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- Almqvist, Linnea, 1987-
(författare)
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Asthma epidemiology : prognosis of asthma with onset in childhood and in adulthood
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: to update the knowledge on the epidemiology of asthma with onset in childhood and adulthood as well as examine the importance of risk factors in early childhood and clinical characteristics on the incidence and prognosis of asthma.Methods: The thesis is based on the epidemiological research program Obstructive Lung Disease in Northern Sweden (OLIN) studies. Pediatric cohort: recruited in 1996 (age 8y, n=3430, 97% of invited) and followed annually by questionnaire about asthma, allergy and risk factors until 19y and a postal questionnaire at 28y. Clinical examinations included skin prick tests (SPT at 8, 12 and 19y) and spirometry (19y). Adult cohort: 309 adults (age 20–60y) with asthma onset in the last 12 months were recruited 1995-99 and re-examined in 2012-14 (n=205). Structured interviews, spirometry and SPT were performed at recruitment and follow-up and bronchial hyperreactivity (BHR) at recruitment.Results: The asthma incidence rate was 10-13/1000/year in childhood and adolescence and 6/1000/year in young adulthood. Several risk factors in early life were associated with asthma onset in childhood, adolescence and young adulthood, e.g. family history of asthma, <3 months breastfeeding, rhinoconjunctivitis and positive SPT at 8y, while low birthweight, maternal smoking during pregnancy, severe respiratory infections and eczema were associated with onset in childhood and adolescence. Among those with asthma at 8y, 62% still had asthma at 28y and this was associated with positive SPT, rhinoconjunctivitis, severe respiratory infection in childhood, and bronchial hyperreactivity (BHR) in adolescence. Coexistence of asthma, rhinitis and eczema increased by age, especially among those with a positive SPT. However, having all three conditions was uncommon. In the 15y follow-up adult onset asthma, 89% had persistent asthma. Better lung function at recruitment and less severe BHR was associated with remission. Remission rate of adult onset asthma was <1% per year.Conclusion: The incidence of asthma was high during childhood and adolescence and then decreased in young adulthood. Factors in early life that were associated with incident asthma during childhood were still associated with the incidence in adult age. Among those with asthma onset by 8 years, 62%, still had asthma as young adults. The coexistence of asthma, rhinitis and eczema varied from 8 to 28y without following a specific pattern, only a small proportion reported having all three conditions. Remission of adult onset asthma was rare.
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| 2. |
- Sawalha, Sami, 1975-
(författare)
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Chronic obstructive pulmonary disease : clinical phenotyping, mortality and causes of death
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is common. The estimated prevalence is about 10% among adults, but varies largely dependent on the major risk factors age and smoking. Under-diagnosis of COPD is substantial and is related to disease severity. Thus, subjects with mild to moderate COPD are underrepresented in medical registers among health care providers as well as in national registers. Post- bronchodilator (BD) spirometry is mandatory for the diagnosis of COPD, but not sufficient to assess and manage COPD. Phenotyping based on spirometry and clinical manifestations can make it easier to apply individual assessment of subjects with COPD. COPD is a systemic disease with pulmonary and extra-pulmonary manifestations and comorbidities are common. Comorbidities most probably contribute to the observed increased mortality among subjects with COPD, however, the impact of comorbidities on mortality and causes of death among subjects with mild to moderate COPD is unclear. Furthermore, there seems to be sex-dependent differences with regard to susceptibility to risk factors, clinical manifestation and outcomes.Aim: The overall aim of this thesis was to identify and characterize clinical relevant COPD phenotypes in population-based studies, using spirometry together with clinical characteristics such as respiratory symptoms, exacerbations, and comorbidities, and their impact on mortality and further, also cause of death.Methods: This thesis is based on data from the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study. The study population was recruited in the years 2002-2004, when all 993 individuals with (FEV1/VC<0.70) were identified after examinations of population-based cohorts, together with age- and sex-matched non-obstructive referents (n=in total 1,986). In this thesis, cross-sectional data from recruitment were used together with mortality data from the Swedish Tax Agency from the date of recruitment in 2002-2004 and onwards. Data on cause of death was collected from the Swedish National Board for Health and Welfare register for all deaths until 31 December 2015. Spirometry was used to identify the following spirometric groups, in paper I: Non-COPD (FEV1/VC≥0.70); COPD (pre- BD FEV1/VC<0.70); in paper II: Non- obstructive (FEV1/VC≥0.70), Pre- not post-BD obstructive (pre- not post-BD FEV1/VC<0.70); COPD (post-BD FEV1/VC<0.70); In paper III: Normal Lung Function (NLF, FEV1/VC≥0.7 & FVC≥80% predicted), COPD (post BD FEV1/VC<0.70) and Lower Limit of Normal COPD (LLN-COPD, the LLN criterion applied among those with COPD); in paper IV: NLF and COPD defined as in paper III, and Restrictive Spirometric pattern (RSP, FEV1/VC≥0.70 & FVC<80% predicted). The OLIN-COPD study and collection of data on causes of death were approved by the regional ethical committee at Umeå University.Results: Paper I: Subjects with COPD had more productive cough than non-COPD, and men more than women. Productive cough increased the risk for exacerbations in COPD and non-COPD and productive cough was associated with worse survival in both groups. In adjusted models (HR;95%CI) the increased risk for death associated with productive cough among those with COPD persisted (1.48;1.13-1.94) when compared with non-COPD without productive cough, significantly so also among men with COPD (1.63;1.17-2.26), but not among women (1.23;0.76-1.99).Paper-II: Pre-BD spirometry misclassified every fourth subject as having COPD. Subjects with pre- but not post-BD obstruction were similar to subjects with COPD regarding reported ‘any respiratory symptoms’, asthma before the age of 40, exacerbations, and comorbidities. The cumulative mortality among subjects with pre- not post-BD obstruction was similar to among subjects in the non-obstructive group, still, the survival was better than among those with COPD. The increased risk for death for COPD persisted also in an adjusted model (1.24; 1.04-1.49) when compared with the non-obstructive group, and the pattern was similar among men and women (1.27; 1.00-1.60 and1.24; 0.92-1.13).Paper III: Men with COPD had more CVD and DM compared to women, while anxiety/depression (A/D) was more common among women than men in all spirometric groups. Men had a higher cumulative mortality than women in all groups. However, CVD seemed to have a greater impact on mortality among women than men, while anxiety/depression increased the risk for death similarly in both sexes. The use of the LLN criterion did not change the observed pattern.Paper IV: CVD was the most common cause of death in all spirometric groups, NLF, RSP and COPD, followed by cancer. Those with COPD and RSP had a similar and higher cumulative mortality than those with NLF. RSP and COPD had an increased risk for CVD death and respiratory death, independent of age, sex, smoking habits and BMI-category, however, the increased risk for CVD death did not reach statistical significance in RSP. In all the groups, the risk for deaths due to cancer was similar, however, lung cancer was more common in COPD than in NLF and RSP. The pattern was fairly similar among men and women. Conclusions: Simple diagnostic procedures like history of respiratory symptoms, exacerbations, and comorbidity can, together with spirometry, contribute with important clinical classification of prognostic importance. Productive cough increased the risk for exacerbations in both COPD and non-COPD. The highest risk for exacerbations and death was observed among subjects with COPD and productive cough. It was impossible to distinguish COPD from those with pre- not post-BD obstruction based on the history of respiratory symptoms, asthma, exacerbations and comorbidities. Still, COPD was associated with an increased risk for death while pre- not post-BD obstruction had better survival than COPD but similar as non-obstructive. There were sex-dependent differences regarding comorbidities and mortality. CVD was less common among women but had a greater impact on mortality compared to among men while A/D, less common among men, increased the risk for death similarly in both sexes. CVD and cancer were the most common causes of death in all spirometric groups. RSP had a similar and higher mortality as COPD when compared with NLF. The risk for cancer-related death was similar in all groups, while the results indicated that COPD and RSP had an increased risk for CVD and respiratory death.
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| 3. |
- Backman, Dan, 1972-
(författare)
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Interaction Studies of Secreted Aspartic Proteases (Saps) from Candida albicans : Application for Drug Discovery
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is focused on enzymatic studies of the secreted aspartic proteases (Saps) from Candida albicans as a tool for discovery of anti-candida drugs. C. albicans causes infections in a number of different locations, which differ widely in the protein substrates available and pH. Since C. albicans needs Saps during virulent growth, these enzymes are good targets for drug development.In order to investigate the catalytic characteristics of Saps and their inhibitor affinities, substrate-based kinetic assays were developed. Due to the low sensitivity of these assays, especially at the sub-optimal pH required to mimic the different locations of infections, these assays were not satisfactory. Therefore, a biosensor assay was developed whereby, it was possible to study interaction between Saps and inhibitors without the need to optimise catalytic efficacy. Furthermore, the biosensor assay allowed determination of affinity, as well as the individual association and dissociation rates for inhibitor interactions.Knowledge about substrate specificity, Sap subsite adaptivity, and the pH dependencies of catalytic efficacy has been accumulated. Also, screening of transition-state analogue inhibitors designed for HIV-1 protease has revealed inhibitors with affinity for Saps. Furthermore, the kinetics and pH dependencies of their interaction with Saps have been investigated. One of these inhibitors, BEA-440, displayed a complex interaction with Saps, indicating a conformational change upon binding and a very slow dissociation rate. A time dependent interaction was further supported by inhibition measurements. The structural information obtained affords possibilities for design of new more potent inhibitors that might ultimately become drugs against candidiasis. The strategy to combine substrate specificity studies with inhibitor screening has led to complementary results that generate a framework for further development of potent inhibitors.
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| 4. |
- de Brun, Maryam, 1991-
(författare)
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Hyperglycaemia during pregnancy : The challenge of screening and deciding diagnostic criteria for gestational diabetes in Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperglycaemia during pregnancy is one of the most common complicationsof pregnancy. In 2013, the World Health Organisation recommended diagnostic criteria (WHO-2013) for gestational diabetes mellitus (GDM), whichremains controversial due to an expected increase in prevalence, and the uncertainty as to the clinical relevance of treating these additional women or its cost-effectiveness.Paper I involves a cross-sectional study of 4 918 pregnant women using riskfactor screening, which was poorly predictive of the WHO-2013 criteria, with an area under the curve of 40% (95% CI 24–32). In Paper II, a systematic review and meta-analysis of the prevalence of GDM according to the WHO2013 criteria in 136 705 women showed a 75% (RR 1.75, 95% CI 1.53-2.01) increased prevalence compared to the other GDM criteria. In Papers III-IV, a national stepped wedge cluster randomised controlled trial of 26 160 pregnancies before and 28 509 after the implementation of the WHO-2013 criteria across eight clusters during 2018 led to a 2.90 fold increase in GDM prevalence. No significant decrease was seen in the primary outcome, large for gestational age (LGA). There were, however, health benefits in secondary outcomes for the mother and neonate. There was a significant decrease in LGA dependent on the definition used, including the clinically used in Sweden (>2SD) with adjusted OR of 0.89 (95% CI 0.82-0.97). In Paper IV, the WHO2013 criteria led to increased resource use and incremental costs (€341.1 (195.9)) per pregnancy. The cost-effectiveness needs to be related to health benefits for the mother and/or neonate.In conclusion, the current screening methods for GDM are in need of revision considering their poor predictive characteristics in finding GDM according to the WHO-2013 criteria. Implementing the WHO-2013 criteria in Sweden resulted in higher GDM prevalence with short-term increased resource use with uncertainty in costs savings and considerable healthcare benefits for the mother and neonate. This thesis provides evidence regarding the consequences of implementing the WHO-2013 criteria compared to former Swedish GDM criteria and may assist future decision-making.
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