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AI-supported versus manual microscopy of Kato-Katz smears for diagnosis of soil-transmitted helminth infections in a primary healthcare setting
No full textSoil-transmitted helminths primarily comprise Ascaris lumbricoides, Trichuris trichiura, and hookworms, infecting more than 600 million people globally, particularly in underserved communities. Manual microscopy of Kato-Katz thick smears is a widely used diagnostic method in monitoring and control programs, but is time-consuming, requires on-site experts and has low sensitivity, especially for light intensity infections. In this study, portable whole-slide scanners and deep learning-based artificial intelligence (AI) were deployed in a primary healthcare setting in Kenya. Stool samples (n = 965) were collected from school children and Kato-Katz thick smears were digitized for AI-based detection. Light-intensity infections accounted for 96.7% of cases. Three diagnostic methods - manual microscopy, autonomous AI and human expert-verified AI - were compared to a composite reference standard, which combined expert-verified helminth eggs in physical and digital smears. Sensitivity for A. lumbricoides, T. trichiura and hookworms was 50.0%, 31.2%, and 77.8% for manual microscopy; 50.0%, 84.4%, and 87.4% for the autonomous AI; and 100%, 93.8%, and 92.2% for expert-verified AI in smears suitable for analysis (n = 704). Specificity exceeded 97% across all methods. The expert-verified AI had higher sensitivity than the other methods while maintaining high specificity for the detection of soil-transmitted helminths in Kato-Katz thick smears, especially in light-intensity infections.</p
Leveraging faith-leaders to prevent violence against women and girls: A qualitative study of evangelical faith-leaders' perceptions in Woliso, Ethiopia.
No full textBackgroundViolence against women and girls (VAWG) affects 1 in 3 women globally. Religion can be both a driver and a potential solution for VAWG. Evidence suggests that faith-leaders can create positive change around VAWG and improve ideas of gender equality, but it is critical to have a context-specific understanding of existing awareness. In Ethiopia, Evangelical faith-leaders' perceptions of VAWG have not been studied.AimTo increase understanding of Evangelical faith-leaders' perceptions of gender equality and VAWG and their views on how they can address VAWG, in Woliso, Ethiopia.MethodsA qualitative study design drawing on 14 semi-structured interviews and observational data from workshops with Evangelical faith-leaders that explored their views on gender equality and VAWG. An inductive reflexive thematic analysis approach was used.ResultsThe data analysis generated 4 themes, 8 sub-themes, and 22 categories. The themes include: (1) differing perceptions of VAWG as a problem in the community; (2) navigating between social and religious norms as explanations of VAWG; (3) differing interpretations of biblical scripture; and (4) navigating who has a role in countering gender inequality and VAWG. Many faith-leaders condemned forms of VAWG and expressed hopes for equality, but some failed to grasp all elements of VAWG and utilized religious reasoning to justify VAWG. The majority of faith-leaders expressed an interest in increasing awareness and held hopes for improved gender equality.ConclusionFaith-leaders hold different understandings of what constitutes VAWG. Faith-leaders' hopes for equality and their willingness to address VAWG indicates the potential of faith-leaders as important actors in VAWG prevention efforts. Yet, trainings and support are critical.</p
Unraveling the impact of bacterial peptidoglycans from gut microbiota on brain development, function and behavior
No full textOver recent decades, the microbiota-gut-brain axis has emerged as a central regulator of neurodevelopment, influencing lifelong brain functions. Increasing preclinical and clinical evidence implicates the gut microbiota as a susceptibility factor for neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD). Additionally, mounting evidence highlights the pivotal role of the maternal gut microbiota during pregnancy and lactation in shaping early-life neural circuits and influencing long-term brain health in offspring. However, the molecular mechanisms through which maternal microbial signals affect fetal brain development remain poorly understood. This thesis investigates how alterations in the maternal and adult gut microbiota influence brain development, function, and behavior, with a particular focus on bacterial peptidoglycan (PGN) fragments as key signaling molecules.Paper I investigated whether disrupting the maternal gut microbiota with antibiotics during late pregnancy and early postnatal life affects early neurobehavioral outcomes relevant to ASD in offspring. Neonatal mice born to treated dams exhibited sex-specific alterations in ultrasonic vocalizations. As juveniles, these mice showed reduced social motivation, impaired social interactions, and altered anxiety-like behavior. These behavioral alterations were accompanied by reduced expression of oxytocin receptor and tight-junction proteins in the prefrontal cortex, low-grade colonic inflammation, and shifts in gut microbiota composition. These findings underscore the vulnerability of the maternal gut microbiota during the perinatal period and its critical role in shaping offspring social and emotional development.Papers Il and Ill explored the role of PGN fragments-specifically muramyl dipeptide (MDP)-as maternal gut microbiota-derived signals that influence fetal brain development. PGN fragments administered during mid- or late pregnancy were detected in the amniotic fluid, confirming their translocation to the fetal compartment in the absence of overt inflammation. Mid-gestation PGN exposure induced widespread transcriptomic alterations in fetal brains, affecting genes involved in chromatin remodeling, estrogen receptor signaling, synaptic plasticity, and glutamatergic transmission. Male offspring exhibited altered neonatal vocalizations and impaired social behavior, accompanied by changes in gut microbiota composition and dysregulated expression of synaptic (e.g., Ppp1r9b, Bdnf, Oxtr) and glutamatergic (Gria1) genes in the prefrontal cortex.In contrast, late gestational PGN exposure led to distinct, sex-specific behavioral outcomes. Male offspring displayed reduced social interaction, while females showed increased social engagement, reduced locomotion, and impaired social recognition. These effects were associated with altered expression of microglial (Trem2, Cx3cr1) and synaptic (Dlg4, Darpp-32) genes. Together, these findings highlight that the timing of PGN exposure and fetal sex critically shape neurodevelopmental responses, likely reflecting differences in developmental stage and hormonal milieu.Paper IV extended these findings into adulthood, examining how short-term exposure to B-lactam antibiotics alters PGN translocation and impacts brain function and behavior. Adult male mice treated with ampicillin showed region- specific increases in brain PGN levels. Expression of PGN transporters (Slc15a4 and Slc46a3) in the brain varied in response to changes in PGN levels. Within 72 hours, antibiotic treatment triggered rapid changes in synaptic and microglial gene expression, disrupted functional brain connectivity, and impaired sociability and social recognition. These effects were accompanied by pronounced shifts in gut microbial composition. Notably, administration of DAP-type PGN fragments (i.e., iE-DAP) derived from Gram-negative bacteria recapitulated key behavioral and molecular effects observed in antibiotic-treated mice, suggesting a direct role of PGN in antibiotic-associated neurobehavioral alterations.Collectively, this thesis identifies PGN as a critical molecular messenger in the microbiota-gut-brain axis, capable of influencing fetal brain programming and shaping long-term neurodevelopmental trajectories. It provides compelling evidence that maternal microbial signals-particularly during sensitive developmental windows-can shape neurodevelopment in a sex- and timing- dependent manner. By linking maternal microbiota alterations to specific molecular and behavioral outcomes, this work offers novel insights into how antibiotic use or dysregulated PGN levels during pregnancy may contribute to atypical neurodevelopment. Ultimately, these findings open new avenues for therapeutic strategies targeting PGN signaling to mitigate neurodevelopmental disorders and promote brain health.List of scientific papersI. Morel C, Martínez Sánchez I, Cherifi Y, Chartrel N, Diaz Heijtz R. Perturbation of maternal gut microbiota in mice during a critical perinatal window influences early neurobehavioral outcomes in offspring. Neuropharmacology. 2023 May 15;229:109479. https://doi.org/10.1016/j.neuropharm.2023.109479II. Perego S#, Martínez Sánchez# I, Hökfelt T, Diaz Heijtz R. Maternal Peptidoglycan overexposure in mid-pregnancy alters neurodevelopmental trajectories and behavioral outcomes in mice. #: These authors contributed equally to the work. [Manuscript]III. Martínez Sanchez I, Spielbauer J, Diaz Heijtz R. Maternal peptidoglycan overexposure during late pregnancy alters neurodevelopment and behavior in juvenile offspring. Brain Behavior and Immunity. 2025 Mar 7;127:96-102. https://doi.org/10.1016/j.bbi.2025.03.014IV. Martínez Sánchez I, Kim WS, Heather C, Nylén S, Shapiro MG, Diaz Heijtz R. Short-term exposure to B-lactam antibiotics enhances peptidoglycan translocation to the brain, disrupting functional connectivity and social recognition in mice. [Submitted]</p
Neuroplasticity across the lifespan : focus on environmental and intrinsic modulators
No full textThe plastic brain is unique in its ability to continuously modify its architecture from early development throughout adulthood. Neural plasticity constitutes both the formation of neuronal networks during development and mechanisms that fine-tune synaptic connections for efficient memory consolidation and learning across the lifespan. It becomes more and more clear that although plasticity mechanisms are very similar across life, we can find several stages of plasticity with specific effects on neuronal circuit formation and brain functioning. Prenatal development is mainly genetically driven by programmes orchestrating the transcription of regulatory cues involved in neuronal migration, cell differentiation and morphogenesis. During this stage small signalling molecules like neurotrophins, chemokines and membrane proteins are of major importance during neurogenesis and synaptogenesis. Throughout life, network stabilising mechanisms are crucial for consolidation of long-term memories. Calibration and tuning mechanisms, keeping homeostasis of synaptic levels, ensure stable and efficient integration, processing and storage of information. Dysregulation of plasticity mechanisms can have detrimental effects on higher cognitive functioning, sociability and learning, often manifested in neurodevelopmental disorders.The gut microbiota-brain axis is an established physiological system referring to the connection of commensal intestinal microbes to the host's brain, which can influence the synaptic strength and neuronal structure via several pathways including microbial metabolites. The bacterial composition in the gut is susceptible to many factors like diet, psychological stress and drugs, which can be reflected in altered levels of released bacterial components and changes in the permeability of the intestinal wall and blood brain barrier (BBB). To investigate the effect of intestinal microbes during the prenatal plasticity phase on functional behaviour in later life, pregnant female mice were overexposed to elevated levels of bacterial cell wall component peptidoglycan (PGN). Female offspring of PGN treated mothers displayed signs of impaired social recognition and motor activity compared to control and male offspring. Functional differences were associated with altered synaptic gene expression between males and females in the prefrontal cortex (PFC). Paper I concludes that exposure to atypically high levels of PGN during late pregnancy might alter prenatal plastic processes, which manifest at juvenile age. Paper II aimed to assess the mechanism behind PGN signalling in immortalised microglia (IMGs) and primary microglia. PGN receptor NOD2 was highly expressed in microglia and upregulated with exposure to increasing PGN levels. NOD2 overactivation stimulated both NF-KB and MAPK downstream signalling, which resulted in increased cytokine and chemokine expression. The first two projects of my thesis show that excessive amounts of maternal PGN can affect prenatal plasticity programmes potentially by changing microglial cytokine and chemokine release, among other possible mechanisms.Throughout life, experience-dependent neuronal activity is crucial for the formation and strengthening of synapses, which on a structural level, can be measured in spine density and dendritic length dynamics. According to the sleep homeostasis hypothesis (SHY) neuronal connections are strengthened by neuronal activity during the wake period. To restore the net synaptic strength, especially slow wave sleep has been shown to be essential. However, studies investigating the effect of sleep deprivation (SD) on dendritic spine density and length in mice have shown contradictory results. By conducting a meta-analysis of the current literature, Paper III aimed to resolve conflicting findings across studies on the effect of SD on dendritic architecture. We would expect that SD leads to an increase of synaptic numbers per spine length and longer dendrites, since the lack of sleeps means a lack of downregulation in net synaptic strength proposed by the SHY. Combining studies in chronically (> 24 h) sleep deprived animals, dendritic length and spine density was significantly decreased. These results need to be interpreted with caution, since effects were driven mainly by the subgroup using a SD protocol with aversive stimuli with a substantial heterogeneity across studies. To draw a conclusion more studies have to be performed using standardised methods for SD and dendrite analysis. To reduce variability across studies a methodological checklist was established addressing core issues identified during the quality assessment.During adulthood neuronal networks are typically stable and only susceptible to structural changes during high frequency stimulation. Strong neuronal activation is subsequently leading to a sustained upregulation of synaptic strength, a term known as long-term potentiation (LTP). To open the window of plasticity, plasticity inhibitory systems like the Nogo system need to be downregulated. Paper IV investigates how plasticity stabilisers like the Nogo system are regulated by using pharmacological agents to induce LTP and long-term depression (LTD) in hippocampal primary cultures. Dendritic and cytosolic NgR1 protein was downregulated by LTP after 60 min, which correlated with time of immediate early gene (IEG) induction. LTD upregulated NgR1 transiently (30-60 min). To further investigate specific pathways and genes that target NgR1 regulation, in Paper V, we performed a CRISPR activation screen in NgRKOGFP reporter cells. NgRKOGFP cells, expressing the reporter protein GFP in the NgR1 locus, were transduced with a whole genome sgRNA library to detect genes that up regulate (GFPhigh population) or down regulate (GFPlow population) NgR1 expression. Several pathways associated with activity-dependent signalling were enriched in the GFPlow population using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases for gene set enrichment analysis (GSEA). To dig deeper into LTP-dependent genes involved in NgR1 downregulation, we correlated our GFPlow to a publicly available RiboTag dataset of upregulated genes following cLTP induction in hippocampal slices. Genes upregulated after LTP induction were positively correlated with downregulation of NgR1 expression. Neuron-specific IEG NPAS4 was identified to play a major role in LTP-dependent control of NgR1.This thesis focuses on different mechanisms engaged in prenatal and postnatal plasticity regulation. By going deeper into environmental factors like the gut microbiota and endogenous systems like sleep and the Nogo system, new potential molecular mechanisms were discovered and existing pathways broadened.List of scientific papersI. Martínez Sánchez I, Spielbauer J, Diaz Heijtz R. Maternal peptidoglycan overexposure during late pregnancy alters neurodevelopment and behavior in juvenile offspring. Brain Behav Immun. 2025;127:96-102.https://doi.org/10.1016/j.bbi.2025.03.014II. Spielbauer J, Glotfelty EJ, Sarlus H, Harris RA, Diaz Heijtz R, Karlsson TE. Bacterial peptidoglycan signalling in microglia: Activation by MDP via the NF-KB/MAPK pathway. Brain Behav Immun. 2024;121:43-55.https://doi.org/10.1016/j.bbi.2024.06.027III. Brodin ATS, Liesecke F, Spielbauer J, Karlsson TE. Sleep deprivation and dendritic architecture: a systematic review and meta-analysis. [Manuscript]IV. Brodin ATS, Spielbauer J, Wellfelt K, Olson L, Karlsson TE. Localisation and regulation of Nogo-66 receptor 1 during chemical long-term potentiation and depression. [Manuscript]V. Spielbauer J, Pfeiffer S, Schick JA, Karlsson TE. Genome-wide CRISPR activation screen identifies key regulators of NgR1. [Manuscript]</p
Oral Status in Relation to Demographic, Socioeconomic, Medical and Psychosocial Risk Factors Among Outpatients in Addiction Treatment Centers, Stockholm, Sweden
No full textObjective: To investigate oral status in relation to demographic, socioeconomic, medical and psychosocial risk factors among outpatients receiving treatment for Substance Use Disorder (SUD). Methods: This cross‐sectional study included 91 outpatients from Stockholm, Sweden. Oral status was assessed using the Decayed, Missing, Filled Teeth (DMFT) index and Probing Pocket Depth (PPD). Psychosocial and functional factors were evaluated using the Addiction Severity Index (ASI), which measures problem severity in areas such as medical and social functioning, and the Global Assessment of Functioning Scale (GAF), which assesses overall social and occupational functioning. Data were analysed using non‐parametric correlations and logistic regression. Results: The mean DMFT was 12.4 (±8.1), with missing teeth (MT) as the dominant component. The median PPD was 28. The logistic regression analysis showed significant associations between risk factors and oral status variables. Age ≥ 40 years was associated with fewer teeth (OR: 3.52, 95% CI: 1.30–9.54), higher DMFT (OR: 8.88, 95% CI: 3.43–23.01) and more severe PPD (OR: 5.64, 95% CI: 1.95–16.32). Low education (< 9 years) was associated with fewer decayed teeth (DT) (OR: 0.23, 95% CI: 0.09–0.59) and lower PPD values (OR: 0.29, 95% CI: 0.10–0.86). These results highlight the significant influence of age and education on oral status among patients with SUD. Conclusion: This study identified relationships between oral status and several demographics, socioeconomic, medical and psychosocial risk factors among patients with SUD. Age was the strongest predictor of oral status, with low education being the only significant socioeconomic risk factor.</p
Anxiety disorders in children of anxious parents : risk and prevention
No full textBackground: Children of parents with anxiety disorders constitute a risk group for developing anxiety disorders themselves, and the parenting behaviors of anxious parents have been suggested to contribute to this elevated risk.Aim: This thesis aimed to advance the understanding of the risk for anxiety disorders in children of anxious parents and to examine whether they can be prevented through a novel parenting intervention. Study I investigated the relative risk of anxiety disorders in children of parents diagnosed with an anxiety disorder, compared to children of parents with no anxiety diagnosis. Study II assessed if the Confident Parents Brave Children (CPBC) program, an online group-intervention for anxious parents, was effective in reducing the risk for child anxiety disorders and symptoms within 12 months, compared to a self-help control condition. Study III aimed to develop a self-assessment tool measuring parental anxious modeling. Lastly, Study IV assessed the psychometric properties of the Parental Overprotection Measure, and developed a short version of the scale.Methods: Study I was a population-based cohort study. Children (N=516,134) living in Stockholm, Sweden, were followed in registers until they were diagnosed with anxiety, moved, or turned 18. The primary and secondary exposures were parental diagnoses of specified and unspecified anxiety disorder, respectively. The outcome was the first occurrence of a specified anxiety diagnosis in the child. In Study II, 215 parents and their children (n=271) were randomly assigned to the CPBC program or a self-help control condition. The primary endpoint was the 12-month follow-up, with the primary outcome being Clinical Severity Rating (CSR) assessed using the Anxiety Disorders Interview Schedule. Secondary outcomes included parent-rated child anxiety symptoms. Study III and IV were based on survey data from 1,092 parents of children aged 4-12 years. The survey included the PROMIS Anxiety short forms (adult and parent proxy report scale) and the Parental Overprotective Measure (POM). Further, it included 51 novel items, generated to describe parental modeling of anxious and non- anxious behaviors. Based on this item pool, Study III developed and validated the Modeling of Parental Anxiety Questionnaire (MPAQ). Study IV examined the psychometric properties of the Parental Overprotection Scale (POM). In Study III and IV, exploratory factor analysis was utilized to determine the factor structure, Rasch model for item reduction, and validity was evaluated by analyzing association between the new scale and related constructs.Results: Study I found that having a parent diagnosed with a specified anxiety disorder was associated with a modest risk increase for anxiety disorders in the child (HR: 1.44, 95% CI: 1.38-1.51). The risk was attenuated after adjustment for other parental psychiatric disorders (HR: 1.27, 95% CI: 1.21-1.34). The risk was higher for parental anxiety recorded in specialized psychiatric care compared to primary care (HR: 1.69, 95% CI: 1.60,1.79, vs. HR: 1.24, 95% CI: 1.17,1.32). No increased risk for anxiety disorders was observed in children of parents diagnosed with unspecified anxiety (HR: 1.02, 95% CI: 0.98-1.07). In Study II, the 12-month assessment was completed by 204 parents (95%). The results demonstrated no statistically significant decrease in risk for CPBC children compared to control children in terms of movement to a higher CSR category (OR=0.67, 95% CI: 0.30-1.48) or the development of anxiety disorders (OR=0.57, 95% CI: 0.24-1.31). In a separate analysis based on child age, 5-6-year-olds in the CPBC condition exhibited a lower risk of increased CSR (OR=0.24, 95% CI: 0.08, 0.77) and anxiety disorders (OR=0.23, 95% CI: 0.05, 0.84) compared to the control group. Regarding secondary outcomes, parent ratings indicated that CPBC children's anxiety symptoms decreased more compared to control children from pre- to the 12-month assessment, Cohen's d = - 0.35 (95% CI: - 0.55, -0.15). In Study III, factor analysis revealed four separate factors, used to form four independent MPAQ subscales: (1) being curious and content, (2) being on guard, (3) displaying anxiety and avoidance, and (4) displaying stress. The internal consistency of the subscales ranged from moderate to good. The anxiety and avoidance subscale showed the strongest positive correlation with child anxiety symptoms. In Study IV, eight out of the original 19 items from the Parental Overprotection Measure (POM) were removed based on poor psychometric performance or expert evaluations indicating misalignment with the construct of parental overprotection. The eleven retained items form the POM-11, a shorter scale with adequate psychometric properties.Conclusion: This thesis provides evidence for a modest risk increase for anxiety disorders in children of parents diagnosed with a specified anxiety disorder. The overall risk was found to be lower than previously reported, however, the risk varied depending on parent care level and type of anxiety diagnosis. The Confident Parents, Brave Children (CPBC) program did not demonstrate overall effectiveness in preventing anxiety disorders in children. However, for children aged 5 to 6, CPBC effectively prevented the onset of anxiety disorders. Additionally, across all age groups, children whose parents participated in CPBC experienced a significant reduction in anxiety symptoms compared to those in the self-help control group. Although further research is warranted, the results give partial support for the potential for parent-only interventions to prevent pediatric anxiety disorders, at least in young children. Further, POM-11 and the MPAQ are measurements with acceptable psychometric properties suitable to use in research and clinical practice.List of scientific papersI. Elfström, S., Wicks, S., Dalman, C., & Åhlén, J. (2024). A detailed investigation of anxiety disorders in children of clinically anxious parents: A population-based study [Manuscript]II. Elfström, S., Rosengren, A., Andersson, R., Engelbrektsson, J., Isaksson, A., Meregalli, M., van Leuven, L., Lalouni, M., Öst, L., Ghaderi, A., & Åhlén, J. (2025). Evaluating a program to prevent anxiety in children of anxious parents: a randomized controlled trial. Journal of Child Psychology and Psychiatry. https://doi.org/10.1111/jcpp.14151III. Elfström, S., & Åhlén, J. (2022). Development and validation of the Modeling of Parental Anxiety Questionnaire. Journal of Anxiety Disorders, 85, 102515. https://doi.org/10.1016/j.janxdis.2021.102515IV. Elfström, S., & Ahlen, J. (2025). Psychometric Evaluation of the Parental Overprotective Measure: Toward a Reliable and Practical Assessment Tool. Journal of Child and Family Studies, 34(1), 164- 173. https://doi.org/10.1007/s10826-024-02967-z</p
Detection of anabolic androgenic steroids in serum and dried blood spots
No full textBackgroundAnabolic androgenic steroids (AAS) is a collective term used for substances that include synthetic substances that exert an anabolic and androgenic effect in various degrees including testosterone (T). Anabolic androgenic steroids are prohibited in sport and in some countries even illegal. In society, AAS is widely used by sport enthusiasts. Urine is the standard matrix of choice when analysing AAS. Due to the wide detection window in urine, misuse of AAS can be detected several months after a single use. To detect AAS, long-term metabolites can be analysed whereas the biomarker T/epitestosterone (T/E) ratio is used to detect T doping. However, there are limitations using urine samples. Testosterone esters are a form of AAS that are used therapeutically but can be abused due to its potent anabolic and androgenic effect. There are no methods in healthcare today to detect T esters, except for the T/E ratio in urine.AimsThe overall aim of study I and II was to develop and validate a method on liquid chromatography tandem mass spectrometry (LC-MS/MS), to detect AAS including T esters in serum and dried blood spot (DBS) samples. As a proof-of- concept, the method was used to test the applicability of AAS detection in clinical samples.Results and ConclusionThe results of both studies show that serum and DBS are suitable matrices for analysis of AAS and can be an appropriate complement to urinary testing. The methods have high sensitivity with a lower limit of quantification (LLOQ) at 0.05- 0.5 ng/ml in study I and a LLOQ at 0.4 ng/ml for the majority of AAS in study Il. In serum, AAS was found in 80% of the samples where positive urine findings had previously been confirmed. When comparing T concentrations measured with LC- MS/MS and immunochemistry assay, there was a notable difference in the measured concentration in samples positive for T esters. This indicates a cross- reaction in T ester positive samples when T is analysed with an immunochemistry assay. In the T enanthate study we could see a clear correlation between positive findings and a T/E ratio >10 except in one individual who was homozygous for UGT2B17 deletion. In study II, the DBS method quantified 72% of the samples above LLOQ even after six months of storage at 20 ℃. Dried blood spots proved to be a matrix with high stability that can improve sample storage in terms of logistics and offers low invasiveness regarding sample taking.List of scientific papersI. Bahare Makvandi, Anton Pohanka, Mats Bergström, Annica Börjesson, Mikael Lehtihet, Lena Ekström, Yufang Zheng. Detection of anabolic androgenic steroids in serum samples. Drug testing and analysis, vol 15(6), (2023): 678-688. https://doi.org/10.1002/dta.3476II. Yufang Zheng, Bahare Makvandi, Anton Pohanka, Mikael Lehtihet, Lena Ekström. Detection of Anabolic Androgenic Steroids, including steroid- esters, in dried blood spots. [Manuscript]</p
Evaluation and optimization of digital psychological self-help interventions
No full textBackground: Mental health problems are widespread, and while evidence-based psychological treatments exist, many individuals still lack access. Digital psychological self-help interventions have been proposed as part of the solution. Their key advantage is accessibility - by allowing individuals to independently work with digital treatment materials, they enable access to care regardless of location and extend treatment reach without increasing the demand for clinicians. However, these interventions often suffer from low treatment engagement and effects, underscoring the need to expand knowledge on how to optimize them.Aim: The overall aim of this thesis was to examine the feasibility of delivering digital psychological self-help interventions to populations with diverse mental health problems, and to evaluate strategies to optimize these interventions in terms of treatment engagement, efficacy, and user experience.Study I was a feasibility study evaluating a digital self-help problem-solving intervention provided to patients (N = 12) with clinically significant symptoms of depression and/or anxiety on the waiting list for routine psychiatric care. Usability and credibility were deemed sufficient. Nine out of twelve engaged with the intervention at least once, and five completed the final step. Most participants reported a positive overall user experience. Symptom improvement varied, with some participants meeting criteria for clinical improvement and recovery. No severe negative effects were reported. The findings indicate that a digital self-help problem-solving intervention may be feasible to provide to patients on the waiting list for routine psychiatric care.Study II was a randomized controlled trial assessing the effect of an optimized versus basic graphical user interface (GUI) in a digital self-help problem-solving intervention provided to a general population sample (N = 397) reporting emotional or practical problems. No significant differences between groups were found in usability or credibility. Participants who used the optimized GUI were significantly more likely to engage with the intervention at least once (71.7% vs. 50%), generated significantly more solutions both overall and per problem, and rated the intervention as significantly easier to understand and less overwhelming. The findings show that incorporating an optimized GUI into a digital self-help problem-solving intervention for the general population can improve engagement, without impacting usability or credibility.Study III was a factorial randomized controlled trial (2x2x2) evaluating the effect of an optimized GUI, automated reminders, and an adaptive treatment strategy, in a digital self-help intervention for individuals with insomnia (N = 447). The optimized GUI significantly improved engagement ratings during treatment (d = 0.34) and up to three months later (d = 0.24), recorded sleep log days, login frequency, and usability. Automated reminders significantly increased sleep log days and logins, while the adaptive treatment strategy significantly improved treatment satisfaction, and required an average of 13.74 minutes of clinician time per individual. Being in all three factors led to a greater symptom improvement during the treatment period (d = 0.50). Negative effects were evenly distributed across factors. No severe negative effects were reported. The findings show that an optimized GUI and automated reminders can independently increase engagement with a digital self-help insomnia intervention, and when combined with an adaptive treatment strategy, symptom improvement can be enhanced.Conclusions: Digital psychological self-help interventions seem to be feasible for both clinical and general populations. In these interventions, improved intervention design can significantly enhance treatment engagement, symptom improvement, and user experience. In summary, they show promise as a complement to clinician-guided treatment methods and as a means of scaling up psychological treatment, provided they are carefully designed for self-help use.List of scientific papersI. Hentati, A., Forsell, E., Ljótsson, B., Lindefors, N., & Kraepelien, M. (2022). A self-guided and monitored digital problem-solving intervention for patients with symptoms of depression or anxiety on the waiting list for treatment in routine psychiatric care: Feasibility study. BJPsych Open, 8(2), e43. https://doi.org/10.1192/bjo.2022.14II. Hentati, A., Forsell, E., Ljótsson, B., Kaldo, V., Lindefors, N., & Kraepelien, M. (2021). The effect of user interface on treatment engagement in a self-guided digital problem-solving intervention: A randomized controlled trial. Internet Interventions, 26, 100448. https://doi.org/10.1016/j.invent.2021.100448III. Hentati, A., Hentati Isacsson, N., Rosén, A., Jernelöv, S., Kaldo, V., Ljotsson, B., Forsell, E., Lindefors, N., & Kraepelien, M. Effects of an optimized graphical user interface, automated reminders, and an adaptive treatment strategy on treatment engagement and outcome in digital self-help for insomnia: A single-blind factorial randomized controlled trial. [Submitted]</p
Benign breast lesions : analysis by artificial intelligence and removal by vacuum-assisted excision
No full textFollowing advances in diagnostic imaging modalities over the last decade, lesions of uncertain malignant potential have been increasingly diagnosed, primarily through mammography and sonography. These diagnoses, however, increase patient anxiety and result in an abundance of work-ups, including biopsies for radiologists, and often lead to unnecessary surgery.One modern field of research is the integration of artificial intelligence (AI) based computer-aided detection (CAD) systems into various types of equipment to improve their accuracy. Our first study (Study 1) investigated the grading of previous benign biopsies using an AI-CAD system that has been integrated into mammography.Another modern field of research has been the use of larger bore needles in breast biopsies, such as vacuum-assisted biopsy needles with an outer diameter of up to 7G (4.6 mm). These needles can provide a sufficient tissue sample with which to obtain a more accurate diagnosis, while at the same time allowing the operator to completely excise the specimen under local anesthesia. Our second study (Study 2) investigated how needle size affected the time and results of the excision procedure. Our third study (Study 3) evaluated the procedure from the patients' perspective, documenting their experiences and any eventual adverse effects after the procedure. Our fourth study (Study 4) compared the first diagnostic pathology report to the reports obtained post-excision to identify lesion characteristics that would help determine which lesions are more susceptible to excision with a larger needle.In Study 1 we retrospectively applied a commercial AI-CAD system (Insight MMG, version 1.1.4.3; Lunit Inc.) to a dataset of screening mammograms from 10,889 women. We divided the study population into three groups: women who did not undergo a biopsy, those who underwent a biopsy before or after screening mammography (with benign results), and those who were diagnosed with breast cancer. The AI system flagged all women above the cutoff threshold, which was defined as 0.4 on a scale of 0.0 to 1.0. The percentages of women flagged were as follows: 3.5% for healthy women without a biopsy, 11% for those with benign biopsy findings, and 84% for those with breast cancer (P In Study 2 we performed a randomized controlled trial to compare the excision completeness and efficacy of the vacuum-assisted excision (VAE) procedure using 7G and 10G vacuum needles. We enrolled 208 patients, and after withdrawal of consent, the trial population included 194 patients. There were no differences in procedure time (P = 0.126) or excision completeness (P = 0.109) between procedures performed using 7G and 10G needles. Of the 127 patients who attended the 24-month follow-up, 88% (112/127) had lesions completely excised, with no statistically significant difference between the 7G and 10G needles.In Study 3 we administered a questionnaire to all of the patients included in Study 2. Patient acceptance of the procedure and short- and long-term complications were also documented. We calculated the total hospital costs of the VAE procedures and compared them with those of open surgical excision (OSE), the previous standard of care for surgical excision. There were no significant differences in pain levels (P = 0.713), complications (P = 0.724), or patient acceptance of the procedure between the 7G and 10G needle groups (P = 0.401). Approximately 97% (173/178) of the patients would recommend the procedure to others, and the total hospital procedural cost of VAE was estimated to be 60% lower than that of OSE.In Study 4 we retrospectively examined the results of the pathology reports of all patients included in Study 2; however, we excluded patients who did not have a cytological or histopathological diagnosis prior to the VAE, during which tissue samples were placed in one, two, or three successive containers, starting at the core of the lesion and moving outwards to the normal tissue. The results of the diagnostic reports from the initial biopsy (cytology and/or histology) were compared with those from the tissues obtained during the VAE. The discrepancy between the diagnoses of fine needle aspiration (FNA) specimens and those from VAE was 38%, while that for core needle biopsy (CNB) was 29%. The upgrade rate to cancer was most common after a diagnosis of atypical ductal hyperplasia (ADH) on CNB.In conclusion, this thesis provides new knowledge on how to improve the performance of AI-CAD systems and broadens our understanding of we can improve the performance of AI. This confirms the necessity for alternative solutions to surgery for the diagnosis and treatment of undetermined lesions and provides data to support a separate personalized approach for different lesion types.List of scientific papersI. Athanasios Zouzos, Aleksandra Milovanovic, Karin Dembrower, Fredrik StrandEffect of Benign Biopsy Findings on an Artificial Intelligence-Based Cancer Detector in Screening Mammography: Retrospective Case-Control StudyJMIR AI 2023 | vol. 2 | e48123 | p. 7https://doi.org/10.2196/48123II. Athanasios Zouzos, Irma Fredriksson, Andreas Karakatsanis, Iliana Aristokleous, Theodoros Foukakis, Fredrik StrandEffect of needle size on outcomes of vacuum-assisted excision of breast lesions. A randomized controlled trialEuropean Journal of Radiology 183 (2025) 111895https://doi.org/10.1016/j.ejrad.2024.111895III. Athanasios Zouzos, Irma Fredriksson, Andreas Karakatsanis, Fredrik StrandPatient experience and healthcare cost aspects of vacuum-assisted excision of breast lesions. A report from the Swedish VAE randomized clinical trial[Manuscript]IV. Athanasios Zouzos, Irma Fredriksson, Andreas Karakatsanis, Johan Hartman, Fredrik StrandVariation in pathological appearance across repeated sampling from probably benign breast lesions[Manuscript]</p
Fragility fractures, self-rated health and treatment with a spinal orthosis in older women in primary health care
No full textFragility fractures, particularly hip fractures and vertebral fractures, are associated with significant morbidity, reduced functional status, and increased mortality in older adults. Identifying reliable predictors of fracture risk and mortality, as well as effective management strategies, is critical for improving outcomes in older adults. This research investigated whether self-rated health (SRH) or combined blood levels of parathyroid hormone (PTH) and insulin-like growth factor-binding protein 1 (IGFBP-1) may provide additional prognostic value. We also evaluated the effects of non-pharmacological interventions, exercise and wearing an activating spinal orthosis, on osteoporosis-related symptoms.In Study I a cohort of 350 community-dwelling women aged 69-79 years (median 72.4) assessed their SRH by answering the question "How would you rate your health right now?" using a visual analogue scale (0-100 mm) at baseline. They were followed for 10 years and data on hip fractures and all-cause mortality were retrieved from healthcare registers. SRH was categorised as low, intermediate, or high (reference). Associations with the 10-year risks of hip fractures and all-cause mortality were analysed using Cox proportional hazards regression model. During the 10-year follow-up, 40 hip fractures and 72 deaths occurred. Women with low and intermediate SRH had a significantly higher risk of hip fracture (HR: 3.17, 95% CI: 1.25-8.01 and HR: 2.75, 95% CI: 1.08-7.04, respectively) compared to those with high SRH. The association remained significant after adjusting for bone mineral density. No association was observed between SRH and all-cause mortality.In Study II the same cohort as in Study I was studied, but this time we investigated whether baseline blood levels of PTH in combination with IGFBP-1 were associated with a 10-year risk of hip fractures and all-cause mortality. Blood samples were collected from 338 women. Participants were divided into four groups: (A) normal PTH and low IGFBP-1, (B) normal PTH and high IGFBP-1, (C) elevated PTH and low IGFBP-1, and (D) elevated PTH and high IGFBP-1 (reference). Ten-year data on hip fractures and all-cause mortality were retrieved from healthcare registers Associations with a 10-year risks of hip fractures and all-cause mortality were analysed using age-adjusted Cox proportional hazards regression models. Women with elevated PTH and high IGFBP-1 (D) had a two- to threefold increased risk of all-cause mortality compared to the other groups. No association was found between PTH and IGFBP- 1 levels and hip fracture risk.Studies III and IV are based on the same randomised controlled trial including 113 women aged >60 years with back pain and osteoporosis, with or without vertebral fractures. The participants were randomised into three groups: spinal orthosis, equipment training, and control. Assessments were performed at baseline, after 3 months and after 6 months. In Study III we analysed the difference between the three groups regarding back pain, back extensor strength, and kyphosis index. Statistical analyses were conducted using mixed models for repeated measures according to intention-to-treat (ITT) and per-protocol (PP) principles. The change in extensor strength in each group was analysed with paired t-test. In Study IV, we analysed differences between the three groups regarding health-related quality of life (HRQoL), which was measured by using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFFO-41) and the Short Form health survey (SF-36). Statistical analyses were conducted using mixed models for repeated measures according to ITT and PP principles. We also used Wilcoxon signed-rank test to compare HRQoL values at baseline, 3 months, and 6 months within groups and Mann-Whitney test to compare controls to intervention groups regarding change of CGRP, IL-6, and SP from baseline to 6 months.A total of 96 participants completed the study. In Study III, no significant differences were observed between groups for back pain, kyphosis index, or back extensor strength after 6 months. However, back extensor strength increased within groups: 26.9% in the spinal orthosis group, 22.1% in the training group, and 9.9% in the control group. In Study IV no significant improvement in quality of life (QoL) was observed. No changes were detected in the levels of calcitonin gene-related peptide (CGRP) or substance P (SP). Interleukin-6 (IL-6) levels were significantly lower at six months in the spinal orthosis group compared to the other groups.In conclusion our findings suggest that SRH may serve as an independent risk marker for hip fractures, complementing assessments based on BMD. Simultaneously elevated PTH and IGFBP-1 levels are associated with increased mortality (all-cause and cardiovascular) but not fracture risk. Non-pharmacological interventions, such as activating spinal orthoses and equipment training, may improve back extensor strength, though their impact on pain, kyphosis and HRQoL remains unclear. Spinal orthosis may be an alternative treatment method in osteoporosis, though further studies are needed.List of scientific papersI. Uzunel E, Lundin H, Wändell P, Salminen H. Association between self-rated health and the risk of hip fracture and mortality in a cohort of older women during a 10-year follow-up. Blank RD, redaktör. PLoS ONE. 05 mars 2021;16(3):e0247924.https://doi.org/10.1371/journal.pone.0247924II. Uzunel E, Ranch Lundin H, Grahn Kronhed AC, Wändell P, Salminen H. Levels of parathyroid hormone and IGF binding protein 1 and associations with mortality and hip fractures in older women. Sci Rep. 26 november 2024;14(1):29399.https://doi.org/10.1038/s41598-024-80527-7III. Kaijser Alin C, Uzunel E, Grahn Kronhed AC, Alinaghizadeh H, Salminen H. Effect of treatment on back pain and back extensor strength with a spinal orthosis in older women with osteoporosis: a randomized controlled trial. Arch Osteoporos. december 2019;14(1):5https://doi.org/10.1007/s11657-018-0555-0IV. Uzunel E, Grahn Kronhed AC, Kajser Alin CK, Ahmed AS, Wändell P, Salminen H. The Effect of Group Training or Spinal Orthosis on Quality of Life and Potential Plasma Markers of Pain in Older Women With Osteoporosis. A Randomized Controlled Trial. Archives of Rehabilitation Research and Clinical Translation. december 2023;5(4):100297.https://doi.org/10.1016/j.arrct.2023.100297</p