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Methodological challenges in pregnancy pharmacoepidemiology : the case of antiseizure medication and offspring neurodevelopment
No full textThis thesis is driven by the overarching aim of elucidating methodological challenges inherent in pharmacoepidemiology during pregnancy, with a particular focus on antiseizure medications. In Study I, a substantial surge in antiseizure medication use in the United Kingdom is observed, notably linked to increases in psychiatric indications. This shift in the medication landscape raises questions about the predominant contributors to this rise and underscores the necessity of understanding evolving patterns in drug utilization during pregnancy. In Study II, a large-scale examination of associations between specific antiseizure medications and neurodevelopmental conditions across Sweden and the United Kingdom emphasizes the importance of considering drug classes and shared confounders, providing valuable insights into the possible causal effect of these drugs.Study III explores the intricate interplay between epilepsy and psychiatric conditions, unveiling a heightened risk of neurodevelopmental conditions in individuals diagnosed with epilepsy. These findings shed light on the complex within-individual links between these conditions, potentially explaining the observed higher likelihood of neurodevelopmental diagnoses in children of women using antiseizure medications in pregnancy. In Study IV, a critical evaluation of drug safety studies warns against indication-based sampling, advocating for comprehensive regression adjustments to mitigate biases. Finally, Study V introduces the marginalized between-within model, a novel approach to derive absolute measures of occurrence in sibling analysis, enhancing the interpretability of findings.This thesis, collectively, calls for a concerted effort to improve the methodology of pharmacoepidemiology during pregnancy, fostering a more nuanced understanding of medication risks, and ultimately enhancing maternal and fetal health outcomes.List of scientific papersI. Madley-Dowd P*, Rast J*, Ahlqvist VH, Zhong C, Martin FZ, Davies NM, Lyall K, Newschaffer C, Tomson T, Magnusson C, Rai D, Lee BK, Forbes H. Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study. BJOG. 2024;131(1):15-25. *Equal contributions. https://doi.org/10.1111/1471-0528.17573 II. Madley-Dowd P*, Ahlqvist VH*, Forbes H, Rast J, Zhong C, Martin FZ, Barry CJS Barry, Berglind D, Lundberg M, Lyall K, Newschaffer C, Tomson T, Davies NM, Magnusson C, Rai D, Lee BK. Antiseizure Medication Use During Pregnancy and Neurodevelopmental Outcomes in Offspring: A Study of Electronic Health Records from the UK and Sweden. *Equal contributions. [Manuscript]III. Ahlqvist VH, Dardani C, Madley-Dowd P, Forbes H, Rast J, Zhong C, Gardner R, Dalman C, Lyall K, Newschaffer C, Tomson T, Lundberg M, Berglind D, Davies N, Lee BK, Magnusson C, Rai D. Psychiatric comorbidities in epilepsy: population co-occurrence, genetic correlations and causal effects. [Accepted] https://doi.org/10.1136/gpsych-2023-101201 IV. Ahlqvist VH, Madley-Dowd P, Ly A, Rast J, Lundberg M, Jonsson-Bachmann E, Berglind D, Rai D, Magnusson C, Lee BK. Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling. Pharmacoepidemiol Drug Saf. 2023;32(8):886-897. https://doi.org/10.1002/pds.5614 V. Ahlqvist VH, Sjöqvist H, Sjölander A, Berglind D, Lee BK, Madley-Dowd P. Moving beyond risk ratios in sibling analysis: estimating clinically useful measures from family-based analysis. [Manuscript]</p
Bone health impairment in childhood cancer : from preclinical studies to clinical insights
No full textSurvival outcomes in childhood cancer have significantly improved over recent decades. While this is a remarkable achievement, it has also led to a growing number of survivors who face a great risk of long-term morbidities. Among the various contributing factors, therapeutic interventions frequently cause skeletal morbidities, mediated through systemic endocrine disruptions or direct cellular impact. These deleterious effects manifest as longitudinal bone growth suppression, lower bone mineral density and susceptibility to fractures. The prevalence of these burdensome conditions underscores the need for heightened awareness and identification of novel therapeutic approaches to safeguard skeletal health in childhood cancer.This thesis aims to investigate the effects of the novel inhibitor venetoclax on bone tissue, explore potential bone growth-rescuing strategies in preclinical models and finally, provide a comprehensive summary of the available evidence on bone mineral density in survivors of childhood cancer.In paper I, we demonstrated that venetoclax, a BCL-2 inhibitor effective in various cancer types, suppressed longitudinal bone growth in different experimental models. In paper II, we expanded our studies to a neuroblastoma cancer model where venetoclax impaired longitudinal bone growth. We also showed that co-treatment with the mitochondrial peptide humanin protected fetal rat metatarsal bones cultured ex vivo against venetoclax-induced bone growth retardation. In paper III, we explored the potential for lithium chloride to prevent dexamethasone-induced bone growth suppression. We also performed RNA sequencing to investigate potential genes and pathways that contribute to the observed effects. In paper IV, we performed a systematic review and meta-analysis of published studies that reported BMD data in childhood cancer survivors.Overall, the present thesis evolves from an initial focus on preclinical investigations into the side effects of a novel antineoplastic drug and the exploration of potential growth-rescuing therapies, advancing toward a clinical outlook, aiming to provide a systematic overview of BMD status in survivors of childhood cancer.List of scientific papersI. Lilly Velentza, Malin Wickström, Per Kogner, Claes Ohlsson, Farasat Zaman #, Lars Sävendahl #. Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth. Scientific Reports. 2023 May 17;13(1):8054. # Denotes equal last-author contribution https://doi.org/10.1038/s41598-023-34965-4 II. Lilly Velentza, Malin Wickström, Per Kogner, Claes Ohlsson, Farasat Zaman #, Lars Sävendahl #. Humanin Treatment Protects Against Venetoclax-Induced Bone Growth Retardation in Ex Vivo Cultured Rat Bones. Journal of the Endocrine Society. 2024 Jan 25;8(3):bvae009. # Denotes equal last-author contribution https://doi.org/10.1210/jendso/bvae009 III. Ondrej Soucek, Ondrej Cinek, Lilly Velentza, Valerij Semjonov, Martin Bezdicka, Farasat Zaman #, Lars Sävendahl #. Lithium rescues cultured rat metatarsals from dexamethasone-induced growth failure. Pediatric Research. 2024 Apr 29. # Denotes equal last-author contribution https://doi.org/10.1038/s41390-024-03192-6 IV. Lilly Velentza, Panagiotis Filis, Mari Wilhelmsson, Per Kogner, Nikolas Herold #, Lars Sävendahl #. Bone mineral density in survivors of childhood cancer: A meta-analysis PEDIATRICS. #Denotes equal last-author contribution. [Accepted]</p
Pathogenesis of IgA nephropathy and diabetic kidney disease : linking molecular profile to morphological and clinical picture
No full textBackground: More than 10% of the global population suffers from chronic kidney disease (CKD), which poses a large impact on society and, more importantly, the life of the affected patient. Two of the most common causes of CKD are IgA Nephropathy (IgAN) and Diabetic Kidney Disease (DKD). As specific, non-invasive biomarkers are lacking, the diagnoses are made based on clinical signs, often together with a kidney biopsy. Moreover, none of the two diseases have as of yet specific treatments. The available medications aim to reduce known risk factors for disease progression but are often not sufficiently efficient. In fact, almost 30 % of patients with IgAN loose half their kidney function or start kidney replacement therapy (KRT) within 10 years from diagnosis. Close to 50% of all patients requiring KRT suffer from DKD.Aims: To gain deeper understanding of the molecular mechanisms underlying disease onset and progression in IgAN and DKD.Material and methods: This thesis includes patients with clinically and histopathologically verified IgAN or DKD that have undergone a kidney biopsy for clinical reasons. All biopsies were scored according to established histopathological scores and a comprehensive clinical review was performed by collecting data from patients’ medical records at time of biopsy and at follow-up. Control material was mainly obtained from living kidney donors (LD). Transcriptomics (microarray or RNA sequencing, RNASeq) was performed on microdissected kidney tissue. Specific proteins were investigated using immunofluorescence (IFL) and immuno electron microscopy (iEM).Results: Study I. The potential biomarker dendrin was investigated in IgAN and its systemic variant IgA Vasculitis with Nephropathy (IgAVN). Dendrin mRNA levels were higher (p = 0.01) in IgAN/IgAVN compared to membranous nephropathy (MN) and controls. This upregulation was more prominent in patients with mild disease. No differences between groups were detected with IFL but on an ultrastructural level, using iEM, higher relative dendrin concentrations were observed in the podocyte nuclei in patients with slower annual estimated glomerular filtration rate (eGFR) decline and milder histopathological changes in IgAN/IgAVN patients. These results indicate that dendrin is protective in IgAN/IgAVN. Study II. RNASeq was performed on microdissected kidney biopsies from 19 patients with DKD and 20 LD. Gene ontology (GO) analysis showed upregulation of pathways related to inflammation and extra cellular matrix organization in the glomeruli, and immune and apoptosis pathways in the tubulointerstitium. We also compared the RNA transcript data to clinical variables at time of biopsy using weighted gene co-expression analysis (WGCNA). This analysis identified several gene modules associated with kidney function. Study III. Our RNASeq data from Study II was further analysed in relation to clinical longitudinal data, including eGFR decline, progression to KF and albuminuria. We found 265 genes that were differently expressed between patients with rapid and non-rapid progression, thus suggesting that a prognostic gene expression profile is associated with outcome in this group of DKD patients. Study IV. RNASeq was performed on microdissected kidney biopsies from 71 adult patients and 13 children with IgAN/IgAVN. Eleven LD were included as controls. We found upregulation of genes and pathways involved in the immune system in both the glomeruli and the tubulointerstitium in IgAN/IgAVN patients compared to LD. In addition, extensive transcriptomic differences were found between adults and children with IgAN/IgAVN, mainly related to cell division and mitochondrial function in glomeruli and inflammatory response in tubulointerstitium.Taken together, the result from this thesis adds important information on molecular events underlying onset and disease progression of IgAN/IgAVN and DKD. We identified compartmental and disease specific transcriptomal patterns that may be useful in the identification of new, specific biomarkers, thus conveying important information on the road towards precision medicine which ultimately may contribute to the development of better treatment options for patients suffering from CKD.List of scientific papersI. Levin A, Schwarz A, Hulkko J, He L, Sun Y, Barany P, Bruchfeld A, Herthelius M, Wennberg L, Ebefors K, Patrakka J, Betsholtz C, Nyström J, Mölne J, Hultenby K, Witasp A, Wernerson A. The Role of Dendrin in IgA Nephropathy. Nephrol Dial Transplant. 2022;gfac208. https://doi.org/10.1093/ndt/gfac208 II. Levin A, Reznichenko A, Witasp A, Liu P, Greasley PJ, Sorrentino A, Blondal T, Zambrano S, Nordström J, Bruchfeld A, Barany P, Ebefors K, Erlandsson F, Patrakka J, Stenvinkel P, Nyström J, Wernerson A. Novel insights into the disease trancriptome of human diabetic glomeruli and tubulointerstitium. Nephrol Dial Transplant. 2020;35(12):2059-2072. https://doi.org/10.1093/ndt/gfaa121 III. Acoba D, Levin A, Witasp A, Greasley P, Mölne J, Barany P, Nyström J, Wernerson A,, Reznichenko A. Kidney transcriptomics patterns predict rapid progression of diabetic kidney disease. [Manuscript]IV. Levin A, Schwarz A, van Hoef V, Wijkström J, Bruchfeld A, Herthelius M, Nordström J, Wennberg L, Barany P, Witasp A, Wernerson A. RNA sequencing of microdissected kidney biopsies from IgA nephropathy patients. [Manuscript]</p
Scare or care? How immunological processes shape perception of sickness-relevant stimuli in humans
No full textHumans and other animals have developed several defense systems to handle living in a pathogen-rich world. These defense systems include immune responses, as well as behavioral responses aimed at supporting immune functions during the fight against the infection, called sickness behavior. Since sickness behavior is believed to be adaptive, it is possible that sickness shifts perception of the world depending on the priorities and needs of the sick individual. For instance, sick humans in general avoid social interactions to save energy, but can also approach specific people that can provide care and support. However, these ambivalent aspects of sickness behavior are understudied. Thus, the aim of this thesis was to investigate perception of sickness-relevant stimuli, and how such perception is modulated during immune activation. In particular, we assessed how immune activation affected cognitive reappraisal of emotions to unpleasant stimuli (Study I), if naïve observers can detect sick others and if this ability is affected by immune activation (Studies II-III), and if immune activation affects perception of unfamiliar caregivers (Study IV).In four studies, we used the model of experimental endotoxemia, consisting in intravenously injecting a low dose of the bacterial endotoxin lipopolysaccharide (LPS) into healthy volunteers. The recognition of LPS by immune cells triggers inflammatory responses, and causes a transient state of sickness for a few hours, allowing studying sickness behavior in an experimental setting. In Study I, participants received an LPS or a saline (placebo) injection, and completed a task in which they were asked to down-regulate or up-regulate their emotions in response to general negative and disgust stimuli. We showed that sick participants reported a greater success in down-regulating their emotions to general negative and disgust stimuli, compared to healthy participants. In Studies II-III, we used sickness detection tasks, in which naïve observers rated the health status of stimuli consisting of photos of faces and video recordings from a walking task obtained from the participants in Study I. In Study II, naïve observers could detect sick others solely from the way they walked. In Study III, participants performed a sickness detection task, once when sick (LPS injection) and once when healthy (no injection). We showed that, when sick themselves, individuals categorized more healthy walkers as sick, and were thus less good at discriminating between sick and healthy walkers, compared to when healthy. In Study IV, we developed the Caregiver Perception Task (CgPT), which participants completed when sick (LPS injection) and when healthy (saline injection). The findings revealed that sick participants were more willing to receive care from unfamiliar care providers, compared to when healthy.This thesis adds to the current knowledge on social sickness behavior. Altogether, these findings highlight that sickness is not all about perceiving the world as more negative. Yes, sick individuals may categorize others more easily as threats, but sickness can also possibly increase the ability to feel less negative emotions, together with making some items and individuals in the environment more appealing (e.g., caregivers). Future studies need to investigate how such changes in perception of sickness-relevant stimuli translate into behavior.List of scientific papersI. Hansson LS, Axelsson J, Petrovic P, Paues Göranson S, Olsson MJ, Lekander M/Lasselin J. (2021). Regulation of emotions during experimental endotoxemia: A pilot study. Brain, Behavior, and Immunity. 93, 420-424. https://doi.org/10.1016/j.bbi.2021.01.013 II. Hansson LS/Lasselin J, Tognetti A, Axelsson J, Olsson MJ, Sundelin T/Lekander M. (2023). The walking sick: Perception of experimental sickness from biological motion. Brain, Behavior, and Immunity. 113, 319-327. https://doi.org/10.1016/j.bbi.2023.07.020 III. Hansson LS, Tognetti A, Tavakoli E , Stache J, Kakeeto M, Melin J, Bredin S, Skarp R, Lensmar C, Demand R, Olsson MJ, Wilhelms DB, Toll John R, Jensen K, Lekander M/Lasselin J. Identifying sick people while sick yourself: a study of identification of facial cues and walking patterns of sick individuals during experimental endotoxemia. [Manuscript]IV. Hansson LS, Tognetti A, Sigurjónsson P, Brück E, Wåhlén K, Jensen K, Olsson MJ, Toll John R, Wilhelms DB, Lekander M/Lasselin J. Perception of unfamiliar caregivers during sickness – using the new Caregiver Perception Task (CgPT) during experimental endotoxemia. [Accepted]</p
Prognostic factors in colorectal cancer
No full textPrognosis in colorectal cancer (CRC) is largely stage dependent. Classification of disease stage is done according to the tumor, node, and metastasis-staging system (TNM). Disease stage often dictates treatment options and follow-up strategies but is not the only influencing factor in prognostic predictions. Patient factors like age, co-morbidity, education level, lifestyle et cetera have a pronounced impact on prognosis. The rapidly evolving understanding of molecular mechanisms is adding more information to the picture. These are factors that will help clinicians tailor more precise and personalized treatment protocols. Comprehensive scientific endeavors like the Cancer Genome Atlas project and the International Genomic Consortium have facilitated the understanding of the molecular basis of cancer regarding oncogenesis, progression, and resistance. The understanding of the molecular background mechanisms of cancer initiation and development provides us with information when designing new and more precise treatments. The evolving information surplus advocates for new technological systems that can help us handle vast amounts of data.Despite the foreseen progress in cancer treatment the need for more reliable prognostic markers is evident. Prognostic factors and prognostic markers will probably be of even greater importance in the future due to the increasing number of patients. Better prognostic tools will help clinicians allocate care and resources more efficiently. This will guide the design of treatment and follow-up and is especially true for CRC stage II patients, in which prognosis can be difficult to predict. This led us to the pursuit and evaluation of prognostic factors and markers, especially in CRC stage II patients.In Paper I, we wanted to evaluate the prognostic significance of microsatellite instability (MSI). MSI is a genetic feature seen in about 15% of patients with sporadic colorectal cancer. This marker is basically part of routine diagnostic workup today. Its clinical and prognostic significance, however, has been long debated. To investigate the independent prognostic significance of MSI a cohort of 463 Swedish CRC patients was evaluated. Patients with MSI tumors were compared to patients with microsatellite stable (MSS) tumors. Patients subject to curative surgery during 2002-2006 in the Swedish Low-risk Colorectal Cancer Study Group cohort were included. Follow-up and treatment data were retrieved from patient records. Statistical analyses to assess MSI status and prognosis were done using logistic regression and survival analyses by the Kaplan-Meier method. Cox regression hazards model adjusted for age, sex, stage, comorbidity, and tumor location. MSI tumors were present in 66 patients (14%). Within 6 years, distant recurrences were present in 9.1% and 20.2% (P=0.049) of MSI and MSS patients, respectively. Death occurred in 25.8% and 31.5% of MSI and MSS patients, respectively. There was no statistically significant difference in overall mortality (HR 0.80, 95%CI 0.46-1.38), relapse-free survival (HR 0.82, 95%CI 0.50-1.36), or cancer-specific mortality (HR 1.60, 95%CI 0.73-3.51). Despite distant metastases being less common in patients with MSI, there was no association between MSI and overall, relapse-free or cancer-specific survival.In Paper II the aim was to investigate the impact of lifestyle factors on survival in CRC stage I-III patients. Modifiable lifestyle factors are associated with CRC risk but the impact on survival is less known. A study of 1098 CRC patients from the Swedish Low-risk Colorectal Cancer Study Group cohort was conducted to investigate the combined effects of a healthy lifestyle and body mass index (BMI) on prognosis following CRC diagnosis. Self-reported data on lifestyle habits, adherence to a Mediterranean diet pattern, and BMI five years before CRC diagnosis were used to construct a healthy lifestyle score (HL). Based on the HL score the patients were grouped from the least to most healthy and divided into four categories. Using the Kaplan–Meier method survival analyses were performed to assess recurrence-free survival and overall survival across categories of exposure, and Cox proportional hazards models adjusted for age, sex, and educational level. Among 1098 participants, 233 (21.2%) had an HL score of 0–1 (least healthy), 354 (32.2%) HL score of 2, 357 (32.5%) HL score of 3 and 154 (14.0%) HL score 4 (most healthy). Patients with the healthiest lifestyle (HL score 4) compared to the least healthy (HL score 0–1) had an improved recurrence-free survival (HL 4 vs HL 0–1, HRadj 0.51 (95% CI 0.31–0.83) and overall survival (HL 4 vs HL 0–1, HRadj 0.52 (95% CI 0.38–0.70). In conclusion, adherence to a healthy lifestyle may increase the recurrence-free and overall survival of patients with stage I–III CRC.In Paper III, a genome-wide association study (GWAS) was performed in order to find prognostic markers in stage II CRC. There is a strong need for additional markers due to the prognostic heterogeneity in stage II patients. Subsets of patients in stage II have a very good prognosis equal to stage I while others seem to join stage III patients in their elevated risk of suffering recurrence and disease progression. Therefore, more reliable prognostic tools are warranted to predict patients at high risk for metastasis. Stage II colorectal cancer patients from a homogenous Swedish cohort were selected in pursuit of germline mutations associated with recurrence. 62 patients who developed metastasis during follow-up were compared with 291 patients without metastasizing disease. A haplotype GWAS was performed to establish associations with metastasis and risk loci. 145 haplotypes were suggested with the lowest P-value (pList of scientific papersI. Rantanen P, Keränen A, Barot S, Ghazi, S, Liljegren A, Nordenvall C, Lindblom A, Lindforss U. The prognostic significance of microsatellite instability in colorectal cancer: a Swedish multicenter study. Int J Colorectal Dis. 2023 Jul 17;38(1):197. https://doi.org/10.1007/s00384-023-04480-z II. Barot S, Rantanen P, Nordenvall C, Lindforss U, Hallqvist Everhov Å, Larsson S, Lindblom A, Liljegren A. Combined associations of a healthy lifestyle and body mass index with colorectal cancer recurrence and survival: a cohort study. Cancer Causes Control. 2024 Feb;35(2):367-376. https://doi.org/10.1007/s10552-023-01802-y III. Rantanen P, Vermani L, Barot S, Nordenvall C, Liljegren A, Lindforss U, Lindblom A. A search for prognostic markers in colorectal cancer using GWAS. [Manuscript]</p
Protein and MRI profiling of genetic frontotemporal dementia
No full textFrontotemporal dementia (FTD) is a group of neurodegenerative diseases with a wide range of symptoms such as loss of inhibition and social cognition, language impairment and motor dysfunction. Genetic FTD, characterized by mutations in one of several disease-causing genes, accounts for 10 - 30% of all cases of FTD. The most common causes for genetic FTD are repeat expansions in C9orf72 and mutations in GRN or MAPT, but there are also many other, rarer causes. Each mutation gives rise to a specific subtype of genetic FTD. These subtypes differ not only in clinical presentation, but also in the underlying pathophysiology. To be able to study, and eventually treat, genetic FTD a thorough understanding of the genetic subtypes is crucial.In this thesis we characterized the effects of a p.Ala417* mutation in TBK1, showing that it causes haploinsufficiency as well as demonstrating systemic effects on the K63 ubiquitination system. We also analyzed blood and cerebrospinal fluid samples from carriers of pathogenic mutations associated with genetic FTD to find biomarkers that can distinguish symptomatic mutation carriers from healthy controls or distinguish between the different genetic subtypes. We also studied how these biomarker candidates correlate with cortical and subcortical atrophy in genetic FTD. The results of these studies have provided a further understanding of genetic FTD as well as new biomarker candidates for several pathological processes.List of scientific papersI. Khoshnood B, Ullgren A, Laffita-Mesa J, Öijerstedt L, Patra K, Nennesmo I, Graff C. TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers. J Neurol. 2022 Jun;269(6):3037-3049. https://doi.org/10.1007/s00415-021-10887-x II. Remnestål J*, Öijerstedt L*, Ullgren A, Olofsson J, Bergström S, Kultima K, Ingelsson M, Kilander L, Uhlén M, Månberg A, Graff C#, Nilsson P#. Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers. Transl Neurodegener. 2020 Jun 23;9(1):27. *Shared first author, #Shared last author. https://doi.org/10.1186/s40035-020-00198-y III. Ullgren A*, Öijerstedt L*, Olofsson J, Bergström S, Remnestål J, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tirabosch P, Santana I, Ducharme S, Butler CR, Gerhard A, Otto M, Bouzigues A, Russell L, Swift IJ, Sogorb-Esteve A, Heller C, Rohrer JD, Månberg A, Nilsson P, Graff C. Altered plasma protein profiles in genetic FTD – a GENFI study. Mol Neurodegener. 2023 Nov 15;18(1):85. *Shared first author. https://doi.org/10.1186/s13024-023-00677-6 IV. Ullgren A, Rydell MT, Bergström S, Öijerstedt L, Olofsson J, Bouzigues A, Russell L, Foster P, Ferry-Bolder E, van Swieten J, Jiskoot L, Seelaar H, Sanchez-Valle R, Laforce R, Galimberti D, Vandenberghe R, Gerhard A, Ducharme S, Butler C, Finger E, Tartaglia MC, Masellis M, Rowe J, Synofzik M, Moreno F, Borroni B, Rohrer J, Månberg A, Rodriguez-Vieitez E, Nilsson P, Westman E, Graff C. CSF protein biomarkers associate with cortical and subcortical atrophy: a GENFI study. [Manuscript]</p
Outcomes of SARS-CoV-2 Omicron Variant Infections Compared With Seasonal Influenza and Respiratory Syncytial Virus Infections in Adults Attending the Emergency Department: A Multicenter Cohort Study.
No full textBACKGROUND: There is a controversy over the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in an era of less virulent variants and an increasing population immunity. We compared outcomes in adults attending the emergency department (ED) with an Omicron, influenza, or respiratory syncytial virus (RSV) infection. METHODS: Retrospective multicenter cohort study including adults attending the ED in 6 acute care hospitals in Stockholm County, Sweden, with an Omicron, influenza, or RSV infection during 2021-2022 and 2015-2019. During 2021-2022, patients were tested for all 3 viruses by multiplex polymerase chain reaction (PCR) testing. The primary outcome was 30-day all-cause mortality. Secondary outcomes were 90-day all-cause mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: A total of 6385 patients from 2021-2022 were included in the main analyses: 4833 Omicron, 1099 influenza, and 453 RSV. The 30-day mortality was 7.9% (n = 381) in the Omicron, 2.5% (n = 28) in the influenza, and 6.0% (n = 27) in the RSV cohort. Patients with Omicron had an adjusted 30-day mortality odds ratio (OR) of 2.36 (95% confidence interval [CI] 1.60-3.62) compared with influenza and 1.42 (95% CI .94-2.21) compared with RSV. Among unvaccinated Omicron patients, stronger associations were observed compared with both influenza (OR 5.51 [95% CI 3.41-9.18]) and RSV (OR 3.29 [95% CI 2.01-5.56]). Similar trends were observed for secondary outcomes. Findings were consistent in comparisons with 5709 pre-pandemic influenza 995 RSV patients. CONCLUSIONS: In patients attending the ED, infections with Omicron were both more common and associated with more severe outcomes compared with influenza and RSV, in particular among unvaccinated patients.</p
Heparin-binding protein and endothelin-1 in acute inflammation and trauma
No full textInflammation in sepsis and trauma is a clinical challenge and despite advances in supportive care, morbidity and mortality are high. The mechanisms behind this inflammation are extremely complicated, involving numerous molecular pathways. One of the crucial consequences of sepsis is macro-and microcirculatory failure which sometimes leads to dysfunction in multiple organs, partly dependent on a progressive capillary leak resulting in oedema and fluid overload. Heparin-binding protein (HBP) originating from polymorphonuclear leukocytes is an inflammatory protein, a mediator of vascular permeability and is associated with sepsis and organ dysfunction. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor with pro-inflammatory properties. Elevated levels of ET-1 are found in patients with sepsis and other inflammatory conditions. This thesis focuses on HBP and ET-1 in acute inflammation and trauma with the overall aim to gain further knowledge on their role in acute inflammation and study them as possible biomarkers in clinical circumstances.Study I investigated the association between HBP and ET-1 during porcine endotoxemia and the effects of a dual ETA and ETB receptor antagonist (tezocentan) were studied. The animals developed pulmonary dysfunction and evidence of increased pulmonary oedema, measured with single thermal indicator dilution (STID) and by gravimetrical assessment. We found that plasma levels of HBP and ET-1 gradually increased during endotoxemia. When the dual ET receptor antagonist tezosentan was administered, it prevented a further increase in HBP and pulmonary oedema. Moreover, we investigated the effects of graded challenge with the ETA and ETB agonist ET-1 and the selective ETB agonist sarafotoxin 6c in animals not receiving endotoxin. Plasma HBP levels increased dose-dependently with both ET-1 and sarafotoxin 6c infusions and to similar levels as seen in endotoxin challenge. These findings show beneficial effects of ET receptor antagonism in experimental sepsis and a possible link between ET-1 and HBP.In study II we measured HBP in trauma patients admitted to the intensive care unit (ICU) with the aim to evaluate HBP as a predictor of post-injury sepsis. We measured HBP on ICU-day one, three and five. The cohort consisted of severely injured patients, and we found that the HBP levels were higher in those with higher injury scores, shock at admission to the trauma centre, and in patients needing massive blood transfusion. Similarly, patients who developed multiple organ failure during the first week had higher HBP at ICU admission. Heparin-binding protein was weakly associated with the development of sepsis and only at a later stage of the observation period of one week.We assessed and compared the predictive performance of HBP, C-reactive protein (CRP) and white blood cell count (WBC) for sepsis development in the following two days after blood sampling. None of the biomarkers regardless of the sample day could predict development of sepsis in the subsequent two days. The results indicate that HBP is weakly associated with post-injury sepsis and shows poor discriminatory properties as an early biomarker of post-injury sepsis. Trauma-induced inflammation may blunt the sepsis predictive performance of HBP.In study III we wanted to investigate if heparins in clinical use affect plasma levels of HBP. In this pilot study we measured HBP repeatedly in three different patient groups receiving unfractionated heparins intravenously or low molecular weight heparin (LMWH) subcutaneously. We found a dose-dependent, rapid (minutes) and substantial (six- to nine-fold) increase in HBP after heparin administration during vascular and cardiac surgery. When patients received LMWH, the levels of HBP increased but to a lower degree and reached their maximum value in three hours.We also compared a recent point-of-care device (Joinstar FIC-Q100) to the standard commercial Axis-Shield ELISA and found a strong correlation between the two methods. However, the plasma HBP levels measured with the standard ELISA method were consistently lower compared to the point-of-care device.In study IV we measured plasma HBP and ET-1 levels at ICU admission in patients with critical COVID-19 disease. We investigated their association with mortality or invasive mechanical ventilation (IMV). The cohort was characterised by severe respiratory failure where 64 % of the patients were subject to IMV during their ICU stay. Plasma HBP was markedly increased in the COVID-19 cohort, but we did not find any association with 60-day mortality or need of IMV. Endothelin-1 levels were modestly elevated, and the levels were significantly higher in patients needing IMV compared to those who did not but when adjusted for age, sex and body mass index, there was no association with either need of IMV or 60-day mortality. In addition, we did not find a correlation between HBP and ET-1 values. In our group of critical COVID-19 patients treated in the ICU, HBP and ET-1 do not seem to be associated with the need of IMV or 60-day mortality.List of scientific papersI. Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema? B. P. Persson, H. Halldorsdottir, L. Lindbom, P. Rossi, H. Herwald, E. Weitzberg, A. Oldner Acta Anaesthesiologica Scand, 2014; 58: 549-559. https://doi.org/10.1111/aas.12301II. Heparin-binding protein as a biomarker of post-injury sepsis in trauma patients. H. D. Halldorsdottir, J. Eriksson, B. P. Persson, H. Herwald, L. Lindbom, E. Weitzberg, A. Oldner Acta Anaesthesiologica Scand, 2018; 62: 962-973. https://doi.org/10.1111/aas.13107III. The effect of heparins on plasma concentration of heparin- binding protein: a pilot study. H. Halldorsdottir, L. Lindbom, A. Ebberyd, A. Oldner, E. Weitzberg BJA Open. 2024, 27; 9: 100256. https://doi.org/10.1016/j.bjao.2023.100256IV. Heparin-binding protein and Endothelin-1 in critical COVID-19. H. Halldorsdottir, J. Eriksson, O. Rooyackers, J. Grip, J. Mårtensson, E. Weitzberg *, A. Oldner *. [Manuscript] *Equal contribution </p
Fracture evaluation and prediction of outcome after a fracture using artificial neural networks
No full textBackground: Improved interpretation of orthopedic trauma could improve patient outcomes. The radiograph is the predominant tool in orthopedic emergency decision-making. Machine learning-guided radiographic interpretation could help improve patient outcomes.Aims: 1) Explore convolutional neural networks (CNN) for orthopedic trauma imaging and fracture and classification in medical imaging. 2) Study CNNs on combined imaging and registry data to predict patient outcomes after trauma. 3) Evaluate the generalizability of this approach through external validation.Methods: Study I used CNNs and transfer learning to detect fractures in auto- labeled wrist, hand, ankle, and foot radiographs. Study II and Study III doubled down on ankle fractures using the AO Foundation-/Orthopedic Trauma Association (AO) 2018 standard. We manually labeled thousands of ankle exams and trained a CNN to classify fractures. In Study III, we externally validated a CNN model against a different site and implemented active learning to improve the model. Study IV linked fractures in the Swedish Fracture Registry (SFR) to the trauma radiographs and developed models that, based on the initial radiograph, predicted patient-reported outcome measures (PROM) or death after one year.ResultsStudy I: Deeper CNN architectures outperformed, with the best correctly classifying 83% of cases, compared to 82% for the human reviewers. For secondary outcomes, the CNN performed near-perfectly for body parts and excellently in exam view. A manual review of 400 random training cases found that the auto-generated labels were the problem.Study II: The CNN performed well on the primary task. However, several outcomes were too rare to be included in the training, testing, or error bounding. For example, type A fractures were challenging to train, and there were many AO subgroups.Study III: The external validation data differed from the training site in important ways. It included weight-bearing studies, mostly type A fractures, with fewer views per study. The CNN external validation performance improved with active learning on type A fractures but decreased somewhat for other types.Study IV: We tried a range of network configurations and found that the CNN's ability to predict PROM after one year (PROM1) or death was variable. At best, the root mean squared errors (RMSE) and mean average errors (MAE) were on par with the standard deviation.ConclusionsStudy I: We succeeded in predicting fractures in radiographs at the level of human reviewers. The CNN performance for individual radiographs was better than indicated by the automatic fracture labels generated for the study.Study II: We successfully implemented a CNN for ankle fracture classification using the AO 2018 standard, looking at the complete exam rather than individual images.Study III: The initial external validation dataset performance was acceptable but not good enough. We successfully improved external validity using internal training data and active learning. External validation is essential when reporting CNN model performance.Study IV: We performed a series of experiments to train a CNN to predict PROM after one year and got our models to learn the most common value or the mean for the PROMs, i.e., overfits. We explore different ways to improve performance.List of scientific papersI. Olczak J, Fahlberg N, Maki A, Razavian A S, Jilert A, Stark A, Sköldenberg O, Gordon M. Artificial intelligence for analyzing orthopedic trauma radiographs. Acta Orthopaedica, 2017, 88:6, 581-586. https://doi.org/10.1080/17453674.2017.1344459 II. Olczak J, Emilson F, Razavian A, Antonsson T, Stark A, Gordon M. Ankle fracture classification using deep learning: automating detailed AO Foundation/Orthopedic Trauma Association (AO/OTA) 2018 malleolar fracture identification reaches a high degree of correct classification. Acta Orthopaedica. 2021a Jan 2;92(1):102-8. https://doi.org/10.1080/17453674.2020.1837420 III. Olczak, J., Prijs, J., IJpma, F. et al. External validation of an artificial intelligence multi-label deep learning model capable of ankle fracture classification. BMC Musculoskelet Disord 25, 788 (2024). https://doi.org/10.1186/s12891-024-07884-2IV. Olczak J and Gordon M. Artificial intelligence for predicting patient- reported outcome measures (PROM) from the Swedish Fracture Registry, based on trauma radiographs [Manuscript].</p
Timing of surgery after neoadjuvant chemoradiotherapy in the treatment of esophageal cancer
No full textEsophageal cancer is a very serious disease with poor prognosis. Merely 20% are alive after 5 years according to our Swedish registers. Early stages of esophageal cancer can be treated with endoscopic resection. However, for most cases of advanced disease surgery is the main treatment. The procedure has over the years incrementally been improved and standardized, and is today usually performed with minimally invasive techniques and often robot-assisted. Nevertheless, this surgery is associated with severe morbidity and mortality.Over the years neoadjuvant treatment has manifested its role as standard of care and new regimes are continuously being evaluated. The oncological treatment is physically demanding and time for recovery after completed treatment, before performing surgery, is required. The standard time to surgery (TTS) after completed neoadjuvant chemoradiotherapy (nCRT) varies somewhat in the world, but has traditionally been 4-6 weeks. Interestingly, several studies have indicated an increased rate of pathologic complete response (pCR) in the resected specimen when surgery was performed 6-12 weeks compared to In this thesis, timing of surgery after nCRT is investigated in depth. In study I the existing data in NREV (national registry of esophageal and gastric cancer) was analyzed. In study II- IV results from the randomized controlled trial NeoRes II on timing of surgery after CROSS type nCRT was reported.In Study I, 643 patients treated with nCRT and esophagectomy were identified in the NREV register and divided into two groups; TTS ≤7 weeks (344 patients, 53.5%) and >7 weeks (299 patients, 46.5%). No significant differences were found between ≤7 and >7 weeks TTS in terms of total postoperative complications, pCR or overall survival.In the NeoRes II trial, on which studies II-IV are based, 249 patients were randomized after receiving CROSS type nCRT and of these 223 patients were resected; 117 allocated to 4-6 weeks and 106 to 10-12 weeks TTS. We found no significant difference concerning overall postoperative complications, severe complications or length of hospital stay. The trial's primary endpoint, complete histological response in the primary tumor, usually referred to as pathological complete response (pCR), for patients with adenocarcinoma (AC) did not differ significantly between allocation to standard versus prolonged TTS (21% versus 26%, P-value 0,429). Nor did it for squamous cell carcinoma (SCC), or for other histological outcomes such as overall TRG, tumor-free resection margins or number of resected or metastatic lymph nodes. With a median follow-up time of 36 months, no significant differences regarding overall survival or recurrence were found. However, the first quartile survival (time point when 25% mortality was reached) was significantly worse in the prolonged TTS group (difference 12.3 months, P=0.003, 95% CI 3.7-21.0). Furthermore, patients with TRG 4 (>50% remaining cancer cells) had significantly worse overall survival (HR 2.5, 95% CI 1.1- 5.8).As the oncological treatment options overall improve over time, some patients may in the future be possible to cure without planned surgery. However, how to safely identify these patients and separate them from the majority of patients who currently still do need surgery, is not known. In study IV the accuracy of clinical response evaluation with endoscopy was investigated comparing findings just before surgery at 4-6 weeks versus at 10-12 weeks after completed nCRT. We found that the accuracy of endoscopic biopsies in predicting residual tumor (TRG 2-4), did not differ significantly between 4-6 and 10-12 weeks TTS.In conclusion, TTS after completed nCRT does not seem to be of any major importance with regard to short-term postoperative morbidity or mortality. Moreover, prolonged TTS does not significantly improve cCR. In addition, our data suggest that routinely prolonging TTS from 4-6 to 10-12 weeks may be detrimental with regard to overall survival, especially for pathological non-responders (TRG 4). Detection of residual tumor by endoscopic biopsies did not improve with prolonged TTS.List of scientific papersI. Association between time interval from neoadjuvant chemoradiotherapy to surgery and complete histological tumor response in esophageal and gastroesophageal junction cancer: a national cohort study. F Klevebro, K Nilsson, M Lindblad, S Ekman, J Johansson, L Lundell, N Ndegwa, J Hedberg, M Nilsson. Diseases of the esophagus. 2020, 33(5). https://doi.org/10.1093/dote/doz078II. Surgical morbidity and mortality from the multicenter randomized controlled NeoRes II trial. Standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for esophageal cancer. K Nilsson, F Klevebro, I Rouvelas, M Lindblad, E Szabo, I Halldestam, U Smedh, B Wallner, J Johansson, G Johnsen, E K Ahlin, H-O Johannessen, G O Hjortland, I Bartella, W Schröder, C Bruns, M Nilsson. Annals of surgery. 2020, 272(5): 684-689. https://doi.org/10.1097/SLA.0000000000004340III. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial. K Nilsson, F Klevebro, B Sunde, I Rouvelas, M Lindblad, E Szabo, I Halldestam, U Smedh, B Wallner, J Johansson, G Johnsen, E K Aahlin, H-O Johannessen, G Alexandersson von Döbeln, G O Hjortland, N Wang, Y Shang, D Borg, A Quaas, I Bartella, C Bruns, W Schröder, M Nilsson. Annals of oncology. 34(11): 1015-1024. https://doi.org/10.1016/j.annonc.2023.08.010IV. Early versus delayed clinical response evaluation after neoadjuvant chemoradiotherapy: Data from the randomized NeoRes II trial. K Nilsson, G Saliba, F Klevebro, B Sunde, I Rouvelas, M Lindblad, E Szabo, I Halldestam, U Smedh, B Wallner, J Johansson, G Johnsen, E K Aahlin, H-O Johannessen, G Alexandersson von Döbeln, G O Hjortland, N Wang, D Borg, A Quaas, I Bartella, C Bruns, W Schröder, M Nilsson. [Manuscript]</p