121 results on '"Berger KI"'
Search Results
2. PCR70 Avalglucosidase Alfa (AVA) Improves Symptoms and Functioning in Late-Onset Pompe Disease (LOPD) Patients vs Alglucosidase Alfa (ALG): Post-Hoc Analyses of Patient-Reported Outcomes (PROs) From COMET Trial
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Toscano, A, primary, van der Ploeg, AT, additional, Berger, KI, additional, Dimachkie, MM, additional, Schoser, B, additional, Gwaltney, C, additional, Msihid, J, additional, Hamed, A, additional, Thibault, N, additional, Pollissard, L, additional, and Kishnani, PS, additional
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- 2022
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3. SA26 Win Ratio Analyses of Multiple Endpoints in Rare Disease Trials: A Case-Study Based on a Trial of Avaglucosidase Alfa in Late-Onset Pompe Disease (LOPD)
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Ishak, KJ, primary, Caro, JJ, additional, Hamed, A, additional, Riou-Franca, L, additional, Thibault, N, additional, Shukla, P, additional, Berger, KI, additional, Diaz-Manera, J, additional, Dimachkie, MM, additional, and Boentert, M, additional
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- 2022
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4. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial
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Diaz-Manera, J, Kishnani, PS, Kushlaf, H, Ladha, S, Mozaffar, T, Straub, V, Toscano, A, Van der Ploeg, AT, Berger, KI, Clemens, PR, Chien, YH, Day, JW, Illarioshkin, S, Roberts, M, Attarian, S, Borges, JL, Bouhour, F, Choi, YC, Erdem-Ozdamar, S, Goker-Alpan, O, Kostera-Pruszczyk, A, Haack, KA, Hug, C, Huynh-Ba, O, Johnson, J, Thibault, N, Zhou, TY, Dimachkie, MM, and Schoser, B
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Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid ti-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphatereceptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late -onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non -inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1.1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to -treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49 -week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2.89% (S E 0.88) compared with 0.46% (0.93) with alglucosidase alfa at week 49 (difference 2.43% [95% CI 0.13 to 4.99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non -inferiority margin but did not exclude 0 (p=0. 0074). Superiority was not reached (p=0. 063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 3001 in [95% CI 1.33 to 58.69]) and percent predicted (4.71% [0. 25 to 9.17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres W.2 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence ofclinically meaningful improvement with avalglucosida se alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended -treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease.
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- 2021
5. Effect of Lung Inflation and Bronchodilator on Lung Mechanics Evaluated by Impulse oscillometry.
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Oppenheimer, BW, primary, Segal, LN, additional, Helwig, A, additional, Goldring, RM, additional, and Berger, KI, additional
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- 2009
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6. Impulse Oscillometry Detects Distal Airway Dysfunction in the Presence of Abnormal Spirometry.
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Abi Fadel, D, primary, Goldring, RM, additional, Oppenheimer, BW, additional, Segal, L, additional, Helwig, A, additional, Reibman, J, additional, and Berger, KI, additional
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- 2009
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7. Distal Airway Dysfunction Detected by Magnetic Resonance Imaging in Subjects with Normal Spirometry.
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Berger, KI, primary, Goldring, RM, additional, Zhang, K, additional, Voorhees, A, additional, Dougherty, L, additional, Oppenheimer, BW, additional, Reibman, J, additional, Rom, WN, additional, Rogers, L, additional, Helwig, A, additional, and Chen, Q, additional
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- 2009
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8. Case-control study of lung function in World Trade Center Health Registry area residents and workers.
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Friedman SM, Maslow CB, Reibman J, Pillai PS, Goldring RM, Farfel MR, Stellman SD, Berger KI, Friedman, Stephen M, Maslow, Carey B, Reibman, Joan, Pillai, Parul S, Goldring, Roberta M, Farfel, Mark R, Stellman, Steven D, and Berger, Kenneth I
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OCCUPATIONAL disease diagnosis ,RESPIRATORY disease diagnosis ,AIR pollution ,DUST ,LONGITUDINAL method ,LUNGS ,OCCUPATIONAL diseases ,PHYSICS ,RESCUE work ,RESEARCH funding ,RESPIRATORY diseases ,RESPIRATORY organ physiology ,SPIROMETRY ,TERRORISM ,TIME ,OCCUPATIONAL hazards ,ENVIRONMENTAL exposure ,RESIDENTIAL patterns ,ACQUISITION of data ,RETROSPECTIVE studies - Abstract
Rationale: Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003-2004 and 2006-2007), but lung function data were lacking.Objectives: To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case-control study of exposed adult residents and area workers 7-8 years after September 11, 2001.Methods: Registrants reporting post September 11th onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential control subjects. Final case-control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed.Measurements and Main Results: We identified 180 cases and 473 control subjects. Cases were more likely than control subjects to have abnormal spirometry (19% vs. 11%; P < 0.05), and impulse oscillometry measurements of elevated airway resistance (R5; 68% vs. 27%; P < 0.0001) and frequency dependence of resistance (R₅₋₂₀; 36% vs. 7%; P < 0.0001). When spirometry was normal, cases were more likely than control subjects to have elevated R₅ and R₅₋₂₀ (62% vs. 25% and 27% vs. 6%, respectively; both P < 0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (body mass index, spirometry, and exposures) were analyzed using logistic regression.Conclusions: This study links persistent respiratory symptoms and oscillometric abnormalities in World Trade Center-exposed residents and area workers. Elevated R₅ and R₅₋₂₀ in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms. [ABSTRACT FROM AUTHOR]- Published
- 2011
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9. Obesity hypoventilation syndrome: diagnosing and treating an old problem.
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Berger KI
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Described more than 100 years ago, obesity hyperventilation syndrome presents diagnostic and treatment challenges. [ABSTRACT FROM AUTHOR]
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- 2008
10. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human n-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or RHASB) and follow-on,...
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Harmatz P, Giugliani R, Schwartz I, Guffon N, Teles EL, Miranda SA, Wraith JE, Beck M, Arash L, Scarpa M, Yu Z, Wittes J, Berger KI, Newman MS, Lowe AM, Kakkis E, and Swiedler SJ
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- 2006
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11. Asthma in the elderly: cockroach sensitization and severity of airway obstruction in elderly nonsmokers.
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Rogers L, Cassino C, Berger KI, Goldring RM, Norman RG, Klugh T, Reibman J, Rogers, Linda, Cassino, Cara, Berger, Kenneth I, Goldring, Roberta M, Norman, Robert G, Klugh, Thomas, and Reibman, Joan
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Study Objectives: To test the hypothesis that the presence of sensitization to indoor allergens is associated with increased severity of airway obstruction in elderly subjects with asthma.Design: Cohort study of subjects enrolled in a public hospital asthma clinic.Setting: Asthma clinic in a municipal public hospital serving an indigent population in New York City.Patients: Subjects aged > or = 60 years with asthma who were enrolled in the Bellevue Hospital Asthma Clinic. Total serum IgE and allergen-specific IgE measurements were performed in a cohort of elderly never-smokers who had asthma (45 patients) who had undergone spirometry before and after bronchodilator (BD) therapy.Measurements and Results: The results of radioallergosorbent tests demonstrated that most subjects (ie, 60%) were sensitized to at least one allergen, with many sensitized to at least one indoor allergen. Cockroach (CR) was the most common allergen to which subjects were sensitized, with 47% displaying an elevated serum-specific IgE level. Fewer subjects were sensitized to dust mite, cat, dog, or ragweed. Subjects sensitized to CR (CR+) had greater reductions in airflow compared to subjects not sensitized to CR (CR-) [64 +/- 4.4% predicted vs 77.1 +/- 4.1% predicted FEV(1), respectively; p < 0.05]. Following BD administration, only 29% of CR+ subjects achieved a normal post-BD FEV(1) compared to 58% of CR- subjects. Lung volume measurements differed between CR+ and CR- subjects, with a greater elevation of functional residual capacity in CR+ subjects.Conclusion: In a population of elderly urban patients with asthma, the presence of CR-specific serum IgE is associated with more severe asthma, as reflected by an increase in airway obstruction and hyperinflation. [ABSTRACT FROM AUTHOR]- Published
- 2002
12. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep.
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Berger KI, Ayappa I, Chatr-amontri B, Marfatia A, Sorkin IB, Rapoport DM, Goldring RM, Berger, K I, Ayappa, I, Chatr-Amontri, B, Marfatia, A, Sorkin, I B, Rapoport, D M, and Goldring, R M
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Objective: To identify the spectrum of respiratory disturbances during sleep in patients with obesity hypoventilation syndrome (OHS) and to examine the response of hypercapnia to treatment of the specific ventilatory sleep disturbances.Designs and Methods: Twenty-three patients with chronic awake hypercapnia (mean [+/- SD] PaCO(2), 55 +/- 6 mm Hg) and a respiratory sleep disorder were retrospectively identified. Nocturnal polysomnography testing was performed, and flow limitation (FL) was identified from the inspiratory flow-time contour. Obstructive hypoventilation was inferred from sustained FL coupled with O(2) desaturation that was corrected with treatment of the upper airway obstruction. Central hypoventilation was inferred from sustained O(2) desaturation that persisted after the correction of the upper airway obstruction. Treatment was initiated, and follow-up awake PaCO(2) measurements were obtained (follow-up range, 4 days to 7 years).Results: A variable number of obstructive sleep apneas/hypopneas (ie, obstructive sleep apnea-hypopnea syndrome [OSAHS]) were noted (range, 9 to 167 events per hour of sleep). Of 23 patients, 11 demonstrated upper airway obstruction alone (apnea-hypopnea/FL) and 12 demonstrated central sleep hypoventilation syndrome (SHVS) in addition to a variable number of OSAHS. Treatment aimed at correcting the specific ventilatory abnormalities resulted in correction of the chronic hypercapnia in all compliant patients (compliant patients: pretreatment, 57 +/- 6 mm Hg vs post-treatment, 41 +/- 4 mm Hg [p < 0.001]; noncompliant patients: pretreatment, 52 +/- 6 mm Hg vs post-treatment, 51 +/- 3 mm Hg; [difference not significant]).Conclusions: This study demonstrates that OHS encompasses a variety of distinct pathophysiologic disturbances that cannot be distinguished clinically at presentation. Sustained obstructive hypoventilation due to partial upper airway obstruction was demonstrated as an additional mechanism for OHS that is not easily classified as SHVS or OSAHS. [ABSTRACT FROM AUTHOR]- Published
- 2001
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13. Clinical insight meets scientific innovation to develop a next generation ERT for Pompe disease.
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Kishnani PS, Chien YH, Berger KI, Thibault N, and Sparks S
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Years of research into the structure, processing, and function of acid alpha-glucosidase led to the development and 2006 approval of alglucosidase alfa (recombinant human acid alpha-glucosidase, Myozyme®/Lumizyme®), an enzyme replacement therapy and the first approved treatment for Pompe disease. Alglucosidase alfa has been a lifesaving treatment for patients with infantile-onset Pompe disease and radically improved daily life for patients with late-onset Pompe disease; however, long-term experience with alglucosidase alfa unraveled key unmet needs in these populations. Despite treatment, Pompe disease continues to progress, especially from a skeletal muscle perspective, resulting in a multitude of functional limitations. Strong collaboration between the scientific and patient communities led to increased awareness of Pompe disease, a better understanding of disease pathophysiology, knowledge of the clinical course of the disease as patients surpassed the first decade of life, and the strengths and limitations of enzyme replacement therapy. Taken together, these advancements spurred the need for development of a next generation of enzyme replacement therapy and provided a framework for progress toward other novel treatments. This review provides an overview of the development of avalglucosidase alfa as a model to highlight the interaction between clinical experience with existing treatments, the role of the clinician scientist, translational research at both system and cellular levels, and the iterative and collaborative process that optimizes the development of therapeutics., Competing Interests: Declaration of competing interest, (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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14. Changes in forced vital capacity over ≤ 13 years among patients with late-onset Pompe disease treated with alglucosidase alfa: new modeling of real-world data from the Pompe Registry.
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Berger KI, Chien YH, Dubrovsky A, Kishnani PS, Llerena JC Jr, Neilan E, Roberts M, Sheng B, Batista JL, Periquet M, Wilson KM, and van der Ploeg AT
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- Humans, Male, Female, Adult, Vital Capacity drug effects, Vital Capacity physiology, Middle Aged, Enzyme Replacement Therapy methods, Young Adult, Adolescent, Child, Follow-Up Studies, Child, Preschool, Glycogen Storage Disease Type II drug therapy, Glycogen Storage Disease Type II physiopathology, alpha-Glucosidases therapeutic use, Registries
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Background: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted., Methods: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation., Findings: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (P
difference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively., Conclusion: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined., Trial Registration: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered., (© 2024. The Author(s).)- Published
- 2024
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15. Switching to e-cigarettes as harm reduction among individuals with chronic disease who currently smoke: Results of a pilot randomized controlled trial.
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Vojjala M, Stevens ER, Nicholson A, Morgan T, Kaneria A, Xiang G, Wilker O, Wisniewski R, Melnic I, El-Shahawy O, Berger KI, and Sherman SE
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Introduction: E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease (PAD) who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes., Methods: In a pilot randomized controlled trial (RCT), patients with COPD, asthma, CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counselling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6-months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, ACT) that assess COPD, asthma, and CAD/PAD symptom change., Results: At 3-months, the EC group (n=63, mean CPD=9±11) reduced their CPD by 54% vs. 60% in the NRT group (n=58, mean CPD=7±6), p=0.56. At 6-months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p=0.03). Participants scored an average of 69±27 for EC effectiveness, 87±23 for convenience, and 75±27 for overall satisfaction., Conclusions: This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs., Implications: The findings from this pilot RCT hold significant implications with chronic conditions such as COPD, asthma, CAD and PAD who smoke CCs. The observed reduction in cigarettes per day and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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16. Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial.
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Toscano A, Pollissard L, Msihid J, van der Beek N, Kishnani PS, Dimachkie MM, Berger KI, DasMahapatra P, Thibault N, Hamed A, Zhou T, Haack KA, and Schoser B
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- Adult, Humans, alpha-Glucosidases therapeutic use, Quality of Life, Treatment Outcome, Glycogen Storage Disease Type II drug therapy
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Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures., Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement)., Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05)., Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD., Competing Interests: Declaration of Competing Interest KAH: is an employee and may hold stock and/or stock options in Sanofi. KIB: has served as a consultant to Sanofi, Amicus Therapeutics, Takeda, Valerion, and has participated in advisory boards for Sanofi, AskBio, Spark Therapeutics and Takeda; he is currently an employee of Sanofi. PD: is an employee and may hold stock and/or stock options in Sanofi. MMD: serves or recently served as a consultant for Abcuro, Amazentis/Vandria, ArgenX, Astellas, Catalyst, Cello, CNSA, Covance/Labcorp, CSL-Behring, Dianthus, EcoR1, EMD Serono/Merck, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc., Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, TACT, Abata/Third Rock, UCB Biopharma, and UpToDate. MMD received research grants, contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH: is an employee and may hold stock and/or stock options in Sanofi. PSK: has received research/grant support from Sanofi Genzyme and Amicus Therapeutics; has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio); is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies; and has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. JM: is an employee and may hold stock and/or stock options in Sanofi. LP: is an employee and may hold stock and/or stock options in Sanofi. BS: Unrestricted research grants from Amicus, Astellas, Marigold Foundation, AMDA Foundation. Speaker honoraria from Kedrion, Alexion. Scientific advisor for Amicus, Argenx, Astellas, Maze, Pepgen, Sanofi, Spark, and Taysha. No stocks or shares. NT: is an employee and may hold stock and/or stock options in Sanofi. AT: has received honorarium as a scientific board component (Sanofi, Amicus, and Aro) and as a speaker for Sanofi, Spark, and Amicus. NvdB: received speaker honoraria from Sanofi and Amicus Therapeutics, and has served as scientific advisor for Sanofi under agreements with Erasmus MC University Medical Center and the relevant industry. TZ: is an employee and may hold stock and/or stock options in Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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17. Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease.
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Boentert M, Berger KI, Díaz-Manera J, Dimachkie MM, Hamed A, Riou França L, Thibault N, Shukla P, Ishak J, and Caro JJ
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- Humans, Orphan Drug Production, Rare Diseases drug therapy, Treatment Outcome, Enzyme Replacement Therapy methods, alpha-Glucosidases therapeutic use, Glycogen Storage Disease Type II drug therapy
- Abstract
Background: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context., Methods: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded., Results: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018)., Conclusion: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains., (© 2024. The Author(s).)
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- 2024
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18. Post-hoc Nonparametric Analysis of Forced Vital Capacity in the COMET Trial Demonstrates Superiority of Avalglucosidase Alfa vs Alglucosidase Alfa.
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Boentert M, Campana ES, Attarian S, Diaz-Manera J, Dimachkie MM, Periquet M, Thibault N, Miossec P, Zhou T, and Berger KI
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- Humans, alpha-Glucosidases, Vital Capacity, Clinical Trials as Topic, Enzyme Replacement Therapy, Glycogen Storage Disease Type II drug therapy
- Abstract
In the COMET trial of patients with late-onset Pompe disease, greater improvement in upright forced vital capacity (FVC) % predicted was observed with avalglucosidase alfa (AVA) vs alglucosidase alfa (ALGLU) (estimated treatment difference: 2.43%). The pre-specified mixed model repeated measures (MMRM) analysis demonstrated non-inferiority of AVA (P = 0.0074) and narrowly missed superiority (P = 0.063; 95% CI: -0.13-4.99). We report superiority of AVA in two post-hoc analyses that account for an extreme outlier participant with low FVC and severe chronic obstructive pulmonary disease at baseline: MMRM excluding the outlier (P = 0.013) and non-parametric analysis of all data with repeated measures analysis of covariance (P = 0.019).
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- 2024
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19. Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.
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Sulaiman I, Wu BG, Chung M, Isaacs B, Tsay JJ, Holub M, Barnett CR, Kwok B, Kugler MC, Natalini JG, Singh S, Li Y, Schluger R, Carpenito J, Collazo D, Perez L, Kyeremateng Y, Chang M, Campbell CD, Hansbro PM, Oppenheimer BW, Berger KI, Goldring RM, Koralov SB, Weiden MD, Xiao R, D'Armiento J, Clemente JC, Ghedin E, and Segal LN
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- Humans, Animals, Mice, Dysbiosis complications, RNA, Ribosomal, 16S, Inflammation complications, Lung pathology, Pulmonary Disease, Chronic Obstructive genetics, Lung Injury complications
- Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.
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- 2023
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20. Role of small airway dysfunction in unexplained exertional dyspnoea.
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Sharpe AL, Reibman J, Oppenheimer BW, Goldring RM, Liu M, Shao Y, Bohart I, Kwok B, Weinstein T, Addrizzo-Harris D, Sterman DH, and Berger KI
- Abstract
Background: Isolated small airway abnormalities may be demonstrable at rest in patients with normal spirometry; however, the relationship of these abnormalities to exertional symptoms remains uncertain. This study uses an augmented cardiopulmonary exercise test (CPET) to include evaluation of small airway function during and following exercise to unmask abnormalities not evident with standard testing in individuals with dyspnoea and normal spirometry., Methods: Three groups of subjects were studied: 1) World Trade Center (WTC) dust exposure (n=20); 2) Clinical Referral (n=15); and Control (n=13). Baseline evaluation included respiratory oscillometry. Airway function during an incremental workload CPET was assessed by: 1) tidal flow versus volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and 2) post-exercise spirometry and oscillometry to evaluate for airway hyperreactivity., Results: All subjects demonstrated normal baseline forced expiratory volume in 1 s (FEV
1 )/forced vital capacity (FVC). Dyspnoea was reproduced during CPET in WTC and Clinical Referral groups versus Control without abnormality in respiratory pattern and minute ventilation. Tidal flow-volume curves uncovered expiratory flow limitation and/or dynamic hyperinflation with increased prevalence in WTC and Clinical Referral versus Control (55%, 87% versus 15%; p<0.001). Post-exercise oscillometry uncovered small airway hyperreactivity with increased prevalence in WTC and Clinical Referral versus Control (40%, 47% versus 0%, p < 0.05)., Conclusions: We uncovered mechanisms for exertional dyspnoea in subject with normal spirometry that was attributable to either small airway dysfunction during exercise and/or small airway hyperreactivity following exercise. The similarity of findings in WTC environmentally exposed and clinically referred cohorts suggests broad relevance for these evaluations., Competing Interests: Conflict of interest: None of the authors have a conflict of interest to declare., (Copyright ©The authors 2023.)- Published
- 2023
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21. Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial.
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Kishnani PS, Diaz-Manera J, Toscano A, Clemens PR, Ladha S, Berger KI, Kushlaf H, Straub V, Carvalho G, Mozaffar T, Roberts M, Attarian S, Chien YH, Choi YC, Day JW, Erdem-Ozdamar S, Illarioshkin S, Goker-Alpan O, Kostera-Pruszczyk A, van der Ploeg AT, An Haack K, Huynh-Ba O, Tammireddy S, Thibault N, Zhou T, Dimachkie MM, and Schoser B
- Subjects
- Male, Humans, Middle Aged, Aged, Female, Quality of Life, Treatment Outcome, Vital Capacity, Double-Blind Method, Glycogen Storage Disease Type II drug therapy
- Abstract
Importance: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa., Objective: To report avalglucosidase alfa treatment outcomes during the COMET trial extension., Design, Setting, and Participants: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021., Interventions: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week., Main Outcomes and Measures: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed., Results: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched., Conclusions and Relevance: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed., Trial Registration: ClinicalTrials.gov Identifier: NCT02782741.
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- 2023
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22. Novel approach to studying effects of inhalational exposure on lung function in civilians exposed to the World Trade Center disaster.
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Wang Y, Berger KI, Zhang Y, Shao Y, Goldring RM, Reibman J, and Liu M
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- Humans, Inhalation Exposure, Lung, Forced Expiratory Volume, September 11 Terrorist Attacks, Disasters
- Abstract
It is increasingly important to study the impact of environmental inhalation exposures on human health in natural or man-made disasters in civilian populations. The members of the World Trade Center Environmental Health Center (WTC EHC; WTC Survivors) had complex exposures to environmental disaster from the destruction of WTC towers and can serve to reveal the effects of WTC exposure on the entire spectrum of lung functions. We aimed to investigate the associations between complex WTC exposures and measures of spirometry and oscillometry in WTC Survivors and included 3605 patients enrolled between Oct 1, 2009 and Mar 31, 2018. We performed latent class analysis and identified five latent exposure groups. We applied linear and quantile regressions to estimate the exposure effects on the means and various quantiles of pre-bronchodilator (BD) % predicted forced expiratory volume in one second (FEV
1 ), forced vital capacity (FVC) and FEV1 /FVC ratio, as well as the resistance at an oscillating frequency of 5 Hz (R5 ), frequency dependence of resistance R5-20 , and reactance area (AX). Compared with Group 5, which had low or unknown exposure and was treated as the reference group, Group 1, the local workers with both acute and chronic exposures, had a lower median of % predicted FVC (-3.6; 95% CI: -5.4, -1.7) and higher (more abnormal) measures of AX at 10th quantile (0.77 cmH2 O L-1 s; 95% CI: 0.41, 1.13) and 25th quantile (0.80 cmH2 O L-1 s; 95% CI: 0.41, 1.20). Results suggested heterogeneous exposures to the WTC disaster had differential effects on the distributions of lung functions in the WTC Survivors. These findings could provide insights for future investigation of environmental disaster exposures., (© 2023. The Author(s).)- Published
- 2023
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23. Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.
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Morris AH, Horvat C, Stagg B, Grainger DW, Lanspa M, Orme J, Clemmer TP, Weaver LK, Thomas FO, Grissom CK, Hirshberg E, East TD, Wallace CJ, Young MP, Sittig DF, Suchyta M, Pearl JE, Pesenti A, Bombino M, Beck E, Sward KA, Weir C, Phansalkar S, Bernard GR, Thompson BT, Brower R, Truwit J, Steingrub J, Hiten RD, Willson DF, Zimmerman JJ, Nadkarni V, Randolph AG, Curley MAQ, Newth CJL, Lacroix J, Agus MSD, Lee KH, deBoisblanc BP, Moore FA, Evans RS, Sorenson DK, Wong A, Boland MV, Dere WH, Crandall A, Facelli J, Huff SM, Haug PJ, Pielmeier U, Rees SE, Karbing DS, Andreassen S, Fan E, Goldring RM, Berger KI, Oppenheimer BW, Ely EW, Pickering BW, Schoenfeld DA, Tocino I, Gonnering RS, Pronovost PJ, Savitz LA, Dreyfuss D, Slutsky AS, Crapo JD, Pinsky MR, James B, and Berwick DM
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- Delivery of Health Care, Computers, Decision Support Systems, Clinical
- Abstract
How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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24. Molecular Clustering Analysis of Blood Biomarkers in World Trade Center Exposed Community Members with Persistent Lower Respiratory Symptoms.
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Grunig G, Durmus N, Zhang Y, Lu Y, Pehlivan S, Wang Y, Doo K, Cotrina-Vidal ML, Goldring R, Berger KI, Liu M, Shao Y, and Reibman J
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- Biomarkers, Cluster Analysis, Dust, Humans, New York City, Receptor for Advanced Glycation End Products, September 11 Terrorist Attacks
- Abstract
The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS ( n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.
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- 2022
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25. COPD in Smoking and Non-Smoking Community Members Exposed to the World Trade Center Dust and Fumes.
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Baba RY, Zhang Y, Shao Y, Berger KI, Goldring RM, Liu M, Kazeros A, Rosen R, and Reibman J
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- Dust, Forced Expiratory Volume, Gases, Humans, Respiratory Function Tests, Spirometry, Pulmonary Disease, Chronic Obstructive epidemiology, Pulmonary Disease, Chronic Obstructive etiology, September 11 Terrorist Attacks
- Abstract
Background: The characteristics of community members exposed to World Trade Center (WTC) dust and fumes with Chronic Obstructive Pulmonary Disease (COPD) can provide insight into mechanisms of airflow obstruction in response to an environmental insult, with potential implications for interventions. Methods: We performed a baseline assessment of respiratory symptoms, spirometry, small airway lung function measures using respiratory impulse oscillometry (IOS), and blood biomarkers. COPD was defined by the 2019 GOLD criteria for COPD. Patients in the WTC Environmental Health Center with <5 or ≥5 pack year smoking history were classified as nonsmoker-COPD (ns-COPD) or smoker-COPD (sm-COPD), respectively. Main Results: Between August 2005 and March 2018, 467 of the 3430 evaluated patients (13.6%) fit criteria for COPD. Among patients with COPD, 248 (53.1%) were ns-COPD. Patients with ns-COPD had measures of large airway function (FEV1) and small airway measures (R5−20, AX) that were less abnormal than those with sm-COPD. More ns-COPD compared to sm-COPD had a bronchodilator (BD) response measured by spirometry (24 vs. 14%, p = 0.008) or by IOS (36 vs. 21%, p = 0.002). Blood eosinophils did not differ between ns-COPD and sm-COPD, but blood neutrophils were higher in sm-COPD compared to ns-COPD (p < 0.001). Those with sm-COPD were more likely to be WTC local residents than ns-COPD (p = 0.007). Conclusions: Spirometry findings and small airway measures, as well as inflammatory markers, differed between patients with ns-COPD and sm-COPD. These findings suggest potential for differing mechanisms of airway injury in patients with WTC environmental exposures and have potential therapeutic implications.
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- 2022
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26. Clinical significance and applications of oscillometry.
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Kaminsky DA, Simpson SJ, Berger KI, Calverley P, de Melo PL, Dandurand R, Dellacà RL, Farah CS, Farré R, Hall GL, Ioan I, Irvin CG, Kaczka DW, King GG, Kurosawa H, Lombardi E, Maksym GN, Marchal F, Oostveen E, Oppenheimer BW, Robinson PD, van den Berge M, and Thamrin C
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- Humans, Oscillometry, Respiratory Function Tests, Spirometry, Airway Resistance, Asthma
- Abstract
Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease., Competing Interests: Conflict of interest: D.A. Kaminsky reports personal payments made as faculty speaker for Cardiorespiratory Diagnostics Seminar from MGC Diagnostics, Inc. outside the submitted work. Past Chair of ATS Proficiency Standards for Pulmonary Function Laboratories Committee, unpaid. Conflict of interest: S.J. Simpson has nothing to disclose. Conflict of interest: K.I. Berger has nothing to disclose. Conflict of interest: P. Calverley reports receiving consulting fees paid by Phillips Respironics for advisory work on a novel COPD ventilator. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from Phillips Respironics, outside the submitted work. Conflict of interest: P.L. de Melo reports patent 28727 issued. Conflict of interest: R.J. Dandurand reports grants or contracts paid to the institution from AstraZeneca, Boehringer-Ingelheim, Covis Pharma, Grifols, MGC Diagnostics, Teva Pharma, Thorasys, and Vyaire, outside the submitted work. Speaking payment from Novartis for L'oscillométrie en clinique: qu'ajoute-t-elle aux évaluations pulmonaires?, 18 September 2019, Boehringer-Ingelheim for L'oscillométrie: vieille physiologie avec un avenir brilliant, 17 November 2020, and Latin American Respiratory Physiology Society for Oscillometry in Asthma and COPD: Interpretation Strategies, 14 November 2020, outside the submitted work. Chairman, Oscillometry Harmonisation Study Group, an international committee academic and industry experts working to standardise oscillometry devices, and Chairman, Respiratory Effectiveness Group Technologies Working Group, Cambridge, U.K. (https://www.regresearchnetwork.org). Conflict of interest: R.L. Dellacà reports royalties or licenses from Restech, Philips and Vyaire. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from Restech and Philips, outside the submitted work. Support for attending meetings from Philips and Vyaire. Patent issued, owned and licensed from Politecnico di Milano University. Member of the Board of Directors for Restech. Stocks owned for Restech. Free loan of equipment for studies received from Vyaire and Restech. Conflict of interest: C.S. Farah has nothing to disclose. Conflict of interest: R. Farré has nothing to disclose. Conflict of interest: G.L. Hall has nothing to disclose. Conflict of interest: I. Ioan has nothing to disclose. Conflict of interest: C.G. Irvin received consulting fees from Medical Graphics Corporation, outside the submitted work. Conflict of interest: D.W. Kaczka reports support for the present manuscript from University of Iowa. Grants or contracts from Dept of Defence and NIH, outside the submitted work. Consulting fees received from ZOLL Medical, Inc. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from CHEST, ASME, Medical Society of New Zealand, and Johns Hopkins University, outside the submitted work. US patent 10,675,423 B2 (patent on MFOV technique, inventor) and PCT patent pending, patent on MFOV technique pending. Stock or stock options held for OscillaVent, Inc. Loan of ventilator for other projects from ZOLL Medical Inc. Conflict of interest: G.G. King reports grants or contracts from Restech Italy, NHMRC, Boehringer Ingelheim, CycloPharm, GlaxoSmithKline, Menarini, MundiPharma, Philanthropic individuals and societies, outside the submitted work. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CycloPharm, GlaxoSmithKline, Menarini, MundiPharma and Novartis, outside the submitted work. Leadership or fiduciary role in other board, society, committee or advocacy group for ERS Technical Standards for Respiratory Oscillometry. Conflict of interest: H. Kurosawa reports receiving a grant from CHEST Co. Ltd. Royalties or licence for CHEST Co. Ltd. Payment or honoraria for lectures received from CHEST Co. Ltd. Nippon, Boehringer Ingelheim, Novartis, and Teijin Pharma, outside the submitted work. Conflict of interest: E. Lombardi reports grants or contracts from Restech and Sanofi, outside the submitted work. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events received from Angelini, Chiesi, GSK, Novartis and Sanofi, outside the submitted work. Participation on a Data Safety Monitoring Board or Advisory Board for GSK and Novartis. Conflict of interest: G.N. Maksym reports grants or contracts from National Research Council of Canada, Cyclomedica Inc. Australia, and Lung Association of Nova Scotia, outside the submitted work. Accommodation Expenses received from Thorasys, Thoracic Medical Systems Inc. for attending European Society Meeting 2019. Patents planned, issued or pending for Method and system to acquire oscillometry measurements, owned by Thorasys, Thoracic Medical Systems Inc. Stock or stock options held for Thorasys, Thoracic Medical Systems Inc. Conflict of interest: F. Marchal has nothing to disclose. Conflict of interest: E. Oostveen has nothing to disclose. Conflict of interest: B.W. Oppenheimer has nothing to disclose. Conflict of interest: P.D. Robinson has nothing to disclose. Conflict of interest: M. van den Berge reports grants or contracts from GlaxoSmithKline, Novartis, Astra Zeneca, Roche, and Genentech, outside the submitted work. Conflict of interest: C. Thamrin report grants or contracts from Restech SRL and THORASYS Thoracic. Equipment on loan for research studies from Restech SRL and THORASYS Thoracic, outside the submitted work., (Copyright ©The authors 2022.)
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- 2022
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27. Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy.
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Korb M, Peck A, Alfano LN, Berger KI, James MK, Ghoshal N, Healzer E, Henchcliffe C, Khan S, Mammen PPA, Patel S, Pfeffer G, Ralston SH, Roy B, Seeley WW, Swenson A, Mozaffar T, Weihl C, and Kimonis V
- Subjects
- Cell Cycle Proteins genetics, Humans, Mutation, Standard of Care, Valosin Containing Protein genetics, Amyotrophic Lateral Sclerosis genetics, Myositis, Inclusion Body, Osteitis Deformans genetics
- Abstract
Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally., (© 2022. The Author(s).)
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- 2022
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28. Electronic cigarettes as a harm reduction strategy among patients with COPD: protocol for an open-label two arm randomized controlled pilot trial.
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Stevens ER, Lei L, Cleland CM, Vojjala M, El-Shahawy O, Berger KI, Kirchner TR, and Sherman SE
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- Harm Reduction, Humans, Pilot Projects, Randomized Controlled Trials as Topic, Tobacco Use Cessation Devices, Electronic Nicotine Delivery Systems, Pulmonary Disease, Chronic Obstructive therapy, Smoking Cessation
- Abstract
Background: Smoking cessation is the most effective means of slowing the decline of lung function associated with chronic obstructive pulmonary disease (COPD). While effective smoking cessation treatments are available, they are underutilized and nearly half of people with COPD continue to smoke. By addressing both nicotine and behavioral dependence, electronic cigarettes (EC) could help people with COPD reduce the harm of combustible cigarettes (CC) through reductions in number of Cigarettes per Day (CPD) or quitting CC completely. The purpose of this pilot study is to identify barriers and facilitators to the use of and assess the preliminary effectiveness of EC as a harm reduction strategy among people with COPD., Methods: In an open-label two-arm randomized controlled trial pilot study, 60 patients identified as smokers with a COPD diagnosis via electronic health records from a large urban health center are randomized in a 1:1 ratio to either standard care [counseling + nicotine replacement therapy (NRT)] or counseling + EC. The NRT arm will receive nicotine patches and nicotine lozenges for 12 weeks. The EC arm will receive EC for 12 weeks. Both cohorts will receive counseling from a licensed mental health counselor. Using ecological momentary assessment, participants will report their use of CC in both arms and EC use in the EC arm daily via text message. Primary outcomes will be feasibility and acceptability of intervention, and secondary outcomes will be reduction in CPD and change in COPD symptoms as measured by COPD Assessment Tool (CAT) score at 12-weeks. EC displacement of CC. To explore attitudes towards the use of EC as a harm-reduction strategy for patients with COPD, interviews will be performed with a sample of participants from both study arms., Discussion: Despite decades of availability of smoking cessation medications, nearly half of people with COPD still smoke. This study aims to address the unmet need for feasible and effective strategies for reducing CC use among those with COPD, which has the potential to significantly improve the health of people with COPD who smoke. Trial Registration ClinicalTrials.gov Identifier: NCT04465318., (© 2021. The Author(s).)
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- 2022
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29. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial.
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Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, Toscano A, van der Ploeg AT, Berger KI, Clemens PR, Chien YH, Day JW, Illarioshkin S, Roberts M, Attarian S, Borges JL, Bouhour F, Choi YC, Erdem-Ozdamar S, Goker-Alpan O, Kostera-Pruszczyk A, Haack KA, Hug C, Huynh-Ba O, Johnson J, Thibault N, Zhou T, Dimachkie MM, and Schoser B
- Subjects
- Child, Preschool, Double-Blind Method, Enzyme Replacement Therapy adverse effects, Enzyme Replacement Therapy methods, Humans, Treatment Outcome, Walking, Glycogen Storage Disease Type II drug therapy, alpha-Glucosidases adverse effects
- Abstract
Background: Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease., Methods: We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49-week primary analysis period., Findings: Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI -0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%])., Interpretation: We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease., Funding: Sanofi Genzyme., Competing Interests: Declaration of interests SA received reimbursement for attending symposia and other expenses. KB has served on advisory boards for Sanofi Genzyme, AskBio, Spark Therapeutics, and Takeda; and received consultant fees from Sanofi Genzyme, Amicus Therapeutics, AskBio, Spark Therapeutics, Takeda and Valerion. Y-HC has received research support, consulting fees, reimbursement for attending symposium and other expenses, and fees for non-continuing medical education or continuing education services from Sanofi Genzyme. PRC has served as a member of the Pompe Registry North American Advisory Board and undertaken contracted research for Amicus, Sanofi Genzyme, Spark, ReveraGen Biopharma, and NS Pharma. She has been a consultant for Roche and Epirium. She has received travel funding from Roche, Spark, and NS Pharma. JWD has received consulting fees from Audentes, Biogen;, Ionis Pharmaceuticals, Cytokinetics, Pfizer, AveXis, Roche/Genentech Pharmaceuticals, AMO Pharmaceuticals, and Sarepta Therapeutics; and has undertaken contracted research for Biogen, Ionis Pharmaceuticals, Cytokinetics, Roche Pharmaceuticals, AveXis, Sanofi- Genzyme, Sarepta Therapeutics, and Scholar Rock. JD-M has served as a consultant or speaker for Sanofi Genzyme, Lupin, Sarepta, and PTC Therapeutics; and received research support from Boehringer Ingelheim and Sanofi Genzyme. MMD has served as a consultant forArgenX, Catalyst, Cello, CSL Behring, EcoR1, Kezar, Momenta, NuFactor, Octapharma, RaPharma/UCB, RMS Medical, Sanofi Genzyme, Shire Takeda, Spark Therapeutics, and UCB Biopharma; and has received grants from Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL Behring, US Food and Drug Administration/Office of Orphan Products Development, Genentech, GlaxoSmithKline, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, US National Institutes of Health (NIH), Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma, Viromed/Healixmith, and TMA. SE-O has served on advisory boards for Sanofi Genzyme. OG-A has served on advisory boards for Amicus, BioMarin, Sanofi, and Takeda; served on speaker's bureau for Sanofi and Takeda; received consulting fees from Amicus, BioMarin, Sanofi Genzyme, Shire Human Genetics Therapies, and Takeda; and undertaken contracted research for Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, and Takeda. SI has received honoraria from Actelion, Boehringher Ingelheim, Ever Pharma, Merz Pharma, Servier, Takeda, and Teva. PSK has served on advisory boards for Amicus, Baebies, and Sanofi Genzyme; received consulting fees from Amicus, AskBio, Sanofi Genzyme, and Vertex; undertaken contracted research for Amicus, Sanofi Genzyme, and Valerion; received honoraria from Amicus, AskBio, Sanofi Genzyme, and Vertex; received travel expenses from Amicus and Sanofi Genzyme; and has ownership interests in AskBio and Baebies. HK has served on advisory boards for Alexion, Catalyst Pharmaceuticals, PTC therapeutics, and Sanofi Genzyme; and is on the speaker's bureau of Akcea, Catalyst Pharmaceuticals, and Sanofi Genzyme. SL has served on advisory boards and speaker's bureau, received consulting fees, and undertaken contracted research for Sanofi Genzyme. TM has served on advisory boards for Amicus, Biomarin, Idera, Novartis, Sanofi Genzyme, Ultragenyx, and received travel subsidies and honoraria for related activities; has served as a consultant to NuFactor, Sarepta Therapeutics, and Walgreens, and received travel subsidies and honoraria; served on the speaker's bureau for Sanofi Genzyme and Grifols and received travel subsidies and honoraria for these; and received research funding from Alexion, Alnylam, Amicus, Baxter, Bio-Blast, Biogen, Biomarin, CSL Behring, Sanofi Genzyme, Grifols, GlaxoSmithKline, Idera, ISIS Pharmaceuticals, NIH, Novartis, and Ultragenyx. MR has received research support from Amicus; received consulting fees, honoraria, and travel reimbursement from Sanofi Genzyme, BioMarin, and Amicus; has received royalties from NIH; is a member of a speaker's bureau for NIH; and is a member of the Pompe Registry Scientific Advisory Board. BS has served within the last 3 years on advisory boards for Amicus Therapeutics, Audentes Therapeutics, Dyne, Lupin, Nexien, Sanofi Genzyme, Spark, and UCB; undertaken contracted research for Amicus, Greenovation Biopharm, and Sanofi Genzyme; received honoraria from Alexion and Kedrion; and travel expenses from Kedrion and Sanofi Genzyme. VS has received consulting fees from AveXis, Exonics Therapeutic, Roche, Sanofi Genzyme, and Sarepta Therapeutics; received honoraria from Sanofi Genzyme; and undertaken contracted research from Sanofi Genzyme and Ultragenyx. AT has received reimbursement for participation either as a speaker for lectures and symposia or as a Pompe Registry board member from Sanofi Genzyme. ATvdP provided consulting services, participated in advisory board meetings, and received grants for pre-marketing studies and research from industries (eg, Sanofi Genzyme, Biomarin, and Amicus, etc) via agreements between Erasmus MC and the industries. KAH and her spouse, CH, OH-B, JJ, NT, and TZ are employees of Sanofi Genzyme. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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30. Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions.
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Morris AH, Stagg B, Lanspa M, Orme J, Clemmer TP, Weaver LK, Thomas F, Grissom CK, Hirshberg E, East TD, Wallace CJ, Young MP, Sittig DF, Pesenti A, Bombino M, Beck E, Sward KA, Weir C, Phansalkar SS, Bernard GR, Taylor Thompson B, Brower R, Truwit JD, Steingrub J, Duncan Hite R, Willson DF, Zimmerman JJ, Nadkarni VM, Randolph A, Curley MAQ, Newth CJL, Lacroix J, Agus MSD, Lee KH, deBoisblanc BP, Scott Evans R, Sorenson DK, Wong A, Boland MV, Grainger DW, Dere WH, Crandall AS, Facelli JC, Huff SM, Haug PJ, Pielmeier U, Rees SE, Karbing DS, Andreassen S, Fan E, Goldring RM, Berger KI, Oppenheimer BW, Wesley Ely E, Gajic O, Pickering B, Schoenfeld DA, Tocino I, Gonnering RS, Pronovost PJ, Savitz LA, Dreyfuss D, Slutsky AS, Crapo JD, Angus D, Pinsky MR, James B, and Berwick D
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- Clinical Decision-Making, Computers, Documentation, Electronic Health Records, Humans, Learning Health System
- Abstract
Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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31. Validation of a Novel Compact System for the Measurement of Lung Volumes.
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Berger KI, Adam O, Dal Negro RW, Kaminsky DA, Shiner RJ, Burgos F, de Jongh FHC, Cohen I, and Fredberg JJ
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- Adult, Aged, Europe, Female, Healthy Volunteers, Humans, Male, Middle Aged, United States, Lung Volume Measurements methods, Plethysmography methods, Total Lung Capacity physiology
- Abstract
Background: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented., Research Question: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography?, Study Design and Methods: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLC
Pleth ) was compared with TLC measured by the MiniBox (TLCMB )., Results: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLCPleth and TLCMB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers., Interpretation: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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32. Respiratory impedance measured using impulse oscillometry in a healthy urban population.
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Berger KI, Wohlleber M, Goldring RM, Reibman J, Farfel MR, Friedman SM, Oppenheimer BW, Stellman SD, Cone JE, and Shao Y
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This study derives normative prediction equations for respiratory impedance in a healthy asymptomatic urban population using an impulse oscillation system (IOS). In addition, this study uses body mass index (BMI) in the equations to describe the effect of obesity on respiratory impedance. Data from an urban population comprising 472 healthy asymptomatic subjects that resided or worked in lower Manhattan, New York City were retrospectively analysed. This population was the control group from a previously completed case-control study of the health effects of exposure to World Trade Center dust. Since all subjects underwent spirometry and oscillometry, these previously collected data allowed a unique opportunity to derive normative prediction equations for oscillometry in an urban, lifetime non-smoking, asymptomatic population without underlying respiratory disease. Normative prediction equations for men and women were successfully developed for a broad range of respiratory oscillometry variables with narrow confidence bands. Models that used BMI as an independent predictor of oscillometry variables (in addition to age and height) demonstrated equivalent or better fit when compared with models that used weight. With increasing BMI, resistance and reactance increased compatible with lung and airway compression from mass loading. This study represents the largest cohort of healthy urban subjects assessed with an IOS device. Normative prediction equations were derived that should facilitate application of IOS in the clinical setting. In addition, the data suggest that modelling of lung function may be best performed using height and BMI as independent variables rather than the traditional approach of using height and weight., Competing Interests: Conflict of interest: K.I. Berger reports grants from CDC/NIOSH during the conduct of the study. Conflict of interest: M. Wohlleber has nothing to disclose. Conflict of interest: R.M. Goldring has nothing to disclose. Conflict of interest: J. Reibman has received funding as a consultant for AstraZeneca, Genentech and Novartis. She has also been a recipient of grant and contract funding from the Centers of Disease Control/NIOSH. Conflict of interest: M.R. Farfel has nothing to disclose. Conflict of interest: S.M. Friedman reports grants from CDC/NIOSH during the conduct of the study. Conflict of interest: B.W. Oppenheimer has nothing to disclose. Conflict of interest: S.D. Stellman has nothing to disclose. Conflict of interest: J.E. Cone reports grants from NIOSH CDC during the conduct of the study. Conflict of interest: Y. Shao reports grants from the National Institute of Occupational Safety and Health, and the National Institute of Environmental Health Science, during the conduct of the study., (Copyright ©ERS 2021.)
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- 2021
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33. Airway Disease Presenting as Restrictive Impairment.
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Miller A, Goldring RM, and Berger KI
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- Humans, Respiratory System, Tomography, Vital Capacity, Asthma, Respiration Disorders
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- 2020
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34. Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start.
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Stockton DW, Kishnani P, van der Ploeg A, Llerena J Jr, Boentert M, Roberts M, Byrne BJ, Araujo R, Maruti SS, Thibault N, Verhulst K, and Berger KI
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- Adolescent, Child, Female, Humans, Male, Prognosis, Respiration, Treatment Outcome, Young Adult, alpha-Glucosidases therapeutic use, Enzyme Replacement Therapy, Glycogen Storage Disease Type II diagnosis, Glycogen Storage Disease Type II drug therapy
- Abstract
Objective: To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation., Methods: Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models., Results: Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3-126.0). FVC remained stable during the 5-year follow-up (slope = - 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years., Conclusion: FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.
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- 2020
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35. Increased Dead Space Ventilation and Refractory Hypercapnia in Patients With Coronavirus Disease 2019: A Potential Marker of Thrombosis in the Pulmonary Vasculature.
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Oppenheimer BW, Bakker J, Goldring RM, Teter K, Green DL, and Berger KI
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Objectives: Mortality rates in intubated coronavirus disease 2019 patients remain markedly elevated. Some patients develop sudden refractory hypercapnia and hypoxemia not explained by worsening pulmonary parenchymal disease. This case series highlights clinical findings and management of coronavirus disease 2019 patients with refractory hypercapnia despite maximal/optimal ventilatory support. Hypercapnia could not be explained by worsening lung disease or other common factors, and thus, a pulmonary vascular etiology was suggested. The pillars of management were targeted to improve pulmonary vascular patency via aggressive anticoagulation and support right ventricular function., Data Sources: Four consecutive patients with confirmed coronavirus disease 2019 infection with sudden hypercapnia and hypoxemia were included., Data Synthesis: There was sequential development of: 1) severe hypercapnia attributable to marked elevation of dead space without radiographic changes; 2) concomitant coagulopathy manifest by an increase in d-dimer levels; 3) progressive shunt with consequent hypoxemia; and 4) right ventricular dysfunction. Management included extracorporeal Co
2 removal, direct thrombin inhibition, pulmonary vasodilators, and inotropic support. Marked improvement in Pao2 allowed reduction in Fio2 in all patients, extracorporeal Co2 removal was discontinued in three patients over the ensuing 3 weeks, and one patient was discharged home., Conclusions: We speculate that thromboinflammation with pulmonary microvasculature occlusion leads to a sudden increase in dead space and shunt resulting in severe hypercapnia and hypoxemia in coronavirus disease 2019 patients. Early identification of these physiologic and clinical biomarkers could trigger the institution of therapies aiming to reverse the hypercoagulable state and support right ventricular function., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)- Published
- 2020
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36. Characterization of Persistent Uncontrolled Asthma Symptoms in Community Members Exposed to World Trade Center Dust and Fumes.
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Reibman J, Caplan-Shaw C, Wu Y, Liu M, Amin MR, Berger KI, Cotrina-Vidal ML, Kazeros A, Durmus N, Fernandez-Beros ME, Goldring RM, Rosen R, and Shao Y
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- Dust, Female, Gases, Humans, Male, Middle Aged, New York City epidemiology, Asthma drug therapy, Asthma epidemiology, Lung Diseases, September 11 Terrorist Attacks
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The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.
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- 2020
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37. Small airway function in obese individuals with self-reported asthma.
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Oppenheimer BW, Goldring RM, Soghier I, Smith D, Parikh M, and Berger KI
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Diagnosis of asthma in obese individuals frequently relies on clinical history, as airflow by spirometry may remain normal. This study hypothesised that obese subjects with self-reported asthma and normal spirometry will demonstrate distinct clinical characteristics, metabolic comorbidities and enhanced small airway dysfunction as compared with healthy obese subjects. Spirometry, plethysmography and oscillometry data pre/post-bronchodilator were obtained in 357 obese subjects in three groups as follows: no asthma group (n=180), self-reported asthma normal spirometry group (n=126), and asthma obstructed spirometry group (n=51). To assess the effects of obesity related to reduced lung volume, oscillometry measurements were repeated during a voluntary inflation to predicted functional residual capacity (FRC). Dyspnoea was equally prevalent in all groups. In contrast, cough, wheeze and metabolic comorbidities were more frequent in the asthma normal spirometry and asthma obstructed spirometry groups versus the no asthma group (p<0.05). Despite similar body size, oscillometry measurements demonstrated elevated R
5-20 (difference between resistance at 5 and 20 Hz) in the no asthma and asthma normal spirometry groups (0.19±0.12; 0.23±0.13 kPa/(L·s-1 ), p<0.05) but to a lesser degree than the asthma obstructed spirometry group (0.34±0.20 kPa/(L·s-1 ), p<0.05). Differences between groups persisted post-bronchodilator (p<0.05). Following voluntary inflation to predicted FRC, R5-20 in the no asthma and asthma normal spirometry groups fell to similar values, indicating a reversible process (0.11±0.07; 0.12±0.08 kPa/(L·s-1 ), p=NS). Persistently elevated R5-20 was seen in the asthma obstructed spirometry group, suggesting chronic inflammation and/or remodelling (0.17±0.11 kPa/(L·s-1 ), p<0.05). Thus, small airway abnormalities of greater magnitude than observations in healthy obese people may be an early marker of asthma in obese subjects with self-reported disease despite normal airflow. Increased metabolic comorbidities in these subjects may have provided a milieu that impacted airway function., Competing Interests: Conflict of interest: B.W. Oppenheimer has nothing to disclose. Conflict of interest: R.M. Goldring has nothing to disclose. Conflict of interest: I. Soghier has nothing to disclose. Conflict of interest: D. Smith has nothing to disclose. Conflict of interest: M. Parikh has nothing to disclose. Conflict of interest: K.I. Berger has nothing to disclose., (Copyright ©ERS 2020.)- Published
- 2020
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38. Technical standards for respiratory oscillometry.
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King GG, Bates J, Berger KI, Calverley P, de Melo PL, Dellacà RL, Farré R, Hall GL, Ioan I, Irvin CG, Kaczka DW, Kaminsky DA, Kurosawa H, Lombardi E, Maksym GN, Marchal F, Oppenheimer BW, Simpson SJ, Thamrin C, van den Berge M, and Oostveen E
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- Adult, Bronchial Provocation Tests, Bronchodilator Agents, Child, Humans, Oscillometry, Lung, Respiration
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Oscillometry (also known as the forced oscillation technique) measures the mechanical properties of the respiratory system (upper and intrathoracic airways, lung tissue and chest wall) during quiet tidal breathing, by the application of an oscillating pressure signal (input or forcing signal), most commonly at the mouth. With increased clinical and research use, it is critical that all technical details of the hardware design, signal processing and analyses, and testing protocols are transparent and clearly reported to allow standardisation, comparison and replication of clinical and research studies. Because of this need, an update of the 2003 European Respiratory Society (ERS) technical standards document was produced by an ERS task force of experts who are active in clinical oscillometry research.The aim of the task force was to provide technical recommendations regarding oscillometry measurement including hardware, software, testing protocols and quality control.The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of "within-breath" analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols ( e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children., Competing Interests: Conflict of interest: G.G. King reports grants from American Thoracic Society and European Respiratory Society, during the conduct of the study; a collaborative research agreement and IP agreement with Restech, grants and personal fees for lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini, MundiPharma and Cyclomedica, grants from NH&MRC, Philanthropic Societies, Sydney University, outside the submitted work. Conflict of interest: J. Bates is a minor shareholder and received personal fees for advisory board work from Oscillavent, LLC, outside the submitted work; and has a patent (patent application US 20160007882 A1; proposes the use of oscillometry in ventilated patients) pending to none, and a patent PCT application WO2015127377 A1 (proposes variable tidal volume ventilation as a means of performing oscillometry in ventilated patients) pending to none. Conflict of interest: K.I. Berger has nothing to disclose. Conflict of interest: P. Calverley has advised Philips Respironics about the clinical application of FOT and spoken on this topic at meetings supported by this company. Conflict of interest: P.L. de Melo has a patent 28727 issued. Conflict of interest: R.L. Dellacà has a patent on the detection of EFL by FOT with royalties paid to Philips Respironics and Restech srl, a patent on monitoring lung volume recruitment by FOT with royalties paid to Vyaire, and a patent on early detection of exacerbations by home monitoring of FOT with royalties paid to Restech, and is co-founder and shareholder of Restech srl, a spin-off company of the Politecnico di Milano University producing medical devices for lung function testing based on FOT. Conflict of interest: R. Farré reports contracts for bench assessment of CPAP devices from Resmed and ANTADIR, outside the submitted work. Conflict of interest: G.L. Hall reports grants from American Thoracic Society and European Respiratory Society, during the conduct of the study. Conflict of interest: I. Ioan has nothing to disclose. Conflict of interest: C.G. Irvin reports other for advisory board work from Methapharm, personal fees and non-financial support for advisory board work from Medical Graphics Corp, grants from NIH and American Lung Association, outside the submitted work. Conflict of interest: D.W. Kaczka reports grants from US Department of Defense (W81XWH-16-1-0434) and National Institutes of Health (R01-HL112986, R01-HL126838 and R41-HL140640), and is co-founder and shareholder from OscillaVent, Inc., during the conduct of the study; grants from ZOLL Medical Corporation, and is shareholder and member of an advisory board for Monitor Mask, Inc., outside the submitted work; and has a patent Systems and methods for multi-frequency oscillator ventilation pending to OscillaVent, Inc. (US20160339191A1), a patent Treatment of respiratory condition using targeted delivery pending (US20150290418A1), a patent System and method for setting positive end expiratory pressure during mechanical ventilation based on dynamic lung function (US20070240717A1, abandoned), a patent Enhanced ventilation waveform device issued (US 6,435,182 B1), and a patent Servo-controlled pneumatic pressure oscillator for respiratory impedance measurements and high-frequency ventilation (US20070006924A1, abandoned). Conflict of interest: D.A. Kaminsky reports personal fees for lectures from MGC Diagnostics, Inc., outside the submitted work. Conflict of interest: H. Kurosawa reports grants and personal fees from Chest M.I. Inc., during the conduct of the study; personal fees from Nippon Boehringer Ingelheim Co. Ltd, outside the submitted work; and has a patent US2012101400 with royalties paid to Tohoku University. Conflict of interest: E. Lombardi reports personal fees from Angelini, Boehringer, GSK, Omron and Vifor, grants and personal fees from Chiesi, Lusofarmaco and Novartis, grants and non-financial support from ResTech, personal fees and non-financial support from Vertex, outside the submitted work. Conflict of interest: G.N. Maksym reports financial support from Thorasys, Thoracic Medical Systems Inc, prior to the submitted work and non-financial support from Thorasys during the submitted work; and has a patent Respiratory Device (design patent) issued to Thorasys, a patent Respiratory Device filter issued to Thorasys, a patent Piezoelectric beam bending actuated Device for measuring respiratory system impedance issued to Thorasys, and a patent Method of assessment of airway variability in airway hyperresponsiveness issued to Thorasys. Conflict of interest: F. Marchal has nothing to disclose. Conflict of interest: B.W. Oppenheimer has nothing to disclose. Conflict of interest: S.J. Simpson has nothing to disclose. Conflict of interest: C. Thamrin has a patent WO 2006130922 A1 issued which is broadly relevant to the work, and has intellectual property arrangements with Thorasys Medical Systems and Restech srl relating to research collaborations, but does not have any financial relationships with either company. Conflict of interest: M. van den Berge reports grants paid to the university from AstraZeneca, TEVA, GSK and Chiesi, outside the submitted work. Conflict of interest: E. Oostveen has nothing to disclose., (Copyright ©ERS 2020.)
- Published
- 2020
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39. Forced vital capacity and cross-domain late-onset Pompe disease outcomes: an individual patient-level data meta-analysis.
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Berger KI, Kanters S, Jansen JP, Stewart A, Sparks S, Haack KA, Bolzani A, Siliman G, and Hamed A
- Subjects
- Age of Onset, Cross-Sectional Studies, Glycogen Storage Disease Type II epidemiology, Humans, Treatment Outcome, Glycogen Storage Disease Type II diagnosis, Glycogen Storage Disease Type II physiopathology, Vital Capacity physiology
- Abstract
Background: Late-onset Pompe disease (LOPD) is a rare, metabolic disease primarily affecting the musculoskeletal and respiratory systems. Forced vital capacity (FVC) is commonly used to measure pulmonary function; however, associations between FVC and other LOPD outcomes remain unclear., Methods: A systematic literature review was conducted on November 2015, updated September 2016 and supplemented with clinical trial data from the sponsor. Outcomes included: 6-min walk test distance (6MWT), FVC, maximal inspiratory/expiratory pressure (MIP/MEP), Medical Research Council-skeletal muscle strength score (MRC), 36-item short-form survey-physical component score (SF-36), Rotterdam Handicap Scale (RHS), Fatigue Severity Scale (FSS) and survival. Individual patient data meta-analysis was used for cross-sectional analyses and longitudinal analyses to determine associations between percent of predicted FVC and LOPD measures and outcomes., Results: Fifteen studies were selected. From cross-sectional analyses, FVC and MRC were most strongly associated. Specifically, patients with 10% higher FVC (a round number for illustrative purposes only) were associated with a 4.72% (95% confidence interval [CI]: 3.37, 6.07) higher MRC score, indicating a positive association. Similarly, slopes for the 6MWT and SF-36 relative to a 10% higher FVC were estimated at 33.2 meters (95% CI 24.0, 42.4) and 1.2% (95% CI 0.24, 2.16%), respectively. From longitudinal analyses, a 10% incremental increase in predicted FVC was associated with an average increase of 4.12% in MRC score (95% CI 1.29, 6.95), 35.6 m in the 6MWT (95% CI 19.9, 51.6), and 1.34% in SF-36 (95% CI 0.08, 2.60). There was insufficient data to conduct analyses for RHS, FSS and survival., Conclusions: FVC is positively associated with LOPD measures and outcomes across multiple domains. Additionally, longitudinal changes in FVC are positively associated with changes in the 6MWT, MRC and SF-36.
- Published
- 2019
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40. Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.
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Akyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, Borgo A, Braunlin E, Eto Y, Gold JI, Jester A, Jones SA, Karsli C, Mackenzie W, Marinho DR, McFadyen A, McGill J, Mitchell JJ, Muenzer J, Okuyama T, Orchard PJ, Stevens B, Thomas S, Walker R, Wynn R, Giugliani R, Harmatz P, Hendriksz C, and Scarpa M
- Subjects
- Chondroitinsulfatases genetics, Enzyme Replacement Therapy methods, Female, Humans, Hypercapnia genetics, Hypercapnia metabolism, Male, Chondroitinsulfatases metabolism, Mucopolysaccharidosis IV metabolism
- Abstract
Introduction: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA., Methods: Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers., Results: A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance)., Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
- Published
- 2019
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41. Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.
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Akyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, Borgo A, Braunlin E, Eto Y, Gold JI, Jester A, Jones SA, Karsli C, Mackenzie W, Marinho DR, McFadyen A, McGill J, Mitchell JJ, Muenzer J, Okuyama T, Orchard PJ, Stevens B, Thomas S, Walker R, Wynn R, Giugliani R, Harmatz P, Hendriksz C, and Scarpa M
- Subjects
- Activities of Daily Living, Consensus, Enzyme Replacement Therapy, Hematopoietic Stem Cell Transplantation, Humans, Mucopolysaccharidoses diagnosis, Mucopolysaccharidoses drug therapy, Mucopolysaccharidoses metabolism, Mucopolysaccharidoses surgery, Mucopolysaccharidosis VI diagnosis, Mucopolysaccharidosis VI drug therapy, Mucopolysaccharidosis VI metabolism, Mucopolysaccharidosis VI surgery, N-Acetylgalactosamine-4-Sulfatase metabolism, Quality of Life, Recombinant Proteins metabolism, Disease Management
- Abstract
Introduction: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI., Methods: 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers., Results: A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance)., Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
- Published
- 2019
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42. Serum perfluoroalkyl substances and lung function in adolescents exposed to the World Trade Center disaster.
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Gaylord A, Berger KI, Naidu M, Attina TM, Gilbert J, Koshy TT, Han X, Marmor M, Shao Y, Giusti R, Goldring RM, Kannan K, and Trasande L
- Subjects
- Adolescent, Adult, Asthma epidemiology, Child, Cohort Studies, Humans, New York City epidemiology, Respiratory Function Tests, Environmental Exposure, Environmental Pollutants blood, Environmental Pollutants toxicity, Fluorocarbons blood, Fluorocarbons toxicity, Lung drug effects, September 11 Terrorist Attacks
- Abstract
The effects of childhood exposure to perfluoroalkyl substances (PFASs) on lung function remain mostly unknown. Previous research indicates that children living or going to school near the World Trade Center (WTC) disaster were exposed to high levels of PFASs, among other toxic chemicals. To explore the effects of PFAS exposure on lung function, we measured serum PFASs in a cohort of children from the WTC Health Registry and a matched control group. Perfluorooctanesulfonate had the highest median concentrations in both groups (WTCHR = 3.72 ng/mL, Comparison = 2.75 ng/mL), while the lowest median concentrations were seen for perfluoroundecanoic acid (WTCHR = 0.12 ng/mL, Comparison = 0.01 ng/mL). Lung function outcomes were measured by spirometry, plethysmography, and oscillometry. Asthma diagnosis and serum eosinophil count were also recorded. We examined the relationships of each PFAS with lung function parameters and eosinophil count using linear regressions. Odds ratios for asthma were obtained for each PFAS using logistic regression. The effect of total PFASs on these outcomes was also assessed. All regression models were adjusted for sex, race/ethnicity, age, body mass index (BMI) and tobacco smoke exposure. We found that serum PFASs were not statistically associated with the measured lung function parameters, asthma diagnosis, or eosinophil count in this cohort (p < 0.05). These findings highlight the need for more longitudinal studies to explore the long-term effects of childhood PFAS exposure on lung function past adolescence and early adulthood., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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43. Bronchodilator Response Predicts Longitudinal Improvement in Small Airway Function in World Trade Center Dust Exposed Community Members.
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Pradhan D, Xu N, Reibman J, Goldring RM, Shao Y, Liu M, and Berger KI
- Subjects
- Bronchi drug effects, Bronchi physiopathology, Female, Humans, Male, Middle Aged, Spirometry, Bronchodilator Agents pharmacology, Dust, Forced Expiratory Volume, September 11 Terrorist Attacks, Vital Capacity
- Abstract
The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV
1 ) and FOT (resistance at 5 Hz, R5 ; resistance at 5 minus 20 Hz, R5-20 ). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R5 and R5-20 ) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.- Published
- 2019
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44. Predictors of Asthma/COPD Overlap in FDNY Firefighters With World Trade Center Dust Exposure: A Longitudinal Study.
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Singh A, Liu C, Putman B, Zeig-Owens R, Hall CB, Schwartz T, Webber MP, Cohen HW, Berger KI, Nolan A, Prezant DJ, and Weiden MD
- Subjects
- Comorbidity, Dust, Female, Firefighters statistics & numerical data, Humans, Leukocyte Count methods, Longitudinal Studies, Male, Middle Aged, New York City epidemiology, Occupational Exposure adverse effects, Predictive Value of Tests, Prevalence, Respiratory Function Tests methods, Risk Factors, Air Pollutants, Occupational adverse effects, Asthma blood, Asthma diagnosis, Asthma epidemiology, Asthma etiology, Eosinophils, Interleukin-4 blood, Pulmonary Disease, Chronic Obstructive blood, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive epidemiology, Pulmonary Disease, Chronic Obstructive etiology, September 11 Terrorist Attacks
- Abstract
Background: Previously healthy firefighters with World Trade Center (WTC) dust exposure developed airway disease. Risk factors for irritant-associated asthma/COPD overlap are poorly defined., Methods: This study included 2,137 WTC-exposed firefighters who underwent a clinically indicated bronchodilator pulmonary function test (BD-PFT) between 9/11/2001 and 9/10/2017. A post-BD FEV
1 increase of > 12% and 200 mL from baseline defined asthma, and a post-BD FEV1 /FVC ratio < 0.7 identified COPD cases. Participants who met both criteria had asthma/COPD overlap. Eosinophil levels were measured on screening blood tests performed shortly after 9/11/2001 and prior to BD-PFT; a subgroup of participants also had serum IgE and 21 cytokines measured (n = 215). Marginal Cox regression models for multiple events assessed the associations of eosinophil levels or serum biomarkers with subsequent diagnosis, with age, race, smoking, WTC exposure, first post-9/11 FEV1 /FVC ratio, and BMI included as covariates., Results: BD-PFT diagnosed asthma/COPD overlap in 99 subjects (4.6%), isolated-asthma in 202 (9.5%), and isolated-COPD in 215 (10.1%). Eosinophil concentration ≥ 300 cells/μL was associated with increased risk of asthma/COPD overlap (hazard ratio [HR], 1.85; 95% CI, 1.16-2.95) but not with isolated-asthma or isolated-COPD. Serum IL-4 also predicted asthma/COPD overlap (HR, 1.51 per doubling of cytokine concentration; 95% CI, 1.17-1.95). Greater IL-21 concentration was associated with both isolated-asthma and isolated-COPD (HRs of 1.73 [95% CI, 1.27-2.35] and 2.06 [95% CI, 1.31-3.23], respectively)., Conclusions: In WTC-exposed firefighters, elevated blood eosinophil and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific T-helper cell type 2 biomarkers present years before diagnosis suggest patient-intrinsic predisposition to irritant-associated asthma/COPD overlap., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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45. Respiratory Health and Lung Function in Children Exposed to the World Trade Center Disaster.
- Author
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Trye A, Berger KI, Naidu M, Attina TM, Gilbert J, Koshy TT, Han X, Marmor M, Shao Y, Giusti R, Goldring RM, and Trasande L
- Subjects
- Child, Child, Preschool, Dust, Female, Humans, Incidence, Infant, Infant, Newborn, Male, New York City epidemiology, Retrospective Studies, Stress Disorders, Post-Traumatic physiopathology, Air Pollutants adverse effects, Disasters, Environmental Exposure adverse effects, Health Status, Registries, Respiratory Physiological Phenomena, Stress Disorders, Post-Traumatic epidemiology
- Abstract
Objectives: To compare lung function in a representative sample of World Trade Center (WTC)-exposed children with matched comparisons, and examine relationships with reported exposures., Study Design: Study population consisted of 402 participants. Oscillometry, spirometry, and plethysmography were performed on WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 (n = 180) and a sociodemographically matched group of New York City residents (n = 222). We compared lung function by study arm (WTCHR and comparison group) as well as dust cloud (acute); home dust (subchronic); and other traumatic, nondust exposures., Results: In multivariable models, post-9/11 risk of incident asthma was higher in the WTCHR participants than in the comparison group (OR 1.109, 95% CI 1.021, 1.206; P = .015). Comparing by exposure rather than by group, dust cloud (OR 1.223, 95% CI 1.095, 1.365; P < .001) and home dust (OR 1.123, 95% CI 1.029, 1.226; P = .009) exposures were also associated with a greater risk of incidence of post-9/11 asthma. No differences were identified for lung function measures., Conclusions: Although we cannot exclude an alternative explanation to the null findings, these results may provide some measure of reassurance to exposed children and their families regarding long-term consequences. Further study with bronchodilation and/or methacholine challenge may be needed to identify and further evaluate effects of WTC exposure. Biomarker studies may also be more informative in delineating exposure-outcome relationships., Trial Registration: ClinicalTrials.gov: NCT02068183., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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46. Obstructive Sleep Apnea in Community Members Exposed to World Trade Center Dust and Fumes.
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Ahuja S, Zhu Z, Shao Y, Berger KI, Reibman J, and Ahmed O
- Subjects
- Adult, Female, Humans, Male, Middle Aged, New York City epidemiology, Polysomnography, Residence Characteristics statistics & numerical data, Retrospective Studies, Sleep Apnea, Obstructive epidemiology, Air Pollutants adverse effects, Particulate Matter adverse effects, September 11 Terrorist Attacks, Sleep Apnea, Obstructive etiology
- Abstract
Study Objectives: A relationship between obstructive sleep apnea (OSA) and exposure to the World Trade Center (WTC) dust and fumes has been suggested in responders but little is known about a possible relationship in community members. We characterized sleep studies performed in community members with WTC dust exposure to improve our understanding of the relationship between the diagnosis and severity of OSA and WTC dust exposure in this population., Methods: Single-center, retrospective study of patients enrolled in a clinical treatment program for community members with WTC dust exposure. Patients were included if they had undergone sleep studies for evaluation of possible OSA through September 2016 and provided written informed consent., Results: The total number of patients included in the analysis was 143. Patients were predominantly male (61%), never smokers (59%) and had a median body mass index of 31 kg/m
2 . Most reported upper and lower respiratory symptoms. An apnea-hypopnea index (AHI) ≥ 5 events/h was measured in 66% of the patients, and respiratory disturbance index was ≥ 5 events/h in 97%. The proportion of patients with moderate-severe OSA (defined by the AHI 4% criteria) was 50%. Multivariate logistic regression revealed that acute WTC dust cloud exposure was associated with severity but not diagnosis of OSA., Conclusions: We identified a high rate of OSA in the WTC community cohort who were referred for sleep studies. Exposure to the massive WTC dust cloud caused by the WTC collapse was independently associated with the severity of OSA in this population. This finding highlights the role that environmental exposures may play in the development of OSA., (© 2018 American Academy of Sleep Medicine.)- Published
- 2018
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47. Small Airway Disease Syndromes. Piercing the Quiet Zone.
- Author
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Berger KI
- Subjects
- Airway Obstruction diagnosis, Humans, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive physiopathology, Respiratory Function Tests, Spirometry, Syndrome, Airway Obstruction physiopathology, Cigarette Smoking adverse effects, Inhalation Exposure adverse effects, Lung physiopathology, Obesity complications
- Abstract
The role for direct assessment of small airway function in subjects with respiratory symptoms but normal airflow by spirometry is discussed. Small airway disease syndrome is described in numerous disease states using a multidisciplinary approach. Data demonstrate that small airway disease is related to presence of respiratory symptoms, exposure to inhaled toxins, presence of local and systemic inflammation, and presence of histologic abnormalities within the distal lung. Investigation of immunological derangements associated with distal airway dysfunction in the setting of normal spirometry may provide insight into pathophysiological mechanisms that are present at disease onset. For the purposes of this symposium, data were reviewed in selected clinical conditions (obesity, environmental inhalational injury, and cigarette smoking) that have been recently studied in the André Cournand Pulmonary Physiology Laboratory at Bellevue Hospital using the forced oscillation technique.
- Published
- 2018
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48. Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa.
- Author
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Berger KI, Burton BK, Lewis GD, Tarnopolsky M, Harmatz PR, Mitchell JJ, Muschol N, Jones SA, Sutton VR, Pastores GM, Lau H, Sparkes R, and Shaywitz AJ
- Abstract
Objective: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities., Methods: Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined)., Results: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO
2 ), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2 /work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost., Conclusions: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.- Published
- 2018
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49. Risk factors for persistence of lower respiratory symptoms among community members exposed to the 2001 World Trade Center terrorist attacks.
- Author
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Jordan HT, Friedman SM, Reibman J, Goldring RM, Miller Archie SA, Ortega F, Alper H, Shao Y, Maslow CB, Cone JE, Farfel MR, and Berger KI
- Subjects
- Adult, Aged, Air Pollutants analysis, Air Pollution adverse effects, Case-Control Studies, Cough, Dyspnea, Environmental Exposure analysis, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, New York City epidemiology, Oscillometry, Registries, Respiration Disorders psychology, Respiratory Sounds, Risk Factors, September 11 Terrorist Attacks, Stress Disorders, Post-Traumatic psychology, Surveys and Questionnaires, Terrorism, Young Adult, Air Pollutants adverse effects, Environmental Exposure adverse effects, Respiration Disorders epidemiology, Respiration Disorders etiology, Stress Disorders, Post-Traumatic epidemiology, Stress Disorders, Post-Traumatic etiology
- Abstract
Objectives: We studied the course of lower respiratory symptoms (LRS; cough, wheeze or dyspnoea) among community members exposed to the 9/11/2001 World Trade Center (WTC) attacks during a period of 12-13 years following the attacks, and evaluated risk factors for LRS persistence, including peripheral airway dysfunction and post-traumatic stress disorder (PTSD)., Methods: Non-smoking adult participants in a case-control study of post-9/11-onset LRS (exam 1, 2008-2010) were recruited for follow-up (exam 2, 2013-2014). Peripheral airway function was assessed with impulse oscillometry measures of R
5 and R5-20 . Probable PTSD was a PTSD checklist score ≥ 44 on a 2006-2007 questionnaire., Results: Of 785 exam 1 participants, 545 (69%) completed exam 2. Most (321, 59%) were asymptomatic at all assessments. Among 192 participants with initial LRS, symptoms resolved for 110 (57%) by exam 2, 55 (29%) had persistent LRS and 27 (14%) had other patterns. The proportion with normal spirometry increased from 65% at exam 1 to 85% at exam 2 in the persistent LRS group (p<0.01) and was stable among asymptomatic participants and those with resolved LRS. By exam 2, spirometry results did not differ across symptom groups; however, R5 and R5-20 abnormalities were more common among participants with persistent LRS (56% and 46%, respectively) than among participants with resolved LRS (30%, p<0.01; 27%, p=0.03) or asymptomatic participants (20%, p<0.001; 8.2%, p<0.001). PTSD, R5 at exam 1, and R5-20 at exam 1 were each independently associated with persistent LRS., Conclusions: Peripheral airway dysfunction and PTSD may contribute to LRS persistence. Assessment of peripheral airway function detected pulmonary damage not evident on spirometry. Mental and physical healthcare for survivors of complex environmental disasters should be coordinated carefully., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2017
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50. Paresthesias Among Community Members Exposed to the World Trade Center Disaster.
- Author
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Marmor M, Shao Y, Bhatt DH, Stecker MM, Berger KI, Goldring RM, Rosen RL, Caplan-Shaw C, Kazeros A, Pradhan D, Wilkenfeld M, and Reibman J
- Subjects
- Adult, Aged, Air Pollutants, Occupational adverse effects, Dust, Environmental Restoration and Remediation, Female, Humans, Lower Extremity, Male, Mental Disorders epidemiology, Middle Aged, New York City epidemiology, Prevalence, Respiratory Tract Diseases epidemiology, Respiratory Tract Diseases physiopathology, Upper Extremity, Young Adult, Occupational Exposure adverse effects, Paresthesia epidemiology, September 11 Terrorist Attacks
- Abstract
Objective: Paresthesias can result from metabolic disorders, nerve entrapment following repetitive motions, hyperventilation pursuant to anxiety, or exposure to neurotoxins. We analyzed data from community members exposed to the World Trade Center (WTC) disaster of September 11, 2001, to evaluate whether exposure to the disaster was associated with paresthesias., Methods: Analysis of data from 3141 patients of the WTC Environmental Health Center., Results: Fifty-six percent of patients reported paresthesias at enrollment 7 to 15 years following the WTC disaster. After controlling for potential confounders, paresthesias were associated with severity of exposure to the WTC dust cloud and working in a job requiring cleaning of WTC dust., Conclusions: This study suggests that paresthesias were commonly associated with WTC-related exposures or post-WTC cleaning work. Further studies should objectively characterize these paresthesias and seek to identify relevant neurotoxins or paresthesia-inducing activities.
- Published
- 2017
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- View/download PDF
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