Drug-induced cardiotoxicity arises primarily when a compound alters the electrophysiological properties of cardiomyocytes. Features of intracellular action potentials (iAPs) are powerful biomarkers ...that predict proarrhythmic risks. In the last decade, a number of vertical nanoelectrodes have been demonstrated to achieve parallel and minimally-invasive iAP recordings. However, the large variability in success rate and signal strength have hindered nanoelectrodes from being broadly adopted for proarrhythmia drug assessment. In this work, we develop vertically-aligned nanocrown electrodes that are mechanically robust and achieve > 99% success rates in obtaining intracellular access through electroporation. We validate the accuracy of nanocrown electrode recordings by simultaneous patch clamp recording from the same cell. Finally, we demonstrate that nanocrown electrodes enable prolonged iAP recording for continual monitoring of the same cells upon the sequential addition of four incremental drug doses. Our technology development provides an advancement towards establishing an iAP screening assay for preclinical evaluation of drug-induced arrhythmogenicity.
Myelodysplastic syndromes (MDS) have varied prognoses and require a risk-adapted treatment strategy for treatment optimization. Recently, a molecular prognostic model (Molecular International ...Prognostic Scoring System IPSS-M) that combines clinical parameters, cytogenetic abnormalities, and mutation topography was proposed. This study validated the IPSS-M in 649 patients with primary MDS (based on the 2022 International Consensus Classification ICC) and compared its prognostic power to those of the IPSS and revised IPSS (IPSS-R). Overall, 42.5% of the patients were reclassified and 29.3% were up-staged from the IPSS-R. After the reclassification, 16.9% of the patients may receive different treatment strategies. The IPSS-M had greater discriminative potential than the IPSS-R and IPSS. Patients with high, or very high-risk IPSS-M might benefit from allogeneic hematopoietic stem cell transplantation. IPSS-M, age, ferritin level, and the 2022 ICC categorization predicted outcomes independently. After analyzing demographic and genetic features, complementary genetic analyses, including KMT2A-PTD, were suggested for accurate IPSS-M categorization of patients with ASXL1, TET2, STAG2, RUNX1, SF3B1, SRSF2, DNMT3A, U2AF1, and BCOR mutations and those classified as MDS, not otherwise specified with single lineage dysplasia/multi-lineage dysplasia based on the 2022 ICC. This study confirmed that the IPSS-M can better risk-stratified MDS patients for optimized therapeutic decision-making.
To develop, validate, and deploy models for predicting delirium in critically ill adult patients as early as upon intensive care unit (ICU) admission.
Retrospective cohort study.
Single university ...teaching hospital in Taipei, Taiwan.
6238 critically ill patients from August 2020 to August 2021.
Data were extracted, pre-processed, and split into training and testing datasets based on the time period. Eligible variables included demographic characteristics, Glasgow Coma Scale, vital signs parameters, treatments, and laboratory data. The predicted outcome was delirium, defined as any positive result (a score ≥ 4) of the Intensive Care Delirium Screening Checklist that was assessed by primary care nurses in each 8-h shift within 48 h after ICU admission. We trained models to predict delirium upon ICU admission (ADM) and at 24 h (24H) after ICU admission by using logistic regression (LR), gradient boosted trees (GBT), and deep learning (DL) algorithms and compared the models' performance.
Eight features were extracted from the eligible features to train the ADM models, including age, body mass index, medical history of dementia, postoperative intensive monitoring, elective surgery, pre-ICU hospital stays, and GCS score and initial respiratory rate upon ICU admission. In the ADM testing dataset, the incidence of ICU delirium occurred within 24 h and 48 h was 32.9% and 36.2%, respectively. The area under the receiver operating characteristic curve (AUROC) (0.858, 95% CI 0.835–0.879) and area under the precision-recall curve (AUPRC) (0.814, 95% CI 0.780–0.844) for the ADM GBT model were the highest. The Brier scores of the ADM LR, GBT, and DL models were 0.149, 0.140, and 0.145, respectively. The AUROC (0.931, 95% CI 0.911–0.949) was the highest for the 24H DL model and the AUPRC (0.842, 95% CI 0.792–0.886) was the highest for the 24H LR model.
Our early prediction models based on data obtained upon ICU admission could achieve good performance in predicting delirium occurred within 48 h after ICU admission. Our 24-h models can improve delirium prediction for patients discharged >1 day after ICU admission.
•A certain proportion of critically ill patients develop delirium within the first 24h after ICU admission.•Traditional delirium prediction models make a prediction time of 24h after ICU admission cannot predict early delirium.•Developing machine learning model to predict delirium upon ICU admission is crucial for early intervention.•Make a second prediction at 24h after ICU admission can improve the prediction of delirium occurred after 24h.
Background: Postarrest acute kidney injury (AKI) is a major health burden because it is associated with prolonged hospitalization, increased dialysis requirement, high mortality, and unfavorable ...neurological outcomes. Managing hemodynamic instability during the early postarrest period is critical; however, the role of quantified vasopressor dependence in AKI development in relation to illness severity remains unclear. Methods: A retrospective, observational cohort study that enrolled 411 non-traumatic adult cardiac arrest survivors without pre-arrest end-stage kidney disease between January 2017 and December 2019, grouped according to their baseline kidney function. The criteria for kidney injury were based on the Kidney Disease: Improving Global Outcomes definition and AKI staging system. The degree of vasopressor dependence within the first 24 h following return of spontaneous circulation (ROSC) was presented using the maximum vasoactive-inotropic score (VISmax). Results: Of the 411 patients, 181 (44%) had early AKI after ROSC. Patients with AKI showed an increased risk of in-hospital mortality (adjusted OR aOR 5.40, 95% CI 3.36–8.69, p < 0.001) and unfavorable neurological outcome (aOR 5.70, 95% CI 3.45–9.43, p < 0.001) compared to patients without AKI. The risk of adverse outcomes increased with illness severity. Patients with vasopressor support had an increased risk of early AKI. A low VISmax was associated with AKI stage 1–2 (aOR 2.51, 95% CI 1.20–5.24), whereas a high VISmax was associated with an increased risk for AKI stage 3 (aOR 2.46, 95% CI 1.28–4.75). Conclusions: Early AKI is associated with an increased risk of in-hospital mortality and unfavorable neurologic recovery in cardiac arrest survivors. Postarrest VISmax is an independent predictor of the development and severity of AKI following ROSC, regardless of baseline kidney function.
Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on ...endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1β were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1β expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1β-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1β-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1β-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with
N
-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1β-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.
The project evaluation and review technique (PERT) is the most well-known method to handle the risk due to uncertain activity durations, previous studies show that the β-distribution-based PERT ...estimation tends to be over-optimistic and it offers no control of the project in terms of risk duration. This study proposes a multiple risk-level (MRL) model that uses a site spatial constraint, environmental effects and the “5 Ms” of construction management to tackle the duration of risk during a construction project. A Risk-based Critical Path Scheduling Method (R-CPSM) that uses MRL is developed to calculate the duration of the project. A case study using a project selected from a previous study is used to compare the four estimation methods: two traditional PERT methods (3.2σs and 6σs), a Monte Carlo Simulation and the proposed MRL model. The results show that, compared with traditional approaches to estimate durations of uncertain activity, the proposed R-CPSM method is more systematic that can be combined with a cost estimation process and offers a rectification mechanism that dynamically monitors and adjusts the important factors that affect the risk duration. This method gives a more realistic estimate that is in agreement with the results of previous studies.
Nearly 95% of Alzheimer's disease (AD) occurs sporadically without genetic linkage. Aging, hypertension, high cholesterol content, and diabetes are known nongenomic risk factors of AD. Aggregation of ...Aβ peptides is an initial event of AD pathogenesis. Aβ peptides are catabolic products of a type I membrane protein called amyloid precursor protein (APP). Aβ40 is the major product, whereas the 2-residue-longer version, Aβ42, induces amyloid plaque formation in the AD brain. Since cholesterol content is one risk factor for sporadic AD, we aimed to explore whether cholesterol in the membrane affects the structure of the APP transmembrane region, thereby modulating the γ-secretase cutting behavior. Here, we synthesized several peptides containing the APP transmembrane region (sequence 693-726, corresponding to the Aβ
sequence) with one or two Cys mutations for spin labeling. We performed three electron spin resonance experiments to examine the structural changes of the peptides in liposomes composed of dioleoyl phosphatidylcholine and different cholesterol content. Our results show that cholesterol increases membrane thickness by 10% and peptide length accordingly. We identified that the di-glycine region of Aβ
(sequence VGGVV) exhibits the most profound change in response to cholesterol compared with other segments, explaining how the presence of cholesterol affects the γ-secretase cutting site. This study provides spectroscopic evidence showing how cholesterol modulates the structure of the APP transmembrane region in a lipid bilayer.
Near fault tip strong motion records from the northern part of the major earthquake (Mw = 7.6), namely the Chi‐Chi earthquake on September 21, 1999 in central Taiwan demonstrated systematic ...differences on the hanging wall and footwall, and simulated by the finite element method. The extraordinary ground motion differences on either side of the northern fault tip can be explained by a 2‐dimension kinematic source model with fault rupture breaking to surface. In this study, the earthquake faulting was considered as bilateral from the center of a low angle thrust fault which is 30 km in length with a dip angle of 31°. Based on waveform modeling, the source rupture velocity, rise‐time and dislocation of 2.0 km/sec, 5 sec and 6 meters, respectively are suggested. The results of this study show that on the northern part of the Chi‐Chi earthquake fault there was lower rupture velocity and longer rise‐time of the fault slip than that previously reported. Furthermore, the effects of surface breaking from the fault movement contributed large ground deformations near the fault tip and, consequently, induced extensive damage.
The SNT309 gene was identified via a mutation that causes lethality of cells in combination with a prp19 mutation. We showed previously that Snt309p is a component of the Prp19p-associated complex ...and that Snt309p, like Prp19p, is associated with the spliceosome immediately after or concomitantly with dissociation of U4 from the spliceosome. We show here that extracts prepared from the SNT309-deleted strain (Δ SNT309) were defective in splicing but could be complemented by addition of the purified Prp19p-associated complex. Isolation of the Prp19p-associated complex from Δ SNT309 extracts indicated that the complex was destabilized in the absence of Snt309p and dissociated on affinity chromatography, suggesting a role of Snt309p in stabilization of the Prp19p-associated complex. Addition of the affinity-purified Prp19p-Snt309p binary complex to Δ SNT309 extracts could reconstitute the Prp19p-associated complex. Genetic analysis further suggests that Snt309p plays a role in modulating interactions of Prp19p with other associated components to facilitate formation of the Prp19p-associated complex. A model for how Snt309p modulates such interactions is proposed.
Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on ...endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1beta were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1beta expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1beta-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1beta-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-kappaB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1beta-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-kappaB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1beta-treated HUVECs was inhibited by Bay11-7082, a NF-kappaB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.
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