Explicit incorporation of discrete fractures into pore network models

Research Funding China Scholarship Council. Grant Number: 201708060457Peer reviewedPublisher PD

A new method for pore structure quantification and pore network extraction from SEM images

C.W. thanks China Scholarship Council’s financial support for his Ph.D. study. The authors thank Anasuria Operating Company Limited (AOC) for making available the core plug samples. We thank the two reviewers for their insight comments and constructive suggestions toward improving our manuscript. Finally, we thank John Still (University of Aberdeen Centre for Electron Microscopy, Analysis and Characterisation (ACEMAC)) for invaluable assistance in the acquisition of SEM images.Peer reviewedPostprin

Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration

10.1194/jlr.M073684Journal of Lipid Research5891785-179

P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure

EAI045 is a fourth-generation allosteric tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR). It targets T790M and C797S EGFR mutants in the treatment of non-small cell lung cancer (NSCLC). EAI045 and cetuximab combined induce tumor regression in mouse models of EGFR-mutant lung cancer. We investigated the pharmacokinetic roles of the multidrug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and of the drug-metabolizing enzyme CYP3A in plasma and tissue distribution of EAI045 and its metabolites, using genetically modified mouse models. In vitro, EAI045 was a good transport substrate of human ABCB1. In vivo, oral EAI045 (20 mg/kg) was rapidly absorbed. Relative to wild-type mice, EAI045 brain-to-plasma ratios were increased 3.9-fold in Abcb1a/1b -/- and 4.8-fold in Abcb1a/1b;Abcg2 -/- mice. However, in single Abcg2 -/- mice they were unchanged. EAI045 oral availability was not markedly altered. Oral coadministration of elacridar, an ABCB1/ABCG2 inhibitor, increased the plasma AUC 0-30min and brain-to-plasma ratios of EAI045 by 4.0-fold and 5.4-fold, respectively, in wild-type mice. EAI045 glucuronide showed an increased plasma AUC 0-30min and a markedly decreased accumulation and tissue-to-plasma ratio in the small intestinal content when Abcb1a/1b and Abcg2 were absent. A large fraction of oral EAI045 was converted to its hydrolyzed metabolite PIA, but Abcb1a/1b, Abcg2, and Oatp1a/1b had little impact on PIA pharmacokinetics. Mouse Cyp3a knockout or transgenic human CYP3A4 overexpression did not significantly affect oral EAI045 pharmacokinetics. Our results show that blood-brain barrier ABCB1 can markedly limit EAI045 brain accumulation. Moreover, elacridar coadministration can effectively reverse this process

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

Is Sensory Loss an Understudied Risk Factor for Frailty? A Systematic Review and Meta-analysis

[Abstract] Background. Age-related sensory loss and frailty are common conditions among older adults, but epidemiologic research on their possible links has been inconclusive. Clarifying this relationship is important because sensory loss may be a clinically relevant risk factor for frailty. Methods. In this systematic review and meta-analysis, we searched 3 databases for observational studies investigating 4 sensory impairments—vision (VI), hearing (HI), smell (SI), and taste (TI)—and their relationships with frailty. We meta-analyzed the cross-sectional associations of VI/HI each with pre-frailty and frailty, investigated sources of heterogeneity using meta-regression and subgroup analyses, and assessed publication bias using Egger’s test. Results. We included 17 cross-sectional and 7 longitudinal studies in our review (N = 34,085) from 766 records. Our cross-sectional meta-analyses found that HI and VI were, respectively, associated with 1.5- to 2-fold greater odds of pre-frailty and 2.5- to 3-fold greater odds of frailty. Our results remained largely unchanged after subgroup analyses and meta-regression, though the association between HI and pre-frailty was no longer significant in 2 subgroups which lacked sufficient studies. We did not detect publication bias. Longitudinal studies largely found positive associations between VI/HI and frailty progression from baseline robustness, though they were inconclusive about frailty progression from baseline pre-frailty. Sparse literature and heterogenous methods precluded meta-analyses and conclusions on the SI/TI–frailty relationships. Conclusions. Our meta-analyses demonstrate significant cross-sectional associations between VI/HI with pre-frailty and frailty. Our review also highlights knowledge gaps on the directionality and modifiability of these relationships and the impact of SI/TI and multiple sensory impairments on frailty