La maladie d’Alzheimer (MA) est actuellement conceptualisée comme un continuum : la démence représentant la conséquence clinique d’une longue période où s’accumule des éléments pathologiques dans le cerveau d’individus indemnes de symptômes comportementaux. Les futures thérapies devront idéalement débuter avant l’apparition des symptômes mais le manque actuel d’outils reproduisant avec pertinence cette phase préclinique empêche leurs développements. Dans ce travail de thèse, nous avons d’abord levé ce verrou technologique. Un nouveau modèle a été créé dans lequel la production de peptides Aβs solubles en quantité faible, mais néanmoins suffisante pour induire une hyper-phosphorylation des protéines Tau, perturbe la fonction cognitive bien avant l’apparition d’éléments caractéristiques de la MA (plaques amyloïdes, dégénérescences neurofibrillaires, inflammation). Cette avancée technologique, nous a ensuite permis d’évaluer l’implication de la protéine kinase DYRK1A et le potentiel thérapeutique de molécules modulant ses fonctions dans l’ensemble de la pathologie Alzheimer. Nos résultats démontrent que l’inhibition de son activité kinase réduit l’hyper-phosphorylation des protéines Tau et améliore la fonction mnésique chez notre animal modélisant la phase préclinique de la MA. A contrario, nous démontrons que DYRK1A est sensible à un clivage protéolytique dans le cerveau de patients atteints de démence Alzheimer et acquiert de nouvelles fonctions biologiques. Dans ce contexte, la prévention de ce clivage réduit l’inflammation et restaure les déficits cognitifs chez la souris modélisant la phase clinique de la MA. En ciblant différentes phases de la MA, ces données ouvrent donc la voie à la médecine personnalisée et à des stratégies de traitement plus ciblées. / Current view conceptualizes Alzheimer’s disease (AD) as a continuum, with dementia representing the clinical outcome of a long period of cumulative pathological events in the brain of individual with free cognitive symptoms. New therapies for AD should ideally be started before the onset of symptoms but the lack of suitable tools mimicking preclinical stage of AD limits their future evaluations. In this work, we break this technological limitation. A new animal model have been developed in which a small amount of soluble Aβs forms able to induce hyper-phosphorylation of Tau is sufficient to disturb cognitive function long before classical lesions occur (amyloid plaques, neurofibrillary tangles and inflammation). This technological breakthrough allows us to evaluate involvement of the protein kinase DYRK1A and therapeutic potential of molecules modifying its functions in different stages of AD. Our results demonstrate that inhibition of its kinase activity reduces hyper-phosphorylation of Tau proteins and alleviates memory function in our preclinical AD-like animal model. In contrast, we provide evidences that DYRK1A undergoes a cleavage in brain of patient with clinical AD and gains new biological functions. Prevention of this proteolysis reduces inflammation and restores cognitive impairments in a clinical AD-like mice model. By targeting distinct phases of the disease, these data open avenue for personalized medicine and more-targeted treatment strategies.

Bakgrund: Överrapportering mellan skiftbyten är en central roll för sjuksköterskan och en viktig del för vårdverksamheten. Dock är den traditionella överrapporteringen identifierad som ett möjligt område för felkommunikation och minskad patientdelaktighet. Bedside överrapportering kan öppna upp för en mer personcentrerad vård och öka delaktigheten för patienten.  Syfte: Att undersöka patientens upplevelser och erfarenheter vid bedside överrapportering. Metod: En litteraturöversikt innehållande tio kvalitativa artiklar. Artiklarna hämtades från PubMed och CINAHL och kvalitetsgranskades med hjälp av SBU:s granskningsmall för bedömning av studier med kvalitativ metodik. Artiklarna analyserades med Graneheim och Lundmans (2004) innehållsanalysmetod.  Resultat: Analysen resulterade i fyra domäner och fyra kategorier där resultatet presenterades. Patientens upplevelser och erfarenheter visade sig till stor del handla om önskan att vara delaktig i sin vård. Vissa patienter uttryckte önskan om delaktighet i större utsträckning än andra och många poängterade fördelar som att kunna korrigera felaktigheter, ställa frågor och tillägga missad information i anslutning till överrapporteringen. Kommunikationen mellan patient och sjuksköterska påpekades vara en viktig del. Förmedlandet av känslig information upplystes som en svårighet och bevarande av patientens integritet ansågs som betydelsefullt.     Slutsats: Patienters upplevelser och erfarenheter av bedside överrapportering visade sig till stor del främja patientdelaktigheten. En del patienter ansåg sig dock vilja vara involverad i en begränsad omfattning. Patienterna ansåg att överlämningen gav en mer personlig relation mellan till sjuksköterskan. Möjligheten att påverka informationsöverföringen ansågs vara positivt. Bevara patientens integritet vid hantering av känslig information ansågs som en svårighet och att patienter ibland ansåg att det var svårt att förstå sjuksköterskornas komplicerade språk. / Introduction: Shift reports between nurses is a central role for the nurses and an important part of health care. The traditional handover has however been identified as a possible source of miscommunication and reduced patient participation. Bedside shift reports can facilitate a more personalized care and increase patient participation. Objective: To examine patient experiences with bedside shift reports. Method: A literary study containing ten qualitative studies. The studies were identified through PubMed and CINAHL and reviewed using SBUs template “assessment of studies with a qualitative method”. The articles were analysed using Graneheim and Lundmans’ (2004) content analysis method. Results: The analysis resulted in four domains and four categories. The results showed that a big part of the patient’s experiences of bedside shift reports was that they wished to participate more in their care. Some patients had a bigger wish to participate than others and a lot of patients emphasized the benefits of bedside shift reports; how they could correct wrong information, ask questions, and add further information. The communication between patients and nurses was another important part of bedside shift reports. The mediation of sensitive information was pointed out as a difficulty, as well as the protection of the patient’s integrity. Conclusion: The patient’s experiences of bedside shift reports has shown increasing patient participation in their care. They said that the handover enabled a more personal relationship between the patient and the nurses, and that this resulted in a feeling of calmness and safety. The opportunity to influence the transfer of information and to correct wrong data or ask questions was a positive aspect of bedside shift reports. The handling of sensitive information was seen as a weakness of bedside shift reports. Patients also had difficulty understanding the nurses' complicated language.

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02–2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05–3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63–3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance.

<p>In recent years, the pharmaceutical industry has embarked on an extensive program to modernize its manufacturing resources. Recognizing the limitations of traditional mass manufacturing, the industry is now focused on developing new production systems that can deliver high-quality medicines with enhanced efficiency, flexibility, agility, and reliability. To realize this vision, innovations in three key areas are being pursued: continuous processing, personalized medicine, and Industry 4.0.</p> <p>This thesis contributes towards the industry’s goal by focusing on the development of an advanced system to manufacture solid oral drug products. This system is centered around a pharmaceutical additive manufacturing technology called drop on demand (DoD) printing. This technology is highly effective in making personalized drug products, which allow for customizing dose attributes such as drug loading, release behavior, formulation type, and dosage form, based on patient requirements. To develop the DoD printer into an advanced production system, technologies such as end-to-end continuous processing, real time quality assurance, and automated operation need to be incorporated into it. </p> <p>The studies presented in this thesis implement different aspects of these technologies in the printer. To enable end to end operation, a novel solvent switch process called three phase settling is developed to integrate the DoD system with upstream steps for synthesizing the active ingredient. To facilitate automated processing of formulations with different active ingredients, excipients, and particle concentrations, a model framework is developed to recommend operating conditions for the DoD platform that can deliver on-spec printer operation. To expand the range of personalized dosage forms offered by the system, the manufacturing of a new category of drug products, called mini-tablets, is demonstrated. To provide reconfigurability and quality assurance capabilities in the platform, modular design and process monitoring tools are implemented. To aid optimization and control of drug production processes, a digital twin is developed by combining the models developed for DoD, solvent switch, synthesis, and crystallization operations. </p> <p>The research presented in this thesis lays the foundation for developing the next generation of manufacturing systems for drug products. Incorporation of scalability, autonomous operation, and real time release prediction are critical steps in facilitating the next phase of its development – deployment in real-world manufacturing scenarios.  </p>

The purpose of this thesis is to examine familial hypercholesterolemia (FH) and emerging pharmacogenomics therapies that propose to lower serum low density lipid (LDL) levels. The search of various data bases resulted in nine research articles being selected for review. Syntheses of the articles suggest emerging phamacogenomic drug therapy can improve treatment outcomes for individuals with a diagnosis of FH. The Human Genome Project (HGP) has had far reaching applications for genomic technologies and pharmacagenomic interventions, tailored to human conditions associated with select genomic traits. Synthesis of nine research articles demonstrate that little is known on the topic and reveals extensive gaps in the evidence. This thesis concludes with implications for nursing education, practice, policy and research along with limitations are noted.

Pancreatic cancer is the seventh leading cause of cancer related mortalities worldwide and incidences are increasing. The prognosis remains poor as the 5-year survival rate is below 10%. This can be partly explained by the silent progression of disease as most patients present with advanced disease at time of diagnosis. In turn, surgical resection, the only potential curative measure, is not possible in nearly 80% of cases due to the occurrence of distant metastasis and/or infiltration of major vessels in close proximity to the pancreas. In patients with localized but advanced disease, resectability can be achieved in some cases by initiation of a neoCTx. However, as neoCTx is commonly conducted by administering multi-drug treatments, severe side effects occur frequently, which require an adaption of drug doses administered. In this study, we revealed the negative impact of these drug dose changes during neoCTx on the patients´ treatment outcome. R0 resections were significantly less frequently observed, and the N-status significantly impacted by the tumor regression grade, which in turn trended towards minor response in the cohort of patients that did not sustain full dose course prior surgery. In turn, treatment of LA PDAC could be improved by increasing the proportion of patients that undergo neoCTx without any changes of the treatment schedule. Patient-derived PDAC organoid could serve as an avatar of patients´ tumor disease on which optimal treatment protocols could be tested. In this study, a large living PDAC PDO biobank successfully has been established from surgical resection specimens as well as EUS guided FNA samples. Subsequently, a new protocol for molecular subtyping of PDAC on organoids was established by assessing the expression level of KRT81 and CFTR, as a replacement for HNF1a, using IF staining. Strikingly, we observed identical PDAC subtypes in PDOs and their respective tissue of origin in nearly all cases. This observation allowed the assumption that PDOs could indeed be used as patient-individual avatars to identify treatment sensitivities and resistances, as they share fundamental molecular properties with the tissue they have been initiated from. Extensive pharmacotyping was performed for many PDO lines by testing the response behavior to the multi-drug regimens FOLFIRINOX and Gem/Pac, as well as their respective single drug compounds. As a result, we observed diverse response patterns for each PDAC PDO line. A poor response to FOLFIRINOX did not necessarily imply a resistance to Gem/Pac. PDO pharmacotyping could guide treatment decision making in the foreseeable future. Moreover, when the non-efficient drug was removed, no changes of overall efficacy of treatment in PDOs was observed, implying that additional therapy improvements could be possible using this ex vivo model. This observation was true for both commonly used chemotherapy protocols, FOLFIRINOX and Gem/Pac and could result in less drug mediated side effects under (neo)adjuvant CTx without impacting treatment efficacy. Yet, the main goal of this study was to assess if PDAC PDOs can be used to predict the neoCTx outcome of PDAC patients. All methods required to address this issue in a prospective clinical trial have been established as a protocol for PDAC PDOs initiation from minimal starting material has been established and subsequently improved resulting in take rates of up to 80%. To support this study, we successfully secured patient enrollment from a second clinical center, which will increase the number of recruited patients in the future. Unfortunately, at the time of writing this thesis, patient numbers were not sufficient to answer the question of the predictive value of PDAC PDOs in regard to the current standard of care.

No description available.

Precision medicine (PM) is “the treatment and prevention of disease that takes into account individual variability in genes, environment, and lifestyle for each person” (NIH, 2015). PM was poised to transform clinical practice in 2003 when the Human Genome Project reached completion but resistance to implementation at virtually all health care providers provides the basis for novel study on the diffusion of innovation as well as operational strategy. Existing studies on resistance to PM explore the role of reimbursement, economics, regulatory affairs, and public policies. Investigation into the antecedent conditions for implementation at the physician and organizational levels has been overlooked, a gap this study fills. The research captures the reasons for resistance at the physician and organizational levels and identifies operational strategies for successful implementation at three health care institutions with fully integrated PM programs. The research produced 42 findings with managerial implications and six testable propositions for future research. The dynamics of resistance to PM has revealed key implications for theories of organizational change. These include the observation that the formulation processes of clinical standards of practice in PM are not predicted by prevailing organizational theory; that conventional theories of resistance to change do not fully anticipate the effects of Kuhnian level historic paradigm shifts; and, that communities of practice play a critical role in transformational clinical change. Further, the research demonstrated that PM implementation is characterizable through reproducible organizational and cultural actions; that positive clinical outcomes are measurable and persuasive; and that the needs of stakeholders can be reconciled by aligning physician standards of practice with patient expectations and organizational needs. / Business Administration/Strategic Management

Cancer may be treated with personalized medicine, meaning that specific patientsmight respond better to specific treatments instead of having a common treatment. TheReference Drug-based Neural Network (RefDNN) predicts whether a particular cancer cellline will resist a determined drug, but it fails to provide an explanations for this prediction.The thesis objective is to research on explainable machine learning methods to extractrule-based explanations from the RefDNN predictions and conclude on how confident wecan be about these explanations and whether they make sense from a biological point ofview. One of such explainable machine learning methods is Local Rule-based Explanation(LORE), which extracts rule-based explanations from any black box model using localdecision trees. In this thesis LORE is applied to explain the predictions of the RefDNNon a drug sensitivity dataset and three experiments are set up. First experiment tests theaccuracy and general performance of the extracted rule-based explanations. Second experimentstests the robustness of the rule-based explanations. Third experiments checks theglobal fidelity of the local decision trees used by LORE to mimic the RefDNN behaviour.Finally, one rule-based decision is explained from a biological point of view and conclusionsare made on the obtained results.

Yes / Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight. We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods. / H.C., R.H., J.B., D.B., S.G., T.E., and N.J.S. are members of the ESA Space Omics Topical Team, funded by the ESA grant/contract 4000131202/20/NL/PG/pt “Space Omics: Towards an integrated ESA/NASA –omics database for spaceflight and ground facilities experiments” awarded to R.H., which was the main funding source for this work. H.C. is also supported by the Horizon Center for Doctoral Training at the University of Nottingham (UKRI grant no. EP/S023305/1). S.G. is supported by the Swedish Research Council VR grant 2020-04864. L.A.R. and M.M. represent the Omics Subgroup of the Japan Society for the Promotion of Science KAKENHI funding group “Living in Space” and are supported by JP15K21745, JP20H03234, and 20F20382. L.A.R. is also supported by the JSPS postdoctoral fellowship P20382. We thank Dr. Sarah Castro-Wallace, the NASA GeneLab Animal AWG, ISSOP, ESA Space Omics Topical Team, ESA Personalized Medicine Topical Team, and Global Alliance for Genomic Health (GA4GH) for useful discussions.