Kenneth Berger | New York University School of Medicine (original) (raw)

Papers by Kenneth Berger

Journal of Applied Physiology, 2000

Goldring. CO 2 homeostasis during periodic breathing in obstructive sleep apnea.

The Journal of Pediatrics, May 1, 2004

Mucopolysaccharidosis type I (MPS I) is a storage disorder caused by the deficiency of the lysoso... more Mucopolysaccharidosis type I (MPS I) is a storage disorder caused by the deficiency of the lysosomal enzyme a-l-iduronidase. MPS I has a chronic progressive evolution with multisystemic symptomatology and wide clinical variability, with its main manifestations in the skeletal, respiratory, cardiac and neurological systems. Until recently, therapeutic options for MPS I were limited to hematopoietic stem cell transplantation for severe cases, and palliative care. Laronidase (Aldurazyme ® , BioMarin/Genzyme, CA, USA), a synthetic variant of the human a-l-iduronidase, is a specific treatment for MPS I. Enzyme replacement therapy with intravenous infusion of laronidase aims to reduce and/or prevent the accumulation of glycosaminoglycans (dermatan and heparan sulfate), which is probably the most important, although possibly not the only, cause of the clinical manifestations of MPS I. This article reviews the data published to date on the clinical indications and user experience of laronidase in patients with MPS I.

Seminars in Respiratory and Critical Care Medicine, May 18, 2009

The term obesity hypoventilation syndrome (OHS) refers to the combination of obesity and chronic ... more The term obesity hypoventilation syndrome (OHS) refers to the combination of obesity and chronic hypercapnia that cannot be directly attributed to underlying cardiorespiratory disease. Despite a plethora of potential pathophysiological mechanisms for gas exchange and respiratory control abnormalities that have been described in the obese, the etiology of hypercapnia in OHS has been only partially elucidated. Of particular note, obesity and coincident hypercapnia are often associated with some form of sleep disordered breathing (apnea/hypopnea or sustained periods of hypoventilation). From a conceptual point of view, even transient reductions of ventilation from individual sleep disordered breathing events must produce acute hypercapnia during the period of low ventilation. What is less clear, however, is the link between these transient episodes of acute hypercapnia and the development of chronic sustained hypercapnia persisting into wakefulness. A unifying view of how this comes about is presented in the following review. In brief, our concept is that chronic sustained hypercapnia (as in obesity hypoventilation) occurs when the disorder of ventilation that produces acute hypercapnia interacts with inadequate compensation (both during sleep and during the periods of wakefulness); neither alone is sufficient to fully explain the final result. The following discussion will amplify on both the potential reasons for acute hypercapnia in the obese and on what is known about the failure of compensation that must occur in these subjects.

JAMA Neurology

ImportanceIn the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGA... more ImportanceIn 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.ObjectiveTo report avalglucosidase alfa treatment outcomes during the COMET trial extension.Design, Setting, and ParticipantsThis 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.InterventionsRandom assignment (1:1) to receive 20 mg/k...

Molecular Genetics and Metabolism, 2022

Molecular Genetics and Metabolism, 2022

D77. TRANSPLANTATION, 2020

Neuromuscular Disorders, 2015

Lung function tests (MIP, MEP, FVC, VC) predict ventilation and wheelchair use in late-onset Pomp... more Lung function tests (MIP, MEP, FVC, VC) predict ventilation and wheelchair use in late-onset Pompe disease M. Roberts *, T. Mozaffar , P. Young , E. Johnson , A. Quartel , K. Berger 5 1 Salford Royal NHS Foundation Trust, Salford, UK; 2 University of California, Irvine, CA, USA; 3 University Hospital Munster, Munster, Germany; 4 BioMarin Pharmaceutical Inc., Novato, CA, USA; 5 New York University School of Medicine, New York, NY, USA

D40. UNDERSTANDING INHALATIONAL DISASTERS, 2009

Journal of Public Health Policy, 2010

The issue of harm reduction has long been controversial in the public health practice of tobacco ... more The issue of harm reduction has long been controversial in the public health practice of tobacco control. Health advocates have been reluctant to endorse a harm reduction approach out of fear that tobacco companies cannot be trusted to produce and market products that will reduce the risks associated with tobacco use. Recently, companies independent of the tobacco industry introduced electronic cigarettes, devices that deliver vaporized nicotine without combusting tobacco. We review the existing evidence on the safety and efficacy of electronic cigarettes. We then revisit the tobacco harm reduction debate, with a focus on these novel products. We conclude that electronic cigarettes show tremendous promise in the fight against tobacco-related morbidity and mortality. By dramatically expanding the potential for harm reduction strategies to achieve substantial health gains, they may fundamentally alter the tobacco harm reduction debate.

The Journal of Pediatrics, Apr 1, 2006

Objective The objective of this Phase 3 study was to confirm the efficacy and safety of recombina... more Objective The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. Study design Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. Results After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p ‫؍‬ .025) and 5.7 stairs per minute more 3MSC (p ‫؍‬ .053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by-227 ؎ 18 g/mg more with rhASB than placebo (p <.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. Conclusion rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

Critical Care Explorations, 2020

The Lancet Neurology, 2021

BACKGROUND Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of ac... more 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.

Chest, 2021

BACKGROUND: Current techniques for measuring absolute lung volumes rely on bulky and expensive eq... more 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 ¼ 197) and restrictive (n ¼ 33) disorders as well as healthy participants (n ¼ 36). TLC measured by conventional plethysmography (TLC Pleth) was compared with TLC measured by the MiniBox (TLC MB). RESULTS: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLC Pleth and TLC MB 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.

ERJ Open Research, 2020

Diagnosis of asthma in obese individuals frequently relies on clinical history, as airflow by spi... more 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 spirome...

D40. UNDERSTANDING INHALATIONAL DISASTERS, 2009

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumula... more MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and

European Respiratory Review, 2022

Recently, “Technical standards for respiratory oscillometry” was published, which reviewed the ph... more 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 dysfunc...

Orphanet Journal of Rare Diseases, 2022

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited d... more 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, c...

Journal of Applied Physiology, 2000

Goldring. CO 2 homeostasis during periodic breathing in obstructive sleep apnea.

The Journal of Pediatrics, May 1, 2004

Mucopolysaccharidosis type I (MPS I) is a storage disorder caused by the deficiency of the lysoso... more Mucopolysaccharidosis type I (MPS I) is a storage disorder caused by the deficiency of the lysosomal enzyme a-l-iduronidase. MPS I has a chronic progressive evolution with multisystemic symptomatology and wide clinical variability, with its main manifestations in the skeletal, respiratory, cardiac and neurological systems. Until recently, therapeutic options for MPS I were limited to hematopoietic stem cell transplantation for severe cases, and palliative care. Laronidase (Aldurazyme ® , BioMarin/Genzyme, CA, USA), a synthetic variant of the human a-l-iduronidase, is a specific treatment for MPS I. Enzyme replacement therapy with intravenous infusion of laronidase aims to reduce and/or prevent the accumulation of glycosaminoglycans (dermatan and heparan sulfate), which is probably the most important, although possibly not the only, cause of the clinical manifestations of MPS I. This article reviews the data published to date on the clinical indications and user experience of laronidase in patients with MPS I.

Seminars in Respiratory and Critical Care Medicine, May 18, 2009

The term obesity hypoventilation syndrome (OHS) refers to the combination of obesity and chronic ... more The term obesity hypoventilation syndrome (OHS) refers to the combination of obesity and chronic hypercapnia that cannot be directly attributed to underlying cardiorespiratory disease. Despite a plethora of potential pathophysiological mechanisms for gas exchange and respiratory control abnormalities that have been described in the obese, the etiology of hypercapnia in OHS has been only partially elucidated. Of particular note, obesity and coincident hypercapnia are often associated with some form of sleep disordered breathing (apnea/hypopnea or sustained periods of hypoventilation). From a conceptual point of view, even transient reductions of ventilation from individual sleep disordered breathing events must produce acute hypercapnia during the period of low ventilation. What is less clear, however, is the link between these transient episodes of acute hypercapnia and the development of chronic sustained hypercapnia persisting into wakefulness. A unifying view of how this comes about is presented in the following review. In brief, our concept is that chronic sustained hypercapnia (as in obesity hypoventilation) occurs when the disorder of ventilation that produces acute hypercapnia interacts with inadequate compensation (both during sleep and during the periods of wakefulness); neither alone is sufficient to fully explain the final result. The following discussion will amplify on both the potential reasons for acute hypercapnia in the obese and on what is known about the failure of compensation that must occur in these subjects.

JAMA Neurology

ImportanceIn the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGA... more ImportanceIn 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.ObjectiveTo report avalglucosidase alfa treatment outcomes during the COMET trial extension.Design, Setting, and ParticipantsThis 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.InterventionsRandom assignment (1:1) to receive 20 mg/k...

Molecular Genetics and Metabolism, 2022

Molecular Genetics and Metabolism, 2022

D77. TRANSPLANTATION, 2020

Neuromuscular Disorders, 2015

Lung function tests (MIP, MEP, FVC, VC) predict ventilation and wheelchair use in late-onset Pomp... more Lung function tests (MIP, MEP, FVC, VC) predict ventilation and wheelchair use in late-onset Pompe disease M. Roberts *, T. Mozaffar , P. Young , E. Johnson , A. Quartel , K. Berger 5 1 Salford Royal NHS Foundation Trust, Salford, UK; 2 University of California, Irvine, CA, USA; 3 University Hospital Munster, Munster, Germany; 4 BioMarin Pharmaceutical Inc., Novato, CA, USA; 5 New York University School of Medicine, New York, NY, USA

D40. UNDERSTANDING INHALATIONAL DISASTERS, 2009

Journal of Public Health Policy, 2010

The issue of harm reduction has long been controversial in the public health practice of tobacco ... more The issue of harm reduction has long been controversial in the public health practice of tobacco control. Health advocates have been reluctant to endorse a harm reduction approach out of fear that tobacco companies cannot be trusted to produce and market products that will reduce the risks associated with tobacco use. Recently, companies independent of the tobacco industry introduced electronic cigarettes, devices that deliver vaporized nicotine without combusting tobacco. We review the existing evidence on the safety and efficacy of electronic cigarettes. We then revisit the tobacco harm reduction debate, with a focus on these novel products. We conclude that electronic cigarettes show tremendous promise in the fight against tobacco-related morbidity and mortality. By dramatically expanding the potential for harm reduction strategies to achieve substantial health gains, they may fundamentally alter the tobacco harm reduction debate.

The Journal of Pediatrics, Apr 1, 2006

Objective The objective of this Phase 3 study was to confirm the efficacy and safety of recombina... more Objective The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. Study design Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. Results After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p ‫؍‬ .025) and 5.7 stairs per minute more 3MSC (p ‫؍‬ .053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by-227 ؎ 18 g/mg more with rhASB than placebo (p <.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. Conclusion rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

Critical Care Explorations, 2020

The Lancet Neurology, 2021

BACKGROUND Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of ac... more 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.

Chest, 2021

BACKGROUND: Current techniques for measuring absolute lung volumes rely on bulky and expensive eq... more 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 ¼ 197) and restrictive (n ¼ 33) disorders as well as healthy participants (n ¼ 36). TLC measured by conventional plethysmography (TLC Pleth) was compared with TLC measured by the MiniBox (TLC MB). RESULTS: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLC Pleth and TLC MB 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.

ERJ Open Research, 2020

Diagnosis of asthma in obese individuals frequently relies on clinical history, as airflow by spi... more 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 spirome...

D40. UNDERSTANDING INHALATIONAL DISASTERS, 2009

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumula... more MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and

European Respiratory Review, 2022

Recently, “Technical standards for respiratory oscillometry” was published, which reviewed the ph... more 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 dysfunc...

Orphanet Journal of Rare Diseases, 2022

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited d... more 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, c...