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Mona Bafadhel,1 Klaus F Rabe,2 Fernando J Martinez,3 Dave Singh,4 Patrick Darken,5 Martin Jenkins,6 Magnus Aurivillius,7 Mehul Patel,6 Paul Dorinsky8 1Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 2LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 4Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Hospitals Trust, Manchester, UK; 5AstraZeneca, Gaithersburg, MD, USA; 6AstraZeneca, Cambridge, UK; 7AstraZeneca, Gothenburg, Sweden; 8Formerly of AstraZeneca, Durham, NC, USACorrespondence: Mona Bafadhel, Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, 5th floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK, Tel +44 0207 188 8717, Email mona.bafadhel@kcl.ac.ukPurpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count.Methods: Patients (40− 80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 μg, BGF 160/14.4/10 μg, GFF 14.4/10 μg, or BFF 320/10 μg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (< 100, ≥ 100, ≥ 100−< 300, ≥ 300 cells/mm3), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety.Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥ 100 cells/mm3. BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥ 100, ≥ 100−< 300, and ≥ 300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George’s Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the < 100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups.Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥ 100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥ 300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥ 100 cells/mm³.Graphical Abstract: Keywords: eosinophils, inhaled corticosteroids, triple therapy

This collaboratively authored piece highlights Poetry Inside Out, a poetry translation program that creates new pathways for culturally and linguistically sustaining literacy education. In Poetry Inside Out, students collaborate to translate world-class poems from their original language (e.g., Spanish, Chinese) into English. Informing PIO's design is the view of translation as an interpretive and creative act and a form of close reading. Drawing on their own and each other's linguistic and cultural repertoires and using a carefully scaffolded translation tool, students come to a deeper understanding of how languages and literacies work, paying keen attention to vocabulary, poetic form, syntax, grammar, rhythm, sound, and other nuances of the source and target language. Highlighted are two 5th-grade teachers', Erica Darken and Lisa Yuk Kuen Yau, and their multilingual students' engagement with Poetry Inside Out. Also highlighted are the teacher's use of allied practices such as Accordion Books and dialogic talk.

Need in Deed's work with Philadelphia public school teachers and their students centers empathy, informed investigation, and civic action. Bolstered by these values and with the support of the My Voice framework and dedicated Need in Deed staff, educators are equipped to co-create authentic classroom communities with their students. In Need in Deed classrooms, students feel a sense of belonging, are supported in taking academic risks, and understand their agency as change makers. In this piece, Need in Deed staff and teachers give an overview of the My Voice framework and share stories from Need in Deed classrooms that highlight Dr. Gholdy Muhammad's five pursuits of culturally and historically responsive teaching - identity, skills, intellectualism, criticality, and joy.

Fernando J Martinez,1 Gary T Ferguson,2 Eric Bourne,3 Shaila Ballal,4 Patrick Darken,5 Magnus Aurivillius,6 Paul Dorinsky,3 Colin Reisner4 1Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 2Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 3AstraZeneca, Durham, NC, USA; 4AstraZeneca, Morristown, NJ, USA; 5AstraZeneca, Wilmington, DE, USA; 6AstraZeneca, Gothenburg, SwedenCorrespondence: Fernando J MartinezJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USATel +1 646 962 2748Email fjm2003@med.cornell.eduPurpose: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥ 1 exacerbation in the 12 months prior to the study.Patients and Methods: Patients received BGF MDI 320/18/9.6 μg, GFF MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study.Results: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count.Conclusion: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.Keywords: fixed-dose combination, COPD, exacerbations of COPD

Marjan Kerkhof,1 Jaco Voorham,1 Paul Dorinsky,2 Claudia Cabrera,3,4 Patrick Darken,5 Janwillem WH Kocks,1,6 Mohsen Sadatsafavi,7,8 Don D Sin,7,8 Victoria Carter,1 David B Price1,9 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2AstraZeneca, Durham, NC, USA; 3AstraZeneca, Mölndal, Sweden; 4Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; 5AstraZeneca, Morristown, NJ, USA; 6General Practitioners Research Institute, Groningen, The Netherlands; 7Respiratory Evaluation Sciences Program, Collaboration for Outcomes Research and Evaluation, University of British Columbia, Vancouver, BC, Canada; 8Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada; 9Academic Primary Care, University of Aberdeen, Aberdeen, UKCorrespondence: David B Price Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UKTel +65 6962 3627Email dprice@opri.sgIntroduction: Early identification of preventable risk factors of COPD progression is important. Whether exacerbations have a negative impact on disease progression is largely unknown. We investigated whether the long-term occurrence of exacerbations is associated with lung function decline at early stages of COPD.Methods: Patients diagnosed with mild/moderate COPD (obstruction and FEV1% predicted 50– 90%), aged ≥ 35 years, and a smoking history, who had ≥ 6 years of UK electronic medical records after initiation of maintenance therapy were studied. Multilevel mixed-effect linear regression was performed to determine the association between the count of any year in which the patient had ≥ 1 exacerbation over a 6-year period and FEV1 decline, adjusted for sex, age, anthropometrics and smoking habits. Exacerbations were defined as any prescription for an acute oral corticosteroid course and/or lower respiratory-related antibiotics and/or any COPD-related emergency or inpatient hospitalization.Results: Of 11,337 patients included (mean age 65 years; 49% female) 31.6%, 23.3%, 16.6%, 11.6%, 8.1%, 5.3% and 3.4% had 0, 1, 2, 3, 4, 5 and 6 years with ≥ 1 exacerbation. The mean annual FEV1 decline accelerated by 1.50 mL/year (95% Confidence Interval 1.02; 1.98) with every additional year with ≥ 1 exacerbation from 31.0 mL/year in subjects without any exacerbation to 40.0 mL/year in patients experiencing ≥ 1 exacerbation every year. Patients with more years with ≥ 1 exacerbation had a lower mean FEV1 at first diagnosis: 14.7 mL (11.7; 17.8) lower with every additional year with exacerbations. When counting years with ≥ 2 exacerbations, greater effects were observed (2.19 [1.50; 2.88] mL/year excess decline per year with ≥ 2 exacerbations; 16.5 mL [12.1; 20.8] lower FEV1 at diagnosis).Conclusion: Patients who experienced a greater exacerbation burden after initiation of maintenance therapy had worse lung function at diagnosis and a more rapid lung function decline thereafter, which emphasizes the need for better treatment strategies.Keywords: COPD, exacerbations, spirometry, inhalation therapy, observational study

Colin Reisner,1,2 James Pearle,3 Edward M Kerwin,4 Earl St Rose,1 Patrick Darken1 1Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 2AstraZeneca, Gaithersburg, MD, USA; 3California Research Medical Group, Inc., Fullerton, CA, USA; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA Purpose: To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 μg) using innovative co‑suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 μg and formoterol fumarate (FF) MDI 9.6 μg, in patients with moderate-to-severe COPD. Methods: In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0–12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed. Results: All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 μg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 μg. No significant differences were observed between GFF MDI and FF MDI 9.6 μg for primary and secondary endpoints. The incidence of adverse events was similar between treatments. Conclusion: While all doses of GFF MDI were superior to GP MDI 36 μg for the primary endpoint, in this study neither superiority of GFF MDI to FF MDI 9.6 μg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings. Keywords: bronchodilator, chronic obstructive pulmonary disease, co-suspension delivery technology, fixed-dose combination, LAMA/LABA, long-acting β2-agonist, long-acting muscarinic antagonist

Edward M Kerwin,1 Thomas M Siler,2 Samir Arora,3 Patrick Darken,4 Earl St Rose,4 Colin Reisner4,5 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Midwest Chest Consultants, St Charles, MO, USA; 3Aventiv Research, Columbus, OH, USA; 4Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 5AstraZeneca, Gaithersburg, MD, USA Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting β2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 μg and FF MDI 9.6 μg, and two of either BFF MDI 160/9.6 μg, BFF MDI 80/9.6 μg, or BD MDI 320 μg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 μg (least squares mean differences 186–221 mL; all p

This article analyzes the development of ecotourism in the Ulytau Nature Park using innovative Geographi c information systems technologies. The main purpose of the study is to create a favorable and innovative environment for the development of the tourist experience, including the search and discovery of historical sites, the development of optimal routes and infrastructure improvements. The use of GIS maps in ecological tourism contributes to the development of optimal routes, improvement of tourist infrastructure and provision of informative services. The analysis of the study makes it possible to identify recommendations for public and private organizations in the field of using GIS technologies for the sustainable development of ecotourism. The created GIS map provides information about the park's territory, the location of objects and routes, which contributes to a more informative and oriented tourist experience. The experience of working with GIS technologies enhances the ability of tourists to navigate, discover and obtain information about historical sites and attractions in ecotourism and help enrich the tourist experience.

This collaboratively authored piece highlights Poetry Inside Out, a poetry translation program that creates new pathways for culturally and linguistically sustaining literacy education. In Poetry Inside Out, students collaborate to translate world-class poems from their original language (e.g., Spanish, Chinese) into English. Informing PIO's design is the view of translation as an interpretive and creative act and a form of close reading. Drawing on their own and each other's linguistic and cultural repertoires and using a carefully scaffolded translation tool, students come to a deeper understanding of how languages and literacies work, paying keen attention to vocabulary, poetic form, syntax, grammar, rhythm, sound, and other nuances of the source and target language. Highlighted are two 5th-grade teachers', Erica Darken and Lisa Yuk Kuen Yau, and their multilingual students' engagement with Poetry Inside Out. Also highlighted are the teacher's use of allied practices such as Accordion Books and dialogic talk. [ABSTRACT FROM AUTHOR]

Need in Deed's work with Philadelphia public school teachers and their students centers empathy, informed investigation, and civic action. Bolstered by these values and with the support of the My Voice framework and dedicated Need in Deed staff, educators are equipped to co-create authentic classroom communities with their students. In Need in Deed classrooms, students feel a sense of belonging, are supported in taking academic risks, and understand their agency as change makers. In this piece, Need in Deed staff and teachers give an overview of the My Voice framework and share stories from Need in Deed classrooms that highlight Dr. Gholdy Muhammad's five pursuits of culturally and historically responsive teaching - identity, skills, intellectualism, criticality, and joy. [ABSTRACT FROM AUTHOR]

Depression and anxiety are some of the most prevalent and debilitating mental health conditions in humans. They can present on their own or as co-morbidities with other disorders. Like humans, non-human primates (NHPs) can develop depression- and anxiety-like signs. Here, we first define human depression and anxiety, examine equivalent species-specific behaviors in NHPs, and consider models and current methods to identify and evaluate these behaviors. We also discuss knowledge gaps, as well as the importance of evaluating the co-occurrence of depression- and anxiety-like behaviors in animal models of human disease. Lastly, we consider ethical challenges in depression and anxiety research on NHPs in order to ultimately advance the understanding and the personalized treatment of these disorders.

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Background: Demographic and disease characteristics have been associated with the risk of chronic obstructive pulmonary disease (COPD) exacerbations. Using previously collected multinational clinical trial data, we developed models that use baseline risk factors to predict an individual’s rate of moderate/severe exacerbations in the next year on various pharmacological treatments for COPD. Methods: Exacerbation data from 20,054 patients in the ETHOS, KRONOS, TELOS, SOPHOS, and PINNACLE-1, PINNACLE-2, and PINNACLE-4 studies were pooled. Machine learning was used to identify predictors of moderate/severe exacerbation rates. Important factors were selected for generalized linear modeling, further informed by backward variable selection. An independent test set was held back for validation. Results: Prior exacerbations, eosinophil count, forced expiratory volume in 1 s percent predicted, prior maintenance treatments, reliever medication use, sex, COPD Assessment Test score, smoking status, and region were significant predictors of exacerbation risk, with response to inhaled corticosteroids (ICSs) increasing with higher eosinophil counts, more prior exacerbations, or additional prior treatments. Model fit was similar in the training and test set. Prediction metrics were ~10% better in the full model than in a simplified model based only on eosinophil count, prior exacerbations, and ICS use. Conclusion: These models predicting rates of moderate/severe exacerbations can be applied to a broad range of patients with COPD in terms of airway obstruction, eosinophil counts, exacerbation history, symptoms, and treatment history. Understanding the relative and absolute risks related to these factors may be useful for clinicians in evaluating the benefit: risk ratio of various treatment decisions for individual patients. Clinical trials registered with www.clinicaltrials.gov (NCT02465567, NCT02497001, NCT02766608, NCT02727660, NCT01854645, NCT01854658, NCT02343458, NCT03262012, NCT02536508, and NCT01970878)

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

New World monkeys represent an important but often poorly understood research resource. The relatively small size and low zoonotic risk of these animals make them appealing as research subjects in a number of areas. However, historic portrayal of many of these species as difficult to manage and handle is one of the factors that has limited their use. Basic guidelines are provided on management and handling approaches for the New World monkeys most commonly used in research: marmosets, squirrel monkeys, owl monkeys, and titi monkeys. Topics include transport and acclimation to a new facility, location changes within a facility, diet changes, removal from and return to social groups, capture and restraint, handling for anesthesia, postprocedural monitoring, and staff training.