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Aspects on heart failure and drug treatment in geriatric patients
No full textBackground: Patients with chronic heart failure (HF) are very common in geriatric care, but the prevalence of different types of HF and comorbidities, as well as the nature of investigations, treatment, planning and outcome in this patient group are less well known. The overall aim of this thesis was to assess central aspects of geriatric care such as strategies for drug changes and in particular, investigations and treatment strategies for geriatric patients with HF prior to and during geriatric care. Finally, treatment in a subgroup of patients with both HF and Alzheimer´s disease (AD) was studied. Study I: Data were extracted during one geriatric care episode in 2005, 2010 and 2015 and prescription trends and factors contributing to drug changes were analyzed. Compared to 2005, patients in 2015 had more comorbidities and used more drugs but had shorter hospital stays and significantly fewer prescription changes. We found that high activity in prescribing correlated to higher quality of drug use and to longer care episodes.Study II: Data on diagnostics and treatment of HF from a cohort of 134 patients prior to admission to geriatric care for worsening of HF were collected. We found that a majority had been investigated with echocardiography (ECHO) and NT-pro-BNP, but most of the investigations were old and not updated, particularly in patients with HF with preserved ejection fraction (HFpEF, 53%). Patients with HF with reduced ejection fraction (HFrEF) were treated according to guidelines, but only to half of target doses. Study III: The same cohort as in Study II was used.In Study III, retrospective data on diagnostics and treatment of HF during an inpatient hospital stay in a clinic specialized in geriatric medicine was obtained. Few additional investigations on etiology and status of HF were performed. The geriatricians did not change the prescriptions of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB) or beta blocking agents (BB) but increased the treatment with furosemide to a large extent and mineralocorticoid receptor antagonists (MRA) to some extent. The information given from the previous caregiver to geriatric care was at discharge significantly washed-out in the referrals from geriatricians to primary care physicians.Study IV: In a (propensity score) matched cohort of individuals with HF and AD where 455 were treated with cholinesterase inhibitors (ChEIs) and 455 were not, we wanted to investigate whether use of ChEI, known to affect cardiovascular function, affect the risk of hospitalization for HF and mortality. Indeed, it was found, that treatment with ChEIs was associated with a significantly lower mortality (21%) and a lower risk of hospitalization for HF (47%).Conclusion: This thesis shows that many geriatric patients with chronic HF do not have up-dated information on type of HF and consequently do not receive adequate drug treatment nor adequate dosing according to guidelines. There is also a significant loss of information on HF etiology and treatment in referrals between caregivers. One reason may be short care episodes. The results of study I indicated that when geriatricians were given more time to treat patients, the result was a higher quality of drug prescribing.It is urgent to increase adherence to HF guidelines regarding investigations and treatment for HF in older people. In addition, the collaboration between specialists in cardiology and geriatric medicine and primary care must be increased and encouraged.Interestingly, we also found that individuals with HF and AD who were treated with ChEIs was associated with improved survival and a decreased risk of hospital care for HF. This may be explained by the anti-inflammatory properties and negative chronotropic effects of the ChEIs and warrants further study.List of scientific papersI. Reimers Wessberg, M., Eriksdotter, M., Seiger, A., Fastbom, J. Prescription Changes During Geriatric Care Episodes: A Trend Analysis Conducted in Sweden. Drugs & Aging. 2018, 35:243–24. https://doi.org/10.1007/s40266-017-0509-z II. Reimers Wessberg, M., Seiger, A., Fastbom, J., Eriksdotter, M. Few Geriatric Heart Failure Patients Investigated According to Clinical Guidelines: A Retrospective Review of Patient Records. BMC Geriatrics. 2023, Mar 21;23(1):155. https://doi.org/10.1186/s12877-023-03773-w III. Reimers Wessberg, M., Fastbom, J., Ugarph-Morawski, A., Seiger, A. Eriksdotter, M. Geriatric Contribution to Heart Failure Care: A Retrospective Review of Patient Records. [Manuscript]IV. Reimers Wessberg, M., Xu, H., A., Fastbom, J., Seiger, A., Eriksdotter, M. Cholinesterase Inhibitors and Reduced Risk of Hospitalization and Mortality in Patients with Alzheimer’s Dementia and Heart Failure. [Submitted]</p
Gaze into literacy : the potential of eye movement analysis for assessing children's word reading skills in ecological contexts
No full textChildren's reading proficiency is reflected in their eye movements during reading, a subject predominantly explored in experimental settings. This doctoral project investigates these dynamics within naturalistic environments. Word reading assessments and eye movement measures were collected from Swedish schoolchildren, revealing patterns consistent with prior research but with increased variability in eye movement data. Analyses showed age-related changes in eye movement characteristics correlating with word reading outcomes. The link between mean fixation duration and tests reliant on lexical processing was particularly strong. Eye movements explained variance in multiple word reading tasks and accounted for nearly half of the overall variance in word reading skill one year post-recording. Among second grade students with below-average performance, those persistently scoring below average in third grade exhibited significantly longer fixations than those who would improve, indicating early eye movements can be used to differentiate between children with persistent difficulties and eventual improvement. The findings of this thesis reinforces previous findings in the participants’ school environments, suggesting that it is feasible to analyze connections between children’s eye movements and reading development under ecologically valid circumstances. Results show that eye movement analysis could be useful to reading assessments, as it offers a means to index children’s word reading ability in concurrent and longitudinal perspectives and can be used to detect true skill deficits. However, the effects of limited experimental control should be considered upon reviewing results. With continued research and careful implementation, eye tracking holds promise for early education practices.List of scientific papersI. Andrea Strandberg, Gustaf Öqvist Seimyr, Mattias Nilsson, Per Östberg. Eye Movements during Reading and their Relationship to Reading Assessment Outcomes in Swedish Elementary School Children. Journal of Eye Movement Research. 2022. https://doi.org/10.16910/jemr.15.4.3 II. Andrea Strandberg, Gustaf Öqvist Seimyr, Mattias Nilsson, Per Östberg. Eye Movements are Stable Predictors of Word Reading Ability in Young Readers. Frontiers in Education. 2023. https://doi.org/10.3389/feduc.2023.1077882 III. Andrea Strandberg, Gustaf Öqvist Seimyr, Mattias Nilsson, Per Östberg. Early Eye Movement Characteristics of Children with Persistently Poor Word Reading Ability. [Submitted]</p
Apolipoprotein CIII in the pathophysiology of diabetes mellitus
No full textIt has previously been shown that high levels of apolipoprotein CIII (apoCIII) are related to both type-1 (T1D) and type-2 diabetes (T2D). In this thesis, mechanisms whereby apoCIII affects diet- and genetically-induced obesity and metabolic derangements, and the role of the environment and apoCIII in the development of T1D, have been studied.In C57BL6/j (B6) mice fed a high-fat diet (HFD), preventing or reversing the increase in apoCIII with antisense oligonucleotides (ASO), resulted in the activation of lipases, and enhanced hepatic clearance and catabolism of circulating lipids. Lipid metabolism in the liver shifted towards ketogenesis and there was a reduction in de novo lipogenesis and gluconeogenesis. The ketone bodies were used for energy production in the brown adipose tissue (BAT). In white adipose tissue (WAT) there was reduced inflammation and increased expression of genes related to thermogenesis. Lowering apoCIII in HFD-fed mice promoted a normal insulin sensitivity and glucose homeostasis and counteracted the metabolic phenotype.Even in obese and diabetic ob/ob and db/db mice, which lack leptin signaling, lowering of apoCIII with ASO twice per week improved glucose metabolism and insulin sensitivity, albeit to a lesser extent in the db/db mice. The ASO-treated mice had a reduced food intake and cessation of body weight gain. This was related to a partial recovery of hypothalamic insulin sensitivity with decreased expression of the orexigenic genes Npy and Agrp, and increased expression of the anorexigenic genes Pomc and Cart.A small-interfering RNA (siRNA) mix, consisting of two mouse-specific siRNAs against apoCIII, was tested in ob/ob mice. The metabolic improvements were comparable to those obtained when ASO was used. However, the siRNA mix was more potent and had a longer duration than ASO, so the treatment was given every second week instead of twice per week.The BioBreeding (BB) rat model, in which the diabetes-prone (DPBB) rats develop a human-like T1D when they are around 60 days old, was used to investigate the role of the environment and apoCIII in the development of T1D. Islets from DPBB or diabetes-resistant (DRBB) rats were transplanted into the anterior chamber of the eye (ACE) of 25 days-old DP or DR recipients. Five weeks after transplantation DR islets in the ACE of DP rats had a changed morphology, loss of functional vascular network, increased vascular leakage and infiltration of phagocytes, as compared to DP islets in DR recipients. This shows that a prediabetic milieu decides the fate of the islets. There was an increase in apoCIII in prediabetic islets and when DP islets were transplanted into the ACE of DP rats treated with siRNA against rat apoCIII, there was a delay in the onset of diabetes.All these data, together with previous results, support that apoCIII has a role in the development of T1D and obesity-induced T2D.List of scientific papersI. Valladolid-Acebes I, Åvall K, Recio-López P, Moruzzi N, Bryzgalova G, Björnholm M, Krook A, Alonso EF, Ericsson M, Landfors F, Nilsson SK, Berggren PO, Juntti-Berggren L. 2021. Lowering apolipoprotein CIII protects against high-fat diet-induced metabolic derangements. Science Advances. 7(11): eabc2931. https://doi.org/10.1126/sciadv.abc2931 II. Recio-López P, Valladolid-Acebes I, Berggren PO, Juntti-Berggren L. 2021. Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice. International Journal of Molecular Sciences. 23(1): 62. https://doi.org/10.3390/ijms23010062 III. Valladolid-Acebes I, Recio-López P, Berggren PO, Juntti-Berggren L. Apolipoprotein CIII interferes with the hypothalamic circuitry controlling hunger and satiety in obese and diabetic mice. [Manuscript]IV. Recio-López P, Valladolid-Acebes I, Hadwiger P, Hossbach M, Krampert M, Prata C, Berggren PO, Juntti-Berggren L. 2022. Treatment of the metabolic syndrome by siRNA targeting apolipoprotein CIII. Biofactors. 49(1): 153-172. https://doi.org/10.1002/biof.1885 V. Recio-López P, Valladolid-Acebes I, Berggren PO, Juntti-Berggren L. The fate of the pancreatic islet is decided by its environment. [Manuscript]</p
Primary cilia in human neuron differentiation
No full textPrimary (non-motile) cilia have long been overlooked, considered vestigial organelles lacking specific functions. In humans, all cell types except sperm, ependymal and bronchial epithelial cells, and oviduct cells extend a single primary cilium. However, it was not until the 1990s that cilia garnered significant interest in biomedical research. Cilia serve as cellular sensors for various stimuli, including mechanical, light, osmotic, and chemoreceptive cues. Their ability to detect, integrate, and transmit external information to the cell is essential for cell signaling, development, and tissue homeostasis.Among ciliary signaling pathways, the WNT pathway is evolutionarily conserved and regulates crucial aspects of organ patterning, cell proliferation, migration, and fate determination during embryogenesis. Not surprisingly, genetic mutations in WNT pathway-related proteins have been linked to several diseases and different types of cancer. Alterations in cilia function may lead to the onset of a heterogeneous group of genetic conditions called ciliopathies. Given that cilia are nearly ubiquitous organelles, ciliopathies may affect multiple organs, including the brain. So far, dysfunction of cilia has also been implicated in a spectrum of complex neurodevelopmental disorders (NDDs) such as autism, schizophrenia, and dyslexia.In Paper I, we established an advanced human neuronal ciliated cell model using Lund human mesencephalic (LUHMES) cells. These cells can differentiate into mature neurons in just about a week of culture, and they exhibit ciliation throughout the proliferative, differentiation, and fully differentiated phases. This in vitro cell model shared a high gene expression profile similarity with in vivo neuronal transcriptomes from humans. LUHMES neuronal cilia were shown to functionally transduce the well-known ciliary Sonic hedgehog (SHH) signaling pathway by regulating its target gene expression.In Paper II we used the LUHMES cell model to explore the role of cilia during human neuron differentiation. Based on a dynamic differentiation ciliation pattern, we identified the functional ciliary time window and found cilia to be relevant in promoting axon outgrowth and branching. Furthermore, we generated a stable LUHMES mutant model for the ciliogenic transcription factor RFX2 and performed transient knockdowns (KDs) of essential ciliary genes IFT88 and IFT172. LUHMES RFX2 -/-, IFT88 KD and IFT172 KD neurons were not as efficient as WT counterparts in promoting the same aspects of neuron differentiation. Altered RFX2 -/- cilia showed deregulation of the ciliary WNT signaling pathway and subsequent cytoskeleton rearrangement required for proper neuron differentiation.In Paper III, we provided an extensive compendium of how neuron differentiation is molecularly regulated. By analyzing enhancer RNAs (eRNAs) using the native elongating transcript-cap analysis of gene expression (NET-CAGE) method, we revealed nearly triple the number of new LUHMES enhancers important for neuron differentiation, as compared to what was previously known. Our analysis also showed enrichment of active enhancers among certain NDDs, including neuropsychiatric disorders. We employed capture Hi-C (HiCap) to locate target genes through promoter-enhancer interaction. Interestingly, the binding motifs of ciliogenic RFX transcription factors and the transcriptional complex activated by WNT signaling were enriched in both promoter and enhancer sequences.Altogether, we elucidated strong implications of cilia in neuron differentiation at the cellular level unveiling a critical ciliary time window, and at the molecular level, describing the regulatory machinery promoting neuron differentiation. We speculate that cilia play an essential role in neuron maturation and brain formation, underpinning the biogenesis of aspects of certain neurodevelopmental conditions when their function is disrupted.List of scientific papersI. Lauter G.*, Coschiera A.*, Yoshihara M., Sugiaman-Trapman D., Ezer S., Sethurathinam S., Katayama S., Kere J., Swoboda P. Differentiation of ciliated human midbrain-derived LUHMES neurons. Journal of Cell Science. 2020 Nov 9;133(21):jcs249789. *Equal contribution - joint first authorship. https://doi.org/10.1242/jcs.249789 II. Coschiera A.*, Yoshihara M.*, Lauter G., Ezer S., Pucci M., Li H., Kavšek A., Riedel C. G., Kere J., Swoboda P. Primary cilia promote the differentiation of human neurons through the WNT signaling pathway. BMC Biology. 2024 Feb 27;22:48. *Equal contribution - joint first authorship. https://doi.org/10.1186/s12915-024-01845-w III. Yoshihara M.*, Coschiera A.*, Bachmann J.*, Pucci M., Li H., Bhagat S., Murakawa Y., Weltner J., Jouhilahti E.-M., Swoboda, P., Sahlén P., Kere J. Transcriptional enhancers in human neuronal differentiation provide clues to neuropsychiatric disorders. *Equal contribution - joint first authorship. [Manuscript]</p
Hantaviruses and SARS-CoV-2 : cell stress and novel antivirals
No full textHantaviruses and coronaviruses are zoonotic viral pathogens that can cause severe disease in humans. The global spread of SARS-CoV-2 demonstrated the full pandemic potential of viral infections and highlighted our need for novel antivirals as well as for a better understanding of the complex interactions between viral pathogens and their hosts.In Paper I and Paper II, we studied the interactions between hantaviruses and SARS-CoV-2 and the integrated stress response (ISR), a cellular pathway through which cells react to stress factors including viral infections. The ISR is activated through the kinases PKR, PERK, GCN2 or HRI, which phosphorylate eIF2α, leading to a translational shutdown and the formation of stress granules (SGs) in the cytoplasm. We found that hantavirus infection triggered a transient PKR dependent formation of SGs in a small fraction of infected cells and that the SG prevalence varies based on cell type and hantavirus species. Moreover, we showed that hantavirus proteins and RNA do not co-localize with SGs. All studied hantaviruses suppressed PKR activation and our data also suggest that they can inhibit activation of PERK.Like hantaviruses, SARS-CoV-2 triggered PKR activation and we detected high levels of phosphorylated eIF2α in infected cells, indicating ISR activation. However, SG formation was inhibited and despite a reduction in translational levels, the expression of the stress-responsive transcription factors ATF4 and CHOP was suppressed. Furthermore, we observed variant-specific differences in ISR activation in comparison to ancestral SARS-CoV-2: Infection with the Delta variant led to weaker PKR activation while infection with Omicron BA.1 induced higher levels of eIF2α phosphorylation and an increased SG prevalence.In Paper III and Paper IV, we screened drug libraries for chemical compounds with antiviral effects against SARS-CoV-2 and Puumala virus (PUUV). By performing a high-throughput microscopy screen, we discovered a previously undescribed chemical, later named virapinib, which reduced the infectivity of a pseudovirus expressing the SARS-CoV-2 spike protein as well as the infectivity of live virus. Virapinib was characterized as an inhibitor of macropinocytosis and was shown to affect the cell entry of different SARS-CoV-2 variants and other viruses like TBEV and MPXV in vitro.By screening the Specs drug repurposing library, we found a variety of drugs with antiviral effects against the hantavirus PUUV in both the lung epithelial cell line A549 and primary human umbilical vein endothelial cells (HUVECs). These PUUV antivirals include nucleotide analogues, HSP inhibitors and immunosuppressants and most of them have previously reached phase I clinical trials. Interestingly, we also found 19 compounds that instead enhanced PUUV infectivity including HDAC inhibitors, integrin inhibitors, and catenin activators.Antivirals are essential tools in the research, prevention, and treatment of viral infections. Our findings can be a starting point in the development of new treatment strategies and can provide valuable insights into SARS-CoV-2 and hantavirus replication cycles.List of scientific papersI. Christ, W.*, Tynell, J.*, and Klingström, J. Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules. 2020. Journal of Virology, 94(3):e01168-19. *Contributed equally. https://doi.org/10.1128/JVI.01168-19 II. Christ, W., Klingström, J., and Tynell, J. SARS-CoV-2 variant-specific differences in inhibiting the effects of the PKR-activated integrated stress response. 2024. Virus Research. 339:199271. https://doi.org/10.1016/j.virusres.2023.199271 III. Porebski, B., Christ, W., Corman, A., Haraldsson, M., Barz, M., Lidemalm, L., Häggblad, M., Ilmain, J., Wright, S.C., Murga, M., Shlegel, J., Sezgin, E., Bhabha, G., Lauschke, V.M., Lafarga, M., Klingström, J., Huhn, D., and Fernandez-Capetillo, O. Discovery of a novel inhibitor of macropinocytosis with antiviral activity. 2023. bioRxiv. Oct 25. [Manuscript] https://doi.org/10.1101/2023.10.25.563967IV. Christ, W.*, Porebski, B.*, Fernandez-Capetillo, O., and Klingström, J. High-Throughput Drug Repurposing Screen for Antivirals Targeting Orthohantaviruses. *Contributed equally. [Manuscript]</p
Advancing cardiovascular shear wave elastography and image registration : method development and safety evaluation
No full textCardiovascular disease remains the leading cause of death and disability worldwide, with its burden on health and healthcare systems projected to rise. In cardiovascular diagnostics and treatment strategy decisions, medical imaging plays a significant role. This thesis aims to improve diagnostic tools for stable coronary artery disease, assess the safety of techniques for guiding treatment decisions in carotid artery stenosis, and develop a novel technique for the elastic characterisation of anisotropic tissues.Accurate diagnosis of stable coronary artery disease demands both anatomical information, on the location and severity of coronary plaques, and functional information, on their haemodynamic impact. A composite image of these types of information could offer greater diagnostic value than examining them separately. In this context, Study I explored image registration of 3d echocardiography with coronary computed tomography angiography. Three image registration algorithms were implemented and validated using patient data. Findings suggest that integrating images from these imaging modalities is feasible, and that iterative closest-point methods can be improved by incorporating orienting landmarks to avoid ventricular rotation.In assessing carotid artery stenosis, plaque composition is increasingly recognised as an important factor for guiding treatment. Ultrasound-based shear wave elastography is emerging as a promising non-invasive method for plaque characterisation, although its mechanical impact on plaques and arterial walls is not completely understood. Studies II and III evaluated the safety of arterial shear wave elastography ex vivo in porcine models and in vivo in human carotid arteries. Results indicate that this technique exposes the arterial wall to significantly less strain than arterial pulsation, at strain rates comparable to those experienced during strenuous exercise.In addition to arterial applications, shear wave elastography is increasingly used to measure elasticity of anisotropic tissues, such as the myocardium. However, current techniques can only fully characterise the elastic properties of isotropic tissues. In Study IV, a novel dual-probe shear wave elastography system was developed for elastic characterisation of transversely isotropic tissues, which exhibit multiple wave modes. Ex-vivo experiments successfully tracked all wave modes and demonstrated the system’s feasibility to measure all elastic parameters.</p
Catheter ablation of atrial fibrillation : methods for improving outcome
No full textIntroduction: The most common arrhythmia world-wide is atrial fibrillation (AF). The arrhythmia is diagnosed through an electrocardiogram (ECG). Patients with AF often experience symptoms including palpitations, dyspnoea, fatigue, and an overall reduced quality of life. Patients with AF also face a higher risk of stroke, which is due to thrombus formation in the left atrial appendage, and heart failure, attributable to a fast heart rate. Numerous risk factors for the development of AF have been identified, including advanced age, male sex, underlying heart disease, obstructive sleep apnoea syndrome (OSAS), and intensive prolonged physical activity, among others. Additionally, epidemiological studies have shown a relationship between gastroesophageal reflux disease (GERD) and AF. The two main treatments for AF are catheter ablation and antiarrhythmic drugs, with catheter ablation being the more effective option. Catheter ablation of AF is known to be associated with certain complications, and as a result, the traditional approach in most centres has been to keep patients hospitalised overnight to monitor for any complications that may occur following the ablation procedure. The cornerstone of catheter ablation of AF is pulmonary vein isolation (PVI). However, this treatment does not benefit all patients, especially those with persistent AF. Approximately 60% of patients with persistent AF achieve arrhythmia freedom through PVI. Fibrosis in the left atrium (LA), when detected through voltage mapping, showing low voltage zones (LVZ), is known to be associated with an even poorer prognosis. Therefore, it is essential to further investigate the mechanisms of AF and to develop additional ablation methods, to help a larger proportion of patients.The aims of this thesis are: 1) to determine the safety of same-day discharge after the ablation procedure, aiming to increase the overall effectiveness of this treatment; 2) to evaluate, in a randomised controlled trial (RCT), whether ablation of LVZs in addition to PVI increases arrhythmia-free survival, compared to PVIonly; 3) to validate the accuracy of an ECG device, the Coala Heart Monitor (CHM), in detecting atrial arrhythmias; 4) to identify independent predictors of the presence of LVZs; and 5) to assess whether symptoms of GERD is a predictor of LVZs in the posteroinferior part of the LA.Methods and results: Study I was a registry-based study that included all AF ablations performed at Karolinska University Hospital over the 2001-2020 period, encompassing a total of 5414 procedures. All complications were registered, and the medical records of patients who suffered from a complication were thoroughly reviewed. The complications were categorised based on the time of occurrence: from intraprocedural up to six hours post-ablation, and from six hours post-ablation until discharge the following day. We found that most complications occurred either intraprocedurally or within the first six hours following ablation. Furthermore, 73 complications were observed between six hours after the ablation until discharge, of which 12 were severe. Of these 12, it appears unlikely that a longer hospital admission would have altered the outcomes.Study II outlines the protocol for an RCT where we aim to randomise 206 patients with LVZs in the LA to PVI-only or to PVI + LVZ ablation. The primary outcome is freedom from atrial arrhythmias at 12 months following one or two ablation procedures conducted within a six-month period with a blanking period of 3 months after the first procedure. As of now, we have randomised 166 patients, however, as the study is still ongoing, the results are not yet available.Study III is a validation study in which a handheld ECG device, the CHM, was validated for detecting AF and atrial tachyarrhythmia (ATA), encompassing both AF and atrial flutter, with a 12-lead ECG serving as the reference standard. A total of 200 12-lead ECGs and simultaneous CHM registrations were collected. All registrations were interpreted in a blinded fashion by two electrophysiologists. The sensitivity and specificity for detecting ATA were found to be 98.9% (95% confidence interval (CI): 94.0–100) and 100% (95% CI: 96.6–100), respectively. The sensitivity and specificity for detecting AF were 100% (95% CI: 95.3–100) and 97.5% (95% CI: 93.0–99.5), respectively.In Studies IV and V, we utilised a subset of the cohort from Study II, which comprised both randomised and non-randomised patients. In Study IV, we conducted a comparison between patients with LVZs in the LA and those without LVZs, with the aim of identifying independent predictors for the presence of LVZs. We discovered that female sex (odds Ratio (OR): 4.83, 95% CI: 2.66–8.76, P Conclusions: Same-day discharge after AF ablation appears to be safe six hours after ablation. The CHM demonstrates high accuracy, in detecting ATA and AF when compared to a 12-lead ECG, suggesting its suitability for follow-up in AF patients, and for screening purposes. Female sex, advanced age, CAD, and an enlarged LA were identified as independent predictors of LVZs. This information can be valuable in the planning process for AF ablation. Patients with symptoms of GERD exhibit increased odds of presenting with LVZs in the posteroinferior wall of the LA, which may partially explain the observed higher risk of AF in patients with GERD.List of scientific papersI. Paul Nordin, A., Drca, N., Insulander, P., Bastani, H., Bourke, T., Braunschweig, F., Kennebäck, G., von Olshausen, G., Sadigh, B., Saluveer, O., Tapanainen, J., Schwieler, J., Åkerström, F., Jensen-Urstad, M. Low incidence of major complications after the first six hours post atrial fibrillation ablation: Is same-day discharge safe and feasible in most patients? Journal of Cardiovascular Electrophysiology. 2021, Sep 17; 32(11): 2953- 2960. https://doi.org/10.1111/jce.15243 II. Paul Nordin, A., Jensen-Urstad, M., Charitakis E., Åkerström, F., Almroth, H., Herczku, C., Tapanainen, J., Höglund, N., Drca, N. Individually DEsigned Ablation of Low voltage areas in persistent Atrial Fibrillation — a randomised controlled trial (IDEAL-AF): Study design. [Manuscript]III. Paul Nordin, A., Carnlöf, C., Insulander, P., Mohammad Ali, A., JensenUrstad, M., Saluveer, O., Drca, N. Validation of diagnostic accuracy of a handheld, smartphone-based rhythm recording device. Expert Review of Medical Devices. 2023, Jan 25; 20(1): 55-61. https://doi.org/10.1080/17434440.2023.2171290 IV. Paul Nordin, A., Jensen-Urstad, M., Charitakis, E., Carnlöf, C., Drca, N. Predictors of low voltage zones in patients with persistent atrial fibrillation eligible for catheter ablation: An observational study. Journal of Cardiovascular Electrophysiology. 2024, April 1; 35(5). https://doi.org/10.1111/jce.16264 V. Paul Nordin, A., Charitakis, E., Carnlöf, C., Åkerström F., Drca, N. Symptoms of gastroesophageal reflux disease predicts low voltage zones in the posteroinferior left atrium in patients with persistent atrial fibrillation. [Submitted]</p
Radiation-induced toxicity and secondary malignant neoplasms in radiotherapy of intrathoracic tumors
No full textRadiation oncology is essential in the treatment of cancer, with approximately fifty percent of oncology patients undergoing radiotherapy (RT) at some stage of their disease management. Significant progress is being made in the diagnosis, surgical, medical, and radiotherapeutic treatment of cancer. Consequently, an increasing number of cancer patients will live long after undergoing RT. Radiotherapy invariably involves exposure of healthy tissue to ionizing radiation, leading to potential acute and chronic adverse effects and, in some instances, the induction of secondary malignancies. The overall aim of this thesis was to investigate the feasibility of using alternative RT techniques to reduce the calculated risks of radiation-induced toxicity and secondary cancer in the RT of intrathoracic tumors compared to standard RT. Additionally, the thesis aimed to assess the feasibility of cardiac magnetic resonance imaging (CMR) for detecting early radiation-induced cardiac changes in comparison to myocardial perfusion scintigraphy (MPS).Study I: In this comparative dosimetric analysis, we evaluated the feasibility of proton beam therapy (PBT) against intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in reducing radiation doses to relevant organs at risk (OARs) in the treatment of thymic tumors. Twelve patients who had previously received 3D-CRT were selected. Retrospective IMRT plans and PBT plans were generated for each patient. The dosimetric comparison demonstrated that PBT significantly reduced the mean doses to numerous OARs, such as the heart, lungs, breasts and esophagus. Utilizing the Lyman-Kutcher-Burman (LKB) model for the calculation of normal tissue complication probability (NTCP), we found that PBT plans could reduce the risks of pneumonitis, esophagitis, and myelopathy when compared to 3DCRT and IMRT.Study II: The goal of the second study was to determine whether myocardial perfusion scintigraphy (MPS) changes in lung cancer patients treated with RT were detectable with late gadolinium enhancement cardiac magnetic resonance imaging (LGE CMR). Twenty-one patients were evaluated before RT and at two and six-month follow-ups. Semi-quantitative methods and the Bull’s-eye-view technique were employed to analyze MPS changes, while LGE CMR studies were examined for visual signs of myocardial damage and cardiac function. The findings indicated that at the six-month follow-up, MPS changes were less pronounced than previously reported, with no visual or functional signs of myocardial damage observed on LGE CMR. The study highlighted the risk of false-positive MPS changes due to attenuation artifacts.Study III: This study sought to compare the calculated risks of radiation-induced secondary malignant neoplasms (SMNs) among patients treated for thymic tumors with 3D-CRT, IMRT, and PBT. A mechanistic model based on the organ equivalent dose (OED) concept was used to estimate the risks of carcinoma induction. Twelve patients treated with 3D-CRT had alternative IMRT and PBT plans created retrospectively. Considering two mechanistic models – the linearexponential and the plateau models, which represent different cellular repair capabilities – the study concluded that PBT presented a lower risk of SMNs for all OARs compared to 3D-CRT and IMRT, suggesting a potential benefit of PBT in reducing risks for SMNs.In study IV we aimed to compare the dosimetric outcomes of Volumetric Modulated Arc Therapy (VMAT), PBT, and conventional External Beam Radiation Therapy (cEBRT) in treating thoracic spinal metastases. Results indicated that both VMAT and PBT achieved better target coverage and delivered lower doses to the spinal cord, heart, esophagus, and lungs than cEBRT. Specifically, VMAT provided optimal target coverage, whereas PBT was superior in minimizing doses to vital organs. These findings suggest that VMAT and PBT may offer dosimetric benefits, particularly in palliative scenarios where sparing of specific OARs is especially important.In conclusion, the cumulative evidence presented in this thesis highlights the potential of advanced radiotherapy techniques, such as PBT and VMAT, to spare various OARs more effectively than traditional methods like cEBRT and 3D-CRT. Across various clinical scenarios, including the treatment of thymic tumors and thoracic spinal metastases, PBT has demonstrated a consistent ability to reduce radiation doses to OARs, thereby reducing the risk of acute and chronic radiation-induced toxicities. The thesis also suggests that PBT could lower the risk of SMNs in RT of thymic tumors, which is a significant consideration for longterm cancer survivorship. Incorporated into the broader conclusions of this thesis, the findings from Study II reinforce the importance of assessing and monitoring cardiac function in patients undergoing radiation therapy for intrathoracic tumors.List of scientific papersI. Lideståhl A, Mondlane G, Gubanski M, Lind PA, Siegbahn A. An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours. Phys Med. 2019 Apr;60:120-126. https://doi.org/10.1016/j.ejmp.2019.03.028 II. Lideståhl, A., Larsson, T., Thorén, L., Brodin, O., & Lind, P. A. Changes on myocardial perfusion scintigraphy and contrastenhanced cardiac magnetic resonance imaging after definitive radiotherapy in patients with lung cancer. Journal of Radiotherapy in Practice. 2021. 21(4), 455-461. https://doi.org/10.1017/S1460396921000091 III. Lideståhl A, Johansson G, Siegbahn A, Lind PA. Estimated Risk of Radiation-Induced Cancer after Thymoma Treatments with Proton- or X-ray Beams. Cancers (Basel). 2021 Oct 14;13(20):5153. https://doi.org/10.3390/cancers13205153 IV. Lideståhl A, Fredén E, Siegbahn A, Johansson G, Lind PA. Dosimetric Comparison of Conventional Radiotherapy, Volumetric Modulated Arc Therapy, and Proton Beam Therapy for Palliation of Thoracic Spine Metastases Secondary to Breast or Prostate Cancer. Cancers (Basel). 2023 Dec 7;15(24):5736. https://doi.org/10.3390/cancers15245736 </p
On cardiovascular complications in people with type 2 diabetes : Aspects of incretin-based therapy and glycemic control
No full textBackground: Hyperglycemia, insulin resistance, and the presence of advanced glycation end products are key features of type 2 diabetes (T2DM) and the leading mechanisms behind the increased cardiovascular risk observed in people with this condition. Percutaneous coronary revascularization has been associated with higher risk of stent failure in people with diabetes mellitus (DM), having greater risk of both in-stent restenosis (ISR) and stent thrombosis (ST). Moreover, the role of glycemic control in stent failure outcomes is uncertain. Glucagon-like pepetide-1 receptor (GLP-1R) agonists (GLP-1RA), a family of glucose-lowering agents, have demonstrated cardioprotective actions with reductions of relative risk of about 16% in subjects with T2DM compared with placebo. Preclinical data have indicated beneficial effects on the cardiac function and vascular healing associated with activation of GLP-1R. However, the specific mechanisms and actions of this class of drugs remain unexplored.Methods: Studies I and II were randomized clinical trials including subjects with T2DM, both open label but assessor-blinded. Study I compared the effects of liraglutide with those of glimepiride on the subclinical systolic and diastolic cardiac function, represented by the longitudinal functional reserve index (LFRI). Study II studied the effects of exenatide over standard treatment on stent strut coverage and the extent of neointima hyperplasia in participants with coronary artery disease revascularized with a contemporary drug-eluting stent (DES). Studies III and IV were observational, retrospective studies with data derived from several Swedish national registers. Study III included all patients with DM revascularized percutaneously with DES in 2007-2017, whereas Study IV comprised only T2DM subjects in whom a DES was implanted in 2010-2020. The primary endpoint for Studies III and IV was stent failure, defined as the occurrence of ISR and ST. The exposure variable in Study III was incretin treatment, i.e., treatment with a GLP-1RA or dipeptidyl peptidase 4 inhibitor. In Study IV, the exposure variable was the level of glycemic control by stratified glycated hemoglobin A1c levels.Results: No differences in LFRIsystolic or LFRIdiastolic were observed between the liraglutide and glimepiride groups in Study I. No significant effect on improved endothelialization of DES or neointima thickness was found for exenatide compared with standard treatment in Study II. A similar risk of stent failure was detected for those treated with incretins and the control group in Study III. An association was found between the risk of stent failure and glycemic control in persons with T2DM, the subgroups with worse glycemic control exhibiting the highest risk.Conclusions: There is no compelling evidence for beneficial effects of GLP-1RA on cardiac function and/or improvement of heart failure (Study I). GLP-1RA treatment did not show any signs of improved endothelialization or reduced risk of stent failure in either Studies II or III. Poor glycemic control associated with the risk of stent failure, driven by ISR (Study IV).List of scientific papersI. Nyström T, Santos-Pardo I, Hedberg F, Wardell J, Witt N, Cao Y, Bojö L, Nilsson B, Jendle J. Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment vs. glimepiride both in combination with metformin: a randomized open parallel-group study. Front Endocrinol (Lausanne). 2017;8:325. https://doi.org/10.3389/fendo.2017.00325 II. Santos-Pardo, I, Witt N, Angerås O, Nyström T. Effects of exenatide on coronary stent’s endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study. Cardiovasc Diabetol. 2023;22(1):337. https://doi.org/10.1186/s12933-023-02071-4 III. Santos-Pardo I, Lagerqvist B, Ritsinger V, Witt N, Norhammar A, Nyström T. Risk of stent failure in patients with diabetes treated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors: A nationwide observational study. Int J Cardiol. 2021;330:23-9. https://doi.org/10.1016/j.ijcard.2021.02.011 IV. Santos-Pardo I, Andersson Franko M, Lagerqvist B, Ritsinger V, Eliasson B, Witt N, Norhammar A, Nyström T. Glycemic control and stent failure in subjects with type 2 diabetes: a nationwide observational study. [Submitted]</p
Enhancing hospital care coordination : a resilience-centric approach to challenges and potential strategies
No full textBackground: The realms of patient flow management and care coordination, both aiming to optimize care delivery, are governed by distinct operational logics. Patient flow management is primarily a strategic tool concerned with optimising resource utilization via efficient movement of patients through the healthcare system. Care coordination emphasizes a holistic patient-centred approach. It focuses on integrating and coordinating services across the continuum of care to meet the individual patient needs.Technological improvements, demands for cost control and a shift toward redirecting lower acuity patients to primary and secondary care levels, accentuates the need for specialized staff and equipment in increasingly specialised hospitals. Resource constraints enhances conflicting quality, safety, and production goals as they keep challenging frontline hospital managers to constantly adapt to new situational demands.The theoretical description of hospitals as complex adaptive systems suggest that resilience is essential for maintaining the systems functions and avoiding loss of control of care delivery. The ability to adapt in response to both critical events and long-term pressures are a hallmark of resilient systems. Adaptations require adaptive capacity, such as extra resources, opportunities, degrees of freedom and/or a flexible goal setting. As well as strategies for control at individual, team, and strategic levels. For this thesis, the system’s ability to adapt is explored through care coordination at the first line management level.Care coordination has been studied primarily in specific single unit settings or for specific type of management roles such as navigators, nurse coordinators and lead medical doctors. There is a need for studies of how adaptive capacity is realised in-situ from a systems perspective, in highly specialised hospital settings, and to harness first line managers experiences of improvisations and informal practices (Invisible work).Aim: This thesis aims to contribute to bridging the gap between theory and practice of how first-line hospital managers realise adaptive capacity to avoid loss of control.Methods: An ethnographic approach that build three cases of care coordination in various in-hospital settings. The studies utilise a broad, inductive-deductive approach to explore how care coordination is realised in-situ using primarily participant shadowing observations and interviews for data collection. Study I. Describes care coordination in a Neonatal Intensive Care Unit. That is an integrated system of intensive care, emergency intake, step down unit and home care nested within one department. This study includes 100 hours of shadowing observations of coordinators, their conversations, tasks, meetings, and artefacts. Data were analysed using an inductive-deductive approach to content analysis from the perspective of resilience engineering. Study II. Explores the intersection of hospital wide patient flow management and care coordination (between wards and units). It incorporates five semistructured individual interviews with high level managers, 56 hours of shadowing observations with hospital bed-coordinators and 14 observations of hospital coordination team huddles. Inductive-deductive content analysis was applied, guided by a framework of Joint Cognitive Systems. Study III. Explores lead-nurses’ strategies and challenges for coordinating care at the emergency department (ED). Data were collected through four focus group interviews guided by a table-top sandbox simulation of the ED. Analysis were conducted using reflexive thematic analysis.Findings: Study I. Describes a functional relationship between operational stress and a progression of adjustments in the actual situation, expressed through recurring patterns of adaptation. Everyday work of the management team was characterised by seamlessly and actively organising and reorganising. Sacrificing low level goals based on up-to-date information and making continuous assessments of what would be minimally intrusive for the overall performance of the ward. Study II. Adds to the exploration of care coordination by describing how situations in the hospital’s patient flow is defined as problematic (or disastrous) by being on a course towards unacceptable quality- and safety trade-offs. And additionally, how the hospital management team huddle is an arena for sensemaking and negotiation between wards, but also act as a threshold and delay for information and decisions. Study III. Describes that the “normal state” of the ward is a moving target depending on the current demands. Activities for monitoring the status of the ward are in competition with coordinating activities as they both require managers attention. Coordinating care within the ED extends beyond the boundaries of the physical department within a variety of temporal demands for “on-the-day” adaptations and anticipatory strategies.Conclusions: The apparent stability of the organisation was found to be a dynamic balance between patient flow and care coordination activities. Care coordination is a team effort that transcend physical or organisational boundaries, teams of managers assert dynamic control as their strategies allow the system to increase the complexity of its control function when needed. The distributed nature of care coordination offers no ‘one point of control’ for tactical or strategic decision makers, which is problematic as a point of control is a common target for patient flow management interventions. Furthermore, frontline managers lacked the aid of tailored decision support systems for matching and visualising current operational stress of their units. It was not obvious outside the head of individual managers what strategies were available for any given situation.List of scientific papersI. Hybinette K, Pukk Härenstam K, Ekstedt M. A First-line management team’s strategies for sustaining resilience in a specialised intensive care unit—a qualitative observational study. BMJ Open. 2021;11:e040358. https://doi.org/10.1136/bmjopen-2020-040358 II. Hybinette K, Praetorius G, Ekstedt M & Pukk Härenstam K. Exploring patient flow management through a lens of cognitive systems engineering. Ergonomics. 2023, 66(12), 2106- 2120. https://doi.org/10.1080/00140139.2023.2186321 III. Hybinette K, Praetorius G, Ekstedt M & Pukk Härenstam K. Navigating complexity of emergency department care coordination: A qualitative exploration of the use of adaptive capacity. [Submitted]</p