Publikationer från Uppsala Universitet
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Ligand and Residue Free Energy Perturbations Solve the Dual Binding Mode Proposal for an A2BAR Partial Agonist
No full textAdenosine receptors, particularly A2BAR, are gaining attention for their role in pathological conditions such as cancer immunotherapy, prompting the exploration for promising therapeutic applications. Despite numerous selective A2BAR antagonists, the lack of selective full agonists makes the partial agonist BAY60-6583 one of the most interesting activators of this receptor. Recent cryo-EM structures have univocally revealed the binding mode of nonselective ribosidic agonists such as adenosine and its derivative NECA to A2BAR; however, two independent structures with BAY60-6583 show alternative binding orientations, raising the question of which is the physiologically relevant binding mode. In situations such as this, computational simulations that accurately predict shifts in binding free energy can complement experimental structures. Our study combines QligFEP and QresFEP protocols to directly compare the binding affinity of BAY60-6583 between alternative binding modes as well as providing a direct comparison of in silico mutagenesis studies on each pose with experimental mutational effects. Both methods converge on the experimentally determined binding mode that better explains both the existing SAR and mutagenesis data for this ligand. Our results allow the elucidation of the experimental binding orientation that should be considered as a basis for designing partial agonist derivatives with improved affinity and selectivity and underscore the value of free energy perturbation methods in aiding structure-based drug design
From exploration to intervention: Enhancing medication communication at hospital discharge
No full textBackground: Older hospitalised patients are particularly prone to drug-related problems (DRPs) following hospital discharge, often due to ineffective medication communication and limited patient involvement. This thesis aimed to explore the discharge medication communication process for older patients and apply these insights to improve it. Methods: A process evaluation of a clinical trial assessed how hospital-based medication reviews and discharge-related communication components were carried out by clinical pharmacists. A retrospective chart review evaluated the adequacy of medication-related referrals (MRRs) at discharge and their association with unplanned hospital revisits. Qualitative studies involving focus groups, interviews, and observations explored the perspectives of healthcare professionals (HCPs) and patients regarding discharge communication. These findings, combined with public co-production, informed the development of an intervention, alongside a study protocol. Results: Intervention fidelity in the clinical trial was high for admission-related components, with clinical pharmacists resolving DRPs and medication discrepancies in three out of four patients. However, discharge-related fidelity was lower: medication reconciliations were completed for half of the patients, and MRRs were sent at similar rates in both intervention and control groups. MRRs were found to be inadequate in a substantial proportion of patients (40 %), with one in twenty cases potentially contributing to an unplanned hospital revisit. HCPs perceived discharge communication as complex and fragmented, hindered by systemic and organisational barriers. Patients experienced it as a one-way transfer of information from HCPs to patients, primarily structured around HCPs' priorities rather than their own needs. In response, a multifaceted intervention was developed, incorporating a structured and integrated role for clinical pharmacists in the discharge process. The intervention included components to enhance the quality of medication-related discharge documents, empower patients through an information package, strengthen informal caregiver involvement, and provide follow-up calls after discharge. A pre-post study design was established to evaluate the intervention’s effects on medication communication and patient outcomes compared to usual care. Conclusions: Medication communication at hospital discharge remains a critical challenge, characterised by information gaps between HCPs and insufficient focus on equipping patients with the prerequisites to resume self-care after returning home. A multifaceted intervention study was developed to address these challenges
Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells
No full textThe human fetal immune system starts to develop in the first trimester and likely plays a crucial role in fetal development and maternal-fetal tolerance. Innate lymphoid cells (ILCs) are the earliest lymphoid cells to arise in the human fetus. ILCs consist of natural killer (NK) cells, ILC1s, ILC2s, and ILC3s that all share a common lymphoid origin. Here, we studied fetal ILC subsets, mainly NK cells and ILC3s and their potential progenitors, across human fetal tissues. Our results show that fetal ILC subsets have distinct distribution, developmental kinetics, and gene expression profiles across human fetal tissues. Furthermore, we identify CD34+RORγt+Eomes− and CD34+RORγt+Eomes+ cells in the fetal intestine, indicating that tissue-specific ILC progenitors exist already during fetal development
Exotic gravity theory in loop space*
No full textAn exotic linearised theory of superconformal gravity in D=6,(4,0) superspace, proposed by C Hull, is discussed in loop space with focus on its bosonic sector. Pursuing an analogy to the loop space version the system of a two form B and its field strength H, we show that the exotic linearised gravitational potential C and curvature G can be reinterpreted as an ultra-local (linearised) metric and curvature on loop space
Tick-Borne Encephalitis: Novel Methods for Improved Serological Diagnostics
No full textTick-borne encephalitis (TBE) is caused by the tick-borne encephalitis virus (TBEV) and is mainly transmitted to humans through bites from infected Ixodes ticks. TBE is a growing public health challenge in Europe, including Sweden, and is a reportable disease in at least 37 European countries. TBEV can infect the central nervous system, causing symptoms from mild illness to severe disease or death. It may lead to lasting sequelae and reduced quality of life, although asymptomatic cases are likely common. TBEV is traditionally classified into three subtypes: European, Siberian, and Far Eastern. It belongs to the Flaviviridae family and the Orthoflavivirus genus and is the only endemic vector-borne flavivirus in Sweden. TBE vaccines are generally effective, though vaccine failures occur. Sweden lacks a national TBE vaccine register and seroprevalence studies are limited. TBEV-specific antibody detection in serum or cerebrospinal fluid is the most common diagnostic method. Antibody detection is generally reliable but occasionally limited by cross-reactivity and false positives. Diagnosing TBE in vaccinated individuals is even more challenging. Traditional serological methods cannot distinguish infection-induced from vaccine-induced antibodies. Viral RNA detection has low clinical sensitivity. This thesis aimed to improve TBE diagnostics by developing and evaluating new methods and to expand knowledge of TBEV, including vaccination data, through a seroprevalence study in Sweden. In Paper I, we developed and validated a method to differentiate between antibodies caused by infection and those from vaccination. Antibody patterns in TBE-infected patients were compared with those in vaccinated individuals to demonstrate the concept. In Paper II, we applied the method to samples from suspected vaccine failure cases. In Paper III, we evaluated the performance of a commercial TBEV test in a European multi-laboratory study. In Paper IV, we investigated TBEV seroprevalence and vaccination coverage in collaboration with eight Swedish regions. Our findings include vaccination and infection rates, estimated totals, and evidence that over 90% of TBEV infections go undiagnosed. In conclusion, this thesis presents improvements in TBEV diagnostics and new data on the seroprevalence of TBEV in Sweden, including vaccination data and information of the ratio between TBEV infections and reported TBE cases
Mechanisms of mast cell activation by bacterial virulence factors : Implications for mucosal infection
No full textMast cells are innate immune cells, which can be found in nearly all tissues of the human body. Activated by receptors for IgE or bacterial compounds, mast cells are complex effector cells which respond in many ways to bacterial infection. However, decades of research did not lead to a general model of how mast cells are activated by bacteria. Examples of pathogenic bacteria include the extracellular Streptococcus equi subspecies equi (S. equi) that colonizes the airways in horses by secretion of powerful toxins, and the invasive enterobacterium Salmonella enterica subspecies Typhimurium (S.Tm). The latter is taken up with contaminated food and invades the epithelium in the distal small and proximal large intestine to reach the deeper layers of the tissue. Mast cells are present as early responders towards both bacteria. In this thesis, I elucidated how pathogenic bacteria activate these versatile immune cells. In Paper I, I demonstrated which virulence factors of S. equi that activate mast cells, by utilizing bacterial knockout mutants of several virulence factors or a combination of those. While superantigens or the protective capsule did not lead to mast cell activation, removal of the pore-forming toxin streptolysin S led to complete ablation of the mast cell response to S. equi, establishing that sublytic pore formation leads to membrane stress, which results in inflammation. To compare our findings from extracellular bacteria with the invasive S.Tm, we explored in Paper II, if its type-three-secretion system induces a similar sublytic pore-mediated immune activation. We found however, that S.Tm triggers mast cell activation by a two-step activation process, involving 1) priming by toll-like receptor (TLR) 4 and 2) effector-induced immunity. While we mainly focused on classical mouse mast cells, we extended our findings further in Paper III. In this study, the use of connective tissue-type and mucosal-type mouse mast cells, as well as a human mast cell line broadened the validity of our two-step activation model. We discovered, moreover, that mucosal-like mast cells lack TLR2 and TLR4, making them only responsive to invasive bacteria. Overall, this thesis contributes to our understanding of the general mechanisms for how mast cells are activated by bacteria
Primary Care Nurses' Experiences of Structured Documentation : A Qualitative Interview Study
No full textHealthcare is undergoing an unprecedented technological transition to structured documentation in electronic health records (EHR), which has the potential to increase the quality of documentation. However, given the rising demand for direct transfer of data, there is a risk that requirements for more documentation will follow. This study seeks to investigate primary care nurses' experiences of structured documentation with direct transfer to a national quality registry. Nine primary care nurses using structured documentation in their management of chronic obstructive pulmonary disease (COPD) patients were recruited from different Swedish regions. The semi-structured interviews addressed experiences and work procedures when using a structured documentation template with direct data transfer to a quality register. Interviews were transcribed verbatim and analyzed using qualitative content analysis. Data were framed according to five key concepts; patient safety, time-saving work methods, quality of care, equitable care, and professional autonomy. The nurses experienced some barriers in relation to structured documentation but mainly observed benefits, raising the potential to enhance equitable care and safety for patients with COPD in primary care. Professional experience and autonomy were described as important prerequisites in achieving these benefits. The findings from this study can contribute to strengthening the documentation work procedures of nurses
Hur personer med fetma upplever bemötandet inom hälso- och sjukvården : En litteraturöversikt
No full textIntroduktion: Övervikt och fetma blir allt vanligare. Fetma är ett kroniskt tillstånd som uppstår till följd av en komplex kombination av olika faktorer, och det är associerat med förhöjd risk för flera sjukdomstillstånd. Fetma är normavvikande, och personer med fetma riskerar att utsättas för stigmatisering och fördomar, vilket kan ha negativa konsekvenser för individen, och för samhället. Syfte: Syftet var att utforska hur personer med fetma upplever bemötandet inom hälso- och sjukvården. Metod: Litteraturöversikt med deskriptiv design baserad på tio originalartiklar med kvalitativ metod som hämtades ur databaserna PubMed och Cinahl. De granskades med hjälp av SBUs granskningsmall och analyserades med hjälp av Popenoes analysmetod. Resultat: Det framkom blandade upplevelser om hur fetma påverkar bemötandet inom hälso- och sjukvården. Vissa upplevde att de fick ett annat bemötande än normalviktiga personer medan vissa inte hade upplevt något negativt bemötande kopplat till sin fetma. Ett gott bemötande associerades med att vårdpersonalen gett personerna tid i mötet, varit engagerade och motiverande, och när bemötandet var respektfullt och utan fördomar. Erfarenheter av dåligt bemötande framkom när bemötandet upplevts respektlöst, skuldbeläggande och stigmatiserande från vårdpersonalen. Erfarenheter av att inte bli sedd som en unik individ, att fetma fick ett överdrivet fokus, och att samtal om övervikt och fetma sköttes undermåligt ledde till känslor av dåligt bemötande. Slutsats: Personer med fetma får både bra och dåligt bemötande inom vården. Det är viktigt att skapa ett förtroende för vården hos dessa personer, vilket inleds med att bemöta dessa personer på ett empatiskt och hänsynsfullt sätt, med en helhetssyn på människan.Introduction: Overweight and obesity are becoming increasingly common. Obesity is a chronic condition that results from a complex combination of various factors and is associated with an increased risk of several health conditions. Obesity is considered atypical, and individuals with obesity are at risk of being stigmatized and facing prejudice, which can have negative consequences for both the individual and society. Aim: The purpose was to explore how individuals with obesity experience the treatment they receive within healthcare settings. Method: A literature review with a descriptive design based on ten original articles using qualitative methods, retrieved from the PubMed and Cinahl databases. The articles were reviewed using the SBU review template and analyzed with Popenoe's analysis method. Results: Mixed experiences emerged regarding how obesity affects treatment within healthcare. Some felt they were treated differently compared to individuals with normal weight, others didn’t experience any negative treatment related to being obese. Experiences of good treatment was associated with healthcare staff giving individuals time during the interaction, being engaged and motivating, and treating them with respect and without prejudice. Experiences of poor treatment were associated with encounters of disrespectful, blame-shifting, and stigmatizing behaviors from healthcare staff. Experiences of being treated poorly were associated with not being seen as a unique individual, weight was excessively focused on, and when discussions about overweight and obesity were handled poorly. Conclusion: Individuals with obesity receive both good and bad treatment in healthcare. It is important to build trust in healthcare among these individuals, which starts with treating them in an empathetic and considerate manner, with a holistic view of the person
Exploring the impact of opioid use on outcomes in allogeneic hematopoietic stem cell transplantation
No full textIntroduction Hematological malignancies and allogeneic hematopoietic cell transplantation (alloHCT) often necessitate the use of opioids due to significant pain. This study aimed to investigate the impact of opioid use on the clinical outcomes of patients undergoing alloHCT. Methods A retrospective cohort study was conducted by merging data from our local transplant database with anonymized pharmacy records obtained from the Institute for Clinical Evaluative Sciences (ICES). We analyzed 681 patients who underwent alloHCT at Princess Margaret Cancer Centre between January 2010 and December 2019. Patients who initiated opioid use within one-year post-alloHCT and had opioid prescriptions for more than 30 days were categorized as intense opioid users (IOU). Additionally, patients who started opioids before or within one-year post-alloHCT and had opioid prescriptions for less than 30 days but died while on opioids were also classified as IOU. The analytical code used for the analysis is available in the Supporting Information file. Results Among the 681 patients, 51 were identified as IOU. The two-year overall survival (OS) was significantly lower in the IOU group, with 29.4% survival compared to 53% in non-IOU (HR 1.77, 95% CI 1.26–2.48, p = 0.0008). Multivariate analysis indicated that IOU status was associated with a 2.32 times higher instantaneous rate of death compared to non-IOU (HR 2.32, 95% CI 1.5–3.5, p = 0.002). The median time for relapse was 147 days in the IOU group (range 52–393) and 209 day for non-IOU (range 96–1793), p = 0.0082. Furthermore, the relapse rate at two years was notably higher in the IOU group (31.4% vs. 16.4%, p = 0.0049). The analysis of factors independently associated with relapse-free survival (LFS) showed that IOU status, age, donor type, and cytogenetic risk were significant predictors. At two years, relapse-free survival was 29.4% in the IOU group compared to 52.5% in the non-IOU group (p < 0.001). Conclusions In our study, we found a correlation between intense opioid use in alloHCT patients and worse overall survival, particularly concerning higher relapse rates. These findings highlight the need for further research into pain management strategies to improve outcomes and reduce potential toxicity
