RESUMO
Thermally degraded engine oil and hydraulic fluid fumes contaminating aircraft cabin air conditioning systems have been well documented since the 1950s. Whilst organophosphates have been the main subject of interest, oil and hydraulic fumes in the air supply also contain ultrafine particles, numerous volatile organic hydrocarbons and thermally degraded products. We review the literature on the effects of fume events on aircrew health. Inhalation of these potentially toxic fumes is increasingly recognised to cause acute and long-term neurological, respiratory, cardiological and other symptoms. Cumulative exposure to regular small doses of toxic fumes is potentially damaging to health and may be exacerbated by a single higher-level exposure. Assessment is complex because of the limitations of considering the toxicity of individual substances in complex heated mixtures.There is a need for a systematic and consistent approach to diagnosis and treatment of persons who have been exposed to toxic fumes in aircraft cabins. The medical protocol presented in this paper has been written by internationally recognised experts and presents a consensus approach to the recognition, investigation and management of persons suffering from the toxic effects of inhaling thermally degraded engine oil and other fluids contaminating the air conditioning systems in aircraft, and includes actions and investigations for in-flight, immediately post-flight and late subsequent follow up.
Assuntos
Poluição do Ar em Ambientes Fechados , Poluição do Ar , Humanos , Aeronaves , Organofosfatos , Literatura de Revisão como AssuntoRESUMO
PURPOSE: Case series on respiratory features of Aerotoxic Syndrome (AS). The term AS has been coined to describe the spectrum of clinical manifestations after aircraft fume events. Among these manifestations, neurological and respiratory symptoms are the most frequently reported complaints. METHODS: Three cases of AS with relevant respiratory features are presented. RESULTS: Cough and shortness of breath for 6 to12 months were the predominant symptoms in the first two cases. The first case also developed neurological symptoms affecting his central nervous system. In the third case, the patient complained for nine years about an unbearable cough triggered by odors, smells, and a variety of indoor and outdoor irritants, among other symptoms of multiple chemical sensitivity. In all three cases, the respiratory symptoms resolved after appropriate treatment. CONCLUSION: Our report aims at raising awareness on AS and calls for actions to improve the management of patients suffering from this syndrome.
Assuntos
Asma/diagnóstico , Asma/etiologia , Aviação , Irritantes/efeitos adversos , Doenças Profissionais/diagnóstico , Doenças Profissionais/etiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SíndromeRESUMO
Work-related asthma (WRA) is one of the most common occupational respiratory conditions, and includes asthma specifically caused by occupational exposures (OA) and asthma that is worsened by conditions at work (WEA). WRA should be considered in all adults with asthma, but especially those with new-onset or difficult to control asthma. Improvement in asthma symptoms when away from work is suggestive of WRA. Clinical history alone is insufficient to diagnose WRA; therefore, objective investigations are required to confirm the presence of asthma and the association of asthma with work activities. Management of WRA requires pharmacotherapy similar to that of non-WRA, however, also needs to take into account control of the causative workplace exposure. Ongoing exposure will likely lead to decline in lung function and worsening asthma control. WRA is a preventable condition but this does rely on increased awareness of WRA and thorough identification and control of all potential occupational respiratory hazards.
Assuntos
Asma , Doenças Profissionais , Exposição Ocupacional , Asma/diagnóstico , Asma/epidemiologia , Asma/etiologia , Asma/prevenção & controle , Austrália/epidemiologia , Humanos , Nova Zelândia/epidemiologia , Doenças Profissionais/diagnóstico , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/prevenção & controle , Saúde Ocupacional , Serviços Preventivos de SaúdeRESUMO
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. METHODS: Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0â¯mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0â¯mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11â¯kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. RESULTS: A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4â¯mg/kg with similar relative reductions in PiZZ patients and HVs at 4â¯mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. CONCLUSION: PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. LAY SUMMARY: Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. CLINICAL TRIAL REGISTRATION NUMBER: NCT02363946.
Assuntos
Cirrose Hepática , Terapêutica com RNAi/métodos , Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Portadores de Fármacos/efeitos adversos , Monitoramento de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/terapia , Masculino , Mutação , Resultado do Tratamento , Inibidores da Tripsina/administração & dosagem , Inibidores da Tripsina/farmacocinética , alfa 1-Antitripsina/administração & dosagem , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/farmacocinética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genéticaAssuntos
Condução de Veículo , Tosse , Humanos , Acidentes de Trânsito , Síncope/diagnóstico , Síncope/etiologia , Veículos AutomotoresRESUMO
AIMS: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1 week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. METHODS: A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels. RESULTS: A dose of 60 mg kg-1 week-1 achieved trough serum levels >11 µmol l-1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l-1 year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%. CONCLUSION: Weight-based A1 -PI dosing reliably raises serum levels above the 11 µmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.
Assuntos
Pulmão/efeitos dos fármacos , Modelos Biológicos , Enfisema Pulmonar/tratamento farmacológico , Inibidores da Tripsina/farmacologia , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Raras/complicações , Doenças Raras/diagnóstico por imagem , Doenças Raras/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Inibidores da Tripsina/uso terapêutico , alfa 1-Antitripsina/farmacologia , alfa 1-Antitripsina/uso terapêutico , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico por imagemRESUMO
BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 µM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING: CSL Behring.
Assuntos
Pulmão/diagnóstico por imagem , Enfisema Pulmonar/tratamento farmacológico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/administração & dosagem , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Capacidade Residual Funcional/efeitos dos fármacos , Capacidade Residual Funcional/fisiologia , Humanos , Infusões Intravenosas , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Tomografia Computadorizada por Raios X , Capacidade Pulmonar Total/efeitos dos fármacos , Capacidade Pulmonar Total/fisiologia , Resultado do Tratamento , Adulto Jovem , alfa 1-Antitripsina/uso terapêutico , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico por imagem , Deficiência de alfa 1-Antitripsina/fisiopatologiaRESUMO
BACKGROUND: Asthma is commonly overlooked or misdiagnosed in adults. Adult-onset asthma differs from asthma that first occurs in childhood as it is less well controlled, more likely to be non-atopic and associated with a faster decline in lung function. Risk factors include exposure to sensitising or irritant substances, obesity, pharmaceutical agents, rhinitis, environmental pollutants, respiratory tract infections and psychological stress. OBJECTIVE: The aim of this article is to provide an overview of adult-onset asthma. DISCUSSION: The clinical presentation of adult-onset asthma is similar to that in any age group. Care needs to be taken to differentiate it from chronic obstructive pulmonary disease and other conditions with similar symptoms. Measurement of reversible airflow obstruction, as demonstrated by an increase in forced expiratory volume in 1 second (FEV1) following inhalation of a short-acting beta-2 agonist (eg salbutamol) of more than 200 ml or 12%, or a positive provocation test is needed to confirm the diagnosis. Management of asthma in adults is based on confirming the diagnosis, assessing the symptoms and their control, asthma education and establishing treatment goals.
Assuntos
Asma/diagnóstico , Asma/tratamento farmacológico , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Idade de Início , Humanos , Fatores de RiscoRESUMO
Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.
Assuntos
Enfisema/tratamento farmacológico , Receptores do Ácido Retinoico/agonistas , Adulto , Idoso , Animais , Método Duplo-Cego , Enfisema/metabolismo , Feminino , Volume Expiratório Forçado , Gases , Genótipo , Humanos , Inflamação , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Placebos , Pirazóis/uso terapêutico , Fumar , Estilbenos/uso terapêutico , Tomografia Computadorizada por Raios X , Receptor gama de Ácido RetinoicoRESUMO
BACKGROUND: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. METHODS: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. FINDINGS: Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. INTERPRETATION: RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. FUNDING: CSL Behring.
Assuntos
Enfisema Pulmonar/tratamento farmacológico , Inibidores de Serina Proteinase/administração & dosagem , Deficiência de alfa 1-Antitripsina/complicações , alfa 1-Antitripsina/administração & dosagem , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Enfisema Pulmonar/congênito , Enfisema Pulmonar/patologia , Análise de Regressão , Testes de Função Respiratória , Capacidade Pulmonar Total , Resultado do Tratamento , Adulto Jovem , Deficiência de alfa 1-Antitripsina/patologiaAssuntos
Dispneia/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , alfa 1-Antitripsina/análise , Diagnóstico Diferencial , Progressão da Doença , Dispneia/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Radiografia Torácica , Testes de Função Respiratória , Índice de Gravidade de Doença , Escarro/citologia , alfa 1-Antitripsina/genéticaRESUMO
OBJECTIVES: This study investigated (i) whether adequate concentrations of secretory leukocyte proteinase inhibitor (SLPI) in the lungs of alpha-1-antitrypsin (A1AT) deficient patients can explain the variability in the development of emphysema in these individuals, and (ii) whether cigarette smoking jeopardises the protective screen provided by functional SLPI. METHODOLOGY: Four subjects [two normal proteinase inhibitor M (PiM), two abnormal PiZ] were selected from patients presenting for diagnostic bronchoscopy and lung function testing (spirometry, DLco). Each subject underwent BAL and had blood taken for A1AT and SLPI estimation. RESULTS: As expected serum and BAL A1AT concentrations were within the normal range in the normal PiM subjects. In normal subjects, SLPI concentrations in serum and BAL were within the normal range. A1AT-deficient subjects had reduced serum and BAL levels of A1AT reflecting their genetic disorder but showed increased concentrations of SLPI in BAL and serum. Percentage neutrophil elastase (NE) inhibitory capacity of BAL fluid was low in both A1AT-deficient subjects and a cigarette-smoking normal subject. In contrast, the NE inhibitory capacity for the normal subject who had never smoked was normal. CONCLUSIONS: These findings suggest that in A1AT deficiency there may be a compensatory increase in SLPI. This may protect the lung against the development of emphysema in A1AT-deficient individuals. Cigarette smokers may have a lower SLPI concentration than non-smokers. This provides an explanation for at least some of the observed variation in the development of emphysema in A1AT deficient subjects.
Assuntos
Líquido da Lavagem Broncoalveolar/química , Enfisema/sangue , Proteínas/análise , Fumar/sangue , Deficiência de alfa 1-Antitripsina/sangue , Idoso , Enfisema/etiologia , Enfisema/patologia , Feminino , Humanos , Elastase de Leucócito , Masculino , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Fenótipo , Proteínas Secretadas Inibidoras de Proteinases , Valores de Referência , Testes de Função Respiratória , Inibidor Secretado de Peptidases Leucocitárias , Fumar/efeitos adversos , alfa 1-Antitripsina/análise , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
OBJECTIVE: Alpha-1-antitrypsin (alpha1antitrypsin) deficiency is a rare hereditary disorder which characteristically presents with emphysema at an early age. The aim of the present study was to determine whether the rate of decline of lung function in alpha1antitrypsin-deficient subjects in Australia was similar to that found elsewhere. METHODOLOGY: Patients registered with the Australian Alpha-1-Antitrypsin Replacement Program were studied. All patients (n = 50) had a serum alpha1antitrypsin concentration of < 0.3 g/L and had had spirometry measured over at least 2 years. They were compared with a group of normal volunteers (hospital staff, n = 107) with normal alpha1antitrypsin levels and phenotypes and with no clinical history of lung disease. All had spirometry measured for periods ranging from 2 to 6 years. The rate of decline of forced expiratory volume in 1 s (FEV1) for each subject was calculated by least squares linear regression using FEV1 against the time from entry into the study. RESULTS: The group mean (+/- SD) rate of decline in FEV1 was significantly greater (P < 0.01) in the alpha1antitrypsin-deficient patients (88 +/- 71 mL/year) than for the normal controls (-15 +/- 48 mL/year). There was no difference in decline in FEV1 when the data was analysed for gender and for index versus non-index cases. CONCLUSION: The results confirm previous reports of an accelerated rate of decline of FEV1 in patients with alpha1antitrypsin deficiency. Our results indicate that the rate of decline of lung function in alpha1antitrypsin deficient subjects in Australia is similar to that found in reported series from elsewhere.