Performance of Non-invasive Tests to Predict Significant Liver Fibrosis in Patients with Morbid Obesity

Non-Alcoholic Fatty Liver Disease (NAFLD) affects more than 90% of patients with morbid obesity (MO) and approximately 30% have significant liver fibrosis and/or cirrhosis. Liver biopsy is the gold standard for diagnosis of significant liver fibrosis and cirrhosis; however, several non-invasive tests have been suggested to predict the presence or absence of significant liver fibrosis and to avoid liver biopsy in these patients. The aim of this study was to determine the ability of these tests to predict significant liver fibrosis, specifically in patients with MO. Methods: Liver biopsies from patients with MO undergoing gastric bypass surgery were studied in retrospective sequence from 2016 to 2014 and determined by histology to show either no significant fibrosis (NSF) or significant fibrosis (SF) based on the presence of no bridges or bridges of fibrosis, respectively; to increase representation of biopsies with SF, additional biopsies with SF were added from 2013-2004. Inclusion criteria after EMR review were diagnosis of MO (BMI ³ 40 kg/m2 or \u3e 35 kg/m2 with Diabetes or hypertension) and availability of data concerning sex, age, BMI, Diabetes, platelet count, AST, ALT and albumin within 6 months before surgery; exclusion criteria were no other potential causes of liver pathology. The non-invasive tests used to estimate SF on liver biopsy included NAFLD fibrosis, BARD, APRI (0.7 cut off) and Fib4 scores, based on combinations of age, BMI, Diabetes, AST, ALT, platelets, and albumin. Test cut-off scores for SF were set using available on-line calculators. Results: One hundred fifty-five patients with MO met study criteria, 31 with SF. Patients were 45 ± 11 years of age, with BMI 46.7 ± 8.6 kg/m2 and 83% female; no significant differences between patients with SF and NSF. Diabetes was more prevalent in patients with SF vs NSF (83 vs 54%, p \u3c 0.0001). Non-invasive test results for Sensitivity and Specificity found: NAFLD - Sensitivity 41.9% (13/31) and Specificity 86.3% (107/124); BARD - 90.3% (28/31) 29.8% (37/124); FIB-4 - 3.2% (1/31) 100% (124/124); APRI - 16% (5/31) 99% (123/124). Conclusions: No single non-invasive test showed sufficient sensitivity and specificity to recommend it as a test to predict SF in patients with MO; however, results suggest that a combination of these non-invasive test results might improve their predictive value. Diabetes was associated with SF in patients with MO and is likely to be a risk factor for progressive liver fibrosis in these patients

Medical Students in Microscopic Anatomy and Pathology Laboratories: Design of an E-Learning Histology and Histopathology Atlas

Computer-assisted learning, also known as e-learning, has been successfully implemented to educate students in anatomical knowledge as well as transferable skills, such as critical analysis, teamwork, leadership and communication. E-learning allows students to self-teach material at their own paces and provides a platform for team-based laboratory approaches. Several institutions have already integrated histology and physiology in team based laboratory approaches, but integration of histology and pathology instruction has been done to a lesser extent. Our aim was to develop an e-learning atlas that integrates microanatomy and pathology laboratory for an interdisciplinary pre-clinical medical curriculum. A multidisciplinary team of teaching faculty and students developed an online atlas (microanatomyatlas.com) that includes a library of histology and histopathology images. Traditional laboratory manual instructions and study objectives were added onto the digital interface and made interactive by linking it to specific labeled images to allow for self- testing. Online clinical case studies involving a disease entity in a specific organ system were incorporated, which allows students to toggle between the normal as well as the pathological slides involving the disease as they apply their clinical reasoning skills to arrive at the correct diagnosis. We are collecting data on the number and frequency of students using the atlas. We are also administering a detailed survey to assess student satisfaction and learning. To assess the impact of this new teaching tool, a comparative study of two years of student performance and course evaluations between students who used the online atlas and students who did not use the online atlas in the pre-clinical medical curriculum will be conducted. Our preliminary data so far shows that student feedback has been positive and an e-learning atlas integrating microanatomy and pathology laboratory may be an essential tool that guides the studies and enhances the performance of students in an interdisciplinary pre-clinical medical curriculum. DISCLOSURES/ACKNOWLEDGEMENTS: American Educational Institute, University and Campus Management (AEIUCM) developed, designed, and maintains the online portal

Medical Students in Microscopic Anatomy and Pathology Laboratories: Design of an E-Learning Histology and Histopathology Atlas as an Evolving Response to Interdisciplinary Pre-Clinical Curricular Needs

E-learning, also known as computer-assisted learning, successfully bridges anatomical knowledge and transferrable skills, such as critical analysis, teamwork, leadership and communication. Several institutions have already integrated histology and physiology in team based laboratory approaches, but integration of histology and pathology instruction has been done to a lesser extent. Our aim was to develop an e-learning atlas that integrates microanatomy and pathology laboratory for an interdisciplinary pre-clinical medical curriculum. A multidisciplinary team of teaching faculty and students developed an online atlas (microanatomyatlas.com) that includes a library of histology and histopathology images. Traditional laboratory manual instructions and study objectives were added onto the digital interface and made interactive by linking it to specific labeled images to allow for self-testing. Online clinical case studies involving a disease entity in a specific organ system were incorporated, which allows students to toggle between the normal as well as the pathological slides involving this disease as they apply their clinical reasoning skills to arrive at the correct diagnosis. Data is being collected on the number and frequency of students using the atlas. Also, a detailed survey to assess student satisfaction and learning will be administered. To assess the impact of this new teaching tool, a comparative study of two years of student performance and course evaluations between students who used the online atlas and students who did not use the online atlas in the pre-clinical medical curriculum will be conducted. Our preliminary data so far shows that student feedback has been positive and an e-learning atlas integrating microanatomy and pathology laboratory may be an essential tool that guides the studies and enhances the performance of students in an interdisciplinary pre-clinical medical curriculum. Disclosures/Acknowledgements: American Educational Institute, University and Campus Management (AEIUCM) developed, designed, and maintains the online portal

Genomes of Fasciola hepatica from the Americas Reveal Colonization with Neorickettsia Endobacteria Related to the Agents of Potomac Horse and Human Sennetsu Fevers.

Food borne trematodes (FBTs) are an assemblage of platyhelminth parasites transmitted through the food chain, four of which are recognized as neglected tropical diseases (NTDs). Fascioliasis stands out among the other NTDs due to its broad and significant impact on both human and animal health, as Fasciola sp., are also considered major pathogens of domesticated ruminants. Here we present a reference genome sequence of the common liver fluke, Fasciola hepatica isolated from sheep, complementing previously reported isolate from cattle. A total of 14,642 genes were predicted from the 1.14 GB genome of the liver fluke. Comparative genomics indicated that F. hepatica Oregon and related food-borne trematodes are metabolically less constrained than schistosomes and cestodes, taking advantage of the richer millieux offered by the hepatobiliary organs. Protease families differentially expanded between diverse trematodes may facilitate migration and survival within the heterogeneous environments and niches within the mammalian host. Surprisingly, the sequencing of Oregon and Uruguay F. hepatica isolates led to the first discovery of an endobacteria in this species. Two contigs from the F. hepatica Oregon assembly were joined to complete the 859,205 bp genome of a novel Neorickettsia endobacterium (nFh) closely related to the etiological agents of human Sennetsu and Potomac horse fevers. Immunohistochemical studies targeting a Neorickettsia surface protein found nFh in specific organs and tissues of the adult trematode including the female reproductive tract, eggs, the Mehlis\u27 gland, seminal vesicle, and oral suckers, suggesting putative routes for fluke-to-fluke and fluke-to-host transmission. The genomes of F. hepatica and nFh will serve as a resource for further exploration of the biology of F. hepatica, and specifically its newly discovered trans-kingdom interaction with nFh and the impact of both species on disease in ruminants and humans

Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women\u27s interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear. In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI). We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P \u3c 0.001, coefficient r = −0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV− except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV− groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA− (P = 0.005). HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals

miR-671-5p inhibits epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer.

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. cDNA microarray data revealed that differentially expressed genes when miR-671-5p was transfected are associated with cell proliferation, invasion, cell cycle, and EMT. These data indicate that miR-671-5p functions as a tumor suppressor miRNA in breast cancer by directly targeting FOXM1. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management

KELT-1b: A Strongly Irradiated, Highly Inflated, Short Period, 27 Jupiter-mass Companion Transiting a mid-F Star

We present the discovery of KELT-1b, the first transiting low-mass companion from the wide-field Kilodegree Extremely Little Telescope-North (KELT-North) survey. The V=10.7 primary is a mildly evolved, solar-metallicity, mid-F star. The companion is a low-mass brown dwarf or super-massive planet with mass of 27.23+/-0.50 MJ and radius of 1.110+0.037-0.024 RJ, on a very short period (P=1.21750007) circular orbit. KELT-1b receives a large amount of stellar insolation, with an equilibrium temperature assuming zero albedo and perfect redistribution of 2422 K. Upper limits on the secondary eclipse depth indicate that either the companion must have a non-zero albedo, or it must experience some energy redistribution. Comparison with standard evolutionary models for brown dwarfs suggests that the radius of KELT-1b is significantly inflated. Adaptive optics imaging reveals a candidate stellar companion to KELT-1, which is consistent with an M dwarf if bound. The projected spin-orbit alignment angle is consistent with zero stellar obliquity, and the vsini of the primary is consistent with tidal synchronization. Given the extreme parameters of the KELT-1 system, we expect it to provide an important testbed for theories of the emplacement and evolution of short-period companions, and theories of tidal dissipation and irradiated brown dwarf atmospheres.Comment: 30 pages, 19 figures. Submitted to Ap

KELT-2Ab: A Hot Jupiter Transiting the Bright (V=8.77) Primary Star of a Binary System

We report the discovery of KELT-2Ab, a hot Jupiter transiting the bright (V=8.77) primary star of the HD 42176 binary system. The host is a slightly evolved late F-star likely in the very short-lived "blue-hook" stage of evolution, with \teff=6148\pm48{\rm K}, $\log{g}=4.030_{-0.026}^{+0.015}$ and \feh=0.034\pm0.78. The inferred stellar mass is $M_*=1.314_{-0.060}^{+0.063}$\msun\ and the star has a relatively large radius of $R_*=1.836_{-0.046}^{+0.066}$\rsun. The planet is a typical hot Jupiter with period $4.11379\pm0.00001$ days and a mass of $M_P=1.524\pm0.088$\mj\ and radius of $R_P=1.290_{-0.050}^{+0.064}$\rj. This is mildly inflated as compared to models of irradiated giant planets at the $\sim$4 Gyr age of the system. KELT-2A is the third brightest star with a transiting planet identified by ground-based transit surveys, and the ninth brightest star overall with a transiting planet. KELT-2Ab's mass and radius are unique among the subset of planets with $V<9$ host stars, and therefore increases the diversity of bright benchmark systems. We also measure the relative motion of KELT-2A and -2B over a baseline of 38 years, robustly demonstrating for the first time that the stars are bound. This allows us to infer that KELT-2B is an early K-dwarf. We hypothesize that through the eccentric Kozai mechanism KELT-2B may have emplaced KELT-2Ab in its current orbit. This scenario is potentially testable with Rossiter-McLaughlin measurements, which should have an amplitude of $\sim$44 m s$^{-1}$.Comment: 9 pages, 2 tables, 4 figures. A short video describing this paper is available at http://www.youtube.com/watch?v=wVS8lnkXXlE. Revised to reflect the ApJL version. Note that figure 4 is not in the ApJL versio

KELT-7b: A hot Jupiter transiting a bright V=8.54 rapidly rotating F-star

We report the discovery of KELT-7b, a transiting hot Jupiter with a mass of $1.28 \pm 0.18$ MJ, radius of $1.53_{-0.047}^{+0.046}$ RJ, and an orbital period of $2.7347749 \pm 0.0000039$ days. The bright host star (HD33643; KELT-7) is an F-star with $V=8.54$, Teff $=6789_{-49}^{+50}$ K, [Fe/H] $=0.139_{-0.081}^{+0.075}$, and $\log{g}=4.149 \pm 0.019$. It has a mass of $1.535_{-0.054}^{+0.066}$ Msun, a radius of $1.732_{-0.045}^{+0.043}$ Rsun, and is the fifth most massive, fifth hottest, and the ninth brightest star known to host a transiting planet. It is also the brightest star around which KELT has discovered a transiting planet. Thus, KELT-7b is an ideal target for detailed characterization given its relatively low surface gravity, high equilibrium temperature, and bright host star. The rapid rotation of the star ($73 \pm 0.5$ km/s) results in a Rossiter-McLaughlin effect with an unusually large amplitude of several hundred m/s. We find that the orbit normal of the planet is likely to be well-aligned with the stellar spin axis, with a projected spin-orbit alignment of $\lambda=9.7 \pm 5.2$ degrees. This is currently the second most rapidly rotating star to have a reflex signal (and thus mass determination) due to a planetary companion measured.Comment: Accepted to The Astronomical Journa

KELT-3b: A Hot Jupiter Transiting a V=9.8 Late-F Star

We report the discovery of KELT-3b, a moderately inflated transiting hot Jupiter with a mass of 1.477 (-0.067, +0.066) M_J, and radius of 1.345 +/- 0.072 R_J, with an orbital period of 2.7033904 +/- 0.000010 days. The host star, KELT-3, is a V=9.8 late F star with M_* = 1.278 (-0.061, +0.063) M_sun, R_* = 1.472 (-0.067, +0.065) R_sun, T_eff = 6306 (-49, +50) K, log(g) = 4.209 (-0.031, +0.033), and [Fe/H] = 0.044 (-0.082, +0.080), and has a likely proper motion companion. KELT-3b is the third transiting exoplanet discovered by the KELT survey, and is orbiting one of the 20 brightest known transiting planet host stars, making it a promising candidate for detailed characterization studies. Although we infer that KELT-3 is significantly evolved, a preliminary analysis of the stellar and orbital evolution of the system suggests that the planet has likely always received a level of incident flux above the empirically-identified threshold for radius inflation suggested by Demory & Seager (2011).Comment: 12 pages, 12 figures, accepted to Ap