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Neural data science for studying visual computations in neuronal populations at single-cell resolution
No full textThis thesis presents applications of neural data analysis to investigate early visual processing and assess the efficacy of vision restoration approaches in neuronal populations at single-cell resolution. Recent advancements in electrophysiological recording techniques have enabled the recording of extracellular activity from hundreds of neurons in parallel. This work examines the concerted computations performed by populations of visual neurons by characterizing their neural response functions utilizing various visual stimuli and analysis methods.
The first part of this thesis addresses the challenge of characterizing the neural response functions of functionally specialized visual neurons. Functional specialization is a fundamental principle in visual processing. While neurons in early visual processing stages respond to unstructured contrast changes, neurons in later stages encode more complex, structured stimuli. A systematic, unbiased approach for estimating the neural response function of a sensory neuron is provided by white noise (WN) analysis, where the neural response is correlated with an unstructured, uncorrelated WN stimulus to estimate the linear white noise receptive field (WN-RF). However, this approach is ineffective for functionally specialized sensory neurons. To overcome this limitation, we developed the reverse correlation against stimulus elements (RCASE) method, which utilizes structured stimuli characterized by uncorrelated stimulus parameters. Here, the neural response is correlated with a nonlinear reparameterization of the stimulus. Using this method, we efficiently mapped nonlinear receptive fields (RFs) of nearly all recorded retinal ganglion cells (RGCs) in the mouse retina by utilizing a stimulus consisting of randomly parameterized moving objects that elicited robust responses across the recorded population.
We applied this approach one synapse downstream to the nucleus of the optic tract (NOT), a subcortical structure receiving direct retinal input. We found that functional specialization was more pronounced in the NOT than in the retina, rendering WN inefficient in estimating WN-RFs for a majority of the recorded population. However, utilizing RCASE allowed us to estimate localized nonlinear RFs in the majority of NOT neurons. The identified RFs were located above and along the horizontal meridian of the visual space. The NOT is necessary for the horizontal optokinetic reflex (HOKR), a visual behavior that stabilizes the retinal image during large horizontal visual shifts. Psychophysical experiments demonstrated that the HOKR was triggered in the same visual regions as predicted by the locations of the RFs, thereby establishing a link between neural activity and behavior. Additionally, unsupervised clustering of functional responses identified distinct functional cell types within the mouse NOT, providing the first comprehensive functional characterization of this area.
We further present the results of a large-scale collaborative study on an optogenetic vision restoration approach aimed at resensitizing non-functional, dormant cone photoreceptors in the human retina. We developed a functional assay and a corresponding data processing pipeline for large-scale functional screening of gene therapy vectors. Through this approach, we identified a candidate vector that effectively restored light responses in previously non-light-sensitive human retinal explants. The functional properties of RGCs in treated human retinal explants were comparable to those in intrinsically photosensitive human retinal explants. We identified five functional cell types in the treated condition that matched those previously characterized in intrinsically photosensitive human retinal explants. These findings led to the identification of a promising gene therapy vector for restoring high-resolution vision in blind patients who retain dormant cone photoreceptors.
Finally, we performed the first functional characterization of human foveal RGCs to date. Through unsupervised clustering of light-evoked activity of human foveal RGCs, we identified five functional cell types, four of which matched to midget and parasol cells, the most abundant RGC types in the human retina. The same methodology enabled the functional identification of midget and parasol cells in the periphery of the primate retina. These findings contributed to a study investigating cell-type-specific intraretinal RGC axonal propagation speeds at different retinal locations in the human retina.
In summary, this thesis presents several applications for studying early visual processing by utilizing existing methods and developing novel approaches in neural data science, both for basic research and translational applications in vision restoration
Hybrid Planar Copolymer Membranes with Dual Functionality against Bacteria Growth
No full textAntibacterial surfaces can be classified into two categories: passive surfaces, which repel bacteria by affecting surface wettability, and active surfaces, which have bactericidal properties that disrupt cell membranes upon contact. With the increasing demand for effective antibacterial solutions that combine these properties, advanced strategies are concentrating on developing surfaces with dual antimicrobial functionalities. Here, we present surfaces with nanotexture resulting from the phase separation of two different amphiphilic block copolymers displaying efficient dual functionality against bacteria growth. This approach combines the inherent antifouling properties of poly(ethylene oxide) as the hydrophilic domain of one copolymer with the antimicrobial effect of a peptide covalently attached to the hydrophilic domain of the second copolymer. The planar membranes are generated by self-assembly of the amphiphilic copolymer mixture deposited by Langmuir–Blodgett and Langmuir–Schaffer methods on a solid support, followed by covalent attachment of the antimicrobial peptides to one of the copolymers, specifically functionalized. Combining both copolymers, in terms of their properties and functionalities on the same surface, significantly limitsEscherichia colibiofilm formation and effectively eradicates bacteria during short-term incubation. While such multifunctional antimicrobial planar polymer membranes show promising potential in the design of fine coatings for small surgical or implantable devices, they are not limited to this application. Their use can be completely changed by attaching other active molecules or assemblies to induce specific multifunctionality for the targeted application
Memory-efficient deep learning methods for brain image analysis
Get PDFThe diverse array of imaging modalities currently in use has profoundly impacted the practice of medicine. In particular, X-ray computed tomography (CT) and magnetic resonance imaging (MRI) have the capacity to record a three-dimensional image of the body with great detail. As a consequence of their widespread use, the amount of available data is continuously increasing at an unprecedented rate. This presents an opportunity to apply machine learning and, in particular, deep learning. Deep learning is a subfield of machine learning that is particularly well-suited to train on large quantities of data and to capture complex features in high-dimensional data.
Currently, deep learning methods rely on graphics processing units (GPUs) to be evaluated with any reasonable speed. However, GPUs with high-performance characteristics – which are directly linked to their memory capacity – contribute significantly to the high implementation costs of deep learning methods. To enable an easier access and a more widespread adoption, it is crucial to reduce this barrier of entry.
In this work, we explore the potential of deep learning methods for a range of tasks involving brain imaging data, with a focus on reducing the GPU-memory consumption. This is particularly relevant for methods that process MR and CT scans, as they inherently are three-dimensional. The first project we present is an unsupervised anomaly detection and localization method for brain CT scans. It employs a novel self-supervised surrogate task. The second project involves a supervised tumor segmentation in MR scans with denoising diffusion models. This method has previously been proposed for two-dimensional slices. As diffusion models already require substantial resources for two- dimensional data, we explore various techniques to reduce the resource consumption, to adapt this model to three-dimensional data. In the last project, we explore implicit neural representations (INRs) to model the development of the neonatal brain on the basis of MR scans. We show that INRs can be trained in sparsely sampled data, explore techniques for disentangling the latent space and illustrate how they can be trained with minimal resources
Climate change and cardiovascular diseases in India and South Africa: impacts, perceptions and policy responses
Get PDFBackground
As a result of anthropogenic climate change, global average temperatures, the severity, frequency and intensity of extreme weather events are on the rise. Several diseases,
including vector borne diseases, mental health, conflicts and non-communicable diseases, such as cardiovascular diseases (CVDs), are climate-sensitive and climate change is
contributing to driving their disease burden.
Primarily a lifestyle disease, CVDs are already the leading cause of mortality worldwide, with environmental factors such as temperature and air pollution further contributing to their burden. The impacts of climate change are highly regional and depend on contextual vulnerabilities. This especially poses a major public health challenge in low- and middle-income (LMIC) countries, which have limited resources availability and capacity to react to the threat.
Despite a growing body of evidence on the association between climate change variables, such as temperature, and CVDs, there remains a large knowledge and evidence gap on this topic in LMICs, including India and South Africa, which have been examined in this body of work. The findings contribute to furthering our understanding of how climate change affects CVDs in India and South Africa.
Methods
A multi-methods approach was used, comprising of quantitative and qualitative approaches. The association between apparent temperature (Tapp) and in-hospital CVD mortalities was modelled using a case crossover approach with a distributed lag non-linear model (dlnm) in
Puducherry, India. A similar approach using a negative binomial distribution with the dlnm was used to model the association between Tapp and CVD morbidity, measured through CVD hospitalizations, in the Limpopo Province of South Africa. Both models considered a 21-day lag period.
Key informant interviews were carried out in Puducherry with medical professionals, environmentalists and government officials to understand their perspectives on climate
change and health, with a focus on CVDs. In light of the paucity of research on climate change and health in India, these interviews were also used to understand the research
barriers and challenges for climate change and health research in Puducherry. The findings were analysed using qualitative thematic analysis following the Framework method.
National and State level policies and document pertaining to climate change, adaptation, health, environment and CVDs were systematically reviewed. The policies were analysed
qualitatively using the Framework method and content analysis to understand how CVDs are represented in the climate change adaptation policy space in India and the gaps therein.
Findings
The optimal Tapp range for Puducherry is between 30 to 36°C, with temperatures above and below this associated with an increased risk of CVD mortality. Up to 17% of in-hospital
mortalities were attributable to non-optimal Tapp in Puducherry between 2011 and 2020. Out of this 9.1% and 8.3% of the burden was attributable to heat and cold respectively, with males being more vulnerable to cold and females over 60 years of age affected predominantly by heat. Patients were more prone to cerebrovascular accidents during hot periods. In Limpopo, the optimal Tapp range is between 25 to 27°C, and 8.5% of CVD hospital admissions were attributable to heat and 1.1% to cold.
In Puducherry, the perceived health risks from climate change were largely a product of individual knowledge of the local public health burden and vulnerabilities, with some level of scepticism on the association between climate change and CVDs. There was a perceived gap in technical education about climate change and health, despite awareness of the same as a concept. Informants also expressed a need for multi-level, inclusive awareness programs targeting different social groups. Data collection systems, access to health data and underdeveloped technical and methodological research capacity were considered the biggest research barriers when it came to climate change and health. The topic was not considered a research or political priority, with limited resources being allocated to most climate sensitive outcomes. Informants also described a tendency for environmental health research to centre on conventional health outcomes, as opposed to CVDs.
Most Indian national and State policies are focused on vector borne diseases and heat-related illnesses, the latter of which does not fully encompass all temperature sensitive
CVDs, as part of the efforts to address climate change impacts on health. Strengthening health surveillance systems to capture CVDs could also contribute to improving research
output on the topic from India and strengthen contextual adaptation planning. The political commitment to addressing the health impacts of climate change as well as CVD management could be used in tandem to facilitate interventions and actions on climate change and CVDs. Many of the State level plans were found to be incomplete or simply templates, and thus there is an urgent need to focus on ensuring the development or completion of these plans.
Conclusion
Climate change impacts on CVDs are an emerging problem of concern for both India and South Africa. Non-optimal temperatures are associated with increasing the risk of CVD
events in both countries. Parallel streams focusing on improving awareness and education and improving monitoring and surveillance systems could potentially contribute to
addressing this issue in India. There is a pressing need to improve evidence synthesis on the topic in both countries, with efforts taken to ensure climate change and health becomes a priority for both research and policy supported interventions and actions for adaptation
Therapeutic leave and coercive measures in inpatient psychiatry a clinical and health economic viewpoint
Get PDFIn inpatient psychiatric care, readmissions and coercive measures can be problematic in various
aspects. More research on treatment variables is needed to improve the quality of care and reduce
readmission and coercive measures. Inpatient care is also a large cost driver of healthcare
systems. With a global increasing economic burden of mental ill health, health economic analyses
are warranted to promote policy change according to scientific evidence. This dissertation,
therefore, integrates a clinical and health-economic perspective to examine two treatment
variables in inpatient care: therapeutic leave and staff resources relating them to readmission,
direct inpatient costs, and coercive measures. Therapeutic leave (TL) is an established practice
in inpatient psychiatry. However, research on its association with readmission and inpatient costs
is scarce. Studies have addressed the association between staff resources and coercion but yield
limited and heterogeneous results.
Study 1 assessed the readmission risk of patients with TL during their inpatient stay compared to
patients without TL applying a survival analysis. The results showed a significantly longer
cumulative survival and a reduced hazard of readmission for patients with TL compared to patients
without TL. Study 2 was a follow-up study of Study 1 and examined whether there is an association
between TL and direct inpatient costs in the months following discharge. We applied a Tweedie
regression model. Study 2 showed TL is associated with lower direct inpatient costs after
discharge. Study 3 examined how efficiently psychiatric clinics maximize inpatient cases without
seclusion and restraint with their given staff number of full-time equivalents. The results suggest
that clinics are relatively efficient at maximizing cases without coercion. However, changes in
management and careful consideration of team composition are necessary to further increase
cases without seclusion and restraint.
In conclusion, Study 1 and Study 2 add to the limited knowledge of TL in relation to readmission
risk and direct healthcare costs. In addition, Study 3 sheds more light on staff-related factors in
reducing coercive methods. By integrating a clinical and health-economic perspective, this
dissertation considers an ever-present and growing conflict between economic motives and a
patient-oriented psychiatry lead in line with ethical principles. This dissertation's results imply a
link between TL during inpatient treatment, a lower readmission risk, and lower direct inpatient
costs after discharge. Regarding TL, randomized controlled trials are needed to assess the
causality of our results. We still need to better understand the underlying mechanisms of TL. More
health economic analyses, especially including indirect costs, are required. TL might be a suitable
intervention to improve the quality of care. Whilst our results of Study 3 show that clinics are
relatively efficient at maximizing cases without coercion, economic and ethical considerations
regarding staff numbers in psychiatric clinics need to be balanced out. Coercive measures should
never, even implicitly, be driven by monetary factors. When it comes to the integrity of human
beings, ethical considerations must outweigh economic motives
Potenzial von nichtlinearem periodisiertem Ausdauertraining zur Verbesserung der kardiorespiratorischen Fitness bei sedentären Erwachsenen mittleren Alters mit erhöhtem kardiovaskulärem Risiko
No full textEinleitung: Die gesundheitlichen Folgen geringer kardiorespiratorischer Fitness betreffen einen grossen Anteil der Bevölkerung. Gängige Trainingsmethoden wie das moderat-intensive kontinuierliche Ausdauertraining oder das hoch-intensive Intervalltraining zur Prävention von oder Rehabilitation nach kardiovaskulären Ereignissen wurden bereits untersucht und weisen Limitationen auf. In dieser Arbeit wird die Effektivität und die Durchführbarkeit des nichtlinearen periodisierten Ausdauertrainings auf die kardiorespiratorische und die mentale Fitness bei sedentären Erwachsenen mittleren Alters mit erhöhtem kardiovaskulärem Risiko untersucht.
Methoden: 35 40-60-jährige männliche Probanden nahmen an einer achtwöchigen Trainingsintervention mittels Fahrradergometer (n=23) teil oder erhielten Anweisungen ihren üblichen Lebensstil zu Hause beizubehalten (n=12). Mittels Spiroergometrie wurde der Spitzen-Sauerstoffverbrauch vor und nach dem Training gemessen. Ein Fragebogen zur mentalen Fitness wurde zu beiden Zeitpunkten ausgefüllt.
Ergebnisse: Die Interventionsgruppe erreichte zum Studienende einen im Mittel um 2,57 ml/kg/min (0,45; 4,68, p = 0,019) höheren Spitzen-Sauerstoffverbrauch und eine im Mittel um 25,90 Watt (14,07; 37,73, p < 0,001) höhere Leistungsfähigkeit als die Probanden der Kontrollgruppe. Zwischen Anfang und Ende der Studie konnte bei der mentalen Fitness zwischen den Gruppen keine Veränderung festgestellt werden. Von ursprünglich 30 Probanden in der Interventionsgruppe haben 23 die Trainingsintervention abgeschlossen. fünf hatten während der Intervention eine Infektion, einem Probanden war es zu anstrengend und einer hatte keine Zeit mehr im Training zu erscheinen.
Schlussfolgerung: Es konnte gezeigt werden, dass eine achtwöchige Trainingsintervention mittels nichtlinearen periodisierten Ausdauertrainings die kardiorespiratorische Fitness verbessert. Die Intervention zeigt unter standardisierten Laborbedingungen keine negativen Effekte auf die mentale Fitness und keine relevanten Nebenwirkungen. Weitere Studien sollten die Umsetzbarkeit sowie die Nachhaltigkeit dieser Trainingsform untersuchen
Molecular Insights into Sequence-Specific Protein Hydrolysis by a Soluble Zirconium-Oxo Cluster Catalyst
No full textThe development of catalysts for controlled fragmentation of proteins is a critical undertaking in modern proteomics and biotechnology. {Zr6O8}-based metal–organic frameworks (MOFs) have emerged as promising candidates for catalysis of peptide bond hydrolysis due to their high reactivity, stability, and recyclability. However, emerging evidence suggests that protein hydrolysis mainly occurs on the MOF surface, thereby questioning the need for their highly porous 3D nature. In this work, we show that the discrete and water-soluble [Zr6O4(OH)4(CH3CO2)8(H2O)2Cl3]+ (Zr6) metal-oxo cluster (MOC), which is based on the same hexamer motif found in various {Zr6O8}-based MOFs, shows excellent activity toward selective hydrolysis of equine skeletal muscle myoglobin. Compared to related Zr-MOFs, Zr6 exhibits superior reactivity, with near-complete protein hydrolysis after 24 h of incubation at 60 °C, producing seven selective fragments with a molecular weight in the range of 3–15 kDa, which are of ideal size for middle-down proteomics. The high solubility and molecular nature of Zr6 allow detailed solution-based mechanistic/interaction studies, which revealed that cluster-induced protein unfolding is a key step that facilitates hydrolysis. A combination of multinuclear nuclear magnetic resonance spectroscopy and pair distribution function analysis provided insight into the speciation of Zr6 and the ligand exchange processes occurring on the surface of the cluster, which results in the dimerization of two Zr6 clusters via bridging oxygen atoms. Considering the relevance of discrete Zr-oxo clusters as building blocks of MOFs, the molecular-level understanding reported in this work contributes to the further development of novel catalysts based on Zr-MOFs
A Prescription for Knowledge: Patient Information and Generic Substitution
Get PDFMarkets require informed participants to function efficiently. This paper examines the impact of providing targeted information directly to patients on their purchasing-decisions regarding pharmaceutical drugs. We analyze the effect of informational letters sent by a Swiss health insurer to clients who had recently purchased a brand-name drug, informing them of available generic alternatives and potential savings. Utilizing the quasi-randomized timing of the letter dispatch, we employ an event study design with staggered treatment adoption to estimate the causal effect of patient information on generic substitution probability. Based on 540,000 drug purchases by 60,000 patients we find that the probability of switching to a generic alternative increases by almost 30 percentage points immediately after receiving the informational letter, representing nearly a fourfold rise in the substitution likelihood among previous brand-name drug buyers. Furthermore, the effect does not substantially depend on whether patients face a copayment for their drug purchase and thus personally financially benefit from switching. Our results highlight the limits of healthcare policies that rely solely on financial incentives, particularly if patients lack sufficient information in their decision-making
Imaging Strain-Controlled Magnetic Reversal in Thin CrSBr
No full textTwo-dimensional materials are extraordinarily sensitive to external stimuli, making them ideal for studying fundamental properties and for engineering devices with new functionalities. One such stimulus, strain, affects the magnetic properties of the layered magnetic semiconductor CrSBr to such a degree that it can induce a reversible antiferromagnetic-to-ferromagnetic phase transition. Using scanning SQUID-on-lever microscopy, we directly image the effects of spatially inhomogeneous strain on the magnetization of layered CrSBr, as it is polarized by a field applied along its easy axis. The evolution of this magnetization and the formation of domains is reproduced by a micromagnetic model, which incorporates the spatially varying strain and the corresponding changes in the local interlayer exchange stiffness. The observed sensitivity to small strain gradients along with similar images of a nominally unstrained CrSBr sample suggest that unintentional strain inhomogeneity influences the magnetic behavior of exfoliated samples
Zusammenhang zwischen kardiorespiratorischer Fitness, körperlicher Aktivität und Lipidprofil bei gesunden älteren Erwachsenen
No full textHintergrund: In der Schweiz (und häufig global) waren im Jahr 2021 die kardiovaskulären Erkrankungen (19‘645 Todesfälle; 1/3 aller Todesfälle) die häufigsten Todesursachen. Eine tiefe kardiorespiratorische Fitness (CRF), gemessen als peak Sauerstoffaufnahme (V̇ O2peak), In-aktivität und schlechte Lipidprofile sind beeinflussbare Hauptrisikofaktoren. Eine hohe körper-liche Aktivität (KA) erhöht die CRF, was das Lipidprofil verbessert und zur Senkung des kar-diovaskulären Risikos führt. Ziel war die Analyse des Lipidprofils bei gesunden älteren Er-wachsenen in Abhängigkeit von der CRF und der KA.
Methodik: In der Querschnittsanalyse (Daten aus EPOCH-Studie) führten 85 Versuchsperso-nen (41% Frauen) im Alter von 60 bis 80 Jahren einen kardiopulmonalen Belastungstest auf dem Fahrradergometer durch. Die KA wurde objektiv und kontinuierlich über 8 Tage durch einen dreiachsigen Beschleunigungsmesser erfasst. Zur Bestimmung des Lipidprofils erfolgte eine Blutentnahme morgens auf nüchternen Magen. Um die Zusammenhänge zwischen Para-metern der CRF, der KA und des Lipidprofils zu bestimmen, wurden 30 multiple lineare Re-gressionen durchgeführt.
Ergebnisse: Die V̇ O2peak absolut (β = -.33, 95%-Konfidenzintervall [KI; -0.72, 0.06], p = .100) und die V̇ O2peak relativ (β = -.20, 95%-KI [-0.49, 0.09], p = .182) korrelierten mit den Trigly-ceriden negativ. Die Inaktivität korrelierte positiv (β = .14, 95%-KI [-0.10, 0.38], p = .252) und die intensive KA korrelierte negativ (β = -.19, 95%-KI [-0.43, 0.04], p = .101) mit dem Non-HDL-Cholesterin.
Schlussfolgerungen: Zusammenfassend scheint der lineare Zusammenhang der CRF und der KA auf das Lipidprofil bei der untersuchten Studienpopulation insgesamt schwach zu sein. Spezifischere und komplexere Analysen sind nötig, um verlässlichere Aussagen über die Ef-fektstärke machen zu können