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1.
Pediatr Pulmonol ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33819390

RESUMO

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than respiratory morbidity are lacking. This study examines the associations of childhood asthma and the occurrence of cardiovascular disease (CVD) events and mortality in adulthood. METHODS: A cohort of 4430 school children (aged 17 years) who attended the Busselton Health Study between 1967 and 1983 were analyzed. Self-reported history of doctor-diagnosed asthma was determined based on the questionnaire. Subsequent CVD events (hospital admissions or death) up to 2014 were identified using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on CVD events and mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analyzed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up, 867 participants experienced a CVD event and 22 participants died from CVD. Childhood asthma was not associated with the risk of CVD events in adulthood (HR, 1.12; 95% CI: 0.91-1.39; p = .2833) and this persisted after adjustment for confounders. Childhood asthma was not associated with coronary heart disease events (HR, 0.72; 95% CI: 0.40-1.30; p = .2761), heart failure events (HR, 0.55; 95% CI: 0.07-4.13; p = .5604) or CVD mortality (HR, 0.91; 95% CI: 0.21-3.89; p = .8987) in adulthood. CONCLUSION: Childhood asthma is not associated with the risk of CVD events and mortality in adulthood.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33658776

RESUMO

Purpose: Spirometry is necessary to confirm COPD, but many patients are diagnosed based on clinical presentation and/or chest x-ray. There are also those who do not present to primary care for case finding and remain undiagnosed. We aimed to identify: (a) factors that are associated with undiagnosed COPD; and (b) factors that are associated with a potential misdiagnosis of COPD. Patients and Methods: This analysis used data from the Burden of Obstructive Lung Disease (BOLD), a cross-sectional study of community dwelling adults randomly selected from six study sites, chosen to provide a representative sample of the Australian population (n= 3357). Participants were grouped by COPD diagnostic criteria based on spirometry and self-reported diagnosis. Odds ratios for predictors of undiagnosed and misdiagnosed were estimated using logistic regression. Results: Of the BOLD Australia sample, 1.8% had confirmed COPD, of whom only half self-reported a diagnosis of COPD. A further 6.9% probably had COPD, but were undiagnosed. The priority target population for case finding of undiagnosed COPD was aged ≥60 years (particularly those ≥75 years), with wheezing, shortness of breath and a body mass index (BMI) <25kg/m2. The priority target population for identifying and reviewing misdiagnosed COPD was aged <60 years, female, with no wheezing and a BMI ≥25kg/m2. Conclusion: Challenges continue in accurately diagnosing COPD and greater efforts are needed to identify undiagnosed and misdiagnosed individuals to ensure an accurate diagnosis and the initiation of appropriate management in order to reduce the burden of COPD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33556295

RESUMO

Platelet activation and pulmonary recruitment occur in patients with asthma and in animal models of allergic asthma, where leukocyte infiltration, airway remodelling, and hyperresponsiveness are suppressed by experimental platelet depletion. These observations suggest the importance of platelets to various characteristics of allergic disease, but the mechanisms of platelet migration and location are not understood. To assess the mechanism of platelet recruitment to extravascular compartments of lungs from asthmatic patients, and following allergen challenge of house dust mite (HDM, containing the DerP1 allergen) sensitized mice; additionally we assessed the role of chemokines in this process. Lung sections were immunohistochemically stained for CD42b+ platelets. Intravital microscopy in allergic mice visualised platelets tagged with an anti-mouse CD49b-PE antibody. Platelet-endothelial interactions were measured in response to HDM (DerP1) exposure in the presence of antagonists to CCR3, CCR4, and CXCR4. Extravascular CD42b+ platelets were detected in the epithelium and submucosa in bronchial biopsies taken from subjects with steroid naïve mild asthma. Platelets were significantly raised in lung parenchyma from patients with fatal asthma compared with post mortem control lung tissue. Furthermore, in DerP1-sensitized mice, subsequent HDM exposure induced endothelial rolling, adhesion; and recruitment of platelets into airway walls compared with sham-sensitized mice, via a CCR3-dependent mechanism in the absence of aggregation or interactions with leukocytes. Localization of singular non-aggregated platelets occurs in lungs of asthmatic patients. In allergic mice, platelet recruitment occurs via recognised vascular adhesive and migratory events, independently of leukocytes via a CCR3 dependent mechanism.

4.
Allergy ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33569770

RESUMO

BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.

5.
Thorax ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414242

RESUMO

Add-on azithromycin (AZM) significantly reduces exacerbations in poorly controlled asthma irrespective of disease phenotype. In a predefined substudy of the original AMAZES protocol (500 mg, three times a week for 48 weeks), we report that AZM treatment reduces key sputum inflammatory proteins (interleukin (IL)-6, IL-1ß and extracellular DNA), which is more evident in non-eosinophilic asthma (NEA). Moreover, AZM reduced Haemophilus influenzae load only in NEA. Our data support the anti-inflammatory effects of AZM in poorly controlled asthma. Prospective studies are required to identify patients that derive greatest benefit from AZM add-on therapy.

6.
Eur Respir Rev ; 30(159)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33472958

RESUMO

Small airways (<2 mm in diameter) are probably involved across almost all asthma severities and they show proportionally more structural and functional abnormalities with increasing asthma severity. The structural and functional alterations of the epithelium, extracellular matrix and airway smooth muscle in small airways of people with asthma have been described over many years using in vitro studies, animal models or imaging and modelling methods. The purpose of this review was to provide an overview of these observations and to outline several potential pathophysiological mechanisms regarding the role of small airways in asthma.

7.
Eur Respir J ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008933

RESUMO

Add-on azithromycin (AZM) results in a significant reduction in exacerbations among adults with persistent uncontrolled asthma. The aim of this study was to assess the cost-effectiveness of add-on AZM in terms of healthcare and societal costs.The AMAZES trial randomly assigned 420 participants to AZM or placebo. Healthcare use and asthma exacerbations were measured during the treatment period. Healthcare use included all prescribed medicine and healthcare contacts. Costs of antimicrobial resistance (AMR) were estimated based on overall consumption and published estimates of costs. The value of an avoided exacerbation was based on published references. Differences in cost between the two groups were related to differences in exacerbations in a series of net monetary benefit estimates. Societal costs included lost productivity, over the counter medicines, steroid induced morbidity and AMR costs.Add-on AZM resulted in a reduction in healthcare costs (mean (95% CI)) including nights in hospital (AUD$433.70 ($48.59-$818.81) or €260.22(€29.15-€491.29)), unplanned healthcare visits (AUD$20.25 ($5.23-$35.27) or €12.15 (€3.14-€21.16)), antibiotic costs (AUD$14.88 ($7.55-$22.21) or €8.93(€4.53-€13.33)) and oral corticosteroid costs (AUD$4.73 ($0.82-$8.64) or €2.84(€0.49-€5.18)), all p<0.05. Overall healthcare and societal costs were lower (AUD$77.30 (€46.38) and AUD$256.22 (€153.73) respectively) albeit not statistically significant. The net monetary benefit of add-on AZM was estimated to be AUD$2072.30 (95% CI $1348.55-$2805.23) or (€1243.38 (€809.13-€1683.14) assuming a willingness to pay per exacerbation avoided of AUD$2651 (€1590.60). Irrespective of the sensitivity analysis applied, the net monetary benefit for total, moderate and severe exacerbations remained positive and significant.Add-on AZM therapy in poorly controlled asthma was a cost-effective therapy. Costs associated with AMR did not influence estimated cost-effectiveness.

8.
Respir Med ; 171: 106095, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32810754

RESUMO

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than lung function are lacking. This study examines the associations of childhood asthma and the occurrence of respiratory events and all-cause mortality in adulthood. METHODS: A cohort of 4430 school children (aged to 17 years) who attended the Busselton Health Study between 1967 and 1983 were analysed. Self-reported history of asthma was determined using questionnaires. Participants were followed until 2014 for respiratory disease-related events (hospital admissions or death) and all-cause mortality using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on respiratory events and all-cause mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analysed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up 791 participants experienced a respiratory event and 140 participants died. Childhood asthma was associated with an increased risk of respiratory events in adulthood (unadjusted HR 1.84, 95% CI 1.52 to 2.23; P < 0.0001). The result remained significant after adjusting for adult-onset asthma, FEV1, body mass index, smoking, dusty job, hay fever, and respiratory symptoms (adjusted HR 1.68, 95% CI 1.07 to 2.64; P = 0.0247). Childhood asthma was not associated with all-cause mortality in adulthood (unadjusted HR 1.08, 95% CI 0.63 to 1.84; P = 0.7821). CONCLUSION: Childhood asthma is associated with increased risk of respiratory disease-related hospital admissions and death but not all-cause mortality in adulthood.

9.
Int J Biochem Cell Biol ; 126: 105818, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32707120

RESUMO

Asthma: A disease characterised by excessive and variable airway narrowing, and pathologies of inflammation and remodelling, particularly thickening of the airway smooth muscle (ASM). Treatment approaches dilate narrowed airways and reduce inflammation; however, remodelling seems largely neglected. This review considers the evolution of remodelling in asthma and whether conventional hypotheses that inflammation causes ASM thickening has mislead the medical community into thinking that anti-inflammatories will remedy this ASM defect. There is instead reasonable evidence that ASM thickening occurs independently of inflammation, such that therapies should employ strategies to directly modify ASM growth. Lessons have been learned from the use of untargeted bronchial thermoplasty and there should also be consideration of pharmacological therapies to ablate ASM. We discuss several new approaches to target ASM remodelling in asthma. A major current obstacle is our inability to image the ASM layer and assess treatment response. In this regard, polarisation-sensitive optical coherence tomography offers future promise.

10.
Respir Physiol Neurobiol ; 279: 103469, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473215

RESUMO

Airway remodelling is a cardinal feature of asthma in which airways undergo structural changes - in particular, increased airway smooth muscle mass and total airway wall area. Remodelling has long been thought to have functional consequences in asthma due to geometric effects that can increase airway narrowing and luminal occlusion. Prior studies have examined the distribution of remodelling between and within patients, but none have yet considered the possibility for spatial correlations in airway remodelling. That is, is remodelling clustered locally, or interrelated along proximal and distal locations of the bronchial tree? In view of recent interest regarding airway remodelling produced by mechanical stimuli, we developed a mathematical model to examine whether spatial correlations in airway remodelling could arise due to cycles of bronchoconstriction and mechanotransduction. Further, we compared modelling predictions to the spatial distribution of airway remodelling in lungs from subjects with and without asthma. Results indicate that spatial correlations in airway remodelling do exist in vivo, and cycles of bronchoconstriction and mechanotransduction are one plausible mechanism for their origin. These findings offer insights into the evolution of airway remodelling in asthma, which may inform strategies for treatment and prevention.

11.
BMJ Open ; 10(3): e032877, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209622

RESUMO

OBJECTIVES: Severe asthma imposes a significant burden on individuals, families and the healthcare system. New treatment and management approaches are emerging as effective options for severe asthma. Translating new knowledge to multidisciplinary healthcare professionals is a priority. We developed 'The Severe Asthma Toolkit' (https://toolkit.severeasthma.org.au) to increase awareness of severe asthma, provide evidence-based resources and support decisionmaking by healthcare providers. SETTING: Roundtable discussions and a survey of Australians clinicians were conducted to determine clinician preferences, format and content for a severe asthma resource. PARTICIPANTS: A reference group from stakeholder and consumer bodies and severe asthma experts provided advice and feedback. A multidisciplinary team of international experts was engaged to develop content. Written content was based on up-to-date literature. Peer and editorial review were performed to finalise content and inform web design. Website design focused on user experience, navigation, engagement, interactivity and tailoring of content for a clinical audience. RESULTS: A web-based resource was developed. Roundtable discussions and a needs assessment survey identified the need for dedicated severe asthma management resources to support skills training. The end-product, which launched 26 March 2018, includes an overview of severe asthma, diagnosis and assessment, management, medications, comorbidities, living with severe asthma, establishing a clinic, paediatrics/adolescents and clinical resources. Analytics indicate access by users worldwide (32 169 users from 169 countries). User survey results (n=394) confirm access by the target audience (72% health professionals), who agreed the toolkit increased their knowledge (73%) and confidence in managing severe asthma (66%), and 75% are likely to use the resource in clinic. CONCLUSIONS: The Severe Asthma Toolkit is a unique, evidence-based internet resource to support healthcare professionals providing optimal care for people with severe asthma. It is a comprehensive, accessible and independent resource developed by leading severe asthma experts to improve clinician knowledge and skills in severe asthma management.

12.
Ann Epidemiol ; 42: 19-24.e2, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32081535

RESUMO

PURPOSE: Few studies have investigated the association of childhood obesity with respiratory disease-related outcomes in adulthood and findings are inconsistent. The aim of this study was to examine the associations of body mass index (BMI) in childhood with the occurrence of respiratory events in adulthood. METHODS: We analyzed a cohort of 4537 school-aged children who attended the Busselton Health Study. Height and weight were measured and generated BMI z-scores were categorized into four groups. Participants were followed for respiratory disease-related hospital admissions or death using the Western Australia Data Linkage System. The associations between childhood BMI and respiratory events in adulthood were investigated using Cox regression models. A subgroup of 2196 that reattended a survey in young adulthood was also analyzed. RESULTS: During the 122,781 person-years of follow-up, 810 participants experienced a respiratory event. Childhood BMI group was not associated with risk of respiratory event in adulthood (hazard ratio for BMI z ≥ 1 vs. < -1 = 0.90; 95% CI, 0.70-1.17; P = .295) and this persisted after adjustment for selected confounders in the subgroup (hazard ratio 0.80; 95% CI, 0.43-1.48; P = .476). CONCLUSIONS: Childhood BMI is not associated with risk of respiratory events in adulthood.


Assuntos
Hospitalização/estatística & dados numéricos , Obesidade/complicações , Obesidade Pediátrica/epidemiologia , Doenças Respiratórias/epidemiologia , Adulto , Austrália/epidemiologia , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade/mortalidade , Doenças Respiratórias/etiologia , Doenças Respiratórias/mortalidade , Adulto Jovem
13.
Intern Med J ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32104958

RESUMO

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened 3 forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to 1) identify areas of consensus among experts, 2) define activities and resources required for the implementation of findings into practice and 3) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma. This article is protected by copyright. All rights reserved.

14.
J Appl Physiol (1985) ; 128(4): 757-767, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105523

RESUMO

The volume fraction of extracellular matrix (ECM) within the layer of airway smooth muscle (ASM) is increased in subjects with fixed airflow obstruction. We postulated that changes in ECM within the ASM layer will impact force transmission during induced contraction and/or in response to externally applied stresses like a deep inspiration (DI). Subjects were patients undergoing lung resection surgery who were categorized as unobstructed (n = 12) or "fixed" obstructed (n = 6) on the basis of preoperative spirometry. The response to a DI, assessed by the ratio of isovolumic flows from maximal and partial inspirations (M/P), was also measured preoperatively. M/P was reduced in the obstructed group (P = 0.02). Postoperatively, bronchial segments were obtained from resected tissue, and luminal narrowing to acetylcholine and bronchodilation to simulated DI were assessed in vitro. Airway wall dimensions and the volume fraction of ECM within the ASM were quantified. Maximal airway narrowing to acetylcholine (P = 0.01) and the volume fraction of ECM within the ASM layer (P = 0.02) were increased in the obstructed group, without a change in ASM thickness. Whereas bronchodilation to simulated DI in vitro was not different between obstructed and unobstructed groups, it was correlated with increased M/P (bronchodilation/less bronchoconstriction) in vivo (P = 0.03). The volume fraction of ECM was inversely related to forced expiratory volume in 1 s FEV1 %predicted (P = 0.04) and M/P (P = 0.01). Results show that in subjects with fixed airflow obstruction the mechanical behavior of the airway wall is altered and there is a contemporaneous shift in the structural composition of the ASM layer.NEW & NOTEWORTHY Cartilaginous airways from subjects with fixed airflow obstruction have an increase in the volume fraction of extracellular matrix within the airway smooth muscle layer. These airways are also intrinsically more reactive to a contractile stimulus, which is expected to contribute to airway hyperresponsiveness in this population, often attributed to geometric mechanisms. In view of these results, we speculate on how changes in extracellular matrix may impact airway mechanics.

15.
ERJ Open Res ; 5(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31886156

RESUMO

Background: Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined. Methods: Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects. Results: Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect. Conclusion: Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.

17.
Eur Respir J ; 54(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31624112

RESUMO

Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in individuals with and without asthma.Transverse airway sections were sampled in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities.BMI ranged from 15 to 45 kg·m-2 and was greater in nonfatal asthma cases (p<0.05). Adipose tissue was identified in the outer wall of large airways (Pbm >6 mm), but was rarely seen in small airways (Pbm <6 mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm >12 mm, p<0.01), and with neutrophils in control subjects (Pbm >6 mm, p=0.04).These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology.


Assuntos
Tecido Adiposo/patologia , Asma/patologia , Membrana Basal/patologia , Índice de Massa Corporal , Brônquios/patologia , Adulto , Asma/fisiopatologia , Estudos de Casos e Controles , Eosinófilos/patologia , Feminino , Humanos , Inflamação/patologia , Contagem de Leucócitos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Obesidade/complicações , Sobrepeso/complicações , Adulto Jovem
18.
Sci Rep ; 9(1): 9439, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.


Assuntos
Glicemia/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Glicemia/análise , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
19.
Am J Respir Crit Care Med ; 200(3): 309-317, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875247

RESUMO

Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith's phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.


Assuntos
Antibacterianos/administração & dosagem , Asma/microbiologia , Azitromicina/administração & dosagem , Farmacorresistência Bacteriana/efeitos dos fármacos , Haemophilus influenzae/isolamento & purificação , Adulto , Idoso , Carga Bacteriana , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moraxella catarrhalis/isolamento & purificação , Pseudomonas aeruginosa/isolamento & purificação , Escarro/microbiologia , Staphylococcus aureus/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificação
20.
J Appl Physiol (1985) ; 126(3): 599-606, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30676870

RESUMO

Bronchial thermoplasty is a recent treatment for asthma in which ablative thermal energy is delivered to specific large airways according to clinical guidelines. Therefore, current practice is effectively "blind," as it is not informed by patient-specific data. The present study seeks to establish whether a patient-specific approach based on structural or functional patient data can improve outcomes and/or reduce the number of procedures required for clinical efficacy. We employed a combination of extensive human lung specimens and novel computational methods to predict bronchial thermoplasty outcomes guided by structural or functional data compared with current clinical practice. Response to bronchial thermoplasty was determined from changes in airway responses to strong bronchoconstrictor simulations and flow heterogeneity after one or three simulated thermoplasty procedures. Structure-guided treatment showed significant improvement over current unguided clinical practice, with a single session of structure-guided treatment producing improvements comparable with three sessions of unguided treatment. In comparison, function-guided treatment did not produce a significant improvement over current practice. Structure-guided targeting of bronchial thermoplasty is a promising avenue for improving therapy and reinforces the need for advanced imaging technologies. The functional imaging-guided approach is predicted to be less effective presently, and we make recommendations on how this approach could be improved. NEW & NOTEWORTHY Bronchial thermoplasty is a recent treatment for asthma in which thermal energy is delivered via bronchoscope to specific airways in an effort to directly target airway smooth muscle. Current practice involves the treatment of a standard set of airways, unguided by patient-specific data. We consider the potential for guided treatments, either by functional or structural data from the lung, and show that treatment guided by structural data has the potential to improve clinical practice.


Assuntos
Brônquios/fisiopatologia , Termoplastia Brônquica/métodos , Músculo Liso/fisiopatologia , Asma/tratamento farmacológico , Asma/fisiopatologia , Broncoconstritores/farmacologia , Humanos , Músculo Liso/efeitos dos fármacos , Resultado do Tratamento
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