELISA assay. After that, alkaline phosphatase (ALP) staining and alizarin red staining were performed respectively in groups A, D, and E, and the expression levels of osteogenic related genes [collagen type Ⅰ alpha 1 chain (Col1a1) and RUNX family transcription factor 2 (Runx2)] were also detected by real time fluorescence quantitative PCR (RT-qPCR). Results: ELISA and Micro-CT assays showed that compared with Sham group, the bone mass of the rats in the OVX group significantly decreased, and the expression levels of serum inflammatory factors (IL-1ß, IL-6, and TNF-α) in OVX group significantly increased (P<0.05). Significantly, the above indicators in OVX+MT group were all improved (P<0.05). Rat BMSCs were successfully extracted, and CCK-8 assay showed that 100 µmol/L was the maximum concentration of MT that did not cause a decrease in cell viability, and it was used in subsequent experiments. ELISA assays showed that compared with group A, the expression levels of inflammatory factors (IL-1ß, IL-6, and TNF-α) in the cell culture medium of groups B-D were significantly increased after lipopolysaccharide stimulation (P<0.05), and in a concentration-dependent manner. Moreover, the expression levels of inflammatory factors in group D were significantly higher than those in groups B and C (P<0.05). After MT intervention, the expression levels of inflammatory factors in group E were significantly lower than those in group D (P<0.05). ALP staining, alizarin red staining, and RT-qPCR assays showed that compared with group A, the percentage of positive area of ALP and alizarin red and the relative mRNA expressions of Col1a1 and Runx2 in group D significantly decreased, while the above indicators in group E significantly improved after MT intervention (P<0.05). Conclusion: MT may affect the bone mass of postmenopausal osteoporosis by reducing inflammation in rats; MT can reduce the inflammation of BMSCs stimulated by lipopolysaccharide and weaken its inhibition of osteogenic differentiation of BMSCs.

A novel animal model of osteonecrosis of the femoral head based on 3D printing technology.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a prevalent orthopedic condition characterized by the disruption of blood supply to the femoral head, leading to ischemia of internal tissues, subchondral bone fractures, necrosis, and eventual collapse of the weight-bearing portion of the femoral head. This condition results in severe functional impairment, pain, and even disability of the hip joint. Existing animal models of ONFH have limitations in replicating the natural disease progression accurately. Thus, there is a critical need to develop a novel animal model capable of better simulating localized pressure on the human femoral head to facilitate ONFH-related research. METHODS: In this study, we present a novel approach for modeling ONFH, which involves integrating stress factors into the modeling process through the utilization of 3D printing technology and principles of biomechanics. A total of 36 animals were randomly assigned to six groups, where they received either the novel modeling technique or the traditional hormone induction method. Subsequently, an 8-week treatment period was implemented, followed by conducting micro-CT scans and histological evaluations to assess tissue outcomes. RESULTS: The study evaluated the cytotoxicity of the material used in the new model, and it was observed that the material did not exhibit any cytotoxic effects on cells. Additionally, the novel model successfully replicated the pathological features of ONFH, including femoral head collapse, along with a substantial presence of empty bone lacunae, cartilage defects, and subchondral bone fractures in the subchondral bone region. CONCLUSION: In conclusion, our study provides evidence that the new model shows the ability to simulate the progression of the disease, making it a valuable tool for research in this field and can contribute to the development of better treatment strategies for this debilitating condition. It holds great promise for advancing our understanding of the pathogenesis of ONFH and the potential therapeutic interventions for this challenging clinical problem.

Role of BraRGL1 in regulation of Brassica rapa bolting and flowering.

Gibberellin (GA) plays a major role in controlling Brassica rapa stalk development. As an essential negative regulator of GA signal transduction, DELLA proteins may exert significant effects on stalk development. However, the regulatory mechanisms underlying this regulation remain unclear. In this study, we report highly efficient and inheritable mutagenesis using the CRISPR/Cas9 gene editing system in BraPDS (phytoene desaturase) and BraRGL1 (key DELLA protein) genes. We observed a loss-of-function mutation in BraRGL1 due to two amino acids in GRAS domain. The flower bud differentiation and bolting time of BraRGL1 mutants were significantly advanced. The expression of GA-regulatory protein (BraGASA6), flowering related genes (BraSOC1, BraLFY), expansion protein (BraEXPA11) and xyloglucan endotransferase (BraXTH3) genes was also significantly upregulated in these mutants. BraRGL1-overexpressing plants displayed the contrasting phenotypes. BraRGL1 mutants were more sensitive to GA signaling. BraRGL1 interacted with BraSOC1, and the interaction intensity decreased after GA3 treatment. In addition, BraRGL1 inhibited the transcription-activation ability of BraSOC1 for BraXTH3 and BraLFY genes, but the presence of GA3 enhanced the activation ability of BraSOC1, suggesting that the BraRGL1-BraSOC1 module regulates bolting and flowering of B. rapa through GA signal transduction. Thus, we hypothesized that BraRGL1 is degraded, and BraSOC1 is released in the presence of GA3, which promotes the expression of BraXTH3 and BraLFY, thereby inducing stalk development in B. rapa. Further, the BraRGL1-M mutant promoted the flower bud differentiation without affecting the stalk quality. Thus, BraRGL1 can serve as a valuable target for the molecular breeding of early maturing varieties.

Delayed 18F-FDG PET imaging provides better metabolic asymmetry in potential epileptogenic zone in temporal lobe epilepsy.

Objective: To investigate the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) two time point imaging for the identification of the potential epileptogenic zone (EZ) in temporal lobe epilepsy (TLE). Methods: Fifty-two patients with TLE were prospectively enrolled in the 18F-FDG PET/CT two time point imaging study. The early imaging was obtained approximately 40 min (43.44 ± 18.04 min) after 18F-FDG injection, and the delayed imaging was obtained about 2 to 3 h (160.46 ± 28.70 min) after the injection. Visual and semi-quantitative analysis of 18F-FDG uptake were performed at the two time points in EZ and contralateral symmetrical region. The mean standardized uptake value (SUVmean) of EZ and contralateral symmetrical region was calculated to determine the asymmetry index (AI) of the early and delayed images, as well as in the MRI positive and negative patient groups. Results: Semi-quantitative analysis demonstrated that AI of the early and delayed 18F-FDG PET/CT images was 13.47 ± 6.10 and 16.43 ± 6.66, respectively. The ΔAI was 2.95 ± 3.05 in 52 TLE patients between the two time points. The AI of the EZ was significantly elevated in delayed images compared to the early images (p < 0.001). The AI of delayed imaging was also significantly elevated compared to the early imaging in both MRI positive (ΔAI = 2.81 ± 2.54, p < 0.001) and MRI negative (ΔAI = 3.21 ± 3.91, p < 0.003) groups, and more pronounced in MRI negative group. Visual analysis also showed that the delayed imaging appeared to be superior to the early imaging for identification of potential EZ. Conclusion: Delayed 18F-FDG PET imaging provided significantly better than the early imaging in the identification of potential EZ, which can be valuable during epilepsy pre-surgical evaluation in patients with TLE.

Giant tumefactive perivascular spaces.

Perivascular spaces are parts of the glymphatic pathway in the brain, which are microscopic but visible on magnetic resonance imaging when enlarged. Here, we described a case of a 16-year-old boy who presented with chronic headaches. Magnetic resonance imaging revealed giant perivascular spaces in the right centrum semiovale. Furtherly, we summarized the literature on classical and rare presentations of massive perivascular spaces and raised awareness that more clinical significance of the giant tumefactive perivascular spaces remains to be elucidated.

Clinical comparative analysis of monophasic and multiphasic acute disseminated encephalomyelitis in adults.

Introduction: This study aims to explore the clinical features and prognostic factors for relapse of acute disseminated encephalomyelitis (ADEM) in adults. Material and methods: 56 patients with ADEM were retrospectively analyzed. The epidemiological characteristics, clinical manifestations, laboratory features, magnetic resonance imaging (MRI), treatment and prognosis data of these patients were analyzed using the χ2 test for categorical variables and Mann-Whitney U-test for continuous variables. Then, the clinical characteristics and recurrence factors were summarized. Results: 56 patients with ADEM, based on the criteria of the International Pediatric Multiple Sclerosis Study Group, were recruited to the study. Among these patients, 31 were male and 25 were female. Furthermore, 13 patients had multiphasic ADEM, and 29 patients (52%) had definite incentive factors before onset. The commonest presenting symptoms and signs were fever (36%), disturbance of consciousness (52%), mental disorder (38%), seizure (14%), headache and dizziness (43%), optic neuritis (34%), autonomic nervous system symptoms (43%), limb paralysis or abnormal sensation (73%), and unilateral or bilateral pyramidal tract signs (48%). Inflammatory changes in the cerebrospinal fluid were prominent. MRI T2-weighted and fluid-attenuated inversion recovery images displayed multiple or large flaky high signals, and the lesions were usually different in the number and distribution of these lesions. Intravenous corticosteroids and/or immunoglobulin were still important treatments in the acute phase. After treatment, 38 patients completely recovered, 9 patients had neurologic deficits, and 9 patients died. Conclusions: ADEM in adults is not uncommon, its clinical features are complex and varied, and some of these are multiphasic. There may be some potential clinical predictors at first onset.

Prediction of early functional outcomes in patients after robotic-assisted total knee arthroplasty: a nomogram prediction model.

BACKGROUND: Robotic-assisted total knee arthroplasty (RA-TKA) is becoming more and more popular as a treatment option for advanced knee diseases due to its potential to reduce operator-induced errors. However, the development of accurate prediction models for postoperative outcomes is challenging. This study aimed to develop a nomogram model to predict the likelihood of achieving a beneficial functional outcome. The beneficial outcome is defined as a postoperative improvement of the functional Knee Society Score (fKSS) of more than 10 points, 3 months after RA-TKA by early collection and analysis of possible predictors. METHODS: This is a retrospective study on 171 patients who underwent unilateral RA-TKA at our hospital. The collected data included demographic information, preoperative imaging data, surgical data, and preoperative and postoperative scale scores. Participants were randomly divided into a training set ( N =120) and a test set ( N =51). Univariate and multivariate logistic regression analyses were employed to screen for relevant factors. Variance inflation factor was used to investigate for variable collinearity. The accuracy and stability of the models were evaluated using calibration curves with the Hosmer-Lemeshow goodness-of-fit test, consistency index and receiver operating characteristic curves. RESULTS: Predictors of the nomogram included preoperative hip-knee-ankle angle deviation, preoperative 10-cm Visual Analogue Scale score, preoperative fKSS score and preoperative range of motion. Collinearity analysis with demonstrated no collinearity among the variables. The consistency index values for the training and test sets were 0.908 and 0.902, respectively. Finally, the area under the receiver operating characteristic curve was 0.908 (95% CI 0.846-0.971) in the training set and 0.902 (95% CI 0.806-0.998) in the test set. CONCLUSION: A nomogram model was designed hereby aiming to predict the functional outcome 3 months after RA-TKA in patients. Rigorous validation showed that the model is robust and reliable. The identified key predictors include preoperative hip-knee-ankle angle deviation, preoperative visual analogue scale score, preoperative fKSS score, and preoperative range of motion. These findings have major implications for improving therapeutic interventions and informing clinical decision-making in patients undergoing RA-TKA.

Learning curve and short-term clinical outcomes of a new seven-axis robot-assisted total knee arthroplasty system: a propensity score-matched retrospective cohort study.

OBJECTIVE: The purpose of the present study was to determine the learning curve for a novel seven-axis robot-assisted (RA) total knee arthroplasty (TKA) system and to explore whether it could provide superior short-term clinical and radiological outcomes compared with conventional surgery. METHODS: In the present retrospective study, 90 patients who underwent RA-TKA were included in robot-assisted system (RAS) group and 90 patients who underwent conventional TKA were included in the conventional group. The duration of surgery and robot-related complications were recorded to evaluate the learning curve through cumulative sum and risk-adjusted cumulative sum methods. The demographic data, preoperative clinical data, preoperative imaging data, duration of surgery, alignment of the prosthesis, lower limb force line alignment, Knee Society score, 10-cm visual analog scale pain score and range of motion were compared between the RAS and conventional groups. In addition, the proficiency group was compared with the conventional group using propensity score matching. RESULTS: RA-TKA was associated with a learning curve of 20 cases for the duration of surgery. There was no significant difference in indicators representing the accuracy of the prosthetic installation between the learning and proficiency phases in RA-TKA group patients. A total of 49 patients in the proficiency group were matched with 49 patients from the conventional group. The number of postoperative hip-knee-ankle (HKA) angle, component femoral coronal angle (CFCA), component tibial coronal angle (CTCA), and sagittal tibial component angle (STCA) outliers in the proficiency phase was lower than that in the conventional group, while deviations of the HKA angle, CFCA, CTCA, and STCA in the proficiency phase were significantly lower than those in the conventional group (P < 0.05). CONCLUSION: In summary, from the learning curve data, 20 cases are required for a surgeon using a novel seven-axis RA-TKA system to enter the proficiency phase. In the proficiency group, compared with the conventional group using propensity score matching, the RAS was found to be superior to the conventional group in prosthesis and lower limb alignment.

Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage.

Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1ß and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy.