Role of Trimethylamine N-Oxide in Heart Failure.

Heart failure (HF) is a clinical syndrome characterizing by typical physical signs and symptomatology resulting from reduced cardiac output and/or intracardiac pressure at rest or under stress due to structural and/or functional abnormalities of the heart. HF is often the final stage of all cardiovascular diseases and a significant risk factor for sudden cardiac arrest, death, and liver or kidney failure. Current pharmacological treatments can only slow the progression and recurrence of HF. With advancing research into the gut microbiome and its metabolites, one such trimethylamine N-oxide (TMAO)-has been implicated in the advancement of HF and is correlated with poor prognosis in patients with HF. However, the precise role of TMAO in HF has not yet been clarified. This review highlights and concludes the available evidence and potential mechanisms associated with HF, with the hope of contributing new insights into the diagnosis and prevention of HF.

Nomogram models predicting prognosis for patients with t(8;21) acute myeloid leukemia: a SEER-based study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) manifests as a diverse hematological malignancy. Although it was categorized into a favorable subtype, 30-40% of patients experience relapse. The objective of this research was to devise a nomogram for the accurate anticipation of both overall survival (OS) and cancer-specific survival (CSS) in t(8;21) AML. METHODS: From the Surveillance, Epidemiology, and End Results (SEER) database, individuals diagnosed with t(8;21) AML from 2000 to 2018 were selected. Prognostic factors for t(8;21) AML were identified using Cox regression analysis and Akaike Information Criterion (AIC), forming the basis for constructing prognostic nomograms. RESULTS: Key variables, including first primary tumor, age group, race, and chemotherapy, were identified and integrated into the nomogram. The C-index values for the nomograms predicting OS and CSS were 0.753 (validation: 0.765) and 0.764 (validation: 0.757), respectively. Ultimately, based on nomogram scores, patients were stratified into high-risk and low-risk groups, revealing significant disparities in both OS and CSS between these groups (P < 0.001). CONCLUSION: This study innovatively crafted nomograms, incorporating clinical and therapeutic variables, to forecast the 1-, 3-, and 5-year survival rates for individuals with t(8;21) AML.

Postmastectomy radiotherapy in breast reconstruction: Current controversies and trends.

Breast cancer is the most common cancer among women worldwide. Postmastectomy radiotherapy (PMRT) is an essential component of combined therapy for early-stage, high-risk breast cancer. Breast reconstruction (BR) is often considered for patients with breast cancer who have undergone mastectomy. There has been a considerable amount of discussion about the optimal approach to combining PMRT with BR in the treatment of breast cancer. PMRT may increase the risk of complications and prevent good aesthetic results after BR, while BR may increase the complexity of PMRT and the radiation dose to surrounding normal tissues. The purpose of this review is to give a broad overview and summary of the current controversies and trends in PMRT and BR in the context of the most recent literature available.

Accelerated partial breast irradiation: Current evidence and future developments.

Whole breast irradiation after breast-conserving surgery for early breast cancer has become one of the standard treatment modes for breast cancer and yields the same effect as radical surgery. Accelerated partial breast irradiation (APBI) as a substitute for whole breast irradiation for patients with early breast cancer is a hot spot in clinical research. APBI is characterised by simple high-dose local irradiation of the tumour bed in a short time, thus improving convenience for patients and saving costs. The implementation methods of APBI mainly include brachytherapy, external beam radiation therapy, and intraoperative radiotherapy. This review provides an overview of the clinical effects and adverse reactions of the main technologies of APBI and discusses the prospects for the future development of APBI.

Analysis of gastric electrical rhythm in patients with type 2 diabetes mellitus.

AIM: To analysis the change of electrogastrogram (EGG) in patients with type 2 diabetes mellitus (T2DM), and evaluate the prevalence of abnormal gastric electrical rhythm (AGER) and its relative influencing factors. METHODS: A total of 65 patients with T2DM hospitalized at the Second Affiliated Hospital of Soochow University from Dec. 2020 to Dec. 2021 were included in the cross-sectional study. General information, clinical data, and medical history data of all study subjects, including name, gender, body mass index (BMI), duration of diabetes, anti-diabetic therapies, high blood pressure (HBP) history, smoking history, and medication history, were completely collected. The results of laboratory tests, including biochemical parameters, glycosylated hemoglobin (HbA1c), fasting C-peptide, 2 h postprandial C-peptide, 24 h urine total protein (24 hUTP), urine microalbumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were recorded. EGG, Gastroparesis Cardinal Symptom Index (GCSI), gastric emptying ultrasound, fundus examination, carotid artery ultrasonography, cardiac autonomic function test, heart rate variability (HRV) were all examined and recorded as well. According to the results of EGG, the subjects were divided into normal gastric electrical rhythm (NGER) group and abnormal gastric electrical rhythm (AGER) group. RESULTS: (1) Fasting blood glucose (FBG), HbA1c, the presence of diabetic peripheral neuropathy (DPN) and diabetic cardiac autonomic neuropathy (DCAN) were significantly higher in the AGER group (p < 0.05). Low frequency (LF) and high frequency (HF), the indicators of HRV, were significantly lower in the AGER group (p < 0.05). In addition, the prevalence of feeling excessively full after meals, loss of appetite, and stomach or belly visibly larger after meals of gastrointestinal symptoms of gastroparesis were significantly higher in the AGER group (p < 0.05). Multiple logistic regression analysis showed that FBG and the prevalence of DCAN were the independent risk factors. CONCLUSION: AGER was associated with high FBG and the presence of DCAN. EGG examination is recommended for patients with gastrointestinal symptoms and clues of DCAN.

Prognostic Factors of Pediatric Acute Myeloid Leukemia Patients with t(8;21) (q22;q22): A Single-Center Retrospective Study.

This retrospective study aimed to analyze the treatment effect and prognostic factors of pediatric acute myeloid leukemia (AML) patients with t(8;21). A total of 268 newly diagnosed pediatric AML (pAML) enrolled from 1 January 2005 to 31 December 2022 were retrospectively reviewed, and 50 (18.7%) patients harbored t(8;21) translocation. CR rate, OS, EFS, and RFS were assessed by multivariate Logistic and Cox regression models in these patients. Of the 50 patients, 2 patients abandoned treatment during the first induction course. Of the remaining 48 patients who received double-induction therapy and were included in the final analyses, CR1 and CR2 were 75.0% (36/48) and 95.8% (46/48), respectively. The overall three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0-85.1), 64.2% (95% CI, 50.7-81.4), and 65.5% (95% CI, 51.9-82.8), respectively. The presence of loss of sex chromosome (LOS) at diagnosis (n = 21) was associated with a better 3-year OS [87.5% (95% CI, 72.7-100) vs. 52.7% (95% CI, 35.1-79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7-100) vs. 49.7% (95% CI, 32.4-76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7-100) vs. 51.7% (95% CI, 33.9-78.9), p = 0.036] than those without LOS (n = 27), and it was also an independent good prognostic factor of OS (HR, 0.08 [95% CI, 0.01-0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05-0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05-0.90], p = 0.035). However, extramedullary leukemia (EML) featured the independent risk factors of inferior OS (HR, 10.99 [95% CI, 2.08-58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10-20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40-30.63], p = 0.017) in pediatric individuals with t(8;21) AML. Further analysis of combining LOS with EML indicated that the EML+LOS- subgroup had significantly inferior OS (92.9%, [95% CI, 80.3-100]), EFS (86.2%, [95% CI, 70.0-100]), and RFS (86.2%, [95% CI, 80.3-100]) compared to the other three subgroups (all p < 0.001). LOS and EML are independent prognostic factors of OS, EFS, and RFS with t(8;21) pAML patients. LOS combined with EML may help improve risk stratification.

Porous Hydrogels for Immunomodulatory Applications.

Cancer immunotherapy relies on the insight that the immune system can be used to defend against malignant cells. The aim of cancer immunotherapy is to utilize, modulate, activate, and train the immune system to amplify antitumor T-cell immunity. In parallel, the immune system response to damaged tissue is also crucial in determining the success or failure of an implant. Due to their extracellular matrix mimetics and tunable chemical or physical performance, hydrogels are promising platforms for building immunomodulatory microenvironments for realizing cancer therapy and tissue regeneration. However, submicron or nanosized pore structures within hydrogels are not favorable for modulating immune cell function, such as cell invasion, migration, and immunophenotype. In contrast, hydrogels with a porous structure not only allow for nutrient transportation and metabolite discharge but also offer more space for realizing cell function. In this review, the design strategies and influencing factors of porous hydrogels for cancer therapy and tissue regeneration are first discussed. Second, the immunomodulatory effects and therapeutic outcomes of different porous hydrogels for cancer immunotherapy and tissue regeneration are highlighted. Beyond that, this review highlights the effects of pore size on immune function and potential signal transduction. Finally, the remaining challenges and perspectives of immunomodulatory porous hydrogels are discussed.

Comparing the efficacy and pregnancy outcome of intrauterine balloon and intrauterine contraceptive device in the prevention of adhesion reformation after hysteroscopic adhesiolysis in infertile women: a prospective, randomized, controlled trial study.

STUDY OBJECTIVE: To evaluate the efficacy and pregnancy outcomes of intrauterine balloon and intrauterine contraceptive devices in the prevention of adhesion reformation following hysteroscopic adhesiolysis in infertile women with moderate to severe intrauterine adhesion. DESIGN: A prospective, randomized, controlled trial study. SETTING: A tertiary university hospital. PATIENTS: A total of 130 patients with moderate (American Fertility Society [AFS] score of 5-8) and severe (AFS score of 9-12) intrauterine adhesions were recruited. INTERVENTIONS: 86 patients were evenly allocated to group treated with an IUD for 1 month and group treated with an IUD for 2 months. 44 patients were allocated to group treated with a Foley catheter balloon.(IUD: Yuangong IUD). MEASUREMENTS AND MAIN RESULTS: The primary outcome measures were the AFS score, endometrial thickness, and pregnancy outcome. After hysteroscopy, the AFS score was significantly decreased(P<0.05), whereas endometrial thickness was significantly increased across the three groups(P<0.001). Notably, the decline in the AFS score in the balloon group was greater than that in the IUD-1-month group and IUD-2-month group(P<0.01), with no significant difference between the IUD groups(P = 0.298). Lastly, In addition, the extent of the increase in endometrial thickness(P = 0.502) and the pregnancy outcomes(P = 0.803) in the three groups were not significantly different. CONCLUSION: Inserting a balloon or placing an IUD for one or two months can effectively lower the risk of adhesion recurrence and restore the shape of the uterine cavity. While the therapeutic effect of the balloon was superior to that of the IUD, no significant differences were observed in the one-month and two-month IUD groups. TRIAL REGISTRATION: This research was registered in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/enIndex.aspx ); Clinical trial registry identification number: ChiCTR-IOR-17,011,943 ( http://www.chictr.org.cn/showprojen.aspx?proj=17979 ). Date of trial registration: July 11, 2017.

Theory and design of parallel decoding for a ternary optical computer.

A hardware-based parallel decoding scheme is proposed to address the problems of correctness and efficiency of software decoding for ternary optical computers. Based on the minimal primitive structure of the ternary optical computer, a hardware decoding voltage divider circuit and single-pixel transcoding of operation results are designed. A parallel decoding scheme is designed for the SJ-MSD unconventional adder based on Shen's theorem and the TW-MSD conventional adder under the degraded design theory, and a corresponding addressing scheme is proposed for the access of decoding results. After comprehensive consideration, the decoding scheme is finally selected as the time-sharing combination. The experiments show that the parallel decoding scheme of the ternary optical computer is practical and feasible.

Attenuation of phytofungal pathogenicity of Ascomycota by autophagy modulators.

Autophagy in eukaryotes functions to maintain homeostasis by degradation and recycling of long-lived and unwanted cellular materials. Autophagy plays important roles in pathogenicity of various fungal pathogens, suggesting that autophagy is a novel target for development of antifungal compounds. Here, we describe bioluminescence resonance energy transfer (BRET)-based high-throughput screening (HTS) strategy to identify compounds that inhibit fungal ATG4 cysteine protease-mediated cleavage of ATG8 that is critical for autophagosome formation. We identified ebselen (EB) and its analogs ebselen oxide (EO) and 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PT) as inhibitors of fungal pathogens Botrytis cinerea and Magnaporthe oryzae ATG4-mediated ATG8 processing. The EB and its analogs inhibit spore germination, hyphal development, and appressorium formation in Ascomycota pathogens, B. cinerea, M. oryzae, Sclerotinia sclerotiorum and Monilinia fructicola. Treatment with EB and its analogs significantly reduced fungal pathogenicity. Our findings provide molecular insights to develop the next generation of antifungal compounds by targeting autophagy in important fungal pathogens.

Relationship between hyperuricemia and the risk of cardiovascular events and chronic kidney disease in both the general population and hypertensive patients: A systematic review and meta-analysis.

BACKGROUND: To explore the relationships between hyperuricemia and the risk of cardiovascular diseases (CVD) and chronic kidney disease (CKD) in both the general population and hypertensive patients through meta-analysis. METHODS AND RESULTS: We systematically searched PubMed, Embase, and Cochrane Library databases from January 2012. The eligibility criteria were predefined, and quality was assessed using the Newcastle-Ottawa Scale (NOS). Stata 15.1 was used for meta-analysis, heterogeneity and sensitivity analysis. Subgroup analysis was used to explore heterogeneity, funnel plots and Egger tests were used to assesse publication bias and applicability. A total of 10,662 studies were retrieved, 45 of which were included in this meta-analysis utilizing a random effects model. Hyperuricemia was significantly associated with an increased risk of new-onset hypertension (RR = 1.36, 95% CI 1.16-1.59; I2 = 98.8%), total CVD (RR = 1.53, 95% CI 1.23-1.89; I2 = 93.7%), stroke (RR = 1.97, 95% CI 1.71-2.26, I2 = 0.0%), coronary heart disease (CHD) (RR = 1.56, 95% CI 1.06-2.30, I2 = 93.3%), and CKD (RR = 1.71, 95% CI 1.56-1.87; I2 = 87.3%). However, subgroup analysis showed no significant associations between hyperuricemia and hypertension in non-Asian populations (RR = 0.88, 95% CI 0.59-1.33), or between hyperuricemia and CVD with a follow-up duration <5 years (RR = 1.26, 95% CI 0.97-1.63). Among hypertensive patients, hyperuricemia was significantly associated with total CVD (RR = 2.32, 95% CI 1.31-4.12, I2 = 90.2%), but not with stroke (RR = 1.48, 95% CI 0.86-2.55; I2 = 90.7%) or CHD (RR = 1.51, 95% CI 0.98-2.33; I2 = 71.7%). CONCLUSION: Hyperuricemia was significantly associated with an increased risk of new-onset hypertension, total CVD, stroke, CHD, and CKD in the general population. Among hypertensive patients, hyperuricemia was associated with an increased risk of CVD but not stroke or CHD alone. REGISTRATION NUMBER: CRD42022370692.

Cardioprotective Strategies After Ischemia-Reperfusion Injury.

Acute myocardial infarction (AMI) is associated with high morbidity and mortality worldwide. Although early reperfusion is the most effective strategy to salvage ischemic myocardium, reperfusion injury can develop with the restoration of blood flow. Therefore, it is important to identify protection mechanisms and strategies for the heart after myocardial infarction. Recent studies have shown that multiple intracellular molecules and signaling pathways are involved in cardioprotection. Meanwhile, device-based cardioprotective modalities such as cardiac left ventricular unloading, hypothermia, coronary sinus intervention, supersaturated oxygen (SSO2), and remote ischemic conditioning (RIC) have become important areas of research. Herein, we review the molecular mechanisms of cardioprotection and cardioprotective modalities after ischemia-reperfusion injury (IRI) to identify potential approaches to reduce mortality and improve prognosis in patients with AMI.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Corneal characteristics of Mongolian population with type 2 diabetic peripheral neuropathy in inner Mongolia, China: an assessment using corneal confocal microscopy.

OBJECTIVE: To quantify corneal nerve fiber parameters in a Mongolian population with diabetic peripheral neuropathy (DPN) by corneal confocal microscopy. METHODS: This study conducted a comprehensive evaluation of 114 participants from Hulunbuir between January 2020 and December 2021. The participants included healthy controls, Mongolian and Han patients with type 2 diabetes mellitus. Demographic, medical, and laboratory data were collected, and neuropathy was evaluated by confocal corneal microscopy. And compare various parameters between Han and Mongolian were performed using SPSS software. RESULTS: The average waist circumference of Mongolian diabetic patients was larger than that of Han diabetic patients (P < 0.05). The mean HbA1c of Mongolian was 9.30 (8.15, 10.30) %, and that of Han was 8.30 (7.20, 9.40) % (P = 0.023). The average values of Corneal Nerve Fiber Density (CNFD), Corneal Nerve Fiber Length (CNFL) and corneal nerve branch density (CNBD) in Mongolian diabetic patients were significantly lower than those in Han diabetic patients (P < 0.05). The correlation coefficient between CNFL and age was - 0.368. ROC results show that CNBD has a certain diagnostic value for DPN in Mongolian patients with type 2 diabetes and the optimal cut-off point value is 24.99(no./mm2), the sensitivity is 80.0%, and the specificity is 77.8%. CONCLUSION: The corneal confocal microscopy could possibly represent a promising adjuvant technique for the early diagnosis and assessment of PDN in Mongolian T2DM patients.

Driving Force Analysis of Natural Wetland in Northeast Plain Based on SSA-XGBoost Model.

Globally, natural wetlands have suffered severe ecological degradation (vegetation, soil, and biotic community) due to multiple factors. Understanding the spatiotemporal dynamics and driving forces of natural wetlands is the key to natural wetlands' protection and regional restoration. In this study, we first investigated the spatiotemporal evolutionary trends and shifting characteristics of natural wetlands in the Northeast Plain of China from 1990 to 2020. A dataset of driving-force evaluation indicators was constructed with nine indirect (elevation, temperature, road network, etc.) and four direct influencing factors (dryland, paddy field, woodland, grassland). Finally, we built the driving force analysis model of natural wetlands changes to quantitatively refine the contribution of different driving factors for natural wetlands' dynamic change by introducing the sparrow search algorithm (SSA) and extreme gradient boosting algorithm (XGBoost). The results showed that the total area of natural wetlands in the Northeast Plain of China increased by 32% from 1990 to 2020, mainly showing a first decline and then an increasing trend. Combined with the results of transfer intensity, we found that the substantial turn-out phenomenon of natural wetlands occurred in 2000-2005 and was mainly concentrated in the central and eastern parts of the Northeast Plain, while the substantial turn-in phenomenon of 2005-2010 was mainly located in the northeast of the study area. Compared with a traditional regression model, the SSA-XGBoost model not only weakened the multicollinearity of each driver but also significantly improved the generalization ability and interpretability of the model. The coefficient of determination (R2) of the SSA-XGBoost model exceeded 0.6 in both the natural wetland decline and rise cycles, which could effectively quantify the contribution of each driving factor. From the results of the model calculations, agricultural activities consisting of dryland and paddy fields during the entire cycle of natural wetland change were the main driving factors, with relative contributions of 18.59% and 15.40%, respectively. Both meteorological (temperature, precipitation) and topographic factors (elevation, slope) had a driving role in the spatiotemporal variation of natural wetlands. The gross domestic product (GDP) had the lowest contribution to natural wetlands' variation. This study provides a new method of quantitative analysis based on machine learning theory for determining the causes of natural wetland changes; it can be applied to large spatial scale areas, which is essential for a rapid monitoring of natural wetlands' resources and an accurate decision-making on the ecological environment's security.

HGR-Net: Hierarchical Graph Reasoning Network for Arbitrary Shape Scene Text Detection.

As a prerequisite step of scene text reading, scene text detection is known as a challenging task due to natural scene text diversity and variability. Most existing methods either adopt bottom-up sub-text component extraction or focus on top-down text contour regression. From a hybrid perspective, we explore hierarchical text instance-level and component-level representation for arbitrarily-shaped scene text detection. In this work, we propose a novel Hierarchical Graph Reasoning Network (HGR-Net), which consists of a Text Feature Extraction Network (TFEN) and a Text Relation Learner Network (TRLN). TFEN adaptively learns multi-grained text candidates based on shared convolutional feature maps, including instance-level text contours and component-level quadrangles. In TRLN, an inter-text graph is constructed to explore global contextual information with position-awareness between text instances, and an intra-text graph is designed to estimate geometric attributes for establishing component-level linkages. Next, we bridge the cross-feed interaction between instance-level and component-level, and it further achieves hierarchical relational reasoning by learning complementary graph embeddings across levels. Experiments conducted on three publicly available benchmarks SCUT-CTW1500, Total-Text, and ICDAR15 have demonstrated that HGR-Net achieves state-of-the-art performance on arbitrary orientation and arbitrary shape scene text detection.

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome.

BACKGROUND: The validation of various risk scores in elderly patients with comorbid atrial fibrillation (AF) and acute coronary syndrome (ACS) has not been reported. The present study compared the predictive performance of existing risk scores in these patients. METHODS: A total of 1252 elderly patients with AF and ACS comorbidities (≥ 65 years old) were consecutively enrolled from January 2015 to December 2019. All patients were followed up for one year. The predictive performance of risk scores in predicting bleeding and thromboembolic events was calculated and compared. RESULTS: During the 1-year follow-up, 183 (14.6%) patients had thromboembolic events, 198 (15.8%) patients had BARC class ≥ 2 bleeding events, and 61 (4.9%) patients had BARC class ≥ 3 bleeding events. For the BARC class ≥ 3 bleeding events, discrimination of the existing risk scores was low to moderate, PRECISE-DAPT (C-statistic: 0.638, 95% CI: 0.611-0.665), ATRIA (C-statistic: 0.615, 95% CI: 0.587-0.642), PARIS-MB (C-statistic: 0.612, 95% CI: 0.584-0.639), HAS-BLED (C-statistic: 0.597, 95% CI: 0.569-0.624) and CRUSADE (C-statistic: 0.595, 95% CI: 0.567-0.622). However, the calibration was good. PRECISE-DAPT showed a higher integrated discrimination improvement (IDI) than PARIS-MB, HAS-BLED, ATRIA, and CRUSADE (P < 0.05) and the best decision curve analysis (DCA). For thromboembolic events, the discrimination of GRACE (C-statistic: 0.636, 95% CI: 0.608-0.662) was higher than CHA2DS2-VASc (C-statistic: 0.612, 95% CI: 0.584-0.639), OPT-CAD (C-statistic: 0.602, 95% CI: 0.574-0.629) and PARIS-CTE (C-statistic: 0.595, 95% CI: 0.567-0.622). The calibration was good. Compared to OPT-CAD and PARIS-CTE, the IDI of the GRACE score slightly improved (P < 0.05). However, NRI analysis showed no significant difference. DCA showed that the clinical practicability of thromboembolic risk scores was similar. CONCLUSIONS: The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS. PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class ≥ 3 bleeding events. The GRACE score showed a slight advantage in predicting thrombotic events.

A novel F8 variant in a Chinese hemophilia A family and involvement of X-chromosome inactivation: A case report.

RATIONALE: Hemophilia A (HA) is an X-linked recessive bleeding disorder, which shows factor VIII (FVIII) deficiency caused by genetic variant in F8 gene. PATIENT CONCERNS: Males with F8 variants are affected, whereas female carriers with a wide range of FVIII levels are usually asymptomatic, it is possible that different X-chromosome inactivation (XCI) may effect the FVIII activity. DIAGNOSES: We identified a novel variant F8: c.6193T > G in a Chinese HA proband, it was inherited from the mother and grandmother with different FVIII levels. INTERVENTIONS: We performed Androgen receptor gene (AR) assays and RT-PCR. OUTCOMES: AR assays revealed that the X chromosome with the F8 variant was severely skewed inactivated in the grandmother with higher FVIII levels, but not in the mother with lower FVIII levels. Further, RT-PCR of mRNA confirmed that only the wild allele of F8 was expressed in the grandmother, with lower expression in the wild allele of the mother. LESSONS: Our findings suggest that F8: c.6193T > G could be the cause of HA and that XCI affected the FVIII plasma levels in female carriers.

Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.