| 1. |
- Edlund, Karolina, et al.
(författare)
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CD99 is a novel prognostic stromal marker in non-small cell lung cancer
- 2012
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 131:10, s. 2264-2273
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Tidskriftsartikel (refereegranskat)abstract
- The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumourstroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.
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| 2. |
- Akinkuolie, Akintunde O, et al.
(författare)
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Group IIA Secretory Phospholipase A2, Vascular Inflammation, and Incident Cardiovascular Disease.
- 2019
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 39:6, s. 1182-1190
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Tidskriftsartikel (refereegranskat)abstract
- Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.
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| 3. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 4. |
- Arshad, F., et al.
(författare)
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Serially Combining Epidemiological Designs Does Not Improve Overall Signal Detection in Vaccine Safety Surveillance
- 2023
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Ingår i: Drug Safety. - 0114-5916. ; 46:8, s. 797-807
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionVaccine safety surveillance commonly includes a serial testing approach with a sensitive method for 'signal generation' and specific method for 'signal validation.' The extent to which serial testing in real-world studies improves or hinders overall performance in terms of sensitivity and specificity remains unknown.MethodsWe assessed the overall performance of serial testing using three administrative claims and one electronic health record database. We compared type I and II errors before and after empirical calibration for historical comparator, self-controlled case series (SCCS), and the serial combination of those designs against six vaccine exposure groups with 93 negative control and 279 imputed positive control outcomes.ResultsThe historical comparator design mostly had fewer type II errors than SCCS. SCCS had fewer type I errors than the historical comparator. Before empirical calibration, the serial combination increased specificity and decreased sensitivity. Type II errors mostly exceeded 50%. After empirical calibration, type I errors returned to nominal; sensitivity was lowest when the methods were combined.ConclusionWhile serial combination produced fewer false-positive signals compared with the most specific method, it generated more false-negative signals compared with the most sensitive method. Using a historical comparator design followed by an SCCS analysis yielded decreased sensitivity in evaluating safety signals relative to a one-stage SCCS approach. While the current use of serial testing in vaccine surveillance may provide a practical paradigm for signal identification and triage, single epidemiological designs should be explored as valuable approaches to detecting signals.
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| 5. |
- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 6. |
- Askling, J., et al.
(författare)
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How comparable are rates of malignancies in patients with rheumatoid arthritis across the world? A comparison of cancer rates, and means to optimise their comparability, in five RA registries
- 2016
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1789-1796
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Tidskriftsartikel (refereegranskat)abstract
- Background The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. Methods Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). Results There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. Conclusion In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.
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| 7. |
- Bergman, David, et al.
(författare)
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Incidence of ICD-based diagnoses of alcohol-related disorders and diseases from swedish nationwide registers and suggestions for coding
- 2020
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Ingår i: Clinical Epidemiology. - Macclesfield, United Kingdom : Dove Medical Press Ltd.. - 1179-1349. ; 12, s. 1433-1442
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To improve consistency between register studies in Sweden and ensure valid comparisons of possible changes in alcohol-related disorders and diseases (ARDDs) over time, we propose a definition of ARDDs. Based on this definition, we examined Sweden’s incidence rates of ARDDs from 1970 to 2018 in non-primary healthcare settings (inpatient and outpatient). Methods: Swedish Society of Epidemiology members were invited to give feedback on the International Classification of Disease (ICD) codes with a potential link to alcohol use. We then calculated age-standardised and age-specific incidence of ARDDs over time according to the National Patient Register, and the lifetime prevalence of ARDDs diagnosed in adults alive in Sweden on Dec 31, 2018. Results: Sweden’s estimated incidence of ARDDs increased substantially after introducing the new ICD-9 codes in 1987. In the past 10 years (2009–2018), the incidence of ARDDs has been stable (males: 110/100,000 person-years, females: 49/100,000 person-years). Requiring at least two ICD records for diagnosed ARDDs led to a somewhat lower incidence of ARDDs (males: 71 per 100,000 person-years, females: 29 per 100,000 person-years). In Sweden, the lifetime prevalence of diagnosed ARDDs in adults on Dec 31, 2018, was 1.9% (95% CI=1.9–1.9). Conclusion: In this nationwide study, we found an incidence of ARDDs of 50–100/ 100,000 person-years. In 2018, 1 in 52 adults in Sweden had been diagnosed with ARDDs in the National Patient Register.
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| 8. |
- Bergthorsdottir, Ragnhildur, 1971, et al.
(författare)
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Increased risk of hospitalization, intensive care and death due to covid-19 in patients with adrenal insufficiency : a Swedish nationwide study
- 2024
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 295:3, s. 322-330
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with adrenal insufficiency (AI) have excess morbidity and mortality related to infectious disorders. Whether patients with AI have increased morbidity and mortality from COVID-19 is unknown.Methods: In this linked Swedish national register-based cohort study, patients with primary and secondary AI diagnosis were identified and followed from 1 January 2020 to 28 February 2021. They were compared with a control cohort from the general population matched 10:1 for age and sex. The following COVID-19 outcomes were studied: incidence of COVID-19 infection, rates of hospitalization, intensive care admission and death. Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for socioeconomic factors and comorbidities were estimated using Cox regression analysis.Results: We identified 5430 patients with AI and 54,300 matched controls: There were 47.6% women, mean age was 57.1 (standard deviation 18.1) years, and the frequency of COVID-19 infection was similar, but the frequency of hospitalization (2.1% vs. 0.8%), intensive care (0.3% vs. 0.1%) and death (0.8% vs. 0.2%) for COVID-19 was higher in AI patients than matched controls. After adjustment for socioeconomic factors and comorbidities, the HR (95% CI) was increased for hospitalization (1.96, 1.59–2.43), intensive care admission (2.76, 1.49–5.09) and death (2.29, 1.60–3.28).Conclusion: Patients with AI have a similar incidence of COVID-19 infection to a matched control population, but a more than twofold increased risk of developing a severe infection or a fatal outcome. They should therefore be prioritized for vaccination, antiviral therapy and other appropriate treatment to mitigate hospitalization and death.
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| 9. |
- Bonander, Carl, et al.
(författare)
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A Capture-Recapture-based Ascertainment Probability Weighting Method for Effect Estimation With Under-ascertained Outcomes.
- 2024
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Ingår i: Epidemiology (Cambridge, Mass.). - : Lippincott Williams & Wilkins. - 1531-5487 .- 1044-3983. ; 35:3, s. 340-348
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Tidskriftsartikel (refereegranskat)abstract
- Outcome under-ascertainment, characterized by the incomplete identification or reporting of cases, poses a substantial challenge in epidemiologic research. While capture-recapture methods can estimate unknown case numbers, their role in estimating exposure effects in observational studies is not well established. This paper presents an ascertainment probability weighting framework that integrates capture-recapture and propensity score weighting. We propose a nonparametric estimator of effects on binary outcomes that combines exposure propensity scores with data from two conditionally independent outcome measurements to simultaneously adjust for confounding and under-ascertainment. Demonstrating its practical application, we apply the method to estimate the relationship between health care work and coronavirus disease 2019 testing in a Swedish region. We find that ascertainment probability weighting greatly influences the estimated association compared to conventional inverse probability weighting, underscoring the importance of accounting for under-ascertainment in studies with limited outcome data coverage. We conclude with practical guidelines for the method's implementation, discussing its strengths, limitations, and suitable scenarios for application.
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| 10. |
- Bouma, F., et al.
(författare)
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Genetic susceptibility to airway inflammation and exposure to short-term outdoor air pollution
- 2023
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Ingår i: Environmental health. - 1476-069X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAir pollution is a large environmental health hazard whose exposure and health effects are unequally distributed among individuals. This is, at least in part, due to gene-environment interactions, but few studies exist. Thus, the current study aimed to explore genetic susceptibility to airway inflammation from short-term air pollution exposure through mechanisms of gene-environment interaction involving the SFTPA, GST and NOS genes.MethodsFive thousand seven hundred two adults were included. The outcome measure was fraction of exhaled nitric oxide (FeNO), at 50 and 270 ml/s. Exposures were ozone (O-3), particulate matter < 10 & mu;m (PM10), and nitrogen dioxide (NO2) 3, 24, or 120-h prior to FeNO measurement. In the SFTPA, GST and NOS genes, 24 single nucleotide polymorphisms (SNPs) were analyzed for interaction effects. The data were analyzed using quantile regression in both single-and multipollutant models.ResultsSignificant interactions between SNPs and air pollution were found for six SNPs (p < 0.05): rs4253527 (SFTPA1) with O-3 and NOx, rs2266637 (GSTT1) with NO2, rs4795051 (NOS2) with PM10, NO2 and NOx, rs4796017 (NOS2) with PM10, rs2248814 (NOS2) with PM10 and rs7830 (NOS3) with NO2. The marginal effects on FeNO for three of these SNPs were significant (per increase of 10 & mu;g/m(3)):rs4253527 (SFTPA1) with O-3 (& beta;: 0.155, 95%CI: 0.013-0.297), rs4795051 (NOS2) with PM10 (& beta;: 0.073, 95%CI: 0.00-0.147 (single pollutant), & beta;: 0.081, 95%CI: 0.004-0.159 (multipollutant)) and NO2 (& beta;: -0.084, 95%CI: -0.147; -0.020 (3 h), & beta;: -0.188, 95%CI: -0.359; -0.018 (120 h)) and rs4796017 (NOS2) with PM10 (& beta;: 0.396, 95%CI: 0.003-0.790).ConclusionsIncreased inflammatory response from air pollution exposure was observed among subjects with polymorphisms in SFTPA1, GSTT1, and NOS genes, where O-3 interacted with SFTPA1 and PM10 and NO2/NOx with the GSTT1 and NOS genes. This provides a basis for the further exploration of biological mechanisms as well as the identification of individuals susceptible to the effects of outdoor air pollution.
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