Non-invasive real-time assessment of hepatic macrovesicular steatosis in liver donors: Hypothesis, design and proof-of-concept study
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ABSTRACT:
SUBMITTER: Rajamani A
PROVIDER: S-EPMC8568585 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThis study aimed to determine the diagnostic performance of the controlled attenuation parameter (CAP) measured using transient elastography (TE) for assessing macrovesicular steatosis (MaS) in potential living liver donors using same-day biopsy as a reference standard.MethodsThis retrospective study included 204 living liver donor candidates who underwent TE and liver biopsy on the same day between July 2013 and June 2014. The histologic degree of MaS was determined. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the performance of CAP for diagnosing MaS of >10%, and the optimal cutoff value was identified using the maximal Youden index.ResultsBased on liver biopsy, 185 subjects had MaS of ≤10% and 19 had MaS of >10%. The CAP value was significantly correlated with the percentage of MaS on liver biopsy (r=0.635, P<0.001), and the median CAP value was significantly higher in subjects with MaS of >10% than in those with MaS of ≤10% (300 dB/m vs. 209 dB/m, P<0.001). The AUROC for diagnosing MaS of >10% by CAP was 0.938 (95% confidence interval, 0.896 to 0.967), and a CAP of >259 dB/m yielded a sensitivity of 84.2% and a specificity of 92.4%.ConclusionThe CAP measured using TE was significantly correlated with MaS and accurately detected substantial MaS in potential living liver donors. The CAP is a promising tool for the noninvasive diagnosis of MaS and may be used to screen unsuitable living liver donor candidates.
| S-EPMC8696135 | biostudies-literature
Project description:Selecting an optimal donor for living donor liver transplantation is crucial for the safety of both the donor and recipient, and hepatic steatosis is an important consideration. We aimed to build a prediction model with noninvasive variables to evaluate macrovesicular steatosis in potential donors by using various prediction models. The study population comprised potential living donors who had undergone donation workup, including percutaneous liver biopsy, in the Republic of Korea between 2016 and 2019. Meaningful macrovesicular hepatic steatosis was defined as >5%. Whole data were divided into training (70.5%) and test (29.5%) data sets based on the date of liver biopsy. Random forest, support vector machine, regularized discriminant analysis, mixture discriminant analysis, flexible discriminant analysis, and deep neural network machine learning methods as well as traditional logistic regression were employed. The mean patient age was 31.4 years, and 66.3% of the patients were men. Of the 1652 patients, 518 (31.4%) had >5% macrovesicular steatosis on the liver biopsy specimen. The logistic model had the best prediction power and prediction performances with an accuracy of 80.0% and 80.9% in the training and test data sets, respectively. A cut-off value of 31.1% for the predicted risk of hepatic steatosis was selected with a sensitivity of 77.7% and specificity of 81.0%. We have provided our model on the website (https://hanseungbong.shinyapps.io/shiny_app_up/) under the name DONATION Model. Our algorithm to predict macrovesicular steatosis using routine parameters is beneficial for identifying optimal potential living donors by avoiding superfluous liver biopsy results.
| S-EPMC9234640 | biostudies-literature
Project description:Background:The purpose of the Living Organ Video Educated Donors (LOVED) program is to address living donor kidney transplantation (LDKT) disparities in African Americans who experience half the rates of LDKTs compared with whites in the United States. Methods:LOVED is an iterative-designed, distance-based, navigator-led, mobile health educational program, developed via guidance from patients, Self-determination Theory and Social Cognitive Theory. The purpose of this study was to assess the feasibility of LOVED using a proof-of-concept design to increase African Americans' knowledge about the living donor process to improve their willingness to approach others about being a potential kidney donor. The 8-week LOVED program consisted of (1) a computer tablet-delivered education program, (2) group video chat sessions with an African American LDKT recipient navigator, and (3) additional communication between group members and the navigator. Results:Twenty-five participants completed the LOVED study. Poststudy focus groups were analyzed using inductive and deductive qualitative descriptive techniques and analysts found 6 themes reporting LOVED being highly acceptable with the program being overall empowering and helpful. The study had 0% attrition, 90.9% adherence to the education videos and 88% adherence to the video chat sessions. Surveys showed statistically significant improvements in LDKT knowledge, higher willingness to communicate to others about their need, lower donor concerns, and higher self-efficacy about LDKT. Conclusions:Findings indicate that participation in LOVED can lead to improvements in predictors to increase the number of evaluations and LDKTs in African Americans; however, these findings need to be confirmed in adequately powered, randomized controlled trials. Using LOVED may reduce barriers to broadly address LDKT disparities. Findings from this study will inform the design of a future statewide randomized controlled trials.
| S-EPMC6089514 | biostudies-literature
Project description:BACKGROUND:The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans. METHODS AND RESULTS:CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups. CONCLUSIONS:The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
| S-EPMC3048024 | biostudies-literature
Project description:Turoctocog alfa (NovoEight®) is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N-terminus and 11 amino acids from the C-terminus of the naturally occurring B-domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII. Viral inactivation is ensured by a detergent inactivation step as well as a 20-nm nano-filtration step. Characterisation of the purified protein demonstrated that turoctocog alfa was fully sulphated at Tyr346 and Tyr1664, which is required for optimal proteolytic activation by thrombin. Kinetic assessments confirmed that turoctocog alfa was activated by thrombin at a similar rate as seen for other rFVIII products fully sulphated at these positions. Tyr1680 was also fully sulphated in turoctocog alfa resulting in strong affinity (low nm Kd ) for binding to von Willebrand factor (VWF). Half-lives of 7.2 ± 0.9 h in F8-KO mice and 8.9 ± 1.8 h haemophilia A dogs supported that turoctocog alfa bound to VWF after infusion. Functional studies including thromboelastography analysis of human haemophilia A whole blood with added turoctocog alfa and effect studies in mice bleeding models demonstrated a dose-dependent effect of turoctocog alfa. The non-clinical data thus confirm the haemostatic effect of turoctocog alfa and, together with the comprehensive clinical evaluation, support the use as FVIII replacement therapy in patients with haemophilia A.
| S-EPMC4232928 | biostudies-literature
Project description:IntroductionHepatic steatosis (HS) negatively impacts transplant outcomes in living liver donors. To date, liver biopsy is preferred for HS evaluation. This study aims to evaluate the measurement of controlled attenuation parameter (CAP) as a diagnostic tool of HS in living liver donors.MethodsCandidates recruited to this study, conducted from April 2016 to February 2020, were potential donors who had undergone transient elastography using Fibroscan® and CAP measurements at liver segments VI and VII, followed by liver biopsy. The HS grades from liver biopsy were classified as S0 (<5%), S1 (5-33%), S2 (33-66%), and S3 (>66%). For CAP, they were S0 (≤218dB/m), S1 (218-249dB/m)), S2 (250-305dB/m)), and S3 (>305dB/m)). The CAP measurements were compared with the liver biopsy results.ResultsOf the 150 potential donors [male, 73.3%; mean age, 30.0±7.0 years; body mass index (BMI), 24.7±3.5kg/m2], 92 (61.3%) had no or mild HS, while 58 (38.7%) and 10% had moderate to severe HS based on CAP and liver biopsy, respectively. Subjects with moderate to severe HS per CAP were mostly males (0.014), and had higher BMI (p = .006), alanine aminotransferase (ALT) (.001), gamma-glutamyl transferase (.026), and high-density lipoprotein (.008). On multivariate analysis, high ALT (OR, 1.051; 95% CI, 1.016-1.087; p = .004) was a predictor of significant HS. The sensitivity, specificity, positive and negative predictive values of CAP to detect significant HS were 93.3%, 67.4, 24.1%, and 98.9%, respectively.ConclusionThe high sensitivity and negative predictive values of CAP make it a good screening test to exclude significant HS in potential living liver donors which, in turn, can help avoid unnecessary liver biopsies.
| S-EPMC8118256 | biostudies-literature
Project description:Background: Currently, 30% macrovesicular steatosis (MaS) content is usually assigned empirically as the boundary between "use" and "refuse" a donor liver for liver transplantation (LT); however, this cut-off is questionable due to the lack of systemic evidence of the efficiency relative to prognosis prediction. Clinicians have tried to identify the threshold for optimized utilization of marginal steatotic allografts, but controversy exists among different studies. Aim: Our study aimed to systematically determine an acceptable donor MaS content cut-off without incurring extra risk in liver transplantation, using meta-analysis. Methods: The relevant literature reporting the relationship between MaS content and post-transplant mortality/morbidity was searched and retrieved in Pubmed, Embase, and ISI Web of Science. Results: Nine studies were enrolled into the final analysis. A categorical comparison revealed that patients who received allografts with moderate steatosis (MaS content >30%) had significantly higher risks of graft failure/dysfunction, but not of mortality. Dose-response analysis showed that donor MaS content affected the graft failure/dysfunction in a non-linear relationship. Risks associated with MaS content in terms of poorer outcomes were independent of other risk covariates for liver transplantation. A non-significant increase in risk of inferior post-transplant outcomes was observed in patients who received allografts with a MaS content <35%. The risks of post-transplant graft failure and dysfunction increased with severe donor MaS content infiltration, without a consistent relationship. Conclusions: The threshold of allograft MaS content can be safely extended to 35% without additional risk burden on post-transplant inferior outcomes. Clarification on "the effects of stratification" for MaS content can provide theoretical evidence for further optimal utilization of marginal steatotic allografts in liver transplantation.
| S-EPMC6494939 | biostudies-literature
Project description:Molecular breast imaging (MBI) is a dedicated nuclear medicine breast imaging modality that employs dual-head cadmium zinc telluride (CZT) gamma cameras to functionally detect breast cancer. MBI has been shown to detect breast cancers otherwise occult on mammography and ultrasound. Currently, a MBI-guided biopsy system does not exist to biopsy such lesions. Our objective was to consider the utility of a novel conical slant-hole (CSH) collimator for rapid (<1 min) and accurate monitoring of lesion position to serve as part of a MBI-guided biopsy system.An initial CSH collimator design was derived from the dimensions of a parallel-hole collimator optimized for MBI performed with dual-head CZT gamma cameras. The parameters of the CSH collimator included the collimator height, cone slant angle, thickness of septa and cones of the collimator, and the annular areas exposed at the base of the cones. These parameters were varied within the geometric constraints of the MBI system to create several potential CSH collimator designs. The CSH collimator designs were evaluated using Monte Carlo simulations. The model included a breast compressed to a thickness of 6 cm with a 1-cm diameter lesion located 3 cm from the collimator face. The number of particles simulated was chosen to represent the count density of a low-dose, screening MBI study acquired with the parallel-hole collimator for 10 min after a ∼150 MBq (4 mCi) injection of Tc-99m sestamibi. The same number of particles was used for the CSH collimator simulations. In the resulting simulated images, the count sensitivity, spatial resolution, and accuracy of the lesion depth determined from the lesion profile width were evaluated.The CSH collimator design with default parameters derived from the optimal parallel-hole collimator provided 1-min images with error in the lesion depth estimation of 1.1 ± 0.7 mm and over 21 times the lesion count sensitivity relative to 1-min images acquired with the current parallel-hole collimator. Sensitivity was increased via more vertical cone slant angles, larger annular areas, thinner cone walls, shorter cone heights, and thinner radiating septa. Full width at half maximum trended in the opposite direction as sensitivity for all parameters. There was less error in the depth estimates for less vertical slant angles, smaller annular areas, thinner cone walls, cone heights near 1 cm, and generally thinner radiating septa.A Monte Carlo model was used to demonstrate the feasibility of a CSH collimator design for rapid biopsy application in molecular breast imaging. Specifically, lesion depth of a 1-cm diameter lesion positioned in the center of a typical breast can be estimated with error of less than 2 mm using circumferential count profiles of images acquired in 1 min.
| S-EPMC3537760 | biostudies-other
Project description:Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell-based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.
| S-EPMC7159917 | biostudies-literature
Project description:Today, novel candidate therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. We present a strategy that allows biological relevance to be assessed in the early stages of drug discovery. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. The technique was applicable to compounds with a range of binding specificities and detected false-positive hits missed by classical phenotypic assays. Our results advocate application of molecular phenotyping in drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade.
2017-05-24 | GSE89972 | GEO