Miracle-dz/UniFAR-FTUs huggingface dataset:
Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective multicentre study

Aims Patients receiving direct oral anticoagulants (DOACs) frequently undergo elective invasive procedures. Their management is challenging. We aimed to determine the optimal duration of DOAC discontinuation that ensures a minimal anticoagulant effect during the procedure. Methods and results This prospective multicentre study included 422 DOAC-treated patients requiring an invasive procedure. Pre-procedural DOAC concentration ([DOAC]) and routine haemostasis assays were performed to determine i/the proportion of patients who achieved a minimal pre-procedural [DOAC] (≤30 ng/mL) according to the duration of DOAC discontinuation, ii/the predictors of minimal [DOAC] and, iii/the ability of routine assays to predict minimal [DOAC]. Lastly, we assessed the predictors of peri-procedural bleeding events. The duration of DOAC discontinuation ranged from 1 to 218 h and pre-procedural [DOAC] from ≤30 to 527 ng/mL. After a 49-72-h discontinuation, 95% of the [DOAC] were ≤30 ng/mL. A 72-h discontinuation predicted concentrations ≤30 ng/mL with 91% specificity. In multivariable analysis, duration of DOAC discontinuation, creatinine clearance <50 mL/min and antiarrhythmics were independent predictors of minimal pre-procedural [DOAC] (concordance statistic 0.869; 95% confidence interval: 0.829-0.912). Conversely, routine haemostasis assays were poor predictors. Last, creatinine clearance <50 mL/min, antiplatelets and high-bleeding risk procedures were predictors of bleeding events. Conclusion A last DOAC intake 3 days before a procedure resulted in minimal pre-procedural anticoagulant effect for almost all patients. Moderate renal impairment, especially in dabigatran-treated patients, and antiarrhythmics in anti-Xa-treated patients should result in a longer DOAC interruption. In situations requiring testing, routine assays should not replace DOAC concentration measurement.
Accurate Inference of Subtle Population Structure (and Other Genetic Discontinuities) Using Principal Coordinates

Background Accurate inference of genetic discontinuities between populations is an essential component of intraspecific biodiversity and evolution studies, as well as associative genetics. The most widely-used methods to infer population structure are model-based, Bayesian MCMC procedures that minimize Hardy-Weinberg and linkage disequilibrium within subpopulations. These methods are useful, but suffer from large computational requirements and a dependence on modeling assumptions that may not be met in real data sets. Here we describe the development of a new approach, PCO-MC, which couples principal coordinate analysis to a clustering procedure for the inference of population structure from multilocus genotype data. Methodology/Principal Findings PCO-MC uses data from all principal coordinate axes simultaneously to calculate a multidimensional “density landscape”, from which the number of subpopulations, and the membership within subpopulations, is determined using a valley-seeking algorithm. Using extensive simulations, we show that this approach outperforms a Bayesian MCMC procedure when many loci (e.g. 100) are sampled, but that the Bayesian procedure is marginally superior with few loci (e.g. 10). When presented with sufficient data, PCO-MC accurately delineated subpopulations with population Fst values as low as 0.03 (G'st>0.2), whereas the limit of resolution of the Bayesian approach was Fst = 0.05 (G'st>0.35). Conclusions/Significance We draw a distinction between population structure inference for describing biodiversity as opposed to Type I error control in associative genetics. We suggest that discrete assignments, like those produced by PCO-MC, are appropriate for circumscribing units of biodiversity whereas expression of population structure as a continuous variable is more useful for case-control correction in structured association studies.
Spatiotemporal Variability of Precipitation, Modeled Soil Moisture, and Vegetation Greenness in North America within the Recent Observational Record

Abstract Dominant spatiotemporal patterns of precipitation, modeled soil moisture, and vegetation are determined in North America within the recent observational record (late twentieth century onward). These data are from a gridded U.S.–Mexico precipitation product, retrospective long-term integrations of two land surface models, and satellite-derived vegetation greenness. The analysis procedure uses three statistical techniques. First, all the variables are normalized according to the standardized precipitation index procedure. Second, dominant patterns of spatiotemporal variability are determined using multitaper method–singular value decomposition for interannual and longer time scales. The dominant spatiotemporal patterns of precipitation generally conform to known and distinct Pacific SST forcing in the cool and warm seasons. Two specific time scales in precipitation at 9 and 6–7 yr correspond to significant variability in soil moisture and vegetation, respectively. The 9-yr signal is related to prec.
IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3

In this study, Reid et al. investigate how cancer cells adapt to low glutamine conditions, which is needed for cancer cell proliferation and survival. They show that IKKβ directly interacts with and phosphorylates PFKFB3, a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low and thus providing new insights into cancer cell adaptation.
A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer

Background In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival. Patients and methods Using 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115). Results A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13-0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P = 0.004 and in the validation set P = 0.002). Conclusions A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.
Morselized Amniotic Membrane Tissue for Refractory Corneal Epithelial Defects in Cicatricial Ocular Surface Diseases

Purpose To evaluate the clinical efficacy of morselized amniotic membrane and umbilical cord tissue (MAU) in treating refractory corneal epithelial defect in ocular cicatricial diseases. Methods Retrospective review of four patients with ocular cicatricial diseases treated with topical MAU for corneal epithelial defects refractory to conventional treatments including topical lubricants, autologous serum, bandage contact lens, and tarsorraphy. Their symptoms, corneal staining, conjunctival inflammation, and visual acuity were compared before and after treatment. Results After topical application of MAU twice daily, two patients demonstrated rapid corneal epithelialization with prompt visual acuity improvement at the first day. All patients showed corneal epithelialization in 7.3 ± 2.6 days accompanied by a significant relief of symptoms, reduction of ocular surface inflammation, and improvement of visual acuity. Conclusion This pilot study suggests topical MAU can be developed into a novel treatment for treating refractory corneal epithelial defects. Translational Relevance Topical MAU can be an effective novel treatment for refractory corneal epithelial defects.
Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer’s disease: preclinical proof of concept

Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of Kv1.3 and Kir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed Kv1.3 and Kir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule Kv1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required Kv1.3 activity in vitro and in hippocampal slices. Since we further observed that Kv1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological Kv1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance Kv1.3 blockers to Alzheimer's disease clinical trials.
Distinct Forms of Mitochondrial TOM-TIM Supercomplexes Define Signal-Dependent States of Preprotein Sorting

ABSTRACT Mitochondrial import of cleavable preproteins occurs at translocation contact sites, where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport form containing the presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23SORT). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23SORT and TOM-TIM23-PAM. These two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import.
Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology

Background Genital inflammation is a key determinant of human immunodeficiency virus (HIV) transmission, and may increase HIV-susceptible target cells and alter epithelial integrity. Several genital conditions that increase HIV risk are more prevalent in African, Caribbean, and other black (ACB) women, including bacterial vaginosis and herpes simplex virus type-2 (HSV-2) infection. Therefore, we assessed the impact of the genital microbiota on mucosal immunology in ACB women and microbiome-HSV-2 interactions. Methods Cervicovaginal secretions and endocervical cells were collected by cytobrush and Instead Softcup, respectively. T cells and dendritic cells were assessed by flow cytometry, cytokines by multiplex enzyme-linked immunosorbent assay (ELISA), and the microbiota by 16S ribosomal ribonucleic acid gene sequencing. Results The cervicovaginal microbiota of 51 participants were composed of community state types (CSTs) showing diversity (20/51; 39%) or predominated by Lactobacillus iners (22/51; 42%), L. crispatus (7/51; 14%), or L. gasseri (2/51; 4%). High-diversity CSTs and specific bacterial phyla (Gardnerella vaginalis and Prevotella bivia) were strongly associated with cervicovaginal inflammatory cytokines, but not with altered endocervical immune cells. However, cervical CD4+ T-cell number was associated with HSV-2 infection and a distinct cytokine profile. Conclusions This suggests that the genital microbiota and HSV-2 infection may influence HIV susceptibility through independent biological mechanisms.
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).

This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and 2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.
Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study

Objective: Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. Methods: This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. Results: Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. Conclusions: In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.
Cassiopeia A: dust factory revealed via submillimetre polarimetry

If Type II supernovae – the evolutionary end points of short-lived, massive stars – produce a significant quantity of dust (>0.1 M⊙) then they can explain the rest-frame far-infrared emission seen in galaxies and quasars in the first Gyr of the Universe. Submillimetre (submm) observations of the Galactic supernova remnant, Cas A, provided the first observational evidence for the formation of significant quantities of dust in Type II supernovae. In this paper, we present new data which show that the submm emission from Cas A is polarized at a level significantly higher than that of its synchrotron emission. The orientation is consistent with that of the magnetic field in Cas A, implying that the polarized submm emission is associated with the remnant. No known mechanism would vary the synchrotron polarization in this way and so we attribute the excess polarized submm flux to cold dust within the remnant, providing fresh evidence that cosmic dust can form rapidly. This is supported by the presence of both polarized and unpolarized dust emission in the north of the remnant where there is no contamination from foreground molecular clouds. The inferred dust polarization fraction is unprecedented (fpol∼ 30 per cent) which, coupled with the brief time-scale available for grain alignment (<300 yr), suggests that supernova dust differs from that seen in other Galactic sources (where fpol= 2−7 per cent) or that a highly efficient grain alignment process must operate in the environment of a supernova remnant.
High resolution numerical study of Rayleigh–Taylor turbulence using a thermal lattice Boltzmann scheme

We present the results of a high resolution numerical study of two-dimensional (2D) Rayleigh–Taylor turbulence using a recently proposed thermal lattice Boltzmann method. The goal of our study is both methodological and physical. We assess merits and limitations concerning small- and large-scale resolution/accuracy of the adopted integration scheme. We discuss quantitatively the requirements needed to keep the method stable and precise enough to simulate stratified and unstratified flows driven by thermal active fluctuations at high Rayleigh and high Reynolds numbers. We present data with spatial resolution up to 4096×10 000 grid points and Rayleigh number up to Ra∼1011. The statistical quality of the data allows us to investigate velocity and temperature fluctuations, scale-by-scale, over roughly four decades. We present a detailed quantitative analysis of scaling laws in the viscous, inertial, and integral range, supporting the existence of a Bolgiano-like inertial scaling, as expected in 2D systems. We.
Variable Lifting Index for Manual-Lifting Risk Assessment

Objective: The aim of this study was to evaluate the efficacy of the new Variable Lifting Index (VLI) method, theoretically based on the Revised National Institute for Occupational Safety and Health [NIOSH] Lifting Equation (RNLE), in predicting the risk of acute low-back pain (LBP) in the past 12 months. Background: A new risk variable termed the VLI for assessing variable manual lifting has been developed, but there has been no epidemiological study that evaluates the relationship between the VLI and LBP. Method: A sample of 3,402 study participants from 16 companies in different industrial sectors was analyzed. Of the participants, 2,374 were in the risk exposure group involving manual materials handling (MMH), and 1,028 were in the control group without MMH. The VLI was calculated for each participant in the exposure group using a systematic approach. LBP information was collected by occupational physicians at the study sites. The risk of acute LBP was estimated by calculating the odds ratio (OR) between levels of the risk exposure and the control group using a logistic regression analysis. Both crude and adjusted ORs for body mass index, gender, and age were analyzed. Results: Both crude and adjusted ORs showed a dose-response relationship. As the levels of VLI increased, the risk of LBP increased. This risk relationship existed when VLI was greater than 1. Conclusion: The VLI method can be used to assess the risk of acute LBP, although further studies are needed to confirm the outcome and to define better VLI categories.
G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination

GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.