RESUMO
Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected proteins in the lung to identify molecular signatures and networks associated with BeS and CBD. BAL cell DNA and RNA were profiled using microarrays from CBD (n = 30), BeS (n = 30), and control subjects (n = 12). BAL fluid proteins were measured using Olink Immune Response Panel proteins from CBD (n = 22) and BeS (n = 22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multiomic integration methods identified correlated features between datasets. We identified 1,546 differentially expressed genes in CBD versus control subjects and 204 in CBD versus BeS. Of the 101 shared transcripts, 24 have significant cis relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation analysis, including genes not previously identified in CBD. A multiomic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated control subjects from remaining samples. The top features on component one were enriched for T-lymphocyte function, and the top features on component two were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD versus BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multiomic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multiomic signatures of CBD that differentiated it from BeS and control subjects.
Assuntos
Beriliose , Humanos , Beriliose/genética , Linfócitos T , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , Imunidade Inata/genética , RNA , Doença CrônicaRESUMO
BACKGROUND: Most phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes. METHODS: We performed a retrospective cohort study of 554 sarcoidosis cases to identify distinct phenotypes of sarcoidosis based on 29 clinical features. Model-based clustering was performed using the VarSelLCM R package and the Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher's exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters. RESULTS: Cluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype (1) supranormal lung function and majority Scadding stage 2/3; phenotype (2) supranormal lung function and majority Scadding stage 0/1; phenotype (3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype (4) obstructive lung function and majority Scadding stage 2/3; phenotype (5) restrictive lung function and majority Scadding stage 2/3; phenotype (6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Although there were differences in the percentages, all Scadding stages were encompassed by all of the phenotypes, except for phenotype 1, in which none were Scadding stage 4. Clusters 4, 5, 6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores. CONCLUSIONS: Cluster analysis produced 6 sarcoidosis phenotypes that demonstrated less severe and severe phenotypes. Phenotypes 1, 2, 3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4, 5, 6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects and to empower clinicians to identify those with more severe disease versus those who have less severe disease, independent of Scadding stage.
Assuntos
Sarcoidose , Análise por Conglomerados , Humanos , Fenótipo , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/epidemiologia , Sarcoidose/genética , Índice de Gravidade de DoençaRESUMO
Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls.
Assuntos
Beriliose/diagnóstico , Beriliose/genética , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/genética , Adulto , Idoso , Biomarcadores/metabolismo , Antígenos CD55/genética , Antígenos CD55/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Doença Crônica , Diagnóstico Diferencial , Proteína Catiônica de Eosinófilo/genética , Proteína Catiônica de Eosinófilo/metabolismo , Feminino , Marcadores Genéticos , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Over 90% of one million annual US joint replacements are highly successful. Nonetheless, 10% do poorly owing to infection or mechanical issues. Many implant components are sensitizers, and sensitization could also contribute to implant failure. OBJECTIVE: To determine the prevalence of implant sensitization in joint failure patients, their clinical characteristics, and implant revision outcomes. We hypothesized that sensitized patients would improve when revised with nonallergenic materials. METHODS: We prospectively enrolled 105 joint failure patients referred by orthopedic surgeons who had already excluded infection or mechanical causes. Patients provided informed consent, completed a history and physical examination, patch testing to metals and bone cement, and a nickel lymphocyte proliferation test. A study coordinator was able to contact 64% of patients (n = 67) 9 to 12 months later to evaluate outcomes. RESULTS: A total of 59% were sensitized to an implant component: 32% to metal and 37% to bone cement. The nickel lymphocyte proliferation test was 60% sensitive and 96% specific in diagnosing nickel sensitization. Most sensitized subjects reported no or uncertain histories of reactions to a specific material. Implant sensitized patients were younger and reported previous eczema, joint itching, and implant loosening. By 9 to 12 months later, most patients with a revised implant (revised) described significant improvement (16 of 22 revised for sensitization [P = .0003] vs 9 of 13 revised without sensitization [P = .047]) compared with patients without implant revision). All revised patients with sensitization used components to which they were not sensitized. Pain (P = .001), swelling (P = .035), and instability (P = .006) were significantly reduced in the revised sensitized group. CONCLUSIONS: Sensitization to implant components is an important cause of unexplained joint replacement failure. Joint revisions based on sensitization information resulted in significant improvements.
Assuntos
Artroplastia de Substituição , Cimentos Ósseos , Humanos , Testes do Emplastro , Próteses e Implantes , ReoperaçãoRESUMO
The global COVID-19 pandemic disrupted supply chains across the world, resulting in a critical shortage of personal protective equipment (PPE) for frontline healthcare workers. To preserve PPE for healthcare providers treating COVID-19 positive patients and to reduce asymptomatic transmission, the Department of Bioengineering at the University of Colorado, Denver | Anschutz Medical Campus collaborated with National Jewish Health to design and test patterns for cloth face coverings. A public campaign to sew and donate the final pattern was launched and over 2500 face coverings have been donated as a result. Now that nearly three million cases of COVID-19 have been confirmed in the United States, many state and local governments are requiring cloth face coverings be worn in public. Here, we present the collaborative design and testing process, as well as the final pattern for non-patient facing hospital workers and community members alike.
Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Máscaras/provisão & distribuição , Pandemias/prevenção & controle , Equipamento de Proteção Individual/provisão & distribuição , Pneumonia Viral/prevenção & controle , Engenharia Biomédica , COVID-19 , Colorado/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Pessoal de Saúde , Hospitais , Humanos , Colaboração Intersetorial , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , SARS-CoV-2 , Têxteis , Estados Unidos/epidemiologia , Desenho UniversalRESUMO
BACKGROUND: The clinical effects of inhaled corticosteroids (ICS) on chronic beryllium disease (CBD) are unknown. Although frequently used for symptoms or disease not requiring systemic therapy, the clinical course of patients on ICS has not been evaluated. METHODS: In a retrospective cohort study, forty-eight subjects with CBD, diagnosed by granulomas on lung biopsy and treated with inhaled corticosteroids, were matched to sixty-eight subjects with CBD who were not treated. Pulmonary function testing, exercise tolerance, blood BeLPT, BAL cell count, and symptoms were evaluated. RESULTS: Treated patients showed no significant change over time in pulmonary function, when compared to controls, by forced vital capacity (FVC, pâ¯=â¯0.28) or diffusion capacity (DLCO, pâ¯=â¯0.45) or in exercise tolerance testing. However, symptoms of cough significantly improved in 58% (compared to 17% in controls) and dyspnea improved in 26% after ICS treatment (compared to 0 in controls). Symptoms of cough were improved in patients with a lower baseline FEV1 and FEV1/FVC ratio. Subgroup analysis showed significant lung function response in cases with lower baseline FEV1/FVC and higher residual volume (RV). CONCLUSION: Although FVC and DLCO did not improve in the ICS treated group, we saw no difference in decline compared to matched controls. Symptoms of dyspnea and cough improved with ICS especially in those with obstruction and air trapping suggesting that these should be considered an indication of ICS use in CBD patients.
Assuntos
Corticosteroides/uso terapêutico , Beriliose/tratamento farmacológico , Tosse/fisiopatologia , Dispneia/fisiopatologia , Administração por Inalação , Idoso , Beriliose/complicações , Beriliose/patologia , Beriliose/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Estudos de Casos e Controles , Estudos de Coortes , Tosse/etiologia , Dispneia/etiologia , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar , Volume Residual , Estudos Retrospectivos , Capacidade VitalRESUMO
A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD.We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus.We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine-cytokine receptor interactions, and Toll-like receptor, chemokine and JAK-STAT signalling pathways.We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways.
Assuntos
Beriliose/fisiopatologia , Berílio/efeitos adversos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Pneumopatias/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Beriliose/genética , Doença Crônica , Feminino , Humanos , Interferon gama/genética , Leucócitos Mononucleares/citologia , Pneumopatias/genética , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Sarcoidose/genética , Sarcoidose/fisiopatologia , Transcrição Gênica , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: The National Supplemental Screening Program (NSSP) uses a Total Worker Health(TM) approach to address U.S. Department of Energy (DOE) former worker health. This article provides the design of the integrated occupational health screening and promotion program. METHODS: The NSSP implemented a web-based relational health records system to process demographic, exposure, and clinical data. We present medical findings for 12,000 DOE former workers that completed an initial NSSP medical screening between October 1, 2005 and October 4, 2013. We discuss the DOE former worker participant population and the exposure-based and non-occupational medical screening tests used. RESULTS: The NSSP identified potential occupationally related health conditions in 40.5% of those screened. Notably, we identified 85.8% of participants with addressable non-occupational health conditions, many of which were previously undiagnosed. CONCLUSION: The NSSP demonstrates that the identification of potential occupational health issues in conjunction with addressable non-occupational health conditions provides former workers with information to more effectively manage health.
Assuntos
Atenção à Saúde/organização & administração , Governo Federal , Promoção da Saúde/organização & administração , Programas de Rastreamento/organização & administração , Doenças Profissionais/diagnóstico , Saúde Ocupacional , Humanos , Energia Nuclear , Centrais Nucleares , Pesquisadores , Estados UnidosRESUMO
OBJECTIVE: In addition to formaldehyde, workers in salons can be exposed to other chemical irritants, sensitizers, carcinogens, reproductive hazards, infectious agents, ergonomic, and other physical hazards. Worker health and safety training is challenging because of current product labeling practices and the myriad of hazards portending risk for a wide variety of health effects. METHODS: Through a Susan B. Harwood Targeted Topic Training grant from the Occupational Safety and Health Administration and assistance from salon development and training partners, we developed, delivered, and validated a health and safety training program using an iterative five-pronged approach. RESULTS: The training was well received and resulted in knowledge gain, improved workplace safety practices, and increased communication about health and safety. CONCLUSIONS: These training materials are available for download from the Occupational Safety and Health Administration's Susan B. Harwood Training Grant Program Web site.
Assuntos
Indústria da Beleza , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/prevenção & controle , Saúde Ocupacional/educação , Adulto , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Avaliação das Necessidades , Avaliação de Programas e Projetos de Saúde , Estados UnidosRESUMO
PURPOSE OF REVIEW: Metals can cause disease of the upper and lower respiratory tract that mirror disease due to other causes, such as asthma, rhinosinusitis, acute bronchitis, chronic bronchitis, acute pneumonitis, bronchogenic carcinoma, and interstitial lung disease. This article will describe some uncommon and unique lung diseases that can be induced by metals. RECENT FINDINGS: Our understanding of old occupational lung diseases, such as chronic beryllium disease, continues to increase. New exposures in the workplace, such as indium, have been identified as novel occupational hazards. New forms of exposure, such as titanium dioxide nanoparticles, create risk of lung disease that is not seen with larger particles. SUMMARY: Knowledge of several unusual and/or unique occupational lung diseases should prompt questioning about a patient's occupational history, which may uncover an occupational, rather than an idiopathic, lung disease.
Assuntos
Berílio/efeitos adversos , Pneumopatias/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Animais , Beriliose , Humanos , Exposição OcupacionalRESUMO
Chronic beryllium disease (CBD) is a granulomatous lung disease that may be pathologically and clinically indistinguishable from pulmonary sarcoidosis, except through use of immunologic testing, such as the beryllium lymphocyte proliferation test (BeLPT). Similar to sarcoidosis, the pulmonary manifestations of CBD are variable and overlap with other respiratory diseases. Definitive diagnosis of CBD is established by evidence of immune sensitization to beryllium and diagnostic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. However, the diagnosis of CBD can also be established on a medically probable basis in beryllium-exposed patients with consistent radiographic imaging and clinical course. Beryllium workers exposed too much higher levels of beryllium in the past demonstrated a much more fulminant disease than is usually seen today. Some extrapulmonary manifestations similar to sarcoidosis were noted in these historic cohorts, although with a narrower spectrum. Extrapulmonary manifestations of CBD are rare today. Since lung-predominant sarcoidosis can very closely resemble CBD, CBD is still misdiagnosed as sarcoidosis when current or past exposure to beryllium is not recognized and no BeLPT is obtained. This article describes the similarities and differences between CBD and sarcoidosis, including clinical and diagnostic features that can help physicians consider CBD in patients with apparent lung-predominant sarcoidosis.
Assuntos
Beriliose/diagnóstico , Berílio/toxicidade , Sarcoidose Pulmonar/diagnóstico , Beriliose/fisiopatologia , Biópsia , Lavagem Broncoalveolar/métodos , Broncoscopia/métodos , Proliferação de Células , Doença Crônica , Humanos , Linfócitos/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Sarcoidose Pulmonar/fisiopatologiaRESUMO
This article describes the different clinical variants of irritant-induced asthma, specifically focusing on high-dose irritant-induced asthma and irritant-induced work-exacerbated asthma, as well as reviews known causes, addresses the often adverse medical and socioeconomic outcomes of this complex condition, and considers issues of causation from an occupational and environmental medicine perspective.
Assuntos
Asma/diagnóstico , Asma/etiologia , Doenças Profissionais/complicações , Exposição Ocupacional/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures. METHODS: Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis. RESULTS: Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted. CONCLUSIONS: We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.