Drug utilization in children with asthma : methodological approaches and practical implications

There is limited research on drug utilization among children, despite them representing 20% of the total population in Europe. In the Priority Medicines report, the World Health Organization suggested that drug utilization in children is one of the priority areas in need of more attention, resources, and research. Asthma is the most common chronic disease in children, and asthma medications are one of the most commonly used drugs by children. Therefore, the overall aim of this thesis was to describe the drug utilization in children with asthma. In studies I and II, questionnaire data from the population-based birth cohort BAMSE were combined with dispensing data from the Swedish Prescribed Drug Register. The concordance between the two data sources was investigated as well as the association between drug usage, patient characteristics, and asthma disease control. We showed that an 18-month time window is preferable when using dispensing data to study the use of asthma medications. Most adolescents with asthma reported use of asthma medications, but a considerable proportion were neither dispensed any drugs nor reported use of someone else’s medications. Girls were less likely to achieve asthma control than boys. In study III, the association between sibship and dispensing patterns of asthma medications in young children was studied. It was a register-based cohort study including all children born in Stockholm, Sweden 2006 – 2007. Sibling status was used as exposure, and incidence of dispensed asthma medications and persistence to therapy over time were used as outcomes. We found that children with siblings had different dispensing patterns of asthma medications compared to singletons regardless of family income and asthma diagnoses. After including the siblings’ asthma medication and comparing with control children, the proportion of children with persistent medication increased which may indicate that siblings share asthma medications. In study IV, we assessed the effect of the eliminated patient fee on the dispensing patterns of asthma medication in children. We used dispensing data two years before and after the intervention (January 1st, 2016) to measure prevalence, incidence, numbers of Defined Daily Doses (DDDs)/child, and persistence to drug treatment before and after the intervention. We found that the intervention had a modest effect on the dispensing patterns of asthma medication, nevertheless the volume dispensed per child increased, particularly in children with low socioeconomic status. In conclusion, this thesis describes drug utilization in children with asthma. Four factors to consider when assessing the dispensing patterns of asthma medications were found to be important: sex, sibship, time window used in the register, and changes in the co-payment system. Different data sources of drug utilization will give different results. Dispensing data from pharmacies will underestimate drug use compared to data from self-reported (or parentalreported) use of asthma medications. Siblings share asthma medications, which may lead to an underestimation of drug use if only one of the siblings’ asthma medications is included in the measurement of drug usage when using data on dispensed drugs

Agnostic studies in epidemiology

In epidemiology there has been an consistent effort to construct refined methods aiming towards the ability to draw casual inference between an exposure and an outcome. This thesis, partly inspired by the genome-wide association studies, has on the contrary strived towards exploration of data. The fundamental idea has been to decipher associations between one or many exposures with one or many outcomes. Using population-based register data from Sweden, this thesis explored the association between ABO blood group and RhD status in 1,217 disease categories, the occurrence of transfusion-transmitted disease examining 1,155 disease categories, the spectrum of adverse events in tyrosine kinase-inhibitor treated patients with chronic phase chronic myeloid leukemia in 670 disease categories, and lastly the occurrence of familial aggregation of 60 cancerous disease. To account for multiple testing we use previously employed methods of adjustment. In Paper I, using the large-scale donation-transfusion database, SCANDAT-3S with 8 million individuals, we identified 49 associations with ABO blood group and disease. Many associations were previously known but we identified a novel association of a protective role for blood group B, as compared to O, in suffering kidney stones. For RhD status, we identified only one disease after adjustment for multiple testing, namely pregnancy-induced hypertension. In Paper II, which used the same database and the unique connection between blood donor, the blood product and the recipients of blood, we identified 15 disease categories that seemed to be transfusion-transmitted. Among them there were strong signals suggesting transmission in hepatitis virus and HIV. For most other findings, the effect sizes were small. A general conclusion was that the current practice in Sweden, regarding transfusion safety, seems acceptable in terms of the risk of transfusion-transmission of disease. In Paper III, we used a database covering the full Swedish chronic myeloid leukemia-population diagnosed since 2002. In this study, also consisting of a matched control cohort, we identified 142 disease categories with increased incidence as compared to the control cohort. We also found 41 associations between tyrosine kinase inhibitors, used for the treatment of chronic myeloid leukemia, and a disease category. No unknown severe adverse events were found. In Paper IV, we created 3.5 million pedigrees using the Multi-generation Register and explored cancerous disease clustering within pedigrees. We identified multiple cancer syndromes, e.g. BRCA1/2 and hereditary colon cancer. The approach, agnostic in that we strive towards testing all possible hypotheses without prejudice, has the advantage of removing or at least reducing the researcher bias – where the research hypothesis is constrained by the environment of the individual researcher. The approach is mainly limited by the problems of misclassification of exposures and outcomes, the inability to optimally construct modelling for a large set of hypotheses, and by false discoveries. We have proposed some solutions to overcome these issues. A main aspect is that the method should not be used to draw inference but rather to generate hypothesis for future refined studies in a world with increasing amounts of high-resolution data

Spatially resolved spectroscopy across stellar surfaces. I. Using exoplanet transits to analyze 3-D stellar atmospheres

CONTEXT: High-precision stellar analyses require hydrodynamic modeling to interpret chemical abundances or oscillation modes. Exoplanet atmosphere studies require stellar background spectra to be known along the transit path while detection of Earth analogs require stellar microvariability to be understood. Hydrodynamic 3-D models can be computed for widely different stars but have been tested in detail only for the Sun with its resolved surface features. Model predictions include spectral line shapes, asymmetries, and wavelength shifts, and their center-to-limb changes across stellar disks. AIMS: To observe high-resolution spectral line profiles across spatially highly resolved stellar surfaces, which are free from the effects of spatial smearing and rotational broadening present in full-disk spectra, enabling comparisons to synthetic profiles from 3-D models. METHODS: During exoplanet transits, successive stellar surface portions become hidden and differential spectroscopy between various transit phases provides spectra of small surface segments temporarily hidden behind the planet. Planets cover no more than about 1% of any main-sequence star, enabling high spatial resolution but demanding very precise observations. Realistically measurable quantities are identified through simulated observations of synthetic spectral lines. RESULTS: In normal stars, line profile ratios between various transit phases may vary by some 0.5%, requiring S/N ratios of 5,000 or more for meaningful spectral reconstruction. While not yet realistic for individual spectral lines, this is achievable for cool stars by averaging over numerous lines with similar parameters. CONCLUSIONS: For bright host stars of large transiting planets, spatially resolved spectroscopy is currently practical. More observable targets are likely to be found in the near future by ongoing photometric searches.Comment: Accepted by Astronomy & Astrophysics; 14 pages, 12 figure

The Securitisation of the International Economic and Financial Crisis

This study explores the development of the Concerted European Response from adoption of the European Action Plan by the euro group, to the adoption of the Economic Recovery Plan by the European Council. The theoretical framework employed to assess this process is based on the works of the Copenhagen School on securitisation. However, In order to analyse the economic and financial crisis through a security perspective this study moves away from the state-centric perspective employed in traditional security analysis and introduces a new conceptualisation of the referent object. The perceived security threat associated with the economic and financial crisis evolved considerably during the course of the autumn. This transition reflects the evolution of the crisis from turmoil in the financial markets to recession. By referring to the crisis as something existentially threatening European policy-makers moved to legitimise measures that during normal circumstances would have been considered impossible. The Heads of State and Government, and the Commission, thus securitised the economic and financial crisis in order to justify the implementation of extraordinary measures to arrest the threatening development

An African perspective on the ILO conventions on minimum age: the case of Ethiopia

The ILO Minimum Age Conventions, adopted from 1919 - 1973, got their form in the post World War I context of industrialization, urbanization, social instability and a growing trade union movement, and were modelled on the late 19th century European labour legislation. It was a time of heavy unemployment, and the workers perceived child labourers as competitors on the labour market. Ethiopia is one of the poorest countries of the world with a population of 90 million and a median age of 17.5 years. Primary education has been expanded and now reaches about 75% of the relevant age-group, while only 15% continue into secondary education. The contribution of the younger generation to productivity is essential and child labour is the prevailing norm. In the Ethiopian Constitution adopted 1995, the rights of children were addressed: the right to life, to education and to protection from labour exploitation. Ethiopia is signatory to the ILOConvention 138 and its national law has set the age-limit to 14 years. Ethiopia is a beneficiary of the World Bank's lending program to strengthen market economy, which has implications for children's employment and working conditions. During 2012 we did a study interviewing children working in the agricultural sector to discern how the globalisation of economy and human rights norms affect their lives. The situation for child agricultural workers in Ethiopia is an illustration of how child workers as agents are finding ways to manage within the legal and economic structures based on experiences from the West

Tort, Social Security, and No-Fault Schemes: Lessons from Real-World Experiments

Background Anthropometric measurements are useful in clinical practice since they are non-invasive and cheap. Previous studies suggest that sagittal abdominal diameter (SAD) may be a better measure of visceral fat depots. The aim of this study was to prospectively explore and compare how laboratory and anthropometric risk markers predicted subclinical organ damage in 255 patients, with type 2 diabetes, after four years. Methods Baseline investigations were performed in 2006 and were repeated at follow-up in 2010. Carotid intima-media thickness (IMT) was evaluated by ultrasonography and aortic pulse wave velocity (PWV) was measured with applanation tonometry over the carotid and femoral arteries at baseline and at follow-up in a cohort of subjects with type 2 diabetes aged 55–65 years old. Results There were significant correlations between apolipoprotein B (apoB) (r = 0.144, p = 0.03), C - reactive protein (CRP) (r = 0.172, p = 0.009) at baseline and IMT measured at follow-up. After adjustment for sex, age, treatment with statins and Hba1c, the associations remained statistically significant. HbA1c, total cholesterol or LDL-cholesterol did not correlate to IMT at follow-up. Baseline body mass index (BMI) (r = 0.130, p = 0.049), waist circumference (WC) (r = 0.147, p = 0.027) and sagittal Abdominal Diameter (SAD) (r = 0.184, p = 0.007) correlated to PWV at follow-up. Challenged with sex, SBP and HbA1c, the association between SAD, not WC nor BMI, and PWV remained statistically significant (p = 0.036). In a stepwise linear regression, entering both SAD and WC, the association between SAD and PWV was stronger than the association between WC and PWV. Conclusions We conclude that apoB and CRP, but not LDL-cholesterol predicted subclinical atherosclerosis. Furthermore, SAD was more independent in predicting arterial stiffness over time, compared with WC, in middle-aged men and women with type 2 diabetes.Funding Agencies|Medical Research Council of Southeast Sweden||Center for Medical Image Science and Visualization (CMIV)||Linkoping University||Futurum||King Gustaf V and Queen Victoria Freemason Foundation||GE Healthcare||Swedish Heart-Lung Foundation||Swedish Research Council Grant|12661|</p

Selection of high-z supernovae candidates

Deep, ground based, optical wide-field supernova searches are capable of detecting a large number of supernovae over a broad redshift range up to z~1.5. While it is practically unfeasible to obtain spectroscopic redshifts of all the supernova candidates right after the discovery, we show that the magnitudes and colors of the host galaxies, as well as the supernovae, can be used to select high-z supernova candidates, for subsequent spectroscopic and photometric follow-up. Using Monte-Carlo simulations we construct criteria for selecting galaxies in well-defined redshift bands. For example, with a selection criteria using B-R and R-I colors we are able to pick out potential host galaxies for which z>0.85 with 80% confidence level and with a selection efficiency of 64-86%. The method was successfully tested using real observations from the HDF. Similarly, we show that that the magnitude and colors of the supernova discovery data can be used to constrain the redshift. With a set of cuts based on V-R and R-I in a search to m_I~25, supernovae at z~1 can be selected in a redshift interval sigma_z <0.15.Comment: 33 pages, 13 figures, accepted for publication in PASP (March 2002 issue

Prevotella intermedia and Prevotella nigrescens serotypes, ribotypes and binding characteristics

type strains and 62 clinical isolates of Prevotella intermedia and Prevotella nigrescens were typed with the use of genomic DNA fingerprints and rRNA gene probes. The strains were further serotyped with monoclonal antibodies and characterized with SDS-PAGE, enzymatic activities, hemolysis and hemagglutination and coaggregation with Streptococcus and Actinomyces spp. P. intermedia and P. nigrescens were found to have distinct ribotype patterns which correspond to previously defined serotypes I and II/III, respectively. No clear phenotypic difference related to hemolysis, hemagglutination and coaggregation with Streptococcus and Actinomyces species, or expression of aminopeptides and lipase was found between P. intermedia and P. nigrescen