42 research outputs found
Role of MALDI-MSI in combination with 3D tissue models for early stage efficacy and safety testing of drugs and toxicants
Introduction: Three-dimensional (3D) cell cultures have become increasingly important materials to investigate biological processes and drug efficacy and toxicity. The ability of 3D cultures to mimic the physiology of primary tissues and organs in the human body enables further insight into cellular behavior and is hence highly desirable in early-stage drug development. Analyzing the spatial distribution of drug compounds and endogenous molecules provides an insight into the efficacy of a drug whilst simultaneously giving information on biological responses. Areas Covered: In this review we will examine the main 3D cell culture systems employed and applications, which describe their integration with mass spectrometry imaging (MSI). Expert Opinion: MSI is a powerful technique that can map a vast range of molecules simultaneously in tissues without the addition of labels that can provide insights into the efficacy and safety of a new drug. The combination of MSI and 3D cell cultures has emerged as a promising tool in early-stage drug analysis. However, the most common administration route for pharmaceutical drugs is via oral delivery. The use of MSI in combination with models of the GI tract is an area that has been little explored to date, the reasons for this are discussed
Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.
BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Recommended from our members
Characterization of hydrogeologic units using matrix properties, Yucca Mountain, Nevada
Determination of the suitability of Yucca Mountain, in southern Nevada, as a geologic repository for high-level radioactive waste requires the use of numerical flow and transport models. Input for these models includes parameters that describe hydrologic properties and the initial and boundary conditions for all rock materials within the unsaturated zone, as well as some of the upper rocks in the saturated zone. There are 30 hydrogeologic units in the unsaturated zone, and each unit is defined by limited ranges where a discrete volume of rock contains similar hydrogeologic properties. These hydrogeologic units can be easily located in space by using three-dimensional lithostratigraphic models based on relationships of the properties with the lithostratigraphy. Physical properties of bulk density, porosity, and particle density; flow properties of saturated hydraulic conductivity and moisture-retention characteristics; and the state variables (variables describing the current state of field conditions) of saturation and water potential were determined for each unit. Units were defined using (1) a data base developed from 4,892 rock samples collected from the coring of 23 shallow and 8 deep boreholes, (2) described lithostratigraphic boundaries and corresponding relations to porosity, (3) recognition of transition zones with pronounced changes in properties over short vertical distances, (4) characterization of the influence of mineral alteration on hydrologic properties such as permeability and moisture-retention characteristics, and (5) a statistical analysis to evaluate where boundaries should be adjusted to minimize the variance within layers. This study describes the correlation of hydrologic properties to porosity, a property that is well related to the lithostratigraphy and depositional and cooling history of the volcanic deposits and can, therefore, be modeled to be distributed laterally
Recommended from our members
Verification of a 1-dimensional model for predicting shallow infiltration at Yucca Mountain
A characterization of net infiltration rates is needed for site-scale evaluation of groundwater flow at Yucca Mountain, Nevada. Shallow infiltration caused by precipitation may be a potential source of net infiltration. A 1-dimensional finite difference model of shallow infiltration with a moisture-dependant evapotranspiration function and a hypothetical root-zone was calibrated and verified using measured water content profiles, measured precipitation, and estimated potential evapotranspiration. Monthly water content profiles obtained from January 1990 through October 1993 were measured by geophysical logging of 3 boreholes located in the alluvium channel of Pagany Wash on Yucca Mountain. The profiles indicated seasonal wetting and drying of the alluvium in response to winter season precipitation and summer season evapotranspiration above a depth of 2.5 meters. A gradual drying trend below a depth of 2.5 meters was interpreted as long-term redistribution and/or evapotranspiration following a deep infiltration event caused by runoff in Pagany Wash during 1984. An initial model, calibrated using the 1990 to 1 992 record, did not provide a satisfactory prediction of water content profiles measured in 1993 following a relatively wet winter season. A re-calibrated model using a modified, seasonally-dependent evapotranspiration function provided an improved fit to the total record. The new model provided a satisfactory verification using water content changes measured at a distance of 6 meters from the calibration site, but was less satisfactory in predicting changes at a distance of 18 meters
Recommended from our members
An Inverse Procedure for Estimating the Unsaturated Hydraulic Conductivities of Volcanic Tuffs
Recommended from our members
Physical and hydrologic properties of rock outcrop samples at Yucca Mountain, Nevada
Studies are underway at Yucca Mountain to characterize physical and hydrologic conditions for a potential high-level radioactive waste repository. Site characterization requires the development of three- dimensional models describing hydrogeologic units in terms of inputs for numerical models. It is also important to understand the spatial distribution of these properties, vertical and horizontally, in order to estimate values at unmeasured points. Deterministic processes of volcanism caused the initial formation of the rock units, and it is useful to be able to correlate rock properties with the more qualitative descriptions of rock lithology that occur on a larger scale. Preliminary data were collected to develop methods and evaluate spatial relations to determine sampling frequency. In addition, a data base was developed to provide some of the parameters needed for preliminary flow-modeling exercises. Surface transects of rock outcrops facilitated rapid collection of closely spaced samples of all units exposed at and around Yucca Mountain. This report presents the data collected, descriptive statistics for various units, preliminary hydrogeologic units, and analyses of porosity compared with flow properties