Association of Triglyceride Glucose-Derived Indexes with Recurrent Events Following Atherosclerotic Cardiovascular Disease.

Background: Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indexes of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction. Methods: This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed. Results: Distribution of the TyAG and TyAG-BMI indexes shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P<0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance. Conclusion: This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.

The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Increased Expression of VCAM1 on Brain Endothelial Cells Drives Blood-Brain Barrier Impairment Following Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH)-triggered blood-brain barrier (BBB) dysfunction is a core pathological change occurring in vascular dementia (VD). Despite the recent advances in the exploration of the structural basis of BBB impairment and the routes of entry of harmful compounds after a BBB leakage, the molecular mechanisms inducing BBB impairment remain largely unknown in terms of VD. Here, we employed a CCH-induced VD model and discovered increased vascular cell adhesion molecule 1 (VCAM1) expression on the brain endothelial cells (ECs). The expression of VCAM1 was directly correlated with the severity of BBB impairment. Moreover, the VCAM1 expression was associated with different regional white matter lesions. Furthermore, a compound that could block VCAM1 activation, K-7174, was also found to alleviate BBB leakage and protect the white matter integrity, whereas pharmacological manipulation of the BBB leakage did not affect the VCAM1 expression. Thus, our results demonstrated that VCAM1 is an important regulator that leads to BBB dysfunction following CCH. Blocking VCAM1-mediated BBB impairment may thus offer a new strategy to treat CCH-related neurodegenerative diseases.

A Set of Artificial Pollination Technical Measures: Improved Seed Yields and Active Ingredients of Seeds in Oil Tree Peonies.

The tree peony, a novel woody oil crop extensively cultivated in China, necessitates further investigation into artificial pollination technology to enhance seed yield. In this study, we conducted artificial pollination experiments with 6-year-old Paeonia ostii 'Feng Dan' seedings for suitable pollen sources, pollen concentration, pollination timing, and pollination frequency. By evaluating seed yields, active ingredients, and oil quality, we derived the following significant conclusions. Firstly, compared to natural pollination, artificial pollination could significantly increase the fruit diameter by 13.94-27.58%, seed yields by 35.17-58.99%, and oil content by 6.45-7.52% in tree peonies. In active ingredients, seeds produced by pollen from Hantai County significantly enhanced starch content (by 48.64%), total phenols (by 41.18%) and antioxidant capacity (by 54.39%). In oil quality, seeds produced by pollen from Heyang County exhibited the highest α-linolenic acid and total fatty acid content with enhancements of 1.68%, 7.41%, and 8.48%. Secondly, hand pollination with pure pollen significantly increased seed yield by 58.99%, total phenol content by 40.97%, antioxidant capacity by 54.39%, and oil content by 1.53% compared to natural pollination. Thirdly, pollination at 2/3 bloom range significantly increased seed number by 63.08% and yield by 45.61% compared to natural pollination. Finally, the effect of one, two, and three pollination events had no difference in seed yield. So, to summarize, applying a 100% concentration of allochthonous pollen once is recommended when the bloom range is more than two thirds.

Influence of Lifshitz Transition on the Intrinsic Resistivity of Cu2N Monolayer.

The Lifshitz transition (LT), a topological structure transition of Fermi surfaces, can induce various intricate physical properties in metallic materials. In this study, through first-principles calculations, we explore the nontrivial effect of the LT on the intrinsic resistivity of the Cu2N monolayer arising from electron-phonon (el-ph) scattering. We find that when the LT is induced by electron doping, the multibranch Fermi surface simplifies into a single-band profile. Such an LT leads to a decoupling of low-frequency flexural phonons from el-ph scattering due to mirror symmetry. Consequently, the resistivity of the Cu2N monolayer at room temperature significantly decreases, approaching that of slightly doped graphene, and highlighting the Cu2N monolayer as a highly conductive two-dimensional metal. Moreover, this LT can bring about a nonlinear temperature dependence of the intrinsic resistivity at a high temperature.

Newborn Screening for 6 Lysosomal Storage Disorders in China.

Importance: Newborn screening (NBS) for lysosomal storage disorders (LSDs) is becoming an increasing concern in public health. However, the birth prevalence of these disorders is rarely reported in the Chinese population, and subclinical forms of diseases among patients identified by NBS have not been evaluated. Objective: To evaluate the birth prevalence of the 6 LSDs in the Shanghai population and determine subclinical forms based on clinical, biochemical, and genetic characteristics. Design, Setting, and Participants: This cohort study included 50 108 newborns recruited from 41 hospitals in Shanghai between January and December 2021 who were screened for 6 LSDs using tandem mass spectrometry (MS/MS). Participants with screen-positive results underwent molecular and biochemical tests and clinical assessments. Data were analyzed from January 2021 through October 2022. Exposures: All participants were screened for Gaucher, acid sphingomyelinase deficiency (ASMD), Krabbe, mucopolysaccharidosis type I, Fabry, and Pompe diseases using dried blood spots. Main Outcomes and Measures: Primary outcomes were the birth prevalence and subclinical forms of the 6 LSDs in the Shanghai population. Disease biomarker measurements, genetic testing, and clinical analysis were used to assess clinical forms of LSDs screened. Results: Among 50 108 newborns (26 036 male [52.0%]; mean [SD] gestational age, 38.8 [1.6] weeks), the mean (SD) birth weight was 3257 (487) g. The MS/MS-based NBS identified 353 newborns who were positive. Of these, 27 newborns (7.7%) were diagnosed with 1 of 6 LSDs screened, including 2 newborns with Gaucher, 5 newborns with ASMD, 9 newborns with Krabbe, 8 newborns with Fabry, and 3 newborns with Pompe disease. The combined birth prevalence of LSDs in Shanghai was 1 diagnosis in 1856 live births, with Krabbe disease the most common (1 diagnosis/5568 live births), followed by Fabry disease (1 diagnosis/6264 live births), and ASMD (1 diagnosis/10 022 live births). Biochemical, molecular, and clinical analysis showed that early-onset clinical forms accounted for 3 newborns with positive results (11.1%), while later-onset forms represented nearly 90% of diagnoses (24 newborns [88.9%]). Conclusions and Relevance: In this study, the combined birth prevalence of the 6 LSDs in Shanghai was remarkably high. MS/MS-based newborn screening, combined with biochemical and molecular genetic analysis, successfully identified and characterized newborns who were screen-positive, which may assist with parental counseling and management decisions.

Genome-wide epigenetic signatures facilitated the variant classification of PURA gene and uncovered the pathomechanism of PURA-related neurodevelopmental disorders.

PURPOSE: Rare genetic variants in the PURA gene cause PURA-related neurodevelopmental disorder (PURA-NDD), characterized by neonatal abnormalities and developmental delay. Using genome-wide DNA methylation analysis on patients with PURA variants, we aim to establish PURA-NDD-specific methylation profile and provide further insights on the molecular basis of the PURA-NDD. METHODS: 23 individuals (including 12 unpublished) carrying PURA variants were enrolled. We conducted the Illumina Infinium EPIC microarray analysis in 17 PURA-NDD individuals. In vitro experiments were performed to examine how PURA variants affect Pur-α expression. RESULTS: Additional phenotypes in 12 newly identified patients were described in this study. Genome-wide DNA methylation analysis unveiled distinctive methylation profiles to PURA-NDD, and the established classifier can reclassify PURA variants of uncertain significance. Patients bearing PURA hapoloinsufficient and missense variants have comparable DNA methylation profiles, and cells expressing these PURA variants showed consistent Pur-α downregulation suggesting a haploinsufficiency mechanism. CONCLUSION: Patients with PURA-NDD exhibit a specific epi-signature, which has potential to aid identification and diagnosis of PURA-NDD patients and offer implications for further functional investigations.

Clinical characteristics and genetic analysis of six children with carnitine palmitoyltransferase 2 deficiency. / å ­ä¾‹è‚‰ç¢±æ£•æ¦ˆé °åŸºè½¬ç§»é ¶2ç¼ºä¹ç—‡æ‚£å„¿ä¸´åºŠç‰¹å¾åŠåŸºå› å˜å¼‚åˆ†æž.

OBJECTIVES: To investigate the clinical characteristic and genetic variants of children with carnitine palmitoyltransferase 2 (CPT2) deficiency. METHODS: The clinical and genetic data of 6 children with CPT2 deficiency were retrospectively analyzed. The blood acylcarnitines and genetic variants were detected with tandem mass spectrometry and whole-exon gene sequencing, respectively. RESULTS: There were 4 males and 2 females with a mean age of 32 months (15 d-9 years) at diagnosis. One case was asymptomatic and with normal laboratory test results, 2 had delayed onset, and 3 were of infantile type. Three cases were diagnosed at neonatal screening, and 3 cases presented with clinical manifestations of fever, muscle weakness, and increased muscle enzymes. Five children presented with decreased free carnitine and elevated levels of palmitoyl and octadecenoyl carnitines. CPT2 gene variants were detected at 8 loci in 6 children (4 harboring biallelic mutations and 2 harboring single locus mutations), including 3 known variants (p.R631C, p.T589M, and p.D255G) and 5 newly reported variants (p.F352L, p.R498L, p.F434S, p.A515P, and c.153-2A>G). It was predicted by PolyPhen2 and SIFT software that c.153-2A>G and p.F352L were suspected pathogenic variants, while p.R498L, p.F434S and p.A515P were variants of unknown clinical significance. CONCLUSIONS: The clinical phenotypes of CPT2 deficiency are diverse. An early diagnosis can be facilitated by neonatal blood tandem mass spectrometry screening and genetic testing, and most patients have good prognosis after a timely diagnosis and treatment.

Tailoring Oxygen Reduction Reaction Kinetics of Fe-N-C Catalyst via Spin Manipulation for Efficient Zinc-Air Batteries.

The interaction between oxygen species and metal sites of various orbitals exhibits intimate correlation with the oxygen reduction reaction (ORR) kinetics. Herein, a new approach for boosting the inherent ORR activity of atomically dispersed Fe-N-C matrix is represented by implanting Fe atomic clusters nearby. The as-prepared catalyst delivers excellent ORR activity with half-wave potentials of 0.78 and 0.90 V in acidic and alkaline solutions, respectively. The decent ORR activity can also be validated from the high-performance rechargeable Zn-air battery. The experiments and density functional theory calculations reveal that the electron spin-state of monodispersed Fe active sites is transferred from the low spin (LS, t2g 6 eg 0) to the medium spin (MS, t2g 5 eg 1) due to the involvement of Fe atomic clusters, leading to the spin electron filling in σ∗ orbit, by which it favors OH- desorption and in turn boosts the reaction kinetics of the rate-determining step. This work paves a solid way for rational design of high-performance Fe-based single atom catalysts through spin manipulation.

Application of System Nursing in the Prevention of Postoperative Nonstructural Scoliosis in Patients With Ear Reconstruction.

OBJECTIVE: To evaluate whether early systematic nursing can reduce the occurrence of postoperative nonstructural scoliosis in patients undergoing ear reconstruction. METHODS: A total of 136 patients with congenital microtia who underwent ear reconstruction surgery at the Department of Plastic Surgery, Chinese Academy of Medical Sciences from, January 2022 to July 2022 were included as study subjects. They were randomly divided into a routine nursing group and a systematic nursing group. After preoperative and postoperative education, as well as continuous follow-up intervention after surgery, spinal CT three-dimensional imaging examination was performed 6 months later to measure the Cobb angle and observe the occurrence of spinal scoliosis. RESULTS: Compared with the routine nursing group, the incidence and severity of postoperative nonstructural scoliosis were significantly reduced in patients who received systematic nursing. CONCLUSIONS: Systematic nursing intervention for patients undergoing ear reconstruction can help prevent the occurrence of postoperative nonstructural scoliosis and has a positive effect on improving patient prognosis. It is worth promoting in clinical treatment.

[Effects of salt stress on bacterial community composition and diversity in rhizosphere soil of Bletilla striata]. / ç›èƒè¿«å¯¹ç™½åŠæ ¹é™ ç»†èŒç¾¤è½ç»„æˆåŠå¤šæ ·æ€§çš„å½±å“.

Salinization environment affects the normal growth and development of plants, as well as the microbial community in the rhizosphere. To explore the succession dynamics of bacterial communities in the rhizosphere soil of Bletilla striata under salt stress condition, we performed 16S rRNA high-throughput sequencing to determine the bacterial community composition and diversity of B. striata in the rhizosphere under different salt stress concentrations, measured the effects of salt stress on the growth and development of B. striata and soil physicochemical pro-perties, and analyzed the correlation between community composition of rhizosphere bacteria and the soil environmental factors. The results showed that compared with the control, salt stress reduced growth rate and health degree of B. striata, and significantly decreased the content of soil organic matter, nitrogen and phosphorus. Under the salt stress treatment, species diversity and evenness of the bacterial communities in the rhizosphere of B. striata showed a trend of first decreasing and then increasing. There were significant differences in the relative abundance and variation trends of the dominant bacterial taxa in the rhizosphere soil of B. striata at the phylum and class levels between the control and the salt stress treatments. Salt stress intensity and duration were important factors affecting bacterial community composition in the rhizosphere soil of B. striata. Soil organic matter, available nitrogen, and total phosphorus content were key environmental factors affecting the structure of rhizosphere bacterial community composition. Functional genes related to cytoskeleton, cell motility, substance metabolism and signal transduction mechanisms may be involved in the adaptation and stress response of bacterial communities to salt stress. This study would provide theoretical basis and reference for the cultivation management of B. striatain saline area.

Metal-free ß,γ-C(sp3)-H difunctionalization of propanols: DMP-initiated asymmetric spirocyclopropanation.

A DMP-initiated metal-free effective ß,γ-asymmetric spirocyclopropanation of propanols strategy using oxidative iminium activation is described. This process has been realized by a synergistic amine-catalyzed one-pot cascade oxidation-Michael addition cyclopropanation for "one-pot" access to various spirocyclopropyl propionaldehydes/propanols from diverse 3-arylpropanols and α-brominated active methylene compounds under mild conditions and with high enantioselectivity (ee up to >99%).

Comparison of calcium magnesium ferrite nanoparticles for boosting biohydrogen production.

Dark fermentation (DF) is an eco-friendly process that simultaneously achieves organic matter degradation and obtains hydrogen (H2). Nonetheless, low H2 yield mainly caused by poor activity of key microbes, is still a problem that requires being resolved. In this work, MgFe2O4 and Ca0.5Mg0.5Fe2O4 nanoparticles (NPs) were synthetized and served as additives to boost H2 form from DF. H2 productivity gradually increased with the rise of NPs, and declined when NPs exceeded their optimal dosages. The highest H2 yield was 183.6 ± 3.2 mL/g glucose at 100 mg/L of MgFe2O4 NPs, being 35.2 % higher than that of the control yield (135.8 ± 3.1 mL/g glucose). However, the highest H2 yield of 171.9 ± 2.5 mL/g glucose occurred at 400 mg/L of Ca0.5Mg0.5Fe2O4 NPs, increasing by 26.6 % over the control. Interestingly, the two NPs favored the butyric acid pathway for H2 synthesis. This provides guidance for multi-element oxide NPs used in DF.

The enhanced hepatotoxicity of isobavachalcone in depigmented zebrafish due to calcium signaling dysregulation and lipid metabolism disorder.

Isobavachalcone (IBC) is a flavonoid component derived from Psoraleae Fructus that can increase skin pigmentation and treat vitiligo. However, IBC has been reported to be hepatotoxic. Current studies on IBC hepatotoxicity are mostly on normal organisms but lack studies on hepatotoxicity in patients. This study established the depigmented zebrafish model by using phenylthiourea (PTU) and investigated the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC and the underlying mechanism. Morphological, histological, and ultrastructural examination and RT-qPCR verification were used to evaluate the effects of IBC on the livers of zebrafish larvae. IBC significantly decreased liver volume, altered lipid metabolism, and induced pathological and ultrastructural changes in the livers of zebrafish with depigmentation compared with normal zebrafish. The RNA-sequencing and RT-qPCR results showed that the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC was closely related to the calcium signaling pathway, lipid decomposition and metabolism, and oxidative stress. This work delved into the mechanism of the enhanced IBC-induced hepatotoxicity in depigmented zebrafish and provided a new insight into the hepatotoxicity of IBC.

Fast Label-Free Metabolic Profile Recognition Identifies Phenylketonuria and Subtypes.

Phenylketonuria (PKU) is the most common inherited metabolic disease in humans. Clinical screening of newborn heel blood samples for PKU is costly and time-consuming because it requires multiple procedures, like isotope labeling and derivatization, and PKU subtype identification requires an additional urine sample. Delayed diagnosis of PKU, or subtype identification can result in mental disability. Here, plasmonic silver nanoshells are used for laser desorption/ionization mass spectrometry (MS) detection of PKU with label-free assay by recognizing metabolic profile in dried blood spot (DBS) samples. A total of 1100 subjects are recruited and each DBS sample can be processed in seconds. This platform achieves PKU screening with a sensitivity of 0.985 and specificity of 0.995, which is comparable to existing clinical liquid chromatography MS (LC-MS) methods. This method can process 360 samples per hour, compared with the LC-MS method which processes only 30 samples per hour. Moreover, this assay enables precise identification of PKU subtypes without the need for a urine sample. It is demonstrated that this platform enables high-performance and fast, low-cost PKU screening and subtype identification. This approach might be suitable for the detection of other clinically relevant biomarkers in blood or other clinical samples.

Intraoperative electroencephalogram features related to frailty in older patients: an exploratory prospective observational study.

Frailty is an independent risk factor for the increased incidence of postoperative delirium (POD). To date, the effect of frailty on intraoperative electroencephalogram (EEG) changes remains unexplored. The present study, an exploratory analysis of a prospective cohort study, aimed to investigate the differences in EEG characteristics between frail and robust patients. This prospective observational study was conducted between December 2020 and November 2021. The preoperative frailty status was assessed using the FRAIL scale. The patients' baseline (before anesthesia) and intraoperative EEG data were collected using a brain function monitor. Finally, 20 robust and 26 frail older patients scheduled for elective spinal surgery or transurethral prostatectomy under propofol-based general anesthesia were included in the final analysis. Baseline and intraoperative EEG spectrogram and power spectra were compared between the frail and robust groups. No differences were observed in baseline EEG between the frail and robust groups. When the intraoperative EEG spectral parameters were compared, the alpha peak frequency (10.56 ± 0.49 vs. 10.14 ± 0.36 Hz, P = 0.002) and alpha peak, delta, theta, alpha, and beta powers were lower in the frail group. After adjusting for age, Charlson Comorbidity Index (CCI), and mini-mental state examination (MMSE) score, the FRAIL score was still negatively associated with total, delta, theta, alpha, and beta powers. Frail patients had reduced EEG (0-30 Hz) power after the induction of propofol-based general anesthesia. After adjusting for age, CCI, and MMSE score, frail patients still showed evidence of reduced δ, θ, α, and ß power.

Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report.

BACKGROUND: Inborn errors of metabolism (IEMs) frequently result in progressive and irreversible clinical consequences if not be diagnosed or treated timely. The tandem mass spectrometry (MS/MS)-based newborn screening (NBS) facilitates early diagnosis and treatment of IEMs. The aim of this study was to determine the characteristics of IEMs and the successful deployment and application of MS/MS screening over a 19-year time period in Shanghai, China, to inform national NBS policy. METHODS: The amino acids and acylcarnitines in dried blood spots from 1,176,073 newborns were assessed for IEMs by MS/MS. The diagnosis of IEMs was made through a comprehensive consideration of clinical features, biochemical performance and genetic testing results. The levels of MS/MS testing parameters were compared between various IEM subtypes and genotypes. RESULTS: A total of 392 newborns were diagnosed with IEMs from January 2003 to June 2022. There were 196 newborns with amino acid disorders (50.00%, 1: 5910), 115 newborns with organic acid disorders (29.59%, 1: 10,139), and 81 newborns with fatty acid oxidation disorders (20.41%; 1:14,701). Phenylalanine hydroxylase deficiency, methylmalonic acidemia and primary carnitine deficiency were the three most common disorders. Some hotspot variations in eight IEM genes (PAH, SLC22A5, MMACHC, MMUT, MAT1A, MCCC2, ACADM, ACAD8), 35 novel variants and some genotype-biochemical phenotype associations were identified. CONCLUSIONS: A total of 28 types of IEMs were identified, with an overall incidence of 1: 3000 in Shanghai, China. Our study offered clinical guidance for the implementation of MS/MS-based NBS and genetic counseling for IEMs in this city.

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

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

Association of ß-blocker use at discharge and prognosis of oldest old with acute myocardial infarction: a prospective cohort study.

PURPOSE: It is uncertain whether ß-blockers are beneficial for long-term prognosis in older patients following acute myocardial infarction (AMI). Thus, this study sought to examine the effect of ß-blockers on long-term cardiovascular mortality (CVM) in the oldest old (≥ 80 years) with AMI. METHODS: In this prospective, consecutive, non-randomized study, a total of 1156 patients with AMI admitted within 24 h after onset of symptoms were enrolled from January 2012 to February 2020. Univariate and multivariate Cox regression analyses were performed to examine the impact of ß-blocker use on prognosis. Furthermore, one-to-one propensity score matching (PSM) and inverse probability treatment weighting (IPTW) analyses were used to control for systemic differences between groups. The primary outcome was long-term CVM. RESULTS: Among the enrolled subjects, 972 (85.9%) were prescribed with ß-blockers at discharge. Over a mean follow-up of 26.3 months, 224 cardiovascular deaths were recorded. Both univariate [hazard ratio (HR), 1.41, 95% confidence interval (CI) 0.93-2.13] and multivariate (HR, 1.29, 95% CI 0.79-2.10) Cox regression analyses showed that ß-blocker use had no significant association with the long-term CVM, which was further demonstrated by PSM (HR, 1.31, 95% CI 0.75-2.28) and IPTW (HR, 1.41, 95% CI 0.73-2.69) analyses. Subgroup analyses according to sex, heart rate, hypertension, diabetes, revascularization, left ventricular ejection fraction, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers use showed consistent results as well. CONCLUSION: Our findings first suggested that the use of ß-blockers at discharge in oldest old with AMI was not useful for reducing post-discharge CVM, which need to be further verified by randomized controlled trials.

Development and validation of a new genotype-phenotype correlation for Niemann-Pick disease type C1.

Hundreds of NPC1 variants cause highly heterogeneous phenotypes. This study aims to explore the genotype-phenotype correlation of NPC1, especially for missense variants. In a well-characterized cohort, phenotypes are graded into three clinical forms: mild, intermediate, and severe. Missense residue structural location was stratified into three categories: surface, partially, and fully buried. The association of phenotypes with the topography of the amino acid substitution in the protein structure was investigated in our cohort and validated in two reported cohorts. One hundred six unrelated NPC1 patients were enrolled. A significant correlation of genotype-phenotype was found in 81 classified individuals with two or one (the second was null variant) missense variant (p < 0.001): of 25 patients with at least one missense variant of surface (group A), 19 (76%) mild, six (24%) intermediate, and none severe; of 31 cases with at least one missense variant of partially buried without surface variants (group B), 11 (35%) mild, 16 (52%) intermediate, and four (13%) severe; of the remaining 25 patients with two or one buried missense variants (group C), eight (32%) mild, nine (36%) intermediate, and eight (32%) severe. Additionally, 7-ketocholesterol, the biomarker, was lower in group A than in group B (p = 0.024) and group C (p = 0.029). A model was proposed that accurately predicted phenotypes of 72 of 90 (80%), 73 of85 (86%), and 64 of 69 (93%) patients in our cohort, Italian, and UK cohort, respectively. This study proposed a novel genotype-phenotype correlation in NPC1, linking the underlying molecular pathophysiology with clinical phenotype and aiding genetic counseling and evaluation in clinical practice.