Publications by authors named "Jason Chien"

100 Publications

A comprehensive analysis of authorship trends in Skeletal Radiology since inception from 1976 to 2020.

Skeletal Radiol 2021 Jun 2. Epub 2021 Jun 2.

Department of Radiology, Icahn School of Medicine At Mount Sinai (West), New York, NY, USA.

Objective: The purpose of this study is to explore authorship trends within the musculoskeletal radiology subspecialty-focused journal, Skeletal Radiology, from inception to 2020.

Materials And Methods: Skeletal Radiology articles published in 1976, 1986, 1996, 2006, 2016, and 2020 were reviewed. For each article, the number of authors, the number of distinct institutions, the names of first and last authors, the country of the first author, the article length, and the number of article references were recorded.

Results: A total of 885 articles passed the exclusion criteria to be included in the study. Since inception, there has been a significant increase in the number of SR articles published (P = 0.02), the mean number of authors per article (P < 0.01), the mean number of references per article (P < 0.01), the mean number of distinct institutions per article (P = 0.02), and the mean number of pages per article (P < 0.01). The proportion of female first and last authors significantly increased (P = 0.02, P = 0.02). There was a significant increase in the proportion of articles published from Asia (P = 0.04). However, no significant changes in the proportion of articles published from other regions were observed.

Conclusion: Similar to authorship trends in other medical journals, Skeletal Radiology demonstrated upward trends in authorship count, distinct institutional count, and article length. A rise in first and last female authorship was observed. Finally, an increase in the proportion of authors from Asia was observed while no significant changes in the proportion of authors from other regions were demonstrated.
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http://dx.doi.org/10.1007/s00256-021-03810-yDOI Listing
June 2021

Cigarette Smoke Exposure Promotes Virulence of Pseudomonas aeruginosa and Induces Resistance to Neutrophil Killing.

Infect Immun 2020 10 19;88(11). Epub 2020 Oct 19.

Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, California, USA

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. , a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of , a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of , increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen.
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http://dx.doi.org/10.1128/IAI.00527-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573448PMC
October 2020

Assessment of the accessibility and content of dermatology fellowship websites.

J Am Acad Dermatol 2021 May 10;84(5):1423-1425. Epub 2020 Jun 10.

Department of Dermatology, The George Washington School of Medicine and Health Sciences, Washington, District of Columbia. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.06.017DOI Listing
May 2021

Trends in Authorship of Original Scientific Articles in Journal of Glaucoma: An Analysis of 25 Years Since the Initiation of the Journal.

J Glaucoma 2020 07;29(7):561-566

The George Washington University School of Medicine and Health Sciences, Washington, DC.

PRéCIS:: Publications in glaucoma have seen an increase in the number of authors and disclosures per article, authors with dual degrees, and international authors, but contributions of women to articles published remains low.

Purpose: Authorship trends have been studied across many medical specialties and in ophthalmology as a whole, but not specifically in glaucoma. The authors explored the authorship trends of original scientific articles in the Journal of Glaucoma.

Materials And Methods: The authors recorded the number of authors and disclosures per article, degree type of first and last authors, geographical origin of the corresponding author, and sex of first and last authors of original content from the Journal of Glaucoma published in 1992, 1997, 2002, 2007, 2012, and 2017.

Results: A total of 642 articles were analyzed. From 1992 to 2017, annual published articles increased from 38 to 242 (P=0.02), the mean number of authors per article increased from 3.2 to 5.2 (P<0.01), the mean number of disclosures per article increased from 0.3 to 1.0 (P=0.04), the proportion of first and last authors with dual degrees (medical plus advanced degrees) also increased (both P<0.03), whereas the proportion with a sole medical degree decreased (both P<0.05). There was a proportional decrease in articles from North America (P=0.03), and proportional increase from the "Far East" (P=0.04) and "Other" regions (P=0.04). No significant changes in proportions of female first and last authors were found (both P>0.28).

Conclusions: Consistent with authorship trends across various other medical specialties, glaucoma has seen an increase in the number of authors and disclosures per article, authors with dual degrees, and authors from the "Far East" and "Other" regions. However, contributions of women to articles published in Journal of Glaucoma remain low.
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http://dx.doi.org/10.1097/IJG.0000000000001503DOI Listing
July 2020

Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Gilead Sciences, Inc., Foster City, California, USA.

This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but they had similar clinical outcomes. Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with genotypic resistance development had decreased virologic responses compared to those without genotypic resistance but had comparable clinical outcomes.
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http://dx.doi.org/10.1128/AAC.02312-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449164PMC
August 2020

Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV.

J Infect Dis 2020 10;222(9):1468-1477

Gilead Sciences, Inc, Foster City, California, USA.

Background: Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner.

Methods: Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed.

Results: Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease.

Conclusions: Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.
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http://dx.doi.org/10.1093/infdis/jiaa028DOI Listing
October 2020

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

Clin Infect Dis 2020 12;71(11):2787-2795

Division of Infectious Disease, City of Hope National Medical Center, Duarte, California, USA.

Background: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).

Methods: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.

Results: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.

Conclusions: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.

Clinical Trials Registration: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.
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http://dx.doi.org/10.1093/cid/ciz1167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108198PMC
December 2020

Evaluating Neuroradiology Fellowship Program Websites: A Critical Analysis of all 84 Programs in the United States.

Curr Probl Diagn Radiol 2021 Mar-Apr;50(2):147-150. Epub 2019 Nov 18.

Saba University School of Medicine, Saba, Dutch Caribbean, the Netherlands.

Purpose: To investigate the accessibility and content of neuroradiology fellowship program websites (NRFW).

Methods: A list of neuroradiology fellowship programs were obtained from the official Accreditation Council for Graduate Medical Education (ACGME) website. A google search was used to identify each NRFW of individual programs. Each NRFW was evaluated for the availability of content under recruitment and education domains.

Results: At the time of the study, there were 84 ACGME accredited neuroradiology fellowship websites available for analysis. In the recruitment domain, evaluators found program description (98.8%), contact address (94.1%), and searchable on google (97.7%) most readily available while, interview day itinerary (3.5%), meal allowance (16.5%), and parking (21.2%) were least readily available. In the education domain, research (91.8%), facility description (89.4%), and faculty listing (82.4%) were most readily available, while postfellowship placement (10.6%), alumni education history (17.7%), and responsibility progression (25.9%) were least readily available.

Conclusions: NRFW vary greatly in the amount of information they display. Programs display their descriptions and contact information most frequently while interview day itinerary was the least likely to be found. There were no statistically significant differences between the amount of recruitment and educational content listed when programs were stratified by rank (top ten vs below top ten), region (west, midwest, northeast, and south), and program size (>3 fellows vs 1-3 fellows). Website content development is relatively low cost and our findings suggest that there is room for improvement in website comprehensiveness.
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http://dx.doi.org/10.1067/j.cpradiol.2019.11.002DOI Listing
November 2019

A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients.

Clin Infect Dis 2020 12;71(11):2777-2786

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Background: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections.

Methods: Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/μL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28.

Results: From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, -0.33 log10 copies/mL; 95% confidence interval [CI] -.64 to -.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22-1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo.

Conclusions: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.

Clinical Trials Registration: NCT02254408; EUDRA-CT#2014-002474-36.
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http://dx.doi.org/10.1093/cid/ciz1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108134PMC
December 2020

Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 02 1;26(2):392-400. Epub 2019 Nov 1.

AP-HP, Université de Paris, Hôpital Saint-Louis, Service de Pneumologie, Paris, France; Université de Paris, ECSTRRA, UMR 1153 CRESS, Biostatistics and Clinical Epidemiology Research Team, Paris, France. Electronic address:

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430235PMC
February 2020

E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation.

Am J Physiol Cell Physiol 2020 01 30;318(1):C205-C214. Epub 2019 Oct 30.

Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California.

E-cigarettes are portrayed as safer relative to conventional tobacco. However, burgeoning evidence suggests that E-cigarettes may adversely affect host defenses. However, the precise mechanisms by which E-cigarette vapor alters innate immune cell function have not been fully elucidated. We determined the effects of E-cigarette exposure on the function and responses to infectious challenge of the most abundant innate immune cell, the neutrophil, using isolated human neutrophils and a mouse model of gram-negative infection. Our results revealed that human neutrophils exposed to E-cigarette vapor had 4.2-fold reductions in chemotaxis toward the bacterial cell-well component f-Met-Leu-Phe ( < 0.001). F-actin polarization and membrane fluidity were also adversely affected by E-cigarette vapor exposure. E-cigarette-exposed human neutrophils exhibited a 48% reduction in production of reactive oxygen species (ROS; < 0.001). Given the central role of ROS in neutrophil extracellular trap (NET) production, NET production was quantified, and E-cigarette vapor exposure was found to reduce NETosis by 3.5-fold ( < 0.01); formulations with and without nicotine containing propylene glycol exhibiting significant suppressive effects. However, noncanonical NETosis was unaffected. In addition, exposure to E-cigarette vapor lowered the rate of phagocytosis of bacterial bioparticles by 47% ( < 0.05). In our physiological mouse model of chronic E-cigarette exposure and sepsis, E-cigarette vapor inhalation led to reduced neutrophil migration in infected spaces and a higher burden of . These findings provide evidence that E-cigarette use adversely impacts the innate immune system and may place E-cigarette users at higher risk for dysregulated inflammatory responses and invasive bacterial infections.
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http://dx.doi.org/10.1152/ajpcell.00045.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985828PMC
January 2020

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY DETECTS SUBCLINICAL RADIAL PERIPAPILLARY CAPILLARY DENSITY REDUCTION AFTER PLAQUE RADIOTHERAPY FOR CHOROIDAL MELANOMA.

Retina 2020 Sep;40(9):1774-1782

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

Purpose: To evaluate radial peripapillary capillary density (RPCD) in irradiated eyes without radiation papillopathy clinically.

Methods: Patients treated with plaque radiotherapy for unilateral choroidal melanoma without radiation papillopathy clinically received optical coherence tomography and optical coherence tomography angiography imaging at ∼12- to 24-month follow-up. Comparison of RPCD globally and meridian closest to plaque and meridian farthest to plaque of irradiated versus nonirradiated eyes was performed.

Results: Mean age was 55 years (n = 10). Mean largest basal diameter and thickness were 10.1 and 4.4 mm, respectively. Mean radiation dose to the optic nerve head and foveola was 41.7 and 66.2 Gy, respectively. No radiation papillopathy was detected by ophthalmoscopy throughout follow-up (mean:14 months). Radial peripapillary capillary density was significantly reduced globally (all P < 0.02). Meridian closest to plaque RPCD was significantly reduced (P < 0.01), but not meridian farthest to plaque RPCD (P = 0.07). Circumpapillary retinal nerve fiber layer thickness was not significantly reduced (P > 0.26). Radiation dose to the optic nerve head was correlated with meridian closest to plaque RPCD reduction (r = 0.76; P < 0.01). Mean radiation dose to the optic nerve head for <5% and ≥5% RPCD reductions was 35.9 ± 12.2 and 55.2 ± 6.4 Gy, respectively.

Conclusion: Radial peripapillary capillary density reduction was found in irradiated eyes before clinical evidence of radiation papillopathy and circumpapillary retinal nerve fiber layer thickness reduction. Radial peripapillary capillary density reduction is correlated to plaque location and radiation dose to the optic nerve head.
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http://dx.doi.org/10.1097/IAE.0000000000002680DOI Listing
September 2020

The Enigmatic Canal-Associated Neurons Regulate Larval Development Through a cAMP Signaling Pathway.

Genetics 2019 12 16;213(4):1465-1478. Epub 2019 Oct 16.

Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden 405 30.

larval development requires the function of the two Canal-Associated Neurons (CANs): killing the CANs by laser microsurgery or disrupting their development by mutating the gene results in early larval arrest. How these cells promote larval development, however, remains a mystery. In screens for mutations that bypass CAN function, we identified the gene , which encodes a member of the Salt-Inducible Kinase (SIK) family and a component of a conserved pathway that regulates various phenotypes. Like loss, gain-of-function mutations in genes that may act upstream of or growth in cyclic-AMP analogs bypassed larval arrest, suggesting that a conserved adenylyl cyclase/PKA pathway inhibits KIN-29 to promote larval development, and that loss of CAN function results in dysregulation of KIN-29 and larval arrest. The adenylyl cyclase ACY-2 mediates CAN-dependent larval development: mutant larvae arrested development with a similar phenotype to mutants, and the arrest phenotype was suppressed by mutations in ACY-2 is expressed predominantly in the CANs, and we provide evidence that the functions in the CANs to promote larval development. By contrast, cell-specific expression experiments suggest that acts in both the hypodermis and neurons, but not in the CANs. Based on our findings, we propose two models for how ACY-2 activity in the CANs regulates KIN-29 in target cells.
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http://dx.doi.org/10.1534/genetics.119.302628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893374PMC
December 2019

Uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use.

J Community Hosp Intern Med Perspect 2019 5;9(4):371-372. Epub 2019 Sep 5.

Department of Medicine, Medstar Harbor Hospital, Baltimore, MD, USA.

Gabapentin is an anticonvulsant medication that reduces synaptic transmission by decreasing presynaptic voltage-gated Ca2+ and Na+ channels. It is approved to treat focal seizures but also used to treat post-herpetic and neuropathic pain. Although uncommon, there have been three reported cases of myasthenia gravis exacerbation associated with gabapentin in the literature. We present a patient with uncontrolled recurrent myasthenia gravis exacerbations secondary to chronic gabapentin use and provide a review for the three published cases.
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http://dx.doi.org/10.1080/20009666.2019.1643220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735302PMC
September 2019

Inhibition of Human Neutrophil Extracellular Trap (NET) Production by Propofol and Lipid Emulsion.

Front Pharmacol 2019 5;10:323. Epub 2019 Apr 5.

Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States.

Uncontrolled bacteremia is a common and life threatening condition that can lead to sepsis and septic shock with significant morbidity and mortality. Neutrophil granulocytes, the most abundant phagocytic leukocyte of the innate immune system, play an essential role in capturing and killing invading pathogens. Their antimicrobial repertoire includes the formation of Neutrophil Extracellular Traps (NETs), chromatin-based, web-like structures of DNA that facilitate the capture and killing of bacteria. In sepsis, however, it has been suggested that the uncontrolled release of NETs worsens disseminated coagulation and promotes venous thrombosis. Here, we describe how clinically relevant concentrations of the commonly used sedative propofol as well as a lipid composition similar to the propofol carrier impair NET production by human neutrophils. Drugs commonly administered in the Intensive Care Unit (ICU) may impact the inflammatory response to either worsen or improve clinical outcomes and may therefore be considered for additional therapeutic effects if clinical studies confirm such findings.
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http://dx.doi.org/10.3389/fphar.2019.00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460395PMC
April 2019

Midturbinate Swabs Are Comparable to Nasopharyngeal Swabs for Quantitative Detection of Respiratory Syncytial Virus in Infants.

J Pediatric Infect Dis Soc 2019 Dec;8(6):554-558

Gilead Sciences, Inc, Foster City, California.

Nasopharyngeal (NP) swabs are generally used to detect respiratory syncytial virus (RSV) in infants. However, midturbinate (MT) swabs may provide comparable results. In this study, we enrolled hospitalized infants aged <24 months with RSV and collected NP and MT swabs. The resulting viral loads measured by real-time reverse-transcription quantitative polymerase chain reaction were similar. Most parents preferred MT swabs over NP swabs.
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http://dx.doi.org/10.1093/jpids/piy115DOI Listing
December 2019

Changes in Iridocorneal Angle and Anterior Chamber Structure in Eyes With Anatomically Narrow Angles: Laser Iridotomy Versus Pilocarpine.

J Glaucoma 2018 12;27(12):1073-1078

Department of Ophthalmology, Manhattan Eye, Ear, and Throat Hospital (Lenox Hill Hospital).

Purpose: To compare the effects of laser iridotomy (LI) and pilocarpine on iridocorneal angle and anterior chamber structure in anatomically narrow angles (ANAs).

Materials And Methods: Temporal LI was performed 90 minutes after 2% pilocarpine administration in patients with occludable ANA. Swept-source optical coherence tomography B-scans of the anterior segment were obtained at baseline, 60 minutes after 2% pilocarpine administration, and 1 week after LI. Angle-opening distance (AOD), trabecular-iris surface area (TISA), and angle recess area (ARA) were measured at the temporal, superior, nasal, and inferior quadrants. Anterior chamber depth (ACD) and lens vault (LV) were also measured. AOD, TISA, ARA, ACD, and LV were compared among 3 time points: at baseline, 60 minutes after 2% pilocarpine administration, and 1 week after LI.

Results: Twenty-four eyes (24 patients; mean age, 55 y) were included. In all 4 quadrants and globally, AOD, TISA, and ARA increased from baseline after pilocarpine and after LI (all P<0.010). The increase in AOD, TISA, and ARA was greater after LI than after pilocarpine globally and in the temporal and superior quadrants (all P<0.040). ACD decreased and LV increased from baseline after pilocarpine (both P<0.001). Postpilocarpine anterior chambers were shallower with higher LV than post-LI (both P<0.016).

Conclusion: LI is more effective than pilocarpine in widening the iridocorneal angle without significant shallowing the anterior chamber in eyes with ANA.
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http://dx.doi.org/10.1097/IJG.0000000000001097DOI Listing
December 2018

Phase 1 First-in-Human, Single- and Multiple-Ascending Dose, and Food Effect Studies to Assess the Safety, Tolerability, and Pharmacokinetics of Presatovir for the Treatment of Respiratory Syncytial Virus Infection.

J Clin Pharmacol 2018 Aug 17;58(8):1025-1034. Epub 2018 Apr 17.

Gilead Sciences, Inc, Foster City, CA, USA.

Respiratory syncytial virus (RSV)-associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS-5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes. Here, results from 2 phase 1 studies that evaluated safety, tolerability, and pharmacokinetics of presatovir in healthy adults following administration of single and multiple (7 days) once- or twice-daily ascending doses (first-in-human study) and in the presence or absence of food (food effect study) are described. Presatovir exhibited favorable safety and pharmacokinetic profiles that supported once-daily dosing. Presatovir exposure increased in an approximately dose-proportional manner across the evaluated dose range (single doses 25-300 mg; multiple doses 10-75 mg once daily for 7 days). Administration of presatovir with a high-fat meal did not alter exposure, supporting administration without regard to a meal in further clinical studies. These data were subsequently used to inform presatovir dosing regimens in a phase 2a challenge study of adults experimentally infected with RSV. Collectively, results from phase 1 evaluations and a phase 2a challenge study support further clinical investigation of presatovir for the treatment of RSV infection.
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http://dx.doi.org/10.1002/jcph.1112DOI Listing
August 2018

The Drug-Drug Interaction Profile of Presatovir.

J Clin Pharmacol 2018 06 7;58(6):771-780. Epub 2018 Feb 7.

Gilead Sciences, Inc., Foster City, CA, USA.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [C ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUC ), and decreased by rifampin (40.3% in C and 82.5% in AUC ) and efavirenz (55.7% in AUC ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.
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http://dx.doi.org/10.1002/jcph.1073DOI Listing
June 2018

Regulation of Axon Guidance by the Wnt Receptor Ror/CAM-1 in the PVT Guidepost Cell in .

Genetics 2017 12 9;207(4):1533-1545. Epub 2017 Oct 9.

Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Sweden

The ventral nerve cord (VNC) consists of two asymmetric bundles of neurons and axons that are separated by the midline. How the axons are guided to stay on the correct sides of the midline remains poorly understood. Here we provide evidence that the conserved Wnt signaling pathway along with the Netrin and Robo pathways constitute a combinatorial code for midline guidance of PVP and PVQ axons that extend into the VNC. Combined loss of the Wnts CWN-1, CWN-2, and EGL-20 or loss of the Wnt receptor CAM-1 caused >70% of PVP and PVQ axons to inappropriately cross over from the left side to the right side. Loss of the Frizzled receptor LIN-17 or the planar cell polarity (PCP) protein VANG-1 also caused cross over defects that did not enhance those in the mutant, indicating that the proteins function together in midline guidance. Strong expression can be detected in the PVQs and the guidepost cell PVT that is located on the midline. However, only when is expressed in PVT are the crossover defects of PVP and PVQ rescued, showing that CAM-1 functions nonautonomously in PVT to prevent axons from crossing the midline.
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http://dx.doi.org/10.1534/genetics.117.300375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714464PMC
December 2017

Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus.

J Infect Dis 2017 12;216(10):1235-1244

Department of Medicine, University of Washington.

Background: Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection.

Methods: Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received.

Results: Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]).

Conclusions: Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.
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http://dx.doi.org/10.1093/infdis/jix390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853655PMC
December 2017

Optical Coherence Tomography Angiography Features of Iris Racemose Hemangioma in 4 Cases.

JAMA Ophthalmol 2017 10;135(10):1106-1110

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

Importance: Optical coherence tomography angiography (OCTA) allows visualization of iris racemose hemangioma course and its relation to the normal iris microvasculature.

Objective: To describe OCTA features of iris racemose hemangioma.

Design, Setting, And Participants: Descriptive, noncomparative case series at a tertiary referral center (Ocular Oncology Service of Wills Eye Hospital). Patients diagnosed with unilateral iris racemose hemangioma were included in the study.

Main Outcomes And Measures: Features of iris racemose hemangioma on OCTA.

Results: Four eyes of 4 patients with unilateral iris racemose hemangioma were included in the study. Mean patient age was 50 years, all patients were white, and Snellen visual acuity was 20/20 in each case. All eyes had sectoral iris racemose hemangioma without associated iris or ciliary body solid tumor on clinical examination and ultrasound biomicroscopy. By anterior segment OCT, the racemose hemangioma was partially visualized in all cases. By OCTA, the hemangioma was clearly visualized as a uniform large-caliber vascular tortuous loop with intense flow characteristics superimposed over small-caliber radial iris vessels against a background of low-signal iris stroma. The vascular course on OCTA resembled a light bulb filament (filament sign), arising from the peripheral iris (base of light bulb) and forming a tortuous loop on reaching its peak (midfilament) near the pupil (n = 3) or midzonal iris (n = 1), before returning to the peripheral iris (base of light bulb). Intravenous fluorescein angiography performed in 1 eye depicted the iris hemangioma; however, small-caliber radial iris vessels were more distinct on OCTA than intravenous fluorescein angiography.

Conclusions And Relevance: Optical coherence tomography angiography is a noninvasive vascular imaging modality that clearly depicts the looping course of iris racemose hemangioma. Optical coherence tomography angiography depicted fine details of radial iris vessels, not distinct on intravenous fluorescein angiography.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.3390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847105PMC
October 2017

Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial.

JAMA 2017 08;318(6):557-566

APHP, Hématologie-Transplantation Hôpital St Louis, Université Denis Diderot and INSERM UMR 1160, Paris, France.

Importance: Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post-lung transplant bronchiolitis obliterans syndrome.

Objective: To evaluate if the early administration of azithromycin can improve airflow decline-free survival after allogeneic HSCT.

Design, Setting, And Participants: The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017.

Interventions: Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen.

Main Outcomes And Measures: The primary efficacy end point was airflow decline-free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years.

Results: Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline-free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70; P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0; P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4; P = .002).

Conclusions And Relevance: Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline-free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation.

Trial Registration: clinicaltrials.gov Identifier: NCT01959100.
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http://dx.doi.org/10.1001/jama.2017.9938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817485PMC
August 2017

A Novel Method for Assessing Lamina Cribrosa Structure Ex Vivo Using Anterior Segment Enhanced Depth Imaging Optical Coherence Tomography.

J Glaucoma 2017 Jul;26(7):626-632

*Moise and Chella Safra Advanced Ocular Imaging Laboratory, Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai §Department of Pathology and Laboratory Medicine, New York Eye and Ear Infirmary of Mount Sinai ‡Bernard and Shirlee Brown Glaucoma Research Laboratory, Harkness Eye Institute, Columbia University Medical Center, Harkness Eye Institute ∥Department of Ophthalmology, Manhattan Eye, Ear and Throat Hospital, New York ¶Department of Ophthalmology, Hofstra Northwell School of Medicine, Hempstead, NY †George Washington University School of Medicine and Health Sciences, Washington, DC.

Purpose: The purpose of this study is to investigate the use of anterior segment enhanced depth imaging (EDI) optical coherence tomography (OCT) for ex vivo lamina cribrosa (LC) imaging.

Materials And Methods: After removing anterior segment and vitreous, the optic nerve head (ONH) tissue of porcine eyes was placed on a customized eye holder for imaging. Serial EDI OCT B-scans (interval, ∼35 μm) of the ONH were obtained using anterior segment module of spectral-domain OCT. Various conditions were tested for better quality LC images. After EDI OCT, serial histologic sections were obtained (distance between sections, ∼5 μm). LC structures in OCT scans were compared with those in histologic sections. Three-dimensional LC reconstructions created using serial OCT scans were compared with LC structures in disc photographs.

Results: ONHs of 3 enucleated eyes were examined. The LC was more clearly imaged when the retina and part of the prelaminar tissue were removed (quality score, 39.01±3.30 vs. 26.40±5.85; P<0.001) and when the tissue was kept moist during imaging (quality score, 38.70±2.11 vs. 36.18±5.98; P<0.001). LC image quality was similar before and after fixation (quality score, 38.84±6.57 vs. 39.21±9.69; P=0.79). LC beams and part of retrolaminar glial columns identified in OCT scans matched those in histologic sections. LC beams and pores in 3-dimensional reconstructions matched those in disc photographs.

Conclusions: High-resolution cross-sectional images of the LC, comparable to histologic sections, can be obtained using anterior segment EDI OCT in ex vivo eyes with proper tissue preparation.
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http://dx.doi.org/10.1097/IJG.0000000000000685DOI Listing
July 2017

Conjunctival Tumors: Review of Clinical Features, Risks, Biomarkers, and Outcomes--The 2017 J. Donald M. Gass Lecture.

Asia Pac J Ophthalmol (Phila) 2017 Mar-Apr;6(2):109-120

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA.

Conjunctival tumors encompass a broad range of diagnoses. The 3 most important malignant tumors include ocular surface squamous neoplasia (OSSN) (14%), melanoma (12%), and lymphoma (7%). Conjunctival malignancies are rarely found in children. Regarding OSSN, pre-disposing conditions include chronic solar radiation, immune deficiency (HIV), organ transplant, autoimmune conditions, xeroderma pigmentosum, and chronic exposure to cigarette smoke. OSSN is managed surgically or with topical/injection immunotherapy or chemotherapy. Metastasis occurs in <1%. Regarding melanoma, predisposing conditions include primary acquired melanosis (PAM), chronic nevus, and chronic solar radiation. Treatment of PAM or nevus can prevent melanoma. Melanoma management involves surgical resection with clean margins and avoidance of direct tumor manipulation ("no touch" technique). The first surgery is most important, to minimize tumor seeding. Biomarkers including BRAF, TERT, and PTEN provide information regarding risk for metastasis and allow for targeted antibiomarker therapies. Ten-year risk for melanoma metastasis is 25%. Tumors >2 mm thickness or those located in fornix, caruncle, or orbit are at highest risk for metastasis. Regarding lymphoma, predisposing conditions include benign reactive lymphoid hyperplasia, immune deficiency (HIV), immune dysfunction, and chronic inflammation/infection (Helicobacter pylori, Chlamydia psittaci). The 4 most important subtypes include extranodal marginal zone lymphoma (ENMZL), follicular lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma. Treatment includes surgical resection, cryotherapy, radiotherapy, systemic chemotherapy, or targeted anti-B-cell therapy (rituximab). Lymphoma-related survival (5-year) depends on subtype and ranges from 97% (ENMZL) to 9% (MCL). Recognizing conjunctival tumors and understanding predisposing factors, biomarkers, and treatment strategies are vital to patient outcomes.
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http://dx.doi.org/10.22608/APO.201710DOI Listing
September 2017

Glaucoma Diagnostic Capability of Circumpapillary Retinal Nerve Fiber Layer Thickness in Circle Scans With Different Diameters.

J Glaucoma 2017 Apr;26(4):335-342

*Moise and Chella Safra Advanced Ocular Imaging Laboratory, Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai§Department of Ophthalmology, Manhattan Eye, Ear and Throat Hospital¶Bernard and Shirlee Brown Glaucoma Research Laboratory, Columbia University Medical Center, Harkness Eye Institute, New York∥Department of Ophthalmology, Hofstra Northwell School of Medicine, Hempstead, NY†George Washington University School of Medicine and Health Sciences, Washington, DC‡Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To compare varying circumpapillary optical coherence tomographic (OCT) scan diameters for glaucoma diagnosis.

Materials And Methods: Prospective, cross-sectional, observational study. Circumpapillary retinal nerve fiber layer thickness (RNFLT) was measured using spectral-domain OCT in 1 randomly selected eye. Scans with diameters of 3.5, 4.1, and 4.7 mm were obtained, each with 7 parameters: mean global (G) RNFLT and mean RNFLT for the temporal-inferior (TI), nasal-inferior (NI), temporal-superior (TS), nasal-superior (NS), nasal (N), and temporal (T) sectors. Areas under the receiver operating characteristic curve (AUCs) were calculated.

Results: Mean age was 55±18 years in 68 healthy eyes and 59±15 years in 95 glaucomatous eyes (P=0.12). Visual field mean deviation was -7.55±6.61 dB in glaucomatous eyes. In all 3 circle scans, mean TI RNFLT had the greatest AUC (0.974 to 0.983), followed by mean G RNFLT (0.949 to 0.956). The AUC of mean TI RNFLT in the 4.1-mm scan (0.983) was greater than the AUCs of mean TI RNFLTs in the 4.7- (0.978; P=0.128) and 3.5-mm (0.974; P=0.049) scans. The AUC of mean TI RNFLT in the 4.1-mm scan (0.983) was greater than the AUCs of mean G RNFLTs in the 3.5- (0.954; P=0.011), 4.1- (0.956; P=0.016), and 4.7-mm (0.949; P=0.011) scans. In 2 eyes with large parapapillary atrophy, RNFL segmentation error was noted only in the 3.5-mm scan in the area of parapapillary atrophy.

Conclusions: Further investigations to find the spectral-domain OCT circle scan diameter with the best diagnostic capability and the least artifacts are warranted, especially focusing on larger-than-conventional circle scans.
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http://dx.doi.org/10.1097/IJG.0000000000000610DOI Listing
April 2017

Optical Coherence Tomography Angiography of Conjunctival Racemose Hemangioma.

Ophthalmology 2017 04;124(4):449

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.ophtha.2016.09.016DOI Listing
April 2017

Choroidal nevus: a review of prevalence, features, genetics, risks, and outcomes.

Curr Opin Ophthalmol 2017 May;28(3):228-237

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Purpose Of Review: To review the prevalence, clinical features, imaging findings, cytogenetics, and risks and outcomes of choroidal nevus.

Recent Findings: Choroidal nevus is a benign melanocytic tumor, often discovered incidentally on ophthalmic examination. This lesion is generally well circumscribed and pigmented. The prevalence of choroidal nevus in postequatorial region in United States adults (≥40 years old) is approximately 5%. Choroidal nevus is associated with higher lifetime unopposed estrogen and greater BMI. In population-based evaluation, the mean nevus basal dimension is approximately 1.25 mm. Giant nevus (basal dimension ≥10 mm) carries greater risk for malignant transformation. Imaging modalities for evaluation of choroidal nevus include ultrasonography, fundus autofluorescence, and optical coherence tomography (OCT). Fluorescein angiography is occasionally employed to detect multifocal pinpoint leaks or choroidal neovascular membrane. Recently, OCT angiography demonstrated nevus with minimal overlying macular microvascular changes compared with melanoma. Cytogenetically, GNA11 or GNAQ mutations have been documented in uveal melanoma in 83% and in some cutaneous nevus subtypes. Further mutations lead to the development of melanoma at a rate of one of 8845 cases. Risk factors for transformation of nevus into melanoma are recalled by the mnemonic 'To find small ocular melanoma using helpful hints daily' representing thickness (T) more than 2 mm, subretinal fluid (F), symptoms (S) of flashes/floaters/blurred vision, orange (O) lipofuscin pigment, margin (M) less than 3 mm from optic disk, ultrasonographic hollowness (UH), halo (H) absence, and drusen (D) absence. The presence of three or more risk factors implies more than 50% chance for transformation to melanoma within 5 years. A new, online ocular oncology reading center can help judge nevus risk.

Summary: Choroidal nevus is a common intraocular lesion, found predominantly in Whites. This mass carries a small risk (<1%) for malignant transformation. Patients with at least three risk factors should be evaluated for possible melanoma at an experienced ocular oncology center.
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http://dx.doi.org/10.1097/ICU.0000000000000361DOI Listing
May 2017

An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

Am J Respir Crit Care Med 2017 07;196(1):82-93

1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.

Objectives: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.

Methods: We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis.

Measurements And Main Results: We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10).

Conclusions: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.
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http://dx.doi.org/10.1164/rccm.201610-2088OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519963PMC
July 2017

Microarchitecture of Schlemm Canal Before and After Selective Laser Trabeculoplasty in Enhanced Depth Imaging Optical Coherence Tomography.

J Glaucoma 2017 Apr;26(4):361-366

*Moise and Chella Safra Advanced Ocular Imaging Laboratory, Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai ‡Bernard and Shirlee Brown Glaucoma Research Laboratory, Harkness Eye Institute, Columbia University Medical Center §Department of Ophthalmology, Manhattan Eye, Ear and Throat Hospital, New York ∥Department of Ophthalmology, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY †Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To characterize the in vivo effect of selective laser trabeculoplasty (SLT) on the Schlemm canal (SC) in eyes with primary open-angle glaucoma (POAG).

Materials And Methods: Eighty-one serial horizontal enhanced depth imaging optical coherence tomograph B-scans (interval between B-scans, ∼35 μm) of the nasal corneoscleral limbus were obtained before and 4 weeks after SLT. Fifty B-scans in the overlapping regions before and after SLT were selected for analysis based on the structures of aqueous and blood vessels as landmarks. The SC cross-sectional area (CSA) was measured in each selected B-scan and averaged to generate the mean SC CSA of the eye. SC volume in the overlapping region was calculated using commercially available 3-dimensional reconstruction software. The mean SC CSA and SC volume were compared between pre-SLT and post-SLT B-scans. Correlation analysis was performed between SC CSA changes and intraocular pressure (IOP) changes.

Results: Thirteen POAG eyes (13 patients) were included for analysis (mean age, 68.2±9.2 y). After SLT, the mean IOP was reduced from 19.8±7.6 to 14.4±3.8 mm Hg (P=0.003); the mean SC CSA increased by 8%, from 2478±550 to 2682±598 μm (P=0.029); and the mean SC volume increased from 4,304,592±954,777 to 4,658,250±1,039,956 μm (P=0.029). Increase in SC CSA had a significant positive correlation with IOP reduction after SLT (P=0.023, R=0.622).

Conclusions: SLT expands SC in POAG patients and even more so with greater IOP reduction after SLT. Post-SLT expansion of SC may be due to increased trabecular aqueous outflow, IOP decrease, or structural changes in trabecular meshwork resulting from SLT.
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http://dx.doi.org/10.1097/IJG.0000000000000624DOI Listing
April 2017
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