Sex and race differences in the association of albumin with cognitive function in older adults.

BACKGROUND: With the increasing aging population, dementia has become a significant socioeconomic burden. However, the effects of albumin on delayed recall (DR) impairment remain unclear, and there are limited reports on sex and race differences in this relationship. This study aimed to investigate the association between albumin levels and DR impairment in older adults. METHODS: A total of 1507 normal cognitive function and 553 DR impairment from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were included in this cross-sectional analysis. Participants aged 60 years and above were assessed using the Consortium to Establish a Registry for Alzheimer's Disease DR (CERAD-DR) test to evaluate cognitive function. Participants were categorized into DR impairment and normal cognitive function groups according to their CERAD-DR scores. Logistic regression analyses, generalized additive models, and fitted smoothing curves were utilized for data analysis. RESULTS: After adjusting for potential confounders, a negative association was found between albumin levels and cognitive function (odds ratio [OR] = 0.60, 95% confidence interval [CI] 0.41-0.87). Subgroup analysis stratified by sex, race/ethnicity, and age revealed that the negative association remained significant in men (OR = 0.53, 95%CI 032-0.87), Blacks (OR = 0.35, 95%CI 0.17-0.74), and the age group of 60-70 years (OR = 0.48, 95%CI 0.28-0.81). However, no significant association was observed in women (OR = 0.72, 95%CI 0.41-1.28), whites (OR = 0.58, 95%CI 0.31-1.07), or Mexican Americans (OR = 1.11, 95%CI 0.35-3.46), as well as the age group of 71-80 years (OR = 0.62, 95%CI 0.37-1.03). CONCLUSIONS: Our study suggests that elevated albumin levels are associated with a decreased incidence of cognitive function impairment, particularly in older men and Blacks. This finding indicates that maintaining high levels of albumin may be beneficial for cognitive function in older adults.

Underwater Undulating Propulsion Biomimetic Robots: A Review.

The traditional propeller-based propulsion of underwater robots is inefficient and poorly adapted to practice. By contrast, underwater biomimetic robots show better stability and maneuverability in harsh marine environments. This is particularly true of undulating propulsion biomimetic robots. This paper classifies the existing underwater biomimetic robots and outlines their main contributions to the field. The propulsion mechanisms of underwater biomimetic undulating robots are summarized based on theoretical, numerical and experimental studies. Future perspectives on underwater biomimetic undulating robots are also presented, filling the gaps in the existing literature.

Chaihu-Longgu-Muli decoction improves sleep disorders by restoring orexin-A function in CKD mice.

Introduction: Chaihu-Longgu-Muli decoction (CLMD) is a well-used ancient formula originally recorded in the "Treatise on Febrile Diseases" written by the founding theorist of Traditional Chinese Medicine, Doctor Zhang Zhongjing. While it has been used extensively as a therapeutic treatment for neuropsychiatric disorders, such as insomnia, anxiety and dementia, its mechanisms remain unclear. Methods: In order to analyze the therapeutic mechanism of CLMD in chronic renal failure and insomnia, An adenine diet-induced chronic kidney disease (CKD) model was established in mice, Furthermore, we analyzed the impact of CLMD on sleep behavior and cognitive function in CKD mice, as well as the production of insomnia related regulatory proteins and inflammatory factors. Results: CLMD significantly improved circadian rhythm and sleep disturbance in CKD mice. The insomnia related regulatory proteins, Orexin, Orexin R1, and Orexin R2 in the hypothalamus of CKD mice decreased significantly, while Orexin and its receptors increased remarkably after CLMD intervention. Following administration of CLMD, reduced neuron loss and improved learning as well as memory ability were observed in CKD mice. And CLMD intervention effectively improved the chronic inflflammatory state of CKD mice. Discussion: Our results showed that CLMD could improve sleep and cognitive levels in CKD mice. The mechanism may be related to the up-regulation of Orexin-A and increased phosphorylation level of CaMKK2/AMPK, which further inhibits NF-κB downstream signaling pathways, thereby improving the disordered inflammatory state in the central and peripheral system. However, More research is required to confirm the clinical significance of the study.

The association between HDL-C and stroke in the middle-aged and elderly: A cross-sectional study.

BACKGROUND: Previous epidemiological studies have indicated that high-density lipoprotein cholesterol (HDL-C) is inversely associated with the risk of cardiovascular disease. However, this issue has aroused controversy in recent years. Besides, the relationship between HDL-C and the risk of total stroke in sex and race is less clear. Thus, we aimed to examine the association between different ranges of HDL-C and the risk of total stroke in adults over 40 years old. METHODS: This cross-sectional study was conducted on a sample of 8643 participants (4222 men and 4421 women) aged ≥40 years old from the National Health and Nutrition Examination Survey 2007-2016. HDL-C was an independent variable and stroke was a dependent variable in this study, with the other variables as potential effect modifiers. To examine the associations between them, we used multivariate logistical regression models and smooth curve fittings, as well as subgroup analyses. RESULTS: HDL-C was inversely associated with stroke when HDL-C was less than 1.55 mmol/L (odds ratio [OR] = 0.36, 95% confidence interval [CI] :0.21-0.62, p < .05). However, above 1.55 mmol/L, the incidence of stroke was not significant (OR = 1.29, 95% CI: 0.79-2.09, p>.05). Stratified by race/ethnicity and sex, the subgroup analyses demonstrated that HDL-C was inversely associated with stroke in men and Whites, but no significant differences among women, Mexicans, blacks, and other races. CONCLUSION: We found a nonlinear relationship between HDL-C and total stroke. Our study reveals a range of inverse associations between HDL-C and stroke (HDL-C<1.55 mmol/L), especially among men and Whites. This finding suggested that maintaining an appropriate HDL-C range may be beneficial in reducing the incidence of stroke.

Large Scale Ex Vivo Expansion of γδ T cells Using Artificial Antigen-presenting Cells.

Higher γδ T cell counts in patients with malignancies are associated with better survival. However, γδ T cells are rare in the blood and functionally impaired in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and interleukin-2 (IL-2). Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a Good Manufacturing Practice (GMP) compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of coculture with aAPC, which exhibited central (47%) and effector (43%) memory phenotypes. In addition, >90% of the expanded γδ T cells expressed NKG2D, although they have low cell surface expression of PD1 and LAG3 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded γδ T cells were effective in killing target cells. Our results demonstrate that large-scale ex vivo expansion of donor-derived γδ T cells in a GMP-like setting can be achieved with the use of quadruplet aAPC and zol/IL-2 for clinical application.

Clinical effect of successful reperfusion in patients presenting with NIHSS < 6 and large vessel occlusion.

PURPOSE: The purpose of this study was to evaluate the impact of reperfusion in patients with large vessel occlusion (LVO) of the anterior circulation and National Institutes of Health Stroke Scale (NIHSS)< 6. METHODS: It was a retrospective cohort study. The reperfusion grade was determined using the modified thrombolysis in cerebral infarction (TICI) score. The modified Rankin Score (mRS) ≤1 were defined as excellent and (mRS) ≤2 as favorable outcome at 3-month. Meanwhile, the all-cause mortality, intracerebral hemorrhage, and complications were recorded. Multivariate logistic regression analyses were performed to evaluate outcomes. RESULTS: Seventy-six patients (86.4%) achieved reperfusion (TICI2B/3). Excellent outcome was achieved in 62 (70.5%) and favorable outcome in 69 (78.4%). All-cause death occurred in 2 (2.3%). The rate of excellent outcome in patients with TICI0,1,2A was 41.7%, with TICI2B 69.2%, and with TICI3 78.0% (p < 0.05). In a multivariate logistic regression analysis related to excellent outcome, the OR(95% CI) was 5.68(1.35,23.95) for TICI3; the test for linear trend by entering categorical variables as continuous variables in the adjusted model (p for trend=0.02<0.05), defining TICI0,1,2A as reference. Subgroup analyses showed without intravenous thrombolysis (IVT) (OR, 14.29; 95% CI, 1.76-116.37) and with middle cerebral artery (MCA) occlusion (OR, 7.97; 95% CI,1.26-50.32), the excellent outcome further improved with TICI3. Findings were similar in favorable outcome. CONCLUSIONS: Our results indicated that successful reperfusion was intensely connected with better functional outcomes for patients with LVO presenting with NIHSS<6 in the anterior circulation, especially MCA occlusion and pretreatment without IVT.

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era.

The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.

In-situ growing of metal-organic frameworks on iron mesh as a recyclable remediation material for removing hexavalent chromium from groundwater.

The recovery and reuse of adsorbents is crucial for the effectiveness and sustainability of mitigation methods for groundwater pollution. Considering the difficulty in recovering powder materials and the low mechanical strength of membrane materials, we developed a sheet material with good recyclability and certain mechanical strength. In this study, an in situ synthesized MIL-100(Fe) film sample was produced by hydrothermal reaction using a commercially available iron mesh as the substrate. The MIL-100(Fe) samples were characterized by SEM, XRD, XPS, and FT-IR. The experiments showed that the material presented excellent removal ability toward Cr(VI) and good recovery performance. In the fourth cycle test, the Cr(VI) removal rate reached more than 95%. The material characterization and adsorption kinetics indicated that the removal mechanism was oxidation-reduction reaction and electrostatic adsorption. The removal experiments at different pH values and with different co-existing ions demonstrated that the material can maintain good removal capacity at pH values between 2 and 8, and common ions in groundwater can promote the removal of Cr(VI) under neutral conditions. The recycling test demonstrated that the sample can be reused. After the sample was recovered and calcined in an inert environment, a network sample containing zero-valent iron was obtained, and it removed Cr(VI) from water at a low pH in 20 min. This study provides a new alternative for the practical removal of Cr(VI) from groundwater.

A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology.

Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.

Activation of T cell checkpoint pathways during ß-cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes.

Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumour therapy. Here, we show that pancreatic ß-cell antigen (BcAg) presentation by engineered tolerogenic dendritic cells (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1 and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function as compared with engineered control-DCs. Non-obese diabetic mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycaemic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in and reversal of hyperglycaemia for a significant duration. Immune cells from the tDC-treated mice not only produced lower amounts of IFNγ and higher amounts of IL10 and TGFß1 upon BcAg challenge, but also failed to induce hyperglycaemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in inducing tolerance, multiligand-DC treatment produced an overall higher suppressive effect on effector T cell function and disease outcome. These studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can modulate T cell function and suppress autoimmunity and progression of the disease in T1D.

CD3 engagement as a new strategy for allogeneic "off-the-shelf" T cell therapy.

Allogeneic "off-the-shelf" (OTS) chimeric antigen receptor T cells (CAR-T cells) hold promise for more accessible CAR-T therapy. Here, we report a novel and simple way to make allogeneic OTS T cells targeting cancer. By engineering T cells with a bispecific T cell engager (BiTE), both TCRαß and CD3ε expression on the T cell surface are dramatically reduced. BiTE-engineered T (BiTE-T) cells show reduced reaction to TCR stimulation in vitro and have low risk of graft-versus-host disease (GvHD) in vivo. BiTE-T cells down-regulated CD3ε/TCRαß on bystander T cells by releasing BiTEs. BiTE-T cells produce much fewer cytokines and are comparable to CAR-T cells on anti-cancer efficacy in xenograft mouse models with pre-existing HLA-mismatched T cells. Co-expressing co-stimulatory factors or T cell-promoting cytokines enhanced BiTE-T cells. Our study suggests CD3ε engagement could be a new strategy for allogeneic T cell therapy worthy of further evaluation.

Emerging CAR T Cell Strategies for the Treatment of AML.

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML).

Decreased expression of protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 contributes to Alzheimer's disease-like pathologies.

Alzheimer's disease (AD) is pathologically characterized by senile plaques and neurofibrillary tangles composed of ß-amyloid peptide (Aß) and tau hyperphosphorylation, respectively. Mannosylation, a particular type of posttranslational modification, may be involved in the pathogenesis of AD. However, its underlying mechanism remains unclear. Protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) catalyzes the formation of the N-acetylglucosamine ß-1,2-Man linkage of O-mannosylglycan, which can increase the protein posttranslational mannosylation level. The defective POMGnT1 gene leads to the hypomannosylation of proteins, which may cause cognitive decline in aged people. This study aimed to investigate whether POMGnT1 participated in the pathogenesis of AD and explore its underlying role using AD mouse and cell models. In this study, the expression of POMGnT1 was measured in AD models [ß-amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, an AD mouse model; N2a cells stably transfected with Swedish mutant APP (N2a/APP), an AD cell model]. The results revealed that the expression of POMGnT1 decreased in AD mouse and cell models. In addition, POMGnT1-overexpressing N2a/APP cells were built by retroviral transfection. POMGnT1 overexpression may lower Aß levels by reducing APP production and downregulating ß- and γ-secretase activities. It also promoted clearance of Aß by upregulating insulin-degrading enzymes and ameliorated tau hyperphosphorylation. Hence, it was concluded that POMGnT1 was involved in the pathogenic process of AD. The decreased expression of POMGnT1 contributes to AD-like pathologies.NEW & NOTEWORTHY This study explored the role of mannosylation in the pathogenesis of AD through a mannosyltransferase-POMGnT1. Results demonstrated that target gene overexpression could ameliorate pathologies of Aß and tau hyperphosphorylation. This study is the first to examine the relationship between mannosylation and AD.

Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes.

Progressive destruction of pancreatic islet ß-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional ß-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase ß-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycaemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin-producing ß-cells and ameliorating the disease progression in T1D.

4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells.

BACKGROUND: Co-stimulatory signals regulate the expansion, persistence, and function of chimeric antigen receptor (CAR) T cells. Most studies have focused on the co-stimulatory domains CD28 or 4-1BB. CAR T cell persistence is enhanced by 4-1BB co-stimulation leading to nuclear factor kappa B (NF-κB) signaling, while resistance to exhaustion is enhanced by mutations of the CD28 co-stimulatory domain. METHODS: We hypothesized that a third-generation CAR containing 4-1BB and CD28 with only PYAP signaling motif (mut06) would provide beneficial aspects of both. We designed CD19-specific CAR T cells with either 4-1BB or mut06 together with the combination of both and evaluated their immune-phenotype, cytokine secretion, real-time cytotoxic ability and polyfunctionality against CD19-expressing cells. We analyzed lymphocyte-specific protein tyrosine kinase (LCK) recruitment by the different constructs by immunoblotting. We further determined their ability to control growth of Raji cells in NOD scid gamma (NSG) mice. We also engineered bi-specific CARs against CD20/CD19 combining 4-1BB and mut06 and performed repeated in vitro antigenic stimulation experiments to evaluate their expansion, memory phenotype and phenotypic (PD1+CD39+) and functional exhaustion. Bi-specific CAR T cells were transferred into Raji or Nalm6-bearing mice to study their ability to eradicate CD20/CD19-expressing tumors. RESULTS: Co-stimulatory domains combining 4-1BB and mut06 confers CAR T cells with an increased central memory phenotype, expansion, and LCK recruitment to the CAR. This enhanced function was dependent on the positioning of the two co-stimulatory domains. A bi-specific CAR targeting CD20/CD19, incorporating 4-1BB and mut06 co-stimulation, showed enhanced antigen-dependent in vitro expansion with lower exhaustion-associated markers. Bi-specific CAR T cells exhibited improved in vivo antitumor activity with increased persistence and decreased exhaustion. CONCLUSION: These results demonstrate that co-stimulation combining 4-1BB with an optimized form of CD28 is a valid approach to optimize CAR T cell function. Cells with both mono-specific and bi-specific versions of this design showed enhanced in vitro and in vivo features such as expansion, persistence and resistance to exhaustion. Our observations validate the approach and justify clinical studies to test the efficacy and safety of this CAR in patients.

Characterization of an Enterococcus faecalis Bacteriophage vB_EfaM_LG1 and Its Synergistic Effect With Antibiotic.

Enterococcus faecalis is a Gram-positive opportunistic pathogen that could cause pneumonia and bacteremia in stroke patients. The development of antibiotic resistance in hospital-associated E. faecalis is a formidable public health threat. Bacteriophage therapy is a renewed solution to treat antibiotic-resistant bacterial infections. However, bacteria can acquire phage resistance quite quickly, which is a significant barrier to phage therapy. Here, we characterized a lytic E. faecalis bacteriophage Vb_EfaM_LG1 with lytic activity. Its genome did not contain antibiotic resistance or virulence genes. Vb_EfaM_LG1 effectively inhibits E. faecalis growth for a short period, and phage resistance developed within hours. However, the combination of antibiotics and phage has a tremendous synergistic effect against E. faecalis, prevents the development of phage resistance, and disrupts the biofilm efficiently. Our results show that the phage-antibiotic combination has better killing efficiency against E. faecalis.

Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression.

Abnormal amyloid beta (Aß) clearance is a distinctive pathological mechanism for Alzheimer's disease (AD). ATP-binding cassette transporter A1 (ABCA1), which mediates the lipidation of apolipoprotein E, plays a critical role in Aß clearance. As an environmental factor for AD, dichlorodiphenyltrichloroethane (DDT) can decrease ATP-binding cassette transporter A1 (ABCA1) expression and disrupt Aß clearance. Liver X receptor α (LXRα) is an autoregulatory transcription factor for ABCA1 and a target of some environmental pollutants, such as organophosphate pesticides. In this study, we aimed to investigate whether DDT could affect Aß clearance by targeting LXRα. The DDT-pretreated H4 human neuroglioma cells and immortalized astrocytes were incubated with exogenous Aß to evaluate Aß consumption. Meanwhile, cytotoxicity and LXRα expression were determined in the DDT-treated cells. Subsequently, the antagonism of DDT on LXRα agonist T0901317 was determined in vitro. The interaction between DDT and LXRα was predicted by molecular docking and molecular dynamics simulation technology. We observed that DDT could inhibit Aß clearance and decrease the levels of LXRα mRNA and LXRα protein. Moreover, DDT is supposed to strongly bind to LXRα and exert antagonistic effects on LXRα. In conclusion, this study firstly presented that DDT could inhibit LXRα expression, which would contribute to Aß clearance decline in vitro. It provides an experimental basis to search for potential therapeutic targets of AD.

Primary empty sella: The risk factors and associations with the cerebral small vessel diseases-An observational study.

OBJECTIVE: To investigate the risk factors of primary empty sella (PES) and its associations with cerebral small vessel diseases (CSVD). METHODS: A total of 132 consecutive patients were recruited from Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University from December 2018 to January 2020, including 69 cases of PES, and age, gender-matched 63 subjects without PES. Demographics and clinical characteristics were recorded. Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH), which are image markers for CSVD, were assessed. Univariate logistic regression models and multivariate logistic regression models were performed to predict the independent risk factors of PES. RESULTS: There was a significant difference in baseline characteristics in terms of hypertension (p < 0.001) and pregnancy (p = 0.019) between PES and the control group; among markers of CSVD, whole WMH (p = 0.030) and periventricular hyperintensities (PVH) (p = 0.027) were significantly different; however, no significant differences concerning deep WMH, total PVS, basilar ganglia-PVS and centrum semiovale-PVS (p > 0.05). After adjusting relevant potential confounders, multivariate logistic regression revealed hypertension (OR=3.158, 95 %CI: 1.452∼6.865, p = 0.004) and pregnancy (OR=2.236, 95 %CI: 1.036-4.826, p = 0.040) were independent risk factors for PES. CONCLUSION: Hypertension and pregnancy are independent risk factors of PES. There is a possible correlation between PES and WMH, especially PVH, however, further studies are required to confirm these findings.

Effects of site, cerebral perfusion and degree of cerebral artery stenosis on cognitive function.

OBJECTIVE: To investigate the effects of site, cerebral perfusion and degree of cerebral artery stenosis (CAS) on cognitive function. METHODS: A total of 57 patients with CAS and 53 controls from January 2019 to December 2019 were included. The former group was further divided into different subgroups according to the site, cerebral perfusion and degree of CAS. A series of neuropsychological tests were performed to evaluate the cognitive domains (such as memory, executive function, psychomotor speed, etc.). Rank sum test, t test, Chi-square test and analysis of variance were used for data analysis. Spearman correlation analysis was used to examine the relationship between the site, cerebral perfusion and degree of CAS and all tests' scores. RESULTS: For patients with CAS who have decreased cerebral perfusion, their global cognitive function, memory, psychomotor speed, executive function and frontal lobe function were significantly impaired (all P < 0.05). There was a significant decrease in global cognitive function, psychomotor speed, memory, executive function and frontal lobe function in patients with anterior circulation stenosis (all P < 0.05). Moderate and severe CAS impaired subjects' global cognitive function, memory, psychomotor speed, executive function and frontal lobe function (all P < 0.05). There was a correlation between the site, cerebral perfusion, the degree of CAS and cognitive function. CONCLUSION: Global cognitive function, memory, psychomotor speed, frontal lobe function and executive function are impaired in patients with CAS, especially in those with anterior circulatory stenosis, moderate to severe stenosis and low cerebral perfusion.See Video Abstract, http://links.lww.com/WNR/A613.

CD28 Costimulatory Domain-Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function.

An obstacle to the development of chimeric antigen receptor (CAR) T cells is the limited understanding of CAR T-cell biology and the mechanisms behind their antitumor activity. We and others have shown that CARs with a CD28 costimulatory domain drive high T-cell activation, which leads to exhaustion and shortened persistence. This work led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP), we could optimize CAR T-cell costimulation and enhance function. In vivo, we found that mice given CAR T cells with only a PYAP CD28 endodomain had a significant survival advantage, with 100% of mice alive after 62 days compared with 50% for mice with an unmutated endodomain. We observed that mutant CAR T cells remained more sensitive to antigen after ex vivo antigen and PD-L1 stimulation, as demonstrated by increased cytokine production. The mutant CAR T cells also had a reduction of exhaustion-related transcription factors and genes such as Nfatc1, Nr42a, and Pdcd1 Our results demonstrated that CAR T cells with a mutant CD28 endodomain have better survival and function. This work allows for the development of enhanced CAR T-cell therapies by optimizing CAR T-cell costimulation.