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Enhancing the efficiency of viral and non-viral gene delivery vectors
No full textGene therapy, which involves the introduction, alteration, or deletion of genetic material within cells to treat or prevent disease, holds great promise for addressing various genetic disorders and other medical conditions. However, several challenges remain in the field, particularly concerning nucleic acid delivery into target cells. Other key challenges than efficacious nucleic acid delivery include immunogenicity, toxicity, stability and payload capacity.In paper I, we used splice-switching oligonucleotides (SSOs), which is a class of synthetic nucleic acid molecules designed to modulate the process of alternative splicing within cells. SSOs are designed to specifically target pre-mRNA, influencing the splicing machinery to alter the inclusion or exclusion of specific exons during mRNA maturation. However, various obstacles need to be addressed, particularly pertaining to their inability to efficiently enter cells for their successful use and widespread application. Cell-penetrating peptides (CPPs) have gained interest in nucleic acid delivery due to their ability to traverse cellular membranes, aiding the intracellular delivery of nucleic acids such as SSOs. To improve the membrane-penetrating abilities of CPPs and further facilitate the delivery of the accompanied therapeutic cargo across cell membranes, lipidation of CPPs is one established strategy but it is typically limited to N- or C-terminal conjugation to the peptides. Hence, we here utilized hydrocarbon modified amino acids which are used in peptide stapling for orthogonal introduction of hydrophobic modified amino acids into the CPPs. Our data showed that incorporating α,α-disubstituted alkenyl-alanine (ie. Pentenyl- or octenyl alanine) was successful to impart hydrophobicity to the CPPs. Furthermore, this newly designed peptides have secondary amphipathic structures that have a propensity to form an alpha helix in solution. Upon mixing these novel CPPs with SSOs, nanoparticles are formed that facilitate effective and well-tolerated delivery both in vitro and in vivo. In conclusion, our discoveries introduce a new and versatile approach to augmenting the delivery properties of CPPs, enabling the introduction of hydrophobic features into their structures with sequence-specific precision.In paper II, we broadened our investigation to include other peptide-based vectors, namely dendrimers, for delivery of SSOs. Dendrimers are highly branched, tree-like macromolecules with well-defined structures that have found extensive applications in various fields, including drug delivery, imaging, and materials science. Peptidedendrimers are a class of dendritic polymers constructed using amino acids as building blocks. In our study, we employed lipophilic peptide dendrimers in which lipophilic components, such as fatty acids or hydrophobic amino acids are conjugated to the dendrimer core structure. We evaluated the transfection efficiency of different lipophilic dendrimers and investigated several factors including composition, stereochemistry, and formulation buffer, in reporter cells for SSOs delivery. The impact of stereochemistry was more notable in third-generation peptide dendrimers favoring D-amino acids over L-amino acids. The potential of lipophilic peptide dendrimers presents promising opportunities for enhancing and evaluating diverse cargos and conjugates in forthcoming investigations.In paper III, our focus shifted towards enhancing the efficacy of viral vectors for gene delivery. The utilization of viral vectors in gene therapy has gained significant traction. However, in certain cell types, the efficiency of viral transduction remains insufficient. To overcome this, different additives such as lipids, peptides, polycationic chemicals, and polymers have been employed. While protamine sulfate and polybrene are among the polycationic additives that enhance transduction efficiency, pyran and heparin are examples of anionic compounds that suppress transduction. In this study, we surprisingly discovered a substantial improvement in the transduction efficiency of lentiviruses and Respiratory Syncytial Virus (RSV) when employing low concentrations of heparin and analogs thereof. Moreover, we show that by using lactoferrin, a specific inhibitor of heparan-sulfate proteoglycans (HSPGs), heparin-induced transduction enhancement is suppressed, suggesting that low concentrations of heparin and its analogues facilitate transduction by bridging between the virus and HSPGs. In contrast, heparin and its analogues compete with viral binding to HSPGs at high concentrations. Our findings indicate that polyanionic compounds display a concentration-dependent impact on viral uptake enhancing viral transduction at lower concentrations. Thus, these compounds hold promise for potential applications in ex vivo gene therapy.In paper IV, we wanted to expand on the concept of bridging observed in paper III by investigating the protein corona components associated with CPP-based nanoparticles utilized in paper I. The formation of the protein corona occurs when nanoparticles interact with biological fluids, creating a complex coating of biomolecules. The composition of this corona is influenced by factors such as the physical properties of nanoparticles and physiological conditions, playing a vital role in determining the fate of nanocarriers during therapeutic delivery. Lipid nanoparticles (LNPs) and CPPs represent two effective types of nanoparticle vectors in gene delivery. Early research indicated that the protein corona surrounding LNPs, tends to contain a significant amount of apolipoprotein E (apoE) that plays an important role in hepatic uptake. In this study, we assessed the protein corona surrounding CPP/mRNA nanoparticle complexes and compared it with the protein corona of mRNA-containing LNPs that are used clinically. Our results demonstrated a greater enrichment of apoE in the protein corona of CPP/mRNA complexes compared to LNPs. Moreover, in our comparison of CPP formulations decorated with apoE and transfected into the HepG2 cell line with undecorated formulations, we observed a dose-dependent increase in the transfection efficiency of the decorated formulations. The outcomes from this study will serve as the foundation for developing safer and more efficient gene delivery vehicles utilizing nanoparticles, advancing our understanding of their interaction with biological fluids.List of scientific papersI. Safa Bazaz*, Tõnis Lehto*, Rahel Tops*, Olof Gissberg, Dhanu Gupta, Burcu Bestas, Jeremy Bost, Oscar P. B.Wiklander, Helena Sork, Eman M. Zaghloul, Doste R. Mamand, Mattias Hällbrink, Rannar Sillard, Osama Saher, Kariem Ezzat, C. I. Edvard Smith#, Samir EL Andaloussi# and Taavi Lehto#. I. Safa Bazaz*, Tõnis Lehto*, Rahel Tops*, Olof Gissberg, Dhanu Gupta, Burcu Bestas, Jeremy Bost, Oscar P. B.Wiklander, Helena Sork, Eman M. Zaghloul, Doste R. Mamand, Mattias Hällbrink, Rannar Sillard, Osama Saher, Kariem Ezzat, C. I. Edvard Smith#, Samir EL Andaloussi# and Taavi Lehto#. Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo. Biomedicines. 2021 Aug 19;9(8):1046. *These authors contributed equally. #These authors contributed equally. https://doi.org/10.3390/biomedicines9081046 II. Haneen Daralnakhla, Osama Saher, Susanna Zamolo, Safa Bazaz, Jeremy P. Bost, Marc Heitz, Karin E. Lundin, Samir EL Andaloussi, Tamis Darbre, Jean-Louis Reymond, Rula Zain, and C. I. Edvard Smith. Lipophilic Peptide Dendrimers for Delivery of Splice-Switching Oligonucleotides. Pharmaceutics. 2021 Jan 18;13(1):116. https://doi.org/10.3390/pharmaceutics13010116 III. Safa Bazaz, Doste R Mamand, Osama Saher, Dara K Mohammad, Samantha Roudi, Wael Chrifi, Taavi Lehto, Manuchehr Abedi Valugerdi, Evren Alici, Kariem Ezzat, Samir EL Andaloussi. Heparin and Its Low Molecular Analogues Improve Transduction Efficiency of Enveloped Viruses. [Manuscript]IV. Safa Bazaz, Helena Sork, Osama Saher, Dara K Mohammad, Doste R Mamand, Taavi Lehto, Kariem Ezzat, Samir EL Andaloussi. Role of Protein Corona and apoE in the Uptake of CPP-mRNA Nanocomplexes. [Manuscript]</p
Comorbidities in early rheumatoid arthritis
No full textAll of the studies that form part of this thesis concern the subject of comorbid conditions in early rheumatoid arthritis (RA). We have used linkage of Swedish clinical and demographic registers as well as the Swedish Rheumatology Quality Register (SRQ) and the Epidemiological Investigation of RA (EIRA) study to investigate the prevalence of comorbidities in early RA, the influence of comorbidities on the choice of antirheumatic treatment and on the chance of remission.In study I, we compared the prevalence of comorbidities in 11 086 patients with early RA with 54 813 matched controls. We found that respiratory, endocrine and certain neurological diseases were more common among RA patients than controls, whereas psychiatric and malignant comorbidities were less common, particularly in patients with seropositive RA. The difference in comorbidity burden was small, but found to be slightly higher in patients with RA compared to controls, especially in patients with seronegative disease.In study II, we examined whether comorbidities were associated with the choice of disease-modifying antirheumatic drugs (DMARDs). We compared the DMARDs at diagnosis and after one year in 13 505 patients with early RA in relation to their comorbidity status. Most patients were treated with methotrexate (MTX) monotherapy, although there were differences among the comorbidity categories, with the lowest use in patients with chronic kidney disease (CKD) and respiratory diseases. After one year, 13% were treated with biological/targeted synthetic (b/ts)DMARDs, with the lowest proportion among patients with a history of cancer. It was more common among older patients and those with a higher comorbidity burden not to be treated with any DMARD one year after diagnosis, particularly patients with CKD, respiratory diseases or previous infections.In study III, we evaluated whether comorbidities affected the likelihood of reaching remission, in 11 001 early RA patients treated with MTX monotherapy. After 3 months, approximately half of the patients failed to reach 28-joint Disease Activity Score (DAS28) remission, with the highest degree among patients with CKD and the lowest degree among patients with a previous cancer. The relative risk of failure to reach remission was increased among patients with endocrine, gastrointestinal, infectious, psychiatric and respiratory diseases. Having a higher overall comorbidity burden was also associated with remission failure. The results were similar at the 6 months follow-up and when assessed with other standard remission measures.In study IV, we examined whether obesity and/or overweight were independently associated with an increased risk of remission failure in 1285 patients with early RA from the EIRA study, or if it could be explained by underlying comorbidities or lifestyle factors. We found that the obese patients (BMI ≥30 kg/m2) were at increased risk of DAS28 remission failure compared to normal weight patients (BMI 18.5-24.9 kg/m2) after 3 and 6 months. This association remained after adjustments for comorbidities and other potential confounders, suggesting that the risk associated with obesity cannot be explained by comorbid conditions. No significant association was observed for the overweight patients (BMI 25-29.9 kg/m2).List of scientific papersI. Tidblad L, Westerlind H, Delcoigne B, Askling J, Saevarsdottir S. Comorbidities at diagnosis of rheumatoid arthritis: a population-based case-control study. Rheumatology (Oxford). 2021 Aug 2;60(8):3760-3769. https://doi.org/10.1093/rheumatology/keaa856 II. Tidblad L, Westerlind H, Delcoigne B, Askling J, Saevarsdottir S. Comorbidities and treatment patterns in early rheumatoid arthritis: a nationwide Swedish study. RMD Open. 2022 Dec;8(2):e002700. https://doi.org/10.1136/rmdopen-2022-002700 III. Tidblad L, Westerlind H, Delcoigne B, Askling J, Saevarsdottir S. Comorbidities and chance of remission in patients with early rheumatoid arthritis receiving methotrexate as first-line therapy: a Swedish observational nationwide study. RMD Open. 2023 Dec 20;9(4):e003714. https://doi.org/10.1136/rmdopen-2023-003714 IV. Tidblad L*, Öberg Sysojev A*, Delcoigne B, Klareskog L, Alfredsson L, Askling J, Westerlind H*, Saevarsdottir S*. Do concurrent comorbidities explain the increased risk of remission failure in obese patients with early rheumatoid arthritis? *These authors contributed equally to the paper. [Manuscript]</p
Imaging the spatial organization of healthy human brain and glioblastoma
No full textMulticellular biological systems have a single genetic plan that contains the set of instructions to shape the three-dimensional architecture of specialized tissues and organs. The genetic plan is contained in the DNA, and information is relayed through RNA to produce proteins that grant cells with the power to carry out different functions. As cells specialize giving rise to differentiated cell types of a particular tissue, they express different RNA molecules that will reshape their protein content and grant them with a certain phenotype. The development of scRNA-seq technologies at the start of the 2010s allowed researcher to quantify RNA expression at high gene throughput, enabling a deep molecular characterization of cell types.However, scRNA-seq methods requires dissociation of tissues and organs into cell suspensions, and the spatial organization is lost. The present thesis features the need for high-throughput spatial transcriptomics methods, to enable the characterization of cell types and the spatial architecture of the adult human healthy brain and adult diffuse high-grade gliomas. The thesis is composed of three parts: first, the evolution of the spatial transcriptomics methods and field; second, cell types of the human healthy brain; and third, the biology of adult high- grade diffuse gliomas, and more specifically glioblastoma.In paper I we present Enhanced Electric Fluorescent In Situ Hybridization, or EEL- FISH, a high-throughput spatial transcriptomics methods that enables to obtain the expression profile of up to 448 RNA species per fluorescent channel over large tissue areas. The ability speedily to image over large tissue area was achieved by enhancing the RNA capture on a surface, which reduced unnecessary imaging time through the tissue thickness (z-axis). Moreover, EEL-FISH enabled imaging of human tissue sections, which are typically challenging for smFISH due to their high autofluorescence. EEL FISH reduces tissue autofluorescence because the tissue is removed after RNA has been captured. Paper II focuses on the direct application of single cell technologies to characterize the cell types of over 100 regions of the human adult brain of healthy individuals. To this end, we employed scRNA-seq to create a census of cell types and combined with EEL-FISH to characterize the spatial organization of cells in specific brain areas. Lastly, we used EEL-FISH to understand the spatial organization of adult high- grade gliomas, more specifically glioblastoma, in paper III. We characterized the expression of 888 RNA species, by using two fluorescent channels, of 57 sections from 27 different high-grade glioma patients (2 oligodendroglioma and 25 glioblastoma). We generalized a model of the spatial organization of glioblastoma, which organizes across a gradient of hypoxia and wound response that are activated on top of a glial-like tumour cell.Along this thesis, I will review the literature of spatial transcriptomics, and the biology of the adult human brain and glioblastoma from a single cell perspective, and discuss the results of the research conducted in papers I, II and III with respect to these topics.List of scientific papersI. Scalable in situ single-cell profiling by electrophoretic capture of mRNA using EEL FISH. Lars E. Borm, Alejandro Mossi Albiach, Camiel C.A. Mannens, Jokubas Janusauskas, Ceren Özgün, David Fernández-García, Rebecca Hodge, Francisca Castillo, Charlotte R.H. Hedin, Eduardo J. Villablanca, Per Uhlén, Ed S. Lein, Simone Codeluppi & Sten Linnarsson. Nature Biotechnology. 2022 September. https://doi.org/10.1038/s41587-022-01455-3 II. Transcriptomic diversity of cell types across the adult human brain. Kimberly Siletti, Rebecca Hodge, Alejandro Mossi Albiach, Lijuan Hu, Ka Wai Lee, Peter Lönnerberg, Trygve Bakken, Song-Lin Ding, Michael Clark, Tamara Casper, Nick Dee, Jessica Gloe, C. Dirk Keene, Julie Nyhus, Herman Tung, Anna Marie Yanny, Ernest Arenas, Ed S. Lein, Sten Linnarsson. Science. 2023 October. https://doi.org/10.1126/science.add7046 III. Glioblastoma is spatially organized by neurodevelopmental programs and a glial-like wound healing response. Alejandro Mossi Albiach, Jokubas Janusauskas, Ivana Kapustová, Egle Kvedaraite, Simone Codeluppi, Johannes B. Munting, Lars E. Borm, Jesper Kjaer Jacobsen, Alia Shamikh, Oscar Persson, Sten Linnarsson. Biorxiv. 2023 September. Preprint. [Manuscript] https://doi.org/10.1101/2023.09.01.555882</p
Risk factors for colorectal cancer and the impact on life in lynch syndrome
No full textColorectal cancer (CRC) constitutes the third most common cancer in Sweden. Approximately 2-4% of CRC cases have a pathogenic variant in a gene known to cause an inherited risk of CRC. The most common hereditary CRC syndrome, Lynch syndrome, is caused by germline pathogenic variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 and in rare cases EPCAM. The lifetime risk of developing CRC in patients with Lynch syndrome is estimated to range between 30-70%. Due to the ranging risk of CRC, patients are not routinely offered prophylactic colectomy but rather surveillance by means of regular colonoscopies.For study I, we aimed to describe different reasons leading to a genetic diagnosis of Lynch syndrome in the cohort of patients referred to Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. Almost a third of patients were diagnosed with Lynch syndrome in association with cancer and that this proportion does not seem to have changed over time. This indicates a significant room for improvement regarding identification of Lynch syndrome patients before cancer develops.For study II, whole exome sequencing was performed in members belonging to a Swedish family carrying a PMS2 missense mutation to study genetic CRC risk modifiers. The most interesting variant was a deletion in the gene BAG1. BAG1 has been linked to the progression of CRC by promoting CRC cell survival. We conclude from this study that the genetic architecture behind CRC development is complicated and to further study these mechanisms, it must be assessed in a genome wide manner.Recommendations on colorectal surveillance in Lynch syndrome tend to differ according to different countries and guidelines. This is in large part due to the previously thought rare nature of Lynch syndrome, which makes it difficult to conduct studies with enough power to draw conclusions from and support recommendations. As more patients hopefully are diagnosed, surveillance is likely to be tailored to each patient. In study III, we evaluated the quality of endoscopic surveillance of the cohort referred to Karolinska University Hospital, Solna, Sweden. More specifically, we collected data regarding endoscopic surveillance to study the correlation between bowel preparation and adenoma detection (with known risk factors for CRC) as well as the correlation between CRC detection and surveillance interval length. Interval was not significant in CRC detection. We found no association between bowel preparation and the number of adenomas, though poor preparation was found to be associated with an older age and obesity, and a high number of detected adenomas was associated with older age, male sex and CRC detected during surveillance. The results indicate that special attention is needed for elderly, men and obese individuals regarding preparation and inspection.For study IV, we conducted a scoping review to understand if and what type of research has been conducted to understand the impact on physical and mental health when living with a high risk of cancer. The impact on life seems to be higher in carriers of Lynch syndrome post-disclosure of a positive test but minimize over time. Worry in regards to children seems to be an especially prominent issue amongst patients. Patients express a lack of knowledge in healthcare services regarding Lynch syndrome, and cancer risk perception seems to influence approach to surveillance. Patients request more information regarding life after surgery.List of scientific papersI. Walton Bernstedt S, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS. Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hered Cancer Clin Pract. 2021;19(1):18.https://doi.org/10.1186/s13053-021-00171-4II. Bryant P, Walton Bernstedt S, Thutkawkorapin J, Backman AS, Lindblom A, Lagerstedt-Robinson K. Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk. Eur J Cancer Prev. 2023;32(2):113-8.https://doi.org/10.1097/CEJ.0000000000000769III. Walton Bernstedt S, Haxhijaj A, Jamizadeh N, Björk J, Andreasson A, Forsberg A, Backman AS. Quality of endoscopic surveillance of Lynch syndrome patients in Stockholm, Sweden—adenoma detection and bowel cleanliness. Endosc Int Open.https://doi.org/10.1055/a-2339-7152IV. Walton Bernstedt S, Backman AS, Fritzell K. Impact on physical and mental health, and general well-being in Lynch syndrome patients: A scoping review. [Manuscript]</p
Gestational weight gain, bariatric surgery, and adverse maternal and infant outcomes
No full textGestational weight gain is a crucial predictor for various adverse maternal and infant outcomes. In 2009, the U.S. Institute of Medicine (IOM) introduced optimal ranges for gestational weight gain based on a woman's pre-pregnancy BMI. Since then, the IOM recommended guidelines for gestational weight gain have found widespread application in both clinical practice and research. Despite this, their calculation of recommended weight gain relies on traditional methods, and these conventional approaches have inherent limitations. Specifically, gestational weight gain is calculated by subtracting pre-pregnancy weight from the woman’s weight before delivery, overlooking the influence of gestational duration on the potential for gaining weight. For instance, a woman delivering preterm (at week 30) will have less time to gain weight, compared to a woman delivering her infant at full term (40 weeks), which would produce a biased association between low gestational weight gain and the risk of preterm birth.Gestational weight gain z-scores are a method that addresses the impact of gestational duration on gestational weight gain by standardizing weight gain according to gestational age. While early-pregnancy body mass index (BMI) specific z-score charts have been established for Swedish pregnant women, using these charts to determine optimal ranges for gestational weight gain remains unexplored. Currently, there is limited research on the relationship between gestational weight gain z-scores and adverse pregnancy outcomes, both generally as well as among women who have undergone bariatric surgery. This thesis explores the association between gestational weight gain z-scores and adverse pregnancy outcomes, both generally as well as specifically among women who have undergone bariatric surgery, providing evidence to contribute to determining optimal ranges of gestational weight gain z-scores.The first study in this thesis is a cohort study comprising singleton pregnancies (n=174,953) that explored the association between gestational weight gain z-scores and various delivery outcomes in each early-pregnancy BMI weight status group. For women with a normal weight, overweight, or obese weight status at the start of pregnancy, increased gestational weight gain was associated with an elevated risk of cesarean section, induction of labor, and postpartum hemorrhage. Low weight gain reduced the risk of cesarean delivery among all early-pregnancy BMI weight status categories, except for underweight.The second study in this thesis is a cohort study comprising singleton pregnancies (n=131,164) that investigated the association between gestational weight gain z-scores - in early pregnancy and before diagnosis - and gestational diabetes. With the exception of women with an obese class III weight status at the start of pregnancy, high gestational weight gain before diagnosis was associated with an increased risk of gestational diabetes. Additionally, for women with an extremely obese status (obese class III) at the start of pregnancy, low gestational weight gain before diagnosis was associated with a reduced risk of gestational diabetes. In women with an overweight status at the start of pregnancy, high gestational weight gain in early pregnancy was associated with an increased risk of gestational diabetes. Meanwhile, in women with an obese weight status (obese I, II, and III) at the start of pregnancy, low weight gain in early pregnancy was associated with a reduced risk gestational diabetes.The third study in this thesis is a matched cohort study comprising singleton pregnancies with a history of bariatric surgery (n=6388) and without (n=6388). The study compared gestational weight gain between women with and without a history of bariatric surgery and investigated whether gestational weight gain differed by surgical procedure, surgery-to conception interval, and/or surgery-to-conception weight loss. Women with a history of bariatric surgery had lower gestational weight gain than matched controls with similar early pregnancy characteristics. While gestational weight gain was lower in women with a shorter surgery-to-conception interval or lower surgery-to-conception weight loss, it did not differ by surgical procedure.The fourth study in this thesis is a cohort study comprising singleton pregnancies with a history of gastric bypass (n=8284) investigating predictors, including gestational weight gain, of delivering a small-for-gestational-age (SGA) infant after gastric bypass surgery, among both nulliparous and parous women, separately. Low gestational weight gain and smoking were both associated with an increased risk of SGA, while having an overweight/obese weight status at the start of pregnancy or high gestational weight gain was associated with a decreased risk of SGA.Overall, the findings from this thesis indicate that excessive gestational weight gain is associated with an increased risk of cesarean section, induction of labor, postpartum hemorrhage and gestational diabetes in women starting pregnancy with a normal weight, overweight, or obese weight status. In these same women, inadequate gestational weight gain is associated with a reduced risk of cesarean section. Additionally, inadequate gestational weight is associated with a reduced risk of gestational diabetes only among women with an obese class III weight status. In women with a history of bariatric surgery, gestational weight gain is lower than for women who have not undergone this surgery, and increased gestational weight gain is associated with a decreased risk of delivering an SGA infant. However, to determine the optimal gestational weight gain range, further studies are required to investigate the association between gestational weight gain and long-term outcomes.List of scientific papersI. Xu H, Arkema EV, Cnattingius S, Stephansson O, Johansson K. Gestational weight gain and delivery outcomes: A population-based cohort study. Paediatr Perinat Epidemiol. 2021;35(1):47-56. https://doi.org/10.1111/ppe.12709 II. Xu H, Hutcheon JA, Liu X, Stephansson O, Cnattingius S, Arkema EV, Johansson K. Risk of gestational diabetes mellitus in relation to early pregnancy and gestational weight gain before diagnosis: A population based cohort study. Acta obstetricia et gynecologica Scandinavica. 2022;101(11):1253-1261. https://doi.org/10.1111/aogs.14450 III. Xu H, Holowko N, Näslund I, Ottosson J, Arkema EV, Neovius M, Stephansson O, Johansson K. Pregnancy weight gain after gastric bypass or sleeve gastrectomy. JAMA network open. 2023;6(12):e2346228. https://doi.org/10.1001/jamanetworkopen.2023.46228 IV. Xu H, Arkema EV, Holowko N, Näslund I, Ottosson J, Stephansson O, Neovius M, Johansson K. Risk factors of small-for-gestational age infants in pregnancies after gastric bypass: A population-based cohort study. [Manuscript]</p
Consumer reported digital immunization records : feasibility, applicability, and public health utility in the Canadian context
No full textBackground: Vaccination is one of the most effective public health interventions of all time. Public health programs collect data on Vaccination Coverage (VC) to determine levels of protection and guide resource allocation for further vaccination campaigns but VC data completeness and utility is a challenge in many settings. Self-report is a sensitive and relatively specific indicator of vaccination status but incorporation into VC analyses is limited. Mobile technologies can enhance Immunization Information Systems, not least by facilitating bi-directional communications with individuals. This permits collection of self-reported immunization records and a channel to deliver reminders and reliable information back to individuals. However, evaluations of consumer apps for immunization are still nascent, often small-scale, and conducted most in controlled research environments.Aim: The overarching aim of this thesis is to shed light on the feasibility, public health utility and applicability of mHealth apps for recording, reporting, and encouraging immunization.Methods: Paper I was an ecological, quality-assurance study describing use of Pan- Canadian mobile immunization app for parental reporting of children’s primary immunization series in Ottawa, Ontario, Canada. Paper II was a single cohort interrupted time series analysis examining the impact of the COVID-19 pandemic in Canada on uptake of a Pan-Canadian mobile immunization app as well as parentally reported pneumococcal series completion rates at the child’s 13-months of age. Paper III was a cross-sectional study describing the characteristics of family/parental characteristics and their association of reporting vaccinating their children against influenza among Pan-Canadian mobile immunization app users in the 2018/2019 influenza season. Paper IV was a systematic review and meta-analysis examining effectiveness of digital push interventions compared to non-digital interventions at increasing vaccine uptake and series completion.Results: Feasibility and Acceptability: The first successful transmission of records occurred April 27, 2015 (Paper I). There were 63,833 pediatric records and 11,381 unique parent-child dyads that met inclusion criteria, respectively in Papers II and III. The onset of COVID-19 restrictions was associated with an abrupt and continued decline in enrollment of children in the app compared to expected values (Paper II). Public Health Utility: 530 (20%) of children were less than 12 months old when their record was first submitted via the app (Paper I). The onset of COVID-19 restrictions was associated with an initial increase in self-reported completion of pneumococcal series, followed by a modest decrease leading to a net effect of -20%, compared to expected values (Paper II). Influenza vaccination was reported for 32.3% (3,675/11,381) of children and 42.0% (4,788/11,381) of parents. Parents receiving the seasonal influenza vaccine was the most strongly associated characteristic with pediatric influenza vaccination (OR 17.05, 95% CI 15.08, 19.28) compared to parents who did not report being vaccinated against influenza that season (Paper III).Applicability: When comparing digital push with non-digital interventions, patients had 1.18 (95% CI 1.11, 1.25) the odds of receiving vaccination or series completion. Analyses had high statistical heterogeneity, but risk of bias was low (Paper IV).Conclusions: Through four studies, this thesis provided supportive evidence on the potential to mobile apps to enhance IIS. Successful transmission of self-reported immunization records to public health via mobile app was demonstrated to be feasible and acceptable. The onset of COVID-19 was associated with decreased app use and reported pediatric pneumococcal series completion. Parents receiving the seasonal influenza vaccine was associated with reporting their children as immunized. Receiving digital push notifications increases the odds of vaccine uptake and series completion. These studies are subject to limitations but show potential for mHealth apps to facilitate self-report of vaccination data, assess trends and associations in vaccine behavior and encourage immunization through push interventions.List of scientific papersI. Atkinson, K.M., El-Khatib, Z., Barnum, G., Bell, C., Turcotte, M.C., Murphy, M.S., Teitelbaum, M., Chakraborty, P., Laflamme, L. and Wilson, K., 2017. Using Mobile Apps to Communicate Vaccination Records: A City-wide Evaluation with a National Immunization App, Maternal Child Registry and Public Health Authorities. Healthcare Quarterly. 20(3), pp.41-46. https://doi.org/10.12927/hcq.2017.25289 II. Atkinson, K.M., Ntacyabukura, B., Hawken, S., Laflamme, L. and Wilson, K., 2022. Effects of the COVID-19 pandemic on selfreported 12-month pneumococcal vaccination series completion rates in Canada. Human Vaccines & Immunotherapeutics. 18(7), p.2158005. https://doi.org/10.1080/21645515.2022.2158005 III. Atkinson, K.M., Ntacyabukura, B., Hawken, S., El-Khatib, Z., Laflamme, L., Wilson, K. Parent and family characteristics associated with selfreported uptake of pediatric influenza vaccine in a sample of Canadian digital vaccination platform users. A cross-sectional study. [Submitted]IV. Atkinson, K.M., Wilson, K., Murphy, M.S., El-Halabi, S., Kahale, L.A., Laflamme, L.L. and El-Khatib, Z., 2019. Effectiveness of digital technologies at improving vaccine uptake and series completion–A systematic review and meta-analysis of randomized controlled trials. Vaccine. 37(23), pp.3050-3060. https://doi.org/10.1016/j.vaccine.2019.03.063 </p
Diabetes, cardiovascular events, and lifestyle : from epidemiology to clinic
No full textToday, the health care system plays an important role in the prevention of diseases, not least through support of a healthy lifestyle, including being physically active. Given the development of digital tools together with the importance of healthy lifestyle habits in prevention of most diseases, mHealth with self-management interventions has the potential to play a greater role than ever before. The growing implementation of digital solutions in health care shows a need for flexible and remote support as a complement to regular visits to the health care provider.Physical activity (PA), a modifiable lifestyle factor, has been shown to be associated with a decreased risk of cardiovascular disease (CVD) in previous epidemiological studies. Some have suggested that PA affects the risk of CVD in women and men differently, and different types of PA may have different effects. Type 2 diabetes (T2D) and CVD share several characteristics including risk factors. Following an aging population and increases in risk factors ascribed to lifestyle, the prevalence of T2D is expected to arise in the coming decades. Currently, there is a rapid development in lifestyle promoting smartphone apps and devices for self-management targeted to persons with T2D. However, few previous app interventions in persons with T2D have targeted objectively measured daily PA alone. Moreover, an elevated blood pressure (BP) is the leading risk factor for CVD, and a common comorbidity in persons with T2D. Hence, a normotensive BP in persons with T2D is of great importance, who are also likely to use digital devices for self-measurement.This thesis aims to study the association between total physical activity (TPA) and leisure time physical activity (LPA), and risk of stroke and myocardial infarction (MI) in women and men (study I), to study if a smartphone app intervention promoting PA by daily steps can improve time spent in moderate-to-vigorous intensity physical activity (MVPA), Health Related Quality of Life (HRQoL), and several other clinical variables in persons with T2D (study II-III), and to validate two automatic BP monitors with a Bluetooth function against manual BP monitoring in persons with T2D (study IV).Study I was a prospective cohort study based on the Swedish National March Cohort (SNMC), following 31,580 individuals from 1997 to 2016. TPA and LPA were self-reported in the baseline questionnaire and outcomes of incident cases of MI and stroke were derived from national registers. A 22% lower risk of MI was seen in women in the highest tertile of TPA compared to the lowest tertile (HR: 0.78; 95% CI: 0.63–0.97). Among men, being in the highest tertile of LPA was associated with a lower risk of MI compared to belonging to the lowest tertile (HR: 0.78; 95% CI: 0.62–0.98), and a lower risk of stroke was seen among men in the highest tertile compared to the lowest (HR: 0.78; 95% CI: 0.61–0.99).Study II-III was based on data from the DiaCert-study, a two-armed randomized controlled trial including 181 women and men with T2D. The intervention group was given access to the step promoting smartphone app DiaCert at baseline and 3 months onwards in addition to standard care, while the control group received standard care only. Outcomes of objectively measured MVPA (min/day) using accelerometers (primary outcome), BP, body mass index (BMI), waist circumference, HbA1c, blood lipids, and HRQoL (secondary outcomes) were assessed at baseline and at follow-ups at 3 and 6 months. The intervention had a positive effect and showed improvements in three HRQoL health concepts; role limitations caused by physical health problems, (−16.9; 95% CI −28.5 to −5.4), role limitations caused by emotional problems (−13.9; 95% CI −25.8 to −2.1), and emotional well-being (−5.7; 95% CI −10.4 to −1.0), in the intervention group compared to the control group after 3 months of intervention. No effect was observed on neither the primary outcome MVPA after 3 months, nor any of the clinical variables measured at 3 and 6 months.In Study IV, two automatic BP monitors were validated against manual BP monitoring using baseline data from the DiaCert-study. The mean difference between the automatic monitor Beurer BM 85 and the manual BP monitor was 11.1 (SD 11.2) mmHg for systolic BP and 8.0 (SD 8.1) mmHg for diastolic BP. For the automatic monitor Andersson Lifesense BDR 2.0, the corresponding mean difference was 3.2 (SD 10.8) mmHg for systolic BP and 4.2 (SD 7.2) mmHg for diastolic BP.In conclusion, our results highlight potential differences regarding LPA and TPA on the risk of MI and stroke between the sexes. The step promoting app intervention DiaCert showed an effect on health concepts reflecting both physical and emotional HRQoL, but no effect was found for MVPA or any of the cardiometabolic markers measured. Hence, future research is needed to conclude what type of mHealth solution that would not only improve HRQoL, but also be effective in supporting PA and improve cardiometabolic factors in this patient group. The validation of the two automatic BP monitors showed that one of the monitors differed in measurements within what could be clinically acceptable (Andersson Lifesense BDR 2.0), while the other did not (Beurer BM 85). Taken together, our results show that evaluation of the efficacy of mHealth PA interventions and validation of automatic BP monitors for home management are of importance to ensure the quality of the care, before implementing those in the health care system.List of scientific papersI. Hummel M, Hantikainen E, Adami HO, Ye W, Bellocco R, Bonn SE, Lagerros YT. Association between total and leisure time physical activity and risk of myocardial infarction and stroke - a Swedish cohort study. BMC Public Health. 2022 Mar 18;22(1):532.https://doi.org/10.1186/s12889-022-12923-5II. Bonn SE, Hummel M, Peveri G, Eke H, Alexandrou C, Bellocco R, Löf M, Trolle Lagerros Y. Effectiveness of a Smartphone App to Promote Physical Activity Among Persons With Type 2 Diabetes: Randomized Controlled Trial. Interact J Med Res.https://doi.org/10.2196/53054III. Hummel M, Bonn SE, Trolle Lagerros Y. The effect of the smartphone app DiaCert on health related quality of life in patients with type 2 diabetes: results from a randomized controlled trial. Diabetol Metab Syndr. 2022 Dec 17;14(1):192.https://doi.org/10.1186/s13098-022-00965-zIV. Wetterholm M, Bonn SE, Alexandrou C, Löf M, Trolle Lagerros Y. Validation of Two Automatic Blood Pressure Monitors With the Ability to Transfer Data via Bluetooth. J Med Internet Res. 2019 Apr 17;21(4):e12772.https://doi.org/10.2196/12772</p
Molecular and functional organization of the locomotor networks : from brainstem to spinal cord
No full textLocomotion is a complex behavior that allows us to move and interact with the surroundings. In mammals, descending locomotor commands from the brainstem act directly onto spinal locomotor circuits to initiate or halt locomotor activity. However, it is the spinal locomotor networks themself that activate and modulate rhythm and pattern generation underlying locomotor activity. The development of genetic tools for manipulating specific neuron populations has significantly advanced our understanding of locomotor circuits extending from the brainstem to the spinal cord.Yet the knowledge of which spinal circuits are targeted by the descending commands and how they transform this supraspinal drive into rhythmicity is not well understood in mammals. Moreover, while pattern-generating circuits are starting to be well characterized in the spinal cord, less is known about the rhythm-generating networks which involve several excitatory spinal populations. However, these populations only comprise a fraction of the excitatory neurons found in the spinal cord. Thus, there is a need to find new molecular markers for excitatory spinal neurons that could depict new excitatory populations involved in rhythm generation or other functions of the spinal locomotor networks.The work of this thesis addresses these questions by using mice genetics to either activate, inhibit, or record the activity of specific neuronal populations.In Paper I of this thesis, we examined the transition node between the descending commands and the spinal locomotor networks. We found that the LPGi/CVL neurons send the final descending commands to the spinal cord and activate different spinal clusters in a spatiotemporal manner. In Paper II, we investigated the transcriptomic profiles of spinal glutamatergic neurons which led us to characterize a new spinal glutamatergic population expressing the transcription factor Lhx9. We showed that this population is involved in the modulation of the locomotor frequency and, therefore, is suggested to be part of the rhythm-generating networks.Overall, the work presented in this thesis widens our understanding of the initiation and modulation of locomotor activity from the brainstem to the spinal cord in mice which may further aid in unraveling the functional organization of locomotor circuits.List of scientific papersI. Hsu, LJ., Bertho, M. & Kiehn, O. (2023). Deconstructing the modular organization and real-time dynamics of mammalian spinal locomotor networks. Nature Communications. 14, 873. https://doi.org/10.1038/s41467-023-36587-w II. Bertho, M., Caldeira, V., Hsu, LJ., Löw, P., Borgius, L., Kiehn, O. (2024). Excitatory spinal Lhx9-derived interneurons modulate locomotor frequency in mice. Journal of Neuroscience. https://doi.org/10.1523/JNEUROSCI.1607-23.2024 </p
Visual perception in infancy and its links to later autism
No full textAlterations in primary sensory areas of the brain have been suggested to be at the roots of the well-documented visual perceptual differences in autism. However, despite the possible key role these sensory processing alterations may play in the early development of autism, few studies have tried to clarify the links. Moreover, not much is known about which specific sensory alterations are most strongly linked to the core autistic symptoms. The purpose of this thesis is to increase our knowledge about whether and how visual sensory processing differences manifest during early infancy and how they relate to later development of cognitive and social communicative abilities as well as to the emerging core social domain symptoms of autism. EEG neuroimaging was used as the means of investigation into infants’ brain activities. Comparisons between infants at elevated familial likelihood of developing autism and typically developing infants were done to see how the brain activity patterns differ.Study I inquired whether differences in low-level global and local visual (motion and form) processing at age 5 months are linked to the acquired motor and language abilities at age 14 months. Only global motion processing was found to be linked to later language ability, and this association was specific to language comprehension.Study II inquired whether differences in low-level global and local visual (motion and form) processing at age 5 months are in any way linked to the emerging core autistic symptoms at age 36 months, and how visual cortical organization that underlies such global and local perceptions differ between infants who later develop high levels of autistic symptoms and infants who do not develop the symptoms. Furthermore, relative influences of genes and environment on these low-level visual perceptual processes were assessed. Only global motion processing was found to be linked to the emerging autistic symptoms at 36 months, and this was specific to the social domain symptoms. Accordingly, and the global motion visual cortical organization in infants with later autism was found to be distinctive from the normative infants, showing an altered balance of activity between midline and lateral area. Global motion processing was found to be lowto-moderately heritable.Study III sought to clarify if the results of Study II could be linked to functional brain connectivity. Specifically, this study inquired whether i) visual cortical functional connectivity during processing of social and non-social stimuli at 5 months are linked to the contemporaneous global visual motion processing investigated in Study II; and ii) whether functional connectivity differences are in any way also linked to the emerging core autistic symptoms at age 36 months. Indeed, visual cortical gamma connectivity during social stimulus processing was found to be linked to global motion processing and it is also linked to the emerging autistic symptoms at 36 months. Furthermore, visual cortical theta connectivity during non-social stimulus processing was found to be strongly associated with the emerging autistic symptoms at 36 months, but not to motion processing.In summary, the results of these three studies demonstrate that atypical global visual motion processing, possibly linked to altered functional connectivity in the visual cortex, may occupy an important position in the pathways leading to the social domain symptoms of autism.List of scientific papersI. Hedenius, M., Hardiansyah, I., & Falck-Ytter, T. (2022). Visual global processing and subsequent verbal and non-verbal development: An EEG study of infants at elevated versus low likelihood for autism spectrum disorder. Journal of autism and developmental disorders. 53(9), 3700-3709. https://doi.org/10.1007/s10803-022-05470-w II. Hardiansyah, I., Nyström, P., Taylor, M. J., Bölte, S., Ronald, A., & FalckYtter, T. (2023). Global motion processing in infants’ visual cortex and the emergence of autism. Communications Biology. 6(1), 339. https://doi.org/10.1038/s42003-023-04707-3 III. Hardiansyah, I., Bussu, G., Bölte, S., Jones, E.J.H., Falck-Ytter, T. (2024). Functional connectivity in infants’ visual cortex: Links to motion processing and autism. [Submitted]</p
Local anaesthetics, fluid balance and perioperative outcomes in surgery for advanced ovarian cancer
No full textThe majority of women with ovarian cancer are diagnosed at an advanced stage with extensive dissemination of tumour to the mesothelial lining of the abdomen, the peritoneum. Moreover, large amounts of ascites are often prevalent. Best chance of prolonged survival comprises the combination of cytoreductive surgery (CRS) and adjuvant chemotherapy. The aim of CRS is to resect all visible tumour to achieve complete macroscopic resection, which often necessitates high complexity surgery with risk of substantial fluid shifts and risk of postoperative complications that prolongs (or inhibits) the time-interval to adjuvant chemotherapy. A prolonged time interval to adjuvant chemotherapy has been associated with inferior survival. Local anaesthetics have anti-inflammatory properties and when applied at site of injury in the abdomen, phase II and III trials have demonstrated an improved postoperative recovery after abdominal surgery and reduced time-interval to adjuvant chemotherapy during CRS.Previous observational studies suggests that scheduling of surgery earlier on the week may be associated with improved outcomes and for ovarian cancer the ability to achieve complete macroscopic resection is increased.In the IPLA-OVCA trial, a Swedish multicenter randomised double-blind, placebo-controlled trial, women with advanced epithelial ovarian cancer (aEOC) were randomised to receive Ropivacaine (local anaesthetics) or Saline (placebo) intraperitoneally during and for 72 hours postoperative. Participating hospitals were Karolinska University hospital and Skåne University hospital, Lund. Primary endpoint was time (days), 173 women were included in the intention-to-treat (ITT) and 166 women in the Per Protocol (PP) analyses. There were no differences between groups in mean time between surgery and start of chemotherapy in the ITT (0.4 days (95% CI: -2.4 to 3.2; p=0.77) or the PP analyses, 0.5 days (95% CI: -2.4 to 3.4; p=0.77). Moreover, there was no difference in postoperative opioid consumption, self-reported pain or postoperative complications.In a register-based cohort study, we investigated the association between weekday of CRS in aEOC and overall survival in 524 women subjected to surgery in the Region of Stockholm-Gotland, Sweden. In the adjusted analysis, a 28% increase in the risk of death (HR 1.28, 95% CI 1.04–1.58, p = 0.02) was evident when surgery was performed later in the week (Wednesday-Thursday) as compared to early week (Monday-Tuesday).Two observational case-series examined the association between fluid balance and major postoperative complications. The first with retrospective design and the other with prospective design and predefined fluid balance categories. Multivariate regression models adjusted for potential confounders in both studies. In the retrospective study of 184 women, a net positive fluid balance of >3000mL in the first 48 perioperative hours increased the risk of major postoperative complications (OR 4.85, 95% CI 1.23–19.2, p=0.02). Similarly, in the prospective study with 162 women included a threshold fluid balance greater than 1750mL was also associated with increased risk of postoperative complication (OR 3.40, 95% CI 1.06-10.9; p=0.04).In this thesis we demonstrate that the addition of intraperitoneal local anaesthetics during and after CRS in aEOC, does not reduce the time-interval to adjuvant chemotherapy. We also suggest that CRS may best be performed early in the week and in addition, to reduce risk of major postoperative complications we suggest that the aim of perioperative fluid balance should be below 1750 mL (excluding initial ascites) or less than 2700 mL (including initial ascites).List of scientific papersI. Perioperative fluid balance and major postoperative complications in surgery for advanced epithelial ovarian cancer. Emma Hasselgren, Daniel Hertzberg, Tina Camderman, Håkan Björne, Sahar Salehi. Gynecol Oncol. 2021 May;161(2)402-407. https://doi.org/10.1016/j.ygyno.2021.02.034 II. Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer. Nina Groes-Kofoed*, Emma Hasselgren*, Håkan Björne, Hemming Johansson, Henrik Falconer, Sahar Salehi. Acta Oncol. 2021 Nov;60(11):1513-1519. *Shared first authorship. https://doi.org/10.1080/0284186X.2021.1970221 III. Effect of intra-peritoneal local anaesthetics during and after cytoreductive surgery in advanced ovarian cancer: A randomised double-blind phase III trial. Emma Hasselgren, Nina Groes-Kofoed, Henrik Falconer, Håkan Björne, Diana Zach, Daniel Hunde, Hemming Johansson, Mihaela Asp, Päivi Kannisto, Anil Gupta, Sahar Salehi. [Manuscript]IV. Prospective assessment of the association between perioperative fluid balance and postoperative complications after surgery for advanced ovarian cancer. Emma Hasselgren, Nina Groes-Kofoed, Henrik Falconer, Håkan Björne, Diana Zach, Daniel Hunde, Hemming Johansson, Mihaela Asp, Karin Thorlacius, Päivi Kannisto, Sahar Salehi. [Submitted]</p