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Improving detection and reducing overtreatment of prostate cancer
No full textProstate cancer is a global health issue being the second most common cancer in men. In Sweden, prostate cancer is the most common cancer in men with one in five Swedish men receiving the diagnosis in their lifetime. The blood biomarker PSA has revolutionized the diagnosis and monitoring of prostate cancer. Unfortunately, PSA is not specific for prostate cancer and has led to overdiagnosis and overtreatment of low-risk cancers. Active surveillance has emerged as an alternative to active treatment of low-risk disease. The guidelines for active surveillance are constantly evolving with emerging research findings.In Study I, we investigated which clinical variables are associated with adverse pathology (ISUP 3 or higher and/or a pathological T-stage of T3 or higher) after radical prostatectomy in a cohort of men initially diagnosed with low-risk prostate cancer and enrolled in active surveillance between 2008 and 2017 in Stockholm County, Sweden. Our results showed that 37.7% of men had adverse pathology at radical prostatectomy. Clinical T-stage and PSA at diagnoses in addition to age, PSA, and PI-RADS on MRI at last re-biopsy were statistically significantly associated with adverse pathology, supporting guidelines incorporating PSA and MRI in active surveillance protocols.The association between use of 5-alpha reductase inhibitors for benign prostate hyperplasia and prostate cancer has long been debated, with most studies showing a decreased incidence, particularly of low-risk prostate cancer. However, studies investigating the association between 5-ARI and prostate cancer mortality have shown more disparate results. Study II evaluated the association between 5-ARI and prostate cancer mortality and all-cause mortality using a population-based cohort study design including 429,977 men in Stockholm, Sweden between 2007 and 2018. Cox proportional hazards regression models were used to compute adjusted hazard ratios. There were 35,767 deaths during follow-up, with 852 deaths attributable to prostate cancer. Longer exposure times were associated with a decreased risk of prostate cancer mortality (0.1-2.0 years: HR, 0.89; 95% CI, 0.64- 1.25; >8 years: HR, 0.44; 95% CI, 0.27-0.74). No association between 5-ARI and all-cause mortality was found, regardless of exposure time. The study suggests that use of 5-ARIs are safe regarding prostate cancer mortality and may decrease the risk, however, it remains unknown if the differences are due to inherent medication properties.Most current clinical guidelines suggest incorporating MRI in the diagnostic chain of prostate cancer after an elevated PSA test. Studies have shown its efficacy in reducing the number of biopsies, overdiagnosis of low-risk disease, and improved detection of clinically significant cancer. However, MRI is still a bottleneck in many healthcare settings with demand exceeding supply. The Stockholm3 test is clinical prediction model of clinically significant prostate cancer incorporating clinical variables, PSA, and a polygenic risk score. Study III compared the detection of clinically significant prostate cancer between two screening pathways: PSA + Stockholm3 + Systematic biopsies and PSA + MRI + Systematic and targeted biopsies. The study was performed within the STHLM3MRI prostate cancer screening randomized clinical trial. Our results showed that the Stockholm3 test with systematic biopsies can detect clinically significant prostate cancer at similar rates as PSA with MRI and systematic/targeted biopsies. However, the Stockholm3 pathway required more biopsies (6.3% vs. 4.4%) and detected more indolent disease cases (1.2% vs. 0.5%), suggesting the approach may be suitable in settings with limited MRI resources.PSA density is more specific for clinically significant prostate cancer compared to PSA alone. In Study IV, we investigated if PSA density could be used as a selection tool for undergoing MRI in men with an elevated PSA. The study took place within the experimental arm of the STHLM3MRI trial. The results showed that a PSA density cutoff of 0.075 mg/ml2 would miss only 5% of clincally significant prostate cancers while reducing the number of MRIs by 28%. However, at a PSA density cutoff of 0.15 mg/ml2, nearly half (44%) of clinically significant prostate cancers would be missed with a 78% reduction in the number of MRIs. The results suggest that PSA density could be used to select men for MRI, however, lower cutoffs than typically recommended in guidelines should be used.In conclusion, the overaching aim of this thesis was to improve detection of prostate cancer as well as reducing overdiagnosis and overtreatment. In addition, a commonly used medication was assessed in regards to its safety concerning prostate cancer mortality.List of scientific papersI. Björnebo, L., Olsson, H., Nordström, T., Jäderling, F., Grönberg, H., Eklund, M., Lantz, A. Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer. World Journal of Urology, 2021, 39, 1797-1804 https://doi.org/10.1007/s00345-020-03394-7II. Björnebo, L., Nordström, T., Discacciati, A., Palsdottir, T., Aly, M., Grönberg, H., Eklund, M., Lantz, A.Association of 5a-reductase inhibitors with prostate cancer mortality. JAMA Oncology, 2022, 8.7, 1019-26 https://doi.org/10.1001/jamaoncol.2022.1501III. Björnebo, L., Discacciati, A., Falagario, U., Vigneswaran, H.T., Jäderling, F., Grönberg, H., Eklund, M., Nordström, T., Lantz, A. Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial. JAMA Network Open, 2024, 7.4, e247131-e247131 https://doi.org/10.1001/jamanetworkopen.2024.7131IV. Björnebo, L., Discacciati, A., Chandra Engel, J., Falagario, U., Abbadi, A., Vigneswaran, H.T., Jäderling, F., Grönberg, H., Eklund, M., Lantz, A, Nordström, T. PSA Density as a Selection Tool before MRI in Prostate Cancer Screening: an Analysis from the STHLM3MRI Trial. [Manuscript]</p
Prediction in rheumatoid arthritis to enable individualised therapy
No full textRheumatoid arthritis (RA) is a chronic inflammatory disorder of autoimmune nature, primarily manifesting as polyarthritis. It is a complex disorder, of combined genetic and environmental etiology, that can lead to substantial loss of mobility and irreversible joint damage, if left untreated. Today, modern breakthroughs have allowed tremendous strides to be made in treating RA, with remission now being an attainable goal following appropriate and efficient treatment. Nevertheless, interpatient-variability remains high within treatment response, where most patients attempt multiple disease-modifying antirheumatic drugs (DMARDs) throughout the course of their disease. In this thesis, we investigated opportunities for tailoring treatment and care at an individualized level, primarily through the identification of factors that would allow stratification of patients, and more rapid advancement towards relevant therapy. We concentrated our attention on common genetic variants and their contribution to aspects of RA patient prognosis, with a particular focus on cardiovascular comorbidity and methotrexate (MTX) treatment response.In Study I, we explored the increased risk of cardiovascular disease experienced by patients with RA, by studying the genetic overlap between RA and myocardial infarction (MI). Employing a sample consisting of 26,637 Swedish RA patients and RA-free controls, we performed a genome-wide association study (GWAS), paired the resulting GWAS summary statistics with publicly available GWAS summary statistic data on MI, and assessed the genetic overlap between the two traits through estimation of genetic correlation. Ultimately, we found that genome-wide genetic correlation between RA and MI was minor overall (rg=0.13, 95%CI -0.03-0.29) with no robust evidence of strong local genetic correlation, concluding that overall genetic overlap between the two phenotypes was minor.The remaining three studies explored the genetic underpinnings of treatment response in patients treated with MTX, focusing on persistence to treatment, i.e. remaining on MTX with no additional DMARDs prescribed. In Study II we investigated whether persistence to treatment with MTX aggregated within families, and quantified the underlying family-based heritability of the phenotype. Using 357 pairs of first-degree relatives concordant for early RA and treatment with MTX as first-line therapy, we found no evidence of familial aggregation of persistence at one year per the estimated risk ratio (RR=1.02, 95%CI 0.87-1.20), with a modest effect for persistence at three years (RR=1.41, 95%CI 1.14-1.71). Heritability estimates supported this, with a minor heritability for persistence at one year (h2=0.08, 95%CI 0-0.43) and a modest heritability for persistence at three years (h2=0.58, 95%CI 0.27-0.89), from which we concluded that a familial component was present for persistence at three years, but not for persistence at one year.Developing on the previous study, in Study III we used data on common genetic variants to study the genetic component of persistence at a molecular level. Here, we used fully imputed genotype data on 3902 early RA patients treated with MTX as first-line therapy to estimate heritability and perform a GWAS on the two phenotypes of persistence at one and three years, respectively. Heritability estimates suggested a modest genetic component for persistence at three years (h2=0.45, 95%CI 0.15-0.75), with minor heritability observed for persistence at one year (h2=0.14, 95%CI 0-0.40). Nevertheless, we were unable to identify any genome-wide significant associations (p Lastly, in Study IV, we used the totality of available data to assess our ability to predict the outcome of persistence to treatment with MTX, using machine learning. We used data from our extensive register linkage, combining data on demographics, clinical presentation as well as medical- and prescribed drug history, with fully imputed genotype data at common genetic variants, for model training. Using a cohort of 2432 early RA patients initiating MTX as firstline therapy, we achieved minor improvements over random chance, per the area under the curve, in predicting persistence at one year (AUC=0.62, 95%CI 0.57-0.68) and persistence at three years (AUC=0.63, 95%CI 0.58-0.68), with negligible improvement in overall prediction quality upon including genotype data. We thereby concluded that despite the extensive and granular training data – including genotype data on a genome-wide set of common genetic variants – predictive quality was generally weak.List of scientific papersI. Sysojev, A.O., et al., Minor Genetic Overlap Among Rheumatoid Arthritis, Myocardial Infarction, and Myocardial Infarction Risk Determinants. Arthritis Rheumatol. 2024. 76(9): p.1344-1352.https://doi.org/10.1002/art.42918II. Sysojev, A.O., et al., Does persistence to methotrexate treatment in early rheumatoid arthritis have a familial component? Arthritis Res Ther. 2022. 24(1): p. 185.https://doi.org/10.1186/s13075-022-02873-zIII. Sysojev, A.O., et al., Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis. Rheumatology (Oxford). 2024. 63(5): p. 1221-1229.https://doi.org/10.1093/rheumatology/kead301IV. Sysojev, A.O., et al., The Impact of Genetics on Predicting Methotrexate Treatment Outcomes in early Rheumatoid Arthritis. [Manuscript]</p
Observations on diagnostic reliability and the surgical treatment of abdominal rectus diastasis
No full textBackgroundAbdominal rectus diastasis (ARD), a condition commonly seen after pregnancy or significant weight loss or resulting from abnormal connective tissue composition can lead to functional disability, abdominal and/or back pain, instability of the trunk, and reduced quality-of-life. By evaluating surgical techniques, function tests, and long-term results, we aimed to improve patient care and outcome. This series of papers investigates various surgical and functional approaches to improve patient outcome after ARD repair and massive weight loss reconstructive surgery. Today there are no objective measurement tools to assess the impact of ARD on patient function and quality-of-life, in particular a tool that correlates with self-reported problems.Methods and MaterialsStudy I: A retrospective cohort study comparing the outcomes of abdominoplasty in three patient groups operated on by general surgeons (Groups A and C) and plastic surgeons (Group B) with varying levels of experience. Group C was assessed after standard management guidelines were introduced. Statistical analyses included X2-test, Fisher's exact test, logistic regression, and ANOVA.Study II: A prospective randomised study in which 57 patients were assigned to ARD repair using either Quill self-retaining sutures or retro muscular mesh. The patients were contacted a median of five years after surgery. Long-term outcomes, including recurrence, quality-of-life (QoL), pain, and muscle strength, were assessed using SF-36 and the Ventral Hernia Pain Questionnaire (VHPQ).Study III: An experimental cross-sectional cohort study evaluating the reliability of surface electromyography (SEMG) performed during isometric abdominal muscle strength testing. The study included ARD patients and age-, BMI-, and sex- matched controls.Study IV: A cross-sectional study with a test-retest design to assess the reliability, validity, and feasibility of the five-time sit-to-stand (5-STS) test from different chair heights in women with and without ARD. Convergent validity was evaluated using correlations with clinically relevant measurements.ResultsStudy I: A significant reduction in early complication rate was seen after improved surgical training and the introduction of standard guidelines. Group C (after training and guidelines), despite having more comorbidities, showed the lowest complication rate (19%) compared to Groups A (70%) and B (44%).Study II: No recurrence of ARD was observed over a median follow-up of five years. Both surgical methods improved Qol and reduced pain, with no significant differences between the groups. The suture technique is recommended due to its lower risk for complications and due to discomfort after the mesh method.Study III: SEMG measurements demonstrated moderate to excellent reliability in assessing muscle activation and fatigue during isometric testing. SEMG provided additional insights into muscle function, correlating significantly with various clinical measures such as back pain and body perception.Study IV: All 5-STS tests showed moderate to excellent reliability. The standard chair height (43 cm) version was the most suitable for assessing functional performance in women with ARD, showing strong correlations with ARD severity, body perception, and QoL.ConclusionsStudy I: Greater surgical experience and the introduction of standard guidelines significantly reduces early complications in abdominoplasty for massive weight loss, improving patient safety and outcomes.Study II: ARD repairs using either double-row self-retaining sutures or retro- muscular mesh provide stable long-term results with no recurrence. The less invasive suture technique is recommended due to its lower complication risk.Study III: Combining SEMG with isometric abdominal strength testing provides reliable and valid assessment of muscle function in ARD patients. A considerable improvement on standard strength tests.Study IV: The 5-STS test, particularly the standard 43 cm chair height version, is a reliable, valid, and feasible tool for assessing functional performance in women with ARD, capturing functional impairments more effectively than traditional strength tests.List of scientific papersI. Swedenhammar E, Stark B, Hållstrand AH, Ehrström M, Gahm J. Surgical Training and Standardised Management Guidelines Improved the 30-Day Complication Rate After Abdominoplasty for Massive Weight Loss. World J Surg. 2018; 42(6): 1647-1654.https://doi.org/10.1007/s00268-017-4341-8II. Swedenhammar E, Strigård K, Emanuelsson P, Gunnarsson U, Stark B. Long-term follow-up after surgical repair of abdominal rectus diastasis: a prospective randomised study. Scand J Surg. 2021 Sep;110(3):283-289.https://doi.org/10.1177/1457496920913677III. Swedenhammar E, Wahlström O, de Brandt J, Strigård K, Häger C, Stark B, Nyberg A. Reliability and validity of surface EMG assessments combined with isometric muscle strength testing in patients with abdominal rectus diastasis and asymptomatic controls. Hernia. 2024 Jun 8.https://doi.org/10.1007/s10029-024-03076-yIV. Wahlström O, Swedenhammar E, Strigård K, Stark B, Nyberg A. Test-retest reliability, convergent validity and feasibility of five- time sit-to-stand tests in women with and without diastasis recti abdominis. [Submitted]</p
Persistent crisis in healthcare : psychological stress reactions and psychological support for healthcare workers during the COVID-19 pandemic
No full textBackground: Even before the COVID-19 pandemic, healthcare workers were affected by high job demands and had an increased risk of developing psychological stress symptoms. During the COVID-19 pandemic, the prevalence of psychological stress symptoms increased among healthcare workers and healthcare organizations implemented psychological support to help their staff cope with the crisis. However, due to the fast development of the pandemic, the support needed to be rapidly implemented and knowledge was lacking on what type of psychological support is meaningful to implement in healthcare during a persistent crisis. Further, it was unclear how psychological stress reactions would unfold among healthcare workers during the persistent crisis of the COVID-19 pandemic, and if increased symptoms may also be related to negative long-term health effects such as sickness absence (SA).Aim: The overall aim of the thesis was to investigate the meaningfulness and feasibility of psychological support (Study I-II), as well as the psychological stress reactions among healthcare workers (Study III-IV) during the persistent crisis of the COVID-19 pandemic (Study I-II). Study I evaluated the acceptability and feasibility of an implemented psychological support model at an Intensive Care Unit (ICU) during the first wave of the COVID-19 pandemic. Study II identified patterns of help-seeking behavior in relation to available psychological support among healthcare workers during the early and mid-phases of the pandemic. Study III examined the association between high burnout symptoms early in the COVID-19 pandemic and high burnout and depressive symptoms later in the crisis. Study IV investigated how different symptoms of psychological stress were interrelated during the COVID-19 pandemic and their relationship with mental health-related sickness absence (SA).Methods: Study I was an observational study using survey data (N = 123 healthcare workers), support participation reports, and interviews with support providers. Descriptive statistics were presented, and interviews were analyzed with thematic analysis. Study II was an observational person-centered study, using survey data from healthcare workers collected in the early (N = 681) and mid-phase (N = 396) of the COVID-19 pandemic. Data on participation in different forms of psychological support were used as indicators of class membership, work-related characteristics as class predictors, and ratings of burnout and sleep disturbance as outcomes. Study III had a case-control design using survey data collected at four timepoints during the COVID-19 pandemic. Participants were healthcare workers (N = 581). Logistic regression tested the association between case group membership (high levels of burnout symptoms) in the early pandemic and high symptoms of burnout and depression at three follow-ups. Frontline work, changes in work tasks, and participation in psychological support were controlled for in separate models. Study IV used survey data on symptoms of psychological stress and register data on SA from the Swedish Social Insurance Agency (N = 1245 healthcare workers). Personcentered analysis was used to investigate the interrelations between different symptoms of psychological stress. Tests of group-level differences were used to analyze the association between symptoms and SA.Findings: Most healthcare workers in Study I were aware of and used group support sessions. Providing support within working hours and engaging in-house psychologists increased the feasibility of the support, but it was difficult to maintain its sustainability over time (Study I). Patterns of help-seeking behavior found in Study II revealed that when engaging in psychological support, healthcare workers leaned more toward different social or group-based activities. During the persistent crisis, the availability of the support declined, and not all occupational groups were equally engaged in it (Study II). Healthcare workers with high burnout symptoms at the beginning of the pandemic (21%) were more likely to report high symptoms of both burnout and depression also later in the pandemic (Study III). Study IV identified that 6.3% of participants were on SA related to mental health and had higher symptoms of psychological stress during the COVID-19 pandemic. Different symptoms of psychological stress were also highly interrelated (Study IV).Conclusions: The findings of this thesis suggest that healthcare organizations will likely benefit from focusing on the implementation of a few psychological support formats that are based on social support. During a persistent crisis, organizational resources should be attributed to the sustainability of the support and making it accessible for all occupational groups of staff. In terms of mitigating the psychological stress reactions among healthcare workers during a persistent crisis, healthcare organizations should be mindful of the development of symptoms of psychological stress among staff early in the crisis. Symptoms of psychological stress were highly interrelated and increased among healthcare workers in Sweden during the COVID-19 pandemic. Although symptoms of psychological stress were related to SA, future research may determine whether this increase in symptoms also led to a rise in mental health-related SA following the crisis.List of scientific papersI. Appelbom, S., Bujacz, A., Finnes, A., Ahlbeck, K., Bromberg, F., Holmberg, J., Larsson, L., Olgren, B., Wanecek, M., Wetterborg, D., & Wicksell, R. (2021). The rapid implementation of a psychological support model for frontline healthcare workers during the Covid-19 pandemic: A case study and process evaluation. Frontiers in Psychiatry. 1460. https://doi.org/10.3389/fpsyt.2021.713251 II. Appelbom, S., Finnes, A., Wicksell, R. K., & Bujacz, A. (2024). When Crisis Hits, Send in the Psychologists? A Latent Transition Analysis of HelpSeeking Behavior Among Swedish Healthcare Workers During the COVID19 Pandemic. Scandinavian Journal of Work and Organizational Psychology. 9(1), 2. https://doi.org/10.16993/sjwop.224III. Appelbom, S., Nordstršm, A., Finnes, A., Wicksell, R. K., & Bujacz, A. (2024). Healthcare worker burnout during a persistent crisis: A case-control study. Occupational Medicine. 74(4), 297-303. https://doi.org/10.1093/occmed/kqae032 IV. Appelbom, S., Finnes, A., Wicksell, R. K., & Bujacz, A. Symptoms of psychological stress and sickness absence among healthcare workers during a persistent crisis. [Submitted]</p
Perspectives on metal-on-metal hip resurfacing
No full textThe overall aim of this thesis was to study patients with metal-on-metal hip resurfacing (MoM-HR). More specifically, we investigated if there are any advantages in patient-reported outcome measures (PROM) after MoM-HR compared to conventional total hip arthroplasty (THA), if there are any factors predicting a failing hip resurfacing prosthesis, and potential socioeconomic differences between patients operated with MoM-HR or uncemented THA. In Study I, the aim was to investigate potential self-reported outcome differences between MoM-HR patients and those operated with conventional hip arthroplasty. It was a nationwide register-based matched cohort study of 726 patients (363 MoM-HR vs. 363 conventional THA). The data was retrieved from the Swedish Hip Arthroplasty Register (SHAR). The outcome measures of interest were postoperative Hip Disability and Osteoarthritis Outcome Score (HOOS), EQ-5D, VAS Pain, and VAS Satisfaction. At a mean 7-year follow-up, MoM-HR patients reported better postoperative adjusted estimates in HOOS ADL (estimate 4.3, 95% CI 1.8Đ6.9) and HOOS Sport/Rec (estimate 7.8, 95% CI 3.8Đ12). There were no differences in the other studied functional outcome measures. I presented this study at the 2018 annual meeting of the Orthopaedic Research Society.Study II was a single-institution cohort study of 288 patients. The aim was to investigate the possibility of eliminating ŇunsafeÓ serum metal ions after MoM-HR by careful patient selection and optimal implant positioning. Potential risk factors of elevated serum metal ions were also studied. The main findings were that even if the risk of elevated serum metals could be reduced when operating patients with ŇoptimalÓ properties and implanting the MoM-HR optimally, the risk was not eliminated. Moreover, insufficient cup anteversion was the strongest risk factor of elevated serum metals >5 µg/l. I presented this study at the 2021 EFFORT Congress.Study III was a cohort study based on the same cohort as study II. The aim was to study factors associated with prosthesis failure and the necessity of serial follow-up including serum metal analysis and hip X-rays. Incorrect cup anteversion on the postoperative X-ray, serum metal concentrations >5 µg/l at initial follow-up, and femoral head component size In Study IV, the aim was to investigate preoperative socioeconomic differences between patients who underwent a MoM-HR and a matched group of patients who underwent uncemented THA in a 1:1 ratio. It was a nationwide register-based case-control study of THA-operated patients in Sweden between 1999 and 2014. The study was based on data from the Swedish Hip Arthroplasty Register, the National Patient Register, and Statistics Sweden. In total, 15,871 patients were included in the study. The matched cohort consisted of 1,481 MoM-HR patients and 1,481 uncemented THA patients. In the matched cohort, the proportion of patients with low education and low-income levels was larger in the uncemented THA group compared to the MoM-HR group. Another finding was that patients with low education levels were associated with a lower probability of undergoing a MoM-HR surgery compared to patients with the highest education level.In conclusion, the potential benefits of MoM-HR do not outweigh its risks, and socioeconomic disparities appear to influence the choice of innovative hip arthroplasty. I hope this thesis provides clarity on the possible advantages and disadvantages of MoM-HR, offering beneficial information to orthopaedic surgeons and patients with hip osteoarthritis in need of hip arthroplasty.List of scientific papersI. Oxblom A, Hedlund H, Nemes S, Brismar H, FellŠnder-Tsai L, Rolfson O. Patient-reported outcomes in hip resurfacing versus conventional total hip arthroplasty: a register-based matched cohort study of 726 patients. Acta Orthop. 90(4):318-323 Aug 2019. https://doi.org/10.1080/17453674.2019.1604343 II. Oxblom A, Hedlund H, Itayem R, FellŠnder-Tsai L, Vidgren M, Rolfson O, Brismar H. Careful patient selection together with an optimal implant positioning may reduce but does not eliminate the risk of elevated serum cobalt and chrome levels following metal-on-metal hip resurfacing. Hip Int. 33(5):872-879 Sep 2023. https://doi.org/10.1177/11207000221124302 III. Oxblom A, Hedlund H, FellŠnder-Tsai L, Rolfson O, Brismar H. A Precision Based Analysis on Risk Factors for Revision of Birmingham Hip Resurfacing (BHR) Metal-on-Metal Hip Arthroplasty. A Single Center Study of 288 Patients at a High-Volume Center With a Median 13 Year Follow-Up. [Submitted]IV. Oxblom A, Bitar C, Rolfson O, Hedlund H, Qureshi AR, Brismar H, Wretenberg P, Palme M, Adami J, and FellŠnder-Tsai L. Socioeconomic disparities in the utilization of metal-on-metal hip resurfacing compared to uncemented total hip arthroplasty: A population-based case-control study in Sweden. [Submitted]</p
Mechanisms controlling the latent HIV-1 provirus
No full textHIV is incurable due the persistence of latent but replication competent HIV proviruses. Lifelong antiretroviral therapy (ART) stops HIV progression to AIDS with minimal side effects. However, a HIV cure has only been achieved in rare cases with stem cell transplants. Multiple epigenetic mechanisms dictate the chromatin environment at the HIV integration site which in turn dictate HIV transcription and latency. In this thesis I will explore how histone marks, in particular histone citrullination, and the immune system affect HIV transcription and latency.List of scientific papersI. Luca Love*, Bianca B Jutte*, Birgitta Lindqvist, Oscar Kieri, Piotr Nowak, J. Peter Svensson. PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription. bioRxiv. 2024.03.17.583304. *Equal Contribution. Preprint. [Manuscript] https://doi.org/10.1101/2024.03.17.583304II. Lindqvist B*, Jźtte BB*, Love L*, Assi W, Roux J, Sšnnerborg A, Tezil T, Verdin E, Svensson JP. T cell stimulation remodels the latently HIV-1 infected cell population by differential activation of proviral chromatin. PLoS Pathogens. 2022;18(6):e1010555. *Equal Contribution. https://doi.org/10.1371/journal.ppat.1010555 III. Furtado Mil‹o J, Love L, Gourgi G, Derhaschnig L, Svensson JP, Sšnnerborg A, van Domselaar R. Natural killer cells induce HIV-1 latency reversal after treatment with pan-caspase inhibitors. Frontiers in Immunology. 2022;13:1067767. https://doi.org/10.3389/fimmu.2022.1067767 </p
Mitochondrial ß-oxidation disorders : from screening to diagnosis, fasting metabolism and optimized treatment
No full textMitochondrial beta-oxidation disorders are a group of recessive diseases characterized by fasting intolerance and symptoms ranging from intermittent myalgia and rhabdomyolysis to cardiomyopathy and severe hypoketotic hypoglycemia. The studies in this thesis have focused on some of the unresolved issues regarding the pathogenesis of these disorders and how to best care for patients: phenotype prediction (study I), mitochondrial function (study II) and fasting metabolism (study III and IV).In study I, the phenotype, biochemical data and clinical outcome of 22 Swedish pediatric patients with VLCADD were related to newborn screening data and VLCAD residual enzyme activity. Patients had a wide phenotypic spectrum, varying from asymptomatic to severely affected cases. The identified correlation between newborn screening results, residual enzyme activity analysis, and clinical outcome could significantly aid in treatment decisions and disease severity prediction.In study II, mitochondrial respiration and glycolysis in peripheral blood mononuclear cells (PBMCs) from 21 patients with VLCADD, MCADD or CUD were determined using an XFe flux analyzer. PMBCs were suitable for analysis within a 6-hour sampling window, and VLCADD and MCADD cells consistently showed lower mitochondrial respiration rates than CUD cells.Study III investigated fasting metabolism during a 9-hour night fast in 12 children with VLCADD or MCADD using subcutaneous microdialysis. The VLCADD group showed an earlier fasting-induced initiation of lipolysis compared to the MCADD group, and all patients maintained euglycemia during the fast. Patients with VLCADD with lower residual enzyme activity had an earlier initiation of lipolysis than those with higher enzyme activity.Study IV investigated the fasting and postprandial hormonal and incretin response after a 4-hour daytime fast and after the intake of a standardized meal in 15 children with LCHADD, VLCADD or MCADD compared to 12 age-matched healthy controls. All participants showed a normal glycemic response, and most fasting hormone fluctuations were similar to those observed in controls. Findings of possible increased risk for insulin resistance in patients with LCHADD and a blunted postprandial incretin response in patients compared to controls warrant further investigation.List of scientific papersI. Olsson, D., M. Barbaro, C. Haglind, M. Halldin, S. Lajic, S. Tucci, R. H. Zetterström and A. Nordenström (2022). Very long-chain acyl-CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics. JIMD Rep 63(2): 181-190. https://doi.org/10.1111/cts.13133II. Stenlid, R., D. Olsson, J. Cen, H. Manell, C. Haglind, A. I. Chowdhury, P. Bergsten, A. Nordenström and M. Halldin (2022). Altered mitochondrial metabolism in peripheral blood cells from patients with inborn errors of B-oxidation. Clin Transl Sci 15(1): 182-194. https://doi.org/10.1111/cts.13133III. Olsson, D., C. Haglind, M. Halldin, S. Lajic and A. Nordenström. Assessment of fasting metabolism with microdialysis indicates earlier lipolysis in children with VLCADD compared to MCADD. [Submitted]IV. Olsson, D., M. Halldin, C. Haglind, T. Gustafsson, S. Lajic and A. Nordenstrom. Hormonal responses to a short daytime fast in children with beta-oxidation disorders. [Manuscript]</p
Brain development and response to injury : focus on microglia and cranial irradiation
No full textPostnatal brain development is crucial for proper brain formation and function in adulthood. Impairment of this process due to external insults such as cranial radiotherapy, used to treat brain tumors and metastases, can lead to severe cognitive sequelae in cancer survivors, particularly children. However, currently, neither a treatment nor established biomarkers exist to alleviate or predict the extent of brain injury and subsequent cognitive impairments following radiotherapy.Microglia, the resident immune cells and macrophages of the brain, play a vital role in the refinement, maturation, and maintenance of neuronal circuits during development. Therefore, understanding microglial dysregulation caused by ionizing radiation (IR) and its impact on neurocognitive outcomes is of great importance.Consequently, the primary objective of this thesis was to analyze the role of microglia in brain development and their response to cranial irradiation. This includes a specific focus on temporary microglial subtypes and their contribution to irradiation-associated neuroinflammation. Additionally, we aimed to identify potential biomarkers for irradiation-induced brain damage that can be measured in easily accessible clinical samples.First, we identified a spatiotemporally distinct microglial subtype, arginase 1- expressing (ARG1+) microglia. This subtype, while morphologically similar to other microglial cells, exhibits a unique molecular profile and is crucial for the maturation of the basal forebrain cholinergic system, synaptic plasticity, and cognitive functions in female mice.Next, we developed a simple, rapid, and reproducible cell isolation method to generate single-cell suspensions from brain subregions, enriched with microglial and vascular cells. This method is suitable for integrative longitudinal molecular studies using single-cell RNA sequencing.Using this method, we performed a single-cell longitudinal analysis of the microglial responses following cranial IR and identified several hippocampal radiation-associated microglia (RAM) subtypes that emerge from hours to one year after IR. We found that IR causes progressive decrease in microglial cells, that fail to repopulate their loss by self-renewal, and this leads to the infiltration of monocytes-derived macrophages that differentiate into microglial-like cells to compensate for the microglial loss. Moreover, all these events were correlated with episodes of neuronal asynchrony.Finally, we propose EDA2R as a promising biomarker candidate for cranial IR- induced brain injury, as its levels rapidly increase in liquid biopsies (cerebrospinal fluid and plasma) following cranial IR.The results presented in this thesis provide new insights into the role of microglia during postnatal brain development and their response to cranial irradiation. They also highlight a potential biomarker for radiotherapy-induced brain damage.In summary, this research is important for the field of neuroscience. It is particularly significant for advancing our understanding of radiotherapy-related neurocognitive complications, with the aim of improving the quality of life of pediatric brain cancer survivors.List of scientific papersI. Vassilis Stratoulias, Rocío Ruiz, Shigeaki Kanatani, Ahmed M. Osman, Lily Keane, Jose A. Armengol, Antonio Rodríguez-Moreno, Adriana- Natalia Murgoci, Irene García-Domínguez, Isabel Alonso-Bellido, Fernando González Ibáñez, Katherine Picard, Guillermo Vázquez- Cabrera, Mercedes Posada-Pérez, Nathalie Vernoux, Dario Tejera, Kathleen Grabert, Mathilde Cheray, Patricia González-Rodríguez, Eva M. Pérez-Villegas, Irene Martínez-Gallego, Alejandro Lastra- Romero, David Brodin, Javier Avila-Cariño, Yang Cao, Mikko Airavaara, Per Uhlen, Michael T. Heneka, Marie-Ève Tremblay, Klas Blomgren, Jose L. Venero & Bertrand Joseph. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain. Nature Neuroscience, volume 26, pages 1008-1020 (2023).https://doi.org/10.1038/s41593-023-01326-3II. Efthalia Preka*, Alejandro Lastra Romero*, Ying Sun, Yara Onetti Vilalta, Thea Seitz, Adamantia Fragkopoulou, Christer Betsholtz, Ahmed M Osman, Klas Blomgren. Rapid and robust isolation of microglia and vascular cells from brain subregions for integrative single-cell analyses. Heliyon. volume 10, issue 16 (2024); e35838. * Denotes equal first-author contributionhttps://doi.org/10.1016/j.heliyon.2024.e35838III. Alejandro Lastra Romero*, Efthalia Preka*, Giusy Pizzirusso, Luis Enrique Arroyo- Garcia, Georgios Alkis Zisiadis, Nuria Oliva-Vilarnau, Thea Seitz, Kai Zhou, Arturo Gonzalez Isla, Lara Friess, Ying Sun, Alia Shamik, Changlian Zhu, Carlos F. D. Rodrigues, André Fisahn, Bertrand Joseph, Lena-Maria Carlson, Adamantia Fragkopoulou, Christer Betsholtz, Volker M Lauschke, Ahmed M Osman, Klas Blomgren. Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony. * Denotes equal first-author contribution. [Manuscript]IV. Alejandro Lastra Romero, Thea Seitz, Georgios Alkis Zisiadis, Holli Jeffery, Ahmed M Osman. EDA2R reflects the acute brain response to cranial irradiation in liquid biopsies. Neuro-Oncology (2024); noae077.https://doi.org/10.1093/neuonc/noae077</p
Using the force : targeting p60AmotL2-mediated invasion in cancer
No full textMechanotransduction is the process by which cells convert mechanical forces into biochemical signals—and vice versa—thanks to a coordinated cascade of effects regulated by mechanomodulatory and cytoskeletal complexes. These complexes transduce force signals to and from the nucleus to elicit cellular adaptations in processes such as proliferation, division, differentiation, and migration.AmotL2 is one of those mechanomodulatory proteins; it acts by forming a complex with cadherins, catenins and actin filaments in cell-cell junctions to transduce force signals to and from the nucleus and elicit a biological response. AmotL2 has been found to play a crucial role in many physiological processes, for instance, by regulating cell shape and organizing actin filaments during development and tissue homeostasis. More recently, AmotL2 has also been implicated in pathological processes—such as cancer invasion and metastasis— through the expression of a shorter isoform of AmotL2 under conditions of extreme hypoxia, termed p60AmotL2. Metastasis account for over 90% of cancer-related deaths, so finding treatments that specifically target invasive cancer cells is of the utmost importance to improve overall survival.In our quest to understand the role of p60AmotL2 in cancer invasion, and how we could target it, our lab has recently uncovered that p60AmotL2 acts as a dominant-negative of p100AmotL2, uncoupling radial actin filaments and impairing force transduction from cell-cell junctions to and from the nucleus. This resulted in an increase in nuclear elasticity that allowed p60AmotL2-expressing cells to migrate through tight spaces and invade in a single-cell ameboid fashion.Interestingly, we have also found that p60AmotL2 induces apical extrusion of individually-expressing cells during cell crowding events. However, neighboring cells were not able to induce extrusion when there were multiple adjacent cells expressing p60AmotL2. We posit that cancer cells might highjack this process in hypoxic conditions to bypass contact inhibition, leading to the formation of tumor masses that can then invade local and distant tissues.To target p60AmotL2-mediated effects in cancer invasion, we have employed a high-throughput phenotypic drug screening approach to find compounds that specifically kill p60AmotL2-expressing cells. Based on the results presented in this thesis, we hypothesize that the activation of pro-invasive phenotypes during metastasis can expose vulnerabilities in nucleocytoskeletal and chromatin dynamics to be exploited by different cancer therapies, such as BET inhibitors or telomere-targeting agents like 6-thio-dG. Work is still ongoing in validating other lead compounds and understanding their mechanism of action in targeting invading cancer cells, with the goal of taking them from bench to bedside and improving patient outcomes.List of scientific papersI. Modulation of E-Cadherin Function through the AmotL2 Isoforms Promotes Ameboid Cell Invasion. Aravindh Subramani, Weiyingqi Cui, Yuanyuan Zhang, Tomas Friman, Zhihai Zhao, Wenmao Huang, Pedro Fonseca, Weng-Onn Lui, Vani Narayanan, Justyna Bobrowska, Małgorzata Lekka, Jie Yan, Daniel E Conway, Lars Holmgren. Cells. 2023 Jun 21;12(13):1682. https://doi.org/10.3390/cells12131682 II. Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment. Weiyingqi Cui, Aravindh Subramani, Pedro Fonseca, Yumeng Zhang, Le Tong, Yuanyuan Zhang, Lars Egevad, Andreas Lundqvist, Lars Holmgren. Cells. 2023 Aug 28;12(17):2158. https://doi.org/10.3390/cells12172158 III. A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells. Pedro Fonseca, Weiyingqi Cui, Nona Struyf, Le Tong, Ayushi Chaurasiya, Felipe Casagrande, Honglei Zhao, Dinura Fernando, Xinsong Chen, Nicholas P. Tobin, Brinton Seashore-Ludlow, Andreas Lundqvist, Johan Hartman, Anita Göndör, Päivi Östling and Lars Holmgren. J Exp Clin Cancer Res. 2024. [Accepted]IV. High-throughput screening for the identification of novel compounds that target p60AmotL2 invasive cancer cells. Pedro Fonseca, Francesco Massai, Hanna Axelson and Lars Holmgren. [Manuscript]</p
Does online parent training measure up to group parent training in real-world settings?
No full textBackground: Disruptive behavior problems involve recurrent patterns of defiance, aggression, and hostility that interfere with normal functioning. Disruptive behaviors are commonly observed in children and adolescents and are linked to a heightened risk of academic and vocational underachievement, substance use, criminal activities, depression, and anxiety in adulthood. Parent training programs are well-established and recommended by guidelines as effective treatments. However, due to limited accessibility, there is a need for alternative approaches to deliver parent training to reach more families beyond traditional methods.Aim: The thesis’ overall aim was to evaluate treatment for children in primary care with disruptive behavior problems. Study I evaluated if a parenting program (Comet) when delivered online (iComet) would be noninferior in reducing disruptive behavior problems in children to Comet when delivered in its standard face-to-face group format (gComet). Study II assessed predictors and moderators of effects, engagement in and completion of treatment. Study III was a health economic evaluation examining costeffectiveness and cost-utility of the treatments.Methods: The three studies were based on data from a randomized noninferiority trial involving 161 children with disruptive behavior problems and their parents. Participants were patients in primary care in Stockholm who consented to participate in the trial. They were randomized to receive either gComet (n=86) or iComet (n=75). Assessments took place at baseline and after 3, 6, and 12 months. In Study I, the primary outcome was disruptive behavior problems measured by the Eyberg Child Behavior Inventory (ECBI). Secondary outcomes encompassed the behaviors and well-being of both children and parents, along with treatment satisfaction. Noninferiority analysis was conducted by examining one-sided 95% confidence intervals for the mean difference between gComet and iComet using multilevel modeling. In Study II, linear mixed effects models analyzed predictors and moderators of change in disruptive behavior and treatment engagement and completion from baseline to 3- and 12-month follow-ups. In Study III, the economic evaluation included a cost-effectiveness analysis and cost-utility analysis. Outcomes included recovered and reliably improved cases of disruptive behavior, quality-adjusted life-years (QALYs), costs from a healthcare perspective as well as a wider societal perspective. Statistical analysis involved logistic regression, generalized linear models, and incremental cost-effectiveness ratios (ICERs).Results: Study I found iComet to be noninferior to gComet at all follow-ups, with small mean differences in reduction of disruptive behavior (d =-0.02 to 0.13) with the upper limit of the one-sided 95% CI below the noninferiority margin of d = 0.43 at 3-, 6-, and 12-month follow-ups (upper limits of 95% CIs between d= .2 and .38). The statistically significant differences in secondary outcomes were clinician-assessed ADHD symptoms, parenting behavior at 3-month follow-up and satisfaction with treatment, all favoring gComet. There were no statistical differences at 12-month follow-up. In Study II, most variables did not predict nor moderate outcomes. Initial problem severity of disruptive behavior and ADHD-symptoms predicted larger decreases in disruptive behavior. Comorbid emotional problems and coercive family dynamics both predicted and moderated effects. Parents’ education level also moderated effect. The three moderators were associated with higher effects in gComet. The only predictor of treatment completion and engagement was matching treatment preference, parents who were allocated to their preferred format completed treatment to a greater extent. Results in Study III showed that healthcare costs were lower for iComet (-$1002., 95% CI -1484, -585), and that gComet resulted in non-significantly higher rates of recovered and reliably improved cases (23 % vs 12 %, p = .129 and 34 % vs 30 %, p = .593). iComet yielded marginally fewer QALYs than gComet for children (-.013, p = .014) and borderline so for the child-parent dyads (-.016, p=0.05). There was no difference in QALYs for parents (-.002, p = .73). The cost-effectiveness results indicate that iComet leads to cost savings while being slightly less effective.Conclusions: iComet was noninferior to gComet in reducing disruptive behavior. Most variables did not predict or moderate treatment effect. Coercive family dynamics, comorbid emotional problems, and parent education level did moderate the treatment effect with gComet leading to stronger effects. Treatment preference predicted treatment completion. iComet demonstrated cost savings with comparable clinical outcomes, except for slightly higher QALY gain for children in gComet. The combined results lead to the conclusion that internet-delivered parent training can be a viable alternative to group parent training in clinical care.List of scientific papersI. Engelbrektsson, J., Salomonsson, S., Högström, J., Sorjonen, K., Sundell, K., & Forster, M. (2023). Parent Training via Internet or in Group for Disruptive Behaviors: A Randomized Clinical Noninferiority Trial. Journal of the American Academy of Child and Adolescent Psychiatry. 62(9), 987–997. https://doi.org/10.1016/j.jaac.2023.01.019 II. Engelbrektsson, J., Salomonsson, S., Högström, J., Sorjonen, K., Sundell, K., & Forster, M. (2023). Is internet-based parent training for everyone? Predictors and moderators of outcomes in group vs. internet-based parent training for children with disruptive behavior problems. Behaviour Research and Therapy. 171, 104426–104426. https://doi.org/10.1016/j.brat.2023.104426 III. Engelbrektsson, J., van Leuven, L. Salomonsson, S., Högström, J., Sundell, K., Forster, M., Sampaio, F. The cost-effectiveness of online versus groupbased delivery of a parenting program: evidence from the Comet trial. [Manuscript]</p