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1. Comparison of the efficacy and safety of SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration

Author

Se Woong Kang, Jaehwan Choi, Veeral S. Sheth, Agnieszka Nowosielska, Marta Misiuk-Hojlo, András Papp, David M. Brown, Jae-Ho Lee, and Yoreh Barak

Subjects
Medicine, Science
Abstract

Abstract To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411—aflibercept) was − 0.4 letters (90% confidence interval = − 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.

Published
2024
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2. Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming

Author

Allan C. deCamp, Martin M. Corcoran, William J. Fulp, Jordan R. Willis, Christopher A. Cottrell, Daniel L. V. Bader, Oleksandr Kalyuzhniy, David J. Leggat, Kristen W. Cohen, Ollivier Hyrien, Sergey Menis, Greg Finak, Lamar Ballweber-Fleming, Abhinaya Srikanth, Jason R. Plyler, Farhad Rahaman, Angela Lombardo, Vincent Philiponis, Rachael E. Whaley, Aaron Seese, Joshua Brand, Alexis M. Ruppel, Wesley Hoyland, Celia R. Mahoney, Alberto Cagigi, Alison Taylor, David M. Brown, David R. Ambrozak, Troy Sincomb, Tina-Marie Mullen, Janine Maenza, Orpheus Kolokythas, Nadia Khati, Jeffrey Bethony, Mario Roederer, David Diemert, Richard A. Koup, Dagna S. Laufer, Juliana M. McElrath, Adrian B. McDermott, Gunilla B. Karlsson Hedestam, and William R. Schief

Subjects
Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

Published
2024
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3. Tree-rings reveal two strong solar proton events in 7176 and 5259 BCE

Author

Nicolas Brehm, Marcus Christl, Timothy D. J. Knowles, Emmanuelle Casanova, Richard P. Evershed, Florian Adolphi, Raimund Muscheler, Hans-Arno Synal, Florian Mekhaldi, Chiara I. Paleari, Hanns-Hubert Leuschner, Alex Bayliss, Kurt Nicolussi, Thomas Pichler, Christian Schlüchter, Charlotte L. Pearson, Matthew W. Salzer, Patrick Fonti, Daniel Nievergelt, Rashit Hantemirov, David M. Brown, Ilya Usoskin, and Lukas Wacker

Subjects
Science
Abstract

Two extreme solar energetic particle events have been found by carbon isotopes measured in ancient tree rings in 7176 and 5259 BCE. The recorded ~2% increases of atmospheric 14 C for both events exceeds in amplitude of all previously observed events.

Published
2022
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4. Muscle Up: Male Athletes’ and Non-Athletes’ Psychobiological Responses to, and Recovery From, Body Image Social-Evaluative Threats

Author

David M. Brown, Cameron Muir, and Kimberley L. Gammage

Subjects
Medicine
Abstract

Negative body image often occurs as a result of social evaluation of the physique in men. Social self-preservation theory (SSPT) holds that social-evaluative threats (SETs) elicit consistent psychobiological responses (i.e., salivary cortisol and shame) to protect one’s social-esteem, status, and standing. Actual body image SETs have resulted in psychobiological changes consistent with SSPT in men; however, responses in athletes have yet to be examined. These responses may differ as athletes tend to experience fewer body image concerns compared with non-athletes. The purpose of the current study was to examine psychobiological (i.e., body shame and salivary cortisol) responses to an acute laboratory body image SET in 49 male varsity athletes from non-aesthetic sports and 63 male non-athletes from a university community. Participants (age range 18–28 years) were randomized into a high or low body image SET condition, stratified by athlete status; measures of body shame and salivary cortisol were taken across the session (i.e., pre, post, 30-min post, 50-min post-intervention). There were no significant time-by-condition interactions, such that athletes and non-athletes had significant increases in salivary cortisol ( F 3,321 = 3.34, p = .02), when controlling for baseline values, and state body shame ( F 2.43,262.57 = 4.58, p = .007) following the high-threat condition only. Consistent with SSPT, body image SETs led to increased state body shame and salivary cortisol, although there were no differences in these responses between non-athletes and athletes.

Published
2023
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5. Computational Imaging Biomarker Correlation with Intraocular Cytokine Expression in Diabetic Macular Edema

Author

Sudeshna Sil Kar, PhD, Joseph Abraham, MD, Charles C. Wykoff, MD, PhD, Duriye Damla Sevgi, MD, Leina Lunasco, BS, David M. Brown, MD, Sunil K. Srivastava, MD, Anant Madabhushi, PhD, and Justis P. Ehlers, MD

Subjects
Diabetic macular edema, OCT, Radiomics, Ultra-widefield fluorescein angiography, Cytokine, Ophthalmology, RE1-994
Abstract

Purpose: Various pathways and cytokines are implicated in pathogenesis of diabetic macular edema (DME). Computational imaging biomarkers (CIBs) of vessel tortuosity from ultra-widefield fluorescein angiography (UWFA) and texture patterns from OCT images have been associated with anti–vascular endothelial growth factor (VEGF) therapy treatment response in DME. This analysis was a radiogenomic assessment of the association between underlying cytokines, UWFA, and OCT-based DME CIBs. Design: Biclustering analysis based on UWFA and OCT CIBs to identify a common imaging phenotype across patients with subsequent assessment of underlying cytokine signatures and treatment response attributes. Participants: The IMAGINE DME study was a post hoc study of cytokine expressions that included 24 eyes with sufficient baseline aqueous humor samples and an in-depth assessment of the imaging studies obtained during the phase I/II DmeAntiVEgf study (DAVE) that measured different cytokine expressions. Methods: A total of 151 graph or morphologic features quantifying leakage shape, size, density, interobject distance, and architecture of leakage spots and 5 vessel tortuosity features were extracted from the baseline UWFA scans, and 494 texture-based radiomics features were extracted from each of the fluid and retinal tissue compartments of OCT images. Biclustering enables simultaneous clustering of patients and features and was used to aggregate patients in terms of their commonality of phenotypes (based on similar imaging attributes) and to identify commonality in terms of cytokine expression and treatment response to anti-VEGF therapy. Main Outcome Measures: Identification of eyes with similar imaging phenotypes to evaluate commonalities of patterns and underlying cytokine expression. Results: Strong correlations between VEGF and 7 UWFA leakage morphologic features (Pearson correlation coefficient [PCC], 0.45–0.51; P < 0.05), 1 vascular tortuosity-based UWFA feature (PCC, 0.45; P = 0.00016), and 2 OCT-derived intraretinal fluid texture features (PCC, 0.58–0.63; P < 0.05) were identified. Strong correlation between intraretinal fluid features and other cytokines (PCC, 0.41–0.59; P < 0.05) were also observed. Conclusions: This study identified groups of eyes with similar imaging phenotypes as defined by UWFA and OCT CIBs that demonstrated similar treatment response patterns and cytokine expression, including a strong association between VEGF with UWFA-derived leakage morphologic and vessel tortuosity features.

Published
2022
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6. Oil Absorbent Polypropylene Particles Stimulate Biodegradation of Crude Oil by Microbial Consortia

Author

Madalina M. Vita, Paul Iturbe-Espinoza, Matthijs Bonte, Bernd W. Brandt, Martin Braster, David M. Brown, and Rob J. M. van Spanning

Subjects
biofilm, bioremediation, polypropylene, crude oil, microbial communities, Microbiology, QR1-502
Abstract

Oil absorbent particles made from surface-modified polypropylene can be used to facilitate the removal of oil from the environment. In this study, we investigated to what extent absorbed oil was biodegraded and how this compared to the biodegradation of oil in water. To do so, we incubated two bacterial communities originating from the Niger Delta, an area subject to frequent oil spills, in the presence and absence of polypropylene particles. One community evolved from untreated soil whereas the second evolved from soil pre-exposed to oil. We observed that the polypropylene particles stimulated the growth of biofilms and enriched species from genera Mycobacterium, Sphingomonas and Parvibaculum. Cultures with polypropylene particles degraded more crude oil than those where the oil was present in suspension regardless of whether they were pre-exposed or not. Moreover, the community pre-exposed to crude oil had a different community structure and degraded more oil than the one from untreated soil. We conclude that the biodegradation rate of crude oil was enhanced by the pre-exposure of the bacterial communities to crude oil and by the use of oil-absorbing polypropylene materials. The data show that bacterial communities in the biofilms growing on the particles have an enhanced degradation capacity for oil.

Published
2022
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7. Comparison of In Vitro Approaches to Assess the Antibacterial Effects of Nanomaterials

Author

Abdulkader Masri, David M. Brown, David G. E. Smith, Vicki Stone, and Helinor J. Johnston

Subjects
nanomaterials, antibacterial, in vitro, nanotoxicology, copper oxide, Biotechnology, TP248.13-248.65, Medicine (General), R5-920
Abstract

The antibacterial properties of nanomaterials (NMs) can be exploited in a range of consumer products (e.g., wound dressings, food packaging, textiles, medicines). There is also interest in the exploitation of NMs as treatments for infectious diseases to help combat antibiotic resistance. Whilst the antibacterial activity of NMs has been assessed in vitro and in vivo in numerous studies, the methodology used is very varied. Indeed, while numerous approaches are available to assess the antibacterial effect of NMs in vitro, they have not yet been systematically assessed for their suitability and sensitivity for testing NMs. It is therefore timely to consider what assays should be prioritised to screen the antibacterial properties of NMs. The majority of existing in vitro studies have focused on investigating the antibacterial effects exhibited by silver (Ag) NMs and have employed a limited range of assays. We therefore compared the antibacterial effects of copper oxide (CuO) NMs to Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis at various concentrations (12.5–200 µg/mL) using a battery of tests (well and disc diffusion, plate counts—time-kill method, optical density measurement—OD, Alamar Blue and live/dead viability assays, and quantitative polymerase chain reaction). CuO NMs were most toxic to B. subtilis and E. coli, while P. aeruginosa was the least sensitive strain. All assays employed detected the antibacterial activity of CuO NMs; however, they varied in their sensitivity, time, cost, technical difficulty and requirement for specialized equipment. In the future, we suggest that a combination of approaches is used to provide a robust assessment of the antibacterial activity of NMs. In particular, we recommend that the time-kill and OD assays are prioritised due to their greater sensitivity. We also suggest that standard operating protocols are developed so that the antibacterial activity of NMs can be assessed using a harmonised approach.

Published
2022
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8. Using 3D gastrointestinal tract in vitro models with microfold cells and mucus secreting ability to assess the hazard of copper oxide nanomaterials

Author

Victor C. Ude, David M. Brown, Vicki Stone, and Helinor J. Johnston

Subjects
Caco-2 cell, Mucus, Microfold cells, TEER, Copper oxide, Nanomaterial, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5
Abstract

Abstract Background Copper oxide nanomaterials (CuO NMs) are exploited in many products including inks, cosmetics, textiles, wood preservatives and food contact materials. Their incorporation into these products may enhance oral exposure in consumer, environmental and occupational settings. Undifferentiated and differentiated monocultures of Caco-2 cells are commonly used to assess NM toxicity to the intestine in vitro. However, the integration of other cell types into Caco-2 in vitro models increases their physiological relevance. Therefore, the aim of this study is to evaluate the toxicity of CuO NMs and copper sulphate (CuSO4) to intestinal microfold (M) cell (Caco-2/Raji B) and mucus secreting (Caco-2/HT29-MTX) co-culture in vitro models via assessment of their impact on barrier integrity, viability and interleukin (IL)-8 secretion. The translocation of CuO NMs and CuSO4 across the intestinal barrier was also investigated in vitro. Results CuO NMs and CuSO4 impaired the function of the intestinal barrier in the co-culture models [as indicated by a reduction in transepithelial electrical resistance (TEER) and Zonular occludens (ZO-1) staining intensity]. Cu translocation was observed in both models but was greatest in the Caco-2/Raji B co-culture. CuO NMs and CuSO4 stimulated an increase in IL-8 secretion, which was greatest in the Caco-2/HT29-MTX co-culture model. CuO NMs and CuSO4 did not stimulate a loss of cell viability, when assessed using light microscopy, nuclei counts and scanning electron microscopy. CuO NMs demonstrated a relatively similar level of toxicity to CuO4 in both Caco-2/Raji B and Caco-2/HT29-MTX co- culture models. Conclusions The Caco-2/Raji B co-culture model was more sensitive to CuO NM and CuSO4 toxicity than the Caco-2/HT29-MTX co-culture model. However, both co-culture models were less sensitive to CuO NM and CuSO4 toxicity than simple monocultures of undifferentiated and differentiated Caco-2 cells, which are more routinely used to investigate NM toxicity to the intestine. Obtained data can therefore feed into the design of future studies which assess the toxicity of substances (e.g. NMs) and pathogens to the intestine (e.g. by informing model and endpoint selection). However, more testing with a wider panel of NMs would be beneficial in order to help select which in vitro models and endpoints to prioritise when screening the safety of ingested NMs. Comparisons with in vivo findings will also be essential to identify the most suitable in vitro model to screen the safety of ingested NMs.

Published
2019
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11. In vitro assessment of the pulmonary toxicity of particulate matter emitted during haze events in Chiang Mai, Thailand via investigation of macrophage responses

Author

Krystyna Maciaszek, Suzanne Gillies, Sawaeng Kawichai, Tippawan Prapamontol, Teetawat Santijitpakdee, Wissanupong Kliengchuay, Narut Sahanavin, William Mueller, Sotiris Vardoulakis, Pawitrabhorn Samutrtai, John W Cherrie, David M Brown, Kraichat Tantrakarnapa, and Helinor J Johnston

Subjects
PM10, haze, air pollution, Thailand, biomass burning, macrophages, Environmental sciences, GE1-350, Public aspects of medicine, RA1-1270
Abstract

Chiang Mai (Thailand) experiences severe haze pollution in the dry season (December–April) each year mainly due to local and regional biomass burning (e.g. of agricultural land). A major component of the haze is airborne particulate matter (PM). During haze events, biomass burning is likely to be the dominant source of PM emissions, and at other times emissions from traffic dominate. The hazard of traffic derived PM has been extensively investigated previously but there are uncertainties regarding the toxicity of PM emitted from biomass burning. The toxicity of PM _10 samples collected during and after haze events in Chiang Mai in 2020 was compared in vitro in J774.1 macrophages as they are responsible for the clearance of inhaled particles. Diesel exhaust particles and ultrafine carbon black were included as benchmark particles as they have been commonly used as a surrogate for PM. Cytotoxicity was evaluated 24 h post exposure at concentrations of 3.9–125 µ g ml ^−1 . Cytokine production (tumour necrosis factor alpha (TNF- α ), interleukin (IL)-6, IL-1 β , macrophage inflammatory protein (MIP-2)) was assessed and cell morphology visualised using light and scanning electron microscopy. The hydrodynamic diameter, zeta potential and endotoxin content of all particles was assessed as well as the metal content of PM samples. All particles induced a concentration dependent decrease in cell viability and increased TNF- α and MIP-2 production. Only PM samples stimulated IL-6 production and only non-haze PM caused IL-1 β production. No change in IL-10 production was detected for any particle. PM samples and DEP caused vacuole formation in cells. The concentrations of endotoxin and metals were highest in non-haze PM, which may explain why it induced the greatest inflammatory response. As non-haze PM was more toxic than haze PM, our results indicate that the source of PM emissions can influence its toxic potency and more specifically, that PM emitted from biomass burning may be less toxic than PM emitted from traffic.

Published
2022
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12. Intravitreal Nesvacumab (Anti-Angiopoietin-2) Plus Aflibercept in Neovascular AMD: Phase 2 ONYX Randomized Trial

Author

Jeffrey S. Heier, Allen C. Ho, David S. Boyer, Karl Csaky, Robert Vitti, Lorah Perlee, Karen W. Chu, Friedrich Asmus, Sergio Leal, Oliver Zeitz, Yenchieh Cheng, Thomas Schmelter, and David M. Brown

Abstract

Purpose: To compare intravitreal nesvacumab (anti-angiopoietin-2) + aflibercept vs intravitreal aflibercept injection (IAI) in neovascular age-related macular degeneration (nAMD). Methods: Eyes were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, week 4, and week 8. The LD combo was continued every 8 weeks (q8w). At week 12, the HD combo was re-randomized to q8w or every 12 weeks (q12w) and IAI was re-randomized to q8w, q12w, or HD combo q8w through week 32. Results: The study comprised 365 eyes. At week 12, the mean best-corrected visual acuity (BCVA) gains from baseline were similar in the LD combo group, HD combo group, and IAI group (5.2 letters, 5.6 letters, and 5.4 letters, respectively); the mean central subfield thickness (CST) reductions were similar (182.2 µm, 200.0 µm, and 178.6 µm, respectively). The mean changes in BCVA and CST through week 36 were similar across groups. At week 12, complete retinal fluid resolution was observed in 49.1% (LD combo), 50.8% (HD combo), and 43.6% (IAI) of eyes; the proportions with a CST of 300 μm or less were similar across groups. Numerical trends at week 32 toward complete retinal fluid resolution with combination treatment were not maintained at week 36. Serious ocular adverse events were infrequent and comparable across groups. Conclusions: In nAMD, nesvacumab + aflibercept showed no additional BCVA or CST benefit over IAI monotherapy.

Published
2022
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13. Demographic and Socioeconomic Factors in Prospective Retina-Focused Clinical Trial Screening and Enrollment

Author

Jessica A. Cao, Sagar B. Patel, Calvin W. Wong, David Garcia, Jose Munoz, Cassandra Cone, Deneva Zamora, Mary Reagan, Tieu V. Nguyen, Will Pearce, Richard H. Fish, David M. Brown, Varun Chaudhary, Charles C. Wykoff, and Kenneth C. Fan

Subjects
Medicine (miscellaneous), demographic, socioeconomic, retina-focused clinical trial
Abstract

Historically marginalized populations are disproportionately affected by many diseases that commonly affect the retina, yet they have been traditionally underrepresented in prospective clinical trials. This study explores whether this disparity affects the clinical trial enrollment process in the retina field and aims to inform future trial recruitment and enrollment. Age, gender, race, ethnicity, preferred language, insurance status, social security number (SSN) status, and median household income (estimated using street address and zip code) for patients referred to at least one prospective, retina-focused clinical trial at a large, urban, retina-based practice were retrospectively extracted using electronic medical records. Data were collected for the 12-month period from 1 January 2022, through 31 December 2022. Recruitment status was categorized as Enrolled, Declined, Communication (defined as patients who were not contacted, were contacted with no response, were waiting for a follow-up, or were scheduled for screening following a clinical trial referral.), and Did Not Qualify (DNQ). Univariable and multivariable analyses were used to determine significant relationships between the Enrolled and Declined groups. Among the 1477 patients, the mean age was 68.5 years old, 647 (43.9%) were male, 900 (61.7%) were White, 139 (9.5%) were Black, and 275 (18.7%) were Hispanic. The distribution of recruitment status was: 635 (43.0%) Enrolled, 232 (15.7%) Declined, 290 (19.6%) Communication, and 320 (21.7%) DNQ. In comparing socioeconomic factors between the Enrolled and Declined groups, significant odds ratios were observed for age (p < 0.02, odds ratio (OR) = 0.98, 95% confidence interval (CI) [0.97, 1.00]), and between patients who preferred English versus Spanish (p = 0.004, OR = 0.35, 95% CI [0.17, 0.72]. Significant differences between the Enrolled and Declined groups were also observed for age (p < 0.05), ethnicity (p = 0.01), preferred language (p < 0.05), insurance status (p = 0.001), and SSN status (p < 0.001). These factors may contribute to patient participation in retina-focused clinical trials. An awareness of these demographic and socioeconomic disparities may be valuable to consider when attempting to make clinical trial enrollment an equitable process for all patients, and strategies may be useful to help address these challenges.

Published
2023
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14. Implantable Collamer Lens Use in a Spaceflight Participant During Short Duration Spaceflight

Author

C. Robert Gibson, Thomas H. Mader, William Lipsky, David M. Brown, Richard Jennings, Jennifer Law, Ashot Sargsyan, Tyson Brunstetter, Sergey N. Danilichev, and Yusaku Maezawa

Subjects
General Medicine
Abstract

BACKGROUND: The purpose of this report is to document the first use of a single piece, posterior chamber phakic implantable collamer lens (ICL) with a central port in the right eye (OD) of a spaceflight participant (SFP) during a 12-d Soyuz mission to the International Space Station (ISS). We also briefly document the stability of a pre-existing pachychoroid pigment epitheliopathy (PPE) in the macula of his left eye (OS) during this mission.CASE REPORT: Ocular examination, including refraction, slit lamp examination, macular examination by optical coherence tomography (OCT), and tonometry were performed before and after his mission and he was questioned regarding visual changes during each portion of his flight.DISCUSSION: We documented no change in ICL position during his spaceflight. He reported stable vision during liftoff, entry into microgravity, 12 d on the ISS, descent, and landing. Our results suggest that the modern ICL with a central port is stable, effective, and well tolerated during short duration spaceflight. His PPE also remained stable during this mission as documented by OCT.Gibson CR, Mader TH, Lipsky W, Brown DM, Jennings R, Law J, Sargsyan A, Brunstetter T, Danilichev SN, Maezawa Y. Implantable collamer lens use in a spaceflight participant during short duration spaceflight. Aerosp Med Hum Perform. 2023; 94(1):48–50.

Published
2023
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15. Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy

Author

Charles C. Wykoff, Muneeswar G. Nittala, Cecilia Villanueva Boone, Hannah J. Yu, Wenying Fan, Swetha Bindu Velaga, Justis P. Ehlers, Michael S. Ip, SriniVas R. Sadda, Brenda Zhou, Alexander M. Rusakevich, Shaun I.R. Lampen, Sunil K. Srivastava, Jamie L. Reese, Amy Babiuch, Katherine Talcott, Natalia Figueiredo, Sari Yordi, Jenna Hach, William C. Ou, Richard H. Fish, Matthew S. Benz, Eric Chen, Rosa Y. Kim, James C. Major, Ronan E. O’Malley, David M. Brown, Ankoor R. Shah, Amy C. Schefler, Tien P. Wong, Christopher R. Henry, Sagar B. Patel, Vy T. Nguyen, and Kelly L. Larkin

Subjects
Ophthalmology, Diabetic Retinopathy, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Intravitreal Injections, Diabetes Mellitus, Visual Acuity, Humans, Prospective Studies, Tomography, Optical Coherence
Abstract

Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR).Prospective, randomized clinical trial with treatment crossover in the second year.Eyes with PDR and RNP.At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing.Change in total RNP area (mmAmong all subjects, from baseline to year 2, the mean RNP increased from 235 mmThrough year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

Published
2022
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16. KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema

Author

David M. Brown, Andrés Emanuelli, Francesco Bandello, Jose Juan Escobar Barranco, João Figueira, Eric Souied, Sebastian Wolf, Vishali Gupta, Nor Fariza Ngah, Gerald Liew, Raman Tuli, Ramin Tadayoni, Dilsher Dhoot, Lixin Wang, Emmanuel Bouillaud, Ying Wang, Lidija Kovacic, Nicolas Guerard, and Justus G. Garweg

Subjects
Diabetic Retinopathy, Recombinant Fusion Proteins, Visual Acuity, Angiogenesis Inhibitors, 610 Medicine & health, Antibodies, Monoclonal, Humanized, Macular Edema, Ophthalmology, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, Intravitreal Injections, Diabetes Mellitus, Humans
Abstract

PURPOSE To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME). DESIGN Double-masked, 100-week, multicenter, active-controlled, randomized trials. METHODS Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits; aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in Diabetic Retinopathy Severity Scale score, and anatomical and safety outcomes. RESULTS At Week 52, brolucizumab 6 mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001), more subjects achieved central subfield thickness (CSFT)

Published
2022
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18. Rescue of Infectious Sindbis Virus by Yeast Spheroplast-Mammalian Cell Fusion

Author

Lin Ding, David M. Brown, and John I. Glass

Subjects
positive-sense single strand RNA virus, Sindbis virus, reverse genetics, Saccharomyces cerevisiae, galactose induction, transformation-associated recombination (TAR) cloning, Microbiology, QR1-502
Abstract

Sindbis virus (SINV), a positive-sense single stranded RNA virus that causes mild symptoms in humans, is transmitted by mosquito bites. SINV reverse genetics have many implications, not only in understanding alphavirus transmission, replication cycle, and virus-host interactions, but also in biotechnology and biomedical applications. The rescue of SINV infectious particles is usually achieved by transfecting susceptible cells (BHK-21) with SINV-infectious mRNA genomes generated from cDNA constructed via in vitro translation (IVT). That procedure is time consuming, costly, and relies heavily on reagent quality. Here, we constructed a novel infectious SINV cDNA construct that expresses its genomic RNA in yeast cells controlled by galactose induction. Using spheroplasts made from this yeast, we established a robust polyethylene glycol-mediated yeast: BHK-21 fusion protocol to rescue infectious SINV particles. Our approach is timesaving and utilizes common lab reagents for SINV rescue. It could be a useful tool for the rescue of large single strand RNA viruses, such as SARS-CoV-2.

Published
2021
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19. Baseline retinal vascular bed area on ultra-wide field fluorescein angiography correlates with the anatomical outcome of diabetic macular oedema to ranibizumab therapy: two-year analysis of the DAVE Study

Author

Wenying Fan, Akihito Uji, Charles C. Wykoff, David M. Brown, Jano van Hemert, Khalil Ghasemi Falavarjani, Kang Wang, SriniVas R. Sadda, and Michael Ip

Subjects
Ophthalmology
Abstract

To determine the relationship between baseline retinal non-perfusion area (NPA) and retinal vascular bed area (RVBA) on ultra-wide field fluorescein angiography (UWF FA) and long-term response to intravitreal ranibizumab therapy in diabetic macular oedema (DMO).A post-hoc, 2-year observational case series. Baseline UWF FA images (Optos 200Tx) of 40 eyes from 29 patients with diabetes mellitus and treatment naïve DMO in the DAVE (NCT01552408) study were montaged and stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The retinal vasculature was automatically extracted to calculate RVBA. NPA was manually delineated by two masked certified graders. RVBA and NPA were computed in mmWhile global NPA at baseline was not correlated to retinal thickness measurements, baseline NPA in the superior retina was associated with the macular volume (MV) improvement (P = 0.022). Multivariate analysis revealed a smaller RVBA at baseline was correlated with a better MV outcome at two-year follow-up after adjusting for confounding factors (P = 0.049).Eyes with smaller baseline RVBA appear to have a better long-term anatomic outcome of DMO.

Published
2022
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20. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials

Author

Charles C Wykoff, Francis Abreu, Anthony P Adamis, Karen Basu, David A Eichenbaum, Zdenka Haskova, Hugh Lin, Anat Loewenstein, Shaun Mohan, Ian A Pearce, Taiji Sakamoto, Patricio G Schlottmann, David Silverman, Jennifer K Sun, John A Wells, Jeffrey R Willis, Ramin Tadayoni, Thomas Aaberg, Ashkan Abbey, Elmira Abdulaeva, Santiago Abengoechea, Prema Abraham, Thomas Ach, Serrhel Adams, Alfredo Adan Civera, Sean Adrean, Hansjurgen Agostini, Suhail Alam, Arturo Alezzandrini, Virgil Alfaro, Daniel Aliseda, Arghavan Almony, Pedro Amat, Payam Amini, Andrew Antoszyk, Luis Arias, Riaz Asaria, Marcos Avila, Carl C Awh, Joaquin Bafalluy, Carl Baker, Francesco Bandello, Mark Barakat, Karen Barraza, Gyorgy Bator, Caroline Baumal, Rubens Belfort Jr, Chris Bergstrom, George Bertolucci, Thomas Bochow, Matthias Bolz, Emilia Borcz, Arnaldo Bordon, David Boyer, Galina Bratko, Michael Brent, Jamin Brown, David M Brown, Maria Budzinskaya, Sylvia Buffet, Stuart Burgess, Ben Burton, Miguel Busquets, Francisco Cabrera, Carlo Cagini, Jorge Calzada, Peter Campochiaro, John Carlson, Alessandro Castellarin, Carlos Cava, Voraporn Chaikitmongkol, Clement Chan, Emmanuel Chang, Jonathan Chang, Andrew Chang, Steve Charles, Nauman Chaudhry, Caroline Chee, Judy Chen, Fred Chen, Shih-Jen Chen, Richard Cheong-Leen, Allen Chiang, Mark Chittum, David Chow, Brian Connolly, Pierre Loic Cornut, Karl Csaky, Carl Danzig, Arup Das, Vesselin Daskalov, Carmen Desco, Amr Dessouki, John Dickinson, Brian Do, Michael Dollin, Pravin Dugel, Jaroslava Dusova, David Eichenbaum, Bora Eldem, Robert Engstrom, Jan Ernest, Joan Josep Escobar, Simona Esposti, Nicole Eter, Naomi Falk, Andrej Farkas, Leonard Feiner, Nicolas Feltgen, Carlos Fernandez, Alvaro Fernandez Vega, Philip Ferrone, Joao Figueira, Marta Figueroa, Oliver Findl, Howard Fine, Jorge Fortun, Gregory M Fox, Scott Foxman, Carsten Framme, Samantha Fraser-Bell, Arthur Fu, Akira Fukutomi, Nicholas Fung, Federico Furno Sola, Roberto Gallego-Pinazo, Renata Garcia, Alfredo Garcia-Layana, Maciej Gawecki, Sheen George, Faruque Ghanchi, Ghassan Ghorayeb, Roger Goldberg, Michaella Goldstein, Nuno Gomes, Francisco Gomez Ulla, Victor Gonzalez, Craig Greven, Sunil Gupta, Miguel Guzman, Martin Harris, Katja Hatz, Vivienne Hau, Vincent Hau, Ken Hayashi, Jeffrey Heier, Ewa Herba, Vrinda Hershberger, Patrick Higgins, Akito Hirakata, Allen Ho, Nancy Holekamp, Shigeru Honda, Jason Hsu, Allen Hu, Maria Hurcikova, Yasuhiro Ikeda, Ricky Isernhagen, Yasuki Ito, Tim Jackson, Rachael Jacoby, Afsar Jafree, Golnaz Javey, Cameron Javid, Chirag Jhaveri, Mark Johnson, Marek Kacerík, Jakub Kaluzny, Daniel Kampik, Se Woong Kang, Kapil Kapoor, Levent Karabas, Tsutomu Kawasaki, Agnes Kerenyi, Arshad Khanani, Rahul Khurana, Brian Kim, Kazuhiro Kimura, Genichiro Kishino, Shigehiko Kitano, Kendra Klein-Mascia, Gregg Kokame, Jean Francois Korobelnik, Alexey Kulikov, Ajay Kuriyan, Henry Kwong, Robert Kwun, Timothy Lai, Chi-Chun Lai, Philip Laird, Laurent Lalonde, Paolo Lanzetta, Michael Larsen, Caroline Laugesen, Daniel Lavinsky, Olivier Lebreton, Seong Lee, Jaime Levy, Blandina Lipkova, Mimi Liu, Judy Liu, Chris P Lohmann, Nikolas London, Katrin Lorenz, Andrew Lotery, David Lozano Rechy, Silvio Lujan, Patrick Ma, Takatoshi Maeno, Sajjad Mahmood, Fuad Makkouk, Khurram Malik, Dennis Marcus, Alan Margherio, Leonardo Mastropasqua, Raj Maturi, Frank McCabe, Martin McKibbin, Hemal Mehta, Geeta Menon, Jale Mentes, Katarzyna Michalska-Malecka, Aneta Misheva, Yoshinori Mitamura, Paul Mitchell, Yasha Modi, Quresh Mohamed, Javier Montero, Jeffrey Moore, Virgilio Morales Canton, Haia Morori-Katz, Tatiana Morugova, Tomoaki Murakami, Maria Muzyka-Wozniak, Marco Nardi, Jan Nemcansky, Kamila Nester-Ostrowska, Julio Neto, Charles Newell, Massimo Nicolo, Jared Nielsen, Kousuke Noda, Akira Obana, Nahoko Ogata, Hideyasu Oh, Kean Oh, Matthew Ohr, Piotr Oleksy, Scott Oliver, Sebastien Olivier, James Osher, Sehnaz Ozcalişkan, Banu Ozturk, Andras Papp, Kyu Hyung Park, D Wilkin Parke, Maria Cristina Parravano, Sugat Patel, Sunil Patel, Ian Pearce, Joel Pearlman, Fernando Penha, Irfan Perente, Stephen Perkins, Grazia Pertile, Iva Petkova, Tunde Peto, Dante Pieramici, Andreas Pollreisz, Pear Pongsachareonnont, Nadezhda Pozdeyeva, Siegfried Priglinger, Jawad Qureshi, Dorota Raczynska, Rajesh Rajagopalan, Juan Ramirez Estudillo, Paul Raskauskas, Rajiv Rathod, Hessam Razavi, Carl Regillo, Federico Ricci, Soraya Rofagha, Dominika Romanczak, Bożena Romanowska-Dixon, Daniel Rosberger, Irit Rosenblatt, Brett Rosenblatt, Adam Ross, Paisan Ruamviboonsuk, Jose Maria Ruiz Moreno, Gustavo Salomão, Sukhpal Sandhu, Dirk Sandner, Laura Sararols, Osamu Sawada, Ramin Schadlu, Patricio Schlottmann, Claudia Schuart, Berthold Seitz, András Seres, Figen Sermet, Sandeep Shah, Ankur Shah, Rohan Shah, Sumit Sharma, Thomas Sheidow, Veeral Sheth, Akito Shimouchi, Masahiko Shimura, Bartosz Sikorski, Rufino Silva, Michael Singer, Lawrence Singerman, Rishi Singh, Eric Souied, David J Spinak, Georg Spital, Nathan Steinle, Jeffrey Stern, Glenn Stoller, Robert Stoltz, Cameron Stone, Amy Stone, Eric Suan, Masahiko Sugimoto, Iichiro Sugita, Jennifer Sun, Xiaodong Sun, Ivan Suner, Lajos Szalczer, Timea Szecsko, Ali Tabassian, Hitoshi Takagi, Kei Takayama, Alexandre Taleb, James Talks, Gavin Tan, Teruyo Tanabe, Stanford Taylor, Allen Thach, John Thompson, Paul Tlucek, Robert Torti, Daniela Tosheva Guneva, Edit Toth-Molnar, Eduardo Uchiyama, Attila Vajas, Deepali Varma, Balazs Varsanyi, Petja Vassileva, Sara Vaz-Pereira, Miroslav Veith, Jose Ignacio Vela, Francesco Viola, Gianni Virgili, Gábor Vogt, Henrik Vorum, Pamela Weber, Thoalf Wecke, Raymond Wee, Martin Weger, Paul Weishaar, Sanjeewa Wickremasinghe, Thomas Reginald Williams, Thomas Williams, Geoff Williams, Armin Wolf, Jeremy Wolfe, James Wong, David Wong, Ian Wong, Robert Wong, Bogumil Wowra, Edward Wylęgała, Chang-Hao Yang, Tsutomu Yasukawa, Paul Yates, Gursel Yilmaz, Glenn Yiu, Young Hee Yoon, Barak Yoreh, Shigeo Yoshida, Hyeong Gon Yu, Seung Young Yu, Tatiana Yurieva, Leandro Zacharias, Karolina Zaczek Zakrzewska, Alberto Zambrano, Barbara Zatorska, Carlos Zeolite, and Jeffrey Zheutlin

Subjects
Male, Vascular Endothelial Growth Factor A, Diabetic Retinopathy, Recombinant Fusion Proteins, Visual Acuity, Angiogenesis Inhibitors, General Medicine, Middle Aged, Drug Administration Schedule, Angiopoietin-2, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, Double-Blind Method, Antibodies, Bispecific, Intravitreal Injections, Edema, Humans, Female, Macula Lutea, Aged
Abstract

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Published
2022
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21. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials

Author

Jeffrey S Heier, Arshad M Khanani, Carlos Quezada Ruiz, Karen Basu, Philip J Ferrone, Christopher Brittain, Marta S Figueroa, Hugh Lin, Frank G Holz, Vaibhavi Patel, Timothy Y Y Lai, David Silverman, Carl Regillo, Balakumar Swaminathan, Francesco Viola, Chui Ming Gemmy Cheung, Tien Y Wong, Ashkan Abbey, Elmira Abdulaeva, Prema Abraham, Alfredo Adan Civera, Hansjurgen Agostini, Arturo Alezzandrini, Virgil Alfaro, Arghavan Almony, Lebriz Altay, Payam Amini, Andrew Antoszyk, Etelka Aradi, Luis Arias, Jennifer Arnold, Riaz Asaria, Sergei Astakhov, Yury Astakhov, Carl C. Awh, Chandra Balaratnasingam, Sanjiv Banerjee, Caroline Baumal, Matthias Becker, Rubens Belfort, Galina Bratko, William Jr. Z Bridges, Jamin Brown, David M. Brown, Maria Budzinskaya, Sylvia Buffet, Stuart Burgess, Iksoo Byon, Carlo Cagini, Jorge Calzada, Stone Cameron, Peter Campochiaro, John Carlson, Angela Carneiro, Clement Chan, Emmanuel Chang, Andrew Chang, Daniel Chao, Nauman Chaudhry, Caroline Chee, Andrew Cheek, Shih-Jen Chen, San-Ni Chen, Gemmy Cheung, Saradha Chexal, Mark Chittum, David Chow, Abosede Cole, Brian Connolly, Pierre Loic Cornut, Stephen Couvillion, Carl Danzig, Vesselin Daskalov, Amr Dessouki, Francois Devin, Michael Dollin, Rosa Dolz, Louise Downey, Richard Dreyer, Pravin Dugel, David Eichenbaum, Bora Eldem, Robert Engstrom, Joan Josep Escobar, Nicole Eter, David W. Faber, Naomi Falk, Leonard Feiner, Alvaro Fernandez Vega, Philip Ferrone, Marta Figueroa, Howard Fine, Mitchell Fineman, Gregory M. Fox, Catherine Francais, Pablo Franco, Samantha Fraser-Bell, Nicholas Fung, Federico Furno Sola, Richard Gale, Alfredo Garcia-Layana, Julie Gasperini, Maciej Gawecki, Faruque Ghanchi, Manjot Gill, Michel Giunta, David Glaser, Michaella Goldstein, Francisco Gomez Ulla, Fumi Gomi, Victor Gonzalez, Jordan Graff, Sunil Gupta, Rainer Guthoff, Robyn Guymer, Anton Haas, Robert Hampton, Katja Hatz, Ken Hayashi, Jeffrey Heier, Ewa Herba, Vrinda Hershberger, Patrick Higgins, Nancy Holekamp, Shigeru Honda, James Howard, Allen Hu, Stephen Huddleston, Tomohiro Iida, Hiroko Imaizumi, Yasuo Ito, Yasuki Ito, Sujit Itty, Golnaz Javey, Cameron Javid, Tatsushi Kaga, Jakub Kaluzny, Se Woong Kang, Kapil Kapoor, Levent Karabas, Tsutomu Kawasaki, Patrick Kelty, Agnes Kerenyi, Arshad Khanani, Ramin Khoramnia, Rahul Khurana, Kazuhiro Kimura, Kendra Klein-Mascia, Namie Kobayashi, Laurent Kodjikian, Hideki Koizumi, Gregg Kokame, Alexey Kulikov, Henry Kwong, Robert Kwun, Timothy Lai, Chi-Chun Lai, Laurent Lalonde, Paolo Lanzetta, Michael Larsen, Adrian Lavina, Won Ki Lee, ji Eun Lee, Seong Lee, Jaime Levy, Lucas Lindsell, Mimi Liu, Nikolas London, Andrew Lotery, David Lozano Rechy, Alan Luckie, David Maberley, Takatoshi Maeno, Sajjad Mahmood, Fuad Makkouk, Dennis Marcus, Alan Margherio, Helene Masse, Hisashi Matsubara, Raj Maturi, Sonia Mehta, Geeta Menon, Jale Mentes, Mark Michels, Yoshinori Mitamura, Paul Mitchell, Quresh Mohamed, Jordi Mones, Rodrigo Montemayor Lobo, Javier Montero, Jeffrey Moore, Ryusaburo Mori, Haia Morori-Katz, Raj Mukherjee, Toshinori Murata, Maria Muzyka-Wozniak, Marco Nardi, Niro Narendran, Massimo Nicolo, Jared Nielsen, Tetsuya Nishimura, Kousuke Noda, Anna Nowinska, Hideyasu Oh, Matthew Ohr, Annabelle Okada, Piotr Oleksy, Shinji Ono, Sengul Ozdek, Banu Ozturk, Luis Pablo, Kyu Hyung Park, D. Wilki Parke, Maria Cristina Parravano, Praveen Patel, Apurva Patel, Sunil Patel, Sugat Patel, Daniel Pauleikhoff, Ian Pearce, Joel Pearlman, Iva Petkova, Dante Pieramici, Nadezhda Pozdeyeva, Jawad Qureshi, Dorota Raczynska, Juan Ramirez Estudillo, Rajiv Rathod, Hessam Razavi, Gayatri Reilly, Federico Ricci, Ryan Rich, Bożena Romanowska-Dixon, Irit Rosenblatt, Jose Maria Ruiz Moreno, Stefan Sacu, Habiba Saedon, Usman Saeed, Min Sagong, Taiji Sakamoto, Sukhpal Sandhu, Laura Sararols, Mario Saravia, Ramin Schadlu, Patricio Schlottmann, Tetsuju Sekiryu, András Seres, Figen Sermet, Sumit Shah, Rohan Shah, Ankur Shah, Thomas Sheidow, Veeral Sheth, Chieko Shiragami, Bartosz Sikorski, Rufino Silva, Lawrence Singerman, Robert Sisk, Torben L. Sørensen, Eric Souied, David-J Spinak, Giovanni Staurenghi, Robert Steinmetz, Glenn Stoller, Robert Stoltz, Eric Suan, Ivan Suner, Yzer Suzanne, Ramin Tadayoni, Kanji Takahashi, Kei Takayama, Alexandre Taleb, James Talks, Hiroko Terasaki, John Thompson, Edit Toth-Molnar, Khoi Tran, Raman Tuli, Eduardo Uchiyama, Attila Vajas, Janneke Van Lith-Verhoeven, Balazs Varsanyi, Gianni Virgili, Gábor Vogt, Michael Völker, David Warrow, Pamela Weber, John A. Wells, Sanjeewa Wickremasinghe, Mark Wieland, Geoff Williams, Thomas Williams, David Wong, King Wong, James Wong, Ian Wong, Robert Wong, Bogumil Wowra, Charles C. Wykoff, Ayana Yamashita, Kanako Yasuda, Gursel Yilmaz, Glenn Yiu, Ai Yoneda, Young Hee Yoon, Barak Yoreh, HyeongGon Yu, Seung Young Yu, Tatiana Yurieva, Alberto Zambrano, Barbara Zatorska, and Carlos Zeolite

Subjects
Aged, 80 and over, Male, Vascular Endothelial Growth Factor A, Recombinant Fusion Proteins, Visual Acuity, Angiogenesis Inhibitors, General Medicine, Drug Administration Schedule, Angiopoietin-2, Macular Degeneration, Receptors, Vascular Endothelial Growth Factor, Treatment Outcome, Double-Blind Method, Antibodies, Bispecific, Intravitreal Injections, Humans, Female, Aged
Abstract

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

Published
2022
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22. Two‐Year Outcomes After Pediatric In‐Office Tympanostomy Using Lidocaine/Epinephrine Iontophoresis and an Automated Tube Delivery System

Author

Erik H. Waldman, Amy Ingram, D. Macy Vidrine, Andrew R. Gould, Jacob W. Zeiders, Randall A. Ow, Christopher R. Thompson, Jonathan R. Moss, Ritvik Mehta, John E. McClay, Amy Brenski, John Gavin, John Ansley, David M. Yen, Neil K. Chadha, Michael T. Murray, Frederick K. Kozak, Christopher York, David M. Brown, Eli Grunstein, Robert C. Sprecher, Denise A. Sherman, Scott R. Schoem, Robert Puchalski, Susannah Hills, Dan Harfe, Laura J. England, Charles A. Syms, and Lawrence R. Lustig

Subjects
Otorhinolaryngology, Surgery
Published
2023
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23. Prediction for 2-Year Vision Outcomes Using Early Morphologic and Functional Responses in the Comparison of Age-related Macular Degeneration Treatments Trials

Author

Katie Xue, Peiying Hua, Maureen G. Maguire, Ebenezer Daniel, Glenn J. Jaffe, Juan E. Grunwald, Gui-shuang Ying, David F. Williams, Sara Beardsley, Steven Bennett, Herbert Cantrill, Carmen Chan-Tram, Holly Cheshier, Kathyrn Damato, John Davies, Sundeep Dev, Julianne Enloe, Gennaro Follano, Peggy Gilbert, Jill Johnson, Tori Jones, Lisa Mayleben, Robert Mittra, Martha Moos, Ryan Neist, Neal Oestreich, Polly Quiram, Robert Ramsay, Edwin Ryan, Stephanie Schindeldecker, John Snater, Trenise Steele, Dwight Selders, Jessica Tonsfeldt, Shelly Valardi, Gary Edd Fish, Hank A. Aguado, Sally Arceneaux, Jean Arnwine, Kim Bell, Tina Bell, Bob Boleman, Patricia Bradley, David Callanan, Lori Coors, Jodi Creighton, Timothy Crew, Kimberly Cummings, Christopher Dock, Karen Duignan, Dwain Fuller, Keith Gray, Betsy Hendrix, Nicholas Hesse, Diana Jaramillo, Bradley Jost, Sandy Lash, Laura Lonsdale, Michael Mackens, Karin Mutz, Michael Potts, Brenda Sanchez, William Snyder, Wayne Solley, Carrie Tarter, Robert Wang, Patrick Williams, Stephen L. Perkins, Nicholas Anderson, Ann Arnold, Paul Blais, Joseph Googe, Tina T. Higdon, Cecile Hunt, Mary Johnson, James Miller, Misty Moore, Charity K. Morris, Christopher Morris, Sarah Oelrich, Kristina Oliver, Vicky Seitz, Jerry Whetstone, Bernard H. Doft, Jay Bedel, Robert Bergren, Ann Borthwick, Paul Conrad, Amanda Fec, Christina Fulwylie, Willia Ingram, Shawnique Latham, Gina Lester, Judy Liu, Louis Lobes, Nicole M. Lucko, Holly Mechling, Lori Merlotti, Keith McBroom, Karl Olsen, Danielle Puskas, Pamela Rath, Maria Schmucker, Lynn Schueckler, Christina Schultz, Heather Shultz, David Steinberg, Avni Vyas, Kim Whale, Kimberly Yeckel, David H. Orth, Linda S. Arredondo, Susan Brown, Barbara J. Ciscato, Joseph M. Civantos, Celeste Figliulo, Sohail Hasan, Belinda Kosinski, Dan Muir, Kiersten Nelson, Kirk Packo, John S. Pollack, Kourous Rezaei, Gina Shelton, Shannya Townsend-Patrick, Marian Walsh, H. Richard McDonald, Nina Ansari, Amanda Bye, Arthur D. Fu, Sean Grout, Chad Indermill, Robert N. Johnson, J. Michael Jumper, Silvia Linares, Brandon J. Lujan, Ames Munden, Meredith Persons, Rosa Rodriguez, Jennifer M. Rose, Brandi Teske, Yesmin Urias, Stephen Young, Richard F. Dreyer, Howard Daniel, Michele Connaughton, Irvin Handelman, Stephen Hobbs, Christine Hoerner, Dawn Hudson, Marcia Kopfer, Michael Lee, Craig Lemley, Joe Logan, Colin Ma, Christophe Mallet, Amanda Milliron, Mark Peters, Harry Wohlsein, Joel A. Pearlman, Margo Andrews, Melissa Bartlett, Nanette Carlson, Emily Cox, Robert Equi, Marta Gonzalez, Sophia Griffin, Fran Hogue, Lance Kennedy, Lana Kryuchkov, Carmen Lopez, Danny Lopez, Bertha Luevano, Erin McKenna, Arun Patel, Brian Reed, Nyla Secor, Iris R. Sison, Tony Tsai, Nina Varghis, Brooke Waller, Robert Wendel, Reina Yebra, Daniel B. Roth, Jane Deinzer, Howard Fine, Flory Green, Stuart Green, Bruce Keyser, Steven Leff, Amy Leviton, Amy Martir, Kristin Mosenthine, Starr Muscle, Linda Okoren, Sandy Parker, Jonathan Prenner, Nancy Price, Deana Rogers, Linda Rosas, Alex Schlosser, Loretta Studenko, Thea Tantum, Harold Wheatley, Michael T. Trese, Thomas Aaberg, Denis Bezaire, Craig Bridges, Doug Bryant, Antonio Capone, Michelle Coleman, Christina Consolo, Cindy Cook, Candice DuLong, Bruce Garretson, Tracy Grooten, Julie Hammersley, Tarek Hassan, Heather Jessick, Nanette Jones, Crystal Kinsman, Jennifer Krumlauf, Sandy Lewis, Heather Locke, Alan Margherio, Debra Markus, Tanya Marsh, Serena Neal, Amy Noffke, Kean Oh, Clarence Pence, Lisa Preston, Paul Raphaelian, Virginia R. Regan, Peter Roberts, Alan Ruby, Ramin Sarrafizadeh, Marissa Scherf, Sarita Scott, Scott Sneed, Lisa Staples, Brad Terry, Matthew T. Trese, Joan Videtich, George Williams, Mary Zajechowski, Daniel P. Joseph, Kevin Blinder, Lynda Boyd, Sarah Buckley, Meaghan Crow, Amanda Dinatale, Nicholas Engelbrecht, Bridget Forke, Dana Gabel, Gilbert Grand, Jennifer Grillion-Cerone, Nancy Holekamp, Charlotte Kelly, Ginny Nobel, Kelly Pepple, Matt Raeber, P. Kumar Rao, Tammy Ressel, Steven Schremp, Merrilee Sgorlon, Shantia Shears, Matthew Thomas, Cathy Timma, Annette Vaughn, Carolyn Walters, Rhonda Weeks, Jarrod Wehmeier, Tim Wright, Daniel M. Berinstein, Aida Ayyad, Mohammed K. Barazi, Erica Bickhart, Tracey Brady, Lisa Byank, Alysia Cronise, Vanessa Denny, Courtney Dunn, Michael Flory, Robert Frantz, Richard A. Garfinkel, William Gilbert, Michael M. Lai, Alexander Melamud, Janine Newgen, Shamekia Newton, Debbie Oliver, Michael Osman, Reginald Sanders, Manfred von Fricken, Pravin Dugel, Sandra Arenas, Gabe Balea, Dayna Bartoli, John Bucci, Jennifer A. Cornelius, Scheleen Dickens, Don Doherty, Heather Dunlap, David Goldenberg, Karim Jamal, Norma Jimenez, Nicole Kavanagh, Derek Kunimoto, John Martin, Jessica Miner, Sarah Mobley, Donald Park, Edward Quinlan, Jack Sipperley, Carol Slagle, Danielle Smith, Miguelina Yafchak, Rohana Yager, Christina J. Flaxel, Steven Bailey, Peter Francis, Chris Howell, Thomas Hwang, Shirley Ira, Michael Klein, Andreas Lauer, Teresa Liesegang, Ann Lundquist, Sarah Nolte, Susan K. Nolte, Scott Pickell, Susan Pope, Joseph Rossi, Mitchell Schain, Peter Steinkamp, Maureen D. Toomey, Debora Vahrenwald, Kelly West, Baker Hubbard, Stacey Andelman, Chris Bergstrom, Judy Brower, Blaine Cribbs, Linda Curtis, Jannah Dobbs, Lindreth DuBois, Jessica Gaultney, Deborah Gibbs, Debora Jordan, Donna Leef, Daniel F. Martin, Robert Myles, Timothy Olsen, Bryan Schwent, Sunil Srivastava, Rhonda Waldron, Andrew N. Antoszyk, Uma Balasubramaniam, Danielle Brooks, Justin Brown, David Browning, Loraine Clark, Sarah Ennis, Susannah Held, Jennifer V. Helms, Jenna Herby, Angie Karow, Pearl Leotaud, Caterina Massimino, Donna McClain, Michael McOwen, Jennifer Mindel, Candace Pereira, Rachel Pierce, Michele Powers, Angela Price, Jason Rohrer, Jason Sanders, Robert L. Avery, Kelly Avery, Jessica Basefsky, Liz Beckner, Alessandro Castellarin, Stephen Couvillion, Jack Giust, Matthew Giust, Maan Nasir, Dante Pieramici, Melvin Rabena, Sarah Risard, Robert See, Jerry Smith, Lisha Wan, Sophie J. Bakri, Nakhleh Abu-Yaghi, Andrew Barkmeier, Karin Berg, Jean Burrington, Albert Edwards, Shannon Goddard, Shannon Howard, Raymond Iezzi, Denise Lewison, Thomas Link, Colin A. McCannel, Joan Overend, John Pach, Margaret Ruszczyk, Ryan Shultz, Cindy Stephan, Diane Vogen, Reagan H. Bradford, Vanessa Bergman, Russ Burris, Amanda Butt, Beth Daniels, Connie Dwiggins, Stephen Fransen, Tiffany Guerrero, Darin Haivala, Amy Harris, Sonny Icks, Ronald Kingsley, Lena Redden, Rob Richmond, Brittany Ross, Kammerin White, Misty Youngberg, Trexler M. Topping, Steve Bennett, Sandy Chong, Mary Ciotti, Tina Cleary, Emily Corey, Dennis Donovan, Albert Frederick, Lesley Freese, Margaret Graham, Natalya Gud, Taneika Howard, Mike Jones, Michael Morley, Katie Moses, Jen Stone, Robin Ty, Torsten Wiegand, Lindsey Williams, Beth Winder, Carl C. Awh, Michelle Amonette, Everton Arrindell, Dena Beck, Brandon Busbee, Amy Dilback, Sara Downs, Allison Guidry, Gary Gutow, Jackey Hardin, Sarah Hines, Emily Hutchins, Kim LaCivita, Ashley Lester, Larry Malott, MaryAnn McCain, Jayme Miracle, Kenneth Moffat, Lacy Palazzotta, Kelly Robinson, Peter Sonkin, Alecia Travis, Roy Trent Wallace, Kelly J. Winters, Julia Wray, April E. Harris, Mari Bunnell, Katrina Crooks, Rebecca Fitzgerald, Cameron Javid, Corin Kew, Erica Kill, Patricia Kline, Janet Kreienkamp, Maricruz Martinez, Roy Ann Moore, Egbert Saavedra, LuAnne Taylor, Mark Walsh, Larry Wilson, Thomas A. Ciulla, Ellen Coyle, Tonya Harrington, Charlotte Harris, Cindi Hood, Ingrid Kerr, Raj Maturi, Dawn Moore, Stephanie Morrow, Jennifer Savage, Bethany Sink, Tom Steele, Neelam Thukral, Janet Wilburn, Joseph P. Walker, Jennifer Banks, Debbie Ciampaglia, Danielle Dyshanowitz, Jennifer Frederick, A. Tom Ghuman, Richard Grodin, Cheryl Kiesel, Eileen Knips, Jonathan McCue, Maria Ortiz, Crystal Peters, Paul Raskauskas, Etienne Schoeman, Ashish Sharma, Glenn Wing, Rebecca Youngblood, Suresh R. Chandra, Michael Altaweel, Barbara Blodi, Kathryn Burke, Kristine A. Dietzman, Justin Gottlieb, Gene Knutson, Denise Krolnik, T. Michael Nork, Shelly Olson, John Peterson, Sandra Reed, Barbara Soderling, Guy Somers, Thomas Stevens, Angela Wealti, Srilaxmi Bearelly, Brenda Branchaud, Joyce W. Bryant, Sara Crowell, Sharon Fekrat, Merritt Gammage, Cheala Harrison, Sarah Jones, Noreen McClain, Brooks McCuen, Prithvi Mruthyunjaya, Jeanne Queen, Neeru Sarin, Cindy Skalak, Marriner Skelly, Ivan Suner, Ronnie Tomany, Lauren Welch, Susanna S. Park, Allison Cassidy, Karishma Chandra, Idalew Good, Katrina Imson, null Sashi, null Kaur, Helen Metzler, Lawrence Morse, Ellen Redenbo, Marisa Salvador, David Telander, Mark Thomas, Cindy Wallace, Charles C. Barr, Amanda Battcher, Michelle Bottorff, Mary Chasteen, Kelly Clark, Diane Denning, Debra Schoen, Amy Schultz, Evie Tempel, Lisa Wheeler, Greg K. Whittington, Thomas W. Stone, Todd Blevins, Michelle Buck, Lynn Cruz, Wanda Heath, Diana Holcomb, Rick Isernhagen, Terri Kidd, John Kitchens, Cathy Sears, Ed Slade, Jeanne Van Arsdall, Brenda VanHoose, Jenny Wolfe, William Wood, John Zilis, Carol Crooks, Larry Disney, Mimi Liu, Stephen Petty, Sandra Sall, James C. Folk, Tracy Aly, Abby Brotherton, Douglas Critser, Connie J. Hinz, Stefani Karakas, Valerie Kirschner, Cheyanne Lester, Cindy Montague, Stephen Russell, Heather Stockman, Barbara Taylor, Randy Verdick, Jean Walshire, John T. Thompson, Barbara Connell, Maryanth Constantine, John L. Davis, null Gwen Holsapple, Lisa Hunter, C. Nicki Lenane, Robin Mitchell, Leslie Russel, Raymond Sjaarda, David M. Brown, Matthew Benz, Llewellyn Burns, JoLene G. Carranza, Richard Fish, Debra Goates, Shayla Hay, Theresa Jeffers, Eric Kegley, Dallas Kubecka, Stacy McGilvra, Beau Richter, Veronica Sneed, Cary Stoever, Isabell Tellez, Tien Wong, Ivana Kim, Christopher Andreoli, Leslie Barresi, Sarah Brett, Charlene Callahan, Karen Capaccioli, William Carli, Matthew Coppola, Nicholas Emmanuel, Claudia Evans, Anna Fagan, Marcia Grillo, John Head, Troy Kieser, Elaine Lee, Ursula Lord, Edward Miretsky, Kate Palitsch, Todd Petrin, Liz Reader, Svetlana Reznichenko, Mary Robertson, Justin Smith, Demetrios Vavvas, John Wells, Cassie Cahill, W. Lloyd Clark, Kayla Henry, David Johnson, Peggy Miller, LaDetrick Oliver, Robbin Spivey, Tiffany Swinford, Mallie Taylor, Michael Lambert, Kris Chase, Debbie Fredrickson, Joseph Khawly, Valerie Lazarte, Donald Lowd, Pam Miller, Arthur Willis, Philip J. Ferrone, Miguel Almonte, Rachel Arnott, Ingrid Aviles, Sheri Carbon, Michael Chitjian, Kristen DAmore, Christin Elliott, David Fastenberg, Barry Golub, Kenneth Graham, AnnMarie Lavorna, Laura Murphy, Amanda Palomo, Christina Puglisi, David Rhee, Juan Romero, Brett Rosenblatt, Glenda Salcedo, Marianne Schlameuss, Eric Shakin, Vasanti Sookhai, Richard Kaiser, Elizabeth Affel, Gary Brown, Christina Centinaro, Deborah Fine, Mitchell Fineman, Michele Formoso, Sunir Garg, Lisa Grande, Carolyn Herbert, Allen Ho, Jason Hsu, Maryann Jay, Lisa Lavetsky, Elaine Liebenbaum, Joseph Maguire, Julia Monsonego, Lucia O’Connor, Lisa Pierce, Carl Regillo, Maria Rosario, Marc Spirn, James Vander, Jennifer Walsh, Frederick H. Davidorf, Amanda Barnett, Susie Chang, John Christoforidis, Joy Elliott, Heather Justice, Alan Letson, Kathryne McKinney, Jeri Perry, Jill A. Salerno, Scott Savage, Stephen Shelley, Lawrence J. Singerman, Joseph Coney, John DuBois, Kimberly DuBois, Gregg Greanoff, Dianne Himmelman, Mary Ilc, Elizabeth McNamara, Michael Novak, Scott Pendergast, Susan Rath, Sheila Smith-Brewer, Vivian Tanner, Diane E. Weiss, Hernando Zegarra, Lawrence Halperin, Patricia Aramayo, Mandeep Dhalla, Brian Fernandez, Cindy Fernandez, Jaclyn Lopez, Monica Lopez, Jamie Mariano, Kellie Murphy, Clifford Sherley, Rita Veksler, Firas Rahhal, Razmig Babikian, David Boyer, Sepideh Hami, Jeff Kessinger, Janet Kurokouchi, Saba Mukarram, Sarah Pachman, Eric Protacio, Julio Sierra, Homayoun Tabandeh, Adam Zamboni, Michael Elman, Jennifer Belz, Tammy Butcher, Theresa Cain, Teresa Coffey, Dena Firestone, Nancy Gore, Pamela Singletary, Peter Sotirakos, JoAnn Starr, Travis A. Meredith, Cassandra J. Barnhart, Debra Cantrell, RonaLyn Esquejo-Leon, Odette Houghton, Harpreet Kaur, Fatoumatta NDure, Ronald Glatzer, Leonard Joffe, and Reid Schindler

Subjects
Ophthalmology
Published
2023
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24. Epidemiology and Sequence-Based Evolutionary Analysis of Circulating Non-Polio Enteroviruses

Author

David M. Brown, Yun Zhang, and Richard H. Scheuermann

Subjects
enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), coxsackievirus A6 (CV-A6), Echovirus 30 (E30), coxsackievirus A24 (CV-A24), enterovirus D68 (EV-D68), Biology (General), QH301-705.5
Abstract

Enteroviruses (EVs) are positive-sense RNA viruses, with over 50,000 nucleotide sequences publicly available. While most human infections are typically associated with mild respiratory symptoms, several different EV types have also been associated with severe human disease, especially acute flaccid paralysis (AFP), particularly with endemic members of the EV-B species and two pandemic types—EV-A71 and EV-D68—that appear to be responsible for recent widespread outbreaks. Here we review the recent literature on the prevalence, characteristics, and circulation dynamics of different enterovirus types and combine this with an analysis of the sequence coverage of different EV types in public databases (e.g., the Virus Pathogen Resource). This evaluation reveals temporal and geographic differences in EV circulation and sequence distribution, highlighting recent EV outbreaks and revealing gaps in sequence coverage. Phylogenetic analysis of the EV genus shows the relatedness of different EV types. Recombination analysis of the EV-A species provides evidence for recombination as a mechanism of genomic diversification. The absence of broadly protective vaccines and effective antivirals makes human enteroviruses important pathogens of public health concern.

Published
2020
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25. The variances in cytokine production profiles from non- or activated THP-1, Kupffer cell and human blood derived primary macrophages following exposure to either alcohol or a panel of engineered nanomaterials.

Author

Ali Kermanizadeh, David M Brown, and Vicki Stone

Subjects
Medicine, Science
Abstract

The portfolio of cytokines is key to the function of macrophages as sentries of the innate immune system as well as being critical for the transition from innate to adaptive immunity. Cytokine bias is critical in the fate of macrophages into a continuum of inflammatory to anti-inflammatory macrophages. Due to advances in the field of toxicology, increasingly advanced multi-cellular in vitro safety assessment models are being developed in order to allow for a better predication of potential adverse effects in humans with many of these models include a macrophage population. The selection of the correct macrophage cells in these advanced in vitro models is critical for a physiologically relevant and realistic immune response. In this study we investigated cytokine response profile (IL1-β, IL6, IL10 and TNF-α) of activated and non-activated THP-1 (immortalized monocyte-like cell line), primary human Kupffer cells (liver resident macrophages) and human primary peripheral blood mononuclear cells following exposure of a panel of nanomaterials or ethanol. The data demonstrated that the THP-1 cell line are not great cytokine producers. The PBMC appear to be a good in vitro surrogate for circulating/pro-inflammatory macrophages but are not a suitable replacement for Kupffer cells. The findings from this study highlight the necessity for the selection of appropriate macrophages populations to meet the specific physiological requirements of in vitro experiment.

Published
2019
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26. Contemporary Circulating Enterovirus D68 Strains Have Acquired the Capacity for Viral Entry and Replication in Human Neuronal Cells

Author

David M. Brown, Alison M. Hixon, Lauren M. Oldfield, Yun Zhang, Mark Novotny, Wei Wang, Suman R. Das, Reed S. Shabman, Kenneth L. Tyler, and Richard H. Scheuermann

Subjects
EV-D68, SH-SY5Y, enterovirus, myelitis, neurotropism, neurovirology, Microbiology, QR1-502
Abstract

ABSTRACT Enterovirus D68 (EV-D68) has historically been associated with respiratory illnesses. However, in the summers of 2014 and 2016, EV-D68 outbreaks coincided with a spike in polio-like acute flaccid myelitis/paralysis (AFM/AFP) cases. This raised concerns that EV-D68 could be the causative agent of AFM during these recent outbreaks. To assess the potential neurotropism of EV-D68, we utilized the neuroblastoma-derived neuronal cell line SH-SY5Y as a cell culture model to determine if differential infection is observed for different EV-D68 strains. In contrast to HeLa and A549 cells, which support viral infection of all EV-D68 strains tested, SH-SY5Y cells only supported infection by a subset of contemporary EV-D68 strains, including isolates from the 2014 outbreak. Viral replication and infectivity in SH-SY5Y were assessed using multiple assays: virus production, cytopathic effects, cellular ATP release, and VP1 capsid protein production. Similar differential neurotropism was also observed in differentiated SH-SY5Y cells, primary human neuron cultures, and a mouse paralysis model. Using the SH-SY5Y cell culture model, we determined that barriers to viral binding and entry were at least partly responsible for the differential infectivity phenotype. Transfection of genomic RNA into SH-SY5Y generated virions for all EV-D68 isolates, but only a single round of replication was observed from strains that could not directly infect SH-SY5Y. In addition to supporting virus replication and other functional studies, this cell culture model may help identify the signatures of virulence to confirm epidemiological associations between EV-D68 strains and AFM and allow for the rapid identification and characterization of emerging neurotropic strains. IMPORTANCE Since the EV-D68 outbreak during the summer of 2014, evidence of a causal link to a type of limb paralysis (AFM) has been mounting. In this article, we describe a neuronal cell culture model (SH-SY5Y cells) in which a subset of contemporary 2014 outbreak strains of EV-D68 show infectivity in neuronal cells, or neurotropism. We confirmed the difference in neurotropism in vitro using primary human neuron cell cultures and in vivo with a mouse paralysis model. Using the SH-SY5Y cell model, we determined that a barrier to viral entry is at least partly responsible for neurotropism. SH-SY5Y cells may be useful in determining if specific EV-D68 genetic determinants are associated with neuropathogenesis, and replication in this cell line could be used as rapid screening tool for identification of neurotropic EV-D68 strains. This may assist with better understanding of pathogenesis and epidemiology and with the development of potential therapies.

Published
2018
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27. (Im)migrants’ appropriation of culture: Reciprocal influence of personal and work contexts

Author

Bidit L. Dey, Youssef Tarek Nasef, David M Brown, Lalnunpuia Samuel, Pallavi Singh, and Chrysostomos Apostolidis

Subjects
Marketing, essentialism, cultural appropriation, boundary spanning, cultural adoption, Business and International Management, acculturation, cultural adaptation, Finance
Abstract

Supplementary materials: Supplementary material associated with this article can be found, in the online version, at doi https://doi.org/10.1016/j.jwb.2022.101417 Copyright © 2022 The Authors. Increasing internationalisation in organisations demands further research on acculturation within international business (IB). Based on triangulated qualitative data on South Asian diasporas’ food consumption in the UK and Bahraini contexts, we introduce two acculturative orientations: essentialism and boundary spanning. We contribute to literature by linking acculturative orientations with relevant drivers and resulting adoption and adaptation of cultures to offer a new perspective towards analysing (im)migrants’ appropriation of culture in personal and work settings. We push the boundary of IB research by highlighting and enriching the understanding of, and reciprocity between, social and occupational contexts that shape (im)migrants’ acculturation.

Published
2022

30. The tenacity of trust in petrochemical communities: Reckoning with risk on the Fawley Waterside (1997–2019)

Author

Gordon Walker, Alice Mah, and David M. Brown

Subjects
HD, TP, Environmental justice, GE, media_common.quotation_subject, 05 social sciences, Geography, Planning and Development, 0507 social and economic geography, 010501 environmental sciences, Development, Management, Monitoring, Policy and Law, Criminology, Anger, 01 natural sciences, Tenacity (mineralogy), Denial, Sociology, 050703 geography, 0105 earth and related environmental sciences, Nature and Landscape Conservation, media_common
Abstract

Around the world, people living close to polluting industries have different perceptions of the risks of toxic exposure, ranging from anger to acceptance to denial. We draw attention to a case with relatively high levels of social trust, but also relatively high levels of risk perception: the communities living adjacent to the Fawley (UK) oil refinery and petrochemical complex, a site that has been operated by Esso since the early 1950s. Our findings are based on a novel comparative analysis of two qualitative studies of local risk perceptions in Fawley conducted more than two decades apart in 1997 and 2019, incorporating focus group and individual interviews with residents, alongside documentary analysis and stakeholder interviews. Perceptions of risk and trust in the local polluting industry have fluctuated over the years, with unease never far from the surface as industrial employment has slowly contracted. Yet overall, the picture in 2019 was not too dissimilar from that in 1997: while community–industry relations were strained amidst periodic risk incidents and a sense of decline, a cautious sense of trust in the polluting enterprise had endured, based on a delicate balance of heritage, risk, and recognition. We draw attention to the residents’ careful reckoning with risks over time and the tenacity of social trust as an act of negotiation that took risk into account but also included other important factors such as recognition and reciprocity. Local risk perceptions in Fawley are closely bound up with the residents’ shared industrial heritage and enduring perceptions of Esso as a ‘good neighbour’. Our longitudinal analysis allowed us to reflect on changes over time in Fawley, providing greater temporal depth to the risk perception literature.

Published
2021
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31. Effect of sodium 4-phenylbutyrate on Clenbuterol-mediated muscle growth.

Author

David M Brown, Sarah Jones, Zoe C T R Daniel, Madelaine C Brearley, Jo E Lewis, Francis J P Ebling, Tim Parr, and John M Brameld

Subjects
Medicine, Science
Abstract

Previously, we highlighted induction of an integrated stress response (ISR) gene program in skeletal muscle of pigs treated with a beta-adrenergic agonist. Hence we tested the hypothesis that the ER-stress inhibitor, sodium 4-phenylbutyrate (PBA), would inhibit Clenbuterol-mediated muscle growth and reduce expression of genes that are known indicators of an ISR in mice. Clenbuterol (1mg/kg/day) administered to C57BL6/J mice for 21 days increased body weight (p

Published
2018
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32. Minimal cell JCVI-syn3B as a chassis to reveal the mechanisms behind Mycoplasma host–pathogen interactions

Author

Daniela M. de C. Bittencourt, David M. Brown, Nacyra Assad-Garcia, Michaela R. Lynott, Lijie Sun, Luis Alberto M. Palhares de Melo, Marcelo Freire, and John I. Glass

Abstract

Mycoplasmas are atypical bacteria that are obligate parasites of animals and plants. They are known for their capacity to contaminate and parasitize mammalian cell cultures, thereby offering fortuitous models to examine the host-microbe interaction. We used a near wildtype strain of the goat pathogen Mycoplasma mycoides (Mmc) and several minimized Mmc strains lacking genes not essential for growth in laboratory media to investigate host-mycoplasma interactions. Stains with near minimal genomes were incapable of surviving in co-culture with mammalian HEK-293T and HeLa cells. We identified a cluster of eight non-essential genes that when added back to the minimized strains enabled mycoplasma attachment to mammalian cells. Those genes did not restore the capacity of the minimal cell to grow when co-cultured with mammalian cells indicating processes of attaching to mammalian cells and parasitism involve different genes. Furthermore, minimized Mmc strains were not phagocytized by human myeloid cells unlike the near wildtype Mmc.

Published
2022
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45. Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression

Author

Charles C. Wykoff, Jamie Reese, Sruthi Arepalli, Joseph R Abraham, Hannah J. Yu, Ming Hu, Justis P. Ehlers, Sunil K. Srivastava, Alison Martin, Leina Lunasco, Christopher J. Mugnaini, and David M. Brown

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, Imaging biomarker, Angiogenesis, medicine.medical_treatment, Visual Acuity, Angiogenesis Inhibitors, Context (language use), Endothelial Growth Factors, Gastroenterology, Cellular and Molecular Neuroscience, Internal medicine, medicine, Humans, Prospective Studies, Fluorescein Angiography, Biological Products, Diabetic Retinopathy, Tissue Inhibitor of Metalloproteinase-1, medicine.diagnostic_test, Interleukin-6, Aqueous humour, business.industry, Cell Adhesion Molecule-1, Interleukin, Microaneurysm, Fluorescein angiography, Urokinase-Type Plasminogen Activator, Sensory Systems, Monocyte Chemoattractant Proteins, Platelet Endothelial Cell Adhesion Molecule-1, Urokinase receptor, Ophthalmology, Phenotype, Cytokine, Intravitreal Injections, Cytokines, business, Angiopoietins, Biomarkers
Abstract

BackgroundThis study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME).MethodsThe IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response.ResultsTwenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (pConclusionsBaseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.

Published
2021
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46. Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence

Author

Ryan P. Gilley, Yanbao Yu, David M. Brown, Peter H. Dube, Norberto Gonzalez-Juarbe, Maryann P. Platt, and Yi-Han Lin

Subjects
0301 basic medicine, Programmed cell death, Heart Diseases, Proteome, Physiology, media_common.quotation_subject, Necroptosis, 030204 cardiovascular system & hematology, Mitochondrion, Proteomics, Bioinformatics, medicine.disease_cause, Article, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Orthomyxoviridae Infections, medicine, Animals, Humans, Myocytes, Cardiac, media_common, business.industry, Convalescence, Phosphoproteomics, Phosphoproteins, Rats, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Influenza A virus, Cardiology and Cardiovascular Medicine, business, Protein Kinases, Oxidative stress
Abstract

Rationale: Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events. Objective: Define the molecular mechanisms underlying influenza virus–induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process. Methods and Results: Hearts from wild-type and necroptosis-deficient (MLKL [mixed lineage kinase domain-like protein]-KO) mice were dissected 12 days after initial influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high-resolution accurate mass-based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain-independent manner. Necroptosis-deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pretreatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection. Conclusions: This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post–pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections. Graphic Abstract: A graphic abstract is available for this article.

Published
2021
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47. Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study

Author

Sunil K. Srivastava, Leina Lunasco, Sruthi Arepalli, Jamie Reese, Hannah J. Yu, Joseph R Abraham, Justis P. Ehlers, David M. Brown, Charles C. Wykoff, and Ming Hu

Subjects
Adult, Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Visual acuity, medicine.medical_treatment, Visual Acuity, Angiogenesis Inhibitors, Gastroenterology, Macular Edema, Article, law.invention, Aqueous Humor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Diabetes mellitus, medicine, Humans, Macula Lutea, Aged, 030304 developmental biology, 0303 health sciences, Diabetic Retinopathy, business.industry, Monocyte, Growth factor, Retinal, Middle Aged, medicine.disease, Vascular endothelial growth factor, Ophthalmology, medicine.anatomical_structure, Bridge (graph theory), chemistry, Intravitreal Injections, 030221 ophthalmology & optometry, Cytokines, Female, medicine.symptom, business, Biomarkers, Tomography, Optical Coherence
Abstract

Purpose To identify biomarkers for predicting response to anti−vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) and evaluate any links between cytokine expression and optical coherence tomography (OCT) phenotype. Design The IMAGINE is a post hoc image analysis and cytokine expression assessment of the Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE) randomized clinical trial. Methods Subjects were categorized as anatomical responders or nonresponders, and within the responder group as rebounders and non-rebounders based on quantitative, longitudinal OCT criteria. Retinal layer and fluid features were extracted using an OCT machine-learning augmented segmentation platform. Responders were further sub-classified by rapidity of response. Aqueous concentrations of 54 cytokines were measured at multiple timepoints. Expression was compared between responder groups and correlated with OCT imaging biomarkers. Results Of the 24 eyes studied, 79% were anatomical responders with 38% super responders, 17% early responders, and 25% slow responders. Twenty-one percent were nonresponders. Super responders had increased baseline vascular endothelial growth factor (VEGF) (880.0 pg/mL vs 245.4 pg/mL; P = .012) and decreased monocyte chemotactic protein-1 (MCP-1) (513.3 pg/mL vs 809.5 pg/mL; P = .0.042) concentrations compared with nonresponders. Interleukin-6 (−24.9 pg/mL vs 442.8 pg/mL; P = .032) concentrations increased among nonresponders during therapy. VEGF concentrations correlated with central subfield thickness (r = 0.49; P = .01). Panmacular retinal volume correlated with increased interleuckin-6 (r = 0.47; P = .02) and decreased MCP-1 (r = −0.45; P = .03). Matrix metallopeptidase-1 correlated with subretinal fluid volume (r = 0.50; P = .01). Conclusions OCT imaging biomarkers correlated with both intraocular cytokines and responsiveness to anti-VEGF therapy, which indicated a possible link to underlying pathways and their relevance to DME prognosis. Baseline concentrations of VEGF and MCP-1 are associated with anatomic response to anti-VEGF therapy.

Published
2021
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48. Sustainable value co-creation at the Bottom of the Pyramid: using mobile applications to reduce food waste and improve food security

Author

Eranjana Kathriarachchi, Dinuka Wijetunga, David M Brown, and Chrysostomos Apostolidis

Subjects
Marketing, Sustainable Value, Food security, Bottom of the pyramid, Strategy and Management, 05 social sciences, G900, food and beverages, Environmental economics, Food waste, Laddering, 0502 economics and business, Sustainability, Co-creation, 050211 marketing, N100, Business, Affordance, 050203 business & management
Abstract

Mobile apps redistributing surplus food are receiving increased attention for their sustainability benefits. Nevertheless, there is limited research on the opportunities created for businesses to penetrate the Bottom of the Pyramid (BoP) market. Drawing on Service-Dominant (S-D) logic, affordance and means-end theories, this study investigates how food waste mobile apps can support sustainable value co-creation at the BoP. Using a laddering approach, data were collected through semi-structured interviews in Sri Lanka. Despite similarities in respondents’ perceptions of app functions, there are noticeable gaps in the perceived affordances and end goals, which may challenge the value co-creation process. Additionally, opportunism, stigma and goal misalignment may result in value co-destruction, i.e. the diminishment of value through stakeholder interactions. Our findings demonstrate that to develop technologies which enable value co-creation, an in-depth understanding of factors driving perceptions of value is essential.

Published
2021
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49. In‐Office Tympanostomy Tube Placement in Children Using Iontophoresis and Automated Tube Delivery

Author

D. Macy Vidrine, John E. McClay, Erik H. Waldman, Amy Ingram, Amy Brenski, David M. Yen, Lawrence R. Lustig, Robert C. Sprecher, Christopher R. Thompson, Charles A. Syms, Eli Grunstein, Frederick K. Kozak, Neil K. Chadha, Ritvik P. Mehta, Denise A. Sherman, Andrew R. Gould, Laura J. England, Scott R. Schoem, Michael T. Murray, Robert Puchalski, David M. Brown, Dan Harfe, Susannah Hills, Randall A. Ow, John Ansley, Christopher York, John Gavin, Audrey P. Calzada, Jonathan R. Moss, and Jacob W. Zeiders

Subjects
Lidocaine, medicine.medical_treatment, Sedation, office surgery, Myringotomy, 03 medical and health sciences, 0302 clinical medicine, tympanostomy tube, 030225 pediatrics, Original Reports, medicine, Local anesthesia, Tympanostomy tube, 030223 otorhinolaryngology, business.industry, Iontophoresis, Publication of this supplement is made possible by Tusker Medical, pediatric, Otorhinolaryngology, Tolerability, Anesthesia, myringotomy, Cohort, medicine.symptom, business, local anesthesia, Cohort study, medicine.drug
Abstract

OBJECTIVES/HYPOTHESIS Evaluate technical success, tolerability, and safety of lidocaine iontophoresis and tympanostomy tube placement for children in an office setting. STUDY DESIGN Prospective individual cohort study. METHODS This prospective multicenter study evaluated in-office tube placement in children ages 6 months through 12 years of age. Anesthesia was achieved via lidocaine/epinephrine iontophoresis. Tube placement was conducted using an integrated and automated myringotomy and tube delivery system. Anxiolytics, sedation, and papoose board were not used. Technical success and safety were evaluated. Patients 5 to 12 years old self-reported tube placement pain using the Faces Pain Scale-Revised (FPS-R) instrument, which ranges from 0 (no pain) to 10 (very much pain). RESULTS Children were enrolled into three cohorts with 68, 47, and 222 children in the Operating Room (OR) Lead-In, Office Lead-In, and Pivotal cohorts, respectively. In the Pivotal cohort, there were 120 and 102 children in the

Published
2020

50. Noncompliance in Prospective Retina Clinical Trials: Analysis of Factors Predicting Loss to Follow-up

Author

Charles C. Wykoff, Travis Mitchell, Brenda Zhou, David M. Brown, and Alexander M. Rusakevich

Subjects
medicine.medical_specialty, Patient Dropouts, Logistic regression, law.invention, 03 medical and health sciences, 0302 clinical medicine, Retinal Diseases, Randomized controlled trial, law, Internal medicine, medicine, Humans, Medical history, Prospective Studies, Prospective cohort study, Adverse effect, Randomized Controlled Trials as Topic, 030304 developmental biology, 0303 health sciences, business.industry, Diabetic retinopathy, Macular degeneration, medicine.disease, Clinical trial, Ophthalmology, 030221 ophthalmology & optometry, Patient Compliance, Regression Analysis, business
Abstract

Purpose Noncompliance during prospective studies can bias results and limit conclusions. The current study retrospectively investigated the relationship between study subject characteristics and rates of noncompliance in interventional trials involving common causes of blindness. Design Retrospective analysis of 10 randomized clinical trials. Methods Subjects were enrolled in investigator-initiated trials studying proliferative diabetic retinopathy, neovascular age-related macular degeneration, diabetic macular edema, and retinal venous occlusive disease. Records were reviewed for hypothesized risk factors of noncompliance and rates of noncompliance, which were defined as at least 1 missed visit or exiting the study early. Demographic information, systemic medical history, and ocular medical history, including visual acuity and central retinal thicknesses, were examined retrospectively using Student t test, Pearson χ2 test, and logistic regression. Results Of 390 subjects included, 212 (54.4%) were compliant with all scheduled study visits and 178 (45.6%) met criteria for noncompliance, with 53 (13.6%) subjects exiting early. Regression models identified 17 variables that were significant in determining subject noncompliance. Among those, distance, comorbidities, diabetic status, concomitant medications, previous clinic visits, length of study, disease under study, and severe adverse events were highly significant risk factors of noncompliance. Conclusion The current research identified a substantial proportion of subjects who met the criteria for noncompliance within the trials analyzed. The factors identified in the current work are consistent with published clinical observations and the results of previous clinical trials. These results highlight the importance of considering study design and medical history when designing prospective clinical trials in an attempt to minimize data loss.

Published
2020
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