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BackgroundNontuberculous pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression.Research QuestionWhat are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis?Study Design and MethodsElectronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle–Ottawa Scale. Data analysis was conducted using the R-based “meta” package. Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis.ResultsOf the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26).InterpretationThe greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD, to drive prompt testing and appropriate initiation of therapy. Nontuberculous pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression. What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis? Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle–Ottawa Scale. Data analysis was conducted using the R-based “meta” package. Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis. Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26). The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD, to drive prompt testing and appropriate initiation of therapy. Take-home PointsStudy Question: What are the risk factors for developing NTM-PD?Results: Comorbid respiratory disease, including bronchiectasis, COPD, and history of tuberculosis, was associated with the highest risk for NTM-PD; the use of inhaled corticosteroids, solid tumors, and the presence of pneumonia were also important factors.Interpretation: This is the first study to provide an overview of risk for NTM-PD for a comprehensive set of potential factors. Study Question: What are the risk factors for developing NTM-PD? Results: Comorbid respiratory disease, including bronchiectasis, COPD, and history of tuberculosis, was associated with the highest risk for NTM-PD; the use of inhaled corticosteroids, solid tumors, and the presence of pneumonia were also important factors. Interpretation: This is the first study to provide an overview of risk for NTM-PD for a comprehensive set of potential factors. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment1Hoefsloot W. van Ingen J. Andrejak C. et al.The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study.Eur Respir J. 2013; 42: 1604-1613Crossref PubMed Scopus (570) Google Scholar,2Zweijpfenning S.M.H. Ingen J.V. Hoefsloot W. Geographic distribution of nontuberculous mycobacteria isolated from clinical specimens: a systematic review.Semin Respir Crit Care Med. 2018; 39: 336-342Crossref PubMed Scopus (45) Google Scholar and encompass more than 200 species, which differ in their propensity to cause pulmonary disease (NTM-PD).2Zweijpfenning S.M.H. Ingen J.V. Hoefsloot W. Geographic distribution of nontuberculous mycobacteria isolated from clinical specimens: a systematic review.Semin Respir Crit Care Med. 2018; 39: 336-342Crossref PubMed Scopus (45) Google Scholar NTM-PD is a serious, chronic, rare infectious disease that often presents in people with underlying lung conditions such as bronchiectasis, cystic fibrosis (CF), and COPD.3Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease.Eur Respir J. 2019; 541900250Crossref PubMed Scopus (121) Google Scholar NTM-PD can be a substantial burden for patients, contributing to lung function decline and reduced health-related quality of life, and is associated with significant morbidity and mortality.4Asakura T. Ishii M. Ishii K. et al.Health-related QOL of elderly patients with pulmonary M. avium complex disease in a university hospital.Int J Tuberc Lung Dis. 2018; 22: 695-703Crossref PubMed Scopus (14) Google Scholar, 5Mehta M. Marras T.K. Impaired health-related quality of life in pulmonary nontuberculous mycobacterial disease.Respir Med. 2011; 105: 1718-1725Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 6Park HY, Jeong BH, Chon HR, et al. Lung function decline according to clinical course in nontuberculous mycobacterial lung disease. Chest.;150(6):1222-1232.Google Scholar, 7Diel R. Lipman M. Hoefsloot W. High mortality in patients with Mycobacterium avium complex lung disease: a systematic review.BMC Infect Dis. 2018; 18: 206Crossref PubMed Scopus (84) Google Scholar Incidence rates of NTM-PD are rising, but the disease remains challenging to diagnose and treat.8van Ingen J. Obradovic M. Hassan M. et al.Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex: disease burden, unmet needs, and advances in treatment developments.Expert Rev Respir Med. 2021; 15: 1387-1401Crossref PubMed Scopus (12) Google Scholar Clinical symptoms of NTM-PD are nonspecific and often overlap with those of other underlying respiratory conditions, leading to a high proportion of patients with NTM-PD remaining undiagnosed.9Doyle O.M. van der Laan R. Obradovic M. et al.Identification of potentially undiagnosed patients with nontuberculous mycobacterial lung disease using machine learning applied to primary care data in the UK.Eur Respir J. 2020; 562000045Crossref PubMed Scopus (11) Google Scholar, 10Ringshausen F.C. Ewen R. Multmeier J. et al.Predictive modeling of nontuberculous mycobacterial pulmonary disease epidemiology using German health claims data.Int J Infect Dis. 2021; 104: 398-406Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 11Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175 (Feb 15): 367-416Crossref PubMed Scopus (4512) Google Scholar Testing for NTM-PD is important to allow for prompt diagnosis and, after this, appropriate management—which should be individualized and may include guideline-based therapy or nonpharmacological treatment such as airway clearance—can be initiated to prevent disease progression.12Wagner D. van Ingen J. Adjemian J. et al.Annual prevalence and treatment estimates of nontuberculous mycobacterial pulmonary disease in Europe: a NTM-NET collaborative study.Eur Respir J. 2014; 44: P1067Google Scholar, 13Park T.Y. Chong S. Jung J.W. et al.Natural course of the nodular bronchiectatic form of Mycobacterium avium complex lung disease: long-term radiologic change without treatment.PLoS One. 2017; 12e0185774Crossref Scopus (15) Google Scholar, 14Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.Eur Respir J. 2020; 562000535Crossref PubMed Scopus (245) Google Scholar Previous data have highlighted that particular groups of patients are at risk of NTM-PD.15Andréjak C. Nielsen R. Thomsen V. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-362Crossref PubMed Scopus (252) Google Scholar Testing for NTM-PD is recommended by some societal guidelines when risk factors, clinical symptoms, or suspicious radiological findings are found14Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.Eur Respir J. 2020; 562000535Crossref PubMed Scopus (245) Google Scholar,16Haworth C.S. Banks J. Capstick T. et al.British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).Thorax. 2017; 72: ii1-ii64Crossref PubMed Scopus (426) Google Scholar; however, no study has provided a comprehensive insight into risk factors for NTM-PD, including underlying comorbidities and patient characteristics. The aim of this current study is to identify risk factors for NTM-PD that can be used to determine which patients are at risk of infection so that prompt and appropriate diagnoses can be made. The systematic literature review has been registered in the International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/prospero; record ID: 347379) and has been conducted in line with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines.17Moher D. Shamseer L. Clarke M. et al.Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.Syst Rev. 2015; 4: 1Crossref PubMed Scopus (13947) Google Scholar Institutional Review Board approval was not required. All authors determined a search strategy that included both free-text words and medical subject headings. The search string can be found in e-Table 1 and was used to perform searches in PubMed and were in July Inclusion and criteria for are in e-Table were to in between and was used to the of between and the and of the criteria authors C. and the of and and was a of to determine which met criteria for review and by the All authors potentially studies to determine their and the of the were the studies study study study and study groups, and patient disease NTM and patient NTM-PD association with comorbidities respiratory disease, disease, and and NTM-PD association with risk factors and and were into a data was determined of the data M. J. J. R. R. and assessed the quality of study using the a recommended by the D. et al.The for the quality of studies in J. J. et for Systematic Reviews of Scholar The review the criteria of the Of Systematic J. et to risk of in systematic was Full Text Full Text PDF PubMed Scopus Google Scholar Data analysis was conducted by C. and using the R-based “meta” package. was that included of study population risk factors, or association 95% CI, of and association Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis. that not include a without NTM-PD or not 95% for the risk estimates were not for the meta-analysis. The data or risk were used but data were used when data were not data was using can be as to not be to may to may substantial to All the studies an study and a was a was used in the meta-analysis. The meta-analysis was with the analysis as population and data (OR, HR, or an of 9,530 publications, which after to the of 99 studies e-Table Of the 99 were and were included primary studies and overview of included studies is in e-Table studies reported a analysis of association (OR, HR, or between risk factors and of NTM-PD, of the studies reporting an association for or risk factors, studies data for and risk factors, e-Table the association between use of particular clinical patient and The comorbidities with a association with NTM-PD were COPD history of TB and and were also reporting an association in more than Other clinical and factors an association with NTM-PD included bronchiectasis, (healthy and radiological infection with or and analysis an increased risk of NTM-PD with of the in at Of the publications, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population without NTM or control subjects without NTM-PD) and were included in the meta-analysis C. Nielsen R. Thomsen V. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-362Crossref PubMed Scopus (252) Google et al.Nontuberculous mycobacterial pulmonary disease and associated risk factors in 2021; Full Text Full Text PDF PubMed Scopus Google Scholar, factors and care in a primary care population with non-tuberculous mycobacterial disease in the UK.Eur J Infect Dis. 2019; PubMed Scopus (14) Google Scholar, J. of pulmonary nontuberculous mycobacterial in patients with cystic fibrosis in the 2018; 15: PubMed Scopus Google Scholar, Adjemian J. of nontuberculous mycobacterial and associated use with cystic J Respir Crit Care Med. 2013; PubMed Scopus Google Scholar, R. et risk of mycobacterial associated with 2015; PubMed Scopus Google Scholar, R. et of non-tuberculous with cystic 2017; Full Text Full Text PDF PubMed Scopus (12) Google Scholar, L. et between non-tuberculous and mycobacteria in Respir J. 2015; Scholar, D. C. et in the and mycobacterial Infect Dis. 2020; PubMed Scopus Google Scholar, factors and outcomes of nontuberculous mycobacterial disease a study in a Scholar, et of with nontuberculous mycobacterial infection in patients with 2021; Scopus Google Scholar, et between inhaled use and pulmonary nontuberculous mycobacterial 2018; 15: PubMed Scopus Google Scholar, C. et factors for nontuberculous mycobacterial in solid a Infect Dis. 2014; PubMed Scopus Google Scholar, D. W. of nontuberculous mycobacterial lung disease in 2017; Full Text Full Text PDF Google Scholar, M. W. D. Non-tuberculous mycobacterial disease is in patients with fibrosis J Infect Dis. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, L. et of pulmonary non-tuberculous mycobacterial after lung Infect Dis. 18: PubMed Scopus Google Scholar, K. of of nontuberculous mycobacterial pulmonary disease.Eur Respir J. 2021; Scopus Google Scholar, S. T. K. et associated with nontuberculous mycobacterial disease in Med. 2020; PubMed Scopus (12) Google Scholar, T. et are to Mycobacterium avium complex lung disease: Infect Dis. 2019; PubMed Scopus Google Scholar, L. C.S. of nontuberculous mycobacteria (NTM) with cystic fibrosis 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Marras T.K. et potentially undiagnosed nontuberculous mycobacterial lung disease patients with pulmonary disease: of a using claims J Respir Crit Care Med. 2021; Scholar, J. J. et in nontuberculous mycobacteria isolated in from a One. 2014; Scopus Google Scholar, J. S. W. and risk factors of pulmonary nontuberculous mycobacterial in the of 2019; PubMed Scopus Google Scholar, et al.The risk of mycobacterial associated with inhaled Respir J. 2017; PubMed Scopus Google Scholar Of 24 reported HR, reported and the reported or of studies reporting possible risk factors associated with NTM-PD were from the analysis for the meta-analysis that comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD, with from to the association (OR, 21.43; 95% CI, by a history of TB (OR, 12.69; 95% CI, interstitial lung disease (OR, 6.39; 95% CI, COPD (OR, 6.63; 95% CI, and asthma (OR, 4.15; 95% CI, Other factors noted to be associated with an increased risk of NTM-PD were including inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), corticosteroids (OR CI, and other such as or (OR 95% CI, as as treatment for (OR, 95% CI, solid tumors (OR, 4.66; 95% CI, the presence of pneumonia (OR, 5.54; 95% CI, disease (OR, 95% CI, and (OR, 95% CI, e-Table (OR, 95% CI, or high (OR, 95% CI, were associated with factors, and long-term use of for underlying disease, not was as against NTM-PD (OR, 95% CI, e-Table was a risk for with an OR of CI, risk factors for All data are as OR risk risk cystic of interstitial lung treatment risk factors for All data are as OR risk risk cystic of interstitial lung treatment Other or with NTM-PD were for lung function (OR, 95% CI, (OR, 95% CI, disease (OR, 95% CI, (OR, 95% CI, (OR, 95% CI, and infection with (OR, 95% CI, or (OR, 95% CI, The systematic literature review and meta-analysis to identify potential risk factors associated with NTM-PD reported in the literature and to The study data into a and of the of risk factors with The reported risk factors were use of COPD and history of or TB which is considered the risk for was assessed in for the meta-analysis that comorbid respiratory disease is associated with a significant increase in the risk of NTM-PD, with the association for bronchiectasis. Other comorbidities noted to be associated with an increased risk of NTM-PD were solid tumors, disease, and use of such as inhaled corticosteroids or treatment for The association between solid tumors and risk of NTM-PD may be a of therapy than the risk for NTM infection in patients with interstitial lung disease may be a of disease than a risk is also the of and the increased use of such as that may mycobacterial disease in The of therapy in clinical and in the 42: PubMed Scopus Google Scholar of may have significant for the of NTM-PD and may not be in of NTM-PD in people be and comorbid conditions, such as were not included in this study of of was highlighted as a risk in the systematic literature review S. M. et first at the pulmonary non-tuberculous mycobacteria Respir J. 2020; Scholar, T. et of nontuberculous mycobacterial lung disease and clinical of Mycobacterium complex disease: analysis for in a of One. 2017; Scopus Google Scholar, S. et epidemiology of nontuberculous mycobacterial lung disease the in a of the 2019; PubMed Scopus Google Scholar, M. V. et non-tuberculous mycobacteria in with COPD and association with increased risk of 2018; PubMed Scopus Google Scholar, F.C. D. et of nontuberculous mycobacterial pulmonary disease, Infect Dis. 22: PubMed Scopus Google Scholar but the studies appropriate data for meta-analysis an M. V. et non-tuberculous mycobacteria in with COPD and association with increased risk of 2018; PubMed Scopus Google Scholar This is clinical that is a risk for NTM-PD of into the and has been associated with burden and more radiologic T. et and medical of disease in non-tuberculous mycobacterial pulmonary disease: a Med. Scopus Google Scholar considered the risk for was than other risk factors in the studies in this was considered an studies high of patients with nodular bronchiectatic NTM-PD and is to be in patients with These patients can be considered to have bronchiectasis, is a risk or of NTM-PD is patients with have the highest of NTM the diagnosis, and management of which study. to be associated with NTM-PD was as a risk and to a against the risk of disease. for patients in studies were is not possible to patients to an increased risk of NTM-PD or with NTM or for NTM-PD reduced and leading to the for pneumonia is in that is risk to pneumonia is a of the underlying respiratory disease, or with such as C. Nielsen R. Thomsen V. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-362Crossref PubMed Scopus (252) Google D. W. of nontuberculous mycobacterial lung disease in 2017; Full Text Full Text PDF Google S. T. K. et associated with nontuberculous mycobacterial disease in Med. 2020; PubMed Scopus (12) Google L. C.S. of nontuberculous mycobacteria (NTM) with cystic fibrosis 15: Full Text Full Text PDF PubMed Scopus Google Marras T.K. et potentially undiagnosed nontuberculous mycobacterial lung disease patients with pulmonary disease: of a using claims J Respir Crit Care Med. 2021; Scholar The studies used for the pneumonia analysis also not include data pneumonia and in those in which data were from patients with data to disease were studies in the the of a solid the risk of D. C. et in the and mycobacterial Infect Dis. 2020; PubMed Scopus Google C. et factors for nontuberculous mycobacterial in solid a Infect Dis. 2014; PubMed Scopus Google Scholar et C. et factors for nontuberculous mycobacterial in solid a Infect Dis. 2014; PubMed Scopus Google Scholar reported that for patients a solid lung increased the risk for NTM infection (OR, 95% CI, and lung conferred the highest risk (OR, 95% CI, C. et factors for nontuberculous mycobacterial in solid a Infect Dis. 2014; PubMed Scopus Google Scholar et D. C. et in the and mycobacterial Infect Dis. 2020; PubMed Scopus Google Scholar the risk for NTM infection in patients and reported that or mycobacterial at the of was associated with an increased risk of mycobacterial infection 95% CI, and HR, 95% CI, D. 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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death. Idiopathic ventricular tachycardia (VT) is a cardiac arrhythmia that is seen in individuals without structural heart disease. Depending on the ECG characteristics, it can be classified as monomorphic VT or polymorphic VT, the latter comprising a number of uncommon, often malignant familial disorders, including catecholaminergic polymorphic VT (CPVT [MIM 604772]).1Badhwar N. Scheinman M.M. Idiopathic ventricular tachycardia: Diagnosis and management.Curr. Probl. Cardiol. 2007; 32: 7-43Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar CPVT is characterized by episodic syncope and/or sudden cardiac arrest induced by exercise or acute emotion.2Coumel P. Fidelle J. Lucet V. Attuel P. Bouvrain Y. Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: Report of four cases.Br. Heart J. 1978; 40: 28-37Google Scholar, 3Napolitano C. Priori S.G. Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia.Heart Rhythm. 2007; 4: 675-678Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar The ECG is usually within normal limits at rest and often displays prominent U waves, but ventricular arrhythmias might arise at times of adrenergic activation.4Aizawa Y. Komura S. Okada S. Chinushi M. Aizawa Y. Morita H. Ohe T. Distinct U wave changes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).Int. Heart J. 2006; 47: 381-389Crossref PubMed Scopus (38) Google Scholar, 5Viitasalo M. Oikarinen L. Väänänen H. Kontula K. Toivonen L. Swan H. U-waves and T-wave peak to T-wave end intervals in patients with catecholaminergic polymorphic ventricular tachycardia, effects of beta-blockers.Heart Rhythm. 2008; 5: 1382-1388Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The arrhythmias, typically bidirectional and/or polymorphic VT, can develop into ventricular fibrillation and sudden death, leading to a high mortality rate (30%–50% by the age of 30) for this disorder.6Fisher J.D. Krikler D. Hallidie-Smith K.A. Familial polymorphic ventricular arrhythmias: A quarter century of successful medical treatment based on serial exercise-pharmacologic testing.J. Am. Coll. Cardiol. 1999; 34: 2015-2022Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar CPVT often manifests in childhood, and a family history of juvenile sudden death and stress-induced syncope is present in approximately one-third of the cases. It can present as sudden death in children without any prior signs or warning,6Fisher J.D. Krikler D. Hallidie-Smith K.A. Familial polymorphic ventricular arrhythmias: A quarter century of successful medical treatment based on serial exercise-pharmacologic testing.J. Am. Coll. Cardiol. 1999; 34: 2015-2022Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and it has been estimated to cause up to 15% of unexplained sudden cardiac deaths in young people.7Liu N. Ruan Y. Priori S.G. Catecholaminergic polymorphic ventricular tachycardia.Prog. Cardiovasc. Dis. 2008; 51: 23-30Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Previously, familial assessment revealed little evidence of the condition in many victims of unexplained sudden death.8Behr E.R. Dalageorgou C. Christiansen M. Syrris P. Hughes S. Tome Esteban M.T. Rowland E. Jeffery S. McKenna W.J. Sudden arrhythmic death syndrome: Familial evaluation identifies inheritable heart disease in the majority of families.Eur. Heart J. 2008; 29: 1670-1680Crossref PubMed Scopus (333) Google Scholar, 9Tester D.J. Spoon D.B. Valdivia H.H. Makielski J.C. Ackerman M.J. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: A molecular autopsy of 49 medical examiner/coroner’s cases.Mayo Clin. Proc. 2004; 79: 1380-1384Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Mutations in the ryanodine receptor 2 gene (RYR2 [MIM 180902]) are known to cause dominantly inherited CPVT10Priori S.G. Napolitano C. Tiso N. Memmi M. Vignati G. Bloise R. Sorrentino V. Danieli G.A. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.Circulation. 2001; 103: 196-200Crossref PubMed Scopus (1145) Google Scholar (CPVT1 [MIM 604772], and more than 70 different mutations are currently known. A less common autosomal-recessive form of the disorder (CPVT2 [MIM 611938]) is caused by mutations in the calsequestrin-2 gene11Lahat H. Pras E. Olender T. Avidan N. Ben-Asher E. Man O. Levy-Nissenbaum E. Khoury A. Lorber A. Goldman B. et al.A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.Am. J. Hum. Genet. 2001; 69: 1378-1384Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar (CASQ2 [MIM 114251]). Mutations in these genes together explain a little more than half of all familial CPVT cases. Mutations in KCNJ2 [MIM 600681] and ANK2 [MIM 106410], normally causing Andersen-Tawil Syndrome (ATS [MIM 170390]) and type 4 long-QT syndrome (LQT4 [MIM 600919]), respectively, have in addition been found in a low number of individuals diagnosed with CPVT.12Mohler P.J. Splawski I. Napolitano C. Bottelli G. Sharpe L. Timothy K. Priori S.G. Keating M.T. Bennett V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.Proc. Natl. Acad. Sci. USA. 2004; 101: 9137-9142Crossref PubMed Scopus (276) Google Scholar, 13Tester D.J. Arya P. Will M. Haglund C.M. Farley A.L. Makielski J.C. Ackerman M.J. Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing.Heart Rhythm. 2006; 3: 800-805Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Finally, a locus for a severe form of CPVT (CPVT3 [MIM 614021]) was in 2007 localized to chromosome 7 without the identification of the disease gene.14Bhuiyan Z.A. Hamdan M.A. Shamsi E.T. Postma A.V. Mannens M.M. Wilde A.A. Al-Gazali L. A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22.J. Cardiovasc. Electrophysiol. 2007; 18: 1060-1066Crossref PubMed Scopus (61) Google Scholar Tightly controlled cycling of the intracellular calcium concentration is the basis for cardiac muscle contraction and determination of the heart rhythm. RYR2 is the sarcoplasmic reticulum (SR) calcium release channel. Upon a small increase in local intracellular Ca2+ concentration (from approximately 100 nM to a few micromolar), this channel switches from a closed to an open conformation, resulting in a large influx of Ca2+ from the SR storage and ultimately causing muscle contraction. The current molecular understanding of RYR2-associated VT is that RYR2 mutations render the tetrameric RYR2 complex “leaky,” thereby leading to increased local Ca2+ concentrations (Ca2+ sparks), untimely activation of nearby RYR2 clusters through calcium-induced calcium release (CICR), and eventual arrhythmia.15Cerrone M. Napolitano C. Priori S.G. Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation.Heart Rhythm. 2009; 6: 1652-1659Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 16Kontula K. Laitinen P.J. Lehtonen A. Toivonen L. Viitasalo M. Swan H. Catecholaminergic polymorphic ventricular tachycardia: Recent mechanistic insights.Cardiovasc. Res. 2005; 67: 379-387Crossref PubMed Scopus (84) Google Scholar The precise molecular mechanism is, however, still unclear, and it has been put forward that an abnormal interaction with one or more of the associated proteins or ions, such as FKBP12.6 or CASQ2, or abnormal activation by extraluminal or intraluminal Ca2+ ions also might play a role, as reviewed by Kontula et al.16Kontula K. Laitinen P.J. Lehtonen A. Toivonen L. Viitasalo M. Swan H. Catecholaminergic polymorphic ventricular tachycardia: Recent mechanistic insights.Cardiovasc. Res. 2005; 67: 379-387Crossref PubMed Scopus (84) Google Scholar and Mohler et al.17Mohler P.J. Wehrens X.H. Mechanisms of human arrhythmia syndromes: Abnormal cardiac macromolecular interactions.Physiology (Bethesda). 2007; 22: 342-350Crossref PubMed Scopus (27) Google Scholar Here we report a Swedish multiplex family presenting with a history of ventricular arrhythmias, syncopes and sudden death, predominantly in association with physical exercise or stress (Figure 1A). The index case (II:6), a now 42-year old man of Swedish ethnic origin, presented with syncope while playing football at the age of 12. The ECG at admission (Figure 1B, upper panel) showed sinus bradycardia (HR = 45/min) and prominent U-wave in V2 and V3, but no evidence of QT prolongation (QTc = 0.42 s). He had a history of loss of consciousness on at least four occasions during physical activity and once in connection with a fire alarm. A 24 hr ECG registration revealed ventricular extrasystoles (VES), bigemini, and paired VES (Figure 1B, lower panel) during football training, but no symptoms were reported. He was started on β1-adrenergic-receptor blocker treatment. At follow up, a 24 hr ECG and exercise test still showed some VES and bigemini under conditions of increasing load and heart rate. A genomic DNA sample from the index case was later screened for mutations in a panel of arrhythmia-associated genes, including RYR2 and CASQ2, where no mutations were identified. An older brother (II:4), aged 23, had a history of repeated syncope during exercise. During an exercise test, he displayed polymorphic VT (an ECG from that time is not available). After treatment with β1-adrenergic-receptor blocker, a follow-up exercise test showed VES at high loads. The family history also included a brother (II:3) who drowned during a swimming competition at age 15 after had prior of syncope and an older who from or After a later of ventricular fibrillation was by treatment with β1-adrenergic-receptor blocker and A presented at the age of 7 with a history of repeated syncope during physical family with syncope from age at age been with β1-adrenergic-receptor blocker for family started syncope at age was under treatment with β1-adrenergic-receptor blocker, and cardiac arrest at age After and and had an An older presented with syncope from age and under treatment with β1-adrenergic-receptor A presented with syncope at age and were put on β1-adrenergic-receptor blocker after syncope and of to the cases of syncope in and was on at the phenotypic of the family is characterized by CPVT-like with symptoms including syncope and cases of sudden death or cardiac The family no were in with the of the and on human After from all the we genomic DNA from samples from all the to linkage and by an in were with the The were all older than at the time of were by the and to the for with were with analysis of genetic maps gene Genet. PubMed Scopus Google Scholar and from the of monomorphic and a of and an of was was with S. B. K. L. M.A. D. J. P. de M.J. A for association and linkage J. Hum. Genet. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar and in a of in linkage with was for the identification of resulting in the of from the A linkage analysis with and a disease gene of was with with from the and genetic from the were identified and with a of (Figure in the A follow-up analysis with and in these was and included an from the family and and and individuals with the were were from the The analysis the locus on chromosome and mapped the disease locus to chromosome (Figure A analysis the of the chromosome disease in all and of the individuals (Figure of the mutation in this The peak on chromosome approximately from to a region that 70 genes (Figure and of the of calmodulin in calcium and heart CALM1 was for the and the and of CALM1 were with S. H. on the for and for PubMed Google Scholar The were and on at Sequencing one family index and one family revealed a heterozygous missense mutation in mutation in a from to without the to the in the index case (Figure A for for the was by with that the was present in all individuals and in all of the individuals in the of individuals medical from and showed that the mutation was among these sample an to a with a of and mutations in J. Hum. Genet. Full Text Full Text PDF PubMed Scopus (113) Google Scholar that the mutation is highly to be a normal but for mutations in we a for of the on the basis of of were with and referred for RYR2 mutation analysis at the in genetic to any RYR2 mutation in 61 of these were in samples with aberrant as as samples with normal were are in this screening a heterozygous CALM1 missense mutation was identified in an individual of Iraqi The mutation was in and in an (Figure DNA revealed that this mutation was in the and the of showed signs of heart arrhythmias, the of a de mutation in this A analysis the The individual with the de CALM1 mutation was a who presented at age 4 with a cardiac arrest to while was a and was by treatment with β1-adrenergic-receptor An ECG and were within normal and was no evidence of QT prolongation of family was An exercise ECG and on and ventricular and were within normal An of idiopathic was at the demonstrated prominent U in the but no evidence of the long-QT or (Figure upper was including cardiac and and were An exercise ECG while was β1-adrenergic-receptor blocker demonstrated ventricular with and of into (Figure lower to be bidirectional at this a of CPVT was but genetic of RYR2, CASQ2, and KCNJ2 to any mutations in these a follow-up genetic test of arrhythmia-associated genes, including and no mutations were more in and at age 15 a cardiac After an was and but was diagnosed with [MIM aged was heart to from treatment. not syncope or An ECG demonstrated and aged had syncope in with ECG was and exercise for had induced changes without An was as and Both CALM1 mutations to an and highly that to the severe end of the of CPVT-like with an to with β1-adrenergic-receptor blocker was with symptoms in the Iraqi case and in individuals and in family The that p.Asn97Ser is a de is with the of the associated disease as a highly malignant form with early and is with the RYR2-associated is caused by de S.G. Napolitano C. Memmi M. B. M. L. Bloise R. R. et and molecular of patients with catecholaminergic polymorphic ventricular tachycardia.Circulation. PubMed Scopus Google Scholar CALM1 missense mutations in the a of all CALM1 were in individuals. missense mutations were identified among these were identified were present among the missense mutations in this A Iraqi was not the mutation was de novo, and the mutation rate is to be the in all missense mutations in CALM1 were found from the through the release an of and from and of A also to present evidence for any identified calmodulin mutations. The of identified missense mutations is not that calmodulin is known as one of the conserved displays an in all and has the from (Figure The of genes in the human [MIM and all encoding calmodulin the any changes in this is a four that one calcium It is as a and is of a of small intracellular changes to a of intracellular in the and for of local and Ca2+ by calmodulin in complex with a Ca2+ 2008; Full Text Full Text PDF PubMed Scopus Google Scholar The the and and the the and The identified are in the is on the of the of in the and the is one of the of in the calmodulin (Figure to and the activity of a large number of intracellular but in of the calmodulin are the in with any or by the peptide complex in the we a to the CALM1 are in from a from M.T. C. Christiansen M. L. J. of and the of in human and 1999; PubMed Scopus Google Scholar and we this into a a mutations were with are in The calmodulin were in and were with and and and all was in and that Ca2+ be The Ca2+ concentration of the was to be and with the calcium and and an proteins were by and concentrations were by at The and of was by the of and calmodulin was calcium to a large in calmodulin and the it is to Ca2+ to the by the changes in M.A. to calmodulin effects on the of 2006; PubMed Scopus Google Scholar were with while the at was on a 4 with a at The Ca2+ demonstrated a in the Ca2+ for the p.Asn97Ser (Figure as by an concentration of to Ca2+ ions calmodulin to Ca2+ for calmodulin Ca2+ The on the demonstrated a but Ca2+ and an half of Ca2+ the is in the of we that this Ca2+ a Ca2+ and to increased of Ca2+ for the to at lower Ca2+ A less is that it an increased the and we that to calcium of calmodulin and that the different effects on the of Ca2+ the and of the interaction the calmodulin and a peptide from RYR2 the calmodulin was the of calmodulin to the peptide from the of calmodulin the of the peptide to RYR2 to calmodulin to an in on the is by a large increase in of the RYR2 calmodulin not any The at of RYR2 was with and without addition of of calmodulin under four different no Ca2+ including conditions conditions of calmodulin by and effects on Ca2+ and for Sci. 6: PubMed Scopus Google Scholar and Ca2+ conditions all in 100 The concentrations for and conditions were controlled with an as C. S. D. in to in 2004; PubMed Scopus Google Scholar A concentration of RYR2 peptide was with no calmodulin (RYR2 calmodulin and 100 nM or calmodulin and of calmodulin were at low calcium concentrations nM a in the was demonstrated for p.Asn97Ser as to and The p.Asn97Ser induced a and no increase in (Figure to the seen calmodulin to the ryanodine receptor J. to calmodulin to an in on the ryanodine 2001; PubMed Scopus Google Scholar peptide in the of little or no in the was and calmodulin at or calcium concentrations and that for the p.Asn97Ser the interaction is at low intracellular Ca2+ concentrations and is at to high Ca2+ concentrations. It is that calmodulin to RYR2, and it has been demonstrated that calmodulin the that RYR2 has an open at concentrations to 100 N. L. G. basis of calmodulin to cardiac muscle Ca(2+) release channel PubMed Scopus Google Scholar to a Ca2+ at we demonstrated a compromised interaction for the p.Asn97Ser the of a interaction at low Ca2+ concentrations to an increased that RYR2 has an open this we that a mutation with to the RYR2 a on the RYR2 channel complex and to RYR2 to is for RYR2 mutations. also explain one calmodulin of encoding proteins is to cause a dominantly inherited have that a calmodulin RYR2 interaction a in arrhythmia and heart N. L. G. basis of calmodulin to cardiac muscle Ca(2+) release channel PubMed Scopus Google Scholar, M. M. A. T. T. H. H. T. S. et of calmodulin from cardiac ryanodine receptor aberrant Ca2+ release in heart Res. PubMed Scopus Google Scholar, M. H. A. T. M. H. T. S. M. et calmodulin to the cardiac ryanodine receptor a in channel Res. PubMed Scopus (61) Google Scholar in a the human RYR2 found to be a for T. M. H. M. A. M. H. S. M. et within ryanodine receptor cause aberrant leading to catecholaminergic polymorphic ventricular tachycardia.Circulation. PubMed Scopus Google Scholar, H. M. T. M. H. T. S. M. S. et polymorphic ventricular tachycardia is caused by of the ryanodine Res. PubMed Scopus (116) Google Scholar and the interaction and found a for calmodulin in to the to conclude that a interaction RYR2 and calmodulin is part of the mechanism for M. H. A. T. M. H. T. S. M. et calmodulin to the cardiac ryanodine receptor a in channel Res. PubMed Scopus (61) Google Scholar are the human to the molecular disease in an aberrant interaction is causative of CPVT-like The not a compromised RYR2 interaction in the of is that we the interaction by a small peptide of the large RYR2 molecular it is at present the the of RYR2 in the of was different from the and p.Asn97Ser and it is that a different molecular mechanism is in play in family be of the mechanism for mutations in CPVT that calmodulin and is for a number of and in contraction. such and the calcium channel, and the P.J. Splawski I. Napolitano C. Bottelli G. Sharpe L. Timothy K. Priori S.G. Keating M.T. Bennett V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.Proc. Natl. Acad. Sci. USA. 2004; 101: 9137-9142Crossref PubMed Scopus (276) Google Scholar the screened included individuals who had arrhythmias or sudden cardiac death and had been referred for RYR2 CALM1 mutations were the family index case and the Iraqi case were included in this the of CALM1 mutations is low from this individuals were found to be for RYR2 the of CALM1 and RYR2 mutations were in this characterized and sample the and phenotypic of CALM1 mutations in CPVT and screening of large this is we that CALM1 is a to we have identified CALM1 missense mutations that to of CPVT or CPVT-like genetic in families in with this severe disorder CALM1 the of treatment for children and young individuals with disease mutations. a of the calmodulin genes are candidates for genetic screening of individuals with CPVT-like arrhythmia and unexplained sudden cardiac death. We all and families for We and K. for was by the the the the and the with and and The for presented are as Sequencing in Man The for the in this are for for for and for

The inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, functions as a dominant negative regulator of hypoxia-inducible transcription factors (HIFs) by forming complexes with those proteins that fail to bind to hypoxia response elements of target genes. We have previously observed that IPAS is predominantly expressed in mice in Purkinje cells of the cerebellum and in corneal epithelium of the eye where it appears to play a role in negative regulation of angiogenesis and maintenance of an avascular phenotype. Sequencing of the mouse IPAS genomic structure revealed that IPAS is a splicing variant of the HIF-3α locus. Thus, in addition to three unique exons (1a, 4a, and 16) IPAS shares three exons (2, 4, and 5) with HIF-3α as well as alternatively spliced variants of exons 3 and 6. In experiments using normal mice and mice exposed to hypoxia (6% O2) for 6 h we observed alternative splicing of the HIF-3α transcript in the heart and lung. The alternatively spliced transcript was only observed under hypoxic conditions, thus defining a novel mechanism of hypoxia-dependent regulation of gene expression. Importantly, this mechanism may establish negative feedback loop regulation of adaptive responses to hypoxia/ischemia in these tissues. The inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, functions as a dominant negative regulator of hypoxia-inducible transcription factors (HIFs) by forming complexes with those proteins that fail to bind to hypoxia response elements of target genes. We have previously observed that IPAS is predominantly expressed in mice in Purkinje cells of the cerebellum and in corneal epithelium of the eye where it appears to play a role in negative regulation of angiogenesis and maintenance of an avascular phenotype. Sequencing of the mouse IPAS genomic structure revealed that IPAS is a splicing variant of the HIF-3α locus. Thus, in addition to three unique exons (1a, 4a, and 16) IPAS shares three exons (2, 4, and 5) with HIF-3α as well as alternatively spliced variants of exons 3 and 6. In experiments using normal mice and mice exposed to hypoxia (6% O2) for 6 h we observed alternative splicing of the HIF-3α transcript in the heart and lung. The alternatively spliced transcript was only observed under hypoxic conditions, thus defining a novel mechanism of hypoxia-dependent regulation of gene expression. Importantly, this mechanism may establish negative feedback loop regulation of adaptive responses to hypoxia/ischemia in these tissues. hypoxia-inducible factor Per/Arnt/Sim inhibitory PAS domain protein annealing temperature von Hippel-Lindau tumor suppressor protein ubiquitin-protein isopeptide ligase reverse transcription expressed sequence tag Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor-1 (HIF-1)1 (1Semenza G.L. Annu. 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Two distinct mechanisms are important for regulation of HIF-1α and HIF-2α activity by oxygen. Under normoxic conditions, HIF-α proteins interact with the von Hippel-Lindau tumor suppressor protein, pVHL (6Maxwell P.H. Wiesener M.S. Chang G.W. Clifford S.C. Vaux E.C. Cockman M.E. Wykoff C.C. Pugh C.W. Maher E.R. Ratcliffe P.J. Nature. 1999; 399: 271-275Crossref PubMed Scopus (4085) Google Scholar). pVHL functions as an E3 ubiquitin ligase that targets HIF-α proteins for degradation by the proteasome (7Cockman M.E. Masson N. Mole D.R. Jaakkola P. Chang G.W. Clifford S.C. Maher E.R. Pugh C.W. Ratcliffe P.J. Maxwell P.H. J. Biol. Chem. 2000; 275: 25733-25741Abstract Full Text Full Text PDF PubMed Scopus (913) Google Scholar, 8Ohh M. Park C.W. Ivan M. Hoffman M.A. Kim T.Y. Huang L.E. Pavletich N. Chau V. Kaelin W.G. Nat. Cell Biol. 2000; 2: 423-427Crossref PubMed Scopus (1253) Google Scholar, 9Tanimoto K. Makino Y. Pereira T. Poellinger L. EMBO J. 2000; 19: 4298-4309Crossref PubMed Google Scholar). HIF-α-pVHL interaction is dependent upon hydroxylation of critical proline residues within the degradation domain of the HIF-α proteins (10Ivan M. Kondo K. Yang H. Kim W. Valiando J. Ohh M. Salic A. Asara J.M. Lane W.S. Kaelin W.G., Jr. Science. 2001; 292: 464-468Crossref PubMed Scopus (3840) Google Scholar,11Jaakkola P. Mole D.R. Tian Y.M. Wilson M.I. Gielbert J. Gaskell S.J. von Kriegsheim A. Hebestreit H.F. Mukherji M. Schofield C.J. Maxwell P.H. Pugh C.W. Ratcliffe P.J. Science. 2001; 292: 468-472Crossref PubMed Scopus (4389) Google Scholar). This posttranslational modification is inhibited under hypoxic conditions, resulting in stabilization of HIF-α protein levels, possibly due to reduced binding of O2 to HIF prolyl hydroxylase enzymes that require Fe(II) and O2 for function (12Bruick R.K. McKnight S.L. Science. 2001; 294: 1337-1340Crossref PubMed Scopus (2091) Google Scholar, 13Epstein A.C. Gleadle J.M. McNeill L.A. Hewitson K.S. O'Rourke J. Mole D.R. Mukherji M. Metzen E. Wilson M.I. Dhanda A. Tian Y.M. Masson N. Hamilton D.L. Jaakkola P. Barstead R. Hodgkin J. Maxwell P.H. Pugh C.W. Schofield C.J. Ratcliffe P.J. Cell. 2001; 107: 43-54Abstract Full Text Full Text PDF PubMed Scopus (2703) Google Scholar). In addition to stabilization of HIF-α protein levels, hypoxia induces the function of the transactivation domains of HIF-α proteins and enhances their ability to interact with transcriptional coactivator proteins (3Ema M. Taya S. Yokotani N. Sogawa K. Matsuda Y. Fujii-Kuriyama Y. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4273-4278Crossref PubMed Scopus (837) Google Scholar, 14Carrero P. Okamoto K. Coumailleau P. O'Brien S. Tanaka H. Poellinger L. Mol. Cell. Biol. 2000; 20: 402-415Crossref PubMed Scopus (322) Google Scholar, 15Kallio P.J. Okamoto K. O'Brien S. Carrero P. Makino Y. Tanaka H. Poellinger L. EMBO J. 1998; 17: 6573-6586Crossref PubMed Google Scholar, 16Kung A.L. Wang S. Klco J.M. Kaelin W.G. Livingston D.M. Nat. Med. 2000; 6: 1335-1340Crossref PubMed Scopus (471) Google Scholar). This interaction has recently been shown to be blocked by hydroxylation under normoxic conditions of a conserved asparagine residue within one of the two transactivation domains of HIF-1α and HIF-2α (17Lando D. Peet D.J. Whelan D.A. Gorman J.J. Whitelaw M.L. Science. 2002; 295: 858-861Crossref PubMed Scopus (1262) Google Scholar). Asparagine hydroxylation is abrogated under hypoxic conditions (17Lando D. Peet D.J. Whelan D.A. Gorman J.J. Whitelaw M.L. Science. 2002; 295: 858-861Crossref PubMed Scopus (1262) Google Scholar), and it has been speculated that both the prolyl and asparagine hydroxylases modulating HIF-α function may serve as oxygen sensors in the hypoxia signal transduction pathway. We have previously identified a novel factor, IPAS, that functions as a dominant negative regulator of HIF-α function. IPAS dimerizes with HIF-α proteins and thereby impairs productive interaction between HIF-α and hypoxia response elements of target genes (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar). Expression of IPAS in the cornea correlates with low levels of expression of the HIF-1α target gene vascular endothelial growth factor under hypoxic conditions (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar). Thus, it is possible that IPAS defines a novel mechanism of negative regulation of angiogenesis and maintenance of an avascular phenotype. Here we demonstrate that IPAS is an alternative splicing product of the HIF-3α locus. Interestingly, accumulation of the IPAS-specific alternative splicing product was hypoxia-inducible in the mouse heart and lung, indicating a previously unknown mode of negative feedback loop regulation of HIF-α-mediated signaling pathways in these tissues. BLAST searches of GenBankTMwere performed using the BLAST (19Altschul S.F. Madden T.L. Schaffer A.A. Zhang J. Zhang Z. Miller W. Lipman D.J. Nucleic Acids Res. 1997; 25: 3389-3402Crossref PubMed Scopus (59382) Google Scholar) service at the National Center for Biotechnology Information (NCBI) home page (www.ncbi.nih.gov) using our previously reported mouse IPAS cDNA sequence (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar), GenBankTM accession number AF416641. Eight-week-old C57Bl6 mice were exposed to either normoxia or hypoxia (maximally 6% O2) for 6 h, and total RNA samples from various tissues were obtained by the guanidine isothiocyanate method. All animal experiments were approved by the local animal research ethics committee of Stockholm, Sweden and the Institute of Medical Science, The University of Tokyo, Japan and conducted according to their guidelines. First-strand cDNA was synthesized using an oligo(dT)25 primer and 2 μg of DNase-treated total RNA as a template followed by a semiquantitative PCR analysis for IPAS- and HIF-3α-specific transcript levels relative to β-actin mRNA expression. To ensure that the PCR was in the exponential phase, different PCR cycles (ranging from 27 to 36) were tested,and 33 cycles of amplification were applied in most experiments unless otherwise specified. The identities of the PCR products were confirmed by sequencing. PCR primer pairs and annealing temperatures (ATs) for amplification of the exons were as follows: (i) exons 1a–16 of IPAS: sense (primer1), 5′-AGGGCGAGCCATGGCGTT-3′; antisense (primer2), 5′-TTTGTGGGTTTCTGGGCTAAG-3′; AT, 58 °C; (ii) exons 1–7 of HIF-3α: sense (primer3), 5′-GCTAAGTCCCGGAGAGGA-3′; antisense (primer4), 5′-TCCAAAGCGTGGATGTATTC-3′; AT, 54 °C; (iii) exon 4a of IPAS: sense (primer5), 5′-GAGGGTTTCGTCATGGTACT-3′; antisense (primer6), 5′-TCTTGAAGTTCCTCTTGGTC-3′; AT, 49 °C; (iv) exons 6–7 of HIF-3α: sense (primer7), 5′-CACTGCTCAGGACATATGAG-3′; antisense (primer8), 5′-TCCAAAGCGTGGATGTATTC-3′; AT, 49 °C; and (v) exons 6–16 of IPAS: sense (primer7), 5′-CACTGCTCAGGACATATGAG-3′; antisense (primer9), 5′-AGAGAGGATTCAGTCCCTT-3′; AT, 49 °C. Sequencing of mouse genomic DNA revealed that the IPAS mRNA species contains a unique first exon (GenBankTMaccession number AF481145) but shares exon 2 with HIF-3α (Fig.1). We have therefore used the exon numbering of the HIF-3α locus (5Gu Y.Z. Moran S.M. Hogenesch J.B. Wartman L. Bradfield C.A. Gene Expr. 1998; 7: 205-213PubMed Google Scholar) and termed the first exon of IPAS exon 1a of the HIF-3α locus. In addition to exon 1a, IPAS mRNA contains the unique exons 4a (GenBankTM accession numberAF481146) and 16 (GenBankTM accession number AF481147). Moreover, a mechanism of IPAS pre-mRNA splice site selection in exon 3 uses an alternative 3′ splice site 14 nucleotides downstream of the HIF-3α 3′ splice site. In a similar fashion in IPAS mRNA exon 6 an alternative 5′ splice site located 87 nucleotides upstream of the HIF-3α 5′ splice site is used (Fig. 1). The inclusion of exon 4a together with the use of the alternative 3′ splice site in exon 3 during IPAS mRNA processing results in a reading frame shift that determines a unique feature of IPAS. In conclusion, the IPAS mRNA is a product of alternative splicing of the HIF-3α locus. We next used primers specific for either IPAS or HIF-3α mRNAs (schematically represented in Fig.2) to monitor by RT-PCR analysis mRNA expression of these two mRNA species in heart tissue from control mice or mice exposed to hypoxia (6% O2) for 6 h. In agreement with earlier observations using RNA blot analysis (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar) we observed that hypoxia induces IPAS mRNA expression levels (Fig. 2). Interestingly, this analysis also indicated a corresponding down-regulation of HIF-3α mRNA levels (Fig. 2). RT-PCR analysis of RNA isolated from several control and hypoxic mouse tissues using a number of primers specific for the 5′ and 3′ untranslated regions of IPAS confirmed that we have obtained the full-length IPAS reading frame (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar), and, importantly, in similar analyses we have not detected any form of mouse HIF-3α mRNA that is generated by transcription of exon 1a. We next monitored the use of the IPAS-specific exon 4a in transcripts isolated from control or hypoxic mouse heart and lung tissues. As shown in Fig. 3, a transcript containing the IPAS-specific exon 4a was detected in these tissues only following exposure of the mice to hypoxia. The analysis was performed following different cycles of PCR amplification, demonstrating that the assay was performed within a linear range of amplification (Fig. 3). Thus, these results strongly suggest that accumulation of the IPAS splicing product is hypoxia-inducible in mouse heart and lung. In support of this model, analysis of the generation of the alternatively spliced form of exon 6, which is specific for IPAS mRNA, demonstrated the presence of this splicing product only in hypoxic mice (Fig.4). Taken together these data demonstrate that accumulation of the IPAS-specific alternative splicing product of the HIF-3α locus in mouse heart and lung is regulated by hypoxia.Figure 4Hypoxia-inducible accumulation of the IPAS-specific transcript of the HIF-3α locus. The presence of the IPAS-specific transcript containing a truncated version of exon 6 was monitored. RNA samples from either heart or lung tissue from control mice (maintained under normoxic conditions (N)) and mice exposed to hypoxia (H) were subjected to semiquantitative RT-PCR analysis using exon-specific sets of primers as indicated. β-Actin mRNA levels were monitored as a reference.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To identify the degree of hypoxia required to induce accumulation of the IPAS-specific splicing product of the HIF-3α gene in mouse heart, mice were exposed for 6 h to increasing degrees of hypoxia ranging from 18 to 6% O2. The IPAS-specific splicing product was first observed following exposure of mice to rather severe hypoxia, i.e. 8–6% O2 (Fig. 5). In summary, our results demonstrate that the dominant negative regulator of HIF-α function, IPAS, is generated by alternative splicing of the HIF-3α locus. Obviously, our data do not preclude the existence of intermediate splicing variants. In fact, as indicated by a comprehensive search of expressed sequence tag (EST) data bases there are human HIF-3α transcript variants that include the IPAS-specific exon 1a and also contain the IPAS-specific variant of exon 3 but lack the IPAS-specific exon 4a (Fig. 6). It is presently premature to conclude whether these EST sequences reflect splicing intermediates or fully processed mature transcripts. Against this background, it will be important to perform a careful genetic analysis in mice to determine the role of IPAS and possibly HIF-3α in regulation of hypoxia signaling. Interestingly, accumulation of the IPAS-specific alternative splicing product of the HIF-3α locus is hypoxia-inducible in mouse heart and lung tissues. During maintenance of mice under normoxic conditions, IPAS mRNA is expressed in a very tissue-restricted manner with readily detectable levels only found in the Purkinje neurons of the cerebellum and the cornea epithelium (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar). In the case of the latter tissue, the function of IPAS appears to provide a strategy of negative regulation of vascular endothelial growth factor gene expression and angiogenesis. This mode of negative regulation of HIF-1α function is important for the avascular phenotype of the cornea (18Makino Y. Cao R. Svensson K. Bertilsson G. Åsman M. Tanaka H. Cao Y. Berkenstam A. Poellinger L. Nature. 2001; 414: 550-555Crossref PubMed Scopus (517) Google Scholar). Hypoxia-inducible alternative splicing of the HIF-3α locus resulting in hypoxia-inducible IPAS mRNA expression in the heart and lung suggests that IPAS may modulate hypoxia- or ischemia-dependent adaptive gene regulatory responses in these tissues as well. Thus, in these tissues, hypoxia-inducible accumulation of the IPAS-specific alternative splicing product of the HIF-3α locus not only defines a novel mechanism of hypoxia-dependent gene regulation but also a potential mechanism of negative feedback loop regulation of HIF-α-mediated signaling pathways, which may be of considerable medical interest.

Academia and Clinic18 August 2009Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA StatementFREEDavid Moher, PhD, Alessandro Liberati, MD, DrPH, Jennifer Tetzlaff, BSc, and Douglas G. Altman, DSc, the PRISMA Group*David Moher, PhDFrom Ottawa Methods Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Università di Modena e Reggio Emilia, Modena, Italy; Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.Search for more papers by this author, Alessandro Liberati, MD, DrPHFrom Ottawa Methods Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Università di Modena e Reggio Emilia, Modena, Italy; Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.Search for more papers by this author, Jennifer Tetzlaff, BScFrom Ottawa Methods Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Università di Modena e Reggio Emilia, Modena, Italy; Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.Search for more papers by this author, and Douglas G. Altman, DScFrom Ottawa Methods Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Università di Modena e Reggio Emilia, Modena, Italy; Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom.Search for more papers by this author, the PRISMA Group*Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-151-4-200908180-00135 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editor's Note: In order to encourage dissemination of the PRISMA Statement, this article is freely accessible on the Annals of Internal Medicine Web site (www.annals.org) and will be also published in PLOS Medicine, BMJ, Journal of Clinical Epidemiology, and Open Medicine. The authors jointly hold the copyright of this article. For details on further use, see the PRISMA Web site (www.prisma-statement.org).Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field (1, 2), and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research (3), and some health care journals are moving in this direction (4). As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews.Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in four leading medical journals in 1985 and 1986 and found that none met all eight explicit scientific criteria, such as a quality assessment of included studies (5). In 1987, Sacks and colleagues (6) evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in six domains. Reporting was generally poor; between one and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement (7).In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized, controlled trials (8). In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1).Box 1. Conceptual Issues in the Evolution From QUOROM to PRISMA Download figure Download PowerPoint TerminologyThe terminology used to describe a systematic review and meta-analysis has evolved over time. One reason for changing the name from QUOROM to PRISMA was the desire to encompass both systematic reviews and meta-analyses. We have adopted the definitions used by the Cochrane Collaboration (9). A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyze data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyze and summarize the results of the included studies. Meta-analysis refers to the use of statistical techniques in a systematic review to integrate the results of included studies.Developing the PRISMA StatementA three-day meeting was held in Ottawa, Ontario, Canada, in June 2005 with 29 participants, including review authors, methodologists, clinicians, medical editors, and a consumer. The objective of the Ottawa meeting was to revise and expand the QUOROM checklist and flow diagram, as needed.The executive committee completed the following tasks, prior to the meeting: a systematic review of studies examining the quality of reporting of systematic reviews, and a comprehensive literature search to identify methodological and other articles that might inform the meeting, especially in relation to modifying checklist items. An international survey of review authors, consumers, and groups commissioning or using systematic reviews and meta-analyses was completed, including the International Network of Agencies for Health Technology Assessment (INAHTA) and the Guidelines International Network (GIN). The survey aimed to ascertain views of QUOROM, including the merits of the existing checklist items. The results of these activities were presented during the meeting and are summarized on the PRISMA Web site (www.prisma-statement.org).Only items deemed essential were retained or added to the checklist. Some additional items are nevertheless desirable, and review authors should include these, if relevant (10). For example, it is useful to indicate whether the systematic review is an update (11) of a previous review, and to describe any changes in procedures from those described in the original protocol.Shortly after the meeting a draft of the PRISMA checklist was circulated to the group, including those invited to the meeting but unable to attend. A disposition file was created containing comments and revisions from each respondent, and the checklist was subsequently revised 11 times. The group approved the checklist, flow diagram, and this summary paper.Although no direct evidence was found to support retaining or adding some items, evidence from other domains was believed to be relevant. For example, Item 5 asks authors to provide registration information about the systematic review, including a registration number, if available. Although systematic review registration is not yet widely available (12, 13), the participating journals of the International Committee of Medical Journal Editors (ICMJE) (14) now require all clinical trials to be registered in an effort to increase transparency and accountability (15). Those aspects are also likely to benefit systematic reviewers, possibly reducing the risk of an excessive number of reviews addressing the same question (16, 17) and providing greater transparency when updating systematic reviews.The PRISMA StatementThe PRISMA Statement consists of a 27-item checklist (Table 1; see also Table S1, for a downloadable Word template for researchers to re-use) and a four-phase flow diagram (Figure 1; see also Figure S1, for a downloadable Word template for researchers to re-use). The aim of the PRISMA Statement is to help authors improve the reporting of systematic reviews and meta-analyses. We have focused on randomized trials, but PRISMA can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions. PRISMA may also be useful for critical appraisal of published systematic reviews. However, the PRISMA checklist is not a quality assessment instrument to gauge the quality of a systematic review.Table 1. Checklist of Items to Include When Reporting a Systematic Review or Meta-AnalysisFigure 1. Flow of information through the different phases of a systematic review. Download figure Download PowerPoint From QUOROM to PRISMAThe new PRISMA checklist differs in several respects from the QUOROM checklist, and the substantive specific changes are highlighted in Table 2. Generally, the PRISMA checklist “decouples” several items present in the QUOROM checklist and, where applicable, several checklist items are linked to improve consistency across the systematic review report.Table 2. Substantive Specific Changes Between the QUOROM Checklist and the PRISMA ChecklistThe flow diagram has also been modified. Before including studies and providing reasons for excluding others, the review team must first search the literature. This search results in records. Once these records have been screened and eligibility criteria applied, a smaller number of articles will remain. The number of included articles might be smaller (or larger) than the number of studies, because articles may report on multiple studies and results from a particular study may be published in several articles. To capture this information, the PRISMA flow diagram now requests information on these phases of the review process.EndorsementThe PRISMA Statement should replace the QUOROM Statement for those journals that have endorsed QUOROM. We hope that other journals will support PRISMA; they can do so by registering on the PRISMA Web site. To underscore to authors, and others, the importance of transparent reporting of systematic reviews, we encourage supporting journals to reference the PRISMA Statement and include the PRISMA Web address in their instructions to authors. We also invite editorial organizations to consider endorsing PRISMA and encourage authors to adhere to its principles.The PRISMA Explanation and Elaboration PaperIn addition to the PRISMA Statement, a supporting Explanation and Elaboration document has been produced (18) following the style used for other reporting guidelines (19–21). The process of completing this document included developing a large database of exemplars to highlight how best to report each checklist item, and identifying a comprehensive evidence base to support the inclusion of each checklist item. The Explanation and Elaboration document was completed after several face-to-face meetings and numerous iterations among several meeting participants, after which it was shared with the whole group for additional revisions and final approval. Finally, the group formed a dissemination subcommittee to help disseminate and implement PRISMA.DiscussionThe quality of reporting of systematic reviews is still not optimal (22–27). In a recent review of 300 systematic reviews, few authors reported assessing possible publication bias (22), even though there is overwhelming evidence both for its existence (28) and its impact on the results of systematic reviews (29). Even when the possibility of publication bias is assessed, there is no guarantee that systematic reviewers have assessed or interpreted it appropriately (30). Although the absence of reporting such an assessment does not necessarily indicate that it was not done, reporting an assessment of possible publication bias is likely to be a marker of the thoroughness of the conduct of the systematic review.Several approaches have been developed to conduct systematic reviews on a broader array of questions. For example, systematic reviews are now conducted to investigate cost-effectiveness (31), diagnostic (32) or prognostic questions (33), genetic associations (34), and policy making (35). The general concepts and topics covered by PRISMA are all relevant to any systematic review, not just those whose objective is to summarize the benefits and harms of a health care intervention. However, some modifications of the checklist items or flow diagram will be necessary in particular circumstances. For example, assessing the risk of bias is a key concept, but the items used to assess this in a diagnostic review are likely to focus on issues such as the spectrum of patients and the verification of disease status, which differ from reviews of interventions. The flow diagram will also need adjustments when reporting individual patient data meta-analysis (36).We have developed an explanatory document (18) to increase the usefulness of PRISMA. For each checklist item, this document contains an example of good reporting, a rationale for its inclusion, and supporting evidence, including references, whenever possible. We believe this document will also serve as a useful resource for those teaching systematic review methodology. We encourage journals to include reference to the explanatory document in their Instructions to Authors.Like any evidence-based endeavor, PRISMA is a living document. To this end we invite readers to comment on the revised version, particularly the new checklist and flow diagram, through the PRISMA Web site. We will use such information to inform PRISMA's continued development.References1. Oxman AD, Cook DJ, Guyatt GH. Users' guides to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA. 1994;272:1367-71. [PMID: 7933399] CrossrefMedlineGoogle Scholar2. Swingler GH, Volmink J, Ioannidis JP. Number of published systematic reviews and global burden of disease: database analysis. BMJ. 2003;327:1083-4. [PMID: 14604930] CrossrefMedlineGoogle Scholar3. Canadian Institutes of Health Research. Randomized controlled trials registration/application checklist. December 2006. Accessed at www.cihr-irsc.gc.ca/e/documents/rct_reg_e.pdf on 19 May 2009. Google Scholar4. Young C, Horton R. Putting clinical trials into context. Lancet. 2005;366:107-8. [PMID: 16005318] CrossrefMedlineGoogle Scholar5. Mulrow CD. 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[PMID: CrossrefMedlineGoogle In to A Article, and Disclosure From Ottawa Methods Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Università di Modena e Reggio Emilia, Modena, Italy; Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Centre for Statistics in Medicine, University of Oxford, Oxford, United The following to the PRISMA Altman, DSc, Centre for Statistics in Medicine United PhD, University Hospital MD, Health Research & Health PLoS Medicine United PhD, Hospital of Ontario, A. & Research and PhD, PLoS Medicine the of United PhD, Cochrane Centre United and of and MD, of Medicine, Clinical Epidemiology and University Ontario, PhD, Università di Modena e Reggio and Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario J. PhD, University of United MD, PhD, of Medicine, Clinical Epidemiology and University Ontario, PhD, of Health MD, of and Medicine, University of MD, PhD, Medical United MD, The Cochrane Centre PhD, Ottawa Hospital Research Institute Ontario, MD, of Medicine, Clinical Epidemiology and University Ontario, PhD, United MD, University of MD, PhD, Systematic Reviews United and for Health and University of the and Alessandro Liberati, MD, Università di Modena e Reggio and Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario MD, Centre for the of the of Health PhD, The United MD, Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Moher, PhD, Ottawa Methods Centre, Ottawa Hospital Research Institute Ontario, MD, Annals of Internal Medicine for Medical MD, Health Research Centre Health and Technology Assessment Ontario, Canada; at the of the first meeting of the group, Ontario, MD, University of Hospital of Ontario, PhD, Health International G. MD, PhD, Evidence-Based Jennifer Tetzlaff, BSc, Ottawa Methods Centre, Ottawa Hospital Research Institute Ontario, The Cochrane Cochrane Collaboration United at the of the first meeting of the group, United and MD, Institute of University of Ottawa Ontario, PRISMA was by the Canadian Institutes of Health Università di Modena e Reggio Emilia, Italy; Research Clinical Evidence The Cochrane Collaboration; and Liberati is in through of the of University and Altman is by Research Moher is by a University of Ottawa Research of the any in the or of the PRISMA no a role in the Moher, PhD, Ottawa Methods Centre, Ottawa Hospital Research Institute, The Ottawa Ottawa, Canada; Moher and Ottawa Methods Centre, Ottawa Hospital Research Institute, The Ottawa Ottawa, Università di Modena e Reggio and Centro Cochrane Italiano, Istituto Ricerche Farmacologiche Mario Negri, Milan, Centre for Statistics in Medicine, University of Oxford, United of the PRISMA is in the PRISMA Statement for Reporting Systematic Reviews and of Studies Health Explanation and Elaboration Alessandro Liberati Douglas G. Altman Jennifer

Some patients with atopic asthma have ongoing symptoms and exacerbations despite normal lung function.1O’Byrne P.M. Barnes P.J. Rodriguez-Roisin R. Runnerstrom E. Sandstrom T. Svensson K. et al.Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.Am J Respir Crit Care Med. 2001; 164: 1392-1397Crossref PubMed Scopus (638) Google Scholar Poor asthma control, or an exacerbation, often results in the need for intervention with oral corticosteroids.2Walsh L.J. Wong C.A. Cooper S. Guhan A.R. Pringle M. Tattersfield A.E. Morbidity from asthma in relation to regular treatment: a community based study.Thorax. 1999; 54: 296-300Crossref PubMed Scopus (73) Google Scholar Many factors contribute to the loss of control including allergen exposure and/or a respiratory infection.3Price D. The use of omalizumab in asthma.Prim Care Respir J. 2008; 17: 62-72Crossref PubMed Scopus (38) Google Scholar Because IgE plays an important role in asthma, treatment to reduce serum IgE, and hence tissue-bound IgE, has been shown to modify the response to inhaled allergen and exacerbations.4Chung K.F. Anti-IgE monoclonal antibody, omalizumab: a new treatment for allergic asthma.Expert Opin Pharmacother. 2004; 5: 439-446Crossref PubMed Scopus (20) Google Scholar, 5Shields R.L. Whether W.R. Zioncheck K. O’Connell L. Fendly B. Presta L.G. et al.Inhibition of allergic reactions with antibodies to IgE.Int Arch Allergy Immunol. 1995; 107: 308-312Crossref PubMed Scopus (169) Google Scholar Omalizumab (Xolair; Genentech Inc, South San Francisco, Calif), an injectable recombinant humanized mAb that selectively binds to free IgE, is currently indicated in the United States for the treatment of patients (aged ≥12 years) with moderate-to-severe allergic asthma who remain inadequately controlled on inhaled corticosteroids (ICS).6Omalizumab (Xolair®) label. Novartis US, Genentech, January 2010. Available at: http://www.gene.com. Accessed December 4, 2012.Google Scholar Here we report the findings of a 24-week, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted to fulfill a postmarketing commitment that evaluated the effectiveness of omalizumab in patients aged 12 to 75 years with atopic asthma (elevated serum total IgE levels ≥30-≤1300 IU/mL) who remained symptomatic and uncontrolled on ICS with or without other controller medications despite having normal lung function (baseline predicted FEV1 ≥80%). The primary end point was the average rate of asthma exacerbations, predefined in the study protocol as a worsening of asthma requiring treatment with oral or intravenous corticosteroids and/or a doubling of the baseline ICS dose for 3 or more days during the treatment period. Further details of study methodology, including secondary and preplanned analyses, are detailed in this article's Online Repository at www.jacionline.org. To investigate what factors might predict treatment outcomes in this patient population, a preplanned analysis was performed in 2 subgroups divided according to eosinophil counts at screening: low (<300/μL) and high (≥300/μL). Overall, 328 randomized patients received at least 1 dose of study treatment and were evaluable for efficacy and safety (omalizumab [n = 157] or placebo [n = 171]; see Fig E1 in this article's Online Repository at www.jacionline.org). Patient demographics and baseline characteristics were well balanced between the 2 treatment groups, as well as in the subgroups with high (≥300/μL) or low (<300/μL) eosinophil counts at baseline (see Tables E1 and E2 in this article's Online Repository at www.jacionline.org). The primary end point of the study was not met. Although there was a 27% reduction in protocol-defined exacerbation rates with omalizumab versus placebo (0.21 vs 0.26 per patient during the 24-week treatment period; relative risk [RR], 0.73; 95% CI, 0.44-1.24), this treatment effect was not statistically significant (Table I). A sensitivity analysis showed that the rate of exacerbations defined according to the recent American Thoracic Society (ATS)/European Respiratory Society (ERS) update7Fuhlbrigge A. Peden D. Apter A.J. Boushey H.A. Camargo Jr., C.A. Gern J. et al.Asthma outcomes: exacerbations.J Allergy Clin Immunol. 2012; 129: S34-S48Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar was reduced by 14% (0.19 vs 0.20; RR, 0.86; 95% CI, 0.48-1.55). In addition, a subgroup analysis demonstrated that there was no information contributed by patients with no prior exacerbations. Because of the fact that patient eligibility for enrollment was highly limited, the study was underpowered to demonstrate a statistically significant treatment effect in the primary end point. As the primary efficacy end point did not reach statistical significance, the improvements in lung function (secondary efficacy end points) observed with omalizumab were not considered statistically significant because of the prespecified gatekeeping strategy used to control the familywise type I error rate (see Fig E2, Fig E3, Fig E4 and Table E3 this article's Online Repository at www.jacionline.org for results of secondary end points/preplanned analyses). Similarly, results for the following subgroup analysis should be interpreted with caution.Table IChange in protocol-defined asthma exacerbation rate over the 24-week treatment period (mITT population), and by high and low eosinophil counts at screeningmITT populationOmalizumab (n = 157)Placebo (n = 171)No. of protocol-defined asthma exacerbations, n (%) 0133 (84.7)138 (80.7) 121 (13.4)25 (14.6) ≥23 (1.9)8 (4.7)Unadjusted exacerbation rate∗Number of protocol-defined asthma exacerbations/total patient-treatment period.0.210.26Poisson regression†Poisson regression with overdispersion model is adjusted for dosing regimen and prior exacerbation status. Ratio of exacerbation rates‡Omalizumab/placebo. (95% CI)0.73 (0.44-1.24) P value.25Eosinophil counts at screeningOmalizumab (n = 51)Placebo (n = 40)HighNo. of protocol-defined asthma exacerbations, n (%) 041 (80.4)25 (62.5) 19 (17.6)9 (22.5) ≥21 (2.0)6 (15.0)Unadjusted exacerbation rate∗Number of protocol-defined asthma exacerbations/total patient-treatment period.0.250.59Poisson regression§Poisson regression with overdispersion model including terms for treatment, dosing regimen, and prior exacerbation status. Ratio of exacerbation rates‡Omalizumab/placebo. (95% CI)0.41 (0.20-0.82) P value.0125Low(n = 56)(n = 70)No. of protocol-defined asthma exacerbations, n (%) 048 (85.7)60 (85.7) 17 (12.5)9 (12.9) ≥21 (1.8)1 (1.4)Unadjusted exacerbation rate∗Number of protocol-defined asthma exacerbations/total patient-treatment period.0.170.16Poisson regression‡Omalizumab/placebo. Ratio of exacerbation rates§Poisson regression with overdispersion model including terms for treatment, dosing regimen, and prior exacerbation status. (95% CI)1.07 (0.45-2.53) P value.8807mITT, Modified intent-to-treat population.∗ Number of protocol-defined asthma exacerbations/total patient-treatment period.† Poisson regression with overdispersion model is adjusted for dosing regimen and prior exacerbation status.‡ Omalizumab/placebo.§ Poisson regression with overdispersion model including terms for treatment, dosing regimen, and prior exacerbation status. Open table in a new tab mITT, Modified intent-to-treat population. It is clinically noteworthy that the treatment response to omalizumab appeared to differ according to patients' blood eosinophil count at baseline. In patients with an eosinophil count of 300/μL or more, omalizumab treatment resulted in a 59% reduction in the rate of protocol-defined exacerbations versus placebo (0.25 vs 0.59; RR, 0.41; 95% CI, 0.20-0.82; Fig 1). In the corresponding sensitivity analysis according to the ATS/ERS exacerbation definition, the omalizumab group exhibited a 45% reduction compared with placebo (0.22 vs 0.40 per patient; RR, 0.55; 95% CI, 0.25-1.22). In patients with low eosinophil counts at baseline, omalizumab showed no improvement versus placebo in the protocol-defined exacerbation rate (0.17 vs 0.16; RR, 1.07; 95% CI, 0.45-2.53) (Table I). Although the primary end point was not achieved in this study, the markedly improved effectiveness of omalizumab in terms of the reduction in the rate of exacerbations in the subgroup with high eosinophil count is a potentially important finding. Although the treatment effect was reduced when the ATS/ERS exacerbation definition was used, there remained a trend toward a lower exacerbation rate in omalizumab-treated patients with high eosinophil counts compared with placebo. Furthermore, patients in the placebo group with eosinophil counts of 300/μL or more had a higher exacerbation rate compared with those in the low eosinophil subgroup, suggesting that high eosinophil counts may be a prognostic indicator for patients at greater risk of exacerbations. Our subgroup analyses therefore indicate that eosinophil count may have value as a biomarker to identify patients with symptomatic asthma despite normal lung function who could potentially benefit from omalizumab treatment. The peripheral blood eosinophil count is a well-recognized marker of inflammation in asthma,8Prussin C. Metcalfe D.D. 4. IgE, mast cells, basophils, and eosinophils.J Allergy Clin Immunol. 2003; 111: S486-S494Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar and previous studies have demonstrated a consistent pattern of improved clinical outcomes associated with decreased eosinophil counts in patients receiving omalizumab.9Massanari M. Holgate S.T. Busse W.W. Jimenez P. Kianifard F. Zeldin R. Effect of omalizumab on peripheral blood eosinophilia in allergic asthma.Respir Med. 2010; 104: 188-196Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Eosinophil count is recommended as a supplemental biomarker measure by the Asthma Outcomes workshop.10Szefler S.J. Wenzel S. Brown R. Erzurum S.C. Fahy J.V. Hamilton R.G. et al.Asthma outcomes: biomarkers.J Allergy Clin Immunol. 2012; 129: S9-23Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar Omalizumab was well tolerated in the present study, and safety data were consistent with the established profile of omalizumab, with no new safety signals observed. Details of the safety findings are included in Table E4 the Online Repository at www.jacionline.org. In summary, our findings suggest that the small subpopulation of patients with normal lung function but ongoing symptoms, despite treatment with ICS, who have high peripheral blood eosinophils may benefit from treatment with omalizumab. Although the present study is limited by the lack of statistical significance for the primary end point, the subgroup analyses indicate that eosinophil count may have potential as a biomarker to predict omalizumab treatment outcomes, and should be further investigated in randomized, double-blind, placebo-controlled trials. To be eligible for inclusion, patients were required to have inadequate symptom control, defined as a daytime asthma symptom score of 1 or more on at least 20 days and a mean symptom score of 1.5 or more, or nighttime awakening due to asthma symptoms more than 4 times during the 4-week run-in period. Patients were excluded if they had received chronic systemic corticosteroids (oral or intravenous) within 3 months or had received a burst of oral corticosteroids within 2 weeks prior to screening; had received omalizumab therapy at any time within 12 months prior to screening; had a significant medical illness/active lung disease other than asthma; were pregnant/lactating; or had taken immunosuppressants or other investigational drugs within the 30 days prior to screening. To increase the rate of enrollment, the study protocol was amended to remove the inclusion criterion requiring that patients had to have had at least 1 exacerbation requiring corticosteroids/a doubling of the dose of ICS. After a 4-week run-in period, eligible patients were randomized to receive omalizumab or placebo in a 1:1 ratio for 24 weeks, stratified by study center and dosing regimen (every 2 or 4 weeks). Omalizumab dose was determined on the basis of pretreatment serum total IgE level (IU/mL) and body weight (kg) according to the European omalizumab dosing table, which ensured a minimum omalizumab dose of 0.008 mg/kg/IgE (IU/mL) every 2 weeks or a minimum of 0.016 mg/kg/IgE (IU/mL) every 4 weeks. No modifications to the doses of omalizumab or concomitant asthma/nonasthma medications (established prior to the 4-week run-in period) were allowed during the study. The study was conducted according to US Food and Drug Administration regulations, the International Conference on Harmonisation E6 Guideline for Good Clinical Practice, and any national requirements, and was approved by local or central institutional review boards. Written informed consent was obtained from all patients (or the patients' parent/legal guardian if the patients were younger than 18 years) prior to enrollment. A permuted block design of randomization was used to ensure treatment balance overall, within each study center, and within the study drug dosing regimens (subcutaneous administration every 2 or 4 weeks). A list of randomization numbers in 10 blocks of 4 was generated for each study center and each of the 2 study drug dosing regimens. A randomization schedule was generated for all sites as an ASCII file by including the following information: randomization number, treatment assignment, site, and dosing frequency. and the study were to the treatment the study. drug were to treatment to each Because of in between the omalizumab and placebo which may have the drug was and/or by an or other who was not in study The primary efficacy was the average rate of asthma exacerbations during the 24-week treatment period, which from the dosing and 30 days following the dosing of study or was The definition of asthma exacerbations used in this study that by a recent ATS/ERS A. Peden D. Apter A.J. Boushey H.A. Camargo C.A. Gern J. et al.Asthma outcomes: exacerbations.J Allergy Clin Immunol. 2012; 129: Full Text Full Text PDF PubMed Scopus Google Scholar A sensitivity analysis was conducted to the effect of omalizumab on exacerbations, which excluded doubling of the baseline ICS dose from the protocol definition of an included from baseline to 24 in and daytime asthma symptom symptom score on a during the and relative from baseline to 24 in predicted Patients asthma symptoms, and use by report by the study which were during the 4-week run-in period and the treatment period. were performed in with Thoracic of J Respir Crit Care Med. 1995; PubMed Scopus Google Scholar was evaluated by and the and of with to of and The of was and clinical were analyses were performed on all randomized patients who received at least 1 dose of the study defined as the intent-to-treat population. patients received treatment of the in this study was to the used for the safety Poisson regression model adjusted for overdispersion was used to the primary efficacy end point to the effect of omalizumab on the rate of protocol-defined asthma exacerbations. A between treatment was performed by the with of all primary and secondary efficacy end was adjusted for 2 dosing schedule (every 2 or 4 and prior exacerbation status. The was and the corresponding 95% was predicted FEV1 were on the basis of the of et and that Respir Google Scholar for patients 18 years or and the of and function in and Scholar for patients younger than 18 from baseline to 24 was compared between treatment by an analysis of model in which the baseline predicted FEV1 dosing regimen, and asthma exacerbation the 12 months prior to or during the run-in period) were from baseline to 24 was compared between treatment by an The was used for of data for patients who from baseline to 24 in and daytime asthma symptom was compared between treatment by an model with including baseline symptom dosing regimen, and asthma exacerbation status. symptom were for more than days of the days prior to a the mean symptom were considered for the and were by the In the of the familywise type I error was controlled a gatekeeping strategy with the end in the following statistical the primary end point of average rate of protocol-defined asthma exacerbations during the 24-week treatment period, in by the secondary end of at 24 from baseline in predicted in symptoms and in daytime symptoms a lack of statistical significance was at any could not that A preplanned subgroup analysis was conducted to the effect on eosinophil counts at with patients divided 2 low (<300/μL) and high (≥300/μL). analysis was prior to of the study data in response to the of eosinophil counts in atopic eosinophil counts were not for all patients at baseline and may therefore have been at on in the subgroup analyses were conducted to the effect of study drug dosing regimen weeks vs 4 and prior exacerbation during the 12 months prior to or during the run-in As this study was to fulfill a postmarketing commitment to study omalizumab in a that was not consistent with that for which treatment is indicated in clinical the of patients eligible for enrollment was highly to for Asthma on asthma omalizumab is recommended as an treatment to a or ICS following of a or for The strategy for asthma and Available at: Accessed December 4, 2012.Google Scholar the end of the period, patients had been a Poisson regression patients to demonstrate a statistically significant treatment effect for the 27% reduction in the asthma exacerbation rate observed in this study. The study was conducted at in the United and patient is shown in Fig The study was by patients of the omalizumab of the placebo Overall, 328 patients received at least 1 dose of study treatment (mITT 2 patients in the omalizumab group and 3 in the placebo group were randomized but did not receive treatment as they were to be Patient demographics and baseline characteristics were well balanced between the treatment E1 and The of patients received concomitant ICS and which included receiving a the 12 months prior to randomization and during the run-in period, of the patients had no exacerbations, had 1 asthma exacerbation, and had 2 or more exacerbations. omalizumab-treated patient had a low baseline FEV1 value of in relative of more than in FEV1 at The data from this patient were considered and were from the FEV1 by from baseline to 24 in the omalizumab compared with a of in the placebo predicted FEV1 by in the omalizumab group and decreased by in the placebo on the the treatment effect in relative of FEV1 was to be (95% CI, in mean asthma symptom at 24 from baseline was as in the omalizumab group and in the placebo in mean daytime asthma symptom was as in the omalizumab group and in the placebo on the the treatment in in and daytime asthma symptom were not statistically significant and to be (95% CI, to and (95% CI, to on the peripheral blood eosinophil counts at were from of 328 patients in the in of a prespecified patients had an eosinophil count of 300/μL or more at baseline. In patients with a high eosinophil count at baseline, the least mean treatment effect for relative in FEV1 from baseline to 24 was to be (95% CI, In patients with a low baseline eosinophil the least mean treatment effect for relative in FEV1 was (95% CI, to were no significant in treatment effect between treatment when patient data were according to exacerbation or dosing regimen in patients with and without a exacerbation protocol-defined exacerbation rates per patient were and in the omalizumab group and 0.40 and in the placebo during the 24-week treatment period. this subgroup analysis demonstrated that there was no information contributed by patients with no prior exacerbations (Table No was between baseline IgE levels and eosinophil counts at not The definition that in clinical a asthma exacerbation should at least 1 of the use of systemic corticosteroids or an increase from a for at least 3 or or because of asthma, and requiring systemic exacerbations are defined as that are to the and that a need for a in treatment, but that are not are clinically by the of asthma Boushey H.A. Busse W.W. et American Thoracic Respiratory Society Asthma and for Clinical Asthma and Clinical J Respir Crit Care Med. PubMed Scopus Google Scholar analyses were conducted to the effect of omalizumab on exacerbations defined according to doubling of ICS from the the total study population, including a patient with mean predicted FEV1 by in the omalizumab group and decreased by in the placebo group from baseline to FEV1 by from baseline to 24 in the omalizumab compared with a of in the placebo on the the treatment effect in relative from baseline in FEV1 at 24 was to be (95% CI, The of with omalizumab was to that of the placebo were mild or in and were (Table patients the study because of an 3 patients in the omalizumab group and 1 patient in the placebo In the omalizumab 1 patient each a and of which was considered to be to the study 1 patient of and that were considered to be to the study The patient in the placebo group a of No were observed during the treatment or No clinically including count were The of of and was low and between treatment No as serum or of relative from baseline in FEV1 (mITT 1 patient with for dosing regimen and prior exacerbation = = = = ratio (95% of protocol-defined asthma exacerbation by prior exacerbation and dosing regimen every 2 every 4 of relative from baseline in FEV1 (mITT for dosing regimen and prior exacerbation = = = = demographics and baseline characteristics (mITT (n = 157)Placebo (n = n (%) mean n (%) n (%) or American weight mean serum IgE mean = FEV1 mean FEV1 mean = during the 12 prior to and during the run-in period. asthma n (%) ICS ICS patients in the other ICS other patients in the other dose mean = of mean = = symptom mean = = counts = = = = n = during the 12 prior to and during the run-in The patients in the other n = n = n = Open table in a new tab Table demographics and baseline characteristics for the subgroups of patients with high or low eosinophil eosinophil subgroup eosinophil subgroup (n = 51)Placebo (n = (n = (n = n (%) mean n (%) n (%) or American weight mean serum IgE mean = FEV1 mean FEV1 mean during the 12 prior to and during the run-in period. (12.9) asthma n (%) ICS ICS patients in the other ICS other patients in the other ICS dose mean of mean symptom mean n = during the 12 prior to and during the run-in The patients in the other Open table in a new tab Table in protocol-defined asthma exacerbation rate over the 24-week treatment period by of having prior exacerbations (mITT prior = = of protocol-defined asthma exacerbations, n (%) ≥23 exacerbation rate∗Number of protocol-defined asthma exacerbations/total patient-treatment regression†Poisson regression with overdispersion model is adjusted for dosing Ratio of exacerbation rates‡Omalizumab/placebo. (95% P = = of protocol-defined asthma exacerbations, n (%) 12 exacerbation rate∗Number of protocol-defined asthma exacerbations/total patient-treatment regression†Poisson regression with overdispersion model is adjusted for dosing Ratio of exacerbation rates‡Omalizumab/placebo. (95% P Number of protocol-defined asthma exacerbations/total patient-treatment period.† Poisson regression with overdispersion model is adjusted for dosing Open table in a new tab Table (%) of patients with (n = 157)Placebo (n = with in any treatment by in the omalizumab respiratory of by in the omalizumab Open table in a new tab Eosinophil count and efficacy of omalizumab of Allergy and Clinical with the by Busse et the effect of omalizumab in a group of patients in relation to eosinophil In study they that the primary end point in asthma was not met. In the subgroup according to the eosinophil count they were to demonstrate efficacy in patients within the PDF

Assistive telecare systems (ATSs) have great potential to be beneficial for informal carers (ICs) providing long-term care to older people (OP). However, little is known about ATS acceptance among ICs. This scoping study aims to investigate various factors that influence the ICs' acceptance of ATSs over time in the pre- and post-implementation phases. A five-stage scoping study was conducted. A systematic search of five bibliographic databases (Science Direct, Scopus, CINAHL, PubMED and Proquest Social Sciences Database) was conducted in September 2020, supplemented by a round of grey literature searches. Using the established selection criteria, 37 publications published between 2000 and September 2020 were included. The data were analysed with Atlas.ti 8 using content-based analysis and a combination of deductive and inductive approaches. The results show that work on understanding acceptance of ATS only gained wider attention after 2010. Seven key factors of ATS acceptance were identified: benefits and concerns about ATS, care situation, the influence of the OP, carer characteristics, perceived need to use and social influence. Several subfactors were also found. The post-intervention acceptance factors were found to be more nuanced than the pre-implementation factors, indicating that first-hand experience with ATSs enabled study participants to provide a more tangible, extensive and in-depth overview of the various ATS acceptance factors. This scoping review is useful for ATS developers, providers, health and social care scholars and practitioners, policy makers and commissioners, all of whom seek to improve and facilitate the provision of long-term care in the community.

In November 2013, Swiss authorities announced a criminal investigation into one of the world’s largest gold refineries on the basis that the company committed a war crime. The Swiss investigation comes a matter of months after the US Supreme Court decided in Kiobel v. Royal Dutch Petroleum Co. that allegations like these could not give rise to civil liability under the aegis of the Alien Tort Statute (“ATS”). Intriguingly, however, the Swiss case is founded on a much earlier American precedent. In 1909, the U.S. Supreme Court approved the novel practice of prosecuting companies. Unlike the Court’s position in Kiobel a century later, the arguments that ultimately led to the open-armed embrace of corporate criminal liability were unambiguously concerned with impunity. For the U.S. Supreme Court, doing without corporate criminal responsibility would create a significant and highly undesirable regulatory gap. Since then, the American fiction that corporations are people for the purposes of criminal law has taken hold, such that the concept is now relatively ubiquitous globally. Even jurisdictions that bravely held out for decades on philosophical grounds have recently adopted corporate criminal liability. Switzerland is one such case. In this paper, I argue that coupling corporate criminal liability with international crimes in national systems, as in this new Swiss case, is the next obvious “discovery” in corporate responsibility. In addition, at least one international court has now adopted corporate criminal liability for international crimes. These moves promise to transcend several of the doctrinal and conceptual problems that plagued the ATS. First, this reframing will move this field beyond polarized debates about the scope of complicity within ATS litigation, which did not fully capture the nuanced meaning of accomplice liability in the criminal law. Second, it will bypass the cumbersome debate about corporate responsibility for international crimes as a matter of international law, which would not arise in criminal trials. Third, while trading the private right to sue under the ATS for prosecutorial discretion in a criminal context is certainly a massive loss, prosecutorial discretion also has its upsides, which we should now explore in greater depth. Finally, reframing ATS cases in international criminal law (principally enforced in national courts) offers corporate guilt and retribution as a justification for accountability, thereby answering many of the criticisms scholars leveled against the ATS process. Corporate criminal liability (in conjunction with individual criminal responsibility of corporate officers for international crimes) always had certain competitive advantages over the ATS, that the Swiss investigation confirms as legally plausible. So, regardless of whether this particular investigation ever results in a trial or conviction, it announces an uncharted set of relationships between commerce, atrocity and international criminal law waiting to be mapped. As I show, by simultaneously mimicking and transcending the ATS, corporate criminal liability for international crimes offers human rights advocates a fresh platform for justice, while also contributing very new perspectives to scholarly debates about the propriety and efficacy of ATS litigation. All in all, the rise of corporate criminal liability for international crimes offers new ideas about the importance of corporate accountability globally, which understandably, never figured within the relatively narrow framing required for the ATS or the business and human rights discourse more broadly.

Abstract Background Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary–critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1) delivery models, 2) comprehensive symptom assessment and management, 3) advance care planning and goals of care discussions, 4) caregiver support, 5) health disparities, 6) mass casualty events and emergency preparedness, and 7) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary–critical care clinicians and policymakers for its proactive integration.

Research Articles| April 15 2008 Studies on the Role of Serum Complement in Allograft Rejection and in Immunosuppression by Antithymocyte Serum (ATS) Subject Area: Surgery H.K. Weitzel; H.K. Weitzel Max-Planck-Institut für Immunbiologie, DFG-Forschungsgruppe Rother, Freiburg i. Br., Germany Search for other works by this author on: This Site PubMed Google Scholar K. Rother K. Rother Max-Planck-Institut für Immunbiologie, DFG-Forschungsgruppe Rother, Freiburg i. Br., Germany Search for other works by this author on: This Site PubMed Google Scholar Eur Surg Res (1970) 2 (4): 310–317. https://doi.org/10.1159/000127527 Article history Published Online: April 15 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation H.K. Weitzel, K. Rother; Studies on the Role of Serum Complement in Allograft Rejection and in Immunosuppression by Antithymocyte Serum (ATS). Eur Surg Res 1 April 1970; 2 (4): 310–317. https://doi.org/10.1159/000127527 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsEuropean Surgical Research Search Advanced Search This content is only available via PDF. 1970Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Article PDF first page preview Close Modal You do not currently have access to this content.

Courts and scholars have struggled to identify the original meaning of the Alien Tort Statute (ATS). As enacted in 1789, the ATS provided [t]hat the district courts... shall... have cognizance... of all causes where an alien sues for a tort only in violation of the law of nations or a treaty of the United The statute was rarely invoked for almost two centuries until, in the 1980s, lower federal courts began reading the statute expansively to allow foreign citizens to sue other foreign citizens for violations of modern customary international law that occurred outside the United States. In 2004 in Sosa v. Alvarez-Machain, the Supreme Court addressed the statute for the first time and took a more restrictive approach than lower courts. Seeking to implement the views of the First Congress, the Court determined that Congress wished to grant federal courts jurisdiction only over a narrow category of actions corresponding to Blackstone’s three primary [criminal] offenses [against the law of nations]: violation of safe conducts, infringement of the rights of ambassadors, and piracy. In this Article, we argue that neither the broader approach initially endorsed by lower federal courts nor the more restrictive approach subsequently adopted by Sosa fully captures the original meaning and purpose of the ATS. In 1789, the United States was a weak nation seeking to avoid conflict with other nations. Every nation had a duty at the time to redress certain violations of the law of nations committed by its citizens or subjects against other nations or their citizens - from the most serious offenses (such as those against ambassadors) to more mundane offenses (such as violence against private foreign citizens). If a nation failed to redress such violations, then it became responsible to the other nation, and gave the other nation just cause for war. In the aftermath of the Revolutionary War, Congress could not rely upon states to redress injuries suffered by British subjects at the hands of Americans. Accordingly, the First Congress enacted the ATS as one of several civil and criminal provisions designed to redress law of nations violations committed by U.S. citizens. The ATS authorized federal court jurisdiction over claims by foreign citizens against U.S. citizens for intentional torts to person or personal property. The statute thereby provided a self-executing means for the United States to avoid military reprisals for the misconduct of its citizens. Neither the ATS nor Article III, however, authorized federal court jurisdiction over claims between aliens. Indeed, federal court adjudication of at least one subset of such claims - alien-alien claims for acts occurring in another nation’s territory - would have contradicted the statute’s purpose by putting the United States at risk of foreign conflict. Despite suggestions that the true import of the ATS may never be recovered, the original meaning of the statute is relatively clear in historical context: the ATS limited federal court jurisdiction to suits by aliens against U.S. citizens, but encompassed any intentional tort to an alien’s person or personal property.

For decision‐making on the attributes and time weights existing in a dynamic intuitionistic fuzzy environment, a new ATS‐generalized weighted intuitionistic fuzzy Bonferroni mean operator MADM model based on dynamic comprehensive time entropy and an ATS‐generalized weighted intuitionistic fuzzy Bonferroni mean operator was established by taking into consideration the intrinsic correlations between attributes. An intuitionistic fuzzy decision matrix with the same time sequence was integrated into the model. According to the idea of “laying more stress on the present than on the past,” a time sequence weight considering both the subjective preferences and the objective information of samples was obtained to overcome the irrationality of subjective value assignment on existing time sequence weight and ideal time weighting. Based on dynamic comprehensive time entropy, the model not only reflects the degree of importance attached to the latest data but also gives consideration to the subjective preferences of decision‐makers in order to set a new vector for time sequence weight. The dynamic intuitionistic fuzzy weighted operator was used to conduct aggregation to obtain a dynamic intuitionistic fuzzy comprehensive value, and the obtained results are sorted by the sorting function of intuitionistic fuzzy sets. The best alternative was selected and applied to a case study on green building project selection. The results indicate that the proposed method is comprehensive, scientific, and feasible.

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Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

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How do activist plaintiffs experience the process of human rights litigation under the Alien Tort Statute (ATS)? Answering this question is key to understanding the impact on transnational legal mobilization of Kiobel v. Royal Dutch Petroleum Co ., in which the US Supreme Court sharply limited the scope of the ATS. Yet sociolegal scholars know remarkably little about the experiences of ATS litigants, before or after Kiobel. This article describes how activist litigants in a landmark ATS class action against former Philippine President Ferdinand Marcos faced a series of strategic dilemmas, and how disagreements over how to resolve those dilemmas played into divisions between activists and organizations on the Philippine left. The article develops an analytical framework focused on litigation dilemmas to explain how and why activists who pursue ATS litigation as an opportunity for legal mobilization may also encounter strategic dilemmas that contribute to dissension within a social movement.

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