Inflammation and "Stress" in Asthma and Allergy : are Oxidative State and Cortisol Levels Involved?

Allergic diseases, such as asthma and allergic rhinitis may be mediated by oxidative stress. Stress in chronic disease is possibly associated with lower secretion of cortisol, with increased production of proinflammatory cytokines typically counter-regulated by cortisol. The aim of this study, in the discipline of allergy and pulmonology, was to investigate the role of oxidative stress and cortisol levels in allergic disease. The thesis was based on two different asthma study populations; a European multicentre-study and the Oslo Environment and Childhood Asthma birth cohort study. Asthma and allergy outcomes were assessed through questionnaires and clinical investigations, allergy and lung-function testing, and measurement of exhaled nitric oxide. Levels of the plasma antioxidant selenium varied throughout Europe, being lowest in the Norwegian children, but with no overall significant association with asthma. Reduced levels of the major serum antioxidant albumin were found in asthmatic children, and reduced albumin was associated with increased nitric oxide, a marker of allergic inflammation. Children with both asthma and allergic rhinitis had reduced albumin levels and increased serum levels of the oxidant ferritin. In poorly controlled asthma we found reduced blood levels of the antioxidants vitamin E and transferrin. Exposure to the pre-oxidant paracetamol in pregnancy was associated with allergic rhinitis at 10 years. The risk of a history of asthma, but not current asthma at 10 years was increased after paracetamol use between 0-6 months age, even in view of concomitant airway infections. Allergic sensitization was associated with infant paracetamol use in female offspring only. Reduced levels of salivary cortisol were found in children with co-morbidity of asthma and allergic rhinitis. The present thesis suggests a significant association between oxidative state and allergic diseases, and salivary cortisols levels are associated with allergic disease

Impact of COVID-19 infection on lung function and nutritional status amongst individuals with cystic fibrosis:A global cohort study

Background: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF). Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV1) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection. Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection. Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF.</p

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020

Background Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). Conclusions SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination

Improved Transient Performance by Lyapunov-based Reset of Dynamic Controllers

Many control applications implemented in the industry are optimized for use in normal conditions. However, special or extreme conditions may occur, i.e. sudden changes in the environmental parameters or the controller set-points. These incidents may lead to unsatisfactory performance of the closed-loop system. A dynamic controller may, in the first place, interpret this as measurement noise to be ignored, as a result of being optimized for steady-state noise performance. Adaptive controllers are often designed in order to achieve asymptotic stability (AS) requirements, hence the transient performance may only be satisfactory for slow varying environmental parameters and controller set-points. In this thesis, a framework for improving controller performance in such situations is presented, followed by three application examples. The framework is presenting a controller strategy using a Lyapunov-based resetting mechanism, changing one or more of the controller states to a different value when an extreme situation is detected. The controller states are reset to a different value if this leads to a drop in the Lyapunov function value. An appropriately selected Lyapunov function is expected to lead to a controller with increased transient performance. In this way, the Lyapunov function is used both as a part in the controller algorithm and as a tool for proving stability for the whole controller system. The system performance may then be divided into two separate regimes, having two separate sets of specifications and tuning variables being decoupled from each other. Performance close to steady-state, being one of the regimes, is typically tuned in order to handle normal conditions. In the other regime, however, a separate part of the controller is having a fast reacting performance, triggered by sudden changes in the environmental parameters or the controller set-points. This regime is referred to as the systems transient regime. The fast reacting performance in this regime typically leads to reduced measurement noise suppressions, but if appropriately tuned, this will only be triggered when severe changes in the environmental parameters or the controller set-points is measured. In this way, the steady-state noise performance of the overall controller system may be improved, without reducing the transient performance. The main challenge encountered developing a controller using this strategy, is the search for a suitable Lyapunov function needed in the resetting strategy. One problem is to find a Lyapunov function, another is to make sure this is a suitable measure for the system’s transient energy. The first problem may be solved in some situations where development of the dynamic controller also yields a Lyapunov function for the closed-loop system. The other problem is only briefly discussed. Optimization theory is, however, being motivated as a promising solution, tried out on a simple example system. A fast observer is needed in order to estimate the Lyapunov function value, since this is not available for measurement in practice. Hence, additional precautions need to be undertaken when implementing the strategy. In particular, filtering effects are studied in detail for a Lyapunovbased resetting mechanism applied on an adaptive backstepping controller for parametric-strictfeedback systems. Tuning guidelines are also provided in order to prevent erroneous resets due to the filtering effects. Simulations of a car braking on a road, partly covered with ice or water, is given as the first example application presented in this thesis. Improved transient performance is shown in these cases of sudden changes in the road/tyre friction parameter. Another challenge in using this resetting strategy is how to ensure parameter convergence of the fast observer described above. In addition to assume that the exciting signal is sufficiently rich during the transient period where typically a reset takes place, some monitoring of the richness of this signal is proposed followed by a suitable action to be taken. This first example system is tested using simulations, hence being able to compare estimated and real values of the plant parameters. The other two examples presented in this thesis are not having this quality, due to plant parameters being unknown, but they illustrate other aspects being important when performing experimental testings. Transient conditions, may also happen for ships operating in rough seas. There is a considerable loss in propeller thrust in case of ventilation and in-and-out-of-water effects. The today’s industrial standard for electrically driven thrusters are shaft speed proportional-integral (PI) controllers, optimized for dynamic positioning (DP) and low speed manoeuvering in normal sea conditions. In extreme sea conditions, however, the propeller may start to spin when severe thrust losses occur. Hence, a Lyapunov-based controller state resetting strategy for the integrator state in the PI-controller is proposed. Increased transient performance in propeller speed is shown by experimental tests, carried out in a test basin, being the second example application presented in this thesis. The reset strategy is also augmented to a thruster controller for transit operations. Additional losses due to operation in transit need to be handled. This is managed by modifying the plant model and upgrading the PI-controller used in the DP case. Experimental tests in a towing tank are carried out in order to show the increased transient performance in the propeller speed, constituting this thesis’ third example application. In this case, also the power fluctuations are reduced, leading to reduced risk of blackout in the vessel power distribution system, in extreme sea conditions