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Aspects on diabetes and diet with special focus on carbohydrates : epidemiological and clinical studies
No full textCarbohydrate intake affects blood glucose levels more than any other dietary factor, providing a conceptually promising area of research in the prevention and management of diabetes. Intake of fruit and vegetables, a mainly carbohydratecontaining food group with low-energy and nutrient-dense content, has shown inconsistent associations with the risk of developing type 2 diabetes (T2D) in prospective cohort studies, and very limited research exists on the association with the risk of developing prediabetes. Current guidelines for the dietary management of type 1 diabetes (T1D) are also very limited. Low carbohydrate diets have shown some promising effects in a few small trials in adults with T1D but their short-term and long-term effects remain to be further investigated. Web-based dietary assessment programs are available to facilitate nutritional research but to ensure the quality of the collected data, these need to be validated first.The overall aim of this thesis was to investigate the effect of food groups, meals and diets with a focus on their carbohydrate content, on the prevention of prediabetes and T2D and the management of T1D.In the prospective cohort study I, the aim was to investigate the association between fruit and vegetable intake and the risk of developing prediabetes and T2D in 6961 Swedish men and women over 20-years of follow-up. The results demonstrated an inverse association between higher total fruit and vegetable intake and T2D risk (HR 0.76, 95% CI 0.60, 0.96) and between higher fruit intake and prediabetes risk (HR 0.76, 95% CI 0.58, 1.00), in men but not in women.In the randomized crossover study II, the aim was to assess the effect of four isocaloric meals with different macronutrient compositions on postprandial blood glucose, lipid, and glucagon levels in 17 adults with T1D, and to compare the effect of the same meals in a control group of 21 healthy subjects. During a 4-hour postprandial period, the two meals with lower carbohydrate content (32-33% of energy), one high in protein and one high in fat, resulted in lower glucose excursions than two isocaloric high-carbohydrate meals (53-54% of energy), one of these including extra fiber. The high-protein meal also resulted in fewer hypoglycemic events and lower postprandial triglyceride excursions compared to the isocaloric high-fat meal. Glucagon concentrations increased more after the high-protein meal. Compared to the control group, the T1D group had higher glycemic peak after all meals.In the validation study III, the aim was to assess relative validity of the web-based program Nutrition Data in measuring energy and macronutrient intake against 24- hour dietary recalls (24HRs) and evaluate the program’s user acceptability in 42 adults with T1D. Nutrition Data showed comparable dietary intake estimates to interviewer-led 24HRs, high correlations for all intakes and no systematic differences between the two methods. However, limits of agreement were relatively wide. Most participants found Nutrition Data easy and fun to use, helpful for carbohydrate counting and would recommend it to others.In study IV, the aim was to investigate the effect of three diets with different carbohydrate intake (low 15-20%, moderate 30-40% and high 50-60% of energy from carbohydrates) on insulin requirements, metabolic control and glycemic variability in 102 adults with T1D. The 3-month preliminary results of the randomized controlled trial DANCE showed that insulin requirements were 0.06 IU/kg (95% CI −0.12, 0.0) or 6.5 IU/day (95% CI −12.5, −0.6) lower after the low carbohydrate diet compared to the diet with higher carbohydrate content. These differences were not significant after adjusting for BMI changes. Notably adherence to the low carbohydrate diet was moderate. However, glycemic control and variability measured with continuous glucose monitoring system metrics still improved in the low carbohydrate diet group compared to the high carbohydrate diet, with between-group differences of 12% (95% CI 3, 22) in time in range, −9% (95% CI −21, −2) in time above range and −0.5 mmoL/L (95% CI −1.0, −0.1) in SD of mean sensor glucose, irrespective of BMI changes. There were no significant differences in changes of HbA1c, lipid status, ketone levels, BMI or anthropometrics between diet groups. The moderately low carbohydrate diet did not result in differences in any endpoints compared to the other two diets.In conclusion, the findings of this thesis support the current recommendations for high intakes of fruit and vegetables in T2D prevention and show an inverse association between high fruit intake and the risk of developing prediabetes, at least in men. For T1D, low carbohydrate meals and diets had a favorable effect on glycemic markers including less variability compared to high-carbohydrate meals and diets, and not in the expense of blood lipids or ketones. Overall, studies I-IV provide new evidence on the effect of diet, with special focus on carbohydrate intake, primarily on the management of T1D and secondarily on the prevention of prediabetes and T2D.List of scientific papersI. Ba routi AA, Tynelius P, Lager A, Björklund A. Fruit and vegetable intake and risk of prediabetes and type 2 diabetes: results from a 20-year long prospective cohort study in Swedish men and women. Eur J Nutr. 2022;61(6):3175-3187. https://doi.org/10.1007/s00394-022-02871-6 II. Ba routi AA, Björklund A, Catrina SB, Brismar K, Rajamand Ekberg N. Effect of Isocaloric Meals on Postprandial Glycemic and Metabolic Markers in Type 1 Diabetes-A Randomized Crossover Trial. Nutrients. 2023;15(14):3092. Published 2023 Jul 10. https://doi.org/10.3390/nu15143092 III. Ba routi AA, Bonn SE, Björklund A. Validation of a web-based dietary assessment program against 24-hour recalls in adults with type 1 diabetes. [Submitted]IV. Ba routi AA and Björklund A. A randomized controlled trial on low, moderate and high carbohydrate diet in adults with type 1 diabetes: The DANCE (Diabetes ANd CarbohydratEs) study protocol, baseline characteristics and 3-month preliminary results. [Manuscript]</p
Exploring synbiotic treatment in ADHD, and immune-mediated prenatal risks for neurodevelopmental disorders
No full textThe etiologies of neurodevelopmental disorders (NDDs) and psychiatric disorders are considered to be multifactorial, with both genetic and environmental factors. NDDs are associated with early atypical brain development and a significant genetic origin. Nonetheless, the genes behind the heritability are still not completely identified, and environmental factors are not fully mapped. Attention deficit hyperactivity disorder (ADHD) and Autism spectrum disorders (ASD) belong to the NDD family. Over the past twenty years, a growing body of evidence indicates an interaction between the gut microbiota and the central nervous system affecting behavior and ASD-like pathophysiology. This interaction is suggested to be mediated in part through the immune system and the bacterial fermentation products, the short-chain fatty acids (SCFAs). In animal studies, prenatal exposure to inflammation or a disturbed maternal gut microbiome has caused the offspring to display changes in CNS and behavior. Epidemiological studies have suggested that prenatal exposure to certain maternal immune mediated disorders such as autoimmune disorders (ADs) increases the risk for offspring ASD. Immune activity upregulation has been shown in NDDs, primarily ASD, and some psychiatric disorders e.g. depression and there is an overrepresentation of co-occurrence of immune-mediated and/or autoimmune disorders (e.g., asthma and eczema) with ADHD specifically, and NDDs in general. Further, there is a high comorbidity between gastro-intestinal symptoms and NDDs, both ADHD and ASD in particular, which has been suggested to co-vary in symptom burden episodes. A few studies, mainly focusing on ASD, have suggested that treatment with oral probiotics can reduce core ASD symptoms. There is a high comorbidity between ASD and ADHD. However, the possible implication for adjuvant treatment through targeting the gut-brain axis has been investigated to a lesser extent in ADHD. In addition, a comprehensive range of prenatal AD exposures in relation to a wide spectrum of offspring NDDs or psychiatric disorders has been investigated to a lesser extent. The aims of this thesis were to investigate (i) treatment effects with a synbiotic in ADHD on clinical and biological aspects, and (ii) effects on child psychopathology of prenatal exposure to maternal immune mediated disorders.1. Investigate treatment effects of Synbiotic2000 on (i) ADHD symptoms, ASD symptoms, daily function and emotion regulation, N=248 participants included, 182 completers (study I) and (ii) plasma immune activity markers and SCFAs, N=156 participant completers with blood samples (study II) in children and adults through a randomized controlled trail (RCT) with a nine week intervention.2. Investigate prenatal exposure to (i) maternal Crohn’s disease (CD), N = 1 105 997 (study III) and (ii) a wide range of maternal ADs, N= 1 107 802 (study IV) on offspring NDDs and psychiatric diagnoses through registry cohort studies.In the RCT there was a reduction in (i) ASD symptoms in children and (ii) emotion regulation difficulties in adults after intervention with Synbiotic2000 compared to placebo. The symptom improvement was most pronounced in the ADHD cohort with higher inflammatory, sVCAM-1, at baseline (study I). At baseline, adults with ADHD had lower levels of SCFAs and higher levels sICAM-1 and sVCAM-1 compared to controls. Children with ADHD had lower level of SCFAs, and higher levels of proinflammatory sICAM-1, sVCAM-1, IL-12/IL-23p40 and IL-2Rα, than adults with ADHD. In the child cohort, Synbiotic2000 significantly reduced IL-12/IL-23p40 and suggestively increased propionic acid. Synbiotic2000 suggestively decreased several additional proinflammatory markers in the child or adult cohorts (study II). In the epidemiological studies, children exposed to maternal CD prenatally had an increased risk of sleeping disorder, feeding disorder and incontinence compared to children without exposure. These associations were not explained by perinatal risk factors nor child inflammatory bowel disorder (IBD), (study III). In study IV, we assessed in utero exposure to several maternal ADs, and show that maternal AD overall was associated with a modestly increased risk for offspring mental disorders combined. Certain specific ADs contributed to a doubled risk for offspring diagnosis, these associations were (i) Systemic Involvement of Connective tissue (SIC) with sleeping disorder, (ii) autoimmune thyroiditis with ASD and (iii) pernicious anemia with other behavioral or emotional disorders (F98). Assessing several maternal ADs and a comprehensive range of offspring diagnoses enables comparisons between different exposures and outcomes.In conclusion, this thesis demonstrates (i) a potentially significant role for Synbiotic2000 in managing symptoms closely associated with ADHD, (ii) higher baseline levels of certain immune activity markers in ADHD, and (iii) modest-to-moderate risk estimates for offspring NDDs and psychiatric disorders, typically manifesting in early childhood, after several prenatal AD exposures. Further studies are needed for confirmation of the findings.List of scientific papersI. Skott, E., Yang, L. L., Stiernborg, M., Söderström, Å., Rȕegg, J., Schalling, M., Forsell, Y., Giacobini, M., & Lavebratt, C. (2020). Effects of a synbiotic on symptoms, and daily functioning in attention deficit hyperactivity disorder – A double-blind randomized controlled trial. Brain, Behavior, and Immunity. 89, 9–19. https://doi.org/10.1016/j.bbi.2020.05.056 II. Yang, L. L., Stiernborg, M., Skott, E., Xu, J., Wu, Y., Landberg, R., & Arefin, S. (2023). Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial. Nutrients. 15(5). https://doi.org/10.3390/nu15051293 III. Skott, E., Söderberg, G., Giacobini, MB., Chen, X., Lindqvist, D., Gissler, M., Sjöberg, K., Lavebratt, C. Offspring exposed to Crohn’s disease during pregnancy and association with psychiatric regulatory disturbances in childhood - a nationwide cohort study. [Manuscript]IV. Skott, E., Nivins, S., Stiernborg, M., Fogdell-Hahn, A., Giacobini, MB., Gissler, M., Lavebratt, C. Associations of prenatal exposure to maternal autoimmune disorders with a wide spectrum of psychiatric and neurodevelopmental disorders in offspring – a nationwide cohort study. [Manuscript]</p
The cellular thermal shift assay (CETSA) for elucidating drug mechanism of action and resistance in cancer
No full textA complete understanding over drug mechanism of action (MoA) is important when attempting to predict treatment outcome or the presence of resistance in patients. Despite decades of scientific efforts, the MoAs of even some of the oldest and most utilized drugs in cancer therapy today remain only partially understood, while resistance continues to be a frequent and often unpredictable occurrence. The absence of a protein-focused systems-wide characterization of drug-induced changes in cellular states contributes to these gaps in knowledge, as proteins are difficult to study yet they are key players in nearly all cellular processes and the targets for most drugs. The cellular thermal shift assay (CETSA) is a recently introduced method that can directly monitor drug target engagement and drug-induced cellular changes at proteome level in intact living cells.The research presented in this thesis focuses on the protein-centric CETSA approach to charting drug MoA and resistance development by evaluating the drug-induced changes in protein thermal stability for several important cancer drugs utilized in the clinic e.g. pyrimidine analogues, taxanes, or apoptosis-blockade releasing compounds in intact living cells or tissues. We report on an extensive set of CETSA responses that reflect on drug-target engagement or other MoA-revealing alterations in cellular processes that are either compound-specific or overlapping between some of the studied drugs. Several of the highlighted proteins or ensembles of proteins show promise for further evaluation as candidate biomarkers for drug efficacy with potential future applications in a clinical setting.List of scientific papersI. CETSA interaction proteomics define specific RNAmodification pathways as key components of fluorouracilbased cancer drug cytotoxicity. Liang YY*, Bacanu S*, Sreekumar L, Ramos AD, Dai L, Michaelis M, Cinatl J, Seki T, Cao Y, Coffill CR, Lane DP, Prabhu N, Nordlund P. Cell Chemical Biology. 2022 Apr 21;29(4):572-585.e8. *Equal contribution. https://doi.org/10.1016/j.chembiol.2021.06.007 II. The mechanism of action of trifluridine and TAS-102 in a colon cancer model: A proteomics study using IMPRINTS-CETSA. Bacanu S, Gerault MA, Nordlund P. [Manuscript]III. CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance. Langebäck A*, Bacanu S*, Laursen H*, Mout L*, Seki T, Erkens-Schulze S, Ramos AD, Berggren A, Cao Y, Hartman J, van Weerden W, Bergh J, Nordlund P, Lööf S. Scientific Reports. 2019 Dec 18;9(1):19384. *Equal contribution. https://doi.org/10.1038/s41598-019-55526-8 IV. Proteome-wide CETSA reveals diverse apoptosis inducing mechanisms converging on an initial apoptosis effector stage focused at the nuclear matrix proximal region. Ramos AD, Liang YY, Surova O, Bacanu S, Gerault MA, Mandal T, Ceder S, Langebäck A, Österroos A, Ward GA, Bergh J, Wiman KG, Lehmann S, Prabhu N, Lööf S, Nordlund P. [Manuscript]</p
Mortality prediction and equity in emergency care
No full textIntroduction: Emergency departments (EDs) face crowding and long patient waiting times due to resource-demand imbalances. Waiting exposes patients to sufferings and risks, such as pain, anxiety, permanent organ damage, or death. Elderly patients, in particular elderly frail, are at greater risk and have longer ED lengths of stay than others. Triage is applied at the ED for timely allocation of medical resources, but makes little compensation for risks associated with patient age. The extent to which age is associated with ED risks and how it can be used for better triage is unknown.Aims and Hypotheses: The overarching aim of this thesis was to improve risk assessment and care for emergency department patients, particularly elderly and frail patients with low triage priorities. The hypotheses were that age-related risks aren’t fully considered in the Rapid Emergency Triage and Treatment System (RETTS), better algorithms could improve early high-risk patient identification, socioeconomic factors influence physician waiting times, and longer stays at the ED for elderly frail patients are primarily due to process differences.Methods and Results: This thesis includes four observational cohort studies using three different data sets derived from electronic health records from seven hospitals in the Stockholm Region in 2012-2016 and 2019 combined with government registry data on mortality and socioeconomic factors. The studied data included ca 1.7 million visits by ca 800 thousand individual patients. Five different analytical approaches were applied.Study I applied logistic regression models to 639.387 triage priority stratified ED visits. It found older age to be associated with increased 7- and 30-day mortality in all triage priorities. The association increased with higher age and with lower priority. In the sex-adjusted model, the 7day mortality odds ratio of priority 4 patients was 15.4 for patients aged 60-79, and 52.4 for patients aged ≥80 when compared to patients aged 18-59.Study II developed and evaluated three 3-day mortality prediction models based on triage priority and/or age on 1.7 million ED visits. Adding age information to a RETTS triage priority model improved predictive performance. A model based on patient age alone was typically superior and always non-inferior to a triage priority-based model in predicting 3day mortality. The largest difference was seen in patients with abdominal or flank pain where the area under the curve increased from 0.729 to 0.925 by adding age information to the triage priority model, while the age only model had an area under the curve of 0.908.Study III applied stepwise linear regression to over 1.7 million ED visits to seven EDs while adjusting for morbidity and process variables, finding residual differences in waiting time to see a physician associated with age, sex, birth region and education level, with a dose-response relationship. While each studied exposure alone had a small impact on waiting times, the most disadvantaged patient category had a 17% longer waiting time.Study IV applied frailty criteria to nurse-assessed care needs and combined it with patient age to identify elderly frail patients. The identified group’s mortality, admission rate, and ED length of stay was similar to previous studies’ elderly frail patient characteristics. Process mining of 45,114 ED visits showed that elderly frail patients spent similar or less time in most ED process steps, but spent longer time in the discharge process and more frequently followed longer arrival-todisposition process paths.Conclusions: Age-related mortality risks are not fully reflected in the RETTS algorithms and age can improve mortality prediction early in the ED visit. Age, sex and socioeconomic background are associated with waiting times to be seen by a physician although the clinical relevance is unclear. In order to reduce ED lengths of stay for elderly frail patients an in-depth understanding of ED process differences and earlier patient disposition decision-making is needed.List of scientific papersI. Ruge T*, Malmer G*, Wachtler C, Ekelund U, Westerlund E, Svensson P, Carlsson AC. Age is associated with increased mortality in the RETTS-A triage scale. BMC Geriatr. 2019 May 23;19(1):139. * = Shared first authorship. https://doi.org/10.1186/s12877-019-1157-4 II. Malmer G, Åhlberg R, Svensson P, Af Ugglas B, Westerlund E. Age in addition to RETTS triage priority substantially improves 3-day mortality prediction in emergency department patients: a multi-center cohort study. Scand J Trauma Resusc Emerg Med. 2023 Oct 18;31(1):55. https://doi.org/10.1186/s13049-023-01123-8 III. Malmer G, Fällman A, Åhlberg R, Svensson P, Westerlund E, af Ugglas B. Equity in the Emergency Department. Sociodemographic characteristics are associated with waiting time to physician. [Manuscript]IV. Malmer G, Fernández Llatas C, Seoane Martinez F, Åhlberg R, Svensson P, af Ugglas B, Westerlund E. Elderly frail patients are subject to longer and more time-consuming pathways in the Emergency Department - a descriptive study leveraging process mining. [Manuscript]</p
Exposures through drinking water and risk of chronic disease
No full textDrinking water is the most important constituent of our diet. Yet, the importance of drinking water quality for population health is understudied. The overall aim of this thesis was to increase this knowledge by examining the relationship between some widespread waterborne exposures with the incidence of several chronic conditions, each with a high global disease burden.In paper I, we estimated the exposure to fluoride through both diet and drinking water as well as measured fluoride in urine from 4,306 women enrolled in a population-based cohort. We assessed the association of each exposure with bone mineral density (BMD) and incidence of fractures and found that both were associated with higher BMD but also increased risk of hip fractures, suggesting denser but more brittle bone.In paper II, we assessed the exposure to drinking water calcium and magnesium in 26,733 women in a population-based cohort using information on residential history from registers in combination with monitoring data from a national drinking water database. We prospectively assessed the association of a combined exposure to calcium and magnesium, as well as each of the minerals with incidence of myocardial infarction and stroke and found that the women with the highest combined exposure and with the highest magnesium exposure had a lower risk of stroke.In paper III and IV, we estimated the exposure to drinking water trihalomethanes (THM), which are the most prevalent disinfection by-products formed in chlorinated water, in 58,602 men and women in two population-based cohorts using data on residential history and drinking water monitoring data. While we in paper III found no overall association with bladder cancer, we in paper IV observed an increased risk of proximal colon cancer in men with the highest exposure to THM.In paper V, we reviewed the epidemiological evidence of exposure to residential drinking water concentrations of THM with risk of cancer using a systematic review and dose-response meta-analysis approach. We found that TMH were associated with increased risk of both bladder cancer and colorectal cancer, mainly in men. Most studies included were judged to have moderate risk of bias, and the overall strength of the evidence was concluded to be limited-suggestive for increased risk of bladder cancer and colorectal cancer.In summary, the five constituent papers in this thesis provide important insight to the relationship between several waterborne exposures that are widespread in drinking water and population health. The results may help guiding future recommendations and regulations on drinking water quality that better protect human health.List of scientific papersI. Helte E, Donat Vargas C, Kippler M, Wolk A, Michaëlsson K, Åkesson A. Fluoride in Drinking Water, Diet, and Urine in Relation to Bone Mineral Density and Fracture Incidence in Postmenopausal Women. Environ Health Perspect. 2021;129(4):47005. https://doi.org/10.1289/EHP7404 II. Helte E, Säve-Söderbergh M, Larsson SC, Åkesson A. Calcium and magnesium in drinking water and risk of myocardial infarction and stroke-a population-based cohort study. Am J Clin Nutr. 2022;116(4):1091-1100. https://doi.org/10.1093/ajcn/nqac186 III. Helte E, Säve-Söderbergh M, Ugge H, Fall K, Larsson SC, Åkesson A. Chlorination by-products in drinking water and risk of bladder cancer - A population-based cohort study. Water Res. 2022;214:118202. https://doi.org/10.1016/j.watres.2022.118202 IV. Helte E, Säve-Söderbergh M, Larsson SC, Martling A, Åkesson A. Disinfection by-products in drinking water and risk of colorectal cancer: a population-based cohort study. J Natl Cancer Inst. 2023;115(12):1597-1604. https://doi.org/10.1093/jnci/djad145 V. Helte E, Söderlund F, Säve-Söderbergh M, Larsson SC, Åkesson A. Exposure to Drinking Water Trihalomethanes and Risk of Cancer: A Systematic Review and Dose-Response Meta-Analysis. [Manuscript]</p
Surgical treatment of lung cancer
No full textBackground: Surgery is a central part in the treatment of lung cancer. There have been recent advances in minimal invasive and lung sparing surgical techniques, but evidence regarding safety and implementability is not well established. There are also differences in outcomes after surgery for lung cancer related to income and patient sex that are not fully explored. Moreover, there are regional differences in rates of surgery for lung cancer in Sweden that are not entirely understood. The studies included in this thesis aimed to explore these aspects.Methods and results: Study I Patients who underwent uniportal and multiportal video-assisted thoracic surgery (uVATS and mVATS) lobectomy at Karolinska University Hospital from 2016 to 2018 were identified in the Swedish National Quality Register for General Thoracic Surgery (ThoR) (122 uVATS and 211 mVATS lobectomies). Baseline differences were handled using Inverse Probability of Treatment Weighting (IPTW). The proportion of uVATS lobectomies increased during the study period and conversions to thoracotomy decreased. Perioperative mortality was low and 94% in both groups had no complication. Patients who underwent uVATS lobectomy were more often discharged directly to home compared to mVATS (76.2% vs. 62.1%, p=0.008).Study II All patients in Sweden who underwent surgery for early-stage non-small cell lung cancer (NSCLC) from 2008 to 2017 were identified in ThoR (5500 patients), and record linkages were made to other national health data registers. The age- and sex-adjusted incidence rate for death per 100 person-years was 9.4 and 15 in the highest and lowest income groups, respectively. Compared to high income patients, poor patients were less likely to have preoperative positron emission tomography or minimally invasive surgery. They were more often older and had more comorbidities. After multivariable adjustment, the hazard ratio (HR) for death was 0.77 (0.62-0.96, 95% confidence interval, CI) in the highest compared to the lowest income group.Study III All patients in Sweden who underwent surgery for lung cancer from 2008 to 2017 were identified in ThoR (6536 patients), and record linkages were made to other national health data registers. Baseline differences were handled using IPTW. Women were found to have a clear and consistent survival benefit compared to men, also in subgroups according to age, histopathology, and stage. The HR for death was 0.73 (0.67-0.79, 95% CI) for women compared to men and the absolute survival difference (95% CI) at 1, 5, and 10 years was 3.0% (2.2%-3.8%), 10% (7.0%-12%), and 12% (8.5%-15%), respectively.Study IV Patients who underwent uVATS segmentectomy (232 patients) and lobectomy (601 patients) at Karolinska University Hospital from 2017 to 2022 were included. Baseline differences were handled using IPTW and an as treated analysis was used. Implementation of uVATS was gradual over the study period. In the segmentectomy and lobectomy groups respectively, 97% and 94% of patients had no postoperative complications, the median number of lymph node stations sampled was 4 vs. 5, and non-radical microscopic resection occurred in 1.7% vs. 1.8%. Drains were removed on postoperative day 1 in 75% vs. 72%, and 90% vs. 89% were discharged directly home after segmentectomy and lobectomy, respectively.Study V All patients in Sweden who underwent surgery for NSCLC from 2013 to 2017 were identified in ThoR (3050 patients), and record linkages were made to other national health data registers. Data on regional lung cancer incidence was gathered from the Swedish National Lung Cancer Register. 14 451 patients were diagnosed with NSCLC in Sweden during the study period. The average yearly rate of surgery was 6.1 per 100 000 inhabitants and varied between regions from 4.4 to 7.9. The proportion of patients with lung cancer who received surgery varied between regions from 12% to 28% with most regions being close to the national average of 21%. In patients with stage I-II disease, the proportion of new cases operated varied between regions from 57% to 116%. No differences in demography, stage at diagnosis, performance status, or presentation at multidisciplinary team stood out as explanatory factors.Conclusions: uVATS lobectomy was safe to implement and had similar postoperative outcomes compared with mVATS lobectomy at our institution. Despite a tax-funded, universal health care system, there was an inverse correlation between household disposable income and mortality after surgery for lung cancer. Women have a consistently better prognosis after surgery for lung cancer compared to men. uVATS segmentectomy was safe to implement and had similar postoperative outcomes compared with uVATS lobectomy at our center. There were regional differences in the rates of surgery for early-stage NSCLC in Sweden that could not be explained by regional differences in lung cancer incidence.List of scientific papersI. Al-Ameri M, Sachs E, Sartipy U, Jackson V. Uniportal versus multiportal video-assisted thoracic surgery for lung cancer. J Thorac Dis. 2019 Dec;11(12):5152-5161. https://doi.org/10.21037/jtd.2019.12.01 II. Sachs E, Jackson V, Sartipy U. Household disposable income and long-term survival after pulmonary resections for lung cancer. Thorax. 2020 Sep;75(9):764-770. https://doi.org/10.1136/thoraxjnl-2019-214321 III. Sachs E, Sartipy U, Jackson V. Sex and survival after surgery for lung cancer: A Swedish Nationwide Cohort. Chest. 2021 May;159(5):2029-2039. https://doi.org/10.1016/j.chest.2020.11.010 IV. Sachs, E, Jackson V, Al-Ameri M, Sartipy U. Uniportal video-assisted thoracic surgery: segmentectomy versus lobectomy-early outcomes. Eur J Cardiothorac Surg. 2024 Mar 29;65(4):ezae127. https://doi.org/10.1093/ejcts/ezae127 V. Sachs E, Jackson V, Sartipy U. Regional Differences in Surgery for Lung Cancer ‒ A Swedish Nationwide Study. [Manuscript]</p
Meeting the needs of women : provision of long-acting reversible contraception at the time of abortion
No full textBackground and aim: Unintended pregnancies represent a notable public health challenge, imposing substantial social and financial burdens on a global scale. In Sweden, approximately 37,000 abortions are conducted annually, with half of these involving women who have had at least one previous abortion. Considering that ovulation may return as early as eight days after an abortion, and that resumption of sexual activity within the first few weeks post-abortion is common, timely access to effective contraception is crucial. Long-acting reversible contraception (LARC), such as intrauterine devices (IUDs) and implants effectively prevent unintended pregnancies, lead to high user satisfaction, and are often chosen by women having an abortion. Surgical abortion presents an opportunity for feasible placement of LARC. However, this practice has not been studied in a Swedish context. During medical abortion, IUDs are routinely placed at a later follow-up visit and women who miss this visit risk being left without contraception. This thesis aimed to study the provision of LARC at the time of abortion.Methods: We performed a nationwide register-based observational study on women having surgical abortion, where we explored women’s sociodemographic factors and psychiatric disorders and their association to provision of LARC at the time of abortion. Additionally, we conducted a randomized, controlled, multicentre, superiority trial of women having medical abortion and opting for post-abortion IUD use. Based on the hypothesis that immediate placement would lead to higher uptake rates compared to later placement, and thereby compensate for a possible increase in IUD expulsion, we randomly assigned women to two groups: the intervention group, with IUD placement within 48 hours after completed abortion, and the control group, with placement during a standard follow-up visit after two to four weeks. The primary outcome measure was the proportion of IUD use after six months in both groups.Results: During surgical abortion in Sweden, social vulnerability and characteristics such as younger age, lower level of education, or not being employed, were associated with LARC provision at the abortion. The overall rate of LARC provision during surgical abortion was 40.2%, and 42.0% of the women having surgical abortion had a history of psychiatric disorders. Women with any psychiatric disorder had a higher likelihood of being provided with LARC, compared with women with no such disorder (aOR 1.21; 95% CI 1.08-1.35). In particular, personality-, substance use-, and neurodevelopmental disorders were associated with LARC provision. In early medical abortion with gestation of ≤9 weeks, the proportions of women using an IUD after six months were 91/111 (82.0%) in the intervention group vs. 87/112 (77.7%) in the control group (p=0.51). Attendance to IUD placement was comparable between groups in early abortion (108/117, 92.3% in the intervention group vs. 103/118, 87.3% in the control group; p=0.28). Moreover, IUD expulsion rates were similar between the groups (intervention group 10/111, 9.0% vs. control group 4/112, 3.6%; p=0.11). Women in the intervention group more often preferred their allocated time of placement and rated pain at placement lower compared to the control group. After one year, IUD continuation and satisfaction rates were high with >94% of IUD users reporting satisfaction with their contraceptive and we found no difference in rates of subsequent pregnancies or abortions. In medical abortion beyond 12 weeks of gestation, the proportions of women using an IUD after six months were 34/67 (50.7%) in the intervention group compared to 48/67 (71.6%) in the control group (p=0.021). Attendance rates for IUD placement were higher in the intervention group compared to the control group (69/77, 89.6% vs. 56/78, 71.8%; p=0.008), but expulsion occurred among 16/48 (33.3%) women with IUD placement within 48 hours compared to 2/27 (4.3%) with later placement (pConclusion: Women with an elevated likelihood of a subsequent unintended pregnancy are more often provided with LARC during a surgical abortion in Sweden. However, the potential of LARC provision during surgical abortion is likely not fully utilized. Contraceptive counselling in connection to the abortion should be tailored to meet the requirements of women. In medical abortion, placement of an IUD within 48 hours was not superior compared to placement after two to four weeks in terms of IUD utilization after six months. After an early medical abortion, IUD placement within 48 hours is safe, preferred by women, and does not increase expulsion rates, compared with later placement. Uptake of IUD is high when IUDs are provided for free at the abortion clinic. After a medical abortion beyond 12 weeks of gestation, IUD placement within 48 hours is associated with an increased risk of expulsion. In this case, an IUD should be placed within 48 hours only in selected cases after counselling patients on the risk for expulsion compared with later placement.List of scientific papersI. Hogmark S, Envall N, Wikman A, Skoglund C, Kopp Kallner H, Hesselman S. Provision of long-acting reversible contraception at surgical abortion—A cross-sectional nationwide register study. Acta Obstet Gynecol Scand. 2022;101:77–83. https://doi.org/10.1111/aogs.14289 II. Hogmark S, Lichtenstein Liljeblad K, Envall N, Gemzell-Danielsson K, Kopp Kallner H. Placement of an intrauterine device within 48 hours after early medical abortion—a randomized controlled trial. Am J Obstet Gynecol. 2023;228:53.e1-9. https://doi.org/10.1016/j.ajog.2022.07.063 III. Hogmark S, Envall N, Gemzell-Danielsson K, Kopp Kallner H. One-year follow up of contraceptive use and pregnancy rates after early medical abortion: Secondary outcomes from a randomized controlled trial of immediate post-abortion placement of intrauterine devices. Acta Obstet Gynecol Scand. 2023;102:1694-1702. https://doi.org/10.1111/aogs.14662 IV. Hogmark S, Rydelius J, Envall N, Teleman P, Gemzell-Danielsson K, Kopp Kallner H. Placement of an intrauterine device within 48 hours after second trimester medical abortion — a randomized controlled trial. [Submitted]</p
Organic electronics and microphysiological systems to interface, monitor, and model biology
No full textBiological processes in the human body are regulated through complex and precise arrangements of cell structures and their interactions. In vivo models serve as the most accurate choice for biological studies to understand these processes. However, they are costly, time-consuming, and raise ethical issues. Microphysiological systems have been developed to create advanced in vitro models that mimic in vivo-like microenvironments. They are often combined with integrated sensing technologies to perform real-time measurements to gain additional information. However, conventional sensing electrodes, made of inorganic materials such as gold or platinum, differ fundamentally from biological materials. Organic bioelectronic devices made from conjugated polymers are promising alternatives for biological sensing applications and aim to improve the interconnection between abiotic electronics and biotic materials. The widespread use of these devices is partly hindered by the limited availability of materials and low-cost fabrication methods. In this thesis, we provide new tools and materials that facilitate the use of organic bioelectronic devices for in vitro sensing applications. We developed a method to pattern the conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate and to fabricate organic microelectronic devices using wax printing, filtering, and tape transfer. The method is low-cost, time-effective, and compatible with in vitro cell culture models. To achieve higher resolution, we further developed a patterning method using femtosecond laser ablation to fabricate organic electronic devices such as complementary inverters or biosensors. The method is maskless and independent of the type of conjugated polymer. Besides fabrication processes, we introduced a newly synthesized material, the semiconducting conjugated polymer p(g42T-T)-8%OH. This polymer contains hydroxylated side chains that enable surface modifications, allowing control of cell adhesion. Using the new femtosecond laser-based patterning method, we could fabricate p(g42T-T)-8%OH-based organic electrochemical transistors to monitor cell barrier formations in vitro. Microphysological systems are further dependent on precise compartmentalization to study cellular interaction. We used femtosecond laser 3D printing to develop a co-culture neurite guidance platform to control placement and interactions between different types of brain cells. In summary, the thesis provides new tools to facilitate the fabrication of organic electronic devices and microphysiological systems. This increases their accessibility and widespread use to interface, monitor, and model biological systems.List of scientific papersI. Rapid prototyping of heterostructured organic microelectronics using wax printing, filtration, and transfer. L. Ouyang*, S. Buchmann*, T. Benselfelt, C. Musumeci, Z. Wang, S. Khaliliazar, W. Tian, H. Li, A. Herland, M. Hamedi. Journal of Materials Chemistry C. 9.41 (2021): 14596-14605. *Equal contribution. https://doi.org/10.1039/d1tc03599a II. Cleanroom-free direct laser micropatterning of polymers for organic electrochemical transistors in logic circuits and glucose biosensors. A. Enrico*, S. Buchman*, F. De Ferrari, Y. Lin, Y. Wang, W. Yue, G. Mårtensson, G. Stemme, M.Hamedi, F. Niklaus, A. Herland, and E Zeglio. Advanced Science. (2024): 2307042. *Equal contribution. https://doi.org/10.1002/advs.202307042 III. In situ functionalization of polar polythiophene based organic electrochemical transistor to interface in vitro models. S. Buchmann, P. Stoop, K. Roekevisch, S. Jain, R. Kroon, C. Müller, M. Hamedi, E. Zeglio, and A. Herland. [Manuscript]IV. Probabilistic cell seeding and non-autofluorescent 3D-printed structures as scalable approach for multi-level co-culture modelling. S. Buchmann*, A. Enrico*, M. Holzreuter, M. Reid, E. Zeglio, F. Niklaus, G. Stemme, A. Herland. Materials Today Bio. (2023): 100706. *Equal contribution. https://doi.org/10.1016/j.mtbio.2023.100706 </p
High mitochondrial DNA levels accelerate lung adenocarcinoma progression.
No full textLung adenocarcinoma is a common aggressive cancer and a leading cause of mortality worldwide. Here, we report an important in vivo role for mitochondrial DNA (mtDNA) copy number during lung adenocarcinoma progression in the mouse. We found that lung tumors induced by KRASG12D expression have increased mtDNA levels and enhanced mitochondrial respiration. To experimentally assess a possible causative role in tumor progression, we induced lung cancer in transgenic mice with a general increase in mtDNA copy number and found that they developed a larger tumor burden, whereas mtDNA depletion in tumor cells reduced tumor growth. Immune cell populations in the lung and cytokine levels in plasma were not affected by increased mtDNA levels. Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.</p
Development and application of modern statistical methods for studies of childbearing among lymphoma survivors
No full textLymphoma is a haematological malignancy commonly originating from B-cells. Each year more than 2,000 new cases are diagnosed in Sweden. Lymphomas are historically categorised into Hodgkin and non-Hodgkin lymphoma. Compared to other cancer forms, Hodgkin lymphoma has a very good prognosis and is especially affecting young adult individuals. Hence, survivors of Hodgkin lymphoma often have a long life ahead after finishing their treatment. But also, many non-Hodgkin lymphoma patients get diagnosed at young ages. Young lymphoma survivors often have not yet finished their family planning, leading to concerns about the impact of treatments and lymphoma on their childbearing. Hence, this thesis aims to investigate childbearing among lymphoma survivors, and develop and apply novel statistical methods to this end where needed.Study I aimed to compare childbirth patterns between young adult classical Hodgkin lymphoma patients treated with intensive chemotherapy treatment (6-8 BEACOPP) and less intensive chemotherapy treatment (ABVD). We identified a cohort of lymphoma survivors diagnosed in Sweden, Denmark, and Norway to estimate hazard ratios and cause-specific cumulative incidence functions of childbirth in the presence of death as competing event, comparing the different treatment regimens. Our study showed that both childbirth rates and cumulative incidences of childbirths after diagnosis were similar in female classical Hodgkin lymphoma survivors treated with ABVD and 6-8 BEACOPP. However, male survivors treated with 6-8 BEACOPP had an estimated 15.9 percentage points lower chance of having children diagnosis compared to males treated with ABVD.Study II aimed to investigate childbirth patterns among non-Hodgkin lymphoma survivors by clinical and histological subtypes. To this end, we utilised data from a matched cohort study of lymphoma survivors diagnosed in Sweden, Denmark, and Norway. Each lymphoma survivor was concurrently matched to 10 (Sweden and Denmark) or 5 (Norway) lymphoma-free comparators from the general population on birth year, sex, and country. We used Cox models to report time-varying hazard ratios, and flexible parametric models to estimate the mean number of childbirths in the presence of the competing risk of death. Overall, we found that non-Hodgkin lymphoma survivors had similar long-term childbirth patterns as their matched comparators, except for patients diagnosed with diffuse large B-cell lymphoma who had a slightly decreased mean number of childbirths up to 10 years after diagnosis.Study III aimed to develop a parametric model for estimating the mean number of events in the presence of competing risks. For this we developed a model that jointly estimates the intensity process of the recurrent and competing event. This model can be used to estimate the mean number of events in the presence of competing risks as well as transformations of the mean number of event function, e.g., difference in the mean number of events and standardised versions thereof. We implemented our model in the R-package JointFPM, which is available on The Comprehensive R Archive Network (CRAN) and tested it under different scenarios in a simulation study. The model showed overall low bias and good coverage in situations in which the intensity function of the recurrent event does not depend on the number of previous events.Study IV aimed to explore patterns of healthcare utilisation in children born to lymphoma survivors. For this, we identified all children born to lymphoma survivors diagnosed between 2000 and 2018 in Sweden and matched them on maternal age to 5 children born to lymphoma-free parents. We used tree-based scan statistic to identify disease and drug prescription clusters associated with increased healthcare utilisation at the pIn conclusion, we found that lymphoma survivors have good chances of having children even after treatment with intensive chemotherapy. Receiving intensive chemotherapy treatment is, however, substantially lowering the chance of having children for male classical Hodgkin lymphoma patients. Having children after being diagnosed with and treated for lymphoma is unlikely to negatively impact the offspring's health. Additionally, we developed and implemented a new parametric estimator of the mean number of events in the presence of competing risks, which offers a useful addition to standard time-to-event analysis.List of scientific papersI Joshua P. Entrop, Caroline E. Weibull, Karin E. Smedby, Lasse H. Jakobsen, Andreas K. Øvlisen, Daniel Molin, Ingrid Glimelius, Anna Marklund, Harald Holte, Alexander Fosså, Knut B. Smeland, Tarec C. El‐Galaly and Sandra Eloranta. ‘Reproduction Patterns among Classical Hodgkin Lymphoma Survivors Treated with BEACOPP and ABVD in Sweden, Denmark and Norway—A Population‐based Matched Cohort Study’. In: International Journal of Cancer 153.4 (15th Aug. 2023), pp. 723–731. https://doi.org/10.1002/ijc.34552II Joshua P. Entrop, Caroline E. Weibull, Karin E. Smedby, Lasse H. Jakobsen, Andreas K. Øvlisen, Ingrid Glimelius, Anna Marklund, Thomas S. Larsen, Harald Holte, Alexander Fosså, Knut B. Smeland, Tarec C. El‐Galaly and Sandra Eloranta. ‘Reproduction Patterns among non‐Hodgkin Lymphoma Survivors by Subtype in Sweden, Denmark and Norway: A Population‐based Matched Cohort Study’. In: British Journal of Haematology 202.4 (Aug. 2023), pp. 785–795. https://doi.org/10.1111/bjh.18938III Joshua P. Entrop, Lasse H. Jakobsen, Michael J. Crowther, Mark Clements, Sandra Eloranta and Caroline E. Dietrich. ‘Parametric Estimation of The Mean Number of Events in The Presence of Competing Risks’. [Manuscript] IV Joshua P. Entrop, V. Wintzell, Caroline E. Dietrich, Ingrid Glimelius, Tarec C. El-Galaly, Karin E. Smedby and Sandra Eloranta. ‘Utilisation of Healthcare in Children Born to Lymphoma Survivors in Sweden’. [Manuscript]</p