A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1

Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder

Optic Nerve Head Quantification in Idiopathic Intracranial Hypertension by Spectral Domain OCT

Objective: To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). Design and Patients: Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. Results:Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). Conclusion: Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumba

Burden of rotavirus gastroenteritis in the Middle Eastern and North African pediatric population

<p>Abstract</p> <p>Background</p> <p>Rotavirus gastroenteritis (RVGE) is the most common cause of severe childhood diarrhea worldwide. Objectives were to estimate the burden of RVGE among children less than five years old in the Middle East (Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, UAE, Yemen), North Africa (Algeria, Egypt, Libya, Morocco, Tunisia) and Turkey.</p> <p>Methods</p> <p>A comprehensive literature search was conducted in major databases on the epidemiology and burden of rotavirus among children less than five years old between 1999 and 2009. Data from each country was extracted and compared.</p> <p>Results</p> <p>The search identified 43 studies. RVGE was identified in 16-61% of all cases of acute gastroenteritis, with a peak in the winter. RVGE-related hospitalization rates ranged from 14% to 45%, compared to 14%-28% for non-RVGE. Annually, RVGE caused up to 112 fatalities per 100,000 in certain countries in the region. Hospitalization costs ranged from $1.8 to$4.6 million annually, depending on the country. The most recent literature available showed that G1P[8] was the most prevalent genotype combination in 8 countries (range 23%-56%). G2P[4] was most prevalent in 4 countries (26%-48%). G9P[8] and G4P[8] were also frequently detected.</p> <p>Conclusions</p> <p>RVGE is a common disease associated with significant morbidity, mortality, and economic burden. Given the variety and diverse rotavirus types in the region, use of a vaccine with broad and consistent serotype coverage would be important to help decrease the burden of RVGE in the Middle East and North Africa.</p

A morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation

© 2019 The Authors. Published by Springer. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/s41467-019-13149-7The hepatopancreatic ductal (HPD) system connects the intrahepatic and intrapancreatic ducts to the intestine and ensures the afferent transport of the bile and pancreatic enzymes. Yet the molecular and cellular mechanisms controlling their differentiation and morphogenesis into a functional ductal system are poorly understood. Here, we characterize HPD system morphogenesis by high-resolution microscopy in zebrafish. The HPD system differentiates from a rod of unpolarized cells into mature ducts by de novo lumen formation in a dynamic multi-step process. The remodeling step from multiple nascent lumina into a single lumen requires active cell intercalation and myosin contractility. We identify key functions for EphB/EphrinB signaling in this dynamic remodeling step. Two EphrinB ligands, EphrinB1 and EphrinB2a, and two EphB receptors, EphB3b and EphB4a, control HPD morphogenesis by remodeling individual ductal compartments, and thereby coordinate the morphogenesis of this multi-compartment ductal system.This work was funded by the Novo Nordisk Foundation (NNF17CC0027852) and Danish National Research Foundation (DNRF116). J.C. and D.G.W. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001217), the UK Medical Research Council (FC001217), and the Wellcome Trust (FC001217). S.C. was supported by an SNSF Early Postdoc Mobility fellowship (P2ZHP3_164840) and a Long Term EMBO Postdoc fellowship (ALTF 511-2016), and L.S. and J.B.A. by the Independent Research Fund Denmark (DFF; Sapere Aude2 4183-00118B).Published versio

A matched-control comparison of serious adverse events after intravitreal injections of bevacizumab for age-related macular degeneration and cataract extraction

Naomi Fischer, Elad Moisseiev, Michael Waisbourd, Michaella Goldstein, Anat Loewenstein Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Purpose: The study reported here investigated the rates of systemic serious adverse events (SAEs) following treatment with intravitreal bevacizumab for age-related macular degeneration (AMD) in comparison with a matched control group. Methods: A retrospective age- and sex-matched case-control design was used. Data were collected using patient charts and telephone surveys. The main outcome measure was difference in number of hospital admissions between the two groups. Hospitalizations were further analyzed according to whether or not they were due to arteriothrombotic SAEs. Results: Each group comprised 65 participants. There were significantly more hospital admissions among bevacizumab-treated patients than in the control group (P = 0.039). Sub-analysis of hospitalizations due to arteriothrombotic causes did not reveal a statistically significant difference between groups (P = 0.629). Conclusion: The results suggest that intravitreal bevacizumab is not associated with an increased risk of arteriothrombotic SAEs. Its widespread use for the treatment of AMD appears to be systemically safe. Keywords: Avastin&reg;, serious adverse events, safet

Tube shunt coverage with gamma-irradiated cornea allograft (VisionGraft)

Feyzahan Ekici, Marlene R Moster, Victor Cvintal, Wanda D Hu, Michael Waisbourd Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA Purpose: To investigate the clinical outcomes of tube shunt coverage using sterile gamma-irradiated cornea allograft.Patients and methods: The Wills Eye Hospital Glaucoma Research Center retrospectively reviewed the medical records of 165 patients who underwent glaucoma tube shunt procedures using sterile gamma-irradiated cornea allograft (VisionGraft) between December 2012 and November 2013. Demographic characteristics, type of tube shunt, and position were noted. Complications were recorded at 1 day; 1 week; 1, 3, 6, and 12 months; and on the final postoperative visit.Results: One hundred and sixty-nine eyes of 165 patients were included. The mean follow-up time was 4.8&plusmn;3.5 (ranging from 1 to 16) months. There was no evidence of immunological reaction, infection, or exposure in 166 eyes (98.2%). Three eyes (1.8%) experienced graft or tube exposure within the first 3 postoperative months. Two of the cases had underlying diseases: bullous pemphigoid and chronic allergic conjunctivitis.Conclusion: Coverage of tube shunts using gamma-irradiated cornea allograft had a low exposure rate and was well tolerated. The graft can be stored long term at room temperature and has an excellent postoperative cosmetic appearance.Keywords: aqueous shunts, gamma-irradiated cornea allograft, glaucoma drainage device, tube shunt surgery&nbsp

Impossibility to eliminate observer effect in the assessment of adherence in clinical trials

Jonathan S Myers,1 Scott J Fudemberg,1 Robert E Fintelmann,2 Lisa A Hark,1 Nitasha Khanna,1 Benjamin E Leiby,3 Michael Waisbourd1 1Wills Eye Hospital, Glaucoma Research Center, Philadelphia, PA, 2Barnet Dulaney Perkins Eye Center, Phoenix, AZ, 3Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, USA Purpose: To utilize the Travoprost Dosing Aid (DA) in the assessment of patient medication adherence, while also determining whether or not altering the functionality of the DA in three randomized subject groups can reduce observer effect. Methods: Forty-five subjects were randomized into three groups: two with monitored DAs and one without monitoring. One group of subjects was given a DA that both monitored drop usage and had visual and audible alarms, while the other monitored group included subjects given a DA that had no alarms but continued to monitor drop usage. The third group was given a DA that had no alarm reminders or dose usage monitoring. Subjects were informed that some monitors would not be functional, in an attempt to reduce observer effect, or the effect of being monitored on subject behavior and adherence. A six-item questionnaire was also utilized to assess how the subjects felt about their adherence and DA use. Results: The overall adherence rates were found to be 78% in the fully functional group (95% confidence interval: 70&ndash;88) and 76% in the no alarms group (95% confidence interval: 65&ndash;89). No association was seen between questionnaire response and medication adherence. The patients in the DA group without alarms had a significantly higher odds ratio of medication adherence if they reported on the questionnaire that using the DA did affect how much they used their drops. Conclusion: Though the use of DA was expected to reveal different rates of adherence depending on the functionality of the DA between groups, patients with a nonfunctioning DA did not have a significant difference in medication adherence compared to those given a fully functional DA. This supports that an observer effect was not reduced despite these interventions, and that the subjects adhered to taking their medications as if they had a functioning DA and were being monitored. Keywords: dosing aid, observer effect, glaucoma, adherenc

Factors contributing to nonadherence to follow-up appointments in a resident glaucoma clinic versus primary eye care clinic

Scott J Fudemberg,1 Brian Lee,1 Michael Waisbourd,1 Rachel A&nbsp;Murphy,1 Yang Dai,1 Benjamin E Leiby,2 Lisa A Hark1 1Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA; 2Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA Purpose: To determine the rate of adherence to follow-up appointment recommendations in a resident glaucoma clinic with no mechanism for reminders, compared to a resident cataract and primary eye care (CPEC) clinic in which telephone reminders were used, and to identify factors that contribute to adherence in each patient group.Methods: This retrospective cohort study included subjects in the CPEC clinic who received telephone reminders and those in the glaucoma clinic who did not. Each sample was selected to have a similar proportion of follow-up recommendations for 1, 3, and 6 months. Subjects were considered adherent if they returned within a specified timeframe.Results: A total of 144 subjects from the glaucoma clinic and 151 subjects from the CPEC clinic were included. There was no significant difference between follow-up adherence rates of patients who received telephone reminders and those who did not (odds ratio [OR] =1.35, 95% confidence interval [CI] 0.79&ndash;2.32, P=0.28). Patients who were on more than two ocular medications were more likely to return for follow-up (OR=3.11, 95% CI 1.53&ndash;6.35, P=0.0018). Subjects between the ages 50 and 80 years were more likely to be adherent compared to their younger and older peers (P=0.02).Conclusion: The follow-up adherence of patients in a CPEC clinic who received telephone reminders was similar to patients in a glaucoma clinic who did not receive any intervention to increase their adherence. Younger (&lt;50 years old) and elderly (&gt;80 years old) subjects, as well as patients using less than two glaucoma medications, were less likely to adhere to their follow-up appointments.Keywords: glaucoma, retrospective studies, patient adherence, telephone reminders, age, medication

Using virtual reality to enable individuals with severe visual disabilities to read books

In this work, we present a bespoke assistive tool for people with severe visual disabilities. We are able to download text from books and present these books to our users in a virtual reality environment. This gives them specific capabilities to manipulate the text and factors such as brightness, size and contrast, in order for them to gain a comfortable reading experience