Genome-Wide Mendelian Randomization Study Reveals Druggable Genes for Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.

Clinical and Prognostic Characteristics of Acute BAD-Related Stroke: A Multicenter MRI-Based Prospective Study.

BACKGROUND: Branch atheromatous disease (BAD)-related stroke has emerged as a meaningful subtype of ischemic stroke yet remained understudied. We aimed to investigate the demographic, clinical, therapeutic, and prognostic characteristics of BAD-related stroke. METHODS: The BAD-study was a nationwide, multicenter, prospective, observational cohort study in 20 Chinese hospitals from June 2021 to June 2023, enrolling patients aged 18 to 80 years with BAD-related stroke within 72 hours of onset. Eligible single subcortical infarct in the territory of lenticulostriate artery and paramedian pontine artery was included. Clinical, laboratory, and treatment data were collected at baseline. The primary outcome was a proportion of good outcomes (modified Rankin Scale score, 0-2) at 90 days. Main secondary outcomes included early neurological deterioration (END), cerebrovascular event, major bleeding, and excellent outcome (modified Rankin Scale score, 0-1) during 90-day follow-up. RESULTS: We finally enrolled 476 patients, with a median age of 60 (interquartile range, 53-68) years, and 70.2% were male. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 2-6) at enrollment. Involvement of the lenticulostriate artery was more common than the paramedian pontine artery (60.7% versus 39.3%). END occurred in 14.7% of patients, with a median time from onset of 38 (interquartile range, 22-62) hours. The rates of good and excellent outcomes were 86.5% and 72%, respectively. Its 90-day stroke recurrence rate was 1.9%. Acute-phase therapy (from onset to 7 days of enrollment) showed heterogeneity and was not associated with prognosis. Multivariable logistic regression analysis identified the National Institutes of Health Stroke Scale score ≥4 at admission and END as negative predictors and extracranial artery stenosis as a positive predictor of good outcomes. Age ≥60 years, National Institutes of Health Stroke Scale score ≥4 at admission, and END were negative predictors of excellent outcomes. CONCLUSIONS: With distinct demographic, clinical, and prognostic characteristics, along with a high incidence of END and a low risk of stroke recurrence, BAD-related stroke could be categorized as a separate disease entity. Moreover, its acute-phase treatment strategies were undetermined, awaiting further high-quality studies.

Automated diffusion-weighted image analysis along the perivascular space index reveals glymphatic dysfunction in association with brain parenchymal lesions.

Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non-invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large-scale population remains under-investigated. In this cross-sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion-weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662-0.898). We found that those with older age and male sex had lower automated ALPS values (ß = -0.051, SE = 0.004, p < .001, per 10 years, and ß = -0.036, SE = 0.008, p < .001, respectively). White matter hyperintensity (ß = -2.458, SE = 0.175, p < .001) and presence of lacunes (OR = 0.004, 95% CI < 0.002-0.016, p < .001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (ß = 0.067, SE = 0.007, p < .001 and ß = 0.040, SE = 0.014, p = .006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction.

Boosting the Luminescence of a Europium(III)-ß-Diketonate Complex-Nanoclay Aqueous Solution by Acetylcholine.

It is a challenging task to prepare lanthanide complex-based luminescent materials with high quantum efficiency in aqueous solution, since the excited state of Ln3+ can be significantly quenched by water through the excitation of the O-H vibrations. Herein, we present a simple and environmentally friendly strategy to prepare strongly red-light-emitting lanthanide complex-based luminescent materials by loading 2-thenoyltrifluoroacetate (TTA) on the Eu3+-exchanged nanoclay (Eu3+(TTAn)-NC, NC = nanoclay) and coadsorption of choline chloride (ChCl) or acetylcholine chloride (AChCl) in water. The coadsorbed molecules remarkably boosted the luminescence of Eu3+(TTAn)-NC, which is tentatively ascribed to the removal of waters coordinated in the Eu3+ coordination sphere via the complete coordination of TTA mediated by ChCl or AChCl. Highly luminescent films were facilely prepared by mixing a Eu3+(TTAn)-NC aqueous solution with PVA-ChCl (PVA-AChCl) deep eutectic solvents. This work provides a simple and environmentally friendly way for preparing highly luminescent emitting luminescent materials in aqueous solution.

Risk factor differences in five-year progression of Intracranial artery stenosis and cerebral small vessel disease in general population.

BACKGROUND: Intracranial artery stenosis (ICAS) and cerebral small vessel disease (CSVD) are associated with a heavy socioeconomic burden; however, their longitudinal changes remain controversial. METHODS: We conducted a longitudinal analysis on 756 participants of Shunyi Cohort who underwent both baseline and follow-up brain magnetic resonance imaging (MRI) and MR angiography in order to investigate the risk factors for ICAS and CSVD progression in community population. Incident ICAS was defined as new stenosis occurring in at least one artery or increased severity of the original artery stenosis. CSVD markers included lacunes, cerebral microbleeds (CMB), and white matter hyperintensities (WMH). RESULTS: After 5.58 ± 0.49 years of follow-up, 8.5% of the 756 participants (53.7 ± 8.0 years old, 65.1% women) had incident ICAS. Body mass index (BMI) (OR = 1.09, 95% CI = 1.01-1.17, p = 0.035) and diabetes mellitus (OR = 2.67, 95% CI = 1.44-4.93, p = 0.002) were independent risk factors for incident ICAS. Hypertension was an independent risk factor for incident lacunes (OR = 2.12, 95% CI = 1.20-3.77, p = 0.010) and CMB (OR = 2.32, 95% CI = 1.22-4.41, p = 0.011), while WMH progression was primarily affected by BMI (ß = 0.108, SE = 0.006, p = 0.002). A higher LDL cholesterol level was found to independently protect against WMH progression (ß = -0.076, SE = 0.027, p = 0.019). CONCLUSIONS: Modifiable risk factor profiles exhibit different in patients with ICAS and CSVD progression. Controlling BMI and diabetes mellitus may help to prevent incident ICAS, and antihypertensive therapy may conduce to mitigate lacunes and CMB progression. LDL cholesterol may play an inverse role in large arteries and small vessels.

Cerebral venous thrombosis at high altitude: more severe symptoms and specific predisposing factors than plain areas.

BACKGROUND: Exposure to a high-altitude environment is a risk factor for cerebral venous thrombosis (CVT) probably due to hypercoagulability. The study aims to explore the unique characteristics of CVT patients in high-altitude areas of China by comparing them with those in plain areas. METHODS: We retrospectively included consecutive patients with CVT admitted to Tibet Autonomous Region People's Hospital (altitude 3650 m) and Peking Union Medical College Hospital (altitude 43.5 m) between January 2015 and December 2023. Patients from the plateau and the plain were considered two independent groups in this study. The risk factors, clinical and radiological presentations, treatment, and outcomes were analyzed and compared between the two groups. RESULTS: A total of 169 patients with CVT were included in the study, 48 patients from plateau and 121 patients from plain. The median age was 27 and 34 years old, and women accounted for 66.7% and 54.5% respectively. Headache (91.7% vs. 71.1%, P = 0.004), altered consciousness (31.3% vs. 16.5%, P = 0.033), hemorrhage (41.7% vs. 19.0%, P = 0.002), and venous infarction (50.0% vs. 25.6%, P = 0.002) on imaging were more common in patients from plateau than those from plain. Pregnancy or puerperium was significantly more common in highland patients (25% vs. 5.8%, P < 0.001). The levels of D-Dimer (1.7 vs. 0.8 mg/L FEU, P = 0.01), fibrinogen (3.7 vs. 3.0 g/L, P < 0.001), hemoglobin (157 vs. 129 g/L, P = 0.01), white blood cells (9.6 vs. 7.5*1012/L, P < 0.001) and highly sensitive C-reactive protein (20.2 vs. 3.2 mg/L, P = 0.005) were remarkably higher in highland patients. The percentage of receiving anticoagulant therapy was lower in high-altitude patients (70.8% vs. 93.4%, P < 0.001). Favorable outcome at follow-up was observed in 81.4% of highland patients and 90.7% of lowland patients, with a median follow-up time of 330 days and 703 days respectively. CONCLUSIONS: The more severe clinical and imaging manifestations along with prominent inflammatory and hypercoagulable states were observed in plateau CVT patients, probably due to exposure to the hypoxic environment at high altitude. Pregnancy or puerperium were more common in highland patients. The overall prognosis of CVT patients from both groups were favorable.

Current status and value of testing antiphospholipid antibody in patients with acute ischemic stroke: a retrospective single-center study in China.

BACKGROUND AND PURPOSE: Testing for antiphospholipid antibodies (aPL) is useful to determine the cause of ischemic stroke in young and female patients. However, the clinical relevance of aPL in older patients with ischemic stroke remains unclear. We aimed to explore the status and diagnostic value of initial aPL testing in all patients with acute ischemic stroke. METHODS: We retrospectively analyzed patients with acute ischemic stroke who were consecutively hospitalized in our hospital between June 2012 and January 2022 and investigated the factors associated with performing aPL screening in real-world clinical practice. Furthermore, factors associated with initial aPL positivity were evaluated by comparing the demographic, etiological, and therapeutic characteristics. RESULTS: Of 1209 patients, 287 (23.7%) were tested for aPL and 58 (20.2%) tested positive. Physicians tended to conduct aPL testing on female patients (P<0.001), younger patients (P<0.001), patients with fewer vascular risk factors (P<0.001), and multiple infarctions in the multivascular blood supply area (P<0.001). Multivariate logistic regression analysis showed that only stroke of other determined etiology type was a significant influencing factor for positive aPL results (OR 2.97, 95% CI 1.137, 7.774, P=0.026), adjusting for sex, age, and causes of stroke, etc. CONCLUSION: Approximately one-quarter of the patients with acute ischemic stroke were tested for aPL. Age, sex, number of vascular risk factors, and neuroimaging features affected the discretion in performing aPL testing. aPL testing may be appropriate in older patients with no identified cause of ischemic stroke and may provide additional diagnostic opportunities for acute ischemic stroke.

Silymarin decreases liver stiffness associated with gut microbiota in patients with metabolic dysfunction-associated steatotic liver disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. OBJECTIVE: To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. METHOD: In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. RESULTS: Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. CONCLUSION: These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).

Correlation between Circle of Willis configuration and intracranial arterial dolichoectasia, and genetic contributions.

OBJECTIVES: Intracranial arterial dolichoectasia (IADE) is characterized by the dilation, elongation, and tortuosity of intracranial arteries. We aimed to investigate the association between variations of the Circle of Willis (COW) and IADE in the general population, as well as estimate the genetic correlation between COW variations and IADE. METHODS: A total of 981 individuals from a population-based cohort were included. Brain magnetic resonance angiography was performed to assess COW variants and measure the diameters of intracranial arteries. IADE was defined as a total intracranial volume-adjusted diameter ≥ 2 standard deviations. Logistic regression models were used to analyze the association between COW variations and IADE. The heritability and genetic correlation were estimated using genome-wide complex trait analysis (GCTA) based on single nucleotide polymorphism (SNP) array data. RESULTS: The prevalence of IADE was 6.2 %. Hypoplastic/absent A1 segments were associated with an increase in contralateral ICA diameter (ß ± SE, 0.279 ± 0.049; p = 0.001) and a decrease in ipsilateral ICA diameter (ß ± SE, -0.300 ± 0.050; p = 0.001). Fetal-type posterior cerebral artery (FTP) was associated with a larger ICA diameter (ß ± SE, 0.326 ± 0.048; p = 0.001) and a smaller BA diameter (ß ± SE, -0.662 ± 0.043; p = 0.001). FTP revealed a positive genetic correlation with ICA dilation (rG = 0.259 ± 0.175; p = 0.0009) and a negative genetic correlation with BA dilation (rG = -0.192 ± 0.153, p = 0.015). CONCLUSIONS: There was an association between COW variations and larger intracranial arterial diameters in the general population. Genetic factors may play a role in the development of intracranial arterial dilation and the formation of COW variants.

Rare RNF213 variants is related to early-onset intracranial atherosclerosis: A Chinese community-based study.

BACKGROUND: The relationship between rare variants in Ring finger protein 213 (RNF213) and intracranial atherosclerosis (ICAS) remained unelucidated. Using whole-exome sequencing (WES) and high-resolution magnetic resonance imaging (HR-MRI), this study aimed at investigating the association between rare RNF213 variants and ICAS within a Chinese community-dwelling population. METHODS: The present study included 821 participants from Shunyi cohort. Genetic data of rare RNF213 variants were acquired by WES and were categorized by functional domains. Intracranial and extracranial atherosclerosis were assessed by brain HR-MRI and carotid ultrasound, respectively. Logistic regression and generalized linear regression were applied to evaluate the effects of rare RNF213 variants on atherosclerosis. Stratification by age were conducted with 50 years old set as the cutoff value. RESULTS: Ninety-five participants were identified as carriers of rare RNF213 variants. Carotid plaques were observed in 367 (44.7 %) participants, while ICAS was identified in 306 (37.3 %). Rare variants of RNF213 was not associated with ECAS. Employing HR-MRI, both the presence of rare variants (ß = 0.150, P = 0.025) and numerical count of variants (ß = 0.182, P = 0.003) were significantly correlated with ICAS within the group of age ≤50 years. Both variant existence (ß = 0.154, P = 0.014) and variant count (ß = 0.188, P = 0.003) were significantly associated with plaques in middle cerebral arteries within younger subgroup, rather than basilar arteries. Furthermore, a significant association was observed between variants that located outside the N-arm domain and ICAS in the younger subgroup (OR = 2.522, P = 0.030). Statistical results remained robust after adjusted for age, gender, and cardiovascular risk factors. CONCLUSIONS: Rare variants of RNF213 is associated with age-related ICAS in general Chinese population, highlighting the potential role of RNF213 as a genetic contributor to early-onset ICAS.

PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with an alarming mortality rate. The development of novel therapeutic targets or drugs for AML is urgently needed. Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Recently, ferroptosis has emerged as a novel method for targeting cancer, including AML. Epigenetic dysregulation is a hallmark of AML, and a growing body of evidence suggests that ferroptosis is subject to epigenetic regulation. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a ferroptosis regulator in AML. The type I PRMT inhibitor GSK3368715 promoted ferroptosis sensitivity in vitro and in vivo. Moreover, PRMT1-knockout cells exhibited significantly increased sensitivity to ferroptosis, suggesting that PRMT1 is the primary target of GSK3368715 in AML. Mechanistically, both GSK3368715 and PRMT1 knockout upregulated acyl-CoA synthetase long-chain family member 1 (ACSL1), which acts as a ferroptosis promoter by increasing lipid peroxidation. Knockout ACSL1 reduced the ferroptosis sensitivity of AML cells following GSK3368715 treatment. Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.

Protein Myristoylation Plays a Role in the Nuclear Entry of the Parvovirus Minute Virus of Mice.

Being nonpathogenic to humans, rodent parvoviruses (PVs) are naturally oncolytic viruses with great potential as anti-cancer agents. As these viruses replicate in the host cell nucleus, they must gain access to the nucleus during infection. The PV minute virus of mice (MVM) and several other PVs transiently disrupt the nuclear envelope (NE) and enter the nucleus through the resulting breaks. However, the molecular basis of this unique nuclear entry pathway remains uncharacterized. In this study, we used MVM as a model to investigate the molecular mechanism by which PVs induce NE disruption during viral nuclear entry. By combining bioinformatics analyses, metabolic labeling assays, mutagenesis, and pharmacological inhibition, we identified a functional myristoylation site at the sequence 78GGKVGH83 of the unique portion of the capsid protein VP1 (VP1u) of MVM. Performing proteolytic cleavage studies with a peptide containing this myristoylation site or with purified virions, we found tryptophan at position 77 of MVM VP1u is susceptible to chymotrypsin cleavage, implying this cleavage exposes G (glycine) 78 at the N-terminus of VP1u for myristoylation. Subsequent experiments using inhibitors of myristoylation and cellular proteases with MVM-infected cells, or an imaging-based quantitative NE permeabilization assay, further indicate protein myristoylation and a chymotrypsin-like activity are essential for MVM to locally disrupt the NE during viral nuclear entry. We thus propose a model for the nuclear entry of MVM in which NE disruption is mediated by VP1u myristoylation after the intact capsid undergoes proteolytic processing to expose the required N-terminal G for myristoylation. IMPORTANCE Rodent parvoviruses (PVs), including minute virus of mice (MVM), have the ability to infect and kill cancer cells and thereby possess great potential in anti-cancer therapy. In fact, some of these viruses are currently being investigated in both preclinical studies and clinical trials to treat a wide variety of cancers. However, the detailed mechanism of how PVs enter the cell nucleus remains unknown. In this study, we for the first time demonstrated a chemical modification called "myristoylation" of a MVM protein plays an essential role in the nuclear entry of the virus. We also showed, in addition to protein myristoylation, a chymotrypsin-like activity, which may come from cellular proteasomes, is required for MVM to get myristoylated and enter the nucleus. These findings deepen our understanding on how MVM and other related PVs infect host cells and provide new insights for the development of PV-based anti-cancer therapies.

The prevalence and prognosis of asymptomatic intracranial atherosclerosis in a community-based population: Results based on high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke in China, but the prevalence and prognosis of asymptomatic ICAD detected using high-resolution magnetic resonance imaging (HR-MRI) is largely unknown. The aim of this study was to investigate the prevalence and prognosis in order to guide neurologists in interpreting ICAD detected on HR-MRI. METHODS: We included stroke-free participants from a community-based prospective cohort (Shunyi study participants) who underwent HR-MRI between July 2014 and April 2016. The participants were divided into two groups: those with or without ICAD (ICAD+ and ICAD- , respectively). ICAD included intracranial artery stenosis and non-stenotic plaque. The primary outcome was ischemic stroke. Cox proportional hazard models were used to evaluate the association between ICAD and event outcomes. RESULTS: A total of 1060 stroke-free participants evaluated by HR-MRI were included from the Shunyi study. The median age at HR-MRI was 56 years and 64.7% were female. The ICAD prevalence was 36.3% (n = 385). The ICAD+ group was older and had more cerebrovascular risk factors. The rates of ischemic stroke in the ICAD- and ICAD+ groups were 1.3% (n = 9) and 5.2% (n = 20), respectively, with a median follow-up time of 54 months. ICAD was associated with an increased risk of ischemic stroke in the unadjusted and adjusted Cox models, with hazard ratios of 4.12 (95% confidence interval [CI] 1.87-9.05) and 2.50 (95% CI 1.05-5.94), respectively. The greatest risk of an event outcome was observed in participants with ≥70% stenosis or occlusion. The features of high-risk plaques were also identified. CONCLUSIONS: We found that ICAD detected using HR-MRI increases the long-term risk of a first-ever ischemic stroke in a stroke-free population, suggesting that the current primary prevention protocol of stroke awaits further optimization.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

Discovery of diaminotriazine carboxamides as potent inhibitors of hematopoetic progenitor kinase 1.

Hematopoietic progenitor kinase 1 (HPK1), a member of mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of Ste20 serine/threonine kinases, is a negative regulator of T-cell receptor (TCR) signaling. Inactivating HPK1 kinase has been reported to be sufficient to elicit antitumor immune response. Therefore, HPK1 has attracted much attention as a promising target for tumor immunotherapy. A few of HPK1 inhibitors have been reported, and none of them have been approved for clinical applications. Hence, more effective HPK1 inhibitors are needed. Herein, a series of structurally novel diaminotriazine carboxamides were rationally designed, synthesized and evaluated for their inhibitory activity against HPK1 kinase. Most of them exhibited potent inhibitory potency against HPK1 kinase. In particular, compound 15b showed more robust HPK1 inhibitory activity than that of 11d developed by Merck in kinase activity assay (IC50 = 3.1 and 8.2 nM, respectively). The significant inhibitory potency against SLP76 phosphorylation in Jurkat T cells further confirmed the efficacy of compound 15b. In human peripheral blood mononuclear cell (PBMC) functional assays, compound 15b more significantly induced the production of interleukin 2 (IL-2) and interferon γ (IFN-γ) relative to 11d. Furthermore, 15b alone or in combination with anti-PD-1 antibodies showed potent in vivo antitumor efficacy in MC38 tumor-bearing mice. Compound 15b represents a promising lead for the development of effective HPK1 small-molecule inhibitors.

Neurophobia among medical students and resident trainees in a tertiary comprehensive hospital in China.

BACKGROUND: Medical students and residents have been revealed to have extraordinary difficulties in managing patients with neurological complaints. However, specific information on Chinese trainees is scarce. Herein, we aimed to uncover the presence of, contributing factors for, and potential solutions to neurophobia among medical students and resident trainees in China. METHODS: Questionnaires were administered to the medical students of Peking Union Medical College and residents of the Internal Medicine Residency Training Program at Peking Union Medical College Hospital. We asked about perceived difficulty, knowledge, interest, and confidence in neurology in contrast to six other specialties. The reasons why neurology is regarded as difficult and approaches for improving neurological teaching have been appraised. RESULTS: A total of 351 surveys were completed by 218 medical students and 133 residents. The response rate exceeded 70% in both groups. The prevalence of neurophobia was 66.1% and 58.6% among medical students and residents, respectively. Respondents declared that greater difficulty was observed in neurology than in other specialties, and the management of patients with neurological problems was the least comfortable (p < 0.0001). Neurophobia has various perceived causes, and neuroanatomy is regarded as the most important contributor. Nearly 80% of medical students felt that improvements in neurology teaching could be achieved through further integration of preclinical and clinical neurological teaching. CONCLUSIONS: The findings of the first survey on neurophobia in China are in accordance with those of previous studies. Neurophobia is highly prevalent in Chinese medical students and residents. Strategies to improve teaching, including enhanced integration of teaching and more online resources, are needed to prevent neurophobia.

Mechanisms of in-hospital acute ischemic stroke and their relevance to prognosis: A retrospective analysis.

OBJECTIVES: In-hospital stroke (IHS) is common and has a poor prognosis. Limited data were about the mechanisms of IHS, posing a challenge in taking measures to prevent stroke during hospitalization. This study aims to investigate the mechanisms of IHS and their relevance to prognosis. MATERIALS AND METHODS: Patients with in-hospital acute ischemic stroke at Peking Union Medical College Hospital from June 2012 to April 2022 were consecutively enrolled. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification of stroke and detailed mechanisms were evaluated by two experienced neurologists. Functional outcome at discharge was evaluated. RESULTS: A total of 204 IHS patients were included, with a median age of 64 (IQR 52-72) and 61.8% male. The most common mechanism was embolism (57.8%), followed by hypoperfusion (42.2%), hypercoagulation (36.3%), small vessel mechanism (19.1%), discontinuation of antithrombotic drugs (13.2%), and iatrogenic injury (9.8%). Iatrogenic injury (P = 0.001), hypoperfusion (P = 0.006), embolism (P = 0.03), and discontinuation of antithrombotic drugs (P = 0.004) were more common in perioperative stroke compared to non-perioperative stroke. Median NIHSS improvement (2 vs 1, P = 0.002) and median mRS improvement (1 vs 0.5, P = 0.02) at discharge were higher in perioperative patients. Advanced age and higher NIHSS at onset were significantly associated with a poorer prognosis, whereas embolism mechanism was associated with a better prognosis. CONCLUSIONS: The etiologies and mechanisms of IHS are complex. Perioperative and non-perioperative IHS have different mechanisms and prognostic features. Determining the causes and mechanisms of IHS will help to identify the population at risk and prevent stroke appropriately during hospitalization.

Incomplete pythagorean fuzzy preference relation for subway station safety management during COVID-19 pandemic.

Completing the Pythagorean fuzzy preference relations (PFPRs) based on additive consistency may exceed the defined domain. Therefore, we develop a group decision-making (GDM) method with incomplete PFPRs. Firstly, sufficient conditions for the expressibility of estimated preference values in PFPRs based on additive consistency are presented. Next, the correction algorithm is developed to correct the inexpressible elements in incomplete PFPRs. Then, a GDM method based on incomplete PFPRs is proposed to determine the objective weights of decision-makers. Finally, an example of subway station safety management during COVID-19 is selected to illustrate the applicability of the developed GDM method. The results show that the developed GDM method effectively identifies the crucial risk factor in subway station safety management and has better performance in terms of computational time complexity than the multiplicative consistency method.

Diverse spillover effects of COVID-19 control measures on air quality improvement: evidence from typical Chinese cities.

The COVID-19 prevention and control measures are taken by China's government, especially traffic restrictions and production suspension, had spillover effects on air quality improvement. These effects differed among cities, but these differences have not been adequately studied. To provide more knowledge, we studied the air quality index (AQI) and five air pollutants (PM2.5, PM10, SO2, NO2, and O3) before and after the COVID-19 outbreak in Shanghai, Wuhan, and Tangshan. The pollution data from two types of monitoring stations (traffic and non-traffic stations) were separately compared and evaluated. We used monitoring data from the traffic stations to study the emission reduction caused by traffic restrictions. Based on monitoring data from the non-traffic stations, we established a difference-in-difference model to study the emission reduction caused by production suspension. The COVID-19 control measures reduced AQI and the concentrations of all pollutants except O3 (which increased greatly), but the magnitude of the changes differed among the three cities. The control measures improved air quality most in Wuhan, followed by Shanghai and then Tangshan. We investigated the reasons for these differences and found that differences in the characteristics of these three types of cities could explain these differences in spillover effects. Understanding these differences could provide some guidance and support for formulating differentiated air pollution control measures in different cities. For example, whole-process emission reduction technology should be adopted in cities with the concentrated distribution of continuous process enterprises, whereas vehicles that use cleaner energy and public transport should be vigorously promoted in cities with high traffic development level.

[Quality evaluation of Commelina communis from different origins based on multicomponent content determination combined with chemometrics].

This research established a high-performance liquid chromatography(HPLC) method for simultaneous determination of isoorientin, orientin, vitexin, and isovitexin in Commelina communis to conduct content difference analysis and quality evaluation of 62 batches of C. communis from different origins. The HPLC content determination was performed on a Dikma Platisil ODS chromatographic column(4.6 mm×250 mm, 5 µm), with acetonitrile-0.1% formic acid(14∶86) as the mobile phase. The detection wavelength was set at 348 nm, the flow rate was 1.0 mL·min~(-1), and the column temperature was 35 ℃. The differences in origins and quality of 62 batches of C. communis were studied by chemometrics. The results showed that the determination of four components mani-fested a good linear relationship in the range of mass concentration(r>0.999 9), and the average recovery rate was 96.17%-103.0%. The relative standard deviations(RSDs) of precision, stability, and repeatability were all less than 2.0%. The content of four components from high to low was isoorientin>isovitexin>orientin>vitexin. Forty-seven batches of C. communis with clear origins were classified into six categories by chemometrics. C. communis from different origins had different qualities. Generally, C. communis from Western China, Central China, and South of China had superior qualities. The HPLC method established in this study is specific, simple, and efficient, which provides references for the comprehensive evaluation of the quality of C. communis. The chemometrics shows that the qualities of C. communis from different origins are largely different. Isoorientin can be used as an index to determine the content of C. communis, and its content limit should be set no less than 0.023%.