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A regularity result for the Fokker-Planck equation with non-smooth drift and diffusion
Get PDFThe goal of this paper is to study weak solutions of the Fokker-Planck equation. We first discuss existence and uniqueness of weak solutions in an irregular context, providing a unified treatment of the available literature along with some extensions. Then, we prove a regularity result for distributional solutions under suitable integrability assumptions, relying on a new, simple commutator estimate in the spirit of DiPerna-Lions' theory of renormalized solutions for the transport equation. Our result is somehow transverse to Theorem 4.3 of [15]: on the diffusion matrix we relax the assumption of Lipschitz regularity in time at the price of assuming Sobolev regularity in space, and we prove the regularity (and hence the uniqueness) of distributional solutions to the Fokker-Planck equation
Digital clinical support tools to improve child health: development, implementation, and evaluation of ePOCT+ to support healthcare providers in the management of sick children at primary care health facilities in Tanzania
Get PDFBacterial antimicrobial resistance due to inappropriate antibiotic use, and poor quality of care are major contributors to the unacceptably high childhood mortality in Tanzania. Electronic Clinical Decision Support Algorithms (CDSAs) are evidence based digital health tools based on clinical guidelines that guide health providers through a consultation to ultimately propose the diagnosis and treatment based on the inputs entered. Such tools have been found to reduce antibiotic prescription and improve quality of care. Nonetheless, there is a lack of pragmatic studies evaluating CDSAs in Tanzania, and there are many remaining challenges with previously developed CDSAs.
The aim of this project was to improve quality of care and reduce antibiotic prescription at primary care level health facilities in Tanzania. This was done by first developing the ePOCT+ clinical decision support algorithm, addressing challenges identified in other CDSAs, and secondly evaluating the effect of ePOCT+ on antibiotic prescription in a pragmatic cluster randomized controlled trial (DYNAMIC Tanzania study).
To improve uptake, adherence, safety, and potential for antibiotic stewardship, ePOCT+ expanded the clinical scope of the clinical algorithms, expanded the age range of patients it could manage, and assured comprehensive input from clinical and digital experts, as well as health provider end-users. Numerous meetings were conducted, Delphi processes were utilized, and comprehensive piloting was performed to develop ePOCT+. In order to assure safety, a systematic review was conducted to identify the best performing predictors of severe disease to integrate within the algorithm.
The DYNAMIC Tanzania study was a pragmatic, open-label, parallel-group, cluster randomized trial in 40 primary health facilities in the Mbeya and Morogoro regions of Tanzania. Randomization of health facilities were stratified by region, council, level of health facility, and attendance rate. The intervention consisted of the ePOCT+ CDSA with supporting IT infrastructure, C-reactive protein rapid test, hemoglobin rapid test, pulse oximeter, training and supportive mentorship. Co-primary outcomes were 1) antibiotic prescription at the time of the initial consultation (superiority analysis), and 2) clinical failure at day 7 defined as “not cured” and “not improved”, or unscheduled hospitalization (non-inferiority analysis). Secondary safety outcomes include unscheduled re-attendance visits, non-referred secondary hospitalization and death by day 7. Analyses were performed using a random effects logistic regression model using the cluster and patient as random effects, with further adjustment using fixed effect terms for randomization stratification factors, and baseline characteristics.
The systematic review on predictors of severe disease in febrile children presenting from the community identified 18 studies evaluating 200 prognostic factors and 25 clinical prediction models in 24 530 children. There were few outpatient and primary care studies identified. The most common and best preforming predictors of severe disease were malnutrition, altered consciousness, markers of acidosis, and poor peripheral perfusion.
In expanding the age scope of ePOCT+ to manage children 1 day to 15 years, and based on feedback from previous studies and CDSAs, additional illnesses were integrated in the ePOCT+ clinical algorithm. These include trauma, urinary tract infection, and abdominal pain, selected based on 1) incidence, 2) morbidity/mortality, and 3) feasibility at primary care. A Delphi survey among 30 Tanzanian health providers evaluated feasibility, acceptability and reliability of integrating specific predictors within ePOCT+, notably predictors identified within the systematic review. Feasibility tests in over 200 patients in 20 health facilities, and pilots in over 2000 consultations, lead to modifications to ePOCT+ based on user-experience feedback and observations, notably providing option to not measure some clinical signs when not feasible, allow health providers to accept or refuse a proposed diagnosis or treatment, provide alternative medicines in case of stock-outs, and highlighting clinical elements that would result in referral.
The DYNAMIC Tanzania cluster randomized trial took place between December 2021 to October 2022. Over 40,000 children under 15 years of age were enrolled in 20 health facilities (clusters) where health providers could use ePOCT+, and 20 health facilities where health providers provided care as usual. The co-primary outcomes found that the use of ePOCT+ resulted in a 3-fold reduction in the likelihood of a sick child receiving an antibiotic prescription compared to children in usual care health facilities. Despite substantially fewer antibiotics prescriptions, the co-primary outcome of clinical failure was non-inferior. There were also no differences in the secondary outcomes of death, secondary hospitalization, and additional medications after the initial consultations between study arms by day 7.
In conclusion, the ePOCT+ electronic clinical decision support algorithm if implemented to scale could help address the urgent problem of antimicrobial resistance by safely reducing antibiotic prescribing. Transfer of ownership to the ministry of health of Tanzania and integration within the Tanzanian digital health landscape will be essential in order to achieve wide scale implementation
Natural Disasters, Investor Attention, and Non-Fundamental Green Asset Demand
Get PDFThis study examines how the occurrence of natural disasters in the U.S. influences investor interest in green assets and actual investments, focusing on inflows into green ETFs as a proxy for non-fundamental demand. Event study analyses demonstrate both increases in investor interest in eco-friendly investments (proxied by Google searches) and inflows into green ETFs following disasters, driven by the period following the 2015 Paris Agreement. The additional inflows average about USD 4.3 million in the week directly following disasters, compared to average inflows of around USD 1.1 million in the non-disaster reference window. Importantly, both effects disappear when other attention-grabbing events, such as terrorist attacks or mass shootings, occur simultaneously with disasters. Analysis of climate change coverage across U.S. media suggests that media attention devoted to climate change concerns drives the documented shifts in investor behavior towards green investments. Furthermore, analysis of flows in brown ETFs (e.g., the oil and gas sector) reveals analogous disinvestments in the wake of disasters, but notably, only in the absence of concurrent distracting events
Safety assessment of malaria vaccines in african populations: exemplified by the assessment of PfSPZ based vaccines in Tanzania and equatorial Guinea
Get PDFMalaria is a major global health problem, with persistent public health challenges especially in sub-Saharan Africa. An upswing in malaria clinical cases is reported by the WHO from 214,200,000 in 2015 to 219,000,000 in 2017. The latest WHO’s World malaria report, has estimated 627,000 malaria deaths worldwide in 2020 representing about 69,000 more deaths in 2020 compared to 2019 (WHO, 2021). Although, disruptions in the provision of malaria prevention, diagnosis and treatment during the Covic-19 pandemic were linked with approximately two thirds of these additional deaths, evidence exists which suggest an existing real threat to the effectiveness of insecticide-based vector control and antimalarial drugs due to developing resistance towards these tools (Namias et al., 2021; Vaulin et al., 2019). Apparently, if the goal of malaria elimination is to be achieved interventions that can prevent infection and thereby block transmission are needed. Integration of malaria interventions with immunization, complements Global Immunization Vision and Strategy (GIVS), an agenda created by the WHO and UNICEF (Lindstrand et al., 2021; WHO, 2020). The WHO rainbow tables outline several malaria vaccine candidates at different clinical development stages including; Pre-erythrocytic stage projects (eg. RTS,S-A01, PfSPZ Vaccine etc), blood stage projects (eg. P27A Vaccine etc), other projects (eg. PfSPZ-CVac (PfSPZ Challenge + chloroquine)) most of which have been or are being tested across different countries including malaria endemic regions in Africa. Complexities of conducting field trials have been the center of discussion since the early periods of searching for malaria vaccine on proper safety assessment involving areas where the prevalence, importance and epidemiology of malaria is known (Liheluka et al., 2013; McGregor, 1979; Powell, 1979). Over years, research institutions in Africa have developed capacity and are now able to conduct good clinical (GCP) and laboratory practices (GLP) compliant clinical trials and such interest is growing. This important milestone will help to accelerate clinical development programs of several vaccine candidates and other investigational products of public health importance in endemic countries. As a matter to assess, build and strengthen the capacity of different sites to implement these trials, early trials were designed to reproduce the results obtained in Europe and America with minor modification of protocols and standard operating procedures (SOPs) to fit the situation. The need to achieve optimal safety assessment, proper interpretation and reporting, for local investigators, cannot be overstated. The broader concept of safety assessment must be understood as, the process beyond mere assessment of findings from the individual parameters following exposure to IMP, but rather as, the process of safety assessment that is adequate for; relevant participant selection, safe administration of IMP, proper safety follow-up, compliance to safety reporting to local regulatory authorities and relevant final clinical safety report. Interpretation of safety findings in reference to the socio-cultural and baseline epidemiological and clinical characteristics of the local population being assessed has potential to provide fundamental bridge between the intervention being assessed and the local healthcare system, enabling proper use of resources as well as the relevant and timely key policy decisions to be made. Known epidemiological characterization among different African populations may provide an indication that, these communities are similar and with further exploration, procedures may be optimized and synchronized at a level that allows operational shift from the so called African sites to African research centers.
Methods and findings
In the first part of this thesis (Chapter 4), the aim was to generate the safety and tolerability profiles of PfSPZ based malaria vaccine candidates namely PfSPZ Vaccine and PfSPZ-cVac in malaria endemic African population, targeting to develop and implement a vaccine that can be used as additional tool for malaria intervention and possibly elimination, that is well tolerated and safe. As a toolkit for malaria control in Africa, the PfSPZ vaccines are designed to prevent infection. We worked on assessing safety of PfSPZ vaccine candidates by conducting a series of randomized, placebo-controlled, double-blind clinical trials in two African countries (Tanzania and Equatorial Guinea) through the program built on strong South-South / North-South collaboration platform. We designed and conducted the clinical trial protocols covering spectrum of age groups ranging from adults (with and without HIV infection) to the target pediatric population of healthy adolescents, children and infants. The clinical development plan that we pursued focused on addressing safety concerns related to PfSPZ vaccines, including; (i) feasibility of administration via direct venous inoculation (DVI) across age groups; (ii) possibility of breakthrough malaria infections due to inadequate attenuation; (iii) possibility of significant local side effects at the injection site that sporozoites may contribute; (iv) possibility of significant systemic reactogenicity caused by PfSPZ Vaccine; (v) possibility of effects on the rates of AEs related to geographical locations among African population, age or dose; (vi) possibility of significant increase in AEs with repeated dosing; (vii) possibility that the accelerated vaccination schedule regimens of PfSPZ Vaccine are significantly intolerable. Through this work, we performed; The first demonstration of PfSPZ Vaccine efficacy against PfSPZ Challenge in healthy adults population (PAPER I); the first demonstration of safety and tolerability of PfSPZ Vaccine in infants and children along with demonstration of the safety and exploration of efficacy of Sanaria’s PfSPZ vaccine using PfSPZ-CHMI in African adults (Paper II and Paper III); the demonstration of safety and tolerability of Sanaria’s chemo-attenuated vaccine (PfSPZ-CVac) in Equatorial Guinea (Paper IV); the first demonstration of safety and tolerability of PfSPZ Vaccine and exploration of efficacy of Sanaria’s PfSPZ vaccine using PfSPZ-CHMI in individuals living with HIV (Paper V); the demonstration of safety and tolerability of accelerated vaccination regimens of PfSPZ Vaccine and down-selection of optimal regimen for pivotal trials in Africa (Paper VI). A meta-analysis of AE data for adults and children using forest plots of total solicited AEs in vaccinees and placebos in the randomized, double-blind, placebo-controlled trials analyzed to date has shown in all cases, 95% confidence intervals cross a ratio of 1, indicating no differences between vaccinees and controls.
In the second part of this thesis (Chapter 5), the aim was to optimize recruitment and enrolment process through better understanding of the social-cultural, epidemiological and clinical characteristics of the local population. Due to factors ranging from social-cultural to the local clinical research implementation and regulation systems, synchronization of recruitment and enrolment strategies with the local population characteristics, will potentially contribute to the successful clinical development plan for interventions. Fundamental to such success are the components such as, proper use of resources, better alignment; to the daily social-cultural activities and the local healthcare systems, timely recruitment, preparation of the risk mitigation plans relevant to the communities being assessed, reliable interpretation of safety results and precision in estimating risk benefit ratio of the intervention to the local community. In these regards, we designed and conducted pilot epidemiological assessments within study areas located in eastern and western parts of Africa, (Bagamoyo, Tanzania) and (Bioko Island, Equatorial Guinea) respectively. The pilot assessments were implemented through separate protocols linked to the processes in main trial protocols on community engagement and sensitization to ensure that, all members of the target population including infants and children, plus HIV positive individuals are able to participate in GCP compliant clinical research in Africa. Through these activities, we formulated a simple and yet very effective categorization of recruitment and screening criteria across the protocols being; (1) criteria assessing GCP compliance; (2) criteria assessing protocol compliance; (3) clinical criteria assessing health status and (4) laboratory criteria assessing health status. By applying this seemingly simple categorization of criteria we piloted relevant allocation of limited resources between community-based and clinic-based recruitment and screening processes. Over 6,000 people were screened with subsequent registration of potential participants for future clinical trials (Paper VII).
In the third part of this thesis (Chapter 6), the aim was to optimize the processes for safety assessment, interpretation and reporting of results through the application of locally relevant toxicity grading tools in reference to the standard toxicity grading systems adopted to the local clinical and laboratory population parameters. Reporting requirements to the local regulatory authorities’ entail expedited reporting for certain AE grades following IP administration. It is critical that, sponsors and investigators adhere to such requirements for compliance and that the local use of standard toxicity grading systems recommended by the US-FDA, CTCAE and other relevant systems must be properly adopted and hence, optimized to enable proper clinical care for participants and to avoid over- or under-reporting of important safety observations. US-FDA recommends for the local reference values to be considered when the parameter limit values are defined in the guidance or some cases may even require the exercise of clinical judgment. The main reason for this is, such reference systems were developed primarily using data collected from certain population, and therefore are only practically relevant if directly used to the population with similar characteristics. Even for population from the same geographical locations, ethnic differences may require proper adjustments to be made. To achieve this optimization, we applied the methodology stipulated by the CLSI for analysis of reference intervals based on local clinical and laboratory data to and developed a listing of clinical and laboratory reference intervals applicable for local populations which were then integrated to the known standard toxicity grading systems (USFDA, CTCAE ect) to develop locally relevant toxicity grading scales. Site based, QA-controlled manual of reference intervals and toxicity grading was developed for the local population and has since been used for standardized interpretation and reporting of results during safety assessments at screening, enrolment and follow-up.
Conclusion
Evaluation of potential relevant health interventions tailored to collaborations involving South-South / North-South partnerships linking multiple sites in Africa, is the peculiar platform to demonstrate and promote the potential reproducibility of processes and results, with reasonable justification for their application across sites. Through such a platform, standardizations that we made on the optimization-approaches for enrolment practices and for interpretation of results and assessment of abnormal clinical and laboratory parameters, played essential role enabling reproducibility of procedures across sites. Fundamental to the benefit of such standardizations, is the potentially reasonable justification for application of results from evaluations across sites. In the scope of this thesis, the assessments that we performed, provided results indicating that, the safety profile of malaria vaccine candidates is determined by the product itself rather than the type of African population in which it is tested. Strategic partnerships created an enabling platform for interactions with multiple regulatory authorities, ethical committees and IRBs, a critical component reflecting independent reviews for the protocols and reporting of results. With the spectrum of available malaria vaccine candidates including the PfSPZ based, these findings will enable accelerations of clinical development plans not only for clinical trials accessing malaria vaccines but all other related interventions. Our perspective is to maintain the portfolio of activities and skill base that will streamline implementation for subsequent programs of work. In addition, this work has spearheaded the establishment of the clinical research capacity for conduct of regulatory trials in Equatorial Guinea, with primary support from the Bagamoyo Clinical Trials Facility investigators from Tanzania, and used the clinical trials platform to support several masters and PhD training of colleagues in Tanzania, Equatorial Guinea and from partner institution’s outside Africa. This work is built on the strong South-South and North-South collaborations enabling and strengthening synchronization of procedures among clinical trials conducted in different African communities at a level that will allow operational shift from the so called African research sites to African research centers
The epidemiology of legionnaires' disease in Switzerland: a re-emerging disease
Get PDFFor almost two decades, the number of Legionnaires’ disease cases, a severe pneumonia caused by the bacterium Legionella spp., has been increasing in Switzerland. An increase in the number of cases has also been observed in many other countries for which case estimates are available, such as countries in Europe, the United States of America and Canada. After the discovery of Legionnaires’ disease in 1976 and a subsequent period of low observed case numbers and little public health attention, the disease has now been described as a re-emerging infectious disease: In 2021, about seven times as many cases were reported in Switzerland as in 2000. However, as with many (re-)emerging infectious diseases, little is known about its epidemiology, specifically the various risk factors and sources of infection. The latter is a particular conundrum because Legionella spp. are ubiquitous in our everyday environment and suspected infection sources are numerous and diverse. The lack of knowledge on the aetiology and population health dynamics of Legionnaires’ disease poses severe challenges for evidence-based prevention and control measures – and to research itself.
The overall aim of this thesis was to provide a comprehensive description of the epidemiology of Legionnaires’ disease in Switzerland to guide and support future research, and to provide a basis for evidence-based decision-making.
The analysis of Legionnaires’ disease national notification data regarding temporal and spatial patterns and data quality marked the starting point of this research. To better understand and interpret this data, we then investigated the processes involved in the diagnosis and reporting of cases. The positivity rate, which relates the number of positive Legionella findings to the number of diagnostic tests performed in Swiss medical laboratories, was determined for a ten-year period. Using a qualitative approach, we further explored physicians’ decision-making pathways and case management of community-acquired pneumonia. These studies were complemented by a comprehensive review of existing recommendations, guidelines and legislation on or in the management of Legionnaires’ disease and Legionella. We looked at four different topics: environmental prevention and control, clinical case management, disease surveillance, and outbreak management. Furthermore, we explored large- and small-scale risk factors for population exposure. For this purpose, we used an ecological model to investigate spatial and environmental infection determinants at the district level and a case-crossover design to identify the short-term associations between the onset of Legionnaires’ disease and the preceding weather and air pollution levels.
The development of a research study to investigate small-scale risk factors and exposure sites for community-acquired and sporadic Legionnaires’ disease is particularly challenging. Legionnaires’ disease remains comparatively rare even today. Rare diseases are usually investigated with case-control studies; however, case-control studies must rely on self-reporting by study participants to evaluate exposure. The challenges and limitations of working with self-reported data are exacerbated by the variable and long incubation period of Legionnaires’ disease and the often-poor health status of patients, resulting in data being collected long after the relevant exposure. Beyond the case-control study, comparative genomics, in conjunction with epidemiological data, provides the most conclusive evidence of a source of infection. It involves comparing Legionella isolates from the lower respiratory tract of patients and the suspected source of infection using whole genome sequencing. However, clinical isolates are rarely available, as lower respiratory tract samples are often not collected or tested for Legionella. The procedure for collecting and analysing environmental samples presents further difficulties. Due to the ecology of Legionella (e.g. their intracellular persistence in amoebae), they cannot always be detected consistently in the environment. In addition, Legionella are difficult to culture. Therefore, the design and implementation of a national prospective case-control and molecular source-attribution study to identify host, behavioural and environmental risk factors and individual exposure sites concludes this thesis.
This thesis synthesizes existing knowledge and generates new evidence on the epidemiology of Legionnaires’ disease in Switzerland. The analysis of the national notification data showed that between 2000 and 2020 the annual crude notification rate for legionellosis cases increased from 1.1 cases (confidence interval (CI): 0.9–1.4) to 5.6 cases (CI: 5.1–6.1) per 100,000 inhabitants. Despite the overall increase, the case numbers in 2020 have been slightly lower than in previous years. Fewer clinical reports were sent in in 2020, likely due to an overburdening of reporting physicians during the COVID-19 pandemic. The lack of clinical notifications may have led to an underestimation of cases, as the case definition only classifies cases with clinically proven pneumonia as Legionnaires’ disease. Additionally, in 2020 we observed a short-term 35% decline in reported cases, which was associated with COVID-19 containment measures, such as travel restrictions and/or related behavioural changes. In 2021, the number of cases increased again; the latest reports from the Federal Office of Public Health show a notification rate of Legionnaires’ disease of now 6.5 per 100,000 inhabitants - one of the highest in Europe.
Apart from the long-term temporal development, Legionnaires’ disease in Switzerland is subject to a pronounced seasonality, with 37% of all cases occurring between June and August. This contrasts with the number of diagnostic tests for Legionnaires’ disease, which generally peaks in winter. The overall number of diagnostic tests more than doubled between 2007 and 2016. The urinary antigen test has been reported as the most widely used test, continuously reflected in over 80% of all reported case diagnoses.
Clinical guidelines for the diagnosis and treatment of community-acquired pneumonia do not recommend aetiological testing of pneumonia in outpatient settings. Hence, the largest proportion of reported Legionnaires’ disease cases stems from hospitals and the hospitalisation rate for notified cases is generally high (89.9%). In our qualitative study, physicians working in hospitals indicated a high level of awareness of Legionnaires’ disease and its diagnostic and treatment approaches. In contrast, general practitioners indicated lower levels of awareness, reflecting the fact that they treat pneumonia cases empirically without identifying the causative agent. Thus, clinical guidelines and shape physicians’ level of awareness. Furthermore, physicians reported concerns about the urinary antigen test’s sensitivity and coverage limited to the detection of Legionella pneumophila serogroup 1. The availability of diagnostic tests and the physicians’ perception of the reliability of the testing procedures also influenced their preference for targeted treatment approaches with antibiotics or the use of broad-spectrum antibiotics. Finally, external constraints such as financial and time considerations also affected physicians’ testing and treatment preferences.
The extent and public health relevance of undetected, mild Legionnaires’ disease cases and the proportion of avoidable severe cases through earlier detection remains unknown. The case fatality rate of Legionnaires’ disease decreased between 2000 and 2020 from 7.7% to 3.6%. A comparison with hospital statistics, however, shows that the case fatality rate is underestimated by 30% on average. Despite this underestimation, the ‘true’ case fatality rate of about 5.1% seems to be somewhat lower than the European average of 8%.
Regarding regional distribution within Switzerland, the canton of Ticino in southern Switzerland consistently reported higher per capita Legionnaires’ disease case numbers than the rest of Switzerland, with a standardised notification rate of 14.3 cases per 100,000 inhabitants (CI: 12.6-16.0). It was also identified as a statistically significant regional hotspot for 2017-2021. However, in recent years, case numbers have decreased in Ticino and increased in all other regions of Switzerland.
We argue that the overall increase in Legionnaires’ disease case numbers is at least partly due to changes in the underlying disease incidence and does not represent only a surveillance artefact. The clinical guidelines for aetiological testing of pneumonia cases, which affect case detection and thereby the observed number of cases, have long been standardised for hospitalised pneumonia patients. Similarly, diagnostic test methods remained largely unchanged. Another hypothesis explaining the increase as a surveillance artefact has been that increasing physician awareness of Legionella as a cause of pneumonia may have led to increased case detection. However, it is reasonable to assume that the testing protocols from the clinical guidelines have been followed in the past, even when the level of awareness of the disease was not as high as it is today. Furthermore, the influence of growing awareness among physicians should diminish over time and lead to a plateau of notified cases. However, after 20 years of sustained increase, the increase in the number of Legionnaires’ disease cases shows no sign of slowing down.
Despite an improved understanding of the Legionnaires’ disease burden in Switzerland, the drivers for infection and causes of regional heterogeneity remained unclear. Using two different methodologies (an ecological regression model and a case-crossover study), we found evidence for the short-term association of elevated daily mean temperature (odds ratio (OR): 2.83; CI: 1.70-4.70) and mean daily vapour pressure (OR: 1.52; CI: 1.15-2.01) 6-14 days before Legionnaires’ disease onset. In the ecological model, we also found a strong association between Legionnaires’ disease incidence and air pollution levels, but no significant results in the case-crossover study. However, as the ecological model can be subject to ecological bias and the case-crossover study was limited in power, future studies are needed to further investigate the association. Knowledge of these large-scale risk factors, such as the impact of weather conditions and air pollution on the occurrence of Legionnaires’ disease, is essential. It contributes to the understanding of regional differences, provides information on the vulnerability of certain at-risk populations/regions and ultimately helps to anticipate disease trends.
The investigation of small-scale risk factors and exposure sites is of central importance for targeted prevention and control measures. However, due to the disease dynamics and the role of water supply systems in the transmission of Legionella, the investigation is complex and requires suitable research methodologies and a broad range of expertise. The studies summarised in this thesis have informed the design of a prospective one-year national case-control and molecular source attribution study. The study set-up includes the establishment of a network of 20 university and cantonal hospitals to facilitate and expedite recruitment of patients with Legionnaires’ disease and promote the sampling of material from the lower respiratory tract to obtain clinical Legionella isolates. In a subset of cases and controls (from the general population), water samples are collected from the shower and kitchen tap, which are then analysed and processed to obtain isolates of Legionella from the environment. In a last step, the clinical and environmental isolates are genetically matched using whole genome sequencing to support infection source attribution. The environmental component of this study has been developed and implemented jointly with experts in water hygiene in buildings and environmental microbiology. The study, thus, provides the framework for a wide range of research on Legionnaires’ disease and Legionella, including clinical aspects, such as long-term health effects, as well as the identification of household characteristics conducive to Legionella contamination. The implementation of this national research project strengthens intersectoral and multidisciplinary collaboration and capacity building to address the ongoing increase in Legionnaires’ disease case numbers.
In light of climate change, and demographic changes, the number of observed cases of Legionnaires’ disease is expected to increase further in Switzerland and abroad. To stop this trend, comprehensive research is needed to allow targeted and evidence-based action. Although Switzerland benefits from strong government support to combat this disease, data gaps remain an obstacle and, in many other countries, the data gap is even larger. The lack of data and, thus, estimates on the disease burden does not translate into the absence of a public health problem and efforts should be made to investigate the attributable Legionnaires’ disease burden globally. In the context of climate change and urbanisation, public health should advocate for healthy (built) environments to curb Legionnaires’ disease and other (re-)emerging infectious diseases
The significance of IgM in autoimmune and infectious diseases
Get PDFIn this work, we first aimed to optimise the methods for recombinant antibodies production starting
from the isolation of circulating antigen-specific B cells. We aimed to produce recombinant antibodies
in their native class in order to dissect their class-specific properties. We took advantage from the
unique setting offered by the COVID-19 pandemic, which gave us the opportunity to collect blood
from donors recently infected by a novel virus and to use them to select SARS-CoV-2 spike-protein
specific B cells, applying MACACS, a technique developed in our laboratory that enables enrichment
of rare antigen-specific B cells from peripheral blood. We applied this technique to produce
recombinant antibodies against a known target and assess their functions when expressed in their native
class, including in vitro neutralisation potential, complement activation, affinity measurement and
epitope mapping. In vitro class switch of recombinant antibodies enabled the direct comparison of the
functional attributes of IgG and IgM.
In the second part of this work, we aimed to identify the target antigen of CSF IgM in MS patients. We
first screened two independent cohorts of CSF samples for CSF antibodies binding to the cell surface
of a panel of neural or glial derived cell lines. After the identification of IgM binding to a peripheral
neuroectodermal tumour (PNET) that reliably differentiates MS from controls, we applied the
optimised pipeline for cloning of SARS-CoV-2 spike-specific monoclonal antibodies to the cloning of
CSF derived PNET-binding IgM from multiple sclerosis patients, with the aim of using the
recombinantly produced IgM for antigen identification by immunoprecipitation and mass
spectrometry.
In the last part, we used the incidental detection of natalizumab in the CSF of treated patients while
looking for antibodies binding to PNET cells to develop a flow-cytometry based assay and use it to
determine natalizumab concentration in CSF, serum, and breastmilk of multiple sclerosis patients
Injectivity and locality: robust deep learning for bayesian imaging
Get PDFImaging inverse problems are crucial in exploring and understanding various phenomena in our universe. Astronomers decode light signals from distant galaxies, physicians use imaging to reveal the internal body structures for clinical analysis, and geophysicists process seismic waves to model the Earth's interior. Each case involves reconstructing images of hidden objects from observed data. Recently, data-driven methods based on deep learning have shown great success in solving various imaging inverse problems resulting in high-quality and fast image reconstruction with fewer noisy observations. One major concern when solving inverse problems with deep learning is generalization; we expect the deep neural network to perform well on data other than training samples. Lack of generalization may lead to unstable reconstructions and wrong interpretations which is problematic, particularly for medical applications.
In the first part of this thesis, we build deep-learning architectures based on implicit neural representation. We show that these coordinate-based reconstruction pipelines including MLPatch, Glimpse, and FunkNN for various imaging modalities like image denoising, super-resolution, computed tomography, and magnetic resonance imaging can produce high-quality reconstructions with strong generalization.
While deep learning models with strong generalization can improve the reliability of reconstructions and downstream interpretations, the estimated images can significantly deviate from the true image. Moreover, due to the noise and ill-posedness of the forward operator, there may exist many images that align with our observations, each resulting in a different scientific interpretation. One way to address this is to learn a distribution of possible reconstructions instead of computing a single estimate. This strategy can also help us evaluate an uncertainty map to pinpoint the regions of the recovered image estimated with lower confidence.
To this end, in the second part of this thesis, we develop Bayesian frameworks based on injective neural networks to learn the distribution of reconstructions for solving ill-posed inverse problems. We show that our Bayesian architectures can generate multiple high-quality reconstructions and evaluate physically meaningful uncertainty estimates for various imaging problems including inverse scattering and computed tomography
Advances in the molecular understanding of GPCR-arrestin complexes
Get PDFArrestins are essential proteins for the regulation of G protein-coupled receptors (GPCRs). They mediate GPCR desensitization after the activated receptor has been phosphorylated by G protein receptor kinases (GRKs). In addition, GPCR-arrestin interactions may trigger signaling pathways that are distinct and independent from G proteins. The non-visual GPCRs encompass hundreds of receptors with varying phosphorylation patterns and amino acid sequences, which are regulated by only two human non-visual arrestin isoforms. This review describes recent findings on GPCR-arrestin complexes, obtained by structural techniques, biophysical, biochemical, and cellular assays. The solved structures of complete GPCR-arrestin complexes are of limited resolution ranging from 3.2 to 4.7 Å and reveal a high variability in the relative receptor-arrestin orientation. In contrast, biophysical and functional data indicate that arrestin recruitment, activation and GPCR-arrestin complex stability depend on the receptor phosphosite sequence patterns and density. At present, there is still a manifest lack of high-resolution structural and dynamical information on the interactions of native GPCRs with both GRKs and arrestins, which could provide a detailed molecular understanding of the genesis of receptor phosphorylation patterns and the specificity GPCR-arrestin interactions. Such insights seem crucial for progress in the rational design of advanced, arrestin-specific therapeutics
Quartier und Nachbarschaft machen: eine stadtethnographische Untersuchung in Basel über (Re-)Produktionen lokaler Räume und Sozialitäten
Get PDFMit ethnographischen Methoden erkundet die Autorin ausgehend von Basel die Praxen unterschiedlicher, vor allem kollektiver Akteur*innen, die sich auf die Konzepte Quartier und Nachbarschaft beziehen und dadurch zugleich auch Quartier und Nachbarschaft, Quartierbewohnende und Nachbar*innen machen. Sie beschäftigt sich unter anderem mit Mitwirkungsverfahren, Vereinen und Apps, die gezielt Nachbar*innen miteinander bekannt machen, oder einer Bewegung, die durch die Entwicklung multifunktionaler Nachbarschaften einen sozio-ökologischen Wandel herbeiführen will.
Die Untersuchung macht deutlich, dass Quartier und Nachbarschaft als lokale Räume und Sozialitäten in gegenwärtigen Kontexten translokaler Vernetzung und umfassender Mediatisierung keineswegs an Bedeutung verlieren, sondern von verschiedensten Akteur*innen als Bezugs- und Orientierungspunkte genutzt und dabei immer wieder neu und anders versammelt, imaginiert, praktiziert und (re-)produziert werden
Crystal-phase defined nanowire quantum dots as a platform for qubits
Get PDFThis thesis aims to study InAs nanowires with built-in crystal-phase defined quantum dots as a platform for quantum computing. We investigate them as a platform for topological qubits, as well as charge and spin qubits. In a first step towards Majorana bound states we investigate the induced superconductivity in a nanowire hybrid device where the superconductor is deposited by standard e-beam evaporation without an epitaxial interface to the nanowire. Using the integrated tunnel barriers as spectrometer, we draw conclusions about the origin of quasiparticle poisoning in our system.
In a second approach we couple a nanowire double quantum dot to a high-impedance resonator. In a first step we will investigate the resonator-nanowire hybrid device as a charge qubit. We observe a very large qubit linewidth. To improve our system, we turn to spin qubits. We take advantage of the intrinsic spin-orbit coupling in our nanowires to couple the resonator to a singlet-triplet qubit, with which we demonstrate strong spin-photon coupling