Publikationer från Uppsala Universitet
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Decomposition of solid polymer electrolytes : Interfaces and interphases
No full textThis thesis explores the anode-less battery concept, where the anode is created by lithium plating during charging. Such devices face problems with electrochemical stability, specifically at the anode interface, where electrolyte decomposition occurs. One strategy for implementing anode-less concepts is using solid polymer electrolytes (SPEs). To make SPEs a viable option, an understanding of the solid electrolyte interphase (SEI) formation at the anode interface is necessary. Conventional post-mortem photoelectron spectroscopy (PES) is challenging for SPEs, thus, herein, two novel PES-based methods are evaluated and used for investigating the decomposition products making up the initial SEI in SPE-based anode-less batteries. The first method is in situ deposition photoelectron spectroscopy (ISDPES), in which lithium is deposited by evaporation onto the SPE surface, intended to emulate the plating of lithium during charging. The second method is operando PES, in which a custom battery cell is cycled and the interface is characterised during operation. Both methods are shown to be highly useful in providing information about SPE decomposition and SEI formation in SPE-based batteries. However, the ISDPES method is limited to emulating only the first charging cycle, and gives no information about reactions at stages other than lithium plating. This limitation is overcome by operando PES, which, while time consuming, allows for the sequential lowering of the potential until lithium plating is reached. In general, these methods show two kinds of compounds forming from the decomposition of the polymers in the studied SPEs. The first is lithium alkoxides, still attached to the polymer chain. The other is hydrocarbons, suggested to take the shape of polyethylene segments or oligomers (the form of which depend on the polymer they originate from). For the salts and additives it depends more on the nature of the salt/additive, but in general they involved far more inorganic products. In the interplay between SPE components (polymers, salts, and additives), it is observed that the presence of one component in an SPE influences the decomposition of the others. It is also found that the stability of the polymer is less important than the stability of the decomposition layer when optimising for coulombic efficiency. The sequential lowering of potential using operando PES shows another dimension to improving the SEI: the order of decomposition. This thesis thereby contributes to the understanding of the SEIs of SPE-based anode-less batteries, where a functional SEI is one necessary part of a viable cell chemistry
High Prevalence of Psychological Symptoms, Sexual Dysfunction, and Prolonged Medical Leave Two Years After Acute Leukemia Diagnosis-Patient Reported Outcome in Sweden
No full textIntroduction With the purpose of identifying unmet needs of patients with acute leukemia, survivors were identified from the Swedish National Acute Leukemia registries. Methods At six months and at two years from diagnosis, patients were requested by mail to report outcome with focus on depression, sick leave, and sexual dysfunction. Results Of 910 patients alive at 6 months, 474 (52%) participated, and of 331 alive at two years, 250 (76%) participated. At two years, the majority <= 65 years, 52%, had returned to work >30 h/week, and 40% were still on medical leave. Economic hardship was common, especially in the latter group. Impaired sexual function, impact on sexual desire, as well as anxiety about infections, were frequently reported. Depression with a PHQ-8 score >= 10 was more prevalent in patients <= 65 years than in older patients. In younger patients, a PHQ-8 score >= 10 was associated with sexual dysfunction, economic hardship, single living, and anxiety of infections, whereas in patients >65 years, single living and economic hardship remained significant. No impact of the Covid-19 pandemic on depression was found. Conclusion The use of depression screening instruments and awareness of sexual dysfunction could be of importance in the routine care of acute leukemia patients two years after diagnosis.Trial Registration The authors have confirmed clinical trial registration is not needed for this submission
A Phase 2a Study of the Early Bactericidal Activity of Rifampicin in Combination with Meropenem plus Amoxicillin/Clavulanate Among Adults with Rifampicin-Resistant Pulmonary Tuberculosis
No full textBackground In vitro, meropenem is shown to restore the activity of rifampicin in rifampicin-resistant Mycobacterium tuberculosis strains. This phase 2a trial aimed to determine if addition of rifampicin increases the early bactericidal activity (EBA) of meropenem plus amoxicillin/clavulanate in patients with rifampicin-resistant tuberculosis (RR-TB). Methods Individuals with RR-TB were randomized to either 2 g meropenem infusion 3 times daily plus amoxicillin/clavulanate 500 mg/125 mg orally 3 times daily with 20 mg/kg rifampicin orally once daily (M-AC-R arm) or the same treatment without rifampicin (M-AC). Sputum samples were collected at baseline and throughout the 14-day treatment. Colony-forming unit (CFU) and time-to-positivity (TTP) data were analyzed using nonlinear mixed-effects modeling. Plasma samples at day 13 were used to derive rifampicin and meropenem pharmacokinetic parameters using noncompartmental analysis. Rifampicin minimum inhibitory concentrations (MICs) were determined from baseline sputum isolates with and without meropenem. Results Of the 52 participants enrolled, 38 participants completed the trial. The majority (67%) were male, and the median age was 37 years. The median (95% prediction interval) predicted 14-day EBA in CFU was 1.33 (−0.15 to 3.64) and 1.20 (0.05–2.66) log10 CFU/mL, and TTP increased by 0.220 (0.098–0.551) and 0.216 (0.126–0.505) log10 hours for the M-AC-R and M-AC arms, respectively. No statistically significant difference was found between the 2 arms. Meropenem pharmacokinetics were similar in both arms, and rifampicin MICs were not meaningfully reduced by meropenem. Conclusions Adding rifampicin to meropenem plus amoxicillin/clavulanate did not enhance short-term antibacterial activity in patients with RR-TB.De två första författarna delar förstaförfattarskapet</p
Types and Time : Languages, Tools, and Methods for Reliable Systems Engineering
No full textSoftware plays a vital role across many areas of modern society. The personal gadgets we carry with us every day, the medical devices many people rely on, and the massive city-spanning systems that keep our critical infrastructure up and running are all powered by software, which is at the heart of every modern computing device. Naturally, we are therefore interested in ensuring that its execution is as error-free as possible, as errors might lead to significant financial loss or even endanger human life. To that end, this dissertation presents work aimed at helping design, implement, and verify reliable software systems. The first part of this dissertation presents a design for a programming language for the development of embedded systems, called Mimosa. Mimosa builds upon MIMOS, a novel model of computation that allows for describing an overall software system as a graph of computation nodes. As this model enjoys both functional and timing determinism, Mimosa is particularly suited for the development of software for real-time systems. The presented work covers formal semantics, simulation, and compilation to a set of tasks running on a real-time operating system. The second part of this dissertation presents broader work in the realm of reliable software engineering, targeting, in particular, software systems developed in the programming language OCaml. First, a tool for dynamic verification of stateful OCaml programs is presented. The primary focus of the tool lies on the automatic extraction of a functional model from formal contracts provided as part of a module's interface. Second, a method for encoding interaction nets, a particular form of graph rewriting, in OCaml is presented. Particular properties of interaction nets enable automatic scaling of the rewriting process across multiple processing cores. Compared to previous work, the presented encoding focuses on correctness guarantees provided by the interaction net type system, which is encoded in the type system of OCaml. It is shown that certain algorithms can exploit the inherent parallelism of the rewriting process, and therefore automatically utilise OCaml's recently added native support for parallel evaluation
Specification Inference for Scala and Stainless
No full textFormal verification uses mathematical methods to ensure the correctness of software. Stainless, a static program verification framework for functional Scala programs, provides robust functionality for verifying the behavior of annotated programs. However, manually coming up with pre- and postconditions for functions is a tedious and complex process. In this project, I develop a frontend for the Daikon invariant detection tool to support a subset of Scala compatible with the Stainless verifier, which in turn, will aid in the process of formal verification of functional Scala programs. The frontend is written in Scala using the Scalameta library and testing is done using Docker in conjunction with Github workflows
Nerve-macrophage association in the pancreas in health and disease : Investigating emerging components of pancreatic neuro-immune communication
No full textThe pancreatic islet provides a site for close communication between sympathetic nerves and macrophages, which together help preserve the immune balance. However, how this neuro-immune dialogue influences the development of type 1 diabetes (T1D) remains unclear. This thesis explores the role of the chemokine receptor CX3CR1 and its ligand CX3CL1(fractalkine) in orchestrating macrophage–nerve interactions within the islet, using a combination of transcriptomic, flow cytometry, live imaging and functional approaches. In Paper 1, single-cell RNA sequencing (scRNA-seq) of non-obese diabetic (NOD) mice identified a subset of nerve-associated macrophages (NAMs) expressing Cx3cr1, Siglech, and Tmem119, showing transcriptional similarities to microglia. These NAMs progressively declined with Type 1 diabetes(T1D) development, paralleling a loss of sympathetic innervation. Gene ontology analysis suggested that NAMs exert immunoregulatory effects through cytokine and chemokine signaling pathways. In Paper 2, confocal microscopy and spectral flow cytometry were used to analyse CX3CR1 deficient mice. The absence of CX3CR1 resulted in reduced islet innervation and macrophage density, while the overall macrophage phenotypes remained unchanged. This disrupted nerve–macrophage association correlated with a delayed onset of T1D, highlighting the role of CX3CR1 in maintaining neuro-immune organization within islets. In Paper 3, live pancreatic slice imaging was used to track macrophage motility and T cell interactions in real time. Neither CX3CR1 deletion nor acute pharmacological inhibition affected short-term macrophage dynamics, suggesting that CX3CR1 predominantly regulates long-term structural organization rather than immediate cellular behaviour. In Paper 4, a 3D co-culture model was established to visualize live interactions between sympathetic neurons, pancreatic islets, and immune cells within an agarose matrix, providing a flexible platform for studying neuro-immune mechanisms in real time. Collectively, these studies reveal that CX3CR1 dependent macrophage–nerve communication is essential for maintaining islet innervation and immune homeostasis. Disruption of this signaling axis alters neuro-immune architecture and delays the onset of T1D
α-Synuclein purification significantly impacts seed amplification assay performance and consistency
No full textα-Synuclein seed amplification assays are a promising diagnostic tool for synucleinopathies such as Parkinson's disease and multiple system atrophy. Standardized conditions are required to ensure a high degree of inter- and intra-laboratory reproducibility when performing these assays. A significant issue that hinders the utility of seed amplification assays is the de novo aggregation propensity of the α-synuclein substrate as well as inter-batch heterogeneity. While much work has focused on determining appropriate seed amplification assay buffer compositions as well as the type and amount of seed used, a robust comparison of α-synuclein substrate purification methods has not been reported. We therefore compared the utility of recombinant alpha-synuclein purified using four different methods as seed amplification assay substrates across two laboratories. Osmotic shock-purified α-synuclein monomer substrate showed the lowest propensity for de novo aggregation, which translated into being the best substrate for seed amplification assay reactions seeded with α-synuclein preformed fibrils or patient brain homogenates. Furthermore, osmotic shock α-synuclein monomer showed the best inter-batch reproducibility compared to all other substrates tested. As α-synuclein seed amplification assays continue to evolve and move towards adoption in the clinical realm, this work showcases the vital importance of standardizing the production and characterization of recombinant α-synuclein substrate. We encourage the widespread adoption of osmotic shock α-synuclein monomer as the universal substrate for seed amplification assays to maximize intra- and inter-laboratory reproducibility
Recommended methodologies for clinical investigations of high-risk medical devices-Conclusions from the European Union CORE-MD Project
No full textBefore a high-risk medical device is approved for implantation into patients, there should be evidence not only of performance and safety with a favourable benefit-risk ratio, but also of its clinical efficacy. Regulatory guidance on study methodologies is lacking, however, so the European Commission funded the CORE-MD project (Coordinating Research and Evidence for Medical Devices) to advise regulators on appropriate designs for clinical trials of high-risk devices. The CORE-MD consortium recommends that evaluation should be planned in four stages. Randomised controlled trials should be performed more often, against active comparators reflecting the best available treatment, using sham interventions with ethical safeguards. Large trials can be managed efficiently using an electronic database or registry. Non-randomised clinical studies can apply objective performance criteria or other validated patient relevant outcome measures, with adjustments to minimise bias. Full transparency of results from clinical investigations is essential. Proportionate regulation of breakthrough or orphan devices for independently-defined serious unmet needs may involve approval with less evidence, but on condition of subsequent confirmatory studies. These CORE-MD consensus proposals have been submitted to European Union medical device regulators, to be considered as a basis for more transparent and predictable requirements for clinical evidence.
Adaptive Experiment Design for Nonlinear System Identification with Operational Constraints
No full textWe consider the joint problem of online experiment design and parameter estimation for identifying nonlinear system models, while adhering to system constraints. We utilize a receding horizon approach and propose a new adaptive input design criterion, which is tailored to continuously updated parameter estimates, along with a new sequential estimator. We demonstrate the ability of the method to design informative experiments online, while steering the system within operational constraints