Associations between multiple urinary metals and metabolic syndrome: Exploring the mediating role of liver function in Chinese community-dwelling elderly.

BACKGROUND: Multiple metals exposure has been revealed to be related to metabolic syndrome (MetS). However, the associations and interactions between multiple metals exposure and MetS are remains controversial, and the potential mechanism of the above-mentioned is still unclear. METHODS: The associations between urinary metals and the MetS were analyzed by multivariable logistic regression model and restricted cubic spline (RCS). Bayesian kernel machine regression (BKMR) model and quantile-based g-computation (qgcomp) were applied to explore the mixed exposure and interaction effect of metals. Mediation analysis was used to explore the role of liver function. RESULTS: In the single metal model, multiple metals were significantly associated with MetS. RCS analysis further verified the associations between 8 metals and MetS. BKMR model and qgcomp showed that zinc (Zn), iron (Fe), and tellurium (Te) were the main factors affecting the overall effect. In addition, mediation analysis indicated that serum alanine aminotransferase (ALT) mediated 21.54% and 13.29% in the associations of vanadium (V) and Zn with the risk of MetS, respectively. CONCLUSIONS: Elevated urinary concentration of Zn, V, Te, copper (Cu), molybdenum (Mo), and thallium (Tl) were related to the increased risk of MetS. Conversely, Fe and selenium (Se) may be protective factors for MetS in mixed exposure. Liver function may play a key role in the association of V and Zn exposure with MetS.

Engineering Plateau Phase Transition in Quantum Anomalous Hall Multilayers.

The plateau phase transition in quantum anomalous Hall (QAH) insulators corresponds to a quantum state wherein a single magnetic domain gives way to multiple domains and then reconverges back to a single magnetic domain. The layer structure of the sample provides an external knob for adjusting the Chern number C of the QAH insulators. Here, we employ molecular beam epitaxy to grow magnetic topological insulator multilayers and realize the magnetic field-driven plateau phase transition between two QAH states with odd Chern number change ΔC. We find that critical exponents extracted for the plateau phase transitions with ΔC = 1 and ΔC = 3 in QAH insulators are nearly identical. We construct a four-layer Chalker-Coddington network model to understand the consistent critical exponents for the plateau phase transitions with ΔC = 1 and ΔC = 3. This work will motivate further investigations into the critical behaviors of plateau phase transitions with different ΔC in QAH insulators.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Divergent Roles of Early Visual Cortex and Inferior Frontal Junction in Visual Working Memory.

BACKGROUND: Recent studies indicate that both prefrontal and visual regions play critical roles in visual working memory (VWM), with prefrontal regions mainly associated with executive functions, and visual cortices linked to representations of memory contents. VWM involves the selective filtering of irrelevant information, yet the specific contributions of the prefrontal regions and visual cortex in this process remain unclear. OBJECTIVE: To understand the dynamic causal roles of prefrontal and visual regions in VWM. METHODS: The differentiation of VWM components was achieved using a computational model that incorporated a swap rate for non-target stimuli. Single-pulse magnetic transcranial stimulation (spTMS) was delivered to the early visual cortex (EVC) and the inferior frontal junction (IFJ) across different phases of an orientation recall task that with or without distractors. RESULTS: Our results indicate that spTMS over the EVC and IFJ influences VWM particularly when distractors are present. VWM precision can be impacted by spTMS applied to either region during the early retention, while spTMS effect is especially prominent when EVC is stimulated during the late retention phase and when directed at the ipsilateral EVC. Conversely, the probability of accurately recalling the target exhibited comparable patterns when spTMS was administered to either the EVC or IFJ. CONCLUSIONS: We highlight the "sensory recruitment" of VWM characterized by critical involvement of EVC particularly in the information-filtering process within VWM. The maintenance of memory content representations necessitates ongoing communication between the EVC and IFJ throughout the entirety of the VWM process in a dynamic pattern.

Relationship between human serum metabolites and angina pectoris: a Mendelian randomization study.

PURPOSE: We aimed to explore the causal relationship between human serum metabolites and angina pectoris. METHODS: This study used two-sample Mendelian randomization (MR) analysis to assess the association between 486 serum metabolites and angina pectoris. The analytical methods employed to reduce study bias included inverse variance weighted, MR-Egger, and weighted median method. A comprehensive sensitivity analysis was performed using the leave-one-out method, while instrumental variable pleiotropy was tested with MR-Pleiotropy RESidual Sum and Outlier. Metabolic pathways of angina-associated metabolites were analysed on the MetaboAnalyst metabolomics analysis tool platform. RESULTS: In this study, 42 serum metabolites were found to be strongly associated with angina pectoris. They mainly belonged to seven groups: amino acids, carbohydrates, cofactors and vitamins, lipids, nucleotides, unknown metabolites, and exogenous substances. Pipecolate posed the highest risk for the development of angina pectoris among the 42 serum metabolites. The main metabolic pathways associated with angina pectoris were glycine, serine, threonine metabolism, primary bile acid biosynthesis, and caffeine metabolism. CONCLUSION: We identified 25 high-risk and 17 protective human serum metabolites associated with angina pectoris. Their associated major metabolic pathways were also determined. The serum metabolite pipecolate was significantly and positively correlated with the risk of angina pectoris. This finding may serve as a valuable reference for testing serum markers associated with angina pectoris.

Tetramethylpyrazine alleviates ferroptosis and promotes functional recovery in spinal cord injury by regulating GPX4/ACSL4.

OBJECTIVE: Tetramethylpyrazine (TMP) has been demonstrated to alleviate neuronal ferroptosis following spinal cord injury (SCI), thereby promoting neural repair. However, the precise underlying mechanisms remain elusive. METHODS: The SCI model was established using a modified version of Allen's method. TMP (40, 80, 120, and 160 mg/kg) and ras-selective lethal 3 (RSL3) (5 mg/kg) were administered intraperitoneally once daily for 7 days. HE and Nissl staining were employed to examine histomorphology and neurons, respectively. Perls staining was used to identify the distribution of iron. A transmission electron microscope was used to observe the microcosmic morphology of mitochondria. Immunofluorescence staining and western blot were used to analyze neuronal nuclear protein (NeuN) and glial fibrillary acidic protein (GFAP) surrounding injury sites. Additionally, glutathione peroxidase 4 (GPX4)/NeuN+ cells and acyl-CoA synthetase long-chain family member 4 (ACSL4)/NeuN+ cells were observed. RT-qPCR was conducted to examine the mRNA expression levels of GPX4 and ACSL4. ELISA were used to quantify the concentrations of GPX4, reactive oxygen species (ROS), L-glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and tissue iron. RESULTS: TMP had an inhibitory effect on the concentrations of tissue iron, ROS, GSH, MDA, and SOD. TMP improved the microcosmic morphology of mitochondria and increased GPX4 level while decreasing that of ACSL4. TMP reduced lesion sizes, enhanced neuronal survival, and inhibited glial scar formation. However, the effect of TMP can be effectively reversed by RSL3. CONCLUSION: TMP alleviates neuronal ferroptosis by regulating the GPX4/ACSL4 axis, thereby protecting the remaining neurons surrounding injury sites and reducing glial scar formation.

Fluoride impairs vascular smooth muscle A7R5 cell lines via disrupting amino acids metabolism.

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

Mobility capillary electrophoresis-native mass spectrometry reveals the dynamic conformational equilibrium of calmodulin and its complexes.

Benefitting from the rapid evolution of artificial intelligence and structural biology, an expanding collection of high-resolution protein structures has greatly improved our understanding of protein functions. Yet, proteins are inherently flexible, and these static structures can only offer limited snapshots of their true dynamic nature. The conformational and functional changes of calmodulin (CaM) induced by Ca2+ binding have always been a focus of research. In this study, the conformational dynamics of CaM and its complexes were investigated using a mobility capillary electrophoresis (MCE) and native mass spectrometry (native MS) based method. By analyzing the ellipsoidal geometries of CaM in the solution phase at different Ca2+ concentrations, it is interesting to discover that CaM molecules, whether bound to Ca2+ or not, possess both closed and open conformations. Moreover, each individual CaM molecule actively "jumps" (equilibrium exchange) between these two distinct conformations on a timescale ranging from milli- to micro-seconds. The binding of Ca2+ ions did not affect the structural dynamics of CaM, while the binding of a peptide ligand would stabilize CaM, leading to the observation of a single, compact conformation of the resulting protein complex. A target recognition mechanism was also proposed based on these new findings, suggesting that CaM's interaction with targets may favor a conformational selection model. This enriches our understanding of the binding principles between CaM and its numerous targets.

Use of artificial intelligence in obstetric and gynaecological diagnostics: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Emerging developments in applications of artificial intelligence (AI) in healthcare offer the opportunity to improve diagnostic capabilities in obstetrics and gynaecology (O&G), ensuring early detection of pathology, optimal management and improving survival. Consensus on a robust AI healthcare framework is crucial for standardising protocols that promote data privacy and transparency, minimise bias, and ensure patient safety. Here, we describe the study protocol for a systematic review and meta-analysis to evaluate current applications of AI in O&G diagnostics with consideration of reporting standards used and their ethical implications. This protocol is written following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 checklist. METHODS AND ANALYSIS: The study objective is to explore the current application of AI in O&G diagnostics and assess the reporting standards used in these studies. Electronic bibliographic databases MEDLINE, EMBASE and Cochrane will be searched. Study selection, data extraction and subsequent narrative synthesis and meta-analyses will be carried out following the PRISMA-P guidelines. Included papers will be English-language full-text articles from May 2015 to March 2024, which provide original data, as AI has been redefined in recent literature. Papers must use AI as the predictive method, focusing on improving O&G diagnostic outcomes.We will evaluate the reporting standards including the risk of bias, lack of transparency and consider the ethical implications and potential harm to patients. Outcome measures will involve assessing the included studies against gold-standard criteria for robustness of model development (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis, model predictive performance, model risk of bias and applicability (Prediction model Risk Of Bias Assessment Tool and study reporting (Consolidated Standards of Reporting Trials-AI) guidance. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review. Findings will be shared through peer-reviewed publications. There will be no patient or public involvement in this study. PROSPERO REGISTRATION NUMBER: CRD42022357024 .

Clinical outcomes of pomalidomide-based and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma: A real-world cohort study in China.

BACKGROUND: Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real-world studies. METHODS: This retrospective cohort study included 140 RRMM patients treated with Pom-based or Dara-based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023. RESULTS: The overall response rates (ORR) for Pom-based (n = 48), Dara-based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression-free survival (PFS) was 5.7 months (95% CI: 5.0-6.5) for the Pom-based group, 10.5 months (5.2-15.8) for the Dara-based group, and 6.7 months (4.0-9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double-refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara-based regimens over Pom-based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara-based and DPd regimens (Pom-based 39.6% vs. Dara-based 64.7% vs. DPd 70.8%, p = 0.009). CONCLUSIONS: In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy.

CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/ß-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

MiR-150-5p Alleviates Renal Tubule Epithelial Cell Fibrosis via the Inhibition of Epithelial-Mesenchymal Transition by Targeting ZEB1.

INTRODUCTION: Although microRNA (miR)-150-5p participates in the progression of renal fibrosis, its mechanism of action remains elusive. METHODS: A mouse model of unilateral ureteral obstruction was used. The in vitro renal fibrosis model was established by stimulating human kidney 2 (HK-2) cells with transforming growth factor beta 1 (TGF-ß1). The expression profiles of miR-150-5p, zinc finger E-box binding homeobox 1 (ZEB1), and other fibrosis- and epithelial-mesenchymal transition (EMT)-linked proteins were determined using Western blot and quantitative reverse transcription polymerase chain reaction. The relationship between miR-150-5p and ZEB1 in HK-2 cells was confirmed by a dual-luciferase reporter assay. RESULTS: Both in vivo and in vitro renal fibrosis models revealed reduced miR-150-5p expression and elevated ZEB1 level. A significant decrease in E-cadherin levels, as well as increases in alpha smooth muscle actin (α-SMA) and collagen type I (Col-I) levels, was seen in TGF-ß1-treated HK-2 cells. The overexpression of miR-150-5p ameliorated TGF-ß1-mediated fibrosis and EMT. Notably, miR-150-5p acts by directly targeting ZEB1. A significant reversal of the inhibitory impact of miR-150-5p on TGF-ß1-mediated fibrosis and EMT in HK-2 cells was observed upon ZEB1 overexpression. CONCLUSION: MiR-150-5p suppresses TGF-ß1-induced fibrosis and EMT by targeting ZEB1 in HK-2 cells, providing helpful insights into the therapeutic intervention of renal fibrosis.

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Accuracy and efficiency of dynamic navigated root-end resection in endodontic surgery: a pilot in vitro study.

BACKGROUND: The operation accuracy and efficiency of dynamic navigated endodontic surgery were evaluated through in vitro experiments. This study provides a reference for future clinical application of dynamic navigation systems in endodontic surgery. MATERIALS AND METHODS: 3D-printed maxillary anterior teeth were used in the preparation of models for endodontic surgery. Endodontic surgery was performed with and without dynamic navigation by an operator who was proficient in dynamic navigation technology but had no experience in endodontic surgery. Optical scanning data were applied to evaluate the length and angle deviations of root-end resection. And the operation time was recorded. T tests were used to analyze the effect of dynamic navigation technology on the accuracy and duration of endodontic surgery. RESULTS: With dynamic navigation, the root-end resection length deviation was 0.46 ± 0.06 mm, the angle deviation was 2.45 ± 0.96°, and the operation time was 187 ± 22.97 s. Without dynamic navigation, the root-end resection length deviation was 1.20 ± 0.92 mm, the angle deviation was 16.20 ± 9.59°, and the operation time was 247 ± 61.47 s. Less deviation was achieved and less operation time was spent with than without dynamic navigation (P < 0.01). CONCLUSION: The application of a dynamic navigation system in endodontic surgery can improve the accuracy and efficiency significantly for operators without surgical experience and reduce the operation time.

Complete spatially resolved gene expression is not necessary for identifying spatial domains.

Spatially resolved transcriptomics (SRT) technologies have revolutionized the study of tissue organization. We introduce a graph convolutional network with an attention and positive emphasis mechanism, termed BINARY, relying exclusively on binarized SRT data to accurately delineate spatial domains. BINARY outperforms existing methods across various SRT data types while using significantly less input information. Our study suggests that precise gene expression quantification may not always be essential, inspiring further exploration of the broader applications of spatially resolved binarized gene expression data.

Deep Learning Model Coupling Wearable Bioelectric and Mechanical Sensors for Refined Muscle Strength Assessment.

Muscle strength (MS) is related to our neural and muscle systems, essential for clinical diagnosis and rehabilitation evaluation. Although emerging wearable technology seems promising for MS assessment, problems still exist, including inaccuracy, spatiotemporal differences, and analyzing methods. In this study, we propose a wearable device consisting of myoelectric and strain sensors, synchronously acquiring surface electromyography and mechanical signals at the same spot during muscle activities, and then employ a deep learning model based on temporal convolutional network (TCN) + Transformer (Tcnformer), achieving accurate grading and prediction of MS. Moreover, by combining with deep clustering, named Tcnformer deep cluster (TDC), we further obtain a 25-level classification for MS assessment, refining the conventional 5 levels. Quantification and validation showcase a patient's postoperative recovery from level 3.2 to level 3.6 in the first few days after surgery. We anticipate that this system will importantly advance precise MS assessment, potentially improving relevant clinical diagnosis and rehabilitation outcomes.

Identifying the risk factors of ICU-acquired fungal infections: clinical evidence from using machine learning.

Background: Fungal infections are associated with high morbidity and mortality in the intensive care unit (ICU), but their diagnosis is difficult. In this study, machine learning was applied to design and define the predictive model of ICU-acquired fungi (ICU-AF) in the early stage of fungal infections using Random Forest. Objectives: This study aimed to provide evidence for the early warning and management of fungal infections. Methods: We analyzed the data of patients with culture-positive fungi during their admission to seven ICUs of the First Affiliated Hospital of Chongqing Medical University from January 1, 2015, to December 31, 2019. Patients whose first culture was positive for fungi longer than 48 h after ICU admission were included in the ICU-AF cohort. A predictive model of ICU-AF was obtained using the Least Absolute Shrinkage and Selection Operator and machine learning, and the relationship between the features within the model and the disease severity and mortality of patients was analyzed. Finally, the relationships between the ICU-AF model, antifungal therapy and empirical antifungal therapy were analyzed. Results: A total of 1,434 cases were included finally. We used lasso dimensionality reduction for all features and selected six features with importance ≥0.05 in the optimal model, namely, times of arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation. The area under the curve of the model for predicting ICU-AF was 0.981 in the test set, with a sensitivity of 0.960 and specificity of 0.990. The times of arterial catheter (p = 0.011, OR = 1.057, 95% CI = 1.053-1.104) and invasive mechanical ventilation (p = 0.007, OR = 1.056, 95%CI = 1.015-1.098) were independent risk factors for antifungal therapy in ICU-AF. The times of arterial catheter (p = 0.004, OR = 1.098, 95%CI = 0.855-0.970) were an independent risk factor for empirical antifungal therapy. Conclusion: The most important risk factors for ICU-AF are the six time-related features of clinical parameters (arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation), which provide early warning for the occurrence of fungal infection. Furthermore, this model can help ICU physicians to assess whether empiric antifungal therapy should be administered to ICU patients who are susceptible to fungal infections.

Biobank-wide association scan identifies risk factors for late-onset Alzheimer's disease and endophenotypes.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.

A real-world prospective observational study of eptinezumab in Asian patients with migraine.

OBJECTIVE: To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. METHODS: This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. RESULTS: Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. CONCLUSION: Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.