| 1. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 2. |
- Östling, Jörgen, et al.
(författare)
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IL-17-high asthma with features of a psoriasis immunophenotype
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required.Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes.Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin.Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
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| 3. |
- Hedman, Linnea, et al.
(författare)
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Receiving support to quit smoking and quit attempts among smokers with and without smoking related diseases : Findings from the EUREST-PLUS ITC Europe Surveys
- 2018
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Ingår i: Tobacco Induced Diseases. - Heraklion : European Publishing. - 1617-9625. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION Having a chronic disease either caused or worsened by tobacco smoking does not always translate into quitting smoking. Although smoking cessation is one of the most cost-effective medical interventions, it remains poorly implemented in healthcare settings. The aim was to examine whether smokers with chronic and respiratory diseases were more likely to receive support to quit smoking by a healthcare provider or make a quit attempt than smokers without these diseases.METHODS This population-based study included a sample of 6011 adult smokers in six European countries. The participants were interviewed face-to-face and asked questions on sociodemographic characteristics, current diagnoses for chronic diseases, healthcare visits in the last 12 months and, if so, whether they had received any support to quit smoking. Questions on smoking behavior included nicotine dependence, motivation to quit smoking and quit attempts in the last 12 months. The results are presented as weighted percentages with 95% confidence intervals (CI) and as adjusted odds ratios with 95% CI based on logistic regression analyses.RESULTS Smokers with chronic respiratory disease, those aged 55 years and older, as well as those with one or more chronic diseases were more likely to receive smoking cessation advice from a healthcare professional. Making a quit attempt in the last year was related to younger age, high educational level, higher motivation to quit, lower nicotine dependence and having received advice to quit from a healthcare professional but not with having chronic diseases. There were significant differences between countries with smokers in Romania consistently reporting more support to quit as well as quit attempts.CONCLUSIONS Although smokers with respiratory disease did indeed receive smoking cessation support more often than smokers without disease, many smokers did not receive any advice or support to quit during a healthcare visit.
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| 4. |
- Angiolillo, Dominick J., et al.
(författare)
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International Expert Consensus on Switching Platelet P2Y(12) Receptor-Inhibiting Therapies
- 2017
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 136:20, s. 1955-
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Tidskriftsartikel (refereegranskat)abstract
- Dual antiplatelet therapy with aspirin and a P2Y(12) inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y(12) inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y(12) inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y(12) inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y(12) inhibitors.
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| 5. |
- Cook, Michael B, et al.
(författare)
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Tobacco and Alcohol in Relation to Male Breast Cancer: An Analysis of the Male Breast Cancer Pooling Project Consortium.
- 2015
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 24:3, s. 520-531
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Tidskriftsartikel (refereegranskat)abstract
- Background: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. Methods: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) odds ratios (OR) and 95% confidence intervals (CI), which were then combined using fixed effects meta-analysis. Results: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one sub-analysis of very high recent alcohol consumption (>60 grams/day) was tentatively associated with male breast cancer (ORunexposed referent=1.29, 95%CI:0.97-1.71; OR>0-<7 g/day referent=1.36, 95%CI:1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. Conclusions: In this analysis of the Male Breast Cancer Pooling Project we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. Impact: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer.
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| 6. |
- Lappalainen, Hanna K., et al.
(författare)
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Pan-Eurasian Experiment (PEEX) : towards a holistic understanding of the feedbacks and interactions in the land-atmosphere-ocean-society continuum in the northern Eurasian region
- 2016
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 16:22, s. 14421-14461
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Tidskriftsartikel (refereegranskat)abstract
- The northern Eurasian regions and Arctic Ocean will very likely undergo substantial changes during the next decades. The Arctic-boreal natural environments play a crucial role in the global climate via albedo change, carbon sources and sinks as well as atmospheric aerosol production from biogenic volatile organic compounds. Furthermore, it is expected that global trade activities, demographic movement, and use of natural resources will be increasing in the Arctic regions. There is a need for a novel research approach, which not only identifies and tackles the relevant multi-disciplinary research questions, but also is able to make a holistic system analysis of the expected feedbacks. In this paper, we introduce the research agenda of the Pan-Eurasian Experiment (PEEX), a multi-scale, multi-disciplinary and international program started in 2012 (https://www.atm.helsinki.fi/peex/). PEEX sets a research approach by which large-scale research topics are investigated from a system perspective and which aims to fill the key gaps in our understanding of the feedbacks and interactions between the land-atmosphereaquatic-society continuum in the northern Eurasian region. We introduce here the state of the art for the key topics in the PEEX research agenda and present the future prospects of the research, which we see relevant in this context.
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| 7. |
- Lowenstern, Angela, et al.
(författare)
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Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome
- 2017
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 44:2, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6 months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6 months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1-6 months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1 month and 1 to 6 months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5 A μg/L, respectively). The mean level of each biomarker was significantly different at 1 month compared to baseline (p < 0.0001). When stratified by treatment group, at 1 month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6 months with those at 1 month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1 month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1 month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6 months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6 months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.
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| 8. |
- Velders, Matthijs A., et al.
(författare)
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Safety and efficacy of ticagrelor and clopidogrel in primary percutaneous coronary intervention
- 2016
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:8, s. 617-625
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).Methods: This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.Results: During a median of 286days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).Conclusions: In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.
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