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Ryanodine receptors in islet cell function : calcium signaling, hormone secretion, and diabetes
No full textRyanodine receptors (RyRs) are large intracellular Ca2+ release channels primarily found in muscle and nerve cells and also present at low levels in pancreatic islet endocrine cells. This review examines the role of RyRs in islet cell function, focusing on calcium signaling and hormone secretion, while addressing the ongoing debate regarding their significance due to their limited expression. We explore conflicting experimental results and their potential causes, synthesizing current knowledge on RyR isoforms in islet cells, particularly in beta and delta cells. The review discusses how RyR-mediated calcium-induced calcium release enhances, rather than drives, glucose-stimulated insulin secretion. We examine the phosphorylation-dependent regulation of beta-cell RyRs, the concept of "leaky ryanodine receptors", and the roles of RyRs in endoplasmic reticulum stress, apoptosis, store-operated calcium entry, and beta-cell electrical activity. The relationship between RyR dysfunction and the development of impaired insulin secretion in diabetes is assessed, noting their limited role in human diabetes pathogenesis given the disease's polygenic nature. We highlight the established role of RyR-mediated CICR in the mechanism of action of common type 2 diabetes treatments, such as glucagon-like peptide-1, which enhances insulin secretion. By integrating findings from electrophysiological, molecular, and clinical studies, this review provides a balanced perspective on RyRs in islet cell physiology and pathology, emphasizing their significance in both normal insulin secretion and current diabetes therapies.</p
Distinct neural mechanisms underlying cognitive difficulties in preterm children born at different stages of prematurity
No full textNo description supplied</p
Suppressing sensation during action across species and sensory modalities : predictive and non-predictive mechanisms of sensory modulation
No full textPerception and action are deeply intertwined processes that require the nervous system to distinguish between self-generated (reafferent) and externally generated (exafferent) sensory inputs. To maintain accurate perception during movement, the brain must attenuate predictable sensory consequences of its own actions while remaining sensitive to unexpected external events. Reafference attenuation is a temporally precise process that suppresses expected feedback, facilitating the detection of novel stimuli. This review examines reafference attenuation across species (rodents, non-human primates, and humans) and sensory systems (vestibular, auditory, and tactile). We also discuss sensory gating (or sensory suppression), a broader and often less selective mechanism that inhibits both self- and externally generated inputs. Although both mechanisms reduce sensory inflow during movement, they differ in function, specificity, and temporal dynamics, and despite growing insight into their underlying circuitry, important questions remain about their generality and implementation.</p
De-escalation of axillary surgery in breast cancer : patient experiences, arm morbidity, and health-related quality of life
No full textIn breast cancer surgery for node-positive disease, axillary staging surgery is typically performed alongside the tumour removal. Arm morbidity is a known consequence of axillary lymph node dissection (ALND). Although current studies are investigating the de-escalation of axillary surgery in sentinel node-positive breast cancer, its consequences on arm morbidity remains insufficiently understood. This thesis aims to increase the knowledge on how different axillary staging surgical methods affect patient-reported arm morbidity, health-related quality of life (HRQoL), and everyday life.Study I evaluated the impact of omitting of ALND on arm morbidity and HRQoL in patients with 1-2 sentinel lymph node macrometastases undergoing primary surgery. One-year patient-reported outcome measures (PROMs) from 976 participants in the randomised SENOMAC trial (Sweden and Denmark) were analysed (sentinel lymph node biopsy [SLNB] only: n=501, SLNB+ALND: n=475). PROMs were reported using EORTC QLQ-C30, EORTC QLQ-BR23, and Lymph- ICF-UL questionnaires between March 2015 and June 2019. One year after surgery, the SLNB only group reported significantly lower arm morbidity than the SLNB+ALND group, although no significant differences in overall HRQoL were seen.Study II was a descriptive qualitative study exploring women's experiences of arm impairment following axillary staging surgery. Six focus group discussions were held with 28 relapse-free, Swedish-speaking women between September and December 2022. The qualitative content analysis resulted in one overall theme, "Balancing challenges and personal resources", and three categories: "Sense-making", "Daily life", and "Driving force". Participants described varying degrees of arm-related challenges. While most were satisfied with their everyday life in relation to arm symptoms, those with more pronounced arm impairment experienced a negative impact on everyday life. Key coping strategies included understanding symptoms, adapting routines, and the use of empowering resources.Study III, a cross-sectional cohort study, evaluated the reliability and validity of the Swedish version of the Lymph-ICF-UL questionnaire. Between October 2024 and March 2025, 27 Swedish-speaking women without diagnosed lymphoedema, who had one year earlier undergone surgery for node-positive breast cancer, participated. The study included back-translation into English, test-retest analysis, assessment of internal consistency and construct validity, as well as evaluation of face and content validity. The instrument demonstrated good stability and internal consistency, with moderate to good construct validity. Face and content validity supported its use in assessing arm dysfunction after axillary staging surgery.Study IV was an international, prospective cohort study examining the association between patient-reported arm morbidity and ALND, targeted axillary dissection (TAD), or SLNB following neoadjuvant chemotherapy (NACT) for breast cancer. PROMs from 1,293 women across 15 countries who had converted to clinical node negativity through NACT were assessed using the Lymph-ICF-UL questionnaire. Data were collected between June 2020 and January 2025, with surgery performed no later than 30 June 2023. Findings indicate that ALND is associated with a worse progression of arm morbidity from preoperative status to one-year post-surgery compared to TAD or SLNB. Adjusted odds indicated a higher likelihood of severe arm-related physical dysfunction following ALND than after TAD or SLNB.In summary, SLNB and TAD seems to be associated with better preservation of arm function compared to ALND. Although significant differences in arm morbidity were observed, HRQoL did not differ between groups. However, women in the interview study who experienced more severe arm impairment also described a negative impact on their everyday lives. These findings support the ongoing de-escalation of axillary staging in breast cancer care. However, the long-term consequences of arm morbidity and HRQoL remain to be fully understood.List of scientific papersI. Appelgren M, Sackey H, Wengström Y, Johansson K, Ahlgren J, Andersson Y, Bergkvist L, Frisell J, Lundstedt D, Rydén L, Sund M, Alkner S, Vrou Offersen B, Filtenborg Tvedskov T, Christiansen P, de Boniface J, on behalf of the SENOMAC Trialists' Group. Patient-reported outcomes one year after positive sentinel lymph node biopsy with or without axillary lymph node dissection in the randomized SENOMAC trial. The Breast. 2022;63(3):16-23. https://doi.org/10.1016/j.breast.2022.02.013II. Appelgren M, Wengström Y, de Boniface J, Sackey H. 'Balancing Challenges and Personal Resources': A Qualitative Study of Women's Experiences of Arm Impairment After Axillary Surgery for Breast Cancer. JAN. 2025; 81(6):3156-3165. https://doi.org/10.1111/jan.16517III. Appelgren M, Sackey H, Lindgren A, Johansson K, de Boniface J, Wengström Y. Validation of the Swedish Lymphoedema Functioning, Disability and Health (Lymph-ICF-UL) Questionnaire: A Cross-Cultural Psychometric study. [Submitted]IV. Appelgren M, Sackey H, Banys-Paluchowski M, Hartmann S, Lundholm C, Wihlfahrt K, Berger T, Aktas Sezen B, Jursik K, Wagner J, Wengström Y, Hauptmann M, Schroth J, Thill M, Ditsch N, Stickeler E, Peintinger F, Vanhoeij M, Dostalek L, Kontos M, Zippel D, Gentilini OD, Di Micco R, Schlichting E, Rebaza LP, Murawa D, Pinto D, Bonci E-A, Rubio I, Gasparri ML, Hein A, Thiemann E, Holmstrand Zetterlund L, Karadeniz Cakmak G, Kühn T, de Boniface J, on behalf of the AXSANA Study Group. Patient-reported arm morbidity following axillary staging surgery after neoadjuvant chemotherapy for breast cancer: one-year results from the EUBREAST-3 AXSANA cohort study. [Manuscript]</p
DNA replication initiation and fidelity : a nanoscale view of the code of life
No full textEvery time a cell divides it needs to copy its entire genome. This is a fragile and challenging task, involving billions of DNA base pairs, tightly bound proteins, DNA damages and DNA secondary structures. The forced proliferation of cancer cells compromises DNA replication fidelity and causes DNA replication stress. The latter fuels cancer progression but also provides therapeutic opportunities, as DNA replication inhibitors are proven to be potent anti-cancer agents. Therapies that impede replication forks are effective in killing cancer cells but typically cause adverse side effects as they target all dividing cells. Thus, treatments that target replication factors overexpressed in cancer cells could prevent them from initiating DNA replication, resulting in the selective inhibition of tumour cell proliferation while minimising effects on normal cells. While many essential steps involved in the initiation of DNA replication have been extensively studied, key aspects - such as the timing, precise selection, and activation of replication origins - remain incompletely understood, obstructing the design and validation of innovative therapies that act at the level of replication initiation.Through three distinct projects, I have developed a novel methodology for studying DNA replication, investigated the molecular mechanisms governing DNA replication initiation and cell cycle regulation, and explored the therapeutic potential of targeting nuclear kinases. Collectively, with this PhD thesis, I have contributed to the advancement of our understanding of DNA replication and cancer therapy.A more detailed abstract for each paper continues on the following pages.Paper I. Spatial mapping of DNA synthesis reveals dynamics and geometry of human replication nanostructureDNA replication is essential to life and ensures the accurate transmission of genetic information, which is significantly disturbed during cancer development and chemotherapy. While DNA replication is tightly controlled in time and space, methods to visualise and quantify replication dynamics within 3D human cells are lacking. Here, we introduce 3D-Spatial Assay for Replication Kinetics (3D- SPARK), an approach enabling nanoscale analysis of DNA synthesis dynamics in situ. 3D-SPARK integrates optimised nucleotide analogue pulse labelling with super-resolution microscopy to detect, classify, and quantify replication nanostructures in single cells. By combining immunofluorescence techniques with click chemistry-based nascent DNA labelling and transfection of fluorescent nucleotide derivatives, we map multi-colour DNA synthesis events in relation to established replication proteins, local RNA-protein condensates or large subnuclear domains. We demonstrate quantitative changes in size, relative abundance and spatial arrangement of nanoscale DNA synthesis events upon chemotherapeutic treatment, CDC6 oncogene expression and loss of chromatin organiser RIF1. The flexibility, precision and modular design of 3D-SPARK helps bridging the gap between spatial cell biology, genomics, and 2D fibre-based replication studies in health and disease.Paper II. Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical geneticsCyclin-dependent kinases (CDKs) coordinate DNA replication and cell division, and play key roles in tissue homeostasis, genome stability and cancer development. The first step in replication is origin licensing, when minichromosome maintenance (MCM) helicases are loaded onto DNA by CDC6, CDT1 and the origin recognition complex (ORC). In yeast, origin licensing starts when CDK activity plummets in G1 phase, reinforcing the view that CDKs inhibit licensing. Here we show that, in human cells, CDK4/6 activity promotes origin licensing. By combining rapid protein degradation and time-resolved EdU-sequencing, we find that CDK4/6 activity acts epistatically to CDC6 and CDT1 in G1 phase and counteracts RB pocket proteins to promote origin licensing. Therapeutic CDK4/6 inhibitors block MCM and ORC6 loading, which we exploit to trigger mitosis with unreplicated DNA in p53-deficient cells. The CDK4/6-RB axis thus links replication licensing to proliferation, which has implications for human cell fate control and cancer therapy design.Paper III. Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 18/ ¿Vaccinia-related kinase 1 (VRK1) and the 8 and & isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumour types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK18 and CK1. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK18 and CK18 inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumours and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.List of scientific papersMy PhD thesis is based on three projects which have produced three papers. The status of each of these papers, at time of printing this thesis, is as follows. The first paper is available on BioRxiv and has been reviewed and resubmitted after addressing reviewer's comments. The second paper has been accepted for publication and the third paper has been published.I. Michael Hawgood, Bruno Urién, Ana Agostinho, Praghadhesh Thiagarajan, Yiqiu Yang, Xue Zhang, Giovanni Giglio, Gemma Quijada, Matilde Fonseca, Jiri Bartek, Hans Blom, Bennie Lemmens. Spatial mapping of DNA synthesis reveals dynamics and geometry of human replication nanostructures. [Submitted]II. Anastasia Sosenko Piscitello, Ann-Sofie Nilsson, Michael Hawgood Abid H Sayyid, Vasilis S Dionellis, Giovanni Giglio, Bruno Urién, Pratikiran Bajgain, Sotirios G Ntallis, Jiri Bartek, Thanos D Halazonetis, Bennie Lemmens. Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics. [Accepted]III. Fernando H. de Souza Gama, Luiz A. Dutra, Michael Hawgood, Caio Vinícius dos Reis, Ricardo A. M. Serafim, Marcos A. Ferreira Jr., Bruno V. M. Teodoro, Jéssica Emi Takarada, André S. Santiago, Dimitrios-Ilias Balourdas, Ann-Sofie Nilsson, Bruno Urien, Vitor M. Almeida, Carina Gileadi, Priscila Z. Ramos, Anita Salmazo, Stanley N. S. Vasconcelos, Micael R. Cunha, Susanne Mueller, Stefan Knapp, Katlin B. Massirer, Jonathan M. Elkins, Opher Gileadi, Alessandra Mascarello, Bennie B. L. G. Lemmens, Cristiano R. W. Guimarães, Hatylas Azevedo, Rafael M. Couñago. Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 18/E. Journal of Medicinal Chemistry. 67(11), pp.8609-8629 (2024). https://doi.org/10.1021/acs.jmedchem.3c02250</p
Functional studies of pathogen-specific T cell responses in patients with chronic lymphocytic leukemia
No full textCLL is the most common type of leukemia in adults and remains an incurable malignancy. Patients with CLL often suffer from non-malignant complications, particularly recurrent infections, which have been highlighted in recent years by the exceptionally high mortality rates during the COVID-19 pandemic. Increasing evidence indicates that T cells in CLL patients become functionally exhausted, potentially contributing to their impaired control of pathogenic infections. To this end, this thesis investigated the pathogen-specific T cell response, functionality, and characteristics across patients with varying tumor burden, different targeted therapies, and diverse vaccination and infection histories, against a broad spectrum of pathogens, including the most common bacteria and viruses.In Study I, we assessed the magnitude and functionality of both bacteria- and virus-specific CD4+ T cells and characterized their phenotypic signatures before and after BTKi therapy. We demonstrated that the impaired functionality of CD4+ T cells was largely irreversible even after a reduction in tumor burden. Moreover, these cells progressively lost their stem-like memory subset during CLL progression.In Study II, we investigate the phenotype and functional property of virus- specific CD8+ T cells. Although the overall magnitude of these responses was largely preserved in CLL patients, their functional capacity remained persistently impaired and did not recover after tumor burden reduction. In parallel, these cells exhibited a gradual loss of self-renewing characteristics and became confined to a terminal effector state despite effective tumor reduction by next- generation BTKi therapy.In Study III, we detected both humoral and cellular responses to variants of the SARS-CoV-2 spike antigen. We first showed the system and mucosal vaccine response in patents with long-term next-generation of zanubrutinib treatment.In Study IV, we demonstrated that memory T cells remained capable of recognizing both the ancestral strain and the highly mutated BA.2.86 variant of COVID-19, in both healthy individuals and patients with CLL.List of scientific papersI. Jinghua Wu, Yu Gao, Curtis Cai, Maria Andersson, Rokeya Sultana Rekha, Takuya Sekine, Sarah Adamo, Kia Heimersson, Oriana Jesus Ribeiro, Marzia Palma, Peter Bergman, Rula Zain, C. I. Edvard Smith, Anders Österborg, Marcus Buggert. Systemic pathogen-specific CD4+ T cell dysfunction persists despite selective BTK inhibition in CLL. [Manuscript]II. Jinghua Wu, Curtis Cai, Maria Andersson, Mily Akhirunnesa, Thomas R. Müller, Takuya Sekine, Kia Heimersson, Akshaya Vidhya, Marzia Palma, Rula Zain, C. I. Edvard Smith, Yu Gao, Anders Österborg, Marcus Buggert. BTKi therapy uncouples tumor control from virus-specific CD8+ T cell functional recovery in CLL. [Manuscript]III. Andersson M*, Wu J*, Wullimann D, Gao Y, Aberg M, Muschiol S, Healy K, Naud S, Bogdanovic G, Palma M, Mellstedt H, Chen P, Ljunggren HG, Hansson L, Sallberg Chen M, Buggert M, Ingelman-Sundberg HM, Osterborg A. Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia. J Hematol. 2023 Aug;12(4):170-175.https://doi.org/10.14740/jh1140IV. Müller TR*, Gao Y*, Wu J, Ribeiro O, Chen P, Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Vesterbacka J, Akber M, Söderdahl G, Smith CIE, Loré K, Chen MS, Ljungman P, Ingelman-Sundberg HM, Ljunggren HG, Österborg A, Sette A, Grifoni A, Aleman S, Buggert M. Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant. Cell Host Microbe. 2024 Feb 14;32(2):156-161.e3. https://doi.org/10.1016/j.chom.2023.12.010*These authors contributed equally</p
Alcohol use as a modifiable risk factor in cardiology : prevalence, patient perspectives, and clinician views
No full textBackground: Alcohol use and cardiovascular disease are major contributors to the global burden of disease and represent key public health challenges in Europe. However, despite increasing emphasis on the role of alcohol use as a modifiable cardiovascular risk factor, there has been little focus on addressing alcohol use in cardiology services. There is a need to understand patient- and clinician-related factors such as risk perceptions, acceptability, and perceived feasibility, to support the implementation of alcohol interventions.Aims: The aim of this doctoral thesis was to understand factors affecting the implementation of alcohol interventions in cardiology services in Sweden, with a view to informing the development of effective implementation strategies.Methods and results: Five studies were conducted, including cross-sectional surveys, qualitative interviews, and integrative mixed methods approaches.Study I found that the prevalence of hazardous alcohol use among cardiology patients at three hospitals in Sweden was approximately 8% (95% CI = 6.2-9.3), while about 1% (95% CI = 0.3-1.5) met the screening threshold for probable alcohol dependence, highlighting a need for screening and brief interventions (SBI) in cardiology services.Study Il indicated that cardiology patients were exposed to mixed messages about the cardiovascular effects of moderate alcohol consumption, often through media reports. Exposure to mixed messages was associated with higher odds of reporting hazardous alcohol use (OR = 1.67, 95% CI = 1.02-2.74).Studies III & IV identified a range of clinician-related barriers to alcohol interventions, including stigma, competing professional priorities, and low competence with SBI, along with opportunities for alcohol interventions in routine cardiology practice. Doctors and outpatient staff tended to view alcohol interventions as clinically feasible.Study V examined patient perspectives and found that alcohol interventions were viewed as acceptable and relevant within cardiology.Conclusions: This doctoral project demonstrated a need for alcohol interventions in cardiology services and identified opportunities for implementation in routine practice. We found that cardiology staff view alcohol interventions as important, but successful implementation will require a range of barriers to be addressed - particularly stigma and a lack of knowledge among clinicians. Findings suggest a possible role for tailored nurse-led interventions in the outpatient setting. Promising strategies include competency-based training for clinicians and engaging key stakeholders, such as arrhythmia and heart failure specialists, during implementation.List of scientific papersI. Welfordsson P, Danielsson AK, Björck C, Grzymala-Lubanski B, Hambraeus K, Löfman IH, Braunschweig F, Lidin M, Wallhed Finn S. Hazardous alcohol use: a cross-sectional study of cardiology patients in Sweden. J Public Health (Oxf). 2025 May 15:fdaf057. PMID: 40369959.https://doi.org/10.1093/pubmed/fdaf057II. Welfordsson P, Danielsson AK, Björck C, Grzymala-Lubanski B, Lidin M, Löfman IH, Wallhed Finn S. Mixed messages? Exposure to reports about alcohol's suggested cardiovascular effects and hazardous alcohol use: a cross-sectional study of patients in cardiology care. BMC Public Health. 2024 May 13;24(1):1302. PMID: 38741107.https://doi.org/10.1186/s12889-024-18783-5III. Welfordsson P, Danielsson AK, Björck C, Grzymala-Lubanski B, Hambraeus K, Lidin M, Haugen Löfman I, Scheffel Birath C, Nilsson O, Braunschweig F, Wallhed Finn S. Feasibility of alcohol interventions in cardiology: a qualitative study of clinician perspectives in Sweden. Eur J Cardiovasc Nurs. 2024 Sep 5;23(6):668-674. PMID: 38445448. https://doi.org/10.1093/eurjcn/zvae033IV. Welfordsson P, Danielsson AK, Björck C, Grzymala-Lubanski B, Hambraeus K, Haugen Löfman I, Nilsson O, Braunschweig F, Lidin M, Wallhed Finn S. Feasibility of alcohol interventions in cardiology: a mixed methods study of clinician perspectives in Sweden. Eur J Cardiovasc Nurs. 2025 Jun 12:zvaf109. PMID: 40505110.https://doi.org/10.1093/eurjcn/zvaf109V. Welfordsson P, Danielsson AK, Björck C, Grzymala-Lubanski B, Hambraeus K, Löfman IH, Braunschweig F, Lidin M, Wallhed Finn S. Alcohol use as a modifiable risk factor in cardiology: A qualitative study of patient perspectives in Sweden. PLoS One. 2025 Aug 4;20(8):e0328990. PMID: 40758666; PMCID: PMC12321063. https://doi.org/10.1371/journal.pone.0328990</p
Investigation of outcomes related to adrenal incidentalomas
No full textBackground: Adrenal incidentalomas (AIs) are increasingly detected through modern imaging. Most are nonfunctional adrenal tumors (NFATs) in which physiological cortisol secretion is assumed, whereas 20-50% have mild autonomous cortisol secretion (MACS), a subtle cortisol excess without clinical signs of Cushing syndrome. MACS has been associated with increased mortality and a higher prevalence of cardiometabolic comorbidities, whereas NFATs have traditionally been regarded as clinically harmless. However, emerging evidence indicates that NFATs may also be linked to adverse cardiometabolic outcomes and related health risk.Aims: To evaluate long-term health risks associated with AIs. Study I: To examine mortality by cortisol secretion status in patients with AIs in a single center. Study II-IV: To characterize major clinical outcomes in patients with Als without overt hormonal secretion (presumed NFATs) compared with matched controls using a nationwide cohort. Specifically, Study II aims to quantify all-cause and cause- specific mortality, Study III to determine overall and site-specific cancer incidence, and Study IV to evaluate fracture prevalence and incidence, including the effects of adrenalectomy.Methods and Results: Study I: Single-center 13-year follow-up of 365 patients with AIs showed highest mortality in patients with MACS (18.2%) vs. patients with NFATs (7.8%), mainly from non-adrenal cancers. Higher cortisol concentrations, age, and tumor size predicted mortality. Study II: Nationwide case-control study (17,726 patients with presumed NFATs; 124,366 controls) found increased all-cause mortality (aHR 1.21), particularly cardiovascular (aHR 1.21) and cancer-related (aHR 1.54), with stronger effects in individuals Study III: Presumed NFATs were linked to higher cancer incidence (aHR 1.31), including thyroid, lung, gastrointestinal, kidney, bladder, pancreatic and breast cancers. Study IV: In 20,390 patients with presumed NFATs, fracture prevalence (aOR 1.27) and incidence (aHR 1.27) were higher, especially vertebral fractures (aHR 1.83) and in younger men. Adrenalectomy eliminated the excess risk of fracture.Conclusions: Both MACS and AIs presumed to be NFATs are associated with adverse long-term outcomes, particularly in younger individuals and men. These entities are better understood as part of a continuum within eucortisolemic individuals, suggesting that even cortisol activity within the normal range may contribute to chronic disease risk.List of scientific papersI. Patrova J, Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine 2017 58(2):267-275. https://doi.org/10.1007/s12020-017-1400-8II. Patrova J, Mannheimer B, Lindh J. D, Falhammar H. Mortality in patients with nonfunctional adrenal tumors. JAMA Intern Med 2023;183(8):832-838. https://doi.org/10.1001/jamainternmed.2023.2442III. Patrova J, Mannheimer B, Larsson M, Lindh J. D, Falhammar H. The incidence of cancers in patients with nonfunctional adrenal tumors: a Swedish population-based national cohort study. J Endocr Soc. 2024;8(10):bvae154. https://doi.org/10.1210/jendso/bvae154IV. Lindh J. D, Patrova J, Mannheimer B, Falhammar H. Prevalence and incidence of fractures in patients with nonfunctional adrenal tumors. JAMA Netw Open. 2024;7(4):e246453. https://doi.org/10.1001/jamanetworkopen.2024.6453</p
Predictors for intracranial hemorrhage in mild traumatic brain injury
No full textTraumatic brain injury (TBI) is a significant contributor to morbidity and mortality globally, especially in its most severe forms. However, the most prevalent type is mild traumatic brain injury (mTBI), which constitutes a significant proportion of patients presenting to emergency departments (EDs) worldwide for assessment. There are existing guidelines to support management of these patients. However, there have been changes in both epidemiology and risk factors in recent years, particularly in the western world where an aging population with medically managed thrombotic disease is becoming an increased proportion of TBI patients. This thesis aims to explore the role of predictors available from the outset at the ED towards prediction of clinically significant outcomes such as traumatic intracranial hemorrhage (tICH), neurosurgical TBI cases and death due to TBI.In Study I, a protocol was designed for the Stockholm scorE of LEsion detection on Computed Tomography following mild Traumatic Brain Injury (SELECT-TBI) study. The aim of the study is to generate an overarching retrospective observational population-based mTBI patient cohort using medical records from the Greater Stockholm Metropolitan Area. The cohort enables a detailed and comprehensive study of how clinically available variables perform as predictors against both the radiological outcome of intracranial lesions and the clinically definite outcome of neurosurgical TBI cases. In total, 73 key variables were determined to be relevant. The study was registered in Clinicaltrials.gov (NCT04995068) and ethical approval was obtained from the Swedish Ethical Review Authority (DNR 2020-05728).In Study II, a systematic review and meta-analysis was performed to identify, quantify, and critically appraise risk factors associated with CT-confirmed tICH in mTBI patients, with the goal of informing future ED management guidelines. Seventeen studies, encompassing 26 040 patients with 2 054 cases of CT- verified tICH (7.9%), were included. Skull base fracture (odds ratio, OR 11.71, 95% confidence interval, CI 5.51-24.86) and Glasgow Coma Scale upon ED presentation Study III is an interim analysis and statistical analysis plan based on the initial 5 000 patients included in the main SELECT-TBI cohort. Three modeling approaches were evaluated: generalized linear models (GLMs), random forest (RF) algorithms, and Lasso-regularized logistic regression (LR). Model performance was assessed using area under the receiver operating characteristic curve (AUC), calibration curves and Brier scores. Across models, the most consistent predictors of ICL were Glasgow Coma Scale (GCS) deterioration and score, signs of basilar skull fracture, high energy trauma mechanisms, and vomiting. S100B emerged as a strong predictor in biomarker-inclusive models. The Lasso regression model incorporating hemoglobin, platelet count, and S100B demonstrated the best performance (AUC 0.807 for any ICL, 0.903 for clinically significant ICLs, defined as ICLs resulting in intubation, neurosurgical transfer, or death).In Study IV, a post-hoc analysis was conducted using data from the SELECT-TBI cohort from six emergency departments in the Stockholm region between 2015- 2020 focusing on the risk of tICH with antithrombotic medication. Logistic regression analyses, both univariable and multivariable, were applied to estimate ORs and 95% CIs, adjusting for confounding variables. Among 28 973 included mTBI patients, 9.6% had CT-verified tICH. Apixaban was associated with a reduced risk of tICH (adjusted OR 0.74, 95% CI 0.62-0.87), while acetylsalicylic acid was associated with increased risk (adjusted OR 1.20, 95% CI 1.07-1.35). In the CT-positive sub-cohort (n = 2 948), no antithrombotic agent predicted transfer to neurosurgical department. However, both warfarin (adjusted OR 3.62, 95% CI 1.76-7.15) and apixaban (adjusted OR 2.36, 95% CI 1.00-5.06) were independent predictors of TBI-related mortality. Over the study period, apixaban use increased markedly in the mTBI population, surpassing warfarin after 2018.In summary, the studies demonstrate findings that reaffirm the validity of some established markers while challenging others, such as the complex risk profiles across antithrombotic subtypes. While aspirin use increased the likelihood of tICH, apixaban appeared safer with respect to initial hemorrhage but was associated with elevated mortality once a traumatic hemorrhage is present.These findings provide some support for potential updates in ED management guidelines for mTBI patients to improve specificity. However, further prospective trials are necessary to validate our results before clinical implementation.List of scientific papersThe present thesis is based on the following studies, which will be referred to by their Roman numerals (*shared authorship):I. Fletcher-Sandersjöö, A., Tatter, C., Yang, L., Pontén, E., Boman, M., Lassarén, P., Forsberg, S., Grönlund, I., Tidehag, V., Rubenson-Wahlin, R., Strömmer, L., Westberg, K., Ängeby, K., Djärv, T., Lundblad, O., Bartek, J., Jr, Thelin, E. P. Stockholm score of lesion detection on computed tomography following mild traumatic brain injury (SELECT-TBI): study protocol for a multicentre, retrospective, observational cohort study. BMJ Open, 2022;12(9):e060679. Published 2022 Sep 1. https://doi.org/10.1136/bmjopen-2021-060679II. Yang, L. J., Lassarén, P., Londi, F., Palazzo, L., Fletcher-Sandersjöö, A., Ängeby, K., Thelin, E. P .* , Rubenson Wahlin, R .* Risk factors for traumatic intracranial hemorrhage in mild traumatic brain injury patients at the emergency department: a systematic review and meta-analysis. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 2024;32(1):91. Published 2024 Sep 17. https://doi.org/10.1186/s13049-024-01262-6III. Yang, L. J .* , Tatter, C .* , Fletcher-Sandersjöö, A., Froese, L., Lassarén, P., Tjerkaski, J., Bergman, E. E., Björkman, F. E., Bronge, J., Antonsson, J., Teromaa, K., Nylander, M., Örtqvist, S., Kylander, W., Lindqvist, W., Ängeby, K., Rubenson Wahlin, R., Thelin, E. P. Stockholm Score of Lesion Detection on Computed Tomography following Mild Traumatic Brain Injury (SELECT-TBI) Study: Pilot Analysis and Statistical Analysis Plan Acta Neurochirurgica, 2025;167(1). Published 2025 Jul 1. https://doi.org/10.1007/s00701-025-06598-1IV. Yang, L. J., Fletcher-Sandersjöö, A., Tatter, C., Froese, L., Lassarén, P., Patel, A., Ibrahim, A., Nykvist, A., Bivner Johansson, A., Brandt, E., Wager, E., Norman, E., Bergman, E. E., Björkman, F. E., Kratz, G., Lidström, H., Bergqvist, H., Hallden Kullander, I., Bronge, J., Antonsson, J., Wallin, K., Teromaa, K., Olofsson, L., Sandgren, L., Nylander, M., Ghorab, M., Mai, M., Hallongren, M., Wellén, R., Vesterlund, R., Clementsson, S., Faisal, S., Hassan, S., Örtqvist, S., Wocalewski, V., Hasselberg, V., Kylander, W., Lindqvist, W., Hallstedt, Z., Ängeby, K., Rubenson Wahlin, R., Thelin, E. P. The Effect of Antithrombotic Therapy on Traumatic Intracranial Hemorrhage and Additional Adverse Outcomes in Mild Traumatic Brain Injury Patients: A Post-hoc Analysis of the SELECT-TBI Cohort [Manuscript]</p
Surviving birth : resuscitation practice in Vietnam and the development of a supraglottic airway device
No full textBackground: Each year, over 500,000 newborns die from intrapartum-related hypoxic events, formerly termed birth asphyxia. The true toll is thought to be nearly double due to misclassified stillbirths, and the associated morbidity is likely to exceed mortality, highlighting a substantial global burden. The overlap between intrapartum-related events and low birth weight is significant. Most of these deaths occur in low-resource settings and are preventable. Adequate resuscitation of the newborn can improve the outcome, with airway management and positive pressure ventilation as its cornerstones. Traditionally, face mask ventilation has been the first-line approach, with endotracheal intubation as the fallback when face mask ventilation fails. However, both methods can be technically challenging. The supraglottic airway device offers a promising alternative, but its role in reducing preventable deaths remains unclear, especially in low-birth-weight neonates, where evidence is scarce. This thesis aims to expand the broader understanding of neonatal morbidity, mortality, and resuscitation practices by illuminating the realities of neonatal care, particularly those related to airway management. It aims to advance the field by providing the first two structured anatomical feasibility studies of small supraglottic airway device prototypes aimed to be used in low-birth-weight neonates. The broader goal is to contribute to global efforts, inform global strategies, and reduce preventable neonatal deaths.Methods: Between 2019 and 2025, two observational and two anatomic feasibility studies were conducted in Vietnam and Sweden. The observational studies took place at the Neonatal Unit, Phu San Hanoi Hospital, Vietnam: a retrospective cross-sectional study (Study I) and a prospective, video-based study (Study II). These explored causes of neonatal morbidity and mortality, detailed airway management during neonatal resuscitation in the delivery room, and broader clinical management practices in the neonatal unit. The feasibility studies were conducted at the Radiology Department, Karolinska University Hospital, Huddinge, Sweden, and assessed the anatomic feasibility of three small supraglottic airway device prototypes using high-fidelity manikins representing low-birth-weight neonates (Study III) and stillborn low-birth-weight neonates (Study IV). The device under investigation was the i-gel®, a cuffless supraglottic airway device previously shown to be safe in low-resource settings when used by midwives. We evaluated the smallest currently commercially available size (1.0) along with three smaller prototypes (sizes 0.85, 0.75, and 0.65).Results: At Phu San Hanoi Hospital (Studies I and II), the most common neonatal diagnoses were prematurity, jaundice, respiratory distress, and infection. Intrapartum-related events were less frequent, as reflected by the need for positive pressure ventilation, accounting for only 5% of admissions to the neonatal unit, and a diagnosis of hypoxic-ischemic encephalopathy, accounting for 1% of admissions. Nearly 40% of the neonates admitted to the neonatal unit had a low birth weight (Conclusions: This thesis provides essential baseline data on the clinical realities of neonatal care at a busy referral hospital in Vietnam, a lower middle- income country. It highlights the strong overlap between low birth weight and intrapartum-related events. It reveals the limitations of endotracheal intubation in real-world practice, including the frequent need for prolonged and repeated attempts. These findings underscore the urgent need for alternative, easier airway management techniques during resuscitation of the newborn, including smaller, more suitable alternatives for low-birth-weight neonates. By delivering the first structured anatomical feasibility data on supraglottic airway device use in low-birth-weight high-fidelity neonatal manikins and stillborn neonates, this thesis advances the field and positions the supraglottic airway device as a promising cornerstone of future strategies to reduce neonatal mortality worldwide.List of scientific papersI. Tina Dempsey, Huong Lien Nguyen, Huong Thu Nguyen, Xuan Anh Bui, Phuong Thi Thu Pham, Toan K. Nguyen, Francesco Cavallin, Daniele Trevisanuto, Susanna Myrnerts Höök, Nicolas Pejovic, Mats Blennow, Linus Olson, Hien Vu, Anh Duy Nguyen, Tobias Alfvén. Incidence of Intrapartum-Related Events at the Largest Obstetric Hospital in Hanoi, Vietnam: A Retrospective Study. Children. 2022; 9: 321. https://doi.org/10.3390/children9030321II. Tina Dempsey*, Huong Thu Nguyen, Huong Lien Nguyen, Xuan Anh Bui, Phuong Thi Thu Pham, Toan K Nguyen, Daniel Helldén, Francesco Cavallin, Daniele Trevisanuto, Susanna Myrnerts Höök, Mats Blennow, Linus Olson, Hien Vu, Anh Duy Nguyen, Tobias Alfvén*, Nicolas Pejovic *. Endotracheal intubation performance at a large obstetric hospital delivery room, Hanoi, Vietnam. Resuscitation Plus. 2022; 12: 100338. *equal contribution https://doi.org/10.1016/j.resplu.2022.100338III. Tina Dempsey, Torkel Brismar, Anders Svensson-Marcial, Mats Blennow, Tobias Alfvén, Susanna Myrnerts Höök, Nicolas Pejovic. Radiologic Evaluation of Three Smaller-Sized Supraglottic Airway Device Prototypes for Low-Birth-Weight Neonates. British Journal of Anaesthesia - published online in July 2025. https://doi.org/10.1016/j.bja.2025.05.038IV. Tina Dempsey, Torkel Brismar, Anders Svensson-Marcial, Mats Blennow, Tobias Alfvén, Nicolas Pejovic, Susanna Myrnerts Höök. Computed Tomography of Three Smaller-Sized Supraglottic Airway Device Prototypes in Stillborn Low-Birth-Weight Neonates. [Manuscript]</p