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Benzodiazepines and Z-drugs in Sweden : pharmacoepidemiological studies on patterns of use and risks
No full textBenzodiazepines and related Z-drugs (BZDR) are effective for the short-term treatment of symptoms like anxiety and insomnia, but their long-term use is discouraged by clinical guidelines. Despite the concerns about adverse effects of BZDR treatment, there existed limited knowledge specifically on associations between BZDR treatment and risks of subsequent infections and alcohol- and drug-related problems. This thesis, therefore, leveraged the unique collection of nationwide Swedish registers to examine the predictors of BZDR prescription patterns and assess the associations of BZDR treatment with risks of serious infections and substance-related problems.Study I assessed BZDR use patterns among 930,465 new users in 2007-2013. We found that the proportion of individuals progressing to long-term BZDR users (>6 months) was substantial and increased with age, from 21% in those who were 0-17 years at BZDR initiation to 57% in individuals aged 265 years. Further, we identified four distinct five-year BZDR use trajectories, including the 'discontinued' trajectory that showed eventual cessation of BZDR use from the third year after the treatment start, and the 'decreasing', 'slow decreasing' and 'maintained' trajectories that indicated continued BZDR use up to five years from the initiation. More BZDR recipients belonged to the 'discontinued' trajectory compared to other trajectories, but the proportions of discontinued users reduced with age. Across all age groups, initiating with multiple BZDRs and having the concurrent use of other medicines were linked with higher risks of subsequent long-term BZDR use (compared with short-term use) and belonging to the 'decreasing', 'slow decreasing' and 'maintained' trajectory memberships (compared with developing the 'discontinued' trajectory). The study highlighted the importance of providing support to prescribers in making evidenced-based decisions when starting and managing BZDR treatment for patients of all ages.Study II assessed the association between BZDR treatment and the risk of serious infections among individuals under 65 years. Infection outcomes were defined by the diagnosis from in- and/or out-patient care or underlying cause of death. We constructed three cohorts, including a demographically matched cohort of 713,896 pairs of incident BZDR users and nonusers matched on sex, birth year and month, and county of residence, a co-twin control cohort of 9197 BZDR users and 9298 unexposed co-twins (co-multiples), and an active comparator cohort of 434,900 BZDR users and 428,074 selective serotonin reuptake inhibitor users. In the demographically matched cohort, BZDR initiation was associated with an 83% increase in the risk of any serious infection. This association persisted, although attenuated, in the co-twin control cohort and active comparator cohort. Further, we found a dose-response relationship between BZDR cumulative dosage and an elevated risk of infections. Future research is called for examining the potential mechanisms underlying the observed association of BZDR treatment and increased risks of serious infections, given such insights may inform safer treatment strategies.Study III assessed the long-term risk of substance-related problems following BZDR initiation in Swedish residents who were aged 10 or older and had no prior BZDR prescriptions 2007. The outcomes included incident alcohol-related problems and drug-related problems, defined by alcohol and drug use disorders, poisoning, suspected criminal offenses, and related deaths. The demographically matched cohort consisted of 960,430 pairs of incident BZDR users and nonusers matched on sex, year and month of birth and residence county, and the co-twin control cohort included 12048 BZDR exposed twins and 12,579 unexposed co-twins (co-multiples). Over a 14-year follow-up, BZDR treatment initiation was linked to a slight yet consistent increase in the risks of alcohol-related and drug-related problems. These associations persisted in the co-twin control comparison and all sensitivity analyses.Study IV subsequently examined the concurrent risk of substance-related problems using a within-individual design. We compared risks of acute alcohol- or drug-related problems during the period on active BZDR treatment to that during the period off BZDR treatment, among individuals born before 1997 who received the first BZDR prescription during 2007-2020. Periods on BZDR treatment were associated with a 9% increase in the risk of alcohol-related problems and a 16% increase in the risk of drug-related problems, compared to periods off BZDR treatment. Additionally, the analyses for specific subgroups of outcomes showed the strongest association for unintentional drug overdose. When we considered timing of these associations by further splitting the on-treatment and off-treatment periods, the observed increased risks of alcohol- and drug-related problems persisted within the first 91 days and beyond 91 days after BZDR treatment start. The findings suggest substance-related risks in patients undergoing BZDR treatment should be monitored.In conclusion, the thesis has explored long-term use of prescribed BZDR and the dynamic use trajectories across different age groups, assessed the associations between BZDR treatment and subsequent infection risks, and examined the relationship between BZDR treatment and risks of substance-related problems. The findings may prompt future research and inform clinical practice on BZDR prescribing.List of scientific papersI. Isomura, K.*, Wang, X.*, Chang, Z., Hellner, C., Hasselström, J., Ekheden, I., ... & Sidorchuk, A. (2023). Factors associated with long-term benzodiazepine and Z-drug use across the lifespan and 5-year temporal trajectories among incident users: a Swedish nationwide register-based study. European Journal of Clinical Pharmacology, 79(8), 1091-1105. https://doi.org/10.1007/s00228-023-03515-2II. Wang, X., Isomura, K., Lichtenstein, P., Kuja-Halkola, R., D'Onofrio, B. M., Brikell, I., ... & Sidorchuk, A. (2024). Incident benzodiazepine and Z-Drug use and subsequent risk of serious infections. CNS drugs, 38(10), 827-838. https://doi.org/10.1007/s40263-024-01108-wIII. Wang, X., Chang, Z., Molero, Y., Isomura, K., de la Cruz, L. F., Lichtenstein, P., ... & Sidorchuk, A. Incident benzodiazepine and Z- drug use and subsequent risk of alcohol-and drug-related problems: a nationwide matched cohort study with co-twin comparison. Journal of Psychopharmacology. [Accepted]IV. Wang, X., Molero, Y., Chang, Z., Isomura, K., Lichtenstein, P., Larsson, H., ... & Sidorchuk, A. Association of benzodiazepine and Z-drug use with alcohol- and drug-related problems: a within-individual comparison. [Manuscript]*Joint first authorship.</p
Supporting person-centred, team-based stroke rehabilitation with ICT : implementation and evaluation of F@ce 2.0
No full textAccess to rehabilitation is crucial for resuming participation in meaningful daily activities. As stroke rehabilitation continues to evolve, key areas include person- centred practices and the integration of digital health. Although both professionals and stroke survivors value person-centred goal setting, achieving collaborative rehabilitation planning remains complex. Similarly, there are promising results regarding digital rehabilitation, but research has often focused on highly specialised solutions rather than accessible technology.This thesis aimed to evaluate the impact and implementation of F@ce 2.0, a person-centred, team-based intervention for rehabilitation after stroke supported by information and communication technology (ICT).Within the thesis project, F@ce 2.0 was implemented in seven Swedish rehabilitation teams, with an additional five teams serving as a control condition. In total, 100 stroke survivors, 48 significant others and 53 healthcare professionals participated in the project. To capture a broad perspective, the evaluation was based on both quantitative and qualitative data.The findings from Study I revealed that both the intervention group and the control group had improved their self-rated activity performance and satisfaction at the 6-month follow-up, with no significant between-group differences. For significant others, only the intervention group showed a decreasing trend in caregiver burden. Findings from studies II-IV conveyed how person-centred rehabilitation was developed through dialogue and support, and revealed a potential for F@ce 2.0 as a means of resuming daily activities. The ICT component was found motivational, but improvements were suggested.Study IV was a process evaluation of F@ce 2.0. Findings underline the importance of creating prerequisites for integrating clinical development and research. The study also contributes to the limited knowledge of using daily activities as an interdisciplinary lens for goal setting in rehabilitation.In summary, this thesis suggests that a focus on daily activities may be fruitful for increasing person-centredness in stroke rehabilitation. It further illustrates the possibilities and challenges of using everyday technology to support goal achievement. The findings also underline the necessity of involving rehabilitation teams, stroke survivors and significant others in the development of new interventions to ensure feasibility.List of scientific papersI. Söderhielm K, Ytterberg C, Eriksson G, von Koch L, Tistad M, Guidetti S. A non-randomised between-group comparison of F@ce 2.0: a person-centred and interdisciplinary rehabilitation intervention after stroke supported by information and communication technology. [Submitted]II. Söderhielm K, Tistad M, Ytterberg C, Guidetti S. (2025). Experiences of F@ce 2.0: a person-centred intervention for home-based rehabilitation after stroke supported by digital technology - a qualitative study. BMJ Open, 15(7), e089147. https://doi.org/10.1136/bmjopen-2024-089147III. Eriksson G*, Söderhielm K*, Erneby M, Guidetti S. (2025). Family Members' Experiences of a Person-Centered Information and Communication Technology-Supported Intervention for Stroke Rehabilitation (F@ce 2.0): Qualitative Analysis. JMIR Rehabilitation and Assistive Technologies, 12, e69878-e69878. *Shared position as first author. https://doi.org/10.2196/69878IV. Söderhielm K, Hawkins J, Ytterberg C, Tistad M, Guidetti S. Process evaluation of F@ce 2.0, a team-based, person-centred intervention for rehabilitation after stroke supported by ICT. [Submitted]</p
Visual motion processing in visual motion hypersensitivity patients ensuing from mild traumatic brain injury
No full textMild traumatic brain injury (mTBI) represents a pervasive public health issue, precipitating a range of persistent post-concussion symptoms (PCS) in up to 82% of individuals. Among the most challenging of these is visual motion hypersensitivity (VMH), where patients experience profound dizziness and disorientation in visually complex environments, a phenomenon often described as "supermarket syndrome." This condition creates a significant diagnostic conundrum, as patients report severe, life-altering symptoms despite the absence of overt structural damage on standard clinical neuroimaging, which has historically led to the misattribution of symptoms to psychosomatic origins. The prevailing theory to explain VMH has been one of "visual dependence," a model that posits the brain over relies on visual cues to compensate for a primary deficit in the vestibular system. While applicable in some cases, this framework is critically insufficient for the substantial and poorly understood cohort of patients who suffer from severe VMH while presenting with a functionally intact vestibular system. This discrepancy highlights a fundamental gap in our understanding and necessitates a new conceptual model of VMH as a primary disorder of visual processing. This thesis was therefore designed to systematically investigate the neurosensory underpinnings of VMH in this specific non-vestibular PCS population, employing a multi-level approach from low-level sensory processing to integrated sensorimotor control.The research involved recruiting and comparing patients with chronic PCS-VMH against age-matched healthy controls across three complementary studies. The methodology was sequential and multi-modal. Study I utilized precisely controlled visual, vestibular and visuo-vestibular stimulation while recording three-dimensional gaze-stabilizing eye movements, specifically ocular torsion and vertical vergence. This allowed for the dissociation of the optokinetic reflex (OKR) and the vestibulo-ocular reflex (VOR), providing a quantitative measure of how visual motion signals modulate subcortical sensorimotor pathways and influence the velocity storage mechanism (VSM). Study II employed complex optokinetic paradigms with varying stimulation patterns (coherent vs. incoherent motion) presented to different visual field locations (central vs. peripheral) to probe the functional consequences of VMH on oculomotor control under challenging conditions that mimic real-world visual stimuli. The objective oculomotor data were then correlated with subjective symptom severity, as measured by the Visual Vertigo Analog Scale (VVAS) and the Dizziness Handicap Inventory (DHI). Study III shifted focus to fundamental perceptual mechanisms, using a custom-developed psychophysical apparatus to measure Critical Flicker Frequency (CFF) thresholds via a staircase procedure at multiple retinal eccentricities. This approach was designed to isolate the integrity of low-level visual processing, using CFF variability as a proxy for internal perceptual noise. Data from all studies were analyzed using advanced statistical models, including generalized linear mixed models (GLMM), to account for repeated measures, covariates and variability between subjects.Study I demonstrated a clear sensory imbalance: patients exhibited pathologically enhanced optokinetic responses, with significantly increased oculomotor gain and slow-phase velocities during visual and visuo-vestibular stimulations, alongside an expedited onset of optokinetic nystagmus during visual stimulations. Crucially, their vestibular-only responses were normal, indicating that the VSM's intrinsic properties were preserved but were being hijacked by a disinhibited, pathologically potent visual feedback loop. Study II confirmed that this hypersensitivity translates into maladaptive motor control, with patients demonstrating exaggerated oculomotor responses with a trend towards complex peripheral motion and a significantly weaker correlation between their torsional and vergence eye movements, suggesting poorer motor coordination. Critically, the magnitude of these objective oculomotor biomarkers was strongly and significantly correlated with the patients' subjective symptom scores on both the VVAS and DHI. Study III traced the origin of this dysfunction to an elemental level, revealing that patients' CFF thresholds were pathologically influenced by perceptual noise. The modulating effect of CFF variability on elevating the final perceptual threshold was five times greater in the PCS group than in controls. Furthermore, a negative correlation was found between CFF variability and time since injury, suggesting slow, partial neurological recalibration or compensatory processes over time.In conclusion, this thesis provides further insight into the ways abnormal visual- motion processing influences visuo-vestibular control and explores plausible pathophysiological mechanisms. The collective findings demonstrate that this debilitating condition is not arising from compensation for vestibular loss but is driven by a primary dysfunction within the visual system itself. The evidence points to a foundational deficit in low-level sensory processing characterized by an abnormal sensitivity to internal neural noise. This sensory instability appears to necessitate a compensatory upregulation of gain across visual pathways, which in turn manifests as the exaggerated and disinhibited oculomotor responses that are directly linked to the patient's clinical symptoms. These results establish specific oculomotors and perceptual measures as potent objective biomarkers that can aid in the diagnosis, stratification, and monitoring of rehabilitation progress in patients with PCS. By re-framing visual motion hypersensitivity as a disorder of pathological gain control rooted in sensory noise, this work provides a new, evidence-based framework to guide the development of more targeted and effective therapeutic strategies for this challenging patient population.List of scientific papersI. Frattini, D., Rosen, N., & Wibble, T. (2024). A Proposed Mechanism for Visual Vertigo: Post-Concussion Patients Have Higher Gain From Visual Input Into Subcortical Gaze Stabilization. Investigative ophthalmology & visual science, 65(4), 26. https://doi.org/10.1167/iovs.65.4.26II. Wibble, T., Frattini, D., Benassi, M., Bolzani, R., & Pansell, T. (2023). Concussed patients with visually induced dizziness exhibit increased ocular torsion and vertical vergence during optokinetic gaze- stabilization. Scientific reports, 13(1), 3690. https://doi.org/10.1038/s41598-023-30668-yIII. Frattini, D., Benassi, M., Wibble, T., Nilsson, M., Bolzani, R. & Pansell, T. (2025). Temporal Visual Processing Deficits in Post-Concussion Syndrome. [Submitted]</p
Molecular modulators of skeletal muscle metabolism in exercise and type 2 diabetes
No full textSkeletal muscle is central to glucose homeostasis and accounts for most postprandial glucose disposal. It has a remarkable metabolic adaptability, especially in response to diet and exercise. Defects in skeletal muscle insulin sensitivity is a major driver of type 2 diabetes mellitus (T2DM). This thesis investigates molecular aspects of skeletal muscle metabolism in health and disease, with a focus on small molecules that may mediate the beneficial effects of exercise or serve as therapeutic modulators in T2DM.In study I, we conducted a comparative transcriptomic and functional analysis of three commonly used skeletal muscle cell models: primary human skeletal muscle cells, mouse C2C12, and rat L6 myotubes. This revealed several model-specific differences in response to insulin, substrate oxidation, and gene expression patterns relevant to glucose handling and contractile function. The study can be used as a companion for selecting the most appropriate cell models for studying different aspects of muscle metabolism.Study II examined the metabolic effects of glutamine in skeletal muscle using human cohorts, rodent models, and cell cultures. In humans, circulating glutamine levels negatively correlated with body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA- IR). In mice with diet-induced obesity and insulin resistance, glutamine supplementation modulated insulin signalling and reduced markers of obesity-associated skeletal muscle inflammation.In study III, we investigated the expression and function of the succinate receptor SUCNR1 (GPR91) in human skeletal muscle. By integrating bulk transcriptomics, single-cell analyses, in situ visualization, and signalling assays, we found SUCNR1 expression to be confined to non- muscle cells; primarily macrophages and smooth muscle cells, within muscle tissue.Study IV explored a novel metabolic role for thromboxane signalling in skeletal muscle. Using human plasma metabolomics, murine models, and in vitro experiments, we identified exercise-associated modulation of circulating thromboxane levels and demonstrated that thromboxane receptor activation influences glucose uptake, glycogen synthesis, and systemic glucose tolerance, partly via PKA/filamin A signalling.These studies broaden our understanding of skeletal muscle metabolism by revealing novel mechanisms, identifying new signalling pathways, and highlighting the challenges of translating mechanistic insights from model systems to human physiology.List of scientific papersI. Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism. Abdelmoez AM, Sardón Puig L, Smith JAB, Gabriel BM, Savikj M, Dollet L, Chibalin AV, Krook A, Zierath JR, Pillon NJ. Am J Physiol Cell Physiol. 2020 Mar 1;318(3):C615-C626. https://doi.org/10.1152/ajpcell.00540.2019II. Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes. Dollet L, Kuefner M, Caria E, Rizo-Roca D, Pendergrast L, Abdelmoez AM, Karlsson HKR, Björnholm M, Dalbram E, Treebak JT, Harada J, Näslund E, Ryden M, Zierath JR, Pillon NJ, Krook A. Diabetes. 2022 Apr 1;71(4):624-636. https://doi.org/10.2337/db20-0814III. Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle. Abdelmoez AM, Dmytriyeva O, Zurke YX, Trauelsen M, Marica AA, Savikj M, Smith JAB, Monaco C, Schwartz TW, Krook A, Pillon NJ. Am J Physiol Endocrinol Metab. 2023 Apr 1;324(4):E289-E298. https://doi.org/10.1152/ajpendo.00009.2023IV. Thromboxane receptor stimulation improves glucose uptake in skeletal muscle cells and whole-body glycaemic control. Abdelmoez AM, Yu X, Rizo-Roca D, Jollet M, Marica AA, Dollet L, Borg M, Björnholm M, Checa A, Olsson T, Otten J, Zierath J, Krook A, Schwartz T, Chibalin AV, Pillon N. [Manuscript]</p
Infections in the risk and prognosis of multiple sclerosis and amyotrophic lateral sclerosis
No full textNeurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are incurable, progressive, and heterogeneous. In MS, autoimmune T- and B-cell attacks against central-nervous-system myelin initiate focal demyelination, axonal injury, and gliosis, leading to clinically evident relapses that may evolve into slowly progressive disability even without further overt inflammation. ALS, by contrast, is characterized by selective degeneration of upper and lower motor neurons accompanied by cytoplasmic TDP-43 aggregation, microglial activation, oxidative stress, and metabolic dysregulation, typically culminating in progressive muscle weakness and respiratory failure within 3-5 years of onset. Although a dysregulated immune response and low-grade neuroinflammation are well-recognized components of both conditions, the contribution of infections to their initiation and course remains unclear. In this thesis, we investigated the bidirectional links between infections and MS and ALS, including post-diagnosis infection risk (Study I), impact of infections on MS progression under different treatments (Study II), role of hospital-treated infections in ALS risk and prognosis (Study III), and subclinical infections detected via a serological screening in ALS (Study IV).In Study I, we conducted both a community-based matched cohort and a twin study, using data from the UK Biobank and Swedish Twin Registry (UK Biobank: 2023 MS, 2200 Alzheimer's disease [AD], 3050 Parkinson's disease [PD] patients, and their individually matched healthy controls; Swedish Twin Registry: 230 twin pairs for the analysis of MS, 885 for AD, and 626 for PD). The aim was to investigate the incidence of serious infections following a diagnosis of MS, AD and PD, as well as the contribution of post-diagnostic infections on mortality after diagnosis of these conditions. Patients with MS, AD or PD exhibited significantly higher rates of hospital-treated infections after diagnosis compared to their matched healthy controls. Notably, an elevation in infection risk was already evident during the years preceding the diagnosis of these conditions, suggesting that immune alterations or preclinical disease processes may contribute to this early vulnerability. Causal mediation analysis indicated that infections experienced after diagnosis explained only a modest portion of the excess mortality risk associated with these diseases. In other words, while individuals with MS (and AD and PD) are more susceptible to infections, these infections only partially mediate the observed increase in mortality.In Study II, we conducted a nationwide registry-based cohort study in Sweden to examine infection risk and disability worsening in MS patients receiving different disease-modifying therapies. This study included over 16,000 MS treatment episodes, comprising 8,759 with the B-cell-depleting antibody rituximab and 7,561 with injectable interferon-ß or glatiramer acetate (IFN/GA). Rituximab-treated patients had approximately double the risk of hospital-treated infections compared to those treated with IFN/GA. Hospital-treated infections were significantly associated with disability worsening, measured as an increase in the Expanded Disability Status Scale scores; this association was most pronounced in progressive MS and in patients treated with IFN/GA. Among patients with relapsing-remitting MS treated with IFN/GA, an inpatient-treated infection was associated with greater subsequent disability progression after adjustment for relapses and MRI activity, whereas no such association was observed in patients treated with rituximab. These findings highlight a trade-off between infection risk and disease control, namely that, to optimize long-term outcomes, clinicians must balance the risk of infection against the benefit of preventing disease progression. Highly effective therapies such as rituximab increase susceptibility to infections but offer superior protection against the accumulation of disability in MS.In Study III, we conducted a nationwide nested case-control study using data from the Swedish Motor Neuron Disease Quality Registry to assess the role of infections in ALS. We identified all individuals newly diagnosed with ALS in Sweden between 2015 and 2023 and matched each case to three control groups: population controls and unaffected full siblings and spouses of ALS patients, thereby accounting for potential confounding by shared genetic and environmental factors between family members. The analysis showed that individuals who developed ALS were more likely to have a history of hospital-treated infections prior to diagnosis than controls, including population, sibling, and spouse controls. This finding suggests that previous serious infections are associated with an elevated risk of ALS, independent of familial background. Moreover, ALS patients with an experience of pre-diagnostic infections tended to present more frequently bulbar onset, lower functional status, and higher levels of anxiety and depressive symptoms at diagnosis. Following ALS diagnosis, the occurrence of a hospital-treated infection was associated with a higher mortality risk in ALS patients, whereas pre-diagnostic infections were not.In Study IV, we used a multiplex serological screening to identify infectious exposures linked to ALS. Within the ALSrisc Study (Biomarkers and Risk Factors for Amyotrophic Lateral Sclerosis), we analyzed blood samples from 500 incident ALS patients and three control groups (105 sibling controls, 170 spouse controls, and 106 mimic controls with other neurological disorders) for antibodies to a broad panel of common pathogens. A higher overall pathogen burden, defined as the total number of seropositive pathogens, was associated with an increased ALS risk. Seropositivity of specific pathogens, particularly Helicobacter pylori and Chlamydia trachomatis, showed the strongest association with case status; other notable pathogens included human herpesvirus 2 (HHV-2), Epstein-Barr virus (EBV/HHV-4), HHV-6B, and Toxoplasma gondii. ALS patients with antibodies to these pathogens also tended to have poorer clinical profiles, including lower functional status at diagnosis; however, we found no strong evidence that these infections influenced post-diagnosis survival.In conclusion, this thesis clarifies the bidirectional relationship between infections and both MS and ALS, highlighting an increased infection susceptibility before and after diagnosis as well as an impact of infection on the risk and progression of these diseases. These findings add novel evidence suggesting infections as modifiable elements that may shape neurodegenerative trajectories and represent potential targets for the development of new therapeutic approaches.List of scientific papersI. Yihan Hu, Kejia Hu, Huan Song, Yudi Pawitan, Fredrik Piehl, Fang Fang. Infections among individuals with multiple sclerosis, Alzheimer's disease and Parkinson's disease. Brain Commun. 2023;5(2):fcad065. https://doi.org/10.1093/braincomms/fcad065II. Yihan Hu, Thomas Frisell, Peter Alping, Huan Song, Yudi Pawitan, Fang Fang, Fredrik Piehl. Hospital-Treated Infections and Risk of Disability Worsening in Multiple Sclerosis. Ann Neurol. 2024;96(4):694-703. https://doi.org/10.1002/ana.27026III. Yihan Hu, Charilaos Chourpiliadis, Caroline Ingre, Viktor H. Ahlqvist, Jiangwei Sun, Huan Song, Yudi Pawitan, Fredrik Piehl, Fang Fang. Hospital-treated infections and the risk and prognosis of amyotrophic lateral sclerosis: A population-based study. J Intern Med. 2025 Aug 5. https://doi.org/10.1111/joim.70008IV. Yihan Hu, Caroline Ingre, Birgitta E. Michels, Christina Seitz, Rayomand Press, Kristin Samuelsson, John Andersson, Huan Song, Yudi Pawitan, Pentti J. Tienari, Pascal Falter-Braun, Fredrik Piehl, Tim Waterboer, Fang Fang. Infections and risk and prognosis of amyotrophic lateral sclerosis: a serological screening. [Manuscript]</p
Prehospital advanced airway and ventilation management (PHAAM) in experimental trauma
No full textEffective prehospital airway management is vital for trauma patients, where securing oxygen delivery, ventilation, and hemodynamic stability is critical yet complicated by airway obstruction and hypovolemia. This thesis evaluates alternative strategies when conventional endotracheal intubation and positive pressure ventilation are impractical or dangerous, using rigorous porcine trauma models to simulate real-world challenges. Study I showed that surgical cricothyroidotomy with the scalpel-bougie-tube method was faster and achieved superior oxygenation than percutaneous Seldinger-based cricothyroidotomy in obese trauma settings, highlighting its potential as the preferred emergency approach. Study II found that permissive hypoventilation maintained oxygen delivery on par with positive pressure ventilation following hemorrhage and resuscitation, suggesting it as a feasible priority when spontaneous breathing is intact. Study III demonstrated that expiratory ventilation assistance via a small-lumen catheter maintained oxygen delivery while reducing intratracheal pressures and lactate, offering a promising alternative in partial airway obstruction. Study IV showed that flow-controlled ventilation with an I:E ratio of 1:1 using 21% oxygen restored oxygenation and ventilation during total airway obstruction more effectively than higher I:E ratios, which caused negative intratracheal pressures. Overall, these findings support a physiology-guided, enhanced airway strategy in trauma care, emphasizing a surgical front-of-neck access in obese patients, permissive hypoventilation to protect hemodynamics, and flow-controlled or expiratory ventilation techniques as potential rescue interventions, thereby advancing prehospital trauma protocols toward adaptable, evidence-based solutions that can be applied swiftly under austere conditions.List of scientific papersI. Comparison of emergency surgical cricothyroidotomy and percutaneous cricothyroidotomy by experienced airway providers in an obese, in vivo porcine haemorrhage airway model. Karlsson T, Brännström A, Gellerfors M, Gustavsson J, Günther M. Mil Med Res. 2022;9(1):57 https://doi.org/10.1186/s40779-022-00418-8II. Permissive hypoventilation is equally effective to maintain oxygenation as positive pressure ventilation after porcine class III hemorrhage and whole blood resuscitation. Karlsson T, Gellerfors M, Gustavsson J, Günther M. Transfusion 2023;63(S3):S213-S221 https://doi.org/10.1111/trf.17344III. Expiratory ventilation assistance versus pressure-controlled ventilation with ambient oxygen in a hemorrhagic trauma model: a prehospital rescue option? Karlsson T, Gustavsson J, Wellfelt K, Günther M. Intensive Care Med Exp. 2025;13(1):31 https://doi.org/10.1186/s40635-025-00742-yIV. Optimizing flow-controlled ventilation: impact of I:E ratios and oxygen concentration in a porcine model of total airway obstruction. Karlsson T, Gustavsson J, Wellfelt K, Günther M. Anesth Analg. 2025 May 16 https://doi.org/10.1213/ANE.0000000000007583</p
Blood in, blood out : aspects of blood transfusions and donations in the realms of obstetric care and beyond
No full textBlood transfusion therapy is a cornerstone of modern obstetric care, commonly administered during childbirth to manage acute hemorrhage. Meanwhile, blood donation represents a vital public health act sustained by healthy individuals, many of whom are women of reproductive age. This thesis examines red-cell transfusion and whole blood donation from multiple perspectives, including clinical patterns, recurrence, long-term outcomes, and the effects of pre- pregnancy donation on maternal and offspring health. It combines four register- based cohort studies using Swedish health data and blood donation data integrated within the SCANDAT3-S database to evaluate how blood, both received and given, intersects with maternal and neonatal health.Aims . To describe the patterns and temporal trends of red-cell transfusion use in obstetric care in Sweden.· To assess the risk of recurrent transfusion in delivery.· To investigate whether red-cell transfusion during childbirth is associated with long-term risks of autoimmune disease and non-Hodgkin lymphoma.· To evaluate whether blood donation before pregnancy is associated with adverse maternal or neonatal outcomes.Study I. Transfusion practices in obstetric care in Sweden have evolved, but national-level data on usage patterns remain limited. This study analyzed a nationwide cohort of 1.6 million deliveries in Sweden between 2003 and 2017. In addition to describing overall transfusion patterns, we examined temporal trends and volume using logistic regression. For analyses of inter-hospital variations in transfusion rates, we used direct standardization to the year 2003, adjusting for parity and maternal age. Overall, 3 percent of women were transfused annually, and there were no considerable changes over the study period. We saw an increasing proportion of low-volume and a decline in high-volume transfusions. The most common number of red-cell units transfused per delivery was two, reflecting a broader pattern where even-numbered transfusions-particularly two or four units-dominated clinical practice. We saw substantial variation in the proportion of transfused deliveries across hospitals.Summary: While overall transfusion rates remained stable, hospital-level variation and the use of paired units may signal inappropriate use and warrant further investigation.Study II. Although transfusion during childbirth is typically viewed as an event determined by the specific circumstances of each delivery, some women experience repeated transfusions across deliveries. We analyzed a nationwide cohort of 825,000 women with deliveries between 2000 and 2017 to investigate the recurrence of transfusion. We used logistic regression to estimate the odds ratios of requiring a repeated transfusion in relation to specific risk factors. Women transfused in their first delivery were overall approximately five times more likely to be transfused in their second delivery (adjusted odds ratio [aOR] 5.4, 95% confidence intervals [CI]; 5.0-5.8) than non-transfused, non- hemorrhaged women. The overall odds of repeat transfusion were similar regardless of hemorrhage diagnosis in the first delivery. When considering specific subtypes, we saw the most pronounced recurrence risk associated with prior diagnoses of atony (aOR 6.7; 95% CI 6.1-7.4), placental retention (aOR 4.4; 95% CI, 3.8-5.1), and caesarian section with hemorrhage (aOR 6.8; 95% CI, 5.8- 8.0). Certain conditions in the second pregnancy (e.g., preeclampsia, placenta previa, iron deficiency anemia) increased the odds of recurrence. Having a sister transfused in childbirth was associated with higher odds of transfusion in childbirth (aOR 1.8; 95% CI, 1.5-2.1).Summary: A prior transfusion is a strong risk factor for future transfusion, underscoring the importance of individualized risk management.Study III. The long-term effects of obstetric transfusion on immune-mediated conditions remain poorly understood. In this study, we followed a large register- based cohort of over one million women, starting in 1987, for up to 25 years to assess the risk of autoimmune disease and non-Hodgkin lymphoma. Cox proportional hazard models were used, adjusting for both fixed and time- dependent maternal factors. To reduce the risk of reverse causation, a six-month lag period was applied before the start of follow-up after each delivery. Transfusion in childbirth was modestly associated with increased risks for later diagnosis of systemic lupus erythematosus (SLE) (adjusted hazard ratio [aHR] 1.38; 95% CI, 1.01-1.87) and systemic sclerosis (aHR 1.89; 95% CI, 1.21-3.21), but not associated with risk of non-Hodgkin lymphoma or rheumatoid arthritis. However, the absolute risk difference at 25 years was slight. Sensitivity analyses, applying various stratifications and restrictions, generally supported the main findings.Summary: Although the absolute risk difference was small, transfusion in childbirth was associated with an increased risk of developing SLE and systemic sclerosis.Study IV. While blood donors are typically healthier than the general population, frequent donation may deplete iron stores and influence pregnancy outcomes. We analyzed a register-based cohort of 2.5 million deliveries between 1985 and 2017 to investigate any potential adverse effects of blood donations on pregnancy and childbirth. We used mixed-effects linear models to estimate birth weight by donation intensity, and logistic regression was applied to assess maternal and neonatal outcomes. When comparing births to non-donors to those to women who donated at least once within five years of delivery, we found that donors were less likely to experience adverse pregnancy outcomes and that the birth weight of their offspring was slightly higher. However, when considering only donors, high-frequency donors (29 donations within five years of delivery) had lower birth weight babies and higher risks of preeclampsia (aOR 1.18; 95% CI, 1.06-1.31), preterm birth (aOR 1.33; 95% CI, 1.22-1.45), and SGA infants (aOR 1.17; 95% CI, 1.03-1.34) than low-frequency donors (1-2 donations). Specific temporal analyses using interaction terms supported the notion of a biological effect. Sensitivity analyses confirmed the main findings.Summary: High-frequency whole blood donation before pregnancy may have adverse effects on maternal health and neonatal outcomes.In conclusion, the thesis reveals that transfusion and donation intersect with maternal health. It underscores the need for consistent transfusion practices, monitoring for recurrence risk, awareness of potential long-term immune effects, and cautious iron management in frequent female donors.List of scientific papersI. Brynolf A., Zhao J., Wikman A., Öberg S., Sandström A., Edgren G. (2021), Patterns of red-cell transfusion use in obstetric practice in Sweden 2003-2017: A nationwide study. Vox Sang, 116: 821-830. Epub 2021 Feb 2. PMID: 33528029https://doi.org/10.1111/vox.13074Il. Brynolf A, Sandstrom A, Edgren G. Risk of recurrent red-cell transfusion in delivery: A nationwide longitudinal study. BJOG. 2024 Mar;131(4):455-462. doi: 10.1111/1471-0528.17672. Epub 2023 Sep 25. PMID: 37749750.https://doi.org/10.1111/1471-0528.17672III. Brynolf A, Sandström A, Hjalgrim H, Edgren G. Association Between Red-Cell Transfusion in Childbirth and Long-Term Risk of Lymphoma and Autoimmune Disease: A Swedish Nationwide Cohort Study. Am J Hematol. 2025 Apr;100(4):735-739. doi: 10.1002/ajh.27610. Epub 2025 Jan 27. PMID: 39868856.https://doi.org/10.1002/ajh.27610IV. Brynolf A, Sandström A, Öberg S, Toss F, Edgren G. Whole blood donations before delivery and the risk of adverse pregnancy, delivery, and neonatal outcomes: A Swedish longitudinal cohort study. [Manuscript]</p
Peripheral neuroimmune interactions in health and arthritis-induced pain
No full textChronic joint pain is one of the leading reasons patients seek primary health care. Although advancements in anti-rheumatic drugs have significantly improved clinical outcomes for patients with rheumatoid arthritis (RA), persistent pain remains a substantial issue for many patients even after achieving clinical remission. Previous research using the collagen antibody-induced arthritis (CAIA) model demonstrated that it effectively recapitulates critical clinical features of RA, showing an inflammatory flare that resolves, while mechanical hypersensitivity, a pain-like behavior, persists beyond the flare resolution. This persistent pain has been linked to alterations in sensory neurons within the dorsal root ganglion (DRG) and the activation of surrounding satellite glial cells. Given the inflammatory nature of RA and the CAIA model, we hypothesized that peripheral neuroimmune interactions contribute to these observed changes. While the synovial immune environment is well characterized, immune heterogeneity in the DRG was less understood.In Study I, we aimed to characterize the DRG neuroimmune landscape in relation to its vasculature and permeability. Immunohistology analysis revealed a greater density of macrophages and blood vessels in the DRG compared to adjacent nerve structures. Using intravenously injected fluorescent tracers, we confirmed that the DRG-blood barrier permits the entry of blood-derived molecules, primarily internalized by macrophages. We identified zonal permeability differences, correlating increased permeability with vessels expressing higher levels of PLVAP and lower levels of CLDN5. We demonstrated that caveolar endocytosis is responsible for this permeability. Single-cell transcriptomics identified two distinct DRG macrophage populations: CD163+ and CCR2+. Further experiments showed that only the CD163+ subset internalized intravenously injected tracers, indicating their specific role in blood surveillance within the DRG. Bone marrow chimera experiments revealed rapid turnover of CCR2+ macrophages from monocytes, while CD163+ macrophages exhibited significantly slower turnover, identifying them as long-lived, tissue-resident cells. This foundational study provided critical insights into the DRG immunovascular unit, paving the way for subsequent studies examining persistent pain.In Study II, we utilized findings from the first study to investigate whether neuroimmune interactions contribute to persistent pain in the CAIA model. Single-cell transcriptomics with hashtagging enabled the creation of a temporal atlas of the DRG-joint axis during CAIA progression, revealing extensive joint remodeling during the inflammatory flare, characterized by neutrophil and monocyte infiltration, loss of long-lived, tissue-resident macrophage subtypes, and alterations in fibroblast architecture. Importantly, the macrophage-fibroblast landscape of the DRG remained altered after the resolution of the inflammatory flare. Interestingly, cellular changes within the DRG were minimal. In vivo depletion experiments demonstrated that inflammation and pain-like behaviors in the CAIA model are neutrophil-dependent. By profiling synovial CGRP+ nerve fiber sprouting, we identified that this sprouting occurs during inflammation resolution, secondary to neutrophil infiltration. Utilizing cell-cell interaction analysis on the DRG-joint atlas, we identified neutrophil-derived Osm and Sema4D as critical ligands driving neuronal remodeling. Examination of publicly available human RA datasets confirmed expression of these molecules by synovial neutrophils in RA patients. Thus, our findings conclusively showed that neutrophils, rather than macrophages, drive inflammation, persistent mechanical hypersensitivity, and nerve fiber sprouting in CAIA via OSM and SEMA4D.Study III emerged as a technical advancement from Study II. Here, we leveraged DRG single-cell data to identify sensory neuron markers, subsequently developing a FACS-based method and gating strategy for their isolation. Microscopic validation confirmed neuronal enrichment based on size and morphology. This new protocol facilitates DRG neuron analysis via flow cytometry, eliminating the need for genetic reporter mice or retrograde dye injections.In Study IV, we explored the anti-nociceptive properties of baricitinib, a JAK-STAT pathway inhibitor approved for RA treatment, noted clinically for superior pain alleviation compared to other RA medications. Baricitinib treatment reversed mechanical hypersensitivity in CAIA mice during the post-inflammatory phase and reduced CGRP+ nerve fiber sprouting. Expression analysis revealed JAK1 and STAT3 presence in both mouse and human sensory neurons, suggesting direct neuronal actions of baricitinib.Collectively, this thesis delineates peripheral neuroimmune interactions in physiological and arthritic contexts, offering novel insights into the DRG macrophage-vascular unit, establishing tools for studying neuroimmune communication along the joint-DRG axis, and identifying novel therapeutic targets for nerve fiber sprouting and pain management. Additionally, it provides methodological improvements for transcriptomic studies of sensory neurons and elucidates previously unknown mechanisms of an existing RA therapeutic. Future research should aim to validate the translational potential of these findings in human RA.List of scientific papersI. CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier. Harald Lund*, Matthew A. Hunt*, Zerina Kurtović, Katalin Sandor, Paul B. Kägy, Noah Fereydouni, Anais Julien, Christian Göritz, Elisa Vazquez-Liebanas, Maarja Andaloussi Mäe, Alexandra Jurczak, Jinming Han, Keying Zhu, Robert A. Harris, Jon Lampa, Jonas Heilskov Graversen, Anders Etzerodt, Lisbet Haglund, Tony L. Yaksh, and Camilla I. Svensson. J Exp Med, 2024, Vol. 221, No. 2. https://doi.org/10.1084/jem.20230675II. Neutrophil-neuronal crosstalk drives arthritis-induced pain. Zerina Kurtović, Juan Antonio Vazquez Mora, Katalin Sandor, Alex Bersellini Farinotti, Nilesh Agalave, Sven David Arvidsson, Matthew A. Hunt, Nils Simon, Julia Dorothea Monika Döring, Alexandra Kuliszkiewicz, Lizeth Ponce Gomez, Sijing Ye, Giovanni Emmanuel López Delgado, Arisai Martinez Martinez, Eduardo Mendoza Sanchez, Khosiyat Makhmudova, Enriqueta Munoz Islas, Juan Miguel Jimenez Andrade, Harald Lund1#, Camilla I. Svensson#. [Manuscript]III. A novel method to sort and enrich sensory neurons. Zerina Kurtović*, Juan Antonio Vazquez Mora*, Sven David Arvidsson*, Alex Bersellini Farinotti, Nils Simon, Sijing Ye, Michael Hagemann-Jensen, Harald Lund, Camilla Svensson. [Manuscript]IV. Characterization of the antinociceptive effect of baricitinib in the collagen antibody-induced arthritis mouse model. Nils Simon*, Resti Rudjito*, Lydia Moll, Katalin Sandor, Juan Antonio Vazquez Mora, Zerina Kurtović, Alexandra Kuliszkiewicz, Carlos E. Morado Urbina, Sven David Arvidsson, Eduardo Mendoza-Sanchez, Giovanni E Lopez-Delgado, Qing Luo, Qiaolin Deng, Arisai Martínez Martínez, Jens Gammeltoft Gerwien, Paul Karila, Venkatesh Krishnan, Juan Miguel Jiménez-Andrade, Camilla I Svensson. Ann Rheum Dis, 2025, 84(3), 421-434. https://doi.org/10.1016/j.ard.2025.01.005*,# contributed equally</p
Work loss, earnings, and educational attainment in patients with rheumatoid arthritis and juvenile idiopathic arthritis
No full textChronic inflammatory diseases such as rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) can have lasting effects on individuals' ability to work and earn a living. While advancements in treatment have improved disease management, their impact on long-term economic outcomes remains uncertain. This thesis examines how RA and JIA affect earnings, work loss, and educational attainment, using Swedish nationwide register data. Individuals with RA and JIA were matched to same-sex siblings (RA) or general population comparators (JIA) based on birth year, sex, and location.Study I compared the earnings of 2,433 RA patients (2006–2017) to those of their same-sex siblings. We found that patients with RA, compared to siblings, earned 5.4% less per year after diagnosis. Stratifying by diagnosis year demonstrated a more pronounced reduction among those diagnosed earlier (2006–2010) (8.2%). Patients diagnosed more recently (2011–2017) showed no statistically significant earnings decline, suggesting that improved treatment and earlier intervention may have mitigated economic losses.Study II investigated work loss, measured as sick leave and disability pension, in a similar RA cohort diagnosed between 2006 and 2020, with slightly extended inclusion and follow-up compared to Study I. In the first year after diagnosis, patients diagnosed between 2006 and 2011 had 47 additional days of work loss per year, and patients diagnosed between 2012 and 2020 had 26 additional days of work loss per year. Work loss was highest in both cohorts in the first year after diagnosis but declined over time. From years 2 to 10 after diagnosis, patients diagnosed between 2006 and 2011 had an additional 29 days annually, and patients diagnosed between 2012 and 2020 had an additional 11 days annually.Study III focused on earnings and work loss in 4,737 individuals diagnosed with JIA, matched to 23,645 general population comparators (2001–2017). Patients with JIA had 5.5% lower earnings than their peers, with the largest gap occurring before age 26. While earnings differences diminished over time, work loss remained consistently higher, with patients with JIA having an average of 11 additional sick leave or disability days per year. A subgroup with more severe disease accounted for the majority of work loss. Among those with systemic JIA (sJIA), a particularly severe form of the disease, work loss was even higher, and earnings were lower compared to other patients with JIA.Study IV examined educational attainment among 4,254 individuals diagnosed with JIA (2001–2017), matched to 4,254 general population comparators. Over up to 16 years of follow-up (median 4 years), 83.1% of patients with JIA and 83.0% of comparators completed high school or more (hazard ratio [HR] 0.99, 95% CI: 0.97–1.01). Similarly, 34.5% of patients and 34.1% of comparators pursued some post-secondary education or more (HR 1.02, 95% CI: 0.97–1.08). No differences were observed by sex, parental education, or diagnosis period. Among individuals followed until age 30, educational outcomes remained comparable: 85.9% of patients with JIA and 86.1% of comparators completed high school, and 48.1% versus 49.9% had post-secondary education. The conditional odds ratio was 0.98 (95% CI: 0.71–1.36) for a high school degree and 0.92 (95% CI: 0.73–1.15) for post-secondary education.To summarize, we found clear improvements in earnings and work loss among patients with RA diagnosed in more recent years, though work loss remained elevated overall, driven by a small subset of patients. In JIA, earnings and employment were lower than those of the general population comparators, with the differences narrowing after age 26. Patients with JIA had consistently higher work loss, about 11 additional days per year, also driven by a more severely affected subgroup. Educational attainment in patients with JIA was comparable to the general population, with similar proportions completing high school or post-secondary education by age 30. These findings suggest that advances in diagnosis and treatment may have improved long-term socioeconomic outcomes.List of scientific papersI. Miller H, Neovius M, Askling J, Bruze G. Impact of Incident Rheumatoid Arthritis on Earnings: A Nationwide Sibling Comparison Study. Rheumatology (Oxford). 2024 Oct 16:keae535. Epub ahead of print. Erratum in: Rheumatology (Oxford). 2025 Jan 06. https://doi.org/10.1093/rheumatology/keae535II. Miller H, Bruze G, Johansson K, Askling J, Neovius M. Incident Rheumatoid Arthritis and Work Loss: A Nationwide Sibling Comparison Study. [Submitted]III. Miller H, Neovius M, Sundberg E, Askling J, Bruze G. Juvenile Idiopathic Arthritis, Earnings and Work Loss: A Nationwide Matched Cohort Study. Arthritis Care Res (Hoboken). 2025 Mar 16. doi:10.1002/acr.25522. Epub ahead of print. https://doi.org/10.1002/acr.25522IV. Miller H, Neovius M, Johansson K, Askling J, Bruze G. Juvenile Idiopathic Arthritis and Attained Education: A Nationwide Matched Cohort Study. [Manuscript]</p
Correlates of outcomes in routine clinical care in patients suffering from severe mental illnesses
No full textBackgroundMental disorders rank among the top ten global contributors to disability, with estimates suggesting an annual global cost of $4.7 trillion. For individuals, mental disorders often result in profound functional impairments, significant distress, and markedly reduced life expectancy. In mental health research, randomized controlled trials (RCTs) are the gold standard for assessing treatment efficacy. However, there has been growing recognition of the need to complement RCTs with real-world data studies, which analyze outcomes in routine clinical settings. The Scandinavian countries are uniquely positioned for such research due to extensive public health registries and the ability to link data via individual civic registration numbers. This thesis investigates associations between aspects of care delivery and key clinical outcomes in populations with severe mental disorders treated in routine healthcare settings.Methods and resultsPaper 1 explored the relationship between aspects of court-mandated forensic psychiatric care and body mass index (BMI) in a cohort of 3,389 individuals treated between 2009 and 2020. Data were retrieved from the Swedish Forensic Psychiatric Register, including BMI, demographic, clinical, and treatment-specific variables. Linear and spline multilevel regression analyses revealed a 1.1% annual increase in BMI during the first four years of care (p Paper 2 examined the relationship between inpatient care duration and relapse into care in individuals with eating disorders (ICD-10 F50.X). Using open-access data from the Swedish Patient Registry (1998-2020), variables analyzed included annual inpatient episodes, unique patients, and total inpatient days. Mean length of stay was calculated as total inpatient days divided by care episodes. Robust linear regression demonstrated an inverse correlation between mean length of stay and relapse in both adolescents (adjusted R2 = 0.5216, p Paper 3 assessed the association between regional bipolar diagnosis rates and adolescent suicide mortality (15-19 year olds) in Sweden (2008-2021). Data from the Swedish National Board of Health and Welfare included bipolar diagnosis rates, suicide rates, lithium dispensation rates, psychiatric care affiliation rates, and inpatient/outpatient visit proportions. Generalized mixed regression revealed an inverse association between bipolar diagnosis rates and male adolescent suicide mortality ( = - 0.00429; 95% CI, -0.0081 to -0.0004; p = . 03), independent of lithium dispensation and psychiatric care affiliation rates. This association persisted in beta-binomial models and after adjusting for schizophrenia and depression diagnosis rates.Paper 4 investigated the relationship between utilization of advanced psychiatric treatments (lithium, clozapine, electroconvulsive therapy) and adolescent excess suicide mortality (AESM). Open-access data (2016-2020) from the Swedish National Board of Health and Welfare and the Swedish ECT Registry were analyzed. AESM was calculated as the difference between adolescent (15-19 years) and young adult (20-24 years) regional suicide rates. Min-max normalization was applied to treatment variables and AESM to reduce outliers. Aggregated utilization of all three treatment modalities was inversely associated with AESM in adolescents overall (B = - 0.613, p = . 0003) and in males (B = - 0.404, p = . 009) but not in females (p = . 197). Post-hoc analyses identified specific associations between lower AESM and utilization of electroconvulsive therapy and lithium.ConclusionsThe findings underscore the potential value of evidence-based and standardized approaches in psychiatric care. Study 1 suggested the need for targeted interventions to address metabolic health, particularly among women, in forensic psychiatric care, while Study 2 provided ecological support for a weight stabilization phase in eating disorder inpatient care as a possible strategy to reduce readmission risk. Study 3 highlighted an inverse association between bipolar disorder diagnosis rates and suicide rates in male adolescents, suggesting that early and accurate diagnosis could play a role in suicide prevention, though no similar association was observed for females. Study 4 indicated that advanced treatments, such as lithium and ECT, might contribute to reduced suicide mortality in adolescents. Across all studies, significant variability in clinical practices and outcomes was observed, pointing to possible systemic gaps in care. While these findings highlight areas for further investigation and potential clinical focus, the correlational nature of the research precludes definitive causal conclusions. Rigorous future research, encompassing both controlled trials and well-designed real-world studies, is essential to clarify these relationships and guide evidence-based improvements in care.List of scientific papersI. Andersson, P., von Schreeb, A., Johansson, L., Sturidsson, K., Wetterborg, D., & Sorjonen, K. (2024). Changes in Body Mass Index During Mandatory Forensic Psychiatric Care: Findings from a Long- Term (2009-2020) Cohort Study Based on Swedish Registry Data. International Journal of Forensic Mental Health. 23(2), 106-116.https://doi.org/10.1080/14999013.2023.2214381II. Andersson, P., Jamshidi, E., Ekman, C., Tedroff, K., Björkander, J., Sjögren, M., Lundberg, J., Jokinen, J., & Desai Boström, A. E. (2023). Mapping length of inpatient treatment duration and year-wise relapse rates in eating disordered populations in a well-defined Western-European healthcare region across 1998- 2020. International Journal of Methods in Psychiatric Research. 32(4), e1960-n/a. https://doi.org/10.1002/mpr.1960III. Andersson, P., Jokinen, J., Jarbin, H., Lundberg, J., & Desai Boström, A. E. (2023). Association of Bipolar Disorder Diagnosis With Suicide Mortality Rates in Adolescents in Sweden. JAMA Psychiatry (Chicago, IlI.). 80(8), 796-802. https://doi.org/10.1001/jamapsychiatry.2023.1390IV. Desai Boström, A. E., Andersson, P., Rask-Andersen, M., Jarbin, H., Lundberg, J., & Jokinen, J. (2023). Regional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents. Nature Communications. 14(1), 1281-1281. https://doi.org/10.1038/s41467-023-36973-4</p