[The use of bronchial occlusion test in a preterm infant with severe bronchopulmonary dysplasia complicated by severe lobar emphysema]. / æ”¯æ°”ç®¡å°å µè¯•éªŒåœ¨æ—©äº§å„¿é‡åº¦æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯ä¼´ä¸¥é‡è‚ºå¶æ°”è‚¿ä¸­çš„åº”ç”¨1例.

In infants with severe bronchopulmonary dysplasia (sBPD), severe pulmonary lobar emphysema may occur as a complication, contributing to significant impairment in ventilation. Clinical management of these infants is extremely challenging and some may require lobectomy to improve ventilation. However, prior to the lobectomy, it is very difficult to assess whether the remaining lung parenchyma would be able to sustain adequate ventilation postoperatively. In addition, preoperative planning and perioperative management are also quite challenging in these patients. This paper reports the utility of selective bronchial occlusion in assessing the safety and efficacy of lobectomy in a case of sBPD complicated by severe right upper lobar emphysema. Since infants with sBPD already have poor lung development and significant lung injury, lobectomy should be viewed as a non-traditional therapy and be carried out with extreme caution. Selective bronchial occlusion test can be an effective tool in assessing the risks and benefits of lobectomy in cases with sBPD and lobar emphysema. However, given the technical difficulty, successful application of this technique requires close collaboration of an experienced interdisciplinary team.

Long-term outcomes and predictive factors of achieving low disease activity status in childhood systemic lupus erythematosus: a Chinese bicentric retrospective registered study.

Background: This study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS. Methods: A total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied. Results: The male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8-13.1 years), the disease duration was 1.0 month (IQR, 0.5-2.0 months), and follow-up was 36.5 months (IQR, 25.7-50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)-these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P < 0.001). Conclusion: Endothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.

Association of plasma lactoferrin levels with disease severity in glaucoma patients.

Objective: To explore the relationship between plasma lactoferrin (Lf) and glaucoma, assessing the clinical utility of Lf in glaucoma. Methods: A cross-sectional study involved 161 glaucoma patients and 115 healthy controls, with a follow-up of 14 subjects after approximately 2 years. Plasma Lf markers were quantified using ELISA, comparing levels between glaucoma patients and healthy controls, and analyzing plasma Lf across different glaucoma severity grades. Results: Glaucoma patients had significantly elevated plasma Lf levels compared to healthy controls (p < 0.001). Higher plasma Lf levels correlated with more severe disease stages (HPA grades showed ρ = 0.435, p < 0.001; AGIS grades showed ρ = 0.436, p < 0.001) and reduced retinal nerve fiber layer (RNFL) thickness (RNFL thickness showed ρ = -0.204, p = 0.024). ROC curve analysis demonstrated the efficacy of glaucoma markers in differentiating early-stage from advanced glaucoma. Conclusion: Plasma Lf levels are significantly associated with glaucoma severity and may be involved in the pathogenic progression of the disease.

Unraveling Estrogen and PCSK9's Roles in Lipid Metabolism Disorders among Ovariectomized Mice.

We explore the interaction between estrogen and PCSK9 and their collective impact on lipid metabolism, especially concerning the regulation of low-density lipoprotein receptor levels. Utilizing both animal and cellular models, including ovariectomized mice and HepG2 cell lines, we demonstrate that estrogen deficiency leads to a disruption in lipid metabolism, characterized by elevated levels of total cholesterol and LDL-C. The study commences with mice undergoing ovariectomy, followed by a diet regimen comprising either high-fat diet or normal feed for a four-week duration. Key assessments include analyzing lipid metabolism, measuring PCSK9 levels in the bloodstream, and evaluating hepatic low-density lipoprotein receptor expression. We will also conduct correlation analyses to understand the relationship between PCSK9 and various lipid profiles. Further, a subset of ovariectomized mice on high-fat diet will undergo treatment with either estrogen or PCSK9 inhibitor for two weeks, with a subsequent re-evaluation of the earlier mentioned parameters. Our findings reveal that estrogen inhibits PCSK9-mediated degradation of low-density lipoprotein receptor, a process crucial for maintaining lipid homeostasis. Through a series of experiments, including immunohistochemistry and western blot analysis, we establish that PCSK9 is involved in lipid metabolism disorders caused by estrogen deficiency and that estrogen regulates PCSK9 and low-density lipoprotein receptor at post-transcriptional level. The study provides a mechanism for the involvement of PCSK9 in elucidating the disorders of lipid metabolism caused by estrogen deficiency due to perimenopause and ovarian decline.

The Human Ganglioside Interactome in Live Cells Revealed Using Clickable Photoaffinity Ganglioside Probes.

Gangliosides, sialic acid bearing glycosphingolipids, are components of the outer leaflet of plasma membranes of all vertebrate cells. They contribute to cell regulation by interacting with proteins in their own membranes (cis) or their extracellular milieu (trans). As amphipathic membrane constituents, gangliosides present challenges for identifying their ganglioside protein interactome. To meet these challenges, we synthesized bifunctional clickable photoaffinity gangliosides, delivered them to plasma membranes of cultured cells, then captured and identified their interactomes using proteomic mass spectrometry. Installing probes on ganglioside lipid and glycan moieties, we captured cis and trans ganglioside-protein interactions. Ganglioside interactomes varied with the ganglioside structure, cell type, and site of the probe (lipid or glycan). Gene ontology revealed that gangliosides engage with transmembrane transporters and cell adhesion proteins including integrins, cadherins, and laminins. The approach developed is applicable to other gangliosides and cell types, promising to provide insights into molecular and cellular regulation by gangliosides.

Recognition of autism spectrum disorder in children based on electroencephalogram network topology.

Although our knowledge of autism spectrum disorder (ASD) has been deepened, the accurate diagnosis of ASD from normal individuals is still left behind. In this study, we proposed to apply the spatial pattern of the network topology (SPN) to identify children with ASD from normal ones. Based on two independent batches of electroencephalogram datasets collected separately, the accurate recognition of ASD from normal children was achieved by applying the proposed SPN features. Since decreased long-range connectivity was identified for children with ASD, the SPN features extracted from the distinctive topological architecture between two groups in the first dataset were used to validate the capacity of SPN in classifying ASD, and the SPN features achieved the highest accuracy of 92.31%, which outperformed the other features e.g., power spectrum density (84.62%), network properties (76.92%), and sample entropy (73.08%). Moreover, within the second dataset, by using the model trained in the first dataset, the SPN also acquired the highest sensitivity in recognizing ASD, when compared to the other features. These results consistently illustrated that the functional brain network, especially the intrinsic spatial network topology, might be the potential biomarker for the diagnosis of ASD.

Clinical treatment patterns, molecular characteristics and survival outcomes of ROS1-rearranged non-small cell lung cancer: A large multicenter retrospective study.

BACKGROUND: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC. METHODS: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes. RESULTS: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy. CONCLUSIONS: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC.

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

An esculentin-1 homolog from a dark-spotted frog (Pelophylax nigromaculatus) possesses antibacterial and immunoregulatory properties.

BACKGROUND: Esculentin-1, initially discovered in the skin secretions of pool frogs (Pelophylax lessonae), has demonstrated broad-spectrum antimicrobial activity; however, its immunomodulatory properties have received little attention. RESULTS: In the present study, esculentin-1 cDNA was identified by analysing the skin transcriptome of the dark-spotted frog (Pelophylax nigromaculatus). Esculentin-1 from this species (esculentin-1PN) encompasses a signal peptide, an acidic spacer peptide, and a mature peptide. Sequence alignments with other amphibian esculentins-1 demonstrated conservation of the peptide, and phylogenetic tree analysis revealed its closest genetic affinity to esculentin-1P, derived from the Fukien gold-striped pond frog (Pelophylax fukienensis). Esculentin-1PN transcripts were observed in various tissues, with the skin exhibiting the highest mRNA levels. Synthetic esculentin-1PN demonstrated antibacterial activity against various pathogens, and esculentin-1PN exhibited bactericidal activity by disrupting cell membrane integrity and hydrolyzing genomic DNA. Esculentin-1PN did not stimulate chemotaxis in RAW264.7, a murine leukemic monocyte/macrophage cell line. However, it amplified the respiratory burst and augmented the pro-inflammatory cytokine gene (TNF-α and IL-1ß) expression in RAW264.7 cells. CONCLUSIONS: This novel finding highlights the immunomodulatory activity of esculentin-1PN on immune cells.

Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target.

Heat shock protein 70 (HSP70) is a highly conserved protein functioning as a "molecular chaperone", which is integral to protein folding and maturation. In addition to its high expression within cells upon stressful challenges, HSP70 can be translocated to the cell membrane or released from cells in free form or within extracellular vesicles (EVs). Such trafficking of HSP70 is also present in cancer cells, as HSP70 is overexpressed in various types of patient samples across a range of common malignancies, signifying that extracellular HSP70 (eHSP70) can serve as a tumor biomarker. eHSP70 is involved in a broad range of cancer-related events, including cell proliferation and apoptosis, extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), angiogenesis, and immune response. eHSP70 can also induce cancer cell resistance to various treatments, such as chemotherapy, radiotherapy, and anti-programmed death-1 (PD-1) immunotherapy. Though the role of eHSP70 in tumors is contradictory, characterized by both pro-tumor and anti-tumor effects, eHSP70 serves as a promising target in cancer treatment. In this review, we comprehensively summarized the current knowledge about the role of eHSP70 in cancer progression and treatment resistance and discussed the feasibility of eHSP70 as a cancer biomarker and therapeutic target.

Visible-Light-Induced C-H Cyanoalkylation of Azauracils with Cycloketone Oxime Esters via Catalytic EDA Complex.

Photoexcitation electron donor-acceptor (EDA) complexes provide an effective approach to produce radicals under mild conditions, while the catalytic version of EDA complex photoactivation remains scarce. Herein, we report a visible-light-induced organophotocatalytic pathway for the cyanoalkylation of azauracils using inexpensive and readily available 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalytic electron donor. This synthetic method exhibits exceptional compatibility with various functional groups and presents 34 examples in high yields. The efficient cyanoalkylation offers an environmentally friendly and sustainable route toward enhancing the structural and functional diversity of azauracils.

Integration of Network Pharmacology and Experimental Validation to Explore Jixueteng - Yinyanghuo Herb Pair Alleviate Cisplatin-Induced Myelosuppression.

Jixueteng, the vine of the bush Spatholobus suberectus Dunn., is widely used to treat irregular menstruation and arthralgia. Yinyanghuo, the aboveground part of the plant Epimedium brevicornum Maxim., has the function of warming the kidney to invigorate yang. This research aimed to investigate the effects and mechanisms of the Jixueteng and Yinyanghuo herbal pair (JYHP) on cisplatin-induced myelosuppression in a mice model. Firstly, ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) screened 15 effective compounds of JYHP decoction. Network pharmacology enriched 10 genes which may play a role by inhibiting the apoptosis of bone marrow (BM) cells. Then, a myelosuppression C57BL/6 mice model was induced by intraperitoneal (i.p.) injection of cis-Diaminodichloroplatinum (cisplatin, CDDP) and followed by the intragastric (i.g.) administration of JYHP decoction. The efficacy was evaluated by blood cell count, reticulocyte count, and histopathological analysis of bone marrow and spleen. Through the vivo experiments, we found the timing of JYHP administration affected the effect of drug administration, JYHP had a better therapeutical effect rather than a preventive effect. JYHP obviously recovered the hematopoietic function of bone marrow from the peripheral blood cell test and pathological staining. Flow cytometry data showed JYHP decreased the apoptosis rate of BM cells and the western blotting showed JYHP downregulated the cleaved Caspase-3/Caspase-3 ratios through RAS/MEK/ERK pathway. In conclusion, JYHP alleviated CDDP-induced myelosuppression by inhibiting the apoptosis of BM cells through RAS/MEK/ERK pathway and the optimal timing of JYHP administration was after CDDP administration.

Synergistic Redox Modulation for High-Performance Nickel Oxide-Based Inverted Perovskite Solar Modules.

Nickel oxide (NiOx)-based inverted perovskite solar cells stand as promising candidates for advancing perovskite photovoltaics towards commercialization, leveraging their remarkable stability, scalability, and cost-effectiveness. However, the interfacial redox reaction between high-valence Ni4+ and perovskite, alongside the facile conversion of iodide in perovskite into I2, significantly deteriorates the performance and reproducibility of NiOx-based perovskite photovoltaics. Here, potassium borohydride (KBH4) is introduced as a dual-action reductant, which effectively avoids the Ni4+/perovskite interface reaction and mitigates the iodide-to-I2 oxidation within perovskite film. This synergistic redox modulation significantly suppresses nonradiative recombination and increases the carrier lifetime. As a result, an impressive power conversion efficiency of 24.17% for NiOx-based perovskite solar cells is achieved, and a record efficiency of 20.2% for NiOx-based perovskite solar modules fabricated under ambient conditions. Notably, when evaluated using the ISOS-L-2 standard protocol, the module retains 94% of its initial efficiency after 2000 h of continuous illumination under maximum power point at 65 °C in ambient air.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

Lead-free Cs2AgBiBr6 double perovskite microcrystals for effective visible-light photocatalytic thio/selenocyanation.

Lead-free perovskite microcrystals (MCs) have been regarded as promising potential photocatalysts, owing to their high molar extinction coefficient, low economic cost, adjustable light absorption range, and ample surface-active sites. Herein, C-3 thio/selenocyanation of indoles is demonstrated in high selectivity and yield by using lead-free double perovskite Cs2AgBiBr6 MCs under visible light irradiation. Moreover, the photocatalyst can be recycled at least 5 times without a significant decrease in catalytic activity.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Knowledge mapping of digital medicine in cardiovascular diseases from 2004 to 2022: A bibliometric analysis.

Objective: To review studies on digital medicine in cardiovascular diseases (CVD), discuss its development process, knowledge structure and research hotspots, and provide a perspective for researchers in this field. Methods: The relevant literature in recent 20 years (January 2004 to October 2022) were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used to demonstrate our knowledge of keywords, co-references and speculative frontiers. VOSviewer was used to chart the contributions of authors, institutions and countries and incorporates their link strength into the table. Results: A total of 5265 English articles in set timespan were included. The number of publications increased steadily annually. The United States (US) produced the highest number of publications, followed by England. Most publications were from Harvard Medicine School, followed by Massachusetts General Hospital and Brigham Women's Hospital. The most authoritative academic journal was JMIR mHealth and uHealth. Noseworthy PA may have the highest influence in this intersected field with the highest number of citations and total link strength. The utilization of wearable mobile devices in the context of CVD, encompassing the identification of risk factors, diagnosis and prevention of diseases, as well as early intervention and remote management of diseases, has been widely acknowledged as a knowledge base and an area of current interest. To investigate the impact of various digital medicine interventions on chronic care and assess their clinical effectiveness, examine the potential of machine learning (ML) in delivering clinical care for atrial fibrillation (AF) and identifying early disease risk factors, as well as explore the development of disease prediction models using neural networks (NNs), ML and unsupervised learning in CVD prognosis, may emerge as future trends and areas of focus. Conclusion: Recently, there has been a significant surge of interest in the investigation of digital medicine in CVD. This initial bibliometric study offers a comprehensive analysis of the research landscape pertaining to digital medicine in CVD, thereby furnishing related scholars with a dependable reference to facilitate further progress in this domain.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Visible-light-driven EDA complex-promoted cascade cyclization to construct 4-cyanoalkyl isoquinoline-1,3-diones.

Visible-light-induced EDA complex-promoted ring-opening of cycloketone oxime esters to synthesise various cyanoalkylated products with N-methacryloyl benzamides was developed. Various radical receptors were compatible with the current reaction system to furnish diverse heterocyclic compounds. Mechanistic analysis shows that the formation of an EDA complex was crucial to the photocatalytic strategy. Importantly, 4-cyanoalkyl isoquinoline-1,3-diones were obtained in high yields by using a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) through prolonging the reaction time, which provided a practical approach to give a variety of isoquinoline-1,3-dione derivatives.