Improvements in implantable cardioverter defibrillator patient stratification

Although the beneficial effect of ICD treatment has been proven in selected patients, the population assessed in large clinical trials does not reflect the population with ICDs in the real world. The aim of the current thesis is to give better insight in these patients at risk for lifethreatening arrhythmias by studying a large population of patients treated with an ICD, outside the setting of a clinical trial. In part I, the actual need for defibrillator backup during long-term follow-up is evaluated. Chapter 2 describes differences in mortality and the occurrence of ventricular arrhythmia between patients receiving an ICD as primary vs. secondary prevention of SCD. The actual need for device replacement after an event-free first battery service-life is studied in Chapter 3. In part II, an attempt is made to improve risk stratification by evaluating currently available parameters and the additive value of novel parameters. In Chapter 4 all classic baseline variables are combined to construct a clinically applicable mortality risk score in primary prevention ICD recipients with ischemic heart disease. Chapter 5 demonstrates the importance of atrial fibrillation in patients with ICD or CRT-D. Chapter 6 shows that usage of a risk model can predict the risk of non-benefit (death, prior to first ventricular arrhythmia) which might have important clinical consequences. In Chapter 7 the spatial QRS-T angle is evaluated in the prediction of ventricular arrhythmia. Chapter 8 demonstrates the risk of lead failure in smalldiameter defibrillation leads compared with a benchmark cohort.UBL - phd migration 201

Prognostic Importance of Atrial Fibrillation in Implantable Cardioverter-Defibrillator Patients

ObjectivesThis study aimed to assess the prevalence of different types of atrial fibrillation (AF) and their prognostic importance in implantable cardioverter-defibrillator (ICD) patients.BackgroundThe prevalence of AF has taken epidemic proportions in the population with cardiovascular disease. The prognostic importance of different types of AF in ICD patients remains unclear.MethodsData on 913 consecutive patients (79% men, mean age 62 ± 13 years) receiving an ICD at the Leiden University Medical Center were prospectively collected. Among other characteristics, the existence and type of AF (paroxysmal, persistent, or permanent) were assessed at implantation. During follow-up, the occurrence of appropriate or inappropriate device therapy as well as mortality was noted.ResultsAt implantation, 73% of patients had no history of AF, 9% had a history of paroxysmal AF, 7% had a history of persistent AF, and 11% had permanent AF. During 833 ± 394 days of follow-up, 117 (13%) patients died, 228 (25%) patients experienced appropriate device discharge, and 139 (15%) patients received inappropriate shocks. Patients with permanent AF exhibited more than double the risk of mortality, ventricular arrhythmias triggering device discharge, and inappropriate device therapy. Patients with paroxysmal or persistent AF did not show a significant increased risk of mortality or appropriate device therapy but demonstrated almost 3 times the risk of inappropriate device therapy.ConclusionsIn the population currently receiving ICD treatment outside the setting of clinical trials, a large portion has either a history of AF or permanent AF. Both types of AF have prognostic implications for mortality and appropriate as well as inappropriate device discharge

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Modelling reservoir dynamics in a data scarce semi-arid region

In order to evaluate measures to increase water availability in and around reservoirs it is necessary to have reliable reservoir water storage models. For that reason, it is necessary to assess the validity of these models. The aim of this research is to do this assessment of two models in data scarce semi- arid regions. The Nakamb ́e catchment is used as a case study. The study covers important aspects of hydrological modelling, such as model input (data) selection, hydrological model choice, calibration, model performance testing, parameter sensitivity, and reservoir water storage simulation.For the selection of the optimal model forcing data diverse precipitation products are reviewed: CHIRPS, ERA5, and local measurements. Among the evaluated datasets, CHIRPS emerges as the superior choice validated against the local measurements. With respect to the potential evaporation, the combination of ERA5 and local measurements results in the most suitable potential evaporation data, leveraging the temporal and spatial aspects of ERA5 and the absolute values of the local measurements.Comparing a lumped hydrological model (HBV) with a distributed model (SBM Wflow) in simulating river discharge reveals that the HBV model outperforms its counterpart in simulating discharge. This contrast in performance is attributed to potential overparameterization in the Wflow model, coupled with the complexities of parameter estimation in data-scarce areas. The HBV model, while bearing simplifications, benefits from a more comprehensive calibration process. The model performance is strongly influenced by the calibration efficiency, where the significantly shorter simulation time of the HBV model facilitates an extensive Monte Carlo sampling-based calibration, in contrast to Wflow’s time consuming manual parameter adjustment.Additionally, the sensitivity analysis showed that in the HBV model, the parameters affecting actual evaporation are the most sensitive one. This emphasizes the importance of accurately simulating this component for the proper model performance. The Wflow model exhibits strong equifinality due to the many parameters within the model. The complexity of this model made it impossible to test all parameters and therefore only some parameters are tested.Both reservoir water storage models studied, the HBV Reservoir Water Storage Model (HBV RWSM) and the Wflow reservoir module, can effectively simulate reservoir water storage fluctuations, although they differ in how the components are calculated. Due to data limitations, it is impossible to determine which, if any, of the models is correct. However, based on the downstream discharge the HBV RWSM displays a more promising performance.In conclusion, the HBV model outperformed the SBM Wflow model in simulating discharge due to its simplicity and ease of calibration. Sensitivity analyses highlighted the significance of accurately representing actual evaporation. Both water balance models, the HBV RWSM and the Wflow reservoir module, performed similarly concerning the NSE values. The fluxes contributing to the water balance in the two reservoir water storage models differ significantly. The lack of data on these fluxes makes it impossible to determine which models performs best. Data limitations remain a significant hurdle in model evaluation, emphasizing the need for additional data collection, particularly upstream and downstream of the reservoir, to enhance reliability and reduce uncertainties.Water Managemen

Blockchain as a Solution to Collective Servitization: A case study on Bundles washing machines and the Circular Service platform

The circular economy is an economic system that aims to replace the linear economy and the accompanying take-make-dispose mindset. It is an economic system that decouples economic growth from finite resource consumption. The Sustainable Finance Lab (SFL) identified two requirements for a high state of circularity. 1) Products are serviced instead of sold and 2) the entire life-cycle of products must be considered. As a solution, the SFL came up with the idea of collective servitization (CS). It meets the previous requirements by aligning the incentives of all the value chain participants involved in a product-service system by compensating each of them as long as the product is in working condition. However, the SFL predicted four implementation barriers related to CS. The SFL expects 1) a need to share innovation costs, 2) high administration costs, 3) increasingly complex devision of ownership, and 4) a need to directly handle micro-transactions. To help overcome CS challenges, the SFL conceptualized the Circular Service (CiSe) platform. It is an administration tool for collectively serviced pay-per-access and pay-per-use products. It aims to use the novel technologies blockchain, cryptocurrency, and smart contracts to overcome these challenges. 1) The CiSe platform reduces transaction costs by automatically handling product use and access payments without an intermediary. 2) The CiSe platform stores the transactions of use and access in a distributed database that is publicly accessible. By viewing all the payments and costs, the SFL expects that companies can better decide on responsibilities. At last, 3) micro-transactions are made possible with the Micro-Euro cryptocurrency. From an Industrial Ecology (IE) perspective, the use of blockchain technology is fascinating. IE is a scientific discipline that takes a systemic approach to sustainability problems. Engineering, environmental, and social perspectives are crucial for the successful and sustainable implementation of new technologies. Blockchain technology has a wide range of technical applications. The question is if these technologies are effective in overcoming CS. In order to get initial insights into the effectiveness of blockchain technology in implementing collective servitization, this master thesis focuses on the company Bundles and their combined pay-per-access and pay-per-use washing machines. The following research question will be answered: “How effective could the Circular Service platform implement collectively serviced Bundles washing machines?” To address this question this thesis used a threefold structure. It consisted of a literature study that identified 51 blockchain designs in the literature and multiple papers oriented on both blockchain and the circular economy and blockchain and product-service systems. These provided insights into the problems and need for CS, insights into the solutions of the CiSe platform and their technical viability, as well as insights into additional challenges for the CiSe platform. Moreover, a business analysis identified 33 blockchain companies. These provided more insights into the technical viability of the CiSe platform. Finally, a case study explored collectively serviced Bundles washing machines on the CiSe platform. The primary stakeholder Miele and Vonk en Co were included in the CS business model. The case study helped identify additional opportunties and challenges of CS and the CiSe platform. The results of this study are not straightforward and mainly raise questions for additional research. This is largely because of the conceptual nature of CS and the CiSe platform, the majority of researched papers being conceptual, the majority of researched companies being in the experimental phase, and the explorative nature of the case study. There are some promising results and some challenges related to the effectiveness of the CiSe paltform. There is some economic potential by including Bundles, Miele, and Vonk en Co in a collectively serviced business model. This is for three reasons. Firstly, the transactional relationship and the cost for added value dissapear between each of the members in the collective servitization business model. Secondly, the CiSe platform further reduces the administration cost related to distributing revenue. Finally, by spreading the initial investments amongst multiple stakeholders the barrier for entry for Miele and Vonk en Co can become lower. However, It is improbable that a collectively serviced Bundles washing machine with Miele and Vonk en Co will happen. It is for four reasons. Firstly, Bundles will lose their role as risk-taker. Moreover, Bundles does not provide any additional value. Furthermore, Miele has the resources available to do the washing machine service themselves. Finally, Miele and Vonk en Co currently have a profitable collaboration with Bundles without long-term risks. Additional challenges are related to the use of blockchain technology. First of all, there is a problem with the flexibility of blockchain systems. Once live, blockchain systems and their smart contracts can not be altered. It can become problematic with a collectively serviced washing machine that is intended to be long-term. Moreover, the vulnerability of the system moves to the sensors. Due to the autonomous and automatic nature of the CiSe platform, a faulty or hacked sensor can wrongfully activate transactions. Furthermore, blockchain systems can generally only handle low transaction volumes. The CiSe platform’s scale is dependent on the number of products and the types of products that are going to be serviced. The main limitation of this study is in its conceptual and explorative nature. It is due to four reasons. Firstly, there is no support of the definition of CS in literature. Secondly, no direct comparison could be found of the CiSe platform concept either. Moreover, the results from the two systemic literature reviews were mainly conceptual papers. Finally, the case study is explorative. All in all, this means that these results are not final. They are indicative and more research is necessary to determine the effectiveness of the CiSe platform in overcoming CS barriers. To move the development of the CiSe platform forward, it is essential that the need for and problems of CS are researched more thoroughly. The case study revealed that CS is not for every value chain. If there is no need for CS, then the CiSe platform is irrelevant. If the CiSe platform does not address the right barriers of CS, the same fate awaits. It is advised to prioritize research into CS before developing the CiSe platform further.Industrial Ecolog