Doctoral Theses / Doktorsavhandlingar Institutionen för kliniska vetenskaper

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Safety of opportunistic salpingectomy for ovarian cancer prevention at laparoscopic sterilization
(2025-10-03) Magarakis, Leonidas
Safety of opportunistic salpingectomy for ovarian cancer prevention at laparoscopic sterilization Leonidas Magarakis Department of Obstetrics and Gynecology, Institute of Clinical Sciences Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden Since the first evidence linking ovarian cancer tumorigenesis to the Fallopian tubes emerged, the idea of removing the Fallopian tubes during benign gynecologic surgery as a preventive strategy has gained attention. This approach is appealing due to its relative simplicity and general belief of minimal additional risk. Retrospective observational studies have demonstrated that salpingectomy is associated with greater ovarian cancer risk reduction compared with tubal occlusion procedures. Consequently, opportunistic salpingectomy has increasingly been performed in place of tubal occlusion during sterilization procedures, despite limited evidence regarding its surgical and endocrine safety. Paper I: This thesis first aimed to systematically review the literature and evaluate the evidence on salpingectomy for sterilization. In this review no studies examined ovarian cancer risk. Regarding ovarian function, one randomized controlled trial during Cesarean section found no difference in anti-Müllerian hormone levels after surgery, while two cohort studies using surrogate measures similarly reported no ovarian function changes. Complication rates showed no significant differences between procedures, though assessment and reporting methods varied. Laparoscopic tubal occlusion proved slightly faster than salpingectomy. The certainty of evidence for all these outcomes was rated as low or very low, highlighting substantial remaining knowledge gaps in this field. Paper II: Given the low certainty evidence, a national, register-based randomized trial with non-inferiority design, the SALSTER trial (SALpingectomy for STERilization), was designed and conducted. The Swedish National Quality Register for Gynecological Surgery (GynOp), augmented with additional modules, served as the digital platform for eligibility screening, study information dissemination, informed consent collection, randomization, intraoperative data registration, and postoperative follow-up. SALSTER’s aim was to assess the safety of salpingectomy for laparoscopic sterilization regarding complications and ovarian function. Age at menopause remains the most reliable indicator of ovarian function and is a long-term primary outcome in SALSTER. To provide early insight into potential effects of salpingectomy on ovarian function, anti-Müllerian hormone (AMH) levels were measured preoperatively and one year postoperatively in a subgroup of the cohort. The difference in change in AMH levels between the groups was compared to evaluate the impact of salpingectomy on ovarian function. Paper III: The trial randomized 1,066 participants. Based on imputed data analysis in the per-protocol population, minor and major complications, within eight weeks occurred in 8.1% (38.5/473) of patients undergoing salpingectomy compared with 6.2% (31.0/499) of those receiving tubal occlusion, yielding a risk difference of 1.9 percentage points (95% CI −1.4 to 5.3). The primary outcome demonstrated that salpingectomy did not increase complication rates beyond the predefined non-inferiority margin, confirming its safety profile relative to tubal occlusion. Salpingectomy required a longer operative time compared with tubal occlusion (44 vs. 29 minutes), with a mean difference of 16 minutes (95% CI 14 to 18). Paper IV: A nested sub-study enrolled 147 participants, of whom 135 (91.8%) met per-protocol criteria. Follow-up blood samples were collected from 75 participants (55.5% of eligible cases). In the complete case analysis, the adjusted mean difference in AMH change was 0.04 μg/L (95% CI −0.63 to 0.71). While both groups exhibited comparable AMH decline, the study could neither establish nor refute non-inferiority. This study addresses a critical gap by providing high-quality evidence on the perioperative safety of laparoscopic opportunistic salpingectomy for sterilization. The follow up of SALSTER will generate essential data on the procedure’s endocrine safety profile, evaluating whether salpingectomy is non-inferior to tubal occlusion in preserving ovarian hormone function. These findings will support clinicians in shared decision-making, while future research investigates salpingectomy’s potential role in ovarian cancer prevention, a disease typically diagnosed at advanced stages with poor survival outcomes.
From Percutaneous to Transcutaneous Hearing Implants: Surgical Techniques, Osseointegration, and Microbiological Insights
(2025-09-30) Ganeyev, Marsel
From the moment a person decides to change their life and steps into the operating room to (re)gain one of the most vital senses—hearing—through to their return to daily routines, multiple factors shape both the decision-making process and overall experience. Thus, optimising functional outcomes in implantable bone conduction devices (BCD) requires a patient-centred approach that integrates clinical insights with advanced diagnostic, surgical, and analytical methods to examine the interplay between biological responses, surgical execution, and the microbiome. This thesis explores these aspects in four studies. Paper I analyses retrieved percutaneous implants, linking clinical symptoms with structural, histological, and microbiological findings. Paper II investigates the peri-abutment microbiome, showing how staphylococcal colonisation, biofilms, and antibiotic resistance drive soft tissue complications. Paper III evaluates the mechanical and thermal effects of different drilling protocols on bone trauma. Lastly, Paper IV introduces a surface-modified transcutaneous implant and a less invasive implantation alternative with translational potential. The first two studies expand our understanding of tissue–implant interactions by investigating the role of the colonising microbiome and integrating clinical findings with structural and microbiological analyses. Findings from Paper I revealed that pain and infection are the most common factors affecting implant success and are influenced by both patient-related and microbiological factors. Paper II demonstrated that biofilm formation and antibiotic resistance in staphylococci colonising percutaneous implants are key drivers of adverse soft tissue outcomes. Paper III examined the thermal and mechanical effects of a single-drill system, highlighting its impact on heat generation and bone preservation. Finally, Paper IV identified surgical bone preparation—rather than surface modification—as the determining factor in early new bone formation and fibrous encapsulation, extending research strategies established in percutaneous implants to transcutaneous implants and providing new evidence to guide their future clinical development. Together, these results support evidence-based refinements in BCD practice and guide the development of next-generation implants with greater longevity, fewer complications, and improved patient outcomes.
Detection and surveillance of exogenous contamination in orthopaedic surgery
(2025-09-29) Stålfelt, Frans
Surgical site infection (SSI) after orthopaedic implant surgery is a serious complication that may result in patient morbidity, prolonged rehabilitation and increased mortality. SSIs also impose considerable economic burden on the healthcare system, as extended resources are needed for these patients. To reduce the risk of SSI, more effective infection prevention strategies are needed. The papers compiled in this thesis contribute to that effort by assessing how airborne bacterial contamination, also referred to as exogenous contamination, affects SSI outcomes in the operating room (OR), by identifying and analysing risk scenarios for particle emissions during surgeries. Conventional methods for measuring exogenous contamination consist of collecting bacterial air samples in the OR, expressed as colony forming units (CFU). Conventional methods are, however, time and resource demanding. The objective of Paper I was to evaluate previously published research investigating the correlation between real-time particle counting and CFU conducted by conventional active air sampling techniques. The paper was designed as a systematic review with narrative synthesis. The results from the reviewed articles were inconsistent and not fully comparable due to differences in applied methodologies. Paper I concludes that while particle counting may have the ability to offer fast and valuable insights on the overall level of exogenous contamination in the OR, more research is needed to further clarify the association between particle counts and CFU. A more modern method to assess exogenous contamination is by utilizing biofluorescent particle counters (BFPCs), which can distinguish between biological and non-biological particles. The aim of Paper II was to analyse the correlation between CFU and biofluorescent particles sampling methods, and to assess the validity of using BFPC as a potential surrogate for exogenous risk assessments. The results demonstrated no significant correlation between the two methods, indicating that BFPC measurements should be interpreted with caution when evaluating the risk for SSI during surgeries. Further validation is needed for BFPCs to be used as a replacement for conventional exogenous risk assessments. Paper III aimed to evaluate the effectiveness of a newly developed surveillance system for monitoring exogenous contamination in ORs. The paper investigated two scenarios believed to influence particle emission and influx: intraoperative team shift changes and the implementation of reusable surgical sheets. The results showed that team shift changes significantly increased the influx of particles, while reusable sheets were associated with reduced particle emissions compared to disposable options. Paper III concluded that there is great potential for the surveillance system to detect high-risk scenarios that may pose a risk for exogenous contamination in the OR. Building on the surveillance system introduced in Paper III, Paper IV aimed to evaluate how OR staff behaviours influence the particle emission and influx in the OR, as well as the risk of SSIs caused by those behaviours. The study focused on three variables: the number of staff members present in the OR, the frequency of intraoperative door openings and the duration of the surgery. The results showed that a higher number of staff members present was associated with increased particle levels, however number of people present did not differ significantly between SSI and no-SSI cases. Furthermore, the results demonstrated that door openings occurred more frequently and surgeries were longer for those operations that resulted in SSIs. These findings underscore the importance of implementing a surveillance system which can provide feedback to the OR staff on intraoperative behaviours, as part of an effective infection prevention strategy.
On tibial plateau fractures Gait function and patient experiences
(2025-09-18) Fändriks, Anna
Clinical and scientific experience has shown that some patients with tibial plateau fractures face persistent issues long after the injury, posing challenges for patients and healthcare providers. The primary aim of this thesis is to comprehensively understand both the objective and subjective aspects of recovery following tibial plateau fractures, focusing on gait function assessed through three-dimensional marker-based motion capture (MOCAP) analysis and patient experiences of the rehabilitation process, captured through qualitative interviews. A validation study (Study I) compared MOCAP analysis with radiostereometric analysis (RSA) for assessing dynamic knee movements (n=12). Studies II (n=20) and III (n=26) followed patients with surgically and non-surgically treated tibial plateau fractures over three to 24 months, utilizing MOCAP analysis. At three months, knee function was also evaluated through a 6-minute walk test and range of motion (ROM) in the knee joint. In Study IV (n=19), surgically treated patients were interviewed 24 months post-injury about their rehabilitation experience, with interviews analysed using qualitative content analysis. Compared with RSA, knee flexion was underestimated using MOCAP analysis, a factor to consider when reviewing patient data. In Studies II and III, patients showed difficulties achieving full knee extension during gait. While knee power generation improved over time, ROM did not show significant improvement six months post-injury. Two themes emerged from the interviews: (i) the desire for individualised care, and (ii) the physical and psychological changes experienced from the time of injury onwards. Patients with tibial plateau fractures continue to experience difficulties up to two years post-injury. While knee power generation improves after six months, range of motion remains limited. Many patients report ongoing challenges, although much of their daily function has returned to normal. Additionally, instrumental gait analysis is considered a valid method for measuring dynamic knee flexion and extension during gait, despite a tendency to underestimate actual movement.
Studies on overdiagnosis in prostate cancer screening
(2025-08-29) Palmstedt, Emmeli
Overdiagnosis can have long-term consequences for both individuals and society, making it an important concern in the context of prostate cancer screening. The overall aim of this thesis was to explore different perspectives on overdiagnosis, from knowledge and understanding to strategies that can reduce the harm of overdiagnosis. Paper I used data from the Göteborg-1 trial to investigate if follow-up with biennial PSA testing is sufficient after an initial benign biopsy for men participating in screening. After 20 years of follow-up, prostate cancer mortality was 1.4%, suggest-ing that biennial testing is safe. Paper II evaluated how participants in the Göteborg-2 trial perceived their lifetime risk of prostate cancer. On average, men overestimat-ed their risk by 10 percentage points. Lower urinary tract symptoms and erectile dysfunction were associated with higher perceived risk, indicating a need for im-proved information. Paper III assessed long-term outcomes of active surveillance in men with screen-detected prostate cancer within the Göteborg-1 trial. Prostate can-cer-specific survival was 94% at 25 years, and treatment-free survival was 38% at 22 years, providing strong evidence that active surveillance is a safe long-term man-agement strategy. Paper IV explored men’s understanding and awareness of overdi-agnosis, and how it affected their willingness to participate in prostate cancer screen-ing. The results showed that prior awareness of overdiagnosis was low, and only 4 out of 10 men could correctly identify the concept after receiving detailed infor-mation. Willingness to participate in screening was significantly higher in a screen-ing scenario with 25% overdiagnosis compared to one with 75%, suggesting that the degree of overdiagnosis influences decision-making, even though the concept is difficult to understand. Overall: Overdiagnosis presents both clinical and communicative challenges in prostate cancer screening. Its negative consequences can be reduced through evi-dence-based screening regimes and surveillance strategies but most importantly, clear and accessible information must be provided so that men can make well-informed decisions about whether to undergo PSA testing or not.
Image-based kidney dosimetry for [177Lu]Lu-DOTATATE treatments Development, validation, and assessment of quantification accuracy and precision
(2025-08-28) Khan, Jehangir
This thesis aims to develop, validate, and evaluate methods for accurate and precise image-based kidney dosimetry in patients with neuroendocrine tumours (NETs) treated with [177Lu]Lu-DOTATATE. Special focus is placed on quantifying and reducing uncertainties in kidney dose estimation. In paper I, an automatic segmentation method for the whole kidney parenchyma (WKP) was developed using a convolutional neural network (CNN). The CNN-based segmentation demonstrated performance comparable to manual (CT-based) segmentation, with a strong correlation in activity concentration measurements (r > 0.96, p < 0.01) indicating its suitability as an alternative for clinical dosimetry workflows. In paper II, the small-volume-of-interest (SV) method was optimized by adjusting VOI size and increasing the number of VOIs per kidney. This reduced dose estimation uncertainty from 14% when using a single 4 mL SV to 8.3% when using five 2 mL SVs, compared to the WKP method used as the reference. Papers II & III established a clinically feasible routine for calculating patient-specific recovery coefficients (RCs) using Monte Carlo simulations, reducing RC-related uncertainty by up to 4% compared to the fixed RC of 0.85 recommended by EANM guidelines. Paper III quantified anatomical changes in kidney volume (up to 10.77%) during treatment due to amino acid infusion. These changes were shown to result in absorbed dose overestimation of up to 2.5% when a single-timepoint CT segmentation was propagated across serial SPECT scans. In paper IV, a novel framework was introduced that uses an empirical power-law model to quantify the accuracy of WKP-based kidney dosimetry using SV data. The model demonstrated a relative precision of 7.27% for 2 mL SV and 6.92% for 0.6 mL SVs. In conclusion, this work presents a systematic evaluation of image-based kidney dosimetry methods, identifying key sources of uncertainty and demonstrating how they can be mitigated through optimized VOI strategies, patient-specific recovery correction, and CNN-based segmentation. A quantitative framework for estimating relative accuracy was also introduced, supporting the development of robust and clinically feasible dosimetry practices for individualized molecular radiotherapy in NET patients.
Development of novel biomarkers for brain injury and neurodevelopmental outcome in birth asphyxia
(2025-08-28) Toorell, Hanna
Background: Hypoxic-ischemic encephalopathy (HIE) in term infants following intrapartum asphyxia remains an important problem occurring in 1-3 of 1000 births with high risk of cerebral palsy, cognitive impairment and functional disability later in life. Therapeutic hypothermia (TH) is the only treatment available today for HIE. To be effective TH must start within 6 hours from delivery. It is not always possible to diagnose HIE in this time frame which can lead to infants at risk of developing brain injuries not receiving TH in time. Antecedent infections are known to increase the risk of adverse outcome. It would therefore be helpful to find biomarkers to assist in early identification of both asphyxia/HIE and infection. Aim: Explore novel biomarkers of brain injury and inflammation/infection in the umbilical cord blood (UCB) to assist in the early identification of cases with HIE and to evaluate association between the biomarkers and neurodevelopmental outcome at 19-42 months of age. Material and methods: In Paper I, II and IV we have analysed UCB levels of biomarkers in neonates with HIE, with asphyxia without HIE and healthy controls without asphyxia and HIE. The concentration of biomarkers was measured and correlated to asphyxia and to the degree of HIE (mild, moderate and severe) and neurodevelopmental outcome at 19-42 months of age. Paper III is a systematic review summarising the research done over the last decades on biomarkers in UCB and their associations with HIE and neurodevelopmental outcome. Results: In Paper I we found that the neuro-specific biomarkers NFL and tau were significantly higher in UCB in neonates with asphyxia compared to a healthy control group. In Paper II we showed that NFL, tau, GFAP and several cytokines were significantly higher in infants with moderate and severe HIE compared to a healthy control group and provided moderate prediction of moderate and severe HIE. The systematic review, Paper III, revealed that there were several studies highlighting promising biomarkers in UCB that could be subjects for future studies, both individually and in combination with existing clinical markers. We also concluded that it can be critical to distinguish between arterial and venous blood. In Paper IV we found an association between levels of immunoinflammatory biomarkers and growth factors and abnormal neurodevelopmental outcome at 19-42 months of age. Conclusion: This thesis concludes that there are several neuro-specific and immuno-inflammatory biomarkers in UCB that can assist in early identification of HIE and long-term neurodevelopmental outcome.
Vasopressin for prevention of blood loss during liver surgery; physiological and clinical studies.
(2025-08-26) Wisén, Ellinor
Background: Hepatic resection is a major surgical procedure, with risk of substantial blood loss and need for blood transfusion. Blood loss and red blood cell transfusion are associated with postoperative morbidity and mortality, including time to recurrence of cancer. Various strategies are used to reduce blood loss, such as mechanical vascular occlusion and low central venous pressure anesthesia. Vasopressin is a non-adrenergic vasoconstrictor with prominent effects on the splanchnic circulation, used in treatment of vasoplegia in septic shock, but not previously evaluated in hepatic resection. Aim: The aim of this thesis was to describe the effects of vasopressin on hepato-splanchnic hemodynamics, blood loss, transfusion requirements and postoperative outcomes during liver resection. Methods: In Paper I, the effects of vasopressin and nitroglycerin on portal and hepatic venous pressure and portal and hepatic venous blood flow, were evaluated in an experimental study on 13 patients. In Paper II, the change of biomarker levels compared to baseline were described in 18 patients scheduled for hepatic resection, and the feasibility of a larger trial was assessed. Paper III described the protocol for a randomized, placebo-controlled double-blinded trial, comparing effects of vasopressin and placebo on blood loss, transfusion requirements and postoperative outcomes in hepatic resection. The trial included 270 patients, and the results are presented in Paper IV. Results: Vasopressin did not affect the portal pressure but reduced the portal blood flow by 47% (SD 19%). Addition of nitroglycerin reduced the portal blood flow further, by 55% (SD 13%) and the hepatic venous blood flow by 30% (SD 13%). The portal pressure was reduced below baseline, but at the cost of hemodynamic instability. In Paper II, creatinine, troponin and lactate increased after hepatic resection, but there was no difference in biomarker levels between the vasopressin and placebo groups in Paper IV. In Paper IV, blood loss at the end of surgery was median 450 ml (min 5; max 26500) in the argipressin group vs median 500 ml (min 10; max 10 000) in the placebo group, RR 0.90 (95% CI: 0.70-1.17). The number of patients who required blood transfusion during the study period was 43 (36.8%) in the vasopressin group and 52 (41.3%) in the placebo group, OR 0.84 (95% CI 0.48-1.49). There were less complications in the vasopressin group at 30 days after surgery, primarily due to less postoperative infections. Conclusion: Vasopressin reduces portal and hepatic blood flow, but this effect does not translate to reduced blood loss or transfusion requirements after hepatic resection performed with low central venous pressure anesthesia and use of Pringle maneuver. The vasopressin-group had less complications at 30 days after surgery.
Health and performance among Swedish climbers: Exploring the challenges affecting mental well-being, injury, and athletic Development
(2025-08-25) Identeg, Fredrik
Climbing has, in the recent decades developed rapidly both as a recreational activity and a competitive sport. The rapid growth of the number of participants, increased media attention, and the sport’s inclusion in the Olympic Games in 2020 has facilitated this expansion. As the sport of climbing matures, there is a growing awareness of health issues associated with the sport. As the transformation of climbing into a mainstream activity and an athletic discipline is in its early stages, scientific research on climbing-related health conditions is still limited. The overall aim of this thesis was to investigate sports-related health issues, previously identified in more established sports, within the context of climbing. Study I is a cross-sectional study, investigating the prevalence of radiographic spinal changes in climbers using Magnetic Resonance Imaging (MRI). The occurrence of spinal changes was compared with a non-climbing control group. No significant differences between the groups could be displayed in terms of spinal changes. The overall occurrence and the severity of spinal changes were low in both groups. Study II is a systematic review examining current practices in MRI classification systems used when examining spinal changes in athletes. The results showed that the use of established classification systems was limited and lacked consistency when examining spinal changes in general athlete cohorts. Study III is a cross-sectional survey-based study examining depressive symptoms, sleep quality, stress, anxiety, and overuse injuries in advanced and elite climbers, compared with non-climbing controls. The results displayed substantial symptoms of mental health problems as well as poor sleep quality in climbers and controls. No significant differences were however found between climbers and controls, nor between advanced and elite rock climbers. Fingers and hands were the most common injury location, with 16.5% of the climbing participants currently experiencing substantial problems. 4 ABSTRACT Study IV is a cross-sectional study examining disordered eating, body dissatisfaction, and climbers’ perceptions of the importance of leanness and low body weight in relation to climbing performance. The climbing group was compared with non-climbing controls. Non-climbers reported significantly higher levels of body dissatisfaction compared with the climbing group. No significant difference was recorded in terms of eating disorders between climbers and non-climbers. Study V is a validation-study of methods for examining maximal finger strength testing, a key indicator of bouldering performance. The study examined six commonly used grip positions among male climbers in the climbing discipline of bouldering. Strength in the half-crimp position was demonstrated the most important performance indicator in the sample, explaining 57% of the variance in bouldering performance. Together, this grip position and the position Front three drag accounted for 66% of the variance in performance. The study provides a dependable and easily reproduceable method for measuring maximum finger strength among bouldering athletes. In summary, climbing athletes experience symptoms of mental ill-health at a high prevalence, but seemingly at a similar level as non-climbers. Widespread ideas of the importance of low body weight for performance are prevalent and alarming. Degenerative changes of the spine were not more prevalent in climbing athletes, but the study was limited by sample size. Given that most observed abnormalities in climbers were minor, climbing does not seem to pose a major risk for the development of these changes. Established classification systems for spinal changes, along with the development of quantitative classification methods are needed to further advance research in this field. Finger strength is a key factor in climbing performance, and the method for assessing finger strength presented in this thesis is applicable for evaluating and improving performance of athletes in the sport.
Child predisposition to attention-deficit/hyperactivity disorder, autism spectrum disorder, and obesity: Predictive variables in the first year of life and growth patterns in a population-based context
(2025-05-23) Fast, Karin
The prevalence of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) has increased in the last decades, together with childhood obesity. These conditions often co-occur and may share early biological, environmental, and behavioural risk factors. This thesis explores early predictors and growth patterns to improve early identification and prevention. Four studies are included: Paper I is a clinical review of changes in body mass index (BMI) in 118 children treated with stimulants for ADHD. Papers II–IV use data from a Swedish population-based birth cohort (n=2,666) to analyse the prevalence and predictors of ADHD and ASD, as well as the impact of breastfeeding. Paper IV also report on early growth in relation to later neurodevelopmental and BMI outcomes. Key findings include that nearly half of children with ADHD and comorbid overweight or obesity reached normal weight after stimulant treatment was initiated. In the population-based birth cohort, the prevalence of ADHD and ASD at age twelve was 7.6% and 1.1%, respectively. Preterm birth, maternal smoking, high maternal BMI, and lack of breastfeeding at three and six months were associated with ADHD in offspring. An earlier adiposity rebound was observed in children with higher BMI at age ten. No statistically significant different growth patterns were associated to ADHD nor ASD. Conclusion: ADHD, ASD, and obesity appear to share early-life risk factors and developmental pathways. Stimulant treatment may offer dual benefits in children with ADHD and obesity. Growth monitoring and early behavioural indicators, such as feeding patterns and self-regulation difficulties, may help identify children at risk. These results emphasise the need for integrated, family-centred, and interdisciplinary approaches in early child health surveillance and intervention.
Mannitol - a new-old marker for measuring glomerular filtration rate
(2025-05-22) Kiss, Katalin
Mannitol – a new-old marker for measuring glomerular filtration rate ABSTRACT Acute kidney injury is a serious complication in critically ill patients, associated with increased morbidity and mortality. Furthermore, chronic kidney disease (CKD) is a growing global health-care concern. In many clinical situations, assessing kidney function through glomerular filtration rate (GFR) may significantly improve patient care. However, access to standard GFR measurement methods is often limited, particularly in patients in the intensive care units (ICU). Thus, GFR is typically estimated (eGFR), using equations based on blood levels of creatinine and/or cystatin C, which can potentially introduce various sources of error. This research project revisits an older concept: using mannitol as a potential marker for measuring GFR. Mannitol fulfils essential criteria for such use, as it is filtered by the kidneys without being metabolized or reabsorbed. It is inexpensive, easy to use, and has no known adverse effects. The recent availability of a highly sensitive analysis method, liquid chromatography–tandem mass spectrometry (LC-MS/MS) enables accurate measurements of plasma mannitol. Patients and methods: In Study I, GFR was assessed using mannitol and 51Cr-EDTA clearances with bolus injection technique in outpatients with normal GFR or CKD stages 1–4 (n=41). In Study II, eGFR using the CKD-EPI or Lund-Malmö formulas was compared to GFR measured with 51CrEDTA or iohexol in two groups: ICU patients (n=43) and outpatients (n=48). In Study III, mannitol GFR and iohexol GFR were compared in 2 groups, ICU (n=20) and outpatients with CKD stages 3-4 (n=20). Mannitol concentrations were analyzed using an enzymatic method in Study I and mass-spectrometry (LC-MS/MS) in study III. Results: A good agreement and very good accuracy were observed when mannitol and 51Cr-EDTA clearance were compared in an outpatient group (Study I). The generally used estimation equations, based on creatinine and cystatin C, alone or in combination, using the CKD-EPI or Lund-Malmö formulas performed poorly in the ICU patient cohort. In comparison, in a group of outpatients the formulas showed a good agreement and accuracy when using combination of creatinine and cystatin C (Study II). Mannitol performed well as a clearance marker in an ICU patient cohort in comparison with iohexol clearance as a reference method, showing good agreement and accuracy, despite two outliers. The agreement and accuracy in the outpatient group with CKD stages 3-4, was excellent (Study III). Conclusion: The studies support the use of mannitol plasma clearance as a promising, reliable and practical alternative for assessing measured GFR, particularly when using LC-MS/MS. Further studies in larger, diverse patient cohorts are warranted to validate this method. Keywords: mannitol, glomerular filtration rate, measured GFR, estimated GFR, LC-MS/MS, clearance, creatinine, cystatin C, kidney function, chronic kidney disease.
Diffusion MRI for tumor microstructure imaging using VERDICT modeling
(2025-05-20) Lundholm, Lukas
VERDICT is a method which uses a mathematical model that provides estimates of microstructural tumor tissue parameters based on diffusion-weighted MRI data. It is a promising imaging method for non-invasive in vivo evaluation of whole-tumor tissue. However, model assumptions may introduce systematic errors in parameter estimates. The aim of this thesis was to assess the use of VERDICT for tumor tissue evaluation and investigate the impact of model assumptions on parameter estimates, as well as to develop and evaluate methods addressing accuracy issues related to some of these assumptions. The standard clinical approach for evaluating tumor treatment response is by measuring changes in gross tumor volume. However, such changes can be slow, and methods sensitive to microstructural changes may detect response earlier. Paper I investigates the use of VERDICT parameters for radiation treatment response assessment and shows that early parameter changes correlate with treatment outcome. Histological analysis remains the gold standard for assessing tumor microstructure, but tumor heterogeneity limits biopsy representativeness. Paper II explores the use of VERDICT for whole-tumor tissue classification as a potential complement to histology. The work shows that multidimensional cluster analysis of VERDICT parameters enables classification of distinct tumor tissue types. Model assumptions can introduce systematic errors in parameter estimates. Paper III investigates the effect of assumptions related to extracellular–extravascular diffu-sion and presents a Monte Carlo-based model which explicitly accounts for diffusion time dependence. Paper IV investigates the impact of including compartment-specific T2 relaxation in the model, in contrast to uniform T2 relaxation across compartments as assumed in conventional VERDICT. These works show that model assumptions can significantly influence parameter estimates and present methods to mitigate their effects. In conclusion, the results of this thesis highlight the importance of accurate model assumptions in VERDICT, and demonstrate the model’s potential for non-invasive, whole-tumor evaluation of tumor tissue in various applications.
Becoming an Anaesthetist – Making the Implicit Explicit in Specialty Training
(2025-05-20) Chin, Hanna
This thesis explores the qualitatively different ways anaesthetists understand learning—both formal and informal—within postgraduate anaesthesia education. Using a phenomenographic approach, it investigates how anaesthetists in Sweden and England experience their educational journeys, with attention to explicit, implicit, relational, and contextual aspects of learning. The thesis comprises four studies: • Study I identifies variation in how Swedish anaesthetists conceptualise learning, ranging from acquiring procedural competencies to developing adaptive expertise and professional judgement. • Study II explores perceptions of professional identity, revealing orientations such as striving to meet external expectations, learning through collaboration, and taking ownership as self-directed caregivers. • Study III investigates how anaesthetists in England’s competency-based training programme experience learning—ranging from structured progression through assessments, to integrated clinical learning, to reflective, experience-driven development. • Study IV examines how trainees engage with the implicit curriculum in both countries. Some focus primarily on formal structures, while others describe the importance of interpersonal dynamics, workplace culture, and unspoken norms in shaping professional growth. Together, these studies reveal that anaesthetists experience learning not as a linear path to competence, but as a dynamic, multifaceted process shaped by social, cultural, and contextual factors. The findings highlight the critical role of the implicit curriculum and professional identity formation, offering practical implications for curriculum design, assessment strategies, and faculty development. Keywords: Anaesthesia education, Learner experiences, Curriculum
Image-Based Dosimetry in Targeted Radionuclide Therapy with Terbium-161: From Technical Foundations to Clinical Application
(2025-05-15) Westerbergh, Frida
This work explores SPECT/CT-based quantification of the novel therapeutic radionuclide terbium-161 (161Tb). The interest in 161Tb stems from its substantial emission of low-energy conversion and Auger electrons, hypothesized to enhance the treatment of microscopic cancer disease. In Paper I, technical aspects of 161Tb imaging were investigated through phantom studies, demonstrating the feasibility of accurate quantification. A medium-energy collimator combined with a 75 keV ± 10% energy window was found preferable, which was attributed to reduced degradation from dead time, septal penetration, and scatter. These effects were further examined in Paper II through characterization of a clinical SPECT/CT system, confirming that 161Tb imaging is particularly susceptible to dead-time effects, owing to the emission of high-intensity X-rays and penetration from high-energy, low-yield γ-photons. These limitations were mitigated by employing a medium-energy collimator, rather than a low-energy one. In Papers III and IV, quantitative 161Tb SPECT/CT imaging was applied in two first-in-human clinical studies, evaluating novel 161Tb-labeled radioligands for neuroendocrine and prostate cancer, respectively. In both studies, initial dosimetry results indicated favorable therapeutic indices compared to clinically available 177Lu-labeled alternatives. Together, these studies underscore both the limitations and potential of 161Tb SPECT/CT imaging, contributing to the groundwork for its future clinical implementation.
Simulated Daylight Photodynamic Therapy for Superficial Basal Cell Carcinoma and Actinic Keratoses
(2025-05-13) Sjöholm, Alexandra
The overall aim of this thesis was to evaluate simulated daylight photodynamic therapy (SDL-PDT) for the treatment of actinic keratoses (AKs) and superficial basal cell carcinoma (sBCC). The included studies assessed this novel lighting system from multiple perspectives. A technical validation study determined whether the light intensity achieved with SDL-PDT met theoretical treatment requirements. Additionally, two randomized controlled trials (RCTs) compared the effectiveness of SDL-PDT and C-PDT in the treatment of sBCC and mild to moderate AKs. Finally, a qualitative study explored patients’ experiences with the two treatment methods. Paper I presents the results of the technical validation study, in which the illuminance of SDL-PDT was evaluated at different angles and distances relative to the light sources. The findings underscore the importance of correct patient positioning, with optimal illumination achieved at angles of 0°-45°, while 90° angles resulted in inadequate exposure. Papers II and III report the outcomes of two RCTs comparing SDL-PDT and conventional PDT (C-PDT) for sBCC and AKs, respectively. After one year, clearance rates were significantly higher with C-PDT for both sBCC (91.8% vs. 62.4%) and AKs (85.3% vs. 71.0%). Paper IV presents a qualitative interview study conducted four weeks post-treatment with participants from the AK trial. The study revealed that while C-PDT caused severe pain and prolonged post-treatment reactions impacting daily life, SDL-PDT was associated with only mild discomfort and skin reactions. Most participants preferred SDL-PDT over C-PDT, although concerns about its long-term effectiveness were also expressed. This thesis highlights the importance of optimal patient positioning for effective SDL-PDT treatment and emphasizes the need to balance treatment effectiveness with patient experience. While SDL-PDT offers a less painful alternative, its effectiveness is lower than that of C-PDT for treating sBCC and mild to moderate AKs.
From extra-skeletal bone growth to re-osseointegration: Osteoinduction and mechanical disruption in bone repair
(2025-05-13) Jolic, Martina
The effort to preserve the integrity and function of the skeletal system has driven scientific innovation for centuries. Clinical challenges—such as tooth loss, joint failure, limb amputation, and large bone voids caused by congenital defects, trauma, disease, or surgery—can be addressed with biomaterials. However, no single material can fully replicate the biological and mechanical complexity of bone across diverse anatomical locations. This thesis investigates two aspects of bone regeneration using clinically relevant biomaterials: (i) the capacity of calcium phosphates (CaPs) to induce heterotopic bone formation both in association with and distant from the skeleton (Papers I-II) and (ii) the biological response to mechanical overload in osseointegrated titanium (Ti) implants, with a focus on re-osseointegration (Papers III-IV). Bone formation, remodelling, and repair processes were studied in two animal models—sheep and rats—and three anatomical locations: the occipital bone, soft tissue, and long bone, using complementary histological, microscopic, and spectroscopic techniques. Papers I and II investigated bone formation in response to multicomponent CaPs composed of monetite, β-tricalcium phosphate, and calcium pyrophosphate (Ca-PP). In Paper I, CaP constructs implanted on the occipital bone of sheep induced bone formation via endochondral and intramembranous ossification. The newly formed bone resembled native bone in structure and composition and showed signs of long-term remodelling. In Paper II, subcutaneous implantation revealed that while increasing Ca-PP content did not inhibit bone formation or accelerate material degradation, it negatively affected bone quality. The long-term persistence of heterotopic bone appeared to be dependent on the continued presence of the CaP material. While CaPs are widely used in non-load-bearing bone repair, metal implants remain the clinical standard for load-bearing skeletal reconstruction. Papers III and IV investigated the impact of mechanical overload on Ti implants and the potential for re-osseointegration. In Paper III, a new rat model simulated overload via snap-disruption of osseointegrated Ti implants. Four weeks after disruption, re-osseointegration was confirmed, with restored biomechanical stability. Paper IV examined the biological cascade following overload, revealing a staged regenerative process leading to re-osseointegration. This thesis demonstrates how CaPs promote bone formation beyond the skeletal envelope and how Ti implants can re-osseointegrate after mechanical failure. These findings offer valuable insights into the adaptive capacity of bone to improve bone-biomaterial performance and support regenerative and reconstructive applications in clinical settings.
Enhancing the Management of High-Risk Basal Cell Carcinoma
(2025-05-13) Ceder, Hannah
Basal cell carcinoma (BCC) is the most common skin cancer, with over 71,000 new cases in Sweden in 2023. High-risk facial BCCs are most appropriately treated with Mohs micrographic surgery (MMS), which is considered the gold standard. However, MMS is rarely performed in Sweden due to resource constraints leading to high rates of incomplete excisions and recurrences. The four papers in this thesis address key topics related to high-risk BCCs including risk factors associated with incomplete excisions, differences in outcomes following MMS for primary and previously treated high-risk BCCs, their dermatoscopic features and the feasibility of hyperspectral imaging for tumor delineation prior to MMS. In Study I, clinical and histopathological risk factors for incomplete excision of high-risk BCCs were evaluated. In our cohort, the overall incomplete excision rate was 20.6%. BCCs located on the nose, ear, scalp, and periorbital areas as well as BCCs with high-risk histopathological subtypes exhibited the highest proportions of incomplete excisions. In study II, we found that primary facial high-risk BCCs required fewer MMS stages and had smaller wound areas after complete surgical removal compared to BCCs that had been treated previously. In Study III, we investigated which clinical and dermoscopic findings characterize high-risk BCCs. A bumpy surface, poorly defined borders, the dermoscopic presence of ‘white porcelain area’ and/or ‘vessels within ulceration’ were indicative of high-risk BCCs. An algorithm was developed for predicting high-risk BCCS preoperatively with a sensitivity of 81.4% and a specificity of 53.3%. Study IV was a prospective pilot study assessing the feasibility of hyperspectral imaging using supervised learning of a convolutional neural network to preoperatively delineate the lateral margins of high-risk BCCs prior to MMS. Hyperspectral imaging achieved a pixel-wise classification accuracy of 0.76, a sensitivity of 0.75, a specificity of 0.78, and an area under the receiver operating characteristic curve of 0.84. In conclusion, the results of this thesis contribute to an expanded understanding of the factors affecting treatment outcomes for high-risk BCC. Better preoperative diagnostics, such as clinical and dermatoscopic findings, are needed to correctly identify high-risk BCC candidates for MMS instead of undergoing incomplete excisions due to traditional surgery. This knowledge ensures that patients receive the most effective treatment from the start. Preoperative margin delineation using hyperspectral imaging could potentially decrease the number of MMS stages required and, in situations where MMS is not an option, it may help reduce the need for additional surgeries in traditional surgery.
Personalized analysis of circulating tumor DNA in childhood malignancies
(2025-05-08) Rahmqvist, Ida
Circulating tumor DNA (ctDNA) analysis has emerged as a powerful technique for precision medicine in pediatric oncology. ctDNA refers to small fragments of tumor-derived genetic material that are released into the bloodstream. ctDNA analysis can enable sensitive monitoring of treatment response, early detection of relapse, and detection of minimal residual disease. Previous studies have used generic cancer gene panels for ctDNA analysis in children which has proven to be challenging in pediatric patients who differ in genotype from adult cancers. In paper I, five patients with relapsed or refractory ALK-driven neuroblastoma were treated with lorlatinib. All patients showed a good response and four were alive three to five years after lorlatinib was started. To investigate if ctDNA analysis could provide a more sensitive method for monitoring residual disease we designed an ALK sequencing panel for sensitive detection of the ALK mutations found in this patient group as well as those mediating resistance to tyrosine kinase inhibitors. ctDNA levels showed a stepwise decline and became negative during lorlatinib treatment in all patients. For two patients with relapsed disease, an increase in ctDNA levels could be seen three and nine months before the clinical relapses, respectively. In paper II and III, we developed personalized sequencing panels for patients diagnosed with neuroblastoma and rhabdomyosarcoma, respectively. We used an ultrasensitive sequencing technique for retrospective longitudinal ctDNA analysis to evaluate the use of ctDNA as a tumor marker. In both studies, ctDNA analysis of patient plasma showed that ctDNA levels at diagnosis correlated with risk group and disease burden. For patients with good response to treatment, ctDNA levels gradually decreased. Follow-up samples from patients who were free from disease were all ctDNA negative. Levels of ctDNA were elevated in all cases of relapse or disease progression. In paper II, one case showed detectable ctDNA 78 days before the clinical relapse. In paper III one patient showed elevated ctDNA levels in several samples five months prior to clinical relapse. In summary, we show that we can accurately and sensitively monitor disease burden using our ALK panel in patients with ALK-driven neuroblastoma and lorlatinib monotherapy shows long-lasting results in this patient cohort. We show that personalized ctDNA analysis is a sensitive and accurate method for longitudinally monitoring of disease burden and detection of relapse in pediatric neuroblastoma and rhabdomyosarcoma, regardless of tumor genetics. ctDNA analysis showed higher sensitivity for relapse detection and treatment monitoring than two serum markers and three urine markers currently used in the clinic for neuroblastoma. As there are no biomarkers in use for rhabdomyosarcoma and the disease is often highly genetically heterogenous showing poor prognosis in metastasized disease, personalized ctDNA analysis could prove a useful complement in disease monitoring and relapse detection also for these patients.
Allergic Rhinitis in Childhood and Young Adulthood: Epidemiology, Prevalence and Risk Factors
(2025-05-08) Vasileiadou, Styliana
Background and Aim: Allergic rhinitis (AR) is a common chronic condition among young people. This thesis examines the prevalence, risk, and protective factors of AR in 12-year-olds. It also compares questionnaire-derived AR data with Swedish national registers. It analyses AR trends, exploring AR risk factors in young adults. Finally, it examines the incidence and remission of AR from childhood into young adulthood and identifies associated risk factors. Methods: Data for the first two papers were derived from a longitudinal cohort of children born in 2003 in Western Sweden. Parents completed questionnaires for their children from 6 months to 12 years (76% response rate at 12 years). Personal identification numbers linked 3,634 children to Swedish national registers. Paper III presents a cross-sectional analysis of 16- to 25-year-olds from the West Sweden Asthma Study; 2,143 participants in 2008 and 2,484 in 2016. Paper IV included children in grades 1-2 in Norrbotten, using a questionnaire and skin prick tests (SPTs) in 2006 (8-year-olds) and 2016-2017 (19-year-olds). In total, 2,250 participants (91% participation rate) completed the questionnaire; 1,338 underwent SPTs at 8 and 19 years of age. Results: At age 12 years, 22% reported AR. Risk factors were parental AR, male sex, food allergy, and eczema at the first year of life, while living on a farm and early fish consumption at least once a month were protective factors. Concordance between questionnaires and registers on AR was weak due to insufficient registry data on over-the-counter medication and primary care. From 2008-2016, AR prevalence remained stable (22.5% to 24.4%, p=0.144). Growing up on a farm reduced AR risk in both 2008 and 2016. AR incidence from ages 8 to 19 years was 33.6% and the remission rate 40%. Sensitisation increased the risk of AR incidence and reduced the odds of remission. Conclusion: AR affects >20% of children at the age of 12 years. Genetic predisposition and environmental exposures play an important role in AR development, with protective factors such as farm living and early fish consumption suggesting potential preventive strategies. Sensitisation significantly impacts AR, indicating the need for early identification of individuals at risk. Integrating reliable parental questionnaires and registry data provides invaluable tools for sustained AR research.
Utmaningar och förbättringsmöjligheter för MR-faskontrast vid diagnostik av kronisk aortainsufficiens
(2025-04-29) Truedsson, Frida
Aortic valve regurgitation (AR) occurs when the valve fails to close properly, allowing blood to flow back into the left ventricle during diastole. This puts extra strain on the heart and, over time, can lead to damage and reduced heart function. Phase contrast magnetic resonance imaging (PC-MRI) is considered an accurate method to assess the AR severity. In some cases, though, complex blood flow, through-plane heart motion, and the presence of metal implants may affect the diagnostic certainty. This thesis aims to determine if and how these factors influence the assessment of AR severity and to develop new potential biomarkers for AR patients using PC-MRI. In Paper I, the blood flow was characterized in detail in patients with chronic AR using PC-MRI. The results showed that patients with larger aortas and greater AR displayed more skewed and complex flow in the ascending aorta. Paper II determines the influence of complex blood flow on PC-MRI in the ascending aorta of patients with chronic AR. The results showed that flow complexity varied with (measurement) position and that a more complex flow was associated with lower measurement repeatability. Paper III determines the influence of through-plane heart motion on the PC-MRI in the ascending aorta in patients with chronic AR. The results showed that such motion errors can lead to underestimation of AR severity, particularly in patients with large aortas. Paper IV evaluates the potential of assessing AR severity using PC-based biomarkers in the descending aorta of patients with chronic AR. With such vi biomarkers, significant and non-significant AR could be separated with high diagnostic certainty. Paper V uses a flow phantom to evaluate the effect of dynamic susceptibility changes due to the movement of metallic aortic valve protheses during the PC-MRI acquisition. The results showed that such effects can further lead to underestimation of the AR severity. In summary, this thesis shows that complex flow, through-plane heart motion, and dynamic susceptibility changes can affect the assessment of AR severity using PC-MRI, particularly in patients with dilated aortas. Furthermore, PC-MRI biomarkers in the descending aorta can be used as a supportive reference and thereby improve the diagnostic certainty for patients with chronic AR.

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