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Parental experiences of therapeutic hypothermia in their newborns and quality of life of the children in early adolescence
No full textThe incidence of perinatal asphyxia, or intrapartum-related conditions, in high- resource countries is 1-3/1000 live births. Perinatal asphyxia may cause hypoxic- ischaemic encephalopathy (HIE) that can lead to cerebral malfunctioning, but treatment with therapeutic hypothermia (TH) improves neurological outcomes and survival in the affected infants. During TH, the infant's body temperature is lowered to a target temperature of 33.5° C within six hours from birth and for 72 hours. During this time and in most cases, parents cannot hold their infants due to the complexity of medical technical equipment and the staff's caution, as the holding during the TH treatment requires nearby supervision from the staff.This thesis consists of three qualitative studies of parental experiences of TH and one quantitative study exploring the correlation between motor performance, health-related quality of life (HRQOL), and self-esteem in early adolescents having received TH as newborns. The first two studies were performed within one year of the infant's birth, and the third study 10 to 13 years afterwards. In the first two studies parents described their emotional situation, their solutions to adapt to the situation, and how the experience changed their approach towards their existential being. The phase after the rewarming was seen as a milestone where parents described a "rebirth moment" when the infant woke up and started to move and behave like a normal newborn baby. Although parents had trepidation about the prognosis, they appreciated the care given in the NICU where the caring philosophy of Family-centred care (FCC) had been implemented.The second study showed that the staff had the competence and capacity to contribute to parental transition into parenthood of a newborn infant treated with TH. In the FGs, where data to the third study were obtained, parents described an insufficiency of participation and communication during their hospital stay in NICU. Despite the insufficiencies, nurses instilled hope and security in parents to cope with the difficulties and trials during the hospital stay. Additionally, parents' concerns and anxiety about their children's challenges in school and in their everyday lives were highlighted.In the fourth study, the instruments MABC-2, PedsQL 4.0 and ITIA-2 were used. Motor function was assessed by a physiotherapist and HRQOL were self- reported by children who had been treated with TH due to neonatal HIE. Likewise, the children's HRQOL was proxy-reported by their parent. Self-esteem was also self-reported by these children. The results show that the median of the HRQOL reported by the children were lower Physical Functioning and School Functioning than proxy-reported by their parents. The median of Social and Emotional Functioning was equal in both children and parents. Only in the summary score of Psychosocial Health did the children report higher HRQOL. Parents reported a somewhat higher Total score of HRQOL than parents. There was no significant difference between the self-reported HRQOL Total score between boys and girls.Significant positive correlations were found between the MABC-2 Total scores and parents' proxy-reports in all PedsQL 4.0 dimensions. Parents of children having existing motor difficulties or at risk of motor difficulties proxy-reported significantly lower HRQOL than parents of children without motor difficulties (median= 69.0 vs 91.85). However, the children reported a high level of HRQOL and higher self-esteem than the average test norm. Motor difficulties did not affect children's HRQOL or self-esteem.List of scientific papersI. Experiences of parents whose newborns undergo hypothermia treatment following perinatal asphyxia. Kokkonen Nassef, S., Blennow Bohlin, M. & Jirwe, M. Journal of Obstetric, Gynecologic & Neonatal Nursing. 2013; Jan-Feb;42(1):38-47. https://doi.org/10.1111/j.1552-6909.2012.01429.xII. Parental viewpoints and experiences of therapeutic hypothermia in a neonatal intensive care unit implemented with Family-Centred Care. Kokkonen Nassef, S., Blennow Bohlin, M. & Jirwe, M. Journal of Clinical Nursing. 2020; Nov;29(21-22):4194-4202. https://doi.org/10.1111/jocn.15448III. Experiences of parents whose school-aged children were treated with therapeutic hypothermia as newborns: A focus group study. Kokkonen Nassef, S., Blennow Bohlin, M. & Jirwe, M. Nursing Open. 2023; Nov;10(11):7411-7421. https://doi.org/10.1002/nop2.1994IV. Motor performance, health-related quality of life and self- esteem in early adolescence after therapeutic hypothermia following hypoxic-ischemic encephalopathy, a cross-sectional study. Eriksson Westblad, M .* , Kokkonen Nassef, S .* , Blennow Bohlin, M., Jirwe, M. &, Lindström K. 2024. *Shared first authorship. [Manuscript]</p
Protocol for accurately annotating circular RNA and microRNA in giant vertebrate genomes
No full textNo description supplied</p
Innate immunity and its link to clinical outcomes in smokers with and without COPD
No full textChronic obstructive pulmonary disease (COPD) is the fourth most common causes of death globally, affecting around ten percent of the adult population. Patients with COPD often suffer from comorbidities that are associated with impaired prognosis, among them chronic bronchitis, emphysema, cardiovascular diseases (CVD) and diabetes mellitus type II. Despite the clinical importance of COPD and its link to comorbidities, there is a limited understanding of the underlying pathogenic mechanisms, which hampers the efficacy of disease monitoring and therapy. Chronic neutrophilic inflammation is a common finding in COPD and several of its comorbidities, representing a feature that responds poorly to currently available therapy.The main aim of this thesis was to characterize clinical and mechanistic aspects of neutrophilic inflammation in COPD and its comorbidities. For this reason, we utilized three human study materials, consisting of healthy non-smokers, smokers without COPD and smokers with COPD. Material 1 included an additional group of ex-smokers with COPD, while material 3 also required a diagnosis of concomitant chronic bronchitis for the COPD group. All study subjects underwent a thorough clinical and radiological investigation whereafter blood samples were harvested. Furthermore, in materials 1 and 3, lower airway samples, including bronchoalveolar lavage and protected bronchial brushes, were obtained during bronchoscopy, whereas sampling from the nasal cavity was provided as an option in material 1 only. Extracellular cytokine protein concentrations were quantified with ELISA, U- Plex® or PEA assays and cytokine expression in defined immune cells was determined using flow cytometry.Paper I was based on study material 1 and addressed the involvement of local neutrophils in the production of the neutrophil-mobilising cytokine IL-26 in the lower airways of smokers with COPD. This paper forwards novel evidence that IL- 26 is expressed in lower airway granulocytes, predominantly consisting of neutrophils. This expression was decreased in smokers without and with COPD, compared with healthy non-smokers and ex-smokers with COPD. Furthermore, the expression of IL-26 in granulocytes of the lower airways correlated with more pronounced airway obstruction in smokers with COPD. In addition, the extracellular concentration of IL-26 protein in this group was increased in smokers with COPD, compared with healthy non-smokers, and correlated with decreasing gas diffusing capacity of the lungs. Finally, the presence of emphysema related to increased extracellular IL-26 protein concentration among smokers without and with COPD.In Paper II, we investigated the local production of IL-26 by T lymphocytes in the nasal cavity of smokers with COPD. We found that both T-helper (Th: CD3+ CD4+) and T-cytotoxic (Tc: CD3+ CD8+) cells express intracellular IL-26. In the case of Th cells, this expression correlated with increased concentration of neutrophils in the lower airways of smokers with COPD. Moreover, when all current smokers were pooled as one group, IL-26 expression in Tc cells displayed a negative correlation with quality of life and dyspnoea. The latter was true even for Th cells. Finally, the nasal concentration of extracellular IL-26 protein was increased in smokers with COPD, and this increase was more pronounced in those without emphysema.In Paper III, we addressed the association of different signs of local and systemic neutrophilic inflammation with glucose homeostasis in smokers with COPD. We found that fasting blood glucose was decreased in this group, and this decrease was correlated with higher protein concentration of the neutrophil-mobilising cytokine IL-36a in the lower airways. Additionally, smokers with COPD displayed a greater change in blood glucose during an oral glucose tolerance test, while a negative correlation was observed between glucose concentration at the end of this test and lower airway concentration of CXC motif chemokine ligand 10 (CXCL10), a chemokine that can be produced by neutrophils.In Paper IV, we investigated alterations during COPD exacerbations in perceived molecular biomarkers of CVD that are related to neutrophils, among smokers with COPD and chronic bronchitis. We found that the protein concentration of oncostatin M (OSM) in serum increased in parallel with blood neutrophils, in stable disease. In addition, during acute exacerbations of COPD, the serum concentration of OSM protein was substantially increased and correlated in a positive manner with the corresponding concentrations of several other neutrophil-related perceived CVD biomarkers. At the same time, the serum concentration of OSM associated with decreasing blood oxygen levels and, therefore, with exacerbation severity.In conclusion, this thesis forwards evidence that specific aspects of chronic neutrophilic inflammation, including IL-26, IL-36a, CXCL10 and OSM, are involved in COPD and/or the risk for developing its comorbidities. This provides a rationale for further investigating the clinical utility of these aspects as targets for disease characterisation, monitoring and/or therapeutic intervention.List of scientific papersI. Pournaras N*, Ramos-Ramírez P*, Bandeira E, Brundin B, Cardenas El, Che KF, Karimi R, Arebro J, Nyren S, Stjärne P, Cardell L-O, Sköld MC, Bossios A and Linden A. Expression of IL-26 protein in granulocytes from the lower airways of long-term smokers with mild to moderate COPD. [Manuscript]II. Arebro J*, Pournaras N*, Ramos-Ramírez P, Cardenas EI, Bandeira E, Che KF, Brundin B, Bossios A, Karimi R, Nyrén S, Stjärne P, Sköld M, Linden A. Nasal production of IL-26 involving T cells in smokers with and without chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2025 Mar 28:S0091-6749(25)00332-X. Epub ahead of print. https://doi.org/10.1016/j.jaci.2025.03.017III. Pournaras N, Andersson A, Kovach MA, Padra M, Che KF, Brundin B, Yoshihara S, Bozinovski S, Linden SK, Jansson P-A, Sköld MC, Qvarfordt I, Linden A. Glucose homeostasis in relation to neutrophil mobilization in smokers with COPD. Int J Chron Obstruct Pulmon Dis. 2022 May 20;17:1179-1194. https://doi.org/10.2147/copd.s353753IV. Cardenas EI*, Andelid K*, Pournaras N, Ekberg-Jansson Ann, Orsini N, Stratelis G, Jernberg T, Linden A. Serum proteomics links the cardiorespiratory biomarkers CTRC, OSM, and MMP-10 to exacerbation severity and number in patients with COPD. Clin Sci (Lond). 2025 May 7:CS20255852. Epub ahead of print. https://doi.org/10.1042/cs20255852*These authors contributed equally to the corresponding work</p
Pharmacologically active antibodies for treatment of cancer and pain
No full textIn collaboration with Oblique Therapeutics AB (OTAB), Göteborg, the Team of Translational Pharmacology, FyFa, Karolinska Institutet, have developed a microfluidics/mass spectrometry platform using kinetically controlled proteolysis for identifying druggable epitopes on difficult-to-drug target proteins. These peptide sequences are identified by proteases in essentially native state proteins in motion capable of capturing structural dynamics of the target protein. The protease binding surface area is of similar size to the antigen binding region of antibodies; thus, they are highly suitable for production of high affinity, pharmacologically active antibodies. Using this platform, a library of candidate antibodies was developed. The targets involve the nociceptive human transient receptor potential cation channel subfamily V member 1 (hTRPV1) and the oncoprotein Kirsten rat sarcoma virus homologue (KRAS) which becomes highly oncogenic after a single missense mutation. TRPV1 is a highly complex ion-channel which is activated by several different modes of stimulation (multimodal) such as heat, low pH, and lipid compounds (vanilloids). The candidate mAb selected qualified due to an inhibitory action on hTRPV1 channels but spared the heat sensitivity of the channel which results in potential analgesic effects whilst avoiding heat-related side-effects. Antibody candidates directed to KRAS exhibited increased KRAS-dependent signalling aberrations as well as increased apoptosis and necrosis of cancer cells expressing the G13D (Gly exchanged for Asp at the 13th position) mutation. Furthermore, we discovered that monoclonal antibodies (mAbs) are readily taken up by cancer cells as collateral cargo from macropinocytosis which provides a venue for pharmacological activity targeting the recycling of KRAS protein in the cytoplasm. When investigating the structural properties of G13D KRAS with X-ray crystallography, we discovered that it is possible to open up G13D KRAS by stripping the Mg2+ ion from the protein's active site. Furthermore, the protein could also be opened in the liquid phase by depleting the buffer media of Mg2+ ions. The binding affinity (EC50-value) of one of the produced monoclonal antibodies (named the 4B8 antibody) was increased about 6-fold comparing Mg2+ -free to Mg2+-containing media. This methodology of stripping Mg2+ and opening up G13D KRAS in a biologically relevant solution environment was further confirmed using Size Exclusion Chromatography coupled to Small Angle X-ray Scattering (SEC-SAXS). Noticeably, when Mg2+ was stripped from the G13D-mutated version, it started to multimerize and aggregate. This aggregation behaviour was not observed in the WT-version of KRAS that was used as a control in these experiments. G13D KRAS is known to have a much higher rate of nucleotide exchange compared to e.g. WT KRAS which can be one reason to that G13D has a higher propensity to stay in an open state and having a higher capacity of Mg2+-release. We also confirmed that G13D-directed mAbs are taken up by cancer cells through macropinocytosis, in line with several recent scientific reports and observations for other KRAS binding monoclonal and polyclonal antibodies. This capacity of internalization of KRAS antibodies will be important to further explore for potential clinical applications.List of scientific papersI. Rational antibody design for undruggable targets using kinetically controlled biomolecular probes. Science Advances. Carolina L. Trkulja†, Oscar Jungholm†, Max Davidson†, Kent Jardemark, Monica M. Marcus, Jessica Hägglund, Anders Karlsson, Roger Karlsson, Joseph Bruton, Niklas Ivarsson, Sreesha P. Srinivasa, Alexandra Cavallin, Peder Svensson, Gavin D. M. Jeffries, Maria-Nefeli Christakopoulou, Anna Reymer, Anaswara Ashok, Gabriella Willman, Daniela Papadia, Emma Johnsson, Owe Orwar*. https://doi.org/10.1126/sciadv.abe6397 *Corresponding author. †These authors contributed equally to this work.II. Novel druggable space in human KRAS G13D discovered using structural bioinformatics and a P-loop targeting monoclonal antibody. Scientific Reports. Oscar Jungholm†, Carolina L. Trkulja†, Martin Moche†, Sreesha P. Srinivasa, Maria-Nefeli Christakopoulou, Max Davidson, Anna Reymer, Kent Jardemark, Rafaela Lenza Fogaça, Anaswara Ashok, Gavin Jeffries, Henry Ampah-Korsah, Emilia Strandback, Juni Andréll, Tomas Nyman, Ghada Nouairia, and Owe Orwar. https://doi.org/10.1038/s41598-024-70217-9†These authors contributed equally to this work.III. Small angle x-ray scattering and structural bioinformatics studies reveal a Mg2+-free, open state human G13D KRAS with high propensity for homodimerization, and aggregation reactions in solution. Oscar Jungholm†, Martin Moche†, Carolina Trkulja, Henry Ampah- Korsah, Emilia Strandback, Tomas Nyman, Jill Trewhella, Sreesha Srinivasa, and Owe Orwar. [Manuscript] †These authors contributed equally to this work</p
Effects of medical treatments on gonadal development in boys
No full textPrepubertal boys diagnosed with cancer face a high risk of spermatogonial stem cell (SSC) loss due to the side effects of cancer treatments, leading to potential fertility issues in the future. With increasing survival rates, fertility preservation is an increasingly vital consideration for many patients and their families. Current fertility preservation strategies are centered on the cryopreservation of testicular tissue containing SSCs. When combined with functional somatic testicular cells, experimental techniques, such as testicular explant tissue culture or cell/tissue transplantation, may offer future fertility restoration options for these patients. Therefore, the studies included in this thesis focus on strategies for quantifying and maintaining spermatogonia in testicular tissue samples obtained from these patients.To better evaluate germ cell quantity in prepubertal boys with various treatments and diagnoses. Z-scores were utilized to account for age-related variations in standardized measures of spermatogonia quantity. A total of 89 testicular samples were analyzed in Study I. We calculated the Z-scores for spermatogonia per tubular cross-section (S/T) and fertility index (FI), based on deviations from the reference mean values (expressed as standard deviations [SDs]) obtained from a meta-analysis published in 2016.The results showed that S/T Z-score values were significantly lower among Klinefelter syndrome patients and those treated with alkylating agents, compared to the control group. Additionally, S/T Z-score values were inversely correlated with exposure to alkylating agents: the higher the cumulative cyclophosphamide equivalent dose (CED), the lower the S/T Z-score. These findings suggest that age- adjusted Z-scores for S/T are a useful metric for quantifying spermatogonia in patients with cancer and genetic disorders.Furthermore, we examined the effects of severe hematological diseases on spermatogonia numbers prior to hematopoietic stem cell transplantation (HSCT). This study involved 43 prepubertal patients, all diagnosed with severe hematological conditions. The patients were categorized into three groups: myelodysplastic/myeloproliferative neoplasms (MDS/MPN), aplastic anemia/bone marrow failure syndromes (AA/BMFS), and immunodeficiencies (IMMUNO). Z-scores for spermatogonia per tubule (S/T) and fertility index (FI) were used to evaluate spermatogonia quantity. The results showed that before undergoing HSCT, approximately half of the patients exhibited reduced spermatogonia numbers, and 19% experienced severe spermatogonia loss. Markedly decreased spermatogonia counts were observed in samples from prepubertal patients with Fanconi anemia (FA) and others with inherited bone marrow failure syndromes. In contrast, patients with MDS/MPN showed variable spermatogonial quantity. In contrast, patients with AA and immune disorders had only slightly decreased or normal spermatogonia numbers. Our findings highlight the importance of testicular tissue cryopreservation for patients with hematological diseases prior to HSCT, following appropriate counselling about the potentially decreased spermatogonial numbers.Finally, we cultured testicular tissue samples using an organotypic culture system supplemented with glial cell line-derived neurotrophic factor (GDNF) for 7 and 14 days. Although cryopreservation of testicular tissue is currently the only available option for potentially restoring fertility in prepubertal boys, there is still no clinical evidence demonstrating its success in preserving fertility.Successful spermatogenesis depends not only on the presence of SSCs but also on a functional somatic testicular microenvironment. To establish a supportive in vitro environment for human germ cell differentiation, we employed an organotypic culture system supplemented with GDNF. GDNF, primarily produced by Sertoli cells in the human testis, plays a key role in the self-renewal and differentiation of SSCs. A total of 47 testicular tissue samples from prepubertal boys were cultured for 0, 7, and 14 days. Immunohistochemistry was used to evaluate the expression of DEAD-Box helicase (DDX4), insulin-like 3 (INSL3), Cytochrome P450 family 17 subfamily A member 1 (CYP17A1), actin alpha 2 (ACTA2), Sex determining region Y-box 9 (SOX9), and cluster of differentiation 14 (CD14). Overall, DDX4 expression in seminiferous cords increased with patient age, while GDNF supplementation had no significant effect at any culture time point. Analysis of CD14 and CYP17A1 expression profiles revealed that these proteins were expressed not only in the interstitial compartment but also in Sertoli cells after 7 and 14 days of culture. These findings indicate aberrant expression of CYP17A1 and CD14, which may contribute to the failure of human testicular explant cultures to support human spermatogenesis.In conclusion, the studies included in this PhD thesis demonstrated the establishment and application of Z-scores for S/T as a tool to evaluate spermatogonia quantity in patients with severe hematological diseases prior to gonadotoxic treatment. Furthermore, Z-scores for S/T were also utilized to assess the impact of genetic conditions and cancer treatments on spermatogonial numbers. In the final part of the study, we observed altered expression of CD14 and CYP17A1 in Sertoli cells cultured in organotypic systems for 7 and 14 days, offering a novel perspective on the dysregulation of human spermatogenesis in vitro.List of scientific papersI. Z-scores for comparative analyses of spermatogonia numbers throughout human development. Miriam Funke*, Yifan Yang*, Atte Lahtinen, Klara Benninghoven-Frey, Sabine Kliesch, Nina Neuhaus, Jan-Bernd Stukenborg, Kirsi Jahnukainen. Fertil Steril. 2021 Sep;116(3):713-720. https://doi.org/10.1016/j.fertnstert.2021.04.019*Both authors contributed equally to the study.II. Decreased spermatogonial numbers in boys with severe haematological diseases. Atte K Lahtinen, Miriam Funke, Claudia Krallmann, Margot J Wyrwoll, Andrea Jarisch, Yifan Yang, Ragnar Bjarnason, Patrik Romerius, Mikael Sundin, Ulrika Norén-Nyström, Cecilia Langenskiöld, Jann-Frederik Cremers, Sabine Kliesch, Jan-Bernd Stukenborg, Nina Neuhaus, Kirsi Jahnukainen. British Journal of Haematology, May 2024, 205(1), 229-235. https://doi.org/10.1111/bjh.19572III. Effects of GDNF on prepubertal testicular tissue samples during organotypic cultures. Yifan Yang, Yanhua Cui, Femke Harteveld, Hajar Ba Omar, Anu Haavisto, Ragnar Bjarnason, Patrik Romerius, Mikael Sundin, Ulrika Norén Nyström, Cecilia Langenskiöld, Hartmut Vogt, Per Frisk, Kaisa Vepsäläinen, Cecilia Petersen, Kirsi Jahnukainen, Jan-Bernd Stukenborg. [Manuscript]</p
The impact of response timing, mobile telephone use, and data collection tools on survey bias : evidence from Rakai, Uganda
No full textBackgroundA credible public health survey or surveillance program is judged by its ability to measure intended outcomes accurately and cost effectively. However, in the pursuit of operational efficiency, such programs risk introducing bias in their estimates. This thesis examines several key potential sources of bias in public health surveys, focusing on three main domains: the characteristics and selection of respondents paying attention to the hard-to-reach late respondents, the use of mobile phone technology for data collection, and the adaptation of standardized measurement tools-specifically the Framingham Risk Score (FRS) and the Finnish Diabetes Risk Score (FINDRISC). The tools are internationally recognized for estimating the 10-year risk of cardiovascular disease and type 2 diabetes, respectively. By exploring these domains, this work aims to highlight critical methodological considerations that survey designers and implementers must consider minimizing measurement bias and enhance data validity.MethodsThe study was conducted within the Rakai Community Cohort Study (RCCS), a long-standing surveillance program in south-central Uganda. Covering 34 diverse communities, the RCCS focuses on HIV and other health priorities. In each round, 70-80% respond on time, while late respondents require extra effort from the researchers to track them. Study I examined whether late respondents differ from early ones and if their (late respondents) exclusion could bias results. We conducted descriptive analyses and compared these groups using Chi-square tests. Multivariable logistic regression was used to adjust for confounders, reporting adjusted odds ratios (AORs) with 95% confidence intervals. We also modelled interactions with age to estimate marginal predictive means (MPMs), illustrating how the likelihood of late response varies across age groups. The results are reported in constituent manuscript I. The use of mobile phones for population-based surveys is an ongoing global discussion, particularly in resource-limited settings. We leveraged RCCS Rounds 19 and 18 data, collected around the COVID-19 period, and data from a concurrent mobile phone-based surveillance in the same population to compare participation rates by survey modality (face-to-face vs. mobile phone surveys), we assessed phone access, and characterized the differences between respondents reached and missed by each method. The primary independent variable was interviewing modality, with adjustments made for sex, age, community type, HIV status, and other covariates. Robust standard errors accounted for clustering at the individual level. We also examined longitudinal trends in mobile phone ownership, including the frequency of mobile phone number change, the time to change of numbers and multiple SIM ownership. Phone number change was defined as the complete replacement of previously recorded numbers between survey rounds, excluding partial changes. Rates and associated factors were estimated using Poisson regression with generalized estimating equations (GEE), while time to number change was assessed using the Andersen-Gill Cox model to account for repeated measurements. The results are reported in studies II (face-to-face vs mobile phone surveys) and study III (mobile phone ownership, numbers change and time to change analyses) We conducted qualitative exit interviews to assess participants' experiences with the FRS and FINDRISC risk score tools. Interviews were held on the same day, immediately after participants completed the questionnaires and measurement procedures. The analysis, based on 15 interviews, followed an iterative approach. Thematic coding was used to identify and summarize key themes that we report in constituent study IV.ResultsOverall, 68,263 participants were included in the late respondent analysis. Men were 22% times more likely to be late respondents than women (23% vs. 19%, respectively). This was true for younger participants 15-19 years old relative to 40+years old participants. Compared to the unemployed, participants engaged in formal employment followed by those engaged in fishing were more likely to be late respondents (28% and 27% respectively). When comparing response times between people living with HIV and those who are HIV-negative, no significant difference was observed (AOR=1.06; 95% C.I .: 0.99, 1.13). In women, HIV status had no effect on the marginal predictive mean (MPM) of being late, which declined with age in both groups. Among young men, MPM of being a late respondent was significantly higher in those with HIV but decreased with age. Conversely, in HIV- negative men, the MPM increased with age. In study II, we observed 90% access to mobile phones, with lower access among older people, and people living with HIV. When including only individuals who participated in the previous RCCS survey round, participation in the face-to-face survey (82%) was higher than participation in the mobile phone survey (75%, p When we examined participants' experiences with FRS and FINDRISC, we found that overall, the tools were clear and acceptable in this setting. Participants were comfortable with having their weights, waists, heights and other measurements taken if it was by a health worker. There were a few challenges with interpretation and measurement of physical activity, and dietary practice questions given the seasonal variations in their availability in the community.ConclusionThe studies reveal that late respondents are different and cannot be ignored therefore means to speed up their participation should be devised. The use of mobile phones is feasible, there are some differentials in those who are missed by phone surveys (especially men). Meanwhile, mobile phone ownership is on a rapid rise across both sexes with men slightly higher and women rapidly catching up (by 2020). However, the rate of phone number change is quite high and this needs to be considered. The FRS and the FINDRISC scores are generally acceptable, however, some adaptation to match local practices and the seasonal dietary practices need to be addressed during survey planning, data analysis and interpretation.Key terms: Late respondents, Mobile phones, Bias, Framingham, Finnish Diabetes Risk Score.List of scientific papersPaper I: Characterizing late respondents in the Rakai Community Cohort Study, 2012-2020, Uganda. Robert Ssekubugu, Zangin Zeebari, Hadija Nakawooya, Ping Teresa Yeh, Anthony Ndyanabo, Fredrick Edward Makumbi, Anna Mia Ekström, Grace Nalwoga Kigozi, Eli. M Binder, Kate Grabowski, David Serwadda, Victor Ssempijja, Larry W Chang, Godfrey Kigozi, Helena Nordenstedt [Manuscript]Paper II: Use of Mobile Phone to collect data on COVID-19; phone access and participation rates in Rakai, Uganda. Robert Ssekubugu, Anthony Ndyanabo, Fredrick Edward Makumbi, Anna Mia Ekström, Laura Bere, Grace Nalwoga Kigozi, Hadijja Nakawooya, Joseph Ssekasanvu, Maria J. Wawer, Fred Nalugoda, Nelson Sewankambo, Victor Ssempijja, Betty Nantume, David Serwadda, Godfrey Kigozi, Ronald H. Gray, Larry W Chang, M. Kate Grabowski, Helena Nordenstedt & Joseph Kagaayi Glob Health Action. 2024 Dec 31;17(1):2419160. https://doi.org/10.1080/16549716.2024.2419160Paper III: Mobile phone ownership, number change, time to change and the implications to public health services delivery in Uganda, 2010-2020. Robert Ssekubugu, Ping Teresa Yeh, Hadija Nakawooya, Victor Ssempijja, Godfrey Kigozi, Joseph Kagaayi, Fred Nalugoda, Anna Mia Ekström, Betty Nantume, David Serwadda, Philip Kreniske, Zangin Zeebari, Michelle A. Moffa, Larry W. Chang, Kate M. Grabowski, Fredrick Makumbi and Helena Nordenstedt [Manuscript]Paper IV: Cardiovascular (Framingham) and type II diabetes (Finnish Diabetes) risk scores: a qualitative study of local knowledge of diet, physical activity and body measurements in rural Rakai, Uganda. Robert Ssekubugu, Fredrick Makumbi1, Rocio Enriquez, Susanne Rautiainen Lagerstrom, Ping Teresa Yeh, Caitlin E. Kennedy, Ronald H. Gray, Lilian Negesa, David M. Serwadda, Godfrey Kigozi, Anna Mia Ekström and Helena Nordenstedt BMC Public Health. 2022 Nov 29;22(1):2214. https://doi.org/10.1186/s12889-022-14620-9</p
Understanding coagulopathy in covid-19 : evaluating clinical outcomes with rotational thromboelastometry
No full textWhen the COVID-19 pandemic struck the world in 2020, it placed enormous demands on healthcare and healthcare workers. Hospitals quickly reorganized to prioritize the growing number of patients experiencing respiratory failure, mobilizing stored ventilators and intensive care medications. Early case reports highlighted that severely ill patients often presented with thromboembolic events, prompting the early adoption of anticoagulant therapy as a standard part of care.The overall aim of this thesis is to investigate how hypercoagulation drives severe COVID-19 disease, impacts clinical outcomes, and its association with the inflammatory response triggered by the SARS-CoV-2 virus.In Study I, we assessed whether thromboelastometry (ROTEM) at hospital admission could identify hypercoagulopathy and predict disease severity, determined by the level of care required, in COVID-19 patients. We found that ROTEM variables indicated a hypercoagulable state at admission, which was more pronounced in patients with higher disease severity, necessitating care in the Intensive Care Unit (ICU) or intermediate wards compared with those in regular wards. Our results suggest that hypercoagulability in COVID-19 patients is evident early in mild to moderate cases and becomes more prominent in severe COVID-19 pneumonia.In Study II, we examined various markers of coagulopathy in hospitalized COVID- 19 patients. We developed a pragmatic risk stratification score incorporating ROTEM and other established risk factors to predict 30-day mortality. Additionally, we analyzed the longitudinal changes in ROTEM test results in severe cases. Our findings showed that hypercoagulation, as measured by ROTEM, is a strong predictor of 30-day mortality in COVID-19. Furthermore, the progression of ROTEM data over time supported the hypothesis that hypercoagulation is a driving factor of severe disease.In Study III, we evaluated the effects of interleukin inhibitors anakinra and tocilizumab on global hemostasis and conventional coagulation tests to determine whether they reduced hypercoagulation patterns compared with standard care alone. Our results indicated that tocilizumab significantly decreased hypercoagulation in hospitalized COVID-19 patients, as evidenced by enhancements in both global coagulation tests and traditional laboratory tests, compared with anakinra or standard care alone.In the literature review included in the appendix, we explored the concept of immunothrombosis/thromboinflammation, where complex interactions between the immune and coagulation systems trigger each other, potentially complicating the treatment of thromboembolic disease. We concluded that a combination of anticoagulant and anti-inflammatory treatments may be beneficial, and even necessary, to effectively prevent and manage thrombotic disease in patients experiencing hyperinflammatory states, such as COVID-19. In summary, the findings from these studies indicate that the state of hypercoagulation observed in COVID-19 is linked to increased disease severity, poor clinical outcomes, and has an intricate connection to the inflammatory response.List of scientific papersI. Almskog L, Wikman A, Svensson J, Wanecek M, Bottai M, van der Linden J, Ågren A. Rotational thromboelastometry results are associated with care level in COVID-19. J Thromb Thrombolysis (2020).7 https://doi.org/10.1007/s11239-020-02312-3II. Almskog L, Wikman A, Svensson J, Bottai M, Kotormán M, Wahlgren C, Wanecek M, van der Linden J, Ågren A. Hypercoagulation Detected by Rotational Thromboelastometry Predicts Mortality in COVID-19: A Risk Model Based on a Prospective Observational Study. TH Open (2021). https://doi.org/10.1055/a-1725-9221III. Almskog L, Sjöström A, Sundén-Cullberg J, Taxiarchis A, Ågren A, Freyland S, Börjesson M, Wikman A, Wahlgren C, Wanecek M, van der Linden J, Antovic J, Lampa J, Magnusson M. Tocilizumab reduces hypercoagulation in COVID-19 - Perspectives from the coagulation and immunomodulation Covid assessment (Coag- ImmCovA) clinical trial. Thrombosis Research (2024). https://doi.org/10.1016/j.thromres.2024.109135</p
Peripheral nerve control of metabolism and inflammation
No full textThe regulation of inflammatory and metabolic pathways in adipose and liver tissues is complex, involving various cellular mechanisms and molecular pathways1-3. It has been demonstrated that the cholinergic vagus nerve, through its efferent branch, regulates inflammatory and anti-inflammatory cytokine release to maintain homeostasis in the spleen and beyond4,5. However, much remains to be explored on the role of cholinergic signaling in specific organs such as liver and adipose tissue homeostasis.Over recent decades, there has been a multitude of impactful discoveries on neural regulation of inflammation and metabolism4,6,7, but we are only at the beginning of understanding the detailed mechanisms of how neural reflexes regulate organ function. This thesis explores aspects of this biology in the liver and adipose tissue with the aim of providing additional insights that ultimately can help improve tools for disease diagnosis, prevention, and treatment of inflammatory and metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and certain adipose tissue dysfunction. Studies over the last thirty years have shown that the central and peripheral nervous systems, along with the immune and metabolic systems, collaboratively regulate inflammation and metabolism4,6,8-10. The vagus nerve is one of the systems that have been widely studied in this context and found to be important in regulating inflammation and metabolism5,11,12. The work in this thesis builds on these studies and aims to further improve the understanding of neural regulation of inflammation and metabolism in liver and adipose tissue.In project I, we found that statin therapy in individuals with metabolic syndrome was associated with increased Patatin-like phospholipase domain-containing 3 (PNPLA3) and liver transcriptional changes linked to worse metabolic control. The observations underscore the importance of considering the implications on liver pathophysiology of lipid-lowering therapy in patients with the metabolic syndrome, including the need for improved mechanistic understanding of the regulation of liver inflammation and metabolism in this patient group.In project II, we investigated the role of the vagus nerve in acute liver inflammation, particularly its effect on the key cells in the development of metabolism- associated steatohepatitis, hepatic stellate cells.In project III, we summarized the available literature on the role of cholinergic signaling in adipose tissue.In project IV, we studied the mechanisms of vagus nerve control of weight loss and adipose tissue physiology in this context and discovered a new role for neutrophils in vagotomy-mediated weight loss.This thesis improves our understanding of the physiological effects of vagus nerve signals in the context of inflammation and metabolism. The observation that a loss of vagus nerve signals affects hepatic stellate cell activity and the discovery of a link between the vagus nerve, neutrophils, and weight loss provide a new perspective on the neural regulation of fatty liver disease and weight loss. The insights certainly encourage further studies on cholinergic control of inflammation and metabolism and suggest a potential for neuro-immune interventions in the regulation of fat turnover and body weight.List of scientific papersI. Ahmed, O., Shavva, V. S., Tarnawski, L., Dai, W., Borg, F., Olofsson, V. V., Liu, T., Saliba-Gustafsson, P., Simini, C., Pedrelli, M., Bergman, O., Norata, G. D., Parini, P., Franco-Cereceda, A., Eriksson, P., Malin, S. G., Björck, H. M., & Olofsson, P. S. (2025). Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease. Journal of internal medicine, 297(1), 47-59.https://doi.org/10.1111/joim.20032II. Ahmed, O., Caravaca, A. S., Crespo, M., Dai, W., Liu, T., Guo, Q., Leiva, M., Sabio, G., Shavva, V. S., Malin, S. G., & Olofsson, P. S. (2023). Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation. Bioelectronic medicine, 9(1), 6.https://doi.org/10.1186/s42234-023-00108-3III. Shavva, V. S., Tarnawski, L., Liu, T., Ahmed, O., Olofsson, P. S. (2024). Cholinergic signaling in adipose tissue. Current Opinion in Endocrine and Metabolic Research. 37. 100546.https://doi.org/10.1016/j.coemr.2024.100546IV. Liu T., Caravaca A.S., Cai M., Mendes P., Dai W., Vacquie J.J., Guo Q., Zhang Y., Schipper R., Simón R.R., Pei S., Karlsson M., Shavva V.S., Hagberg C.E., Tarnawski L .* , Olofsson P.S .* A lymphocyte antigen 6G-dependent mechanism regulates hormone-sensitive lipase phosphorylation in white adipose tissue. [Manuscript]</p
Studies on cortisol deficiency with focus on biochemical and clinical characteristics and self-management
No full textBackground: Autoimmune Addison's disease (AAD) develops gradually with vague symptoms, which contributes to delayed diagnosis. However, systematic investigations of the clinical presentation are scare. Early detection could help prevent adrenal crisis (AC). The course of AAD has been considered irreversible, but case reports suggest that some patients retain corticosteroid production. Whether residual adrenocortical function (RAF) in patients with AAD is of importance for adrenomedullary function is not known. In adrenal insufficiency (AI) replacement therapy with glucocorticoids (GCs), requires ability to self-management, and patient education. However, few studies have evaluated GC education group meetings regarding its effectiveness and even fewer have involved relatives.Aim: Study I, to characterize changes in routine blood tests, and clinical signs of undiagnosed AAD. Study II, to evaluate RAF and potential clinical implications in patients with AAD. Study III, to investigate any influence of RAF on adrenomedullary function. Study IV, to assess the perceived safety and level of knowledge regarding appropriate GC dose adjustments in patients with AI and their relatives. Design: I retrospective multicenter study. II, III a two-staged cross-sectional clinical multicenter study. IV an observational, multicenter study.Results: At time of AAD diagnosis, hyponatremia was present in 84% of patients, hyperkalemia in one-third, 52 % had an elevated TSH level. RAF was observed in 30.2% of patients with AAD, more common in men and patients with shorter disease duration. Among 70 patients with AAD, metanephrine (MN) was detectable in 33% and positively correlated to the level of cortisol. After the GC education group meeting, significant improvements were observed in safety, knowledge of GC dose adjustments and correct actions in high-risk situations of developing AC. Unexplained hyponatremia and/or elevated TSH should raise suspicion of AAD. One-third of patients with AAD retain RAF even years after diagnosis, with small amounts of endogenous cortisol affecting MN levels. Perceived safety in self-management and GC dose adjustments improved in patients with AAD and their relatives following GC education group meeting.List of scientific papersI. Sævik Å.B*, Åkerman A-K*, Grønning K, Nermoen I, Valland S.F, Finnes T.E, Isaksson M, Dahlqvist P, Bergthorsdottir R, Ekwall O, Skov J, Nedrebø B.G, Hulting A-L, Svartberg J, Hoybye C, Bleskestad I.H, Jørgensen A.P, Kämpe O, Øksnes M, Bensing S, Husebye E.S. Clues to detect undiagnosed autoimmune Addison's disease - myths and realities J Intern Med 2017 Nov 283 (2): 190-199. * Equally contributed to the paper https://doi.org/10.1111/joim.12699II. Sævik Å.B, Åkerman A-K, Methlie P, Quinkler M, Palmstrøm Jørgensen A, Höybye C, Debowska A.J, Nedrebø B.G, Dahle A.L, Carlsen S, Tomkowicz A. Sollid S.T, Nermoen I, Grønning K, Dahlqvist P, Grimnes G, Skov J, Finnes T, Valland S.F, Wahlberg J, Emblem Holte S, Simunkova K, Kampe O, Husebye E.S, Bensing S, Øksnes M. Residual corticosteroid production in autoimmune Addisons's disease J Clin Endocrinol Metab. 2020 July 105 (7):2430-2441. https://doi.org/10.1210/clinem/dgaa256III. Åkerman A-K, Sævik Å.B, Medbøe Thorsby P, Methlie P, Quinkler M, Palmstrøm Jørgensen A.P, Höybye C, Debowska A.J, Nedrebø B.G, Dahle A.L, Carlsen S, Tomkowicz A. Sollid S.T, Nermoen I, Grønning K, Dahlqvist P, Grimnes G, Skov J, Finnes T, Wahlberg J, Emblem Holte S, Simunkova K, Kämpe O, Husebye E.S, Øksnes M, Bensing S. Plasma-metanephrines in patients with autoimmune Addison's disease with and without residual adrenocortical function J Clin Med 2023 May 12 (10):3602. https://doi.org/10.3390/jcm12103602IV. Åkerman A-K, Höybye C, Berinder K, Wahlberg J, Petersson M, Dahlqvist P, Bensing S. Self-management and quality of life in Swedish patients with adrenal insufficiency, and their relatives. [Manuscript]</p
Intraoperative imaging, navigation and monitoring
No full textNeurosurgery involves significant risks due to the intricate anatomy and delicate structures of the brain and spine. Developing techniques to improve surgical accuracy, thereby minimizing these risks, has been a key focus throughout the evolution of neurosurgery. This thesis explores intraoperative navigation, imaging and monitoring technologies designed to enhance accuracy, efficiency and seamless integration into the surgical workflow.Study I was a systematic review on the use of hybrid operating rooms in neurosurgery. It was found that publications on hybrid operating rooms mainly focus on vascular and spinal uses, the main advantages being the possibility to easily acquire pre-, intra- and postoperative images, thereby increasing surgical precision.Study II aimed to evaluate the feasibility of performing intraoperative MRI by using a non- dedicated MRI scanner in the radiology department and to outline the workflow. The study showed that this method is feasible, safe and only adds about an hour to the surgical procedure. This extra time is no longer than that reported in studies with a dedicated MRI scanner.In Study III the registration accuracy between traditional surface matching and automatic image registration was compared in patients undergoing cranial surgery. The mean accuracy for surface match registration was 6.6 + 3.1 mm and for automatic image registration 1.0 + 0.3 mm. Thus, automatic image registration was found to be superior to surface matching.In Study IV the registration accuracy between surface matching and automatic image registration was compared in patients undergoing spinal surgery. Automatic image registration at 1.20 + 0.42 mm was not found to be inferior to surface matching at 1.94 + 0.64 mm. The accuracy of both methods was clinically acceptable for spinal surgery, but automatic image registration minimized user errors and provided a more standardized workflow.Study V was a feasibility and accuracy study, in which augmented reality navigation was used in combination with a conventional navigation system to place pedicle screws in a spine phantom. An augmented reality head mounted device was used to plan and place 48 screws with a clinical accuracy of 94%. The addition of the augmented reality device is feasible and contributes benefits in the planning and minimally invasive placing of pedicle screws. The accuracy achieved is in line with conventional navigation systems and other publications on augmented reality devices.Study VI was a retrospective study describing our workflow when conducting intraoperative neurophysiological monitoring for intramedullary spinal tumor surgery. In addition, intraoperative neurophysiological data from 70 patients were analyzed for correlation between intraoperative signal change and postoperative neurological outcome. A highly trained neurophysiologist was responsible for monitoring our workflow and always present in the operating room. A complete loss of somatosensory evoked potential response intraoperatively was significantly associated with sensory deficits and lower modified McCormick scores at short and long-term follow-up. Intraoperative loss of motor evoked potential correlated with a significant decline in modified McCormick scores at long-term follow up.List of scientific papersI. Gharios M*, El-Hajj VG*, Frisk H*, Ohlsson M, Omar A, Edström E, Elmi-Terander A. The use of hybrid operating rooms in neurosurgery, advantages, disadvantages, and future perspectives: a systematic review. Acta Neurochir (Wien), 2023, 165, 2343-2358. https://doi.org/10.1007/s00701-023-05756-7II. Frisk H, Persson O, Fagerlund M, Jensdottir M, El-Hajj VG, Burström G, Sunesson A, Kits A, Majing T, Edström E, Kaijser M, Elmi-Terander A. Intraoperative MRI without an intraoperative MRI suite: a workflow for glial tumor surgery. Acta Neurochir (Wien), 2024, 166, 292-300. https://doi.org/10.1007/s00701-024-06165-0III. Frisk H, Jensdottir M, Coronado L, Conrad M, Hager S, Arvidsson L, Bartek J Jr, Burström G, El-Hajj VG, Edström E, Elmi-Terander A, Persson O. Automatic image registration provides superior accuracy compared to surface matching in cranial navigation. Sensors (Basel). 2024 Nov 18;24(22):7341. https://doi.org/10.3390/s24227341IV. Frisk. H, Burström. G, Persson. O, El-Hajj. V.G, Coronado. L. Hager. S, Edström. E, Elmi-Terander. A. Automatic image registration on intraoperative CBCT compared to Surface Matching registration on preoperative CT for spinal navigation: accuracy and workflow. Int J Comput Assist Radiol Surg, 2024, 19, 665-675. https://doi.org/10.1007/s11548-024-03076-4V. Frisk H, Lindqvist E, Persson O, Weinzierl J, Bruetzel LK, Cewe P, Burström G, Edström E, Elmi-Terander A. Feasibility and Accuracy of Thoracolumbar Pedicle Screw Placement Using an Augmented Reality Head Mounted Device. Sensors (Basel), 2022, 22, 522. https://doi.org/10.3390/s22020522VI. Frisk H*, Margaryan G*, Buwaider A*, Sargsyan D, El-Hajj VG, Majing T, Singh A, Fletcher- Sandersjöö A, Persson O, K.E. Persson J, Edström E, Elmi Terander A. Intraoperative Neurophysiological Monitoring in Intramedullary Spinal Surgery - Workflow, Setup and Outcomes. [Manuscript]*Shared first authorship</p