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Background and aimsHypercholesterolemia has been identified as risk factor for severe acute pancreatitis (AP). We aimed to identify the common differentially expressed genes (DEGs) between a high-cholesterol diet and AP.MethodsWe retrived gene expression profiles from the GEO database. DEGs were assessed using GEO2R. For AP hub genes, we conducted functional enrichment analysis and protein–protein interaction (PPI) analysis. GeneMANIA and correlation analysis were employed to predict potential DEG mechanisms. Validation was done across various healthy human tissues, pancreatic adenocarcinoma, peripheral blood in AP patients, and Sprague–Dawley rats with AP.ResultsThe gene “Fabp5” emerged as the sole common DEG shared by a high-cholesterol diet and AP. Using the 12 topological analysis methods in PPI network analysis, Rela, Actb, Cdh1, and Vcl were identified as hub DEGs. GeneMANIA revealed 77.6% physical interactions among Fabp5, TLR4, and Rela, while genetic correlation analysis indicated moderate associations among them. Peripheral blood analysis yielded area under the ROC curve (AUC) values of 0.71, 0.63, 0.74, 0.64, and 0.91 for Fabp5, TLR4, Actb, Cdh1 genes, and artificial neural network (ANN) model respectively, in predicting severe AP. In vivo immunohistochemical analysis demonstrated higher Fabp5 expression in the hyperlipidemia-associated AP group compared to the AP and control groups.ConclusionFabp5 emerged as the common DEG connecting a high-cholesterol diet and AP. Rela was highlighted as a crucial hub gene in AP. Genetic interactions were observed among Fabp5, TLR4, and Rela. An ANN model consisting of Fabp5, TLR4, Actb, and Cdh1 was helpful in predicting severe AP.

ObjectiveIn recent years, motor imagery-based brain–computer interfaces (MI-BCIs) have developed rapidly due to their great potential in neurological rehabilitation. However, the controllable instruction set limits its application in daily life. To extend the instruction set, we proposed a novel movement-intention encoding paradigm based on sequential finger movement.ApproachTen subjects participated in the offline experiment. During the experiment, they were required to press a key sequentially [i.e., Left→Left (LL), Right→Right (RR), Left→Right (LR), and Right→Left (RL)] using the left or right index finger at about 1 s intervals under an auditory prompt of 1 Hz. The movement-related cortical potential (MRCP) and event-related desynchronization (ERD) features were used to investigate the electroencephalography (EEG) variation induced by the sequential finger movement tasks. Twelve subjects participated in an online experiment to verify the feasibility of the proposed paradigm.Main resultsAs a result, both the MRCP and ERD features showed the specific temporal–spatial EEG patterns of different sequential finger movement tasks. For the offline experiment, the average classification accuracy of the four tasks was 71.69%, with the highest accuracy of 79.26%. For the online experiment, the average accuracies were 83.33% and 82.71% for LL-versus-RR and LR-versus-RL, respectively.SignificanceThis paper demonstrated the feasibility of the proposed sequential finger movement paradigm through offline and online experiments. This study would be helpful for optimizing the encoding method of motor-related EEG information and providing a promising approach to extending the instruction set of the movement intention-based BCIs.

BackgroundDue to disparities in medical resources in rural and urban areas as well as in different geographic regions in China, the effect of weekend versus weekday admission on the outcomes of acute ischemic stroke (AIS) patients is unknown. Our aim was to investigate whether the outcomes of AIS patients differ according to the day of admission in China.MethodsThe data were extracted from the Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR), a multicenter prospective study database of patients diagnosed with AIS. The chi-square test (χ2) and logistic regression were used to assess mortality for weekday and weekend admissions among AIS patients stratified by rural or urban status and geographic region (including the eastern, northeastern, central, and western regions).ResultsIn total, 9,256 patients were included in this study. Of these patients, 57.2% were classified as urban, and 42.8% were classified as rural. A total of 6,760 (73%) patients were admitted on weekdays, and 2,496 (27%) were admitted on weekends. There was no significant difference in the mortality rate among patients admitted on weekends compared with those admitted on weekdays in urban (7.5% versus 7.4%) or rural areas (8.8% versus 8.1%; p > 0.05). The mortality rate was the highest among patients admitted on weekends and weekdays (11.6% versus 10.3%) in the northeastern area, without statistical significance before and after adjusting for the patients’ background characteristics (p > 0.05). In addition, regression analysis revealed that the mortality of patients admitted on weekdays was more likely to be influenced by regional subgroup, hospital level and intravenous thrombolysis than that of patients admitted on weekends.ConclusionThe weekend effect was not observed in the mortality of patients with AIS regardless of rural–urban status or geographic region in China.

BackgroundPrevious studies involving uric acid (UA) in some specialized disease populations have found that high UA is associated with enhanced patient function. The mechanism to explain this association may be that UA, an important antioxidant, exerts neuroprotective effects. Patients with schizophrenia (SCZ) have severe oxidative stress abnormalities, and cognitive impairment is a major obstacle to their rehabilitation. Only few studies have been conducted on UA and cognitive impairment in SCZ. This study aims to clarify the relationship between UA and cognitive impairment and explore whether UA could be used as a potential biological marker of cognition in SCZ during maintenance period.MethodsA total of 752 cases of SCZ during maintenance period from Baiyun Jingkang Hospital were included. Cognition was measured using the Mini-Mental State Examination scale. UA was measured using the Plus method. The participants were grouped on the basis of UA to evaluate the association of cognition with low-normal (3.50–5.07 mg/dL for men, 2.50–4.19 mg/dL for women), middle-normal (5.07–6.39 mg/dL for men, 4.19–5.18 mg/dL for women), high-normal (6.39–7.00 mg/dL for men, 5.18–6.00 mg/dL for women), and high (>7.00 mg/dL for men, >6.00 mg/dL for women) levels of UA. Multiple logistic regression and linear regression models and restricted cubic spline (RCS) were utilized to evaluate the relationship.ResultsUric acid was positively associated with cognitive function. Subgroup analyses showed that high UA was associated with enhanced cognition in participants with low anticholinergic cognitive burden (ACB).ConclusionUric acid may be used as a simple objective biological indicator to assess cognition in SCZ during maintenance period.

Background and purposeCerebral small-vessel disease (CSVD) is prevalent worldwide and one of the major causes of stroke and dementia. For patients with CSVD at high altitude, a special environmental status, limited information is known about their clinical phenotype and specific neuroimaging change. We investigated the clinical and neuroimaging features of patients residing at high altitude by comparing with those in the plain, trying to explore the impact of high altitude environment on CSVD.MethodsTwo cohorts of CSVD patients from the Tibet Autonomous Region and Beijing were recruited retrospectively. In addition to the collection of clinical diagnoses, demographic information and traditional vascular risk factors, the presence, location, and severity of lacunes and white matter hyperintensities were assessed by manual counting and using age-related white matter changes (ARWMC) rating scale. Differences between the two groups and influence of long-term residing in the plateau were analyzed.ResultsA total of 169 patients in Tibet (high altitude) and 310 patients in Beijing (low altitude) were enrolled. Fewer patients in high altitude group were found with acute cerebrovascular events and concomitant traditional vascular risk factors. The median (quartiles) ARWMC score was 10 (4, 15) in high altitude group and 6 (3, 12) in low altitude group. Less lacunes were detected in high altitude group [0 (0, 4)] than in low altitude group [2 (0, 5)]. In both groups, most lesions located in the subcortical (especially frontal) and basal ganglia regions. Logistic regressions showed that age, hypertension, family history of stroke, and plateau resident were independently associated with severe white matter hyperintensities, while plateau resident was negatively correlated with lacunes.ConclusionPatients of CSVD residing at high altitude showed more severe WMH but less acute cerebrovascular events and lacunes in neuroimaging, comparing to patients residing at low altitude. Our findings suggest potential biphasic effect of high altitude on the occurrence and progression of CSVD.

Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.

BackgroundThe association between blood lipids and cognitive function in schizophrenia is still controversial. Thus, the present study aimed to verify the association between various lipid parameters and cognitive impairment in schizophrenic patients and potential lipid pathways.MethodsA total of 447 adult inpatients with schizophrenia were divided into cognitive normal and cognitive impairment groups based on the Mini-Mental State Examination with a cut-off of 26. The blood lipid parameters were defined as abnormal levels based on the guideline. The liquid chromatography-mass spectrometry method was used to preliminarily explore the potential lipid metabolism pathway associated with cognitive impairment.ResultsThere were 368 (82.3%) patients who had cognitive impairment. Herein, apolipoprotein B was positively associated with cognitive function in overall patients and age (≥45 and

VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.

Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.

The relationship between body mass index (BMI) and cognitive impairment remains controversial, especially in older people. This study aims to confirm the association of phenotypic and genetic obesity with cognitive impairment and the benefits of adhering to a healthy lifestyle. This prospective study included 10,798 participants (aged ≥ 50 years) with normal cognitive function from the Health and Retirement Study in the United States. Participants were divided into low (lowest quintile), intermediate (quintiles 2–4), and high (highest quintile) groups according to their polygenic risk score (PRS) for BMI. The risk of cognitive impairment was estimated using Cox proportional hazard models. Higher PRS for BMI was associated with an increased risk, whereas phenotypic obesity was related to a decreased risk of cognitive impairment. Never smoking, moderate drinking, and active physical activity were considered favourable and associated with a lower risk of cognitive impairment compared with current smoking, never drinking, and inactive, respectively. A favourable lifestyle was associated with a low risk of cognitive impairment, even in subjects with low BMI and high PRS for BMI. This study suggest that regardless of obesity status, including phenotypic and genetic, adhering to a favourable lifestyle is beneficial to cognitive function.

Background and Purpose: Studies on the regional differences in hospital costs of acute ischemic stroke (AIS) are scarce in China. We aimed to explore the regional differences in hospital costs and identify the determinants of hospital costs in each region.Methods: Data were collected from the Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR), a multicenter prospective study on patients diagnosed with AIS and hospitalized from 2015 to 2017. Univariate and multivariate analyses were undertaken to identify the determinants of hospital costs of AIS.Results: A total of 8,547 patients were included in the study, of whom 3,700 were from the eastern area, 2,534 were from the northeastern area, 1,819 were from the central area, and 494 were from the western area. The median hospital costs presented a significant difference among each region, which were 2175.9, 2175.1, 2477.7, and 2282.4 dollars in each area, respectively. Each region showed a similar hospital cost proportion size order of cost components, which was Western medicine costs, other costs, diagnostic costs, and traditional medicine costs, in descending order. Male sex, diabetes mellitus, severe stroke symptoms, longer length of stay, admission to the intensive care unit, in-hospital complications of hemorrhage, and thrombectomy were independently associated with hospital costs in most regions.Conclusion: Hospital costs in different regions showed a similar proportion size order of components in China. Each region had different determinants of hospital costs, which reflected its current medical conditions and provided potential determinants for increasing medical efficiency according to each region's situation.

Background and Purpose: There is limited information on symptomatic intracranial hemorrhage (sICH) in stroke patients without thrombolysis. This study aimed to evaluate the risk factors of sICH and the association between sICH and the prognosis at 3 and 12 months in acute ischemic stroke patients without thrombolysis.Methods: Data originated from the Chinese Acute Ischemic Stroke Treatment Outcome Registry. Univariate analysis and multivariate logistic regression were used to screen the risk factors of sICH. Multivariable logistic regression models were used to assess the association of sICH with poor outcome and all-cause mortality.Results: Totally, 9,484 patients were included, of which 69 (0.73%) had sICH. Atrial fibrillation (odds ratio [OR], 3.682; 95% confidence interval [CI], 1.945–6.971; p < 0.001), history of tumors (OR, 2.956; 95% CI, 1.115–7.593; p = 0.024), and the National Institutes of Health Stroke Scale (NIHSS) score on admission ([6–15: OR, 2.344; 95% CI, 1.365–4.024; p = 0.002] [>15: OR, 4.731; 95% CI, 1.648–13.583; p = 0.004]) were independently associated with sICH. After adjustment of the confounders, patients with sICH had a higher risk of poor outcome (OR, 1.983; 95% CI, 1.117–3.521; p = 0.018) at 3 months and that of all-cause mortality at 3 (OR, 6.135; 95% CI, 2.328–16.169; p < 0.001) and 12 months (OR, 3.720; 95% CI, 1.513–9.148; p = 0.004).Conclusion: sICH occurred in 0.73% of acute ischemic stroke patients without thrombolysis and was associated with a worse prognosis at 3 and 12 months. Atrial fibrillation, history of tumors, and NIHSS score at admission were independent risk factors of sICH.

Objective: This study evaluated iron overload after intracerebral hemorrhage (ICH) using ESWAN sequences.Methods: This single-center prospective observational cohort study enrolled supratentorial ICH patients. MRI was obtained with a 3.0-T scanner at day 1, day 14, day 30, and follow-up (300 days or later). R2* mapping was generated based on the ESWAN. R2* value of the ipsilateral side represented iron deposition, and the R2* value of the contralateral side served as control. R2* value was adjusted by volume and used to assess total iron overload. Brain edema was measured on T2 FLAIR-weighted images. Brain atrophy was calculated as the contralateral hemisphere volume minus the injured hemisphere volume.Results: Twnety-seven patients with a spontaneous supratentorial ICH were included in this analysis. The ipsilateral R2* value was 40.27 ± 11.62, 41.92 ± 13.56, and 60.89 ± 14.09 at days 1, 14, and 30, respectively. The R2* value was significantly higher in the ICH side than the contralateral side (p < 0.01). Increased R2* value was seen on day 30 compared to day 14 (p < 0.01). The R2* value showed logistic decay with the distance to the hematoma margin (p < 0.01). Brain edema at day 14 and brain atrophy at follow-up correlated with R2* value adjusted by volume at day 14 (p < 0.01).Conclusions: After ICH, the iron deposition in the perihematomal region was progressively increased during the first month. R2* value adjusted by volume predicted acute brain edema and chronic brain atrophy.

Vascular endothelial cell (EC) and blood–brain barrier (BBB) dysfunction is the core pathogenesis of cerebral small vessel disease (CSVD). Moreover, animal experiments have shown the importance of connexin (Cx)-43 in EC and BBB function. In this study, we recruited 200 patients diagnosed with sporadic CSVD. Initially, we examined imaging scores of white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB). Additionally, we performed next-generation sequencing of the GJA1 gene (Cx43 coding gene) to examine correlation between these single-nucleotide polymorphisms and the burden and distribution of CSVD. Fourteen target loci were chosen. Of these, 13 loci (92.9%) contributed toward risk for cerebellar LI, one locus (7.1%) was shown to be a protective factor for lobar CMB after FDR adjustment. In conclusion, single-nucleotide polymorphisms in the GJA1 gene appear to affect the distribution but not severity of CSVD.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. More than 25 ALS-related genes have been identified, accounting for approximately 10% of sporadic ALS (SALS) and two-thirds of familial ALS (FALS) cases. Several recent studies showed that genetic factors might have a larger contribution to young-onset ALS than to ALS cases overall. However, the genetic profile of young-onset ALS patients is not yet fully understood. Here, we investigated a cohort of 27 young-onset ALS patients (onset age < 45 years) through whole-exome sequencing (WES). Genetic analysis identified pathogenic variants of FUS (25.9%), SOD1 (22.2%), TARDBP (3.7%), and VCP (3.7%) in 27 young-onset ALS patients. Of 12 identified types of mutations, c.1528A > C in FUS and c.266G > A in VCP were novel. All of the cases in this study reflect a monogenic origin with an autosomal dominant mode of inheritance. Notably, a novel de novo missense mutation, c.1528A > C (p.K510Q), in FUS was identified in a 29-year-old ALS patient. Expression of the K510Q mutant FUS resulted in cytoplasmic mislocalization of FUS in cultured cells and induced neural toxicity in a fly model. This study provides further evidence of the genetic profile of young-onset ALS patients from China and expands the mutational spectrum of the FUS gene, with one new K510Q mutation identified.

VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4-S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTAantibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications. [ABSTRACT FROM AUTHOR]