Nasal CPAP support of newborn infants : measurements of interface leakage and performance of selected systems

Objective: The most common treatment for newborns in respiratory distress is nasal continuous positive airway pressure (nCPAP). Comparing clinical studies have shown a better outcome and a lower risk of chronic lung disease compared to invasive mechanical ventilation (MV) when used as primary treatment. Still, when CPAP fails, mechanical ventilation is the available rescue treatment. Since the clinical use of non-invasive CPAP caught on in the 1970’s, a range of devices and interfaces have been developed, of which some are no longer used. Still today, there is a lack of knowledge to guide clinicians around the world as to what device, interface and settings will maximize the clinical CPAP benefit. The overall aim of my dissertation is to evaluate CPAP equipment´s mechanical properties and factors that can affect CPAP performance in patients to identify possible improvements that can reduce the need for harmful mechanical ventilation. Methods: 1. Selected flow meters were tested with mechanical lung simulations to determine their performance in the in-line and flow-through position. 2. Resistance, CPAP performance and mechanism of action were determined for the MediJet pressure generators using mechanical lung simulations. 3. The unconventionally designed Pumani bubble-CPAP system, aimed for developing countries, was tested with regard to resistance and CPAP performance using mechanical lung simulations. A traditional bubble-CPAP system was added for comparison. 4. A scoping review was performed to determine common alterations to the original bubbleCPAP design in clinical use. The effects of these modifications on CPAP performance were tested in-vitro using mechanical lung simulations. 5. A randomized, clinical cross-over study was performed, comparing absolute interface leakage with prongs and nasal mask. The effects of common leakage-reducing care maneuvers were evaluated. Results: 1. In the in-line position, the flow meter volume added dead space. An increased flow meter resistance increased the work of breathing, both in the in-line and flow-through position and added to the CPAP pressure in the flow-through position. 2. The encapsulated versions of MediJet created pressure by resistance, were pressure unstable and had high imposed work of breathing. 3. The Pumani system was pressure unstable and induced a high work of breathing. Pressure was mainly created by resistance and the achieved pressure correlated poorly with submersion level. 4. An increased interface resistance caused pressure instability and an increased imposed work of breathing. An increased expiratory tubing resistance resulted in an increased imposed work of breathing compared to traditional bubble-CPAP systems and a higher CPAP pressure than indicated by submersion depth. 5. Interface leakages were significantly lower with prongs than nasal mask. Simple reducing maneuvers, such as adjusting the interface fit, were successful in most cases. Conclusions: 1. To measure flows without affecting the child is best achieved with a low resistance flow meter in the flow-through position. 2. The MediJet pressure generators, based on the Benveniste valve, have changed their mechanism of action and CPAP properties due to their encapsulation. 3. The Pumani adds more to the work of breathing than a traditional bubble-CPAP system. The achieved pressure cannot be determined by submersion depth. 4. The patient interface should be placed close to the breathing circuit. Low-resistance interfaces and expiratory tubing should be used to minimize the imposed work of breathing and to achieve the desired pressure indicated by submersion depth. 5. During neonatal CPAP treatment, prongs leak less than nasal mask. In most cases, leakage can be reduced with simple reducing care maneuvers

Charakterisierung der molekularen Rolle von Caspasen bei der Proliferation von Fibroblasten und T-Lymphozyten

Recently the proapoptotic caspase family has been described to be involved also in proliferative processes. Initially, in this work, the relevance of the FADD/Caspase signaling pathway for cell growth was investigated using murine fibroblasts. Expression of a dominant-negative FADD mutant caused a reduced growth rate of these cells compared to the wildtype. Subsequently the molecular contribution of caspases during mitogen-induced proliferation of human T lymphocytes was characterized. Experiments using human T cells showed an impaired proliferative response of mitogen-activated T cells, when caspase activity was blocked by pharmacological inhibitors. Moreover, caspase inhibition led to a G1-cell cycle arrest of cells and caused inappropriate regulation of cell cycle-associated proteins. Proliferation assays implicated a positive contribution of caspases to the autocrine IL-2/IL-2R system, since exogeneous IL-2 could partially revert the proliferative defects mediated by caspase inhibitors. Along those lines, caspase inhibition caused a strong reduction in the activation-induced IL-2 secretion of primary T cells. Jurkat T cells lacking functional caspase-8 also exhibited a disability to produce physiological amounts of IL-2. This inhibition occurred at the transcriptional level as shown by quantitative RT-PCR. Luciferase-reporter assays using the human T cell line Jurkat revealed an impaired transcriptional activity of NFkB and the composite RE/AP element within the IL-2 promoter. Finally, caspases might be involved in activation-induced cytokine production of human monocytes, since caspase inhibition led to a reduced TNF secretion after stimulation with bacterial antigens

Hyperhidrosis: a central nervous dysfunction of sweat secretion

Hyperhidrosis (HH) is a central nervous dysfunction characterized by abnormally increased sweating due to a central dysregulation of sweat secretion. HH significantly affects the quality of life of patients in their private, social and professional environments. Physiologically, sweating is a mechanism that regulates body temperature, but it may also be triggered by emotional or gustatory stimuli. There are two main types of sweat glands: eccrine and apocrine glands. The central nervous system controls sweat secretion through the release of neurotransmitters into the autonomous nervous system (ANS) that activate the sweat glands. The hypothalamus has two separate neuronal pathways, one for thermoregulation and one for emotions. HH may thus be due to either a neuronal dysfunction of ANS regulation leading to a hyperactivity of the sympathetic nervous system, or to abnormal central processing of emotions. Crucially, there is no dysfunction of the sweat glands themselves. Various pathogenic mechanisms have been proposed to be involved in pathological sweat secretion in HH, ranging from structural changes within the ANS to increased expression of aquaporin 5 and upregulation of activin A receptor type 1 in eccrine sweat glands. Although a genetic predisposition has been demonstrated, it remains unclear exactly which genes are involved. To identify new, potential therapeutic targets and to improve treatment options, a good understanding of the signaling pathways involved, the underlying mechanisms, and the genetic components is essential. In this review we discuss the various aspects of sweat physiology and function that are necessary to explain pathological sweating. Our aim is to raise awareness of the complexity of HH to promote a better understanding of the disorder

Assessment of a SARS-CoV-2 population-wide rapid antigen testing in Italy: a modeling and economic analysis study

This study aimed to compare the cost-effectiveness of coronavirus disease 2019 (COVID-19) mass testing, carried out in November 2020 in the Italian Bolzano/Su¨ dtirol province, to scenarios without mass testing in terms of hospitalizations averted and quality-adjusted life-year (QALYs) saved

Evaluating Business Process Improvement Patterns by Simulation

Existing approaches for business process improvement often lack systematic guidelines to transform a business process into an enhanced state, which we refer to as the “act of improvement”. To close this gap, a pattern-based approach has been designed and developed in previous works. In this paper, the usefulness of “Business Process Improvement Patterns” (BPI-Patterns) as a means of improving business processes is analyzed. For this purpose, a simulation experiment is performed in which several BPI-Patterns are applied to evaluate whether their anticipated effects can be confirmed for real-life business processes. From the analysis of the simulation results, i.e. how the application of BPI-Patterns affects the business processes, we investigate enabling as well as hindering factors that influence the implementation of BPI-Patterns. These factors may serve as a means to further specify instances of BPI-Patterns and also contribute to the overall evaluation of the BPI-Pattern approach

Modelling Dominant Tree Heights of Fagus sylvatica L. Using Function-on-Scalar Regression Based on Forest Inventory Data

European beech (Fagus sylvatica L.) is an important tree species throughout Europe but shifts in its suitable habitats are expected in the future due to climate change. Finding provenances that are still economically viable and ecologically resilient is an ongoing field of research. We modelled the dominant tree heights of European beech as a trait reflecting growth performance dependent on provenance, climate and soil conditions. We derived dominant tree heights from national forest inventory (NFI) data from six European countries spanning over large ecological gradients. We performed function-on-scalar regression using hierarchical generalized additive models (HGAM) to model both the global effects shared among all provenances and the effects specific to a particular provenance. By comparing predictions for a reference period of 1981-2010 and 2071-2100 in a RCP 8.5 scenario, we showed that changes in growth performance can be expected in the future. Dominant tree heights decreased in Southern and Central Europe but increased in Northern Europe by more than 10 m. Changes in growth performance were always accompanied by a change in beech provenances, assuming assisted migration without dispersal limitations. Our results support the concept of assisted migration for the building of resilient future forests and emphasize the use of genetic data for future growth predictions

Recovery of donor hearts after circulatory death with normothermic extracorporeal machine perfusion

OBJECTIVES A severe donor organ shortage leads to the death of a substantial number of patients who are listed for transplantation. The use of hearts from donors after circulatory death could significantly expand the donor organ pool, but due to concerns about their viability, these are currently not used for transplantation. We propose short-term ex vivo normothermic machine perfusion (MP) to improve the viability of these ischaemic donor hearts. METHODS Hearts from male Lewis rats were subjected to 25 min of global in situ warm ischaemia (WI) (37°C), explanted, reconditioned for 60 min with normothermic (37°C) MP with diluted autologous blood and then stored for 4 h at 0-4°C in Custodiol cold preservation solution. Fresh and ischaemic hearts stored for 4 h in Custodiol were used as controls. Graft function was assessed in a blood-perfused Langendorff circuit. RESULTS During reconditioning, both the electrical activity and contractility of the ischaemic hearts recovered rapidly. Throughout the Langendorff reperfusion, the reconditioned ischaemic hearts had a higher average heart rate and better contractility compared with untreated ischaemic controls. Moreover, the reconditioned ischaemic hearts had higher tissue adenosine triphosphate levels and a trend towards improved tissue redox state. Perfusate levels of troponin T, creatine kinase and lactate dehydrogenase were not significantly lower than those of untreated ischaemic controls. The micro- and macroscopic appearance of the reconditioned ischaemic hearts were improved compared with ischaemic controls, but in both groups myocardial damage and oedema were evident. CONCLUSIONS Our results indicate that functional recovery from global WI is possible during short-term ex vivo reperfusion, allowing subsequent cold storage without compromising organ viability. We expect that once refined and validated, this approach may enable safe transplantation of hearts obtained from donation after circulatory deat