Exploring and redefining Autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic, childhood-onset disorder caused by mutations in the autoimmune regulator (AIRE) gene. Multi-organ autoimmune disease and chronic mucocutaneous candidiasis (CMC) dominate the clinical phenotype, making it an important model disease for autoimmunity. The objective of this thesis was to perform a detailed clinical, genetic and immunological characterisation of Norwegian APS-1 patients and explore the mechanisms behind CMC susceptibility. Fifty-two patients were included, revealing highly variable phenotypes. Most patients presented with one of the major disease components during childhood, hypoparathyroidism, primary adrenal insufficiency or CMC; enamel hypoplasia, hypoparathyroidism and CMC were the most frequent features. The prevalence of CMC indicates a specific immunodeficiency, which was underpinned by our finding of dysregulated immune responses to a Candida challenge. Specifically, monocytes produced significantly less interleukin-23p19 (IL), an important mediator in the Candida defence. Properly treatment of Candida infections is important as long-term inflammation in the oral cavity contributes to the development of oral malignancies, described here as a novel entity of APS-1. All Norwegian patients presented tissue-specific autoantibodies, and most had reactivity against IL-17, IL-22, and interferon-ω. The most common AIRE mutation was c.967_979del13. The splice mutation c.879+1G>A was associated with a mild adult-onset phenotype. Possible explanations are partial activity by AIRE lacking exon 7 and/or a certain amount of wild-type transcripts being produced despite mutation in a conserved splice donor site. Finally, the influence of environmental factors was explored by characterizing the oral microbiome. Indeed, APS-1 patients have significantly altered oral microbiota, with a general reduction in the total number of bacterial genera and species and altered relative abundance of major phyli compared to healthy subjects. This research has implications for the diagnosis and clinical care of patients with APS-1 and organ-specific autoimmune diseases and offers further insight into some of the mechanisms underlying autoimmune disorders and CMC

Pubertal development in Norwegian girls

Background: Evidence suggests that girls worldwide are experiencing a decrease in age at pubertal onset, but data from Norwegian girls have not been available. Early pubertal timing is associated with adverse health outcomes. Pubertal breast development is currently categorized using the Tanner B scale and relies on visual inspection and/or palpation. Breast ultrasound appears to be a good alternative to this Tanner B assessment because it can separate adipose tissue from breast tissue and facilitates both staging and volumetric measurements. Objectives: The objectives were to explore ultrasound as an alternative method to assess breast development throughout puberty, to investigate the timing of puberty in Norwegian girls and construct pubertal references, and to shed light on the relationship between anthropometric indicators of body composition and the timing of puberty. Methods: This thesis is based on data from the Bergen Growth Study 1 (BGS1; 2003–2006, n = 1485, aged 8–15.5 years) and the Bergen Growth Study 2 (BGS2; 2016 and 2017, n = 703, aged 6–16 years). Data on menarche were recorded in both studies, while breast development was assessed only in the BGS2. Six distinct ultrasound-based breast stages were described, and the performance of these were evaluated in terms of observer agreement and in relation to the standardized Tanner B scale. Descriptive pubertal references were estimated from the BGS2. The associations between indirect (body mass index, BMI) and direct (skinfolds and waist circumference (WC)) measurements of fat with the timing of menarche were explored based on data from the BGS1. The ages at menarche between the studies were compared. Results: The ultrasound staging system performed well in terms of the agreement between one and two observers; however, direct measurements of size and volume lacked the necessary precision. When comparing ultrasound staging and Tanner B staging, an overall good agreement was found. A modest decline in the age at menarche was observed during the last decade, although pubertal references suggest that pubertal timing in Norway is similar to that of neighbouring countries. After adjustment for age and sex, both high and low levels of BMI, WC, subscapular skinfold (SSF) and triceps skinfold were all associated with an earlier and later menarche. In a fully adjusted analysis of all the measurements together, only a high BMI was related to earlier menarche, while a low BMI and a low SSF were associated with later menarche. Conclusions: Ultrasound is a feasible method to determine the breast developmental stage. This research has clinical implications for the evaluation of puberty in paediatric and adolescent female patients in Norway by providing descriptive references based on a healthy sample of girls. The decline in age at menarche was not explained by BMI and therefore warrants further investigations in population-based studies. BMI was the strongest anthropometric predictor of early and late menarche

Joint description of waves and currents applied in a simplified load case

In order to perform a more accurate analysis of marine structures, joint probability distributions of different metocean parameters have received an increasing interest during the last decade, facilitated by improved availability of reliable joint metocean data. There seems to be no general consensus with regard to the approach of estimating joint probability distributions of metocean parameters and a general overview of recent studies exploring different joint models for metocean parameters is presented. The main objective of this article is twofold: first to establish a joint distribution of significant wave height and current speed and then to assess the possible conservatism in the Norwegian design standard by applying this joint distribution in a simplified load case. Based on NORA10 wave data and simulated current data, a joint model for significant wave height and current speed at one location in the northern North Sea is presented. Since episodes of wind-generated inertial oscillations are governing the current conditions at this location, a joint conditional model with current speed conditional on significant wave height is suggested. A peak-over-threshold approach is selected. The significant wave height is found to be very well modelled by a 2-parameter Weibull distribution for significant wave height exceeding 8 m, while a log-normal distribution describes the current speed well. This model is used to Monte-Carlo simulate joint significant wave heights and current speeds for periods corresponding to the ultimate and accidental limit states (ULS and ALS), i.e. 100 and 10 000 years. The possible conservatism in the Norwegian design standard is assessed by a simplified case study. The results give a clear indication that the Norwegian design standard in not necessarily conservative, neither at ULS nor ALS level.acceptedVersio

Simulated wind-generated inertial oscillations compared to current measurements in the northern North Sea

This is a pre-print of an article published in Ocean Dynamics. The final authenticated version is available online at: https://doi.org/10.1007/s10236-018-1150-zMeasured current speed data show that episodes of wind-generated inertial oscillations dominate the current conditions in parts of the northern North Sea. In order to acquire current data of sufficient duration for robust estimation of joint metocean design conditions, such as wind, waves and currents, a simple model for episodes of wind-generated inertial oscillations is adapted for the northern North Sea. The model is validated with and compared against measured current data at one location in the northern North Sea and found to reproduce the measured maximum current speed in each episode with considerably accuracy. The comparison is further improved when a small general background current is added to the simulated maximum current speeds. Extreme values of measured and simulated current speed are estimated and found to compare well. To assess the robustness of the model and also the sensitivity of current conditions from location to location, the validated model is applied at three other locations in the northern North Sea. In general, the simulated maximum current speeds are smaller than the measured, suggesting that wind-generated inertial oscillations are not as prominent at these locations and that other current conditions may be governing. Further analysis of the simulated current speed and joint distribution of wind, waves and currents for design of offshore structures will be presented in a separate paper.submittedVersio

Hematopoiesis, Inflammation and Aging—The Biological Background and Clinical Impact of Anemia and Increased C‐Reactive Protein Levels on Elderly Individuals

Anemia and systemic signs of inflammation are common in elderly individuals and are associated with decreased survival. The common biological context for these two states is then the hallmarks of aging, i.e., genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Such aging-associated alterations of hematopoietic stem cells are probably caused by complex mechanisms and depend on both the aging of hematopoietic (stem) cells and on the supporting stromal cells. The function of inflammatory or immunocompetent cells is also altered by aging. The intracellular signaling initiated by soluble proinflammatory mediators (e.g., IL1, IL6 and TNFα) is altered during aging and contributes to the development of both the inhibition of erythropoiesis with anemia as well as to the development of the acute-phase reaction as a systemic sign of inflammation with increased CRP levels. Both anemia and increased CRP levels are associated with decreased overall survival and increased cardiovascular mortality. The handling of elderly patients with inflammation and/or anemia should in our opinion be individualized; all of them should have a limited evaluation with regard to the cause of the abnormalities, but the extent of additional and especially invasive diagnostic evaluation should be based on an overall clinical evaluation and the possible therapeutic consequences.publishedVersio

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients

Allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies. However, this treatment is associated with severe treatment-related morbidity and mortality. The metabolic status of the recipient may be associated with the risk of development of transplant-associated complications such as graft-versus-host disease (GVHD). To better understand the impact of the lipidomic profile of transplant recipients on posttransplant complications, we evaluated the lipid signatures of patients with hematological disease using non-targeted lipidomics. In the present study, we studied pretransplant serum samples derived from 92 consecutive patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). A total of 960 lipid biochemicals were identified, and the pretransplant lipidomic profiles differed significantly when comparing patients with and without the risk factors: (i) pretransplant inflammation, (ii) early fluid overload, and (iii) patients with and without later steroid-requiring acute GVHD. All three factors, but especially patients with pretransplant inflammation, were associated with decreased levels of several lipid metabolites. Based on the overall concentrations of various lipid subclasses, we identified a patient subset characterized by low lipid levels, increased frequency of MDS patients, signs of inflammation, decreased body mass index, and an increased risk of early non-relapse mortality. Metabolic targeting has been proposed as a possible therapeutic strategy in allotransplant recipients, and our present results suggest that the clinical consequences of therapeutic intervention (e.g., nutritional support) will also differ between patients and depend on the metabolic context.publishedVersio

Pretransplant systemic metabolic profiles in allogeneic hematopoietic stem cell transplant recipients - identification of patient subsets with increased transplant-related mortality

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, the treatment has high risk of severe transplantation-related mortality (TRM). In this study, we examined pretransplantation serum samples derived from 92 consecutive allotransplant recipients with AML or MDS. Using nontargeted metabolomics, we identified 1274 metabolites including 968 of known identity (named biochemicals). We further investigated metabolites that differed significantly when comparing patients with and without early extensive fluid retention, pretransplantation inflammation (both being associated with increased risk of acute graft-versus-host disease [GVHD]/nonrelapse mortality) and development of systemic steroid-requiring acute GVHD (aGVHD). All three factors are associated with TRM and were also associated with significantly altered amino acid metabolism, although there was only a minor overlap between these three factors with regard to significantly altered individual metabolites. Furthermore, steroid-requiring aGVHD was especially associated with altered taurine/hypotaurine, tryptophan, biotin, and phenylacetate metabolism together with altered malate-aspartate shuttle and urea cycle regulation. In contrast, pretransplantation inflammation was associated with a weaker modulation of many different metabolic pathways, whereas extensive fluid retention was associated with a weaker modulation of taurine/hypotaurine metabolism. An unsupervised hierarchical cluster analysis based on the 13 most significantly identified metabolites associated with aGVHD identified a patient subset with high metabolite levels and increased frequencies of MDS/MDS-AML, steroid-requiring aGVHD and early TRM. On the other hand, a clustering analysis based on metabolites that were significantly altered for aGVHD, inflammation, and fluid retention comparison groups identified a patient subset with a highly significant association with TRM. Our study suggests that the systemic pretransplantation metabolic profiles can be used to identify patient subsets with an increased frequency of TRM.publishedVersio