Doctoral Theses / Doktorsavhandlingar Institutionen för medicin

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Investigating the Association Between Household Gender Dynamics, Intimate Partner Violence, Mothers' Mental Health, Child Abuse, and Child Stunting in Rwanda
(2025-09-29) Utumatwishima, Jean Nepo
Background: Many low- and middle-income countries still encounter the persistent challenge of child stunting, despite the widespread implementation of public health interventions aimed at reducing it. Most studies and interventions have primarily focused on child-related factors, often overlooking the broader household conditions. A deeper understanding of the household environment, including the health and behaviors of mothers and the family dynamics surrounding child-rearing, is crucial for addressing the stunting problem more effectively. Aim: This thesis aims to investigate the association between household dynamics, such as gender roles, social support, women’s decision-making, intimate partner violence (IPV), mothers' behaviors related to child disciplining, and mothers’ mental health disorders, with stunting of children aged between one month and three years. Methods: The studies in this thesis are based on a cross-sectional, population-based study design. Data was collected through interviews with mothers using an investigator-administered questionnaire, which included standardized WHO questions for assessing IPV, the Mini International Neuropsychiatric Interview questionnaire for evaluating mental health, and UNICEF Multiple Indicator Cluster Surveys (MICS)-guided questions for assessing child abuse. The Multidimensional Poverty Index (MPI), created by Oxford University, was used to evaluate the household’s socioeconomic status. In total, 601 mothers along with their children, who were between one month and three years old, participated in the study. Using a geographic grid method in collaboration with Lund University, villages in Rwanda’s Northern Province were identified, and households were selected through a simple random sampling process. Child age, along with weight and height measurements, served to compute height-for-age z-scores for assessing stunting, per WHO anthropometric guidelines. Descriptive measures and logistic regression models, both bi-variable and multivariable, were employed in the data analysis, showing adjusted odds ratio (aOR) and 95% confidence intervals. Results: Among the 601 mother–child pairs, 27.1% of the children were stunted. Within the stunted group, 60.1% were boys and 39.9% were girls. Stunting increased with age, peaking at 39.9% in children aged 25–36 months. The mothers were predominantly from low-income backgrounds (88.4%), over 30 years old (56.4%), had low educational attainment (78.2%), and worked in unskilled jobs (97.3%). The average MPI was 0.265 across the sample. There was no statistical difference in the MPI scores between households with stunted children and those without stunted children. Nearly half (47.4%) of mothers endured IPV both prior to and during pregnancy. Mothers’ experience of physical IPV prior to pregnancy [aOR=1.29 (1.01 to 2.03)], along with sexual IPV encountered during pregnancy [aOR=1.25 (1.04 to 2.01)], were associated with child stunting. Depression was also a key risk factor, as children of mothers with current major depressive disorder had stunted growth [aOR = 1.67 (1.06–2.61)]. Both insufficient support while ill and lack of personal guidance of mothers were associated with child stunting, with [aOR=1.93 (1.13 to 3.28)] and [aOR=2.44 (1.41 to 4.26)], respectively. Harsh disciplining methods used by mothers, especially when both physical and non-physical approaches were employed, were linked to a higher odds ratio of child stunting [OR = 1.92 (1.08–3.41)]. Conclusions: Despite ongoing public health interventions in Rwanda, child stunting remains a significant problem. The findings highlight that child undernutrition is not only influenced by direct nutritional factors but is also deeply rooted in household dynamics, mothers’ well-being, and gendered social structures. Mental health disorders, exposure to IPV, lack of social support, and violent child-disciplining practices were all strongly associated with child stunting. Integrating mental health screening for pregnant women, educating expectant mothers on the importance of social support, and raising awareness about the dangers of violent child disciplining methods and encouraging non-violent alternatives are essential additions to the ANC content. These results underscore the need for a holistic, interdisciplinary, multisectoral approach that incorporates mental health services, IPV prevention, gender-sensitive interventions, enhanced ANC, and parental support programs into existing nutrition and child health initiatives. Tackling these broader determinants is essential for sustainable improvements in child growth and long-term public health gains.
Health, well-being, and outcomes after aortic valve replacement
(2025-09-26) Lachonius, Maria
Background: Aortic stenosis is the most common heart valve disease requiring intervention. Without aortic valve replacement, the mortality is approximately 50% within 2 years after onset of severe symptoms. Aim: To explore factors influencing patients’ motivation to undergo aortic valve replacement, and to study associations between social factors and mortality risk, and associations between preoperative frailty and health-related quality of life, before and after aortic valve replacement. Methods: This thesis comprises one qualitative study, three registry-based observational studies and one questionnaire-based study on patient reported outcome measures. Paper I explored 18 patients’ motivation to undergo transcatheter aortic valve implantation (TAVI). Paper II explored associations between income, education, marital status, and long-term mortality risk in 14,537 patients who had undergone surgical aortic valve replacement (SAVR). Paper III explored the association between marital status, educational level, and mortality risk in 5,924 TAVI patients. Paper IV assessed the risk of all-cause mortality in 5,924 TAVI patients compared to 10,928 age- and sex-matched controls who had not undergone TAVI. Paper V compared changes in health-related quality of life (HRQoL) in relation to preoperative frailty level in 209 TAVI patients. Results: Patients’ motivations to undergo TAVI were driven by a longing to have a few more good years and to be independent of others. Survival after SAVR was three years shorter in patients with the lowest socioeconomic status compared to those with the highest. Never having been married and low education were associated with an increased mortality risk after both SAVR and TAVI. Low income was associated with an increased mortality risk after SAVR. Patients who underwent TAVI had a lower adjusted risk of mid-term mortality compared to age- and sex-matched individuals from the general population. TAVI patients’ HRQoL improved one year after TAVI independently of the preoperative frailty level. Conclusions: Patients’ motivation to undergo TAVI was strongly linked to their hopes of restoring well-being. Social factors are associated with increased morbidity and mortality after aortic valve replacement. TAVI is associated with longer adjusted survival. Improvements in HRQoL after TAVI is independent of preoperative frailty level.
PFAS elimination and PFAS effects on COVID-19 vaccine response
(2025-09-25) Andersson, Axel
Background and aims: Per- and polyfluoroalkyl substances (PFAS) are persistent compounds, some of which have long serum half-lives in humans. Yet, details about how PFAS are eliminated from the human body are limited. PFAS exposure has been associated with lower vaccine responses in children, but it is unclear whether this also occurs in adults. Therefore, the first theme of this thesis was to describe PFAS elimination in humans and investigate if it can be enhanced, while the second theme was to evaluate PFAS effects on COVID-19 vaccine response in adults. The studies were conducted in Ronneby, Sweden, where drinking water had previously been highly contaminated from firefighting foams. Methods and results: Firstly, PFAS were repeatedly measured in highly exposed individuals after the end of exposure, from which half-lives in serum were estimated. Shorter half-lives were associated with younger age, female sex during the fertile age, higher kidney function, higher gut inflammation, and lower gut permeability. Secondly, fecal and urinary elimination were estimated, both of which were found to be important, with variations between individuals and PFAS compounds. Thirdly, in an experimental, cross-over trial, bile acid sequestrants markedly increased PFAS elimination, substantially lowering serum PFAS levels. Finally, in an mRNA COVID-19 vaccination study in adults aged 20-60 years, no associations were found between PFAS levels and serum anti-spike antibody and T cell responses. Conclusions and implications: PFAS serum half-lives vary between individuals, and PFAS are eliminated through both urine and feces. This implies that PFAS exposure models, aiming to predict serum levels from external exposure, need to properly include population characteristics and both fecal and urinary elimination routes. PFAS elimination can be substantially enhanced; however, the net health benefits of such interventions are not yet known. The mRNA vaccine response was not reduced in adults with high PFAS exposure. Whether this indicates a more mature immune system in adulthood, a specific effect of the mRNA vaccine, or other mechanisms needs to be further explored.
Through Children’s Ears
(2025-09-19) Sandström, Loisa
Background. In Sweden, nearly all children aged 4 to 6 attend preschool, making it a major source of daily indoor sound exposure. Existing standards are derived from adult occupational contexts and may not reflect children’s exposure or perception. Methods. This thesis employed child-centred approaches across three studies. Paper I combined child-worn dosimeter data (LAeqTi, LAFmax, LAFmax,95) with cochlear function assessed by distortion-product otoacoustic emissions (DPOAEs) in a repeated-measures design. Paper II applied the same design using pressurised DPOAEs (pDPOAEs) with systematic tympanometry to reduce middle-ear influence. Paper III analysed binaural recordings with Child and Adult Head and Torso Simulators (HATS) to derive Loudness and Sharpness, compared with children’s responses from the Inventory of Noise and Children’s Health (INCH) interview. Results. Mean personal exposure was 80–81 dB LAeqTi, with LAFmax often exceeding 115 dB. In Paper I, higher exposure was associated with reduced DPOAE amplitudes at high frequencies. Paper II found no consistent exposure–response patterns, although pDPOAEs varied by time of day and sex. Paper III found no robust statistical associations; however, about one quarter to one third of the children reported disturbing sounds accompanied by negative emotions, while most rated their overall well-being as positive. Conclusions. Preschool children are exposed to sound levels that approach or at times surpass adult occupational and environmental limits. Paper I showed frequency-specific reductions in cochlear responses consistent with short-term outer hair cell effects. Paper II, using pDPOAEs with systematic tympanometry, found no exposure–response links; observed amplitude increases later in the day and week probably reflected selective retention after tympanometric exclusions. Paper III found no statistical associations; however, a minority of children frequently reported disturbing sounds accompanied by negative emotions. Together, the studies demonstrate the feasibility of child-centred dosimetry, otoacoustic emission testing, and psychoacoustic modelling, and underline the need for child-specific acoustic models, event-based metrics, and closer temporal alignment of exposure and outcomes to guide protective measures in early childhood settings.
Gut microbiota metabolism linked to metabolic health and cardiovascular diseases
(2025-09-03) Mitteregger, Matthias Georg
Positioned at the interface of nutrition and host physiology, the gut microbiota produces bioactive metabolites that modulate host lipid and glucose metabolism as well as immune function. Many of these metabolites, although produced in the gut, exert influence on physiological processes in the whole body, with an impact on host cardiometabolic health. Despite increasing associations between individual microbiome features and disease reported, mechanistic insights and ecological understanding remain limited. This thesis aimed to explore the ecology of microbial functions and host interactions relevant to cardiometabolic disease using a combination of metagenomics, metabolomics, in vitro fermentation assays, and characterization of isolates. In Paper I, we show that the ismA gene, involved in microbial cholesterol reduction to coprostanol, robustly predicts fecal cholesterol conversion and characterizes a microbiome enriched in fermentative and anti-inflammatory features, linked to favorable cardiometabolic profiles in populations at risk. In Paper II we demonstrate that microbiota individuality drives short-chain fatty acid and bile acid profiles in vitro, with a larger impact than fiber type. These results may have implications for personalized nutrition. In Paper III, we characterize three strains initially classified as Desulfovibrio piger, revealing major phenotypic and metabolic differences. These results support the designation of a novel species Desulfovibrio aggregans sp. nov. and underscore the limitations of current species-level taxonomy. Paper IV highlights the predictive power of microbiota-associated circulating metabolites for type 2 diabetes, identifying specific microbe-metabolite-host interactions that are relevant for glucose control and can be modified through lifestyle interventions. These findings emphasize the importance of acknowledging and understanding the ecological complexity and metabolic impact of the gut microbiota in cardiometabolic disease, and point towards functional, context-dependent microbial signatures as targets for diagnosis, prevention or therapy.
Sex-specific responses to ischemic conditioning in myocardial infarction and stunning: Experimental insights
(2025-08-28) Elmahdy Soliman, Ahmed
This thesis investigates how ischemic conditioning strategies interact with biological sex and hormonal status to modulate myocardial responses to ischemia-reperfusion injury. It addresses both irreversible myocardial necrosis, defined as infarction, and reversible post-ischemic dysfunction, defined as myocardial stunning. Using well-established in vivo models in male and female Sprague-Dawley rats, the studies assessed the effects of ischemic preconditioning (IPC), remote perconditioning, postconditioning, and their combinations. Functional recovery was evaluated through serial echocardiography, infarct size was measured by TTC staining, and mechanistic insights were derived from phosphoproteomic and hormonal analyses. Study I: This study examined the dual effects of IPC in male rats, demonstrating that IPC not only limited infarct size but also increased the incidence of reversible contractile dysfunction. Phosphoproteomic profiling revealed early phosphorylation of sarcomeric and cytoskeletal proteins, suggesting that IPC may confer structural stabilization contributing to myocardial resilience. Study II: This study explored the role of sex and hormonal status in modulating the infarct-sparing effects of IPC. Infarct size varied across the estrous cycle, with proestrus-phase females, characterized by peak estradiol levels, exhibiting the smallest infarcts. Although IPC reduced infarct size across all groups, its v protective effect was attenuated under high-estrogen conditions, suggesting partial mechanistic overlap between IPC and endogenous hormonal signaling. Estradiol emerged as an independent predictor of reduced infarct size. Study III: This study compared the infarct-reducing efficacy of individual and combined conditioning strategies. While all interventions significantly reduced infarct size, combining them conferred no additional benefit. These findings support the existence of a protective ceiling effect, likely due to convergence on shared downstream signaling pathways. Study IV: This study established a female rat model of myocardial stunning and assessed whether estrous phase influenced the extent or resolution of dysfunction. IPC markedly increased the occurrence of stunning; however, no differences were observed between proestrus and estrus, suggesting that under mild ischemic conditions or following IPC, hormonal modulation of stunning may be limited or obscured. Conclusion: Collectively, these studies demonstrate that ischemic conditioning affects both the severity of irreversible injury and the course of functional recovery, with its efficacy influenced by biological sex and hormonal milieu. The findings underscore the importance of assessing functional outcomes alongside structural endpoints and support the systematic integration of sex-specific variables in experimental cardioprotection research.
Memory B Cells in Autoimmune Diseases
(2025-08-19) Nilsson Grimstad, Kristoffer
B cells are central components of the adaptive immune system. On their surface, they express a B-cell receptor (BCR), a membrane-bound form of an antibody. Upon activation, B cells differentiate into either antibody-secreting plasma cells (PCs) or memory B cells (MBCs), which are integral parts of the immunological memory. Recently, a heterogeneous subset of MBCs lacking the complement receptor CD21 (CD21–/low) has received much attention due to its accumulation in chronic inflammatory and autoimmune disease, including rheumatoid arthritis (RA), primary Sjögren’s disease (SjD), and systemic lupus erythematosus (SLE). This thesis aimed to investigate CD21–/low B cells in the context of RA and SjD to determine their functional role in contributing to disease pathogenesis. To this end, we analyzed peripheral blood MBCs from untreated RA (uRA) patients using flow cytometry and 5’ single-cell RNA sequencing (scRNA-seq) and scV(D)J-seq, and B cells from SjD patients using 5’ scRNA-seq and scV(D)J-seq. Paper I assessed how BCR and T-cell receptor genes influence 5’ scRNA-seq analysis of B and T cells. Paper II combined flow cytometry and scRNA-seq to analyze CD21–/low B cells in uRA and investigate their role in RA pathology. Paper III extended our analysis of CD21–/low B cells to SjD, comparing their transcriptional and functional profiles to those in uRA, and to current literature. In conclusion, we have established an analytical protocol for 5’ scRNA-seq data to generate biologically meaningful clusters of B and T cells. Using this protocol alongside flow cytometric analyses, cell cultures and statistical modeling, we propose that CD21–/low MBC subsets play a functional role in RA pathogenesis as antigen-presenting cells, driving Th17 polarization and bone destruction in synovial joints. This contrasts with CD21–/low B cells in SLE, which are PC precursors. We found that CD21–/low MBC subsets in SjD exhibit a transcriptional profile mirroring their counterparts in RA, acting as antigen-presenting cells. Our findings challenge the view that these cells universally serve as PC precursors, instead suggesting disease-dependent functions.
Obesity treatment - examining the influence of eating behavior
(2025-08-19) Björkman, Sofia
Background: Obesity is a complex, multifactorial chronic disease linked to severe co-morbidity, reduced quality of life, and lower life expectancy. Despite numerous treatment options, sustained long-term weight loss remains challenging for many. Aim: To assess how self-reported baseline eating behavior and binge eating disorder (BED) influence weight loss outcomes in clinical treatment for individuals with severe obesity (BMI ≥35 kg/m2). Four studies were conducted, each examining aspects of eating behavior, BED, and psychological factors (motivation, locus of control, self-efficacy) in relation to weight loss outcome over 1 to 5 years and treatment adherence. Methods: All studies were carried out at Sahlgrenska University Hospital among patients beginning treatment for severe obesity between 2012 and 2017. Paper I and II were retrospective clinical cohort studies with 12-month follow-up after a structured weight loss program. Nocturnal eating (NE) and BED were assessed by self-reporting questionnaire QEWP-R (Paper I), and personality traits by a visual analogue scale (VAS) (Paper II). Paper III and IV were prospective cohort studies, involving medical treatment and bariatric surgery with 2- and 5-year follow-up, respectively. BED and eating behavior were assessed using the QEWP-R and TFEQ-R21 questionnaires. Results: BED was not associated with weight loss outcomes at any follow-up point or treatment modality. Nocturnal eating (NE) was linked to less weight loss up to 2 years, but not at 5 years. Higher self-efficacy was associated with achieving ≥15% weight loss after 12 months of medical (diet and lifestyle) treatment. Higher level of emotional eating (EE) was associated with less weight loss outcomes following sleeve gastrectomy (SG) up to 2 years, but not at 5 years. No association was seen between eating behavior and recurrent weight gain. Drop-outs and those lost to follow-up were younger, lost less weight at earlier timepoints, and reported NE and higher levels of EE, and uncontrolled eating. Conclusion: Several eating behaviors, but not BED, were associated with weight loss outcomes up to 2 years but not in those conducting the 5-year follow-up. Weight loss early in treatment appears to be a stronger predictor of long-term success than eating behaviors alone. Addressing problematic eating behavior early in treatment may improve weight loss outcomes in individuals with severe obesity.
Extracellular Vesicles - Roles in mRNA-Based Therapies
(2025-05-20) Tangruksa, Benyapa
Efficient and targeted delivery of therapeutic mRNA remains a major challenge in RNA-based medicine. This thesis explores how lipid nanoparticles (LNPs) and extracellular vesicles (EVs) cooperate in the delivery and redistribution of vascular endothelial growth factor A (VEGFA) mRNA, therapeutic mRNA that induces blood vessel formation and holds strong potential for treating cardiovascular diseases through regenerative angiogenesis. Paper I demonstrates that LNPs efficiently deliver VEGFA mRNA to human cells, leading to rapid uptake and translation. A portion of the internalized mRNA is subsequently secreted within EVs, which also acquire enriched proangiogenic transcripts. Among tested EVs, those derived from cardiac progenitor cells (CPC-EVs) showed superior angiogenic potential and minimal inflammatory response. In Paper II, biodistribution studies in mice revealed that CPC-EVs outperformed LNPs and non-cardiac EVs in delivering VEGFA mRNA to heart tissue, with reduced liver accumulation. CPC-EVs induced local protein expression and minimal transcriptomic disruption, highlighting their tissue-targeting advantage and safety. Paper III investigates how LNP treatment alters EV transcriptomes and how these modified EVs affect recipient tissues. VEGFA mRNA was the most enriched transcript across all EV types. CPC-EVs upregulated VEGFR-1 and VEGFR-2 specifically in cardiac tissue. Further analysis revealed that human mRNA transcripts were detectable in recipient mouse hearts. In summary, this thesis explores the interplay between LNPs and EVs in transporting VEGFA mRNA for therapeutic angiogenesis. LNPs enable efficient cellular uptake and subsequently trigger re-packaging of mRNA into EVs. CPC-EVs showed superior heart targeting and angiogenic potential with low inflammation. The findings highlight a promising strategy for regenerative treatment of cardiovascular diseases.
Endovascular shunting techniques in vascular surgery
(2025-05-13) Millinger, Johan
Abstract Background: Acute tissue ischaemia can lead to significant tissue damage and, in severe cases, permanent loss of organ or limb function. Temporary arterial shunting is an established technique to mitigate ischaemic effects. This can also be achieved using endovascular or hybrid methods, so called endoshunting. Aims: This thesis aimed to evaluate the efficacy and feasibility of endovascular shunting. Materials and Methods: The endoshunt technique was assessed through a series of experimental studies. Initially, an in vitro bench test was conducted to optimise system components and volume flow rates. Two subsequent animal studies evaluated endoshunting for functional outcomes and tissue perfusion when applied to extremities and renal circulation. Finally, a retrospective clinical study examined patients undergoing complex open aortic reconstructions, with a subgroup that received endoshunting to the renal artery. Results: The efficacy of endoshunting was highly dependent on the choice of system components. A flow-optimised endoshunt successfully restored extremity tissue perfusion in a porcine model. In renal applications, endoshunting facilitated rapid recovery of perfusion and urine production when used during prolonged periods of renal artery cross-clamping, indicating its potential utility in renal artery interventions. Clinical analysis of complex open abdominal aortic repairs demonstrated favourable outcomes when performed by a specialised surgical team, with results comparable to those of elective infrarenal surgeries. Conclusion: Endoshunting achieved volume flow rates comparable to conventional shunting techniques over both short and long distances. The technique showed significant promise in mitigating extremity ischaemia and protecting renal function during complex aortic surgeries requiring suprarenal aortic clamping.
Computational phenotyping of obstructive airway diseases and allergy
(2025-05-13) Lisik, Daniil
Allergy and obstructive airway diseases, e.g., asthma, are common and may inflict substantial hardship. They are also interlinked and heterogeneous in their clinical presentations (phenotypes). Artificial intelligence (AI) is useful for phenotyping, by facilitating pattern discovery in complex data. The aim of this thesis was, using AI, to further our understanding of phenotypes of obstructive airway diseases (focusing on asthma), symptoms thereof, and allergies. In addition, potential risk factors and outcomes were evaluated to provide further clinical utility. Paper I was a systematic review on AI-derived longitudinal phenotypes (trajectories) of asthma and allergy in children. A total of 71 studies were identified with differing methodologies and populations. However, overall, few trajectories were consistently identified. The methodological approaches were generally flawed, with insufficient reporting. Further, most studies used binary measures of disease, without inclusion of assessment of severity or other disease characteristics, which may have underestimated the variety of identified phenotypes. Meta-analyses were limited by heterogeneity, but confirmed the association with actionable risk factors, e.g., prenatal/childhood smoking exposure. Paper II was a trajectory analysis on phenotypes of asthma, allergic rhinitis, and eczema in a population-based cohort of children. The input data consisted of parental report of disease and register data on dispensed medication. Nine trajectories were identified, differing in disease and medication patterns, even between trajectories that appeared similar from a binary disease/no disease perspective. These findings illustrate how richer data enable identification of more informative phenotypes. Paper III was a cluster analysis of late-onset asthma phenotypes, utilizing interview/clinical data from representative adult samples. Clustering was done separately on those with asthma debuting at ≥12 years, ≥20 years, and ≥40 years. The identified sets of clusters were similar across onset age groups, but varied substantially among each other in symptoms, lung function, asthma control, and comorbidities. Importantly, they appeared relatively easy to distinguish in the clinical setting. Paper IV was a cluster analysis based on self-reported respiratory symptoms, utilizing data from population-based adult cohorts. Five clusters were identified, ranging widely in symptom locality (e.g., lower respiratory symptoms), type, and frequency/persistence. Further, it was found that all clusters, except the allergic nasal symptoms cluster, even the low-symptomatic cluster, were associated with increased (cause-specific) mortality. As the clusters only partially overlapped with diagnosed respiratory disease, our findings underscore the clinical relevance of respiratory symptoms in their own right. In conclusion, the present work demonstrates that AI, particularly on multimodal data, can guide us towards a more comprehensive subtyping of obstructive respiratory disease and allergy, ultimately paving way for personalized management and preventive measures.
The role of the gut microbiota and frailty on bone metabolism, and the risk of injurious falls and fractures
(2025-05-13) Gregori, Giulia
Aging is intrinsically linked to musculoskeletal decline, culminating in increased risk of frailty, falls, fractures, and associated morbidity and mortality. This thesis investigates the association between gut microbiota composition, physical function, and skeletal integrity in older adults, with the aim of identifying novel predictors and preventive strategies for fracture risk. Utilizing both observational and interventional approaches, this work combines four distinct studies to examine: the predictive value of functional mobility assessments for fracture risk; the efficacy of the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L. reuteri 6475) in mitigating bone loss in early postmenopausal women and in healthy adults undergoing glucocorticoid therapy; and the associations between gut microbiota composition and frailty outcomes in elderly women. In Paper I, a prospective analysis from the SUPERB cohort demonstrated that one-leg standing (OLS) and walking speed are independent and robust predictors of fracture risk in older women, outperforming traditional metrics such as bone mineral density (BMD). Paper II, a two-year randomized clinical trial, evaluated L. reuteri 6475 supplementation in early postmenopausal women found no significant effect on bone loss prevention, although subgroup analyses suggested BMI-dependent responses. Paper III assessed the potential of L. reuteri 6475 to mitigate glucocorticoid-induced bone turnover suppression in healthy adults but found no protective effect on bone or glucose metabolism. Manuscript IV employed metagenomic sequencing in the SUPERB cohort and identified distinct gut microbial signatures associated with frailty, reduced physical performance, increased risk of injurious falls, and mortality. Importantly, a newly developed Frailty-Mortality Index (FMI) showed strong associations with microbial diversity, suggesting its utility as a composite predictor of musculoskeletal aging. Collectively, this thesis underscores the multifaceted contributions of gut microbiota and frailty to skeletal decline and fracture risk in aging populations. While L. reuteri 6475 did not significantly prevent bone loss in two interventional settings, microbial profiling revealed novel taxa linked to frailty and falls, highlighting opportunities for future development of targeted, next-generation probiotics. These findings advocate for a personalized, preventive approach to bone health, integrating physical function assessments and microbiota-based diagnostics to refine fracture risk prediction and inform novel therapeutic strategies for healthy aging.
Birth weight and childhood overweight - exploring parental influences and future risk of coronary heart disease
(2025-04-29) Bramsved, Rebecka
Overweight and obesity now affect individuals of all ages in all parts of the world. Obesity leads to individual suffering as well as increased risk of future disease and premature death from several causes, among which coronary heart disease (CHD) is the most common. The disease pathway to increased risk of CHD likely begins already before conception and may be further influenced by later weight development during childhood and adolescence. There is a need for increased understanding of how parental factors such as smoking and maternal weight status, and family socioeconomic position influence developmental weight, as well as how weight development from birth up to young adult age influence the risk of CHD. This thesis applies a life course perspective on these associations through four cohort studies. Low family socioeconomic position is a well-established risk factor for childhood obesity. However, the separate influences of parental education and family income are not known. Using a cohort of 3,030 children born 1998-2002, we found that low parental education was a risk factor for developing obesity at eight years of age, independent of family income and maternal body mass index (BMI). (Paper I) Smoking and obesity at the start of pregnancy are associated with birth weight and future adverse metabolic risk profile of the child. However, their role in late adolescence, several years before start of pregnancy, for later pregnancy outcomes, have not yet been explored. In a cohort of 1,256 mother-and-child-pairs, we found that smoking and BMI at 19 years of age were not associated with the birth weight of the first child. (Paper II) Low birth weight is a well-studied risk factor for adult CHD, but studies are scarce regarding how this risk is affected by BMI development during childhood and adolescence. Using a cohort of 35,659 men born 1945-1961, we found that a birth weight below 3.6 kg was associated with increased risk of CHD and this risk was further augmented for men who had overweight in young adult age. (Paper III) Childhood overweight and obesity have been linked to increased risk of adult CHD. We studied a cohort of 103,232 men and women born 1945-1968 and found that this risk was normalized for children who had remission of overweight before young adult age. (Paper IV) The findings in this thesis identify several modifiable risk factors important for future risk of CHD. The results clearly highlight the importance of prevention, early identification, and treatment of childhood overweight and obesity.
Cardiovascular and renal effects of long-term particle exposure
(2025-04-25) Kilbo Edlund, Karl
Background and aims Long-term particle exposure is a major risk factor for cardiovascular disease, claiming millions of lives annually. However, it remains uncertain if atherosclerosis mediates the cardiovascular effects of particle exposure. Similarly, the impact of ambient and occupational particle exposure on the kidneys is not sufficiently understood. This thesis explores how particle exposure is associated with atherosclerosis, renal function, and chronic kidney disease. Methods Ambient particle exposure was assessed in the general population using large air pollution models validated against monitoring station data. Occupational particle exposure in a cohort of construction workers was estimated via a job-exposure matrix developed by experienced occupational hygienists. Coronary and carotid atherosclerosis, as well as cardiovascular biomarkers and estimated renal function, were measured cross-sectionally and analysed using multivariable-adjusted robust Poisson, ordinal logistic, and linear regression models. Incident chronic kidney disease was identified longitudinally from healthcare registers and analysed using multivariable-adjusted Cox proportional hazard models. Results Fine particle exposure appeared to be associated with more rupture-prone non-calcified plaques, but not with total coronary atherosclerosis, and with elevated levels of a biomarker of plaque vulnerability. Traffic-related pollutants were suggestively linked to a higher prevalence of carotid plaques and greater carotid plaque area. Both ambient and occupational particle exposure were associated with an increased risk of chronic kidney disease. Ambient particle exposure was associated with slight hyperfiltration, which may be due to chance or an early sign of renal stress. Conclusions These results highlight plaque vulnerability, rather than calcification, as a mechanism linking long-term low-level particle exposure to cardiovascular disease. They also underscore the importance of considering chronic kidney disease in health impact assessments of particle exposure. From a policy perspective, these findings support that stricter regulations of particle exposure in both ambient and occupational settings would have substantial benefits for public health, even at low exposure levels.
Evaluations of diet strategies in improving risk factor control in adults with type 1 diabetes
(2025-04-16) Sterner Isaksson, Sofia
Achieving optimal glucose control remains challenging for many individuals with type 1 diabetes (T1D), leading them to explore various dietary strategies. However, evidence from dietary trials in T1D remains limited. The aim of this thesis was to evaluate dietary approaches for risk factor management in T1D and examine associations and deviations between different glucose metrics. In Paper I, a 12-month randomized multicenter trial compared two group education methods, carbohydrate counting and a food-based approach, with a control group receiving individual education. Paper II assessed the impact of carbohydrate intake levels in a randomized crossover trial. Paper III analyzed associations between HbA1c and continuous glucose monitoring (CGM) metrics using 2.5 years of data from a randomized trial and its follow-up. Paper IV explored dietary intake and challenges among adults with T1D through a survey. In Paper I, both group education methods led to significant HbA1c reductions at 3 months compared to the control group, but the effects were not sustained at 12 months. However, diet quality improved in the food-based approach group. In Paper II, a moderate carbohydrate diet improved glucose control, measured by masked CGM, compared to a traditional diet, with no observed adverse effects. Paper III demonstrated strong associations between HbA1c and mean glucose, and time in range, but also revealed clinically significant discordance among many participants. Paper IV found that many participants struggled with carbohydrate counting, specific foods, and meal-time situations, and expressed a need for greater dietary support. These findings highlight the potential of diverse dietary strategies to improve glucose control and diet quality, while also indicating a need for enhanced dietary support for individuals with T1D. More research is needed to determine the optimal dietary approach. Additionally, the significant discordance between HbA1c and mean glucose for many individuals should be carefully considered in clinical practice.
Bridging the gaps in mortality data and healthcare access: A novel verbal autopsy application using subnational T2DM register in Saudi Arabia
(2025-04-14) Alyazidi, Faleh
Background: Diabetes mellitus is an increasingly critical health concern in Saudi Arabia, often with other comorbidities and mortality causes, such as cardiovascular disease (CVD). National sociodemographic changes entail the urgent need for reliable insights on the scale and causes of mortality in order to develop appropriate healthcare policy. Where death certification is inadequate, verbal autopsy (VA) can serve as a useful tool to fill crucial gaps in vital data. This thesis aims to explore various contextual dimensions using the validated VA method. Specifically, this thesis aims to explore the community perception of causes of death, measure the circumstantial barriers (social and health system) to accessing healthcare, assess and validate the adequacy of medical certification of cause of death at population level, and investigate the clinical and demographic factors influencing out of hospital deaths among deceased individuals with specific health conditions T2DM and CVD. Methods: Studies I-IV utilized mortality data from the T2DM register at a major hospital in Makkah City, while Study V used data from the CVD registers at two major hospitals. For the first three studies, 302 VA assessments were conducted with the deceased’s next of kin. The VA data were analyzed using the computerized InterVA-5 software, which provided probable causes of death and circumstances of mortality categories (COMCATs). Study I employed Lin’s concordance correlation coefficient (CCC) to assess the concordance between verbal autopsy causes of death (VACoD) as a presumed reference standard and family-reported causes of death. Also, the study employed multiple logistic regression to identify factors influencing community perception of causes of death. Study II applied epidemiological estimations of absolute measures and Causes Specific Mortality Fractions (CSMFs), while also using numerical and graphical assessment to describe trends and patterns in the VA data. The COMCATs were ranked across the causes of death based on their derived probabilities. Study III employed Lin’s CCC to assess the concordance between physician reviewed causes of death (PRCoD) and VACoD at the population level. Study IV employed multiple logistic regression to identify factors influencing out of hospital deaths among deceased with T2DM, while Study V focused on CVD. Findings: Study I demonstrated broad community perceptions of causes of death, with notable misconceptions related to type of death and marital status. Study II found most deaths were seen as inevitable, with the COMCATs ‘recognition’ and ‘traditions’ being identified as avoidable barriers. Study III showed moderate concordance between PRCoD and VACoD, though discrepancies were apparent in the CSMFs, particularly for the most prevalent causes. Studies IV and V uncovered that cause and year of death in addition to nationality significantly influenced out of hospital deaths, with both studies illustrating decreasing trend of out of hospital mortality. Conclusion: This thesis uncovers challenges for Saudi public health policy concerning T2DM-related mortality, identifying issues in access to healthcare, community perceptions, and medical certification. Misconceptions about mortality causes of death hamper prevention strategies, while health system and sociocultural barriers heighten latent problems. The findings underscore the requirement to enhance the medical certification, as discrepancies between PRCoD and VA data suggest challenges in current practices on population level.
Abdominal pain-related disorders of gut-brain interaction from childhood to adulthood: A birth cohort study on natural history, risk factors, and quality of life
(2025-04-03) Sjölund, Jessica
Recurrent abdominal pain (RAP) is a common issue across the lifespan and a defining feature of abdominal pain-related disorders of gut-brain interaction (AP-DGBI), including irritable bowel syndrome (IBS). These disorders are highly prevalent and impose significant burdens on both individuals and society. This thesis, based on a longitudinal, population-based Swedish birth cohort, examines the natural history of RAP and AP-DGBI from childhood to adulthood, identifies childhood risk factors for their presence and persistence, and investigates their impact on health-related quality of life (HRQoL). Study I demonstrated that RAP is prevalent in childhood, peaking in adolescence. While preadolescent RAP is a strong risk factor for adolescent RAP and AP-DGBI, most affected children do not experience persistent abdominal pain through adolescence. Study II found that childhood eczema and food hypersensitivity are associated with an increased risk of adolescent AP-DGBI, while childhood asthma and food hypersensitivity are linked to adolescent IBS, suggesting a shared pathophysiology between these conditions. Study III showed that adolescents and young adults with IBS have significantly impaired HRQoL, with overall HRQoL impairment and anxiety/depression in adolescence predicting new-onset IBS in adulthood, while adolescent AP-DGBI increases the risk of new-onset anxiety/depression in adulthood. Study IV identified multiple childhood risk factors for adult IBS, with adolescent IBS being the strongest predictor. However, nearly 70% of adolescents with IBS do not have IBS as young adults. Other risk factors include female sex, impaired HRQoL, psychological distress, somatic pain, cumulative antibiotic use, short sleep, and parental IBS history, the latter also being a strong predictor of IBS persistence from adolescence into adulthood. Similar results were found for RAP presence and persistence. In conclusion, this thesis provides valuable insights into the natural history and long-term impact of childhood RAP and AP-DGBI into adulthood. It identifies several risk factors for their development and suggests potential targets for interventions aimed at reducing the risk of developing adult AP-DGBI.
Navigating digital transformation in primary care: Implementation, intention, normalization, and institutional logics
(2025-04-02) Maack, Karl
This compilation thesis examines the implementation of video consultations in primary care, focusing on how healthcare professionals navigate the digital transformation amidst conflicting priorities. It explores the value conflicts arising from the introduction of video consultations and how these are managed in practice. The research delves into the perceptions of practitioners, including doctors, nurses, and psychologists, as well as other actors involved like IT-specialists and implementation coordinators. By employing frameworks such as the theory of planned behavior and normalization process theory, this study analyzes factors influencing the successful integration of video consultations. It highlights the importance of balancing managerial, market, patient, and professional logics during the digital transformation process. The findings in this thesis suggest three key strategies for implementation of video consultations in primary care. First, healthcare professionals must continuously adapt and adjust to multiple institutional logics, balancing clinical values with organizational and technological demands. Second, managing nodes of adjustmentalisation, are central in coordinating interactions between different logics and actors. Third, an active governance though engaging in the development of standards and protocols ensures alignment with both clinical and organizational requirements. The thesis contributes to both theoretical understanding and practical strategies for managing digital transformations in healthcare, emphasizing the need for a nuanced approach that considers diverse stakeholder perspectives.
Maternal Dietary Intake and Associated Pregnancy Outcomes in the United Arab Emirates - The Dietary Subcohort of the Mutaba’ah Study
(2025-03-21) Almulla, Aisha A.
This thesis aimed to assess dietary intake and its associations with pregnancy outcomes in the United Arab Emirates (UAE). Within the Mutaba’ah Study, 1556 pregnant women were recruited into a dietary subcohort. Data collection using a semi-quantitative food frequency questionnaire (FFQ) was performed during antenatal care visits throughout the pregnancy. The relative validity of the FFQ was assessed using a 24-hour dietary recall as a reference method. Adherence to dietary patterns (Alternate Healthy Eating Index for Pregnancy [AHEI-P], Alternate Mediterranean Diet [aMED], Dietary Approaches to Stop Hypertension [DASH]) were identified, and ultra-processed food (UPF) intake was assessed. Gestational weight gain (GWG) was calculated as the difference in weight between the first and the last recorded weight, and excessive GWG (EGWG) was defined according to the Institute of Medicine guidelines, based on the first trimester body mass index. Gestational diabetes mellitus (GDM) diagnosis was based on the National Institute for Health and Clinical Excellence criteria. Paper Ⅰ showed that the FFQ overestimated intake of most nutrients and food groups but could be used to rank the pregnant women based on some aspects of their dietary intake. Paper Ⅱ showed that the three dietary indices (AHEI-P, aMED, DASH) were moderately correlated. Some differences were observed in what distinct aspects of dietary intakes they captured. In paper Ⅲ, the prevalence of EGWG was 29%. No associations were found between aMED and GWG or EGWG. However, intake of some aMED components (fruit, vegetables, ratio of monounsaturated fatty acids to saturated fatty acids) showed associations with GWG and/or EGWG. In paper Ⅳ, UPF intake was associated with lower diet quality but not with GDM. Further, no association was found between aMED and GDM. These findings show that the FFQ estimates intakes of nutrients and food groups with poor to acceptable validity. Adherence to healthy dietary patterns was associated with a favorable intake of nutrients and food groups, while high UPF intake was associated with poorer intake. Further research is needed to clarify the role of dietary intake in pregnancy outcomes.
Neutrophil free fatty acid receptors
(2025-02-18) Mårtensson, Jonas
The human immune system protects against threats that range from microorganisms to damaged cells. Neutrophils, which are the most numerous cells of the innate immune system, circulate in the bloodstream in abundance. In the case of infection or damage, neutrophils are rapidly mobilized from the blood to affected tissues to eliminate the threat. The rapid response of neutrophils is dependent upon the ability to recognize structures that are predetermined as harmful, which is mediated by pattern recognition receptors expressed on the cell surface. Neutrophils express multiple receptors that not only detect danger but also other signals that orchestrate their functional responses. FFA2R and GPR84 are neutrophil-expressed receptors that are capable of detecting short- and medium-chain free fatty acids, respectively. Whereas short-chain fatty acids are essentially produced by bacteria in the gut, medium-chain fatty acids are mainly acquired through the diet. Although the underlying physiological reason for neutrophil recognition of free fatty acids remains elusive, emerging evidence suggests that free fatty acids and their receptors exert a distinct and substantial influence on the inflammatory response. Based on four original papers, this thesis highlights the intracellular signaling, regulatory processes and functional responses mediated by the neutrophil free fatty acid receptors. This thesis presents an overview of the current state of the art and aims to place the neutrophil free fatty acid receptors in a relevant context. The focus is on the FFA2R, to showcase the importance of this receptor in the control of inflammation.

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