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Doctoral student Anthony Larsson will defend his doctoral thesis on 12 December at Karolinska Institutet.  The thesis covers the fate of biobank initiative BBMRI.se, which was ultimately discontinued by the Swedish Research Council following an investigation. In his thesis, Anthony Larsson describes why the initiative failed. However, his work began on completely different premises. Anthony Larsson was recruited to Karolinska Institutet, KI, in august 2011 and was employed as a doctoral student at KI in January 2012, to analyse the process of building a biobank infrastructure. But as time progressed, a lingering discontent was directed towards KI, which served as the host university for the biobank initiative, BBMRI.se. Some of the six other member universities that also participated in the initiative felt that KI gave itself undue favours. “I hope this thesis will provide a scientific contribution to something that is new and unchartered, such as this complex type of infrastructure that is spread across several geographic areas and buildings, but it may also be seen as a form of “cautionary tale” regarding what could happen if you fail to respond to warning signals in time,” says Anthony Larsson, doctoral student at the Department of Learning, Informatics, Management and Ethics (LIME) at Karolinska Institutet. A biobank stores human tissue samples and blood samples etc. for research purposes. When BBMRI.se (BioBanking and Molecular Resource Infrastructure of Sweden) was launched in 2009, it was the hitherto largest investment ever made in a medical infrastructure by the Swedish Research Council (VR) and was part of the EU-initiated umbrella organisation BBMRI.eu. Different interpretations about funding distribution BBMRI.se had a rather distinct structure with eight work packages, containing for example molecular analytics resources, ethics and law, biobanks informatics, physical biobanks, etc. “Reports were submitted to KI in a yearly basis, which in turn reported to VR. This meant that the organisation was very segmented and created some friction with the BBMRI.se management at KI because there were different interpretations as to how the funds were to be distributed,” says Anthony Larsson. Apart from literature studies, the core of his thesis is comprised by qualitative interviews with the organisation’s leading researchers, which allowed Anthony Larsson to follow the development. Further funding was halted After KI found itself on the receiving end of criticism, VR decided in 2016, following an internal and external investigation, to halt further funding and discontinue the venture. The critics alleged that KI did not adhere to the stipulations made by the consortium agreement as originally agreed upon. Already in VR’s first evaluation from 2012, it was indicated that there were unclear structures, particularly in relation to the host university, KI, and the other actors. As the discontent escalated, the premises for Anthony Larsson’s thesis were altered. From the outset there had been a common vision within BBMRI.se, but this dissipated in time. One of the articles in the thesis discusses what happens when actors in an organisation have different perceptions of the mission statement and act according to their own convictions. “When there’s no insight into what’s being done on an overarching level or in the other work packages, it leads to uncertainty, whereby actors  start pulling in different directions while only focussing on their own affairs, which leads to fragmentation in the organisation,” says Anthony Larsson. A problematic vertical-oriented organisation The thesis shows that a large part of the problem was that BBMRI.se had a vertical-oriented organisation without intermediate level feedback. “The organisation had needed more checks and balances during the different projects to ensure that it was progressing in the right direction. KI also reacted much too late to the criticism and much could have been resolved through talks,” says Anthony Larsson. The thesis work has not been without its challenges, especially after the VR decision to cancel further funding to BBMRI.se. “I’ve had to revise some my articles to get them to reflect the reality since the outcome was something altogether different, but this also made it more interesting and powerful,” says Anthony Larsson. New national organisation for biobanks in 2018 In 2018, BBMRI.se became part of a new national organisation for biobanks, Biobank Sweden, this time with Uppsala University as the host university. “Upon defending my thesis, I shall look forward to having an opportunity to discuss my dissertation and its outcome,” says Anthony Larsson. After obtaining his Ph.D., Anthony Larsson will continue his research on digitalisation  at the Stockholm School of Economics. He will also participate in a two-year research project, which seeks to understand how artificial intelligence may be used to affect the decision-making process for corporate boards in the future. Text: Helena Mayer

The human papilloma virus (HPV) can cause cervical cancer. According to new guidelines in Sweden, women over thirty therefore undergo initial screening for the virus rather than a smear test. But younger women also have a much higher risk of pre-cancerous lesions if they carry HPV 16 or 18, a study from Karolinska Institutet in Sweden published in the scientific journal Cancer shows. Four out of five women of fertile age are infected at some time in their lives with HPV. Most of these infections clear on their own, but for some five per cent of the women, the infection turns chronic. Chronic HPV infection can cause pre-cancerous lesions and cancer of the cervix. HPV types 16 and 18 cause some 70 per cent of all cases of cervical cancer and the majority of high-grade pre-cancerous lesions. There are also several other high-risk HPV types that can cause pre-cancerous lesions and cervical cancer. So that doctors can catch pre-cancerous lesions in time, women in Sweden between the ages of 23 and 64 are screened using ectocervical smear tests. If the smear test is abnormal, the sample is tested for HPV. According to new guidelines, screening from the age of 32 is to take the form, in the first instance, of an HPV test instead. If the woman tests HPV positive, a cell sample is then taken that, if aberrant, occasions further gynaecological investigation. However, in the event of a normal cell test but a positive HPV test, the woman is invited only routinely to screening after three to seven years, depending on age. Normal smear tests are no guarantee “This is odd when we know that HPV is associated with cervical cancer,” says Sonia Andersson, professor of gynaecology at the Department of Women’s and Children’s Health, Karolinska Institutet. “So we wanted to examine the cervical cancer risk for patients with normal smear results.” The study included over 9,000 normal smear tests from women between the ages of 20 and 60 who took their tests under the Swedish screening programme from 2005 to 2007. During the follow-up period ending 2014, almost 100 of these women developed high-grade pre-cancerous lesions or in a few cases actual cervical cancer. These patients’ cell samples were then tested for HPV and compared individually with samples from healthy women. The researchers found that women over the age of 30 who were carriers of high-risk HPV had, regardless of HPV type, an eight times higher risk of developing high-grade pre-cancerous lesions or cancer than women with negative HPV findings. “Normal cell tests are therefore no guarantee that a woman won’t develop precancerous changes that can lead to cervical cancer,” says Professor Andersson. “So we need to follow up women with positive HPV findings more frequently.” Should test for HPV type Women below the age of 30 who tested positive for HPV types 16 and 18 had a much higher risk of developing high-grade pre-cancerous lesions or cervical cancer compared to women with negative HPV findings. The HPV tests used in screening programmes today do not show which type of HPV a woman is carrying, only that she has a high-risk type of the virus. “This should be changed. If we test for HPV type, we can screen low-risk individuals less often and instead follow up younger carriers of HPV 16 or 18 and older HPV-positive women more often. In the USA, they’re called in for a new HPV test within the year.” “It should be remembered that most HPV infections clear on their own, including HPV 16/18,” explains Professor Andersson. “But HPV is the most common risk factor for developing cervical cancer and should be followed up methodically. In this way, more pre-cancerous lesions can be treated on time and more cases of cancer prevented.” The study was conducted in association with the University of Ljubljana, Slovenia, and the Scientific Institute of Public Health in Brussels, Belgium and financed with grants from the Swedish Cancer Society, Karolinska Institutet, Stockholm County Council and the King Gustaf V Jubilee Foundation. Publication “The impact of HPV status on development of high-grade cervical intraepithelial neoplasia in women negative for intraepithelial lesions or malignancy at baseline: 9‐year Swedish nested case control follow‐up study” Maria Fröberg, Ellinor Östensson, Karen Belkić, Anja Oštrbenk, Mario Poljak, Miriam Mints, Marc Arbyn, Sonia Andersson. Cancer, online 10 December 2018, doi: 10.1002/cncr.31788.

Cognitive behavioural therapy (CBT) online can be useful in treating gastrointestinal disorders in children when no physical cause can be found. This is the viewpoint of researchers at Karolinska Institutet in Sweden that is described in a new study published in the journal Clinical Gastroenterology and Hepatology.  About 13 per cent of all children suffer from FAPD (functional abdominal pain disorders), which means that they experience pain and other stomach symptoms without any clear physical cause. Many children with FAPD have a reduced quality of life and their families often seek medical care, resulting in large costs for society. So far there is no scientific evidence that medication or changes to their diet help children with these problems. Researchers at Karolinska Institutet have previously shown that online CBT can be effective for teenagers with irritable bowel syndrome (IBS), which is one of the diagnoses included in FAPD. Ninety children with FAPD from the whole of Sweden in the age group 8-12 took part in the new study, together with their parents. All the children were examined by a doctor and a psychologist before they participated in the study to check that they specifically had FAPD. The children were randomly assigned to either ten weeks of exposure-based online CBT or standard medical care. Several positive effects The results show that the children who accessed online CBT had an improved quality of life, fewer stomach problems and a reduced fear of symptoms, as well as avoiding fewer situations compared with children who received standard medical care. "Online CBT can be offered to patients regardless of where they live, and does not require them or their families to take time off school or work to undergo treatment," says Maria Lalouni, psychologist and researcher at the Department of Clinical Neuroscience at Karolinska Institutet, who carried out the study for her doctoral thesis. Children in the online CBT group were exposed to symptoms, i.e. they practised accepting the symptoms and coping with situations that they would normally prefer to avoid. Examples of exposure exercises were to eat food that produced symptoms (such as pizza or ice cream) or to go to school despite having a stomach ache. The parents were given the task of paying less attention to their children's symptoms and giving more attention to other things, such as participation in recreational activities. Families had the treatment in their homes and were able to contact a psychologist using text messages on an internet platform. Big cost savings Online CBT led to large savings in costs compared with standard medical care: on average SEK 9,500 for every child who participated in the online treatment over a ten-week period. These savings are partly from reduced healthcare consumption and partly from reduced indirect costs such as children’s absence from school and parents’ absence from work. "We show that online CBT can increase the accessibility of evidence-based healthcare for a large group of children with considerable suffering, at the same time as reducing costs for society,” says Ola Olén, consultant and researcher at the Department of Medicine, Solna, Karolinska Institutet, who led the study. The study was funded by the Jane and Dan Olsson Foundation, the Swedish Research Council, the Kempe-Carlgrenska Foundation, the Ruth and Richard Julins Foundation, Majblomman, ìShizu Matsumuraîs Donation, the Bengt Ihre Research Fellowship, the Swedish Society of Medicine, Forte, the Centre for Psychiatric Research, and ALF funds. Publication “Clinical and Cost Effectiveness of Online Cognitive Behavioral Therapy in Children with Functional Abdominal Pain Disorders” Maria Lalouni, Brjánn Ljótsson, Marianne Bonnert, Richard Ssegonja, Marc Benninga, Johan Bjureberg, Jens Högström, Hanna Sahlin, Magnus Simrén, Inna Feldman, Erik Hedman-Lagerlöf, Eva Serlachius and Ola Olén. Clinical Gastroenterology and Hepatology, online 28 November 2018, doi:  10.1016/j.cgh.2018.11.043

Researchers at KI are to be awarded over 37 percent of the Swedish Research Council’s funds granted for clinical treatment research in 2018. Of the 200 million kronor for the period 2019‑2021, no less than 75 million kronor is going to research at KI. The Council also granted funds for research into children’s and young people’s mental health. Out of a total of 137.4 million kronor in grants for the period 2018‑2023, almost 50 million kronor is going to KI researchers. The project grants went to the following researchers at KI: Jonas Bergh of the Department of Oncology-Pathology was awarded a total of 13.5 million kronor for the fine-adjustment of pre-operative system therapy and repeated therapy assessment; crossover-design in a prospective, randomised, phase II study for HER2-positive breast cancer. Annika Bergquist of the Department of Medicine, Huddinge, was awarded a total of 18.9 million kronor for her research into treatment with atorvastatin for primary sclerosing cholangitis (PSC) – a randomised controlled study.  Cecilia Ekeus of the Department of Women’s and Children’s Health was awarded a total of 300 thousand kronor for her research into neurological morbidity in children affected by cerebral haemorrhage in connection with suction cap delivery. Bo Göran Ericzon of the Department of Clinical Science, Intervention and technology was awarded a total of 18 million kronor for his research into immunotherapy with organ transplantation in order to minimise the need for immunosuppression.  Christina Dalman of the Department of Public Health Sciences was awarded a total of 24.9 million kronor for her research into early interventions in mental illness – How can barriers to care be overcome for newly-admitted children and young people?  David Mataix-Cols of the Department of Clinical Neuroscience was awarded a total of 4.7 million kronor for his research into clinical and cost-effectiveness of internet-mediated behavioural therapy for children and young people with Tourette’s syndrome. Ellenor Mittendorfer-Rutz of the Department of Clinical Neuroscience was awarded a total of 24.9 million kronor for her research into mental illness and social integration among immigrant children - causes, prognosis, prevention and treatment. Anna Norhammar of the Department of Medicine, Solna, was awarded a total of 19.5 million kronor for her research into myocardial infarction and starting metformin (MIMET) – a register-randomised controlled study.

Real world data from a large Nordic study shows that use of liraglutide, a drug for type 2 diabetes, is associated with a lower risk of myocardial infarction, stroke or cardiovascular death. The study, led by researchers from Karolinska Institutet in Sweden, is published in The Lancet Diabetes & Endocrinology. The number of patients with type 2 diabetes is increasing rapidly in the world. Cardiovascular disease is a serious complication of diabetes and represents a major cause of mortality in this patient group. Liraglutide, a diabetes medication, became available for clinical use in 2009. This drug is a glucagon-like peptide 1 receptor agonist that lowers blood sugar and reduces body weight. A large clinical trial published previously showed that liraglutide reduced the risk of major cardiovascular events among patients with diabetes who had established cardiovascular disease or were at high cardiovascular risk. It has been unclear if these findings also translate to cardiovascular benefit in the broad patient population seen in routine clinical practice. 46.000 patients included in the Nordic study The current study was a collaborative project between researchers at Karolinska Institutet in Sweden, Statens Serum Institut in Denmark, NTNU in Norway and the Swedish National Diabetes Register. The researchers used several nationwide registers with information on prescription drugs, diseases and other data from more than 46.000 patients in Sweden and Denmark, 2010–2016. Around 23.000 patients initiating treatment with liraglutide were compared with the same number of patients initiating treatment with another diabetes drug, DPP4 inhibitors. The main outcome in the study was major cardiovascular events, defined as myocardial infarction, stroke, or cardiovascular death. The rate of major cardiovascular events was 14.0 per 1000 person-years among patients using liraglutide and 15.4 per 1000 among patients using DPP4 inhibitors, a statistically significant difference. This corresponded to 5 fewer major cardiovascular events per 1000 patients followed up for 3 years. Reduced risk of cardiovascular death and any cause of death Use of liraglutide was also associated with reduced risk of cardiovascular death and any cause of death. In a subgroup analysis, patients with a history of major cardiovascular disease appeared to benefit most from treatment with liraglutide, although this was not a statistically significant difference compared with patients without such history. “Our study provides support for the cardiovascular effectiveness of liraglutide among a broader unselected group of patients, providing important confirmatory evidence from routine clinical practice. We believe it may be of interest to drug regulators, clinical guidelines, physicians, and patients,” says last author Björn Pasternak, senior researcher at the Department of Medicine, Solna, Karolinska Institutet, and affiliated with Statens Serum Institut. In addition to Björn Pasternak, the study was also led by Henrik Svanström, senior statistician, and Peter Ueda, postdoctoral researcher, both at the Department of Medicine, Solna, Karolinska Institutet. The study was conducted with support from the Heart and Lung Foundation, Novo Nordisk Foundation, Swedish Society for Medical Research, and the strategic research area in epidemiology at Karolinska Institutet. Publication "Use of liraglutide and risk of major cardiovascular events: a register-based cohort study in Denmark and Sweden" Henrik Svanström, Peter Ueda, Mads Melbye, Björn Eliasson, Ann-Marie Svensson, Stefan Franzén, Soffia Gudbjörnsdottir, Kristian Hveem, Christian Jonasson, Björn Pasternak. The Lancet Diabetes & Endocrinology, online 5 December 2018, doi: 10.1016/S2213-8587(18)30320-6   For more information, please contact: Björn Pasternak, senior researcher Department of Medicine, Solna, Karolinska Insitutet E-mail: bjorn.pasternak@ki.se Tel: 08-524 860 77 (contact through the press office)

There is a large, untapped potential for developing drugs against cancer, fibrosis and cardiovascular diseases by targeting a family of receptors known as Frizzleds, researchers at Karolinska Institutet in Sweden believe. In a new study published in Science Signaling, they identify how these receptors are activated in the cell membrane and the processes that are then triggered within the cell. G protein-coupled receptors are one of the largest families of proteins, with some 800 representatives in humans of importance to a wide range of physiological functions. The receptors sit in the cell membrane and are activated by messenger molecules such as adrenalin, dopamine, histamine and endorphin, which trigger a cascade of processes within the cell. G protein-coupled receptors are involved in the progress of many diseases and are very common targets for drugs. Examples of drugs include beta blockers, antihistamines, morphine and L-DOPA. Many attractive targets “Since this is a large family of receptors, there are still many attractive but still unexploited targets for the future treatment of cancer, cardiovascular disease, diabetes, fibrosis and neurodegenerative diseases,” says Professor Gunnar Schulte at the Department of Physiology and Pharmacology at Karolinska Institutet. He is researching a group of G protein-coupled receptors called Frizzleds, which are important for numerous processes, including fetal development. Signaling via these receptors has also been linked to a large number of diseases, including different forms of tumour. There are currently no drug molecules in the clinics that affect Frizzled receptors, even though, structurally, they resemble the receptors that are effective targets for drug therapy. New screening method The new study shows that one of the receptors in the Frizzled family, Frizzled 5, could be targeted by drugs in the same way as histamine, adrenaline or dopamine receptors. Professor Schulte has led the research, which has been conducted in collaboration with Uppsala University and SciLifeLab in Sweden and research teams in Germany and Canada. The researchers also present a new method that can be used for screening substance libraries in the search for new drug molecules. “This opens up completely new opportunities and concepts for developing drugs for cancer, fibrosis and cardiovascular diseases based on targeting Frizzled proteins,” says Shane Wright, first author of the study and doctoral student in Professor Schulte’s research group at Karolinska Institutet. Better understanding of receptors Work on G protein-coupled receptors was recognized by the Nobel Committee in 2012 awarding the Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz. Recent technological developments have given scientists a better understanding of how G protein-coupled receptors and other receptors on the cell surface are activated and which processes are then triggered within the cell. Such information can prove vital to the development of new drugs.  “The reason there are no drug molecules that target Frizzled receptors is that these mechanisms are not fully understood, a situation that we hope to change,” says Professor Schulte. The study was financed by Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Novo Nordisk Foundation, the Knut & Alice Wallenberg Foundation, the Engkvist Foundations, Marie Curie ITN WntsApp, the Swedish Society for Medical Research, the Science for Life Laboratory, Deutsche Forschungsgemeinschaft and the Canadian Institute for Health Research. Publication “FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs” Shane C. Wright, Maria Consuelo Alonso Cañizal, Tobias Benkel, Katharina Simon, Christian Le Gouill, Pierre Matricon, Yoon Namkung, Viktoria Lukasheva, Gabriele M. König, Stéphane A. Laporte, Jens Carlsson, Evi Kostenis, Michel Bouvier, Gunnar Schulte and Carsten Hoffmann Science Signaling, online 4 December 2018

Three researchers at Karolinska Institutet are being awarded prestigious grants from the European Research Council (ERC). Jens Hjerling Leffler, Anna Rising and Maja Jagodic each receive the ERC Consolidator Grant 2018 for research on, respectively, brain cell type-specific interactions in schizophrenia; the generation of artificial spider-silk super fibers; and epigenetics in multiple sclerosis. This funding programme awards up to EUR 2 million per project over a five year period, and is aimed at mid-career researchers who have recently started their own group and strive to strengthen their role as research leaders. Awarded researchers and projects at KI in 2018:   Principal investigator: Dr. Jens Hjerling Leffler, Department of Medical Biochemistry and Biophysics Project: Brain cell type-specific interactions and schizophrenia Summary: Schizophrenia is a devastating psychiatric disorder that is caused by many minor disturbances or variations in the regulation of hundreds of genes. This makes it difficult to understand where in the brain the most important errors occur, and if malfunctions in one type of cells can also cause pathological changes in adjacent cells. In the project now funded by the ERC, Dr. Jens Hjerling Leffler and his colleagues will investigate a new way of measuring the overall impact of the many minor genetic variations in specific cells, in both mice and humans. The researchers will then recreate this overall impact in only one type of brain cell in an otherwise healthy mouse, in order to be able to systematically investigate how disease-related changes in one cell can affect the function of nearby cells. Increased knowledge on how, when and where genetic changes lead to schizophrenia could hopefully contribute to the development of new therapies that can be used earlier in the disease process – or perhaps even before disease onset. More about Jens Hjerling Leffler’s research More about schizophrenia   Principal Investigator: Dr. Anna Rising, Department of Neurobiology, Care Sciences and Society. Project: Novel approaches to the generation of artificial spider-silk super fibers Summary: Spider silk is nature’s high performance material and has the potential to be used as a biomaterial for medical applications. However, production and spinning of artificial spider silk fibers are very challenging, and current methods to produce silk fibers include conditions which prevent the silk proteins from assembling into fibers in the same complex way that native silk proteins do. Recently, Dr. Anna Rising and her colleagues succeeded in spinning biomimetic spider silk using the same mild conditions as the spider does. In the project now funded by the ERC, the researchers will build further on these technical leaps – aiming to generate artificial silk fibers that are equal or superior to native spider silk in terms of toughness and tensile strength. To reach this goal, they will use genetic information and protein engineering to design new silk proteins, and decipher the relationships between protein structure and mechanical properties of the fibers. This information will be important not only for the generation of strong fibers, but also for the basic understanding of protein fibrillation in, for example, Alzheimer’s disease. More about Anna Rising’s research   Principal investigator: Dr. Maja Jagodic, Department of Clinical Neuroscience Project: Epi4MS – targeting the epigenome for a better understanding of disease pathogenesis and novel therapeutic strategies in Multiple Sclerosis  Summary: Multiple Sclerosis (MS) is a leading cause of incurable progressive disability in young adults. The Epi4MS project aims to identify epigenetic causes of MS and to develop novel therapeutic strategies based on inducing self-sustained reversal of aberrant epigenetic states. Dr. Maja Jagodic and her colleagues will utilize unique MS biomaterial combined with cutting-edge methodologies to capture relevant cells and measure their functional states. The impact of MS-associated changes will be evaluated using innovative in vitro epigenome screens. We will then utilize animal models to dissect the molecular mechanisms of MS-associated changes in vivo and test the therapeutic potential of targeted epigenome-editing. Epi4MS aims at a paradigm-shift in studying and treating complex inflammatory diseases. More about Maja Jagodic’s research About epigenetics at Wikipedia

Eight projects at Karolinska Institutet have been awarded the recently established KI Engagement Grants, which aim to help KI researchers get started along a path to societal impact. These grants are part of an internal ‘impact and outreach’ effort approved by KI President Ole Petter Ottersen. Research is increasingly being judged — by funding agencies and governments alike — not only on its scientific merit but also on its potential to have a tangible impact on society. And while it’s a given that academic research benefits society by creating new knowledge, using this new knowledge to directly benefit society at large, or co-creating new knowledge in a way that is most relevant to societal needs, requires that researchers actively engage with actors outside of academia. To promote such engagement activities, Grants Office set up the KI Engagement Grant, which is financed through government funds distributed to Swedish universities to promote the impact of research and education. The eight winners of the KI Engagement Grants 2018 were selected during the summer 2018 and have received up to SEK 200 000 for a period of up to one year (total budget for the call was SEK 1.2 million). A follow-up call within the framework of promoting KI’s impact will be announced next year. More about the KI Engagement Grant Awarded researchers and their projects:   Researcher: Pernilla Lagergren, Department of Molecular Medicine and Surgery Project: An oesophageal cancer day for stakeholders Summary: The KI Engagement Grant will be used to arrange a day with seminars, presentations and discussions for all patients who have been treated for oesophageal cancer, their relatives and clinical personnel working with these patients, as well as researchers in the field. This Oesophageal Cancer Day will be organised in Stockholm in spring 2019. Together with a patient collaborative group, the researchers will create an agenda with the most important subjects, to promote a better exchange of information and increase contact, networking and collaboration between the stakeholders.   Researcher: Ulrica von Thiele Schwarz, Department of Learning, Informatics, Management and Ethics Project: A structured approach to managing use of evidence-based methods in practice: co-creating a toolkit Summary: There is a substantial gap between what is known from research and what is done in practice. It is often challenging for healthcare professionals to translate research evidence such that it is useful in their context. To support professionals in this process, the researchers behind this project have written a book titled Användbar evidens (Useful evidence). Together with health- and social-care professionals, they will now create a hands-on, practical toolkit to facilitate a more structured decision process for the use of evidence-based interventions in health and social care. In this way, the material produced will contribute to making research more accessible and applicable.   Researcher: Zarina Nahar Kabir, Department of Neurobiology, Care Sciences and Society Project: Engaging family caregivers of persons with dementia and nurses in the development of a stress alleviating mobile application Summary: The study aims to assess feasibility of a mobile application — Stress Alleviating Mobile Application for Caregivers (SAMAC) — by collecting the views of dementia nurses and of caregivers of persons with dementia (PWD) on its use to alleviate caregivers’ stress and depressive symptoms. Dementia nurses and family caregivers of PWD will be engaged in developing the mobile application in terms of its content and features, and any other expectations of how it should function.   Researcher: Christoph Nowak, Department of Neurobiology, Care Sciences and Society Project: Engaging young people in diabetes epidemiology through popular social media influencers Summary: Research on the epidemiology of common cardiovascular and metabolic diseases, such as heart attack or diabetes, aims to identify risk factors for the disease as well as ways to prevent it. Getting young people to actively engage in these issues is crucial for many reasons; for example, for raising awareness of the risk factors and securing public support for future research. Whereas traditional media often does not engage young people, social-media profiles reach vast audiences among under-30-year-olds in Sweden. In this project, KI researcher Christoph Nowak aims to produce several videos together with at least one established social-media profile — a so-called influencer — to illustrate in an easy-to-understand way what his own research is all about, why it matters for young people, and how one can become a scientist. He will also engage with the audience through chat and website comments.   Researcher: Max Kleijberg, Department of Learning, Informatics, Management and Ethics Project: Studio DöBra toolbox Summary: DöBra Studio is an initiative with the goal of creating intergenerational meeting places and stimulating conversations between children and elderly people about dying, death, and loss. Various forms of art are used as tools to support these conversations. The initiative was developed as part of the DöBra research program in collaboration with community-based stakeholders, such as artistic organizations, activity centers for elderly people, and organizations for children. With support from the KI Engagement Grant, the stakeholders involved in DöBra Studio will work together to develop “DöBra Studio Toolbox” — a toolbox enabling others to develop similar initiatives as well as allowing stakeholders to disseminate the knowledge developed through this collaboration.   Researcher: Lena Wettergren, Department of Women’s and Children’s Health Project: Building partnership with stakeholders in the project Fex-Can; fertility and sexuality following cancer Summary: The Fex-Can research program has a co-creative track including an established long-term collaboration with a group of patient research partners. Researchers and patients have met regularly during the last four years to discuss the development of a web-based psycho-educational intervention that now is being tested in a randomized controlled trial. The KI Engagement Grant will fund an evaluation of this ongoing collaboration, through interviews with researchers and patient research partners, aiming to identify how to best sustain long-term engagement. The project group will also develop ways to engage a new group of stakeholders in a long-term collaboration: nurses and physicians working in cancer care.   Researcher: Anders Sönnerborg, Department of Medicine, Huddinge Project: Elements of an integrated and patient-centred approach to long-term care of people living with HIV Summary: Sweden is the first country in the world to reach the UNAIDS/WHO goal of HIV care, the so-called 90-90-90 goal. The KI Engagement Grant will support the dissemination of Sweden’s best practices in HIV care, with the aim of informing and inspiring the development and adoption of analogous approaches in the European arena. Specifically, a working group — comprising physicians and nurses with longstanding experience of HIV clinical care, academic HIV researchers, as well as representatives from the patient organisation HIV Sweden — will compile a report that analyses how these diverse actors have jointly achieved success in HIV care and how they will extend their research to address new challenges. The resulting report will be presented for the EU parliament at a special session on the 27th of November 2018.   Researchers: Agneta Richter Dahlfors and Ferdinand Choong, Department of Neuroscience Project: Art and gastronomy brings science to society Summary: Through the medium of art and gastronomy, Agneta Richter-Dahlfors and Ferdinand Choong at the Swedish Medical Nanoscience Center, Department of Neuroscience aim to establish a platform for two-way exchange between scientists and the public. They have developed a novel imaging technique (optotracing) that reveals the carbohydrates in plant tissues in striking, colourful images. The goal of this engagement project is ultimately to showcase this research by co-creating a public “Molecular Gastronomy Art Exhibition”, in which researchers present optotracing images of the carbohydrates in edible plants while well-known chefs give talks about ‘The New Conscious Kitchen’, a trending concept of sustainable, plant-based eating. The KI Engagement Grant will allow the researchers to prepare the ground: they will produce an image portfolio and initiate workshops with members of select communications channels to discuss image selection and refinement, as well as the next steps for making the exhibition a reality.

Eight projects at Karolinska Institutet have been awarded the recently established KI Engagement Grants, which aim to help KI researchers get started along a path to societal impact. These grants are part of an internal ‘impact and outreach’ effort approved by KI President Ole Petter Ottersen. Research is increasingly being judged — by funding agencies and governments alike — not only on its scientific merit but also on its potential to have a tangible impact on society. And while it’s a given that academic research benefits society by creating new knowledge, using this new knowledge to directly benefit society at large, or co-creating new knowledge in a way that is most relevant to societal needs, requires that researchers actively engage with actors outside of academia. To promote such engagement activities, Grants Office set up the KI Engagement Grant, which is financed through government funds distributed to Swedish universities to promote the impact of research and education. The eight winners of the KI Engagement Grants 2018 were selected during the summer 2018 and have received up to SEK 200 000 for a period of up to one year (total budget for the call was SEK 1.2 million). A follow-up call within the framework of promoting KI’s impact will be announced next year. More about the KI Engagement Grant Awarded researchers and their projects:   Researcher: Pernilla Lagergren, Department of Molecular Medicine and Surgery Project: An oesophageal cancer day for stakeholders Summary: The KI Engagement Grant will be used to arrange a day with seminars, presentations and discussions for all patients who have been treated for oesophageal cancer, their relatives and clinical personnel working with these patients, as well as researchers in the field. This Oesophageal Cancer Day will be organised in Stockholm in spring 2019. Together with a patient collaborative group, the researchers will create an agenda with the most important subjects, to promote a better exchange of information and increase contact, networking and collaboration between the stakeholders.   Researcher: Ulrica von Thiele Schwarz, Department of Learning, Informatics, Management and Ethics Project: A structured approach to managing use of evidence-based methods in practice: co-creating a toolkit Summary: There is a substantial gap between what is known from research and what is done in practice. It is often challenging for healthcare professionals to translate research evidence such that it is useful in their context. To support professionals in this process, the researchers behind this project have written a book titled Användbar evidens (Useful evidence). Together with health- and social-care professionals, they will now create a hands-on, practical toolkit to facilitate a more structured decision process for the use of evidence-based interventions in health and social care. In this way, the material produced will contribute to making research more accessible and applicable.   Researcher: Zarina Nahar Kabir, Department of Neurobiology, Care Sciences and Society Project: Engaging family caregivers of persons with dementia and nurses in the development of a stress alleviating mobile application Summary: The study aims to assess feasibility of a mobile application — Stress Alleviating Mobile Application for Caregivers (SAMAC) — by collecting the views of dementia nurses and of caregivers of persons with dementia (PWD) on its use to alleviate caregivers’ stress and depressive symptoms. Dementia nurses and family caregivers of PWD will be engaged in developing the mobile application in terms of its content and features, and any other expectations of how it should function.   Researcher: Christoph Nowak, Department of Neurobiology, Care Sciences and Society Project: Engaging young people in diabetes epidemiology through popular social media influencers Summary: Research on the epidemiology of common cardiovascular and metabolic diseases, such as heart attack or diabetes, aims to identify risk factors for the disease as well as ways to prevent it. Getting young people to actively engage in these issues is crucial for many reasons; for example, for raising awareness of the risk factors and securing public support for future research. Whereas traditional media often does not engage young people, social-media profiles reach vast audiences among under-30-year-olds in Sweden. In this project, KI researcher Christoph Nowak aims to produce several videos together with at least one established social-media profile — a so-called influencer — to illustrate in an easy-to-understand way what his own research is all about, why it matters for young people, and how one can become a scientist. He will also engage with the audience through chat and website comments.   Researcher: Max Kleijberg, Department of Learning, Informatics, Management and Ethics Project: Studio DöBra toolbox Summary: DöBra Studio is an initiative with the goal of creating intergenerational meeting places and stimulating conversations between children and elderly people about dying, death, and loss. Various forms of art are used as tools to support these conversations. The initiative was developed as part of the DöBra research program in collaboration with community-based stakeholders, such as artistic organizations, activity centers for elderly people, and organizations for children. With support from the KI Engagement Grant, the stakeholders involved in DöBra Studio will work together to develop “DöBra Studio Toolbox” — a toolbox enabling others to develop similar initiatives as well as allowing stakeholders to disseminate the knowledge developed through this collaboration.   Researcher: Lena Wettergren, Department of Women’s and Children’s Health Project: Building partnership with stakeholders in the project Fex-Can; fertility and sexuality following cancer Summary: The Fex-Can research program has a co-creative track including an established long-term collaboration with a group of patient research partners. Researchers and patients have met regularly during the last four years to discuss the development of a web-based psycho-educational intervention that now is being tested in a randomized controlled trial. The KI Engagement Grant will fund an evaluation of this ongoing collaboration, through interviews with researchers and patient research partners, aiming to identify how to best sustain long-term engagement. The project group will also develop ways to engage a new group of stakeholders in a long-term collaboration: nurses and physicians working in cancer care.   Researcher: Anders Sönnerborg, Deartment of Medicine, Huddinge Project: Elements of an integrated and patient-centred approach to long-term care of people living with HIV Summary: Sweden is the first country in the world to reach the UNAIDS/WHO goal of HIV care, the so-called 90-90-90 goal. The KI Engagement Grant will support the dissemination of Sweden’s best practices in HIV care, with the aim of informing and inspiring the development and adoption of analogous approaches in the European arena. Specifically, a working group — comprising physicians and nurses with longstanding experience of HIV clinical care, academic HIV researchers, as well as representatives from the patient organisation HIV Sweden — will compile a report that analyses how these diverse actors have jointly achieved success in HIV care and how they will extend their research to address new challenges. The resulting report will be presented for the EU parliament at a special session on the 27th of November 2018.   Researchers: Agneta Richter Dahlfors and Ferdinand Choong, Department of Neuroscience Project: Art and gastronomy brings science to society Summary: Through the medium of art and gastronomy, Agneta Richter-Dahlfors and Ferdinand Choong at the Swedish Medical Nanoscience Center, Department of Neuroscience aim to establish a platform for two-way exchange between scientists and the public. They have developed a novel imaging technique (optotracing) that reveals the carbohydrates in plant tissues in striking, colourful images. The goal of this engagement project is ultimately to showcase this research by co-creating a public “Molecular Gastronomy Art Exhibition”, in which researchers present optotracing images of the carbohydrates in edible plants while well-known chefs give talks about ‘The New Conscious Kitchen’, a trending concept of sustainable, plant-based eating. The KI Engagement Grant will allow the researchers to prepare the ground: they will produce an image portfolio and initiate workshops with members of select communications channels to discuss image selection and refinement, as well as the next steps for making the exhibition a reality.

In November 2018, Karolinska Institutet was visited by Michel Sadelain, a pioneer in the field of cancer immunotherapy called ”CAR T-cell therapy”. He visited KI for a symposium celebrating the ten year anniversary of Dr Åke Olsson's foundation for haematology research. Michel Sadelain is also director of the Center for Cell Engineering at the Memorial Sloan Kettering Cancer Center in New York. Here he tells us about his field of research.    

Depression is a common disorder for which cognitive behavioural therapy (CBT) is the recommended treatment for most patients. Researchers at Karolinska Institutet have now studied how genetic factors relate to differences in outcome of CBT in 894 people with depression, and show for the first time how genetic risk scores is associated with CBT outcome. “Understanding how genetic variation effects the outcome of psychological treatment can help us understand why some people don’t respond to it,” says study-leader Christian Rück, psychiatrist and senior lecturer at the Department of Clinical Neuroscience, Karolinska Institutet. “Ultimately this can lead to improved treatment options.” All 894 participants in the study, which was published recently in the scientific journal Molecular Psychiatry, had been diagnosed with depression and had undergone a 12-week course of online CBT. Before the treatment, the researchers extracted their DNA from blood samples in order to analyze how outcomes correlated with genetic variation. This they did by comparing genetic variations in the participants with genetic risk scores for 6 different psychiatric conditions, education level and IQ. Risk score for autism A genetic risk score indicates how many genetic risk variants an individual has for a particular condition. Doing this, the researchers found that a higher genetic risk score for autism was associated with a poorer outcome after CBT for depression. This is the first time that genetic variation has been linked to outcomes of psychological treatment in a so-called genome-wide analysis – i.e. a study that analyses genetic variation across the entire genome.  The researchers are now aiming to substantiate their finding with new, larger studies. The study was conducted with the support of the internet psychiatry clinic of the Stockholm County Council, and the Swedish Research Council. Publication Genetics of response to cognitive behaviour therapy in adults with major depression: a preliminary report Evelyn Andersson, James J. Crowley, Nils Lindefors,  Brjánn Ljótsson, Erik Hedman-Lagerlöf, Julia Boberg, Samir El Alaoui,  Robert Karlsson, Yi Lu, Manuel Mattheisen, Anna K Kähler, Cecilia Svanborg,  David Mataix-Cols, Simon Mattsson, Erik Forsell, Viktor Kaldo, Martin Schalling, Catharina Lavebratt, Patrick F. Sullivan, Christian Rück Molecular Psychiatry, online 8 November 2018

A new study by researchers at Karolinska Institutet supports the theory that replacement of dysfunctional immune cells in the brain has therapeutic potential for neurodegenerative diseases like ALS and Alzheimer’s disease. The study, which involved repopulating the brain with new immune cells in an experimental disease model, is published in Nature Communications. Macrophages are immune cells present throughout the body, and are specialised according to the organ in which they operate; in the brain they are known as microglia. In a healthy brain, microglia are involved in many caretaking functions that support the activities and health of nerve cells. In diseases like ALS and Alzheimer’s disease, microglia instead function to harm nerve cells. New model of microglia depletion The researchers behind the current study believe that replacement of the dysfunctional microglia with healthy cells will potentially be of therapeutic benefit in such neurodegenerative diseases. Therefore they have developed a new disease model in which the animal’s own microglia are removed from the central nervous system (CNS). This leads to a rapid influx of monocytes, precursors of macrophages, into the brain and spinal cord, giving rise to new microglia-like cells. Microglia in the brain, however, have a different embryonic origin to blood-borne monocytes. “We knew that blood monocytes would infiltrate the CNS in our experimental mouse model, but we did not know to what degree they would adapt to the new microenvironment,” says first author Harald Lund, a recently graduated doctoral student at the Department of Clinical Neuroscience, Karolinska Institutet. “So we dissected the process of repopulation and fully characterised what happened to these cells with time.” Nurture trumps nature The infiltrating cells adapted to the ‘empty’ tissue but did not fully differentiate into microglia. However, the monocytes started to express many genes characteristic of microglia, adopted their morphology and exhibited similar functions to microglia. A meta-analysis of several recent studies of microglia repopulation further confirmed the gene signatures as being specific to infiltrating monocytes adapting to the CNS microenvironment, which goes against their nature. The apparent dominance of the tissue microenvironment in dictating cell functionality could be exploited therapeutically, the researchers believe. The study provides support for the researchers’ current projects aiming to develop novel immunotherapies for neurodegenerative diseases. “There are several incurable neurodegenerative diseases in humans, but a complete lack of efficient immunotherapies,” says Professor Bob Harris at the Center for Molecular Medicine, Karolinska University Hospital and the Department of Clinical Neuroscience, Karolinska Institutet. “We believe that efficient replacement of dysfunctional microglia has the potential to be an effective therapy, so understanding the molecular events and consequences of repopulation of a microglia-depleted CNS are critical in working towards this goal.” The study was financed by the Swedish Alzheimer’s Foundation, the Swedish Research Council, the Margaretha af Ugglas Foundation, the Swedish Brain Foundation and Alltid Litt Sterkere. Publication “Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells” Harald Lund, Melanie Pieber, Roham Parsa, Jinming Han, David Grommisch, Ewoud Ewing, Lara Kular, Maria Needhamsen, Alexander Espinosa, Emma Nilsson, Anna K. Överby, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang & Robert A. Harris Nature Communications, online 19 November 2018, doi: 10.1038/s41467-018-07295-7

Katarina Bjelke is Karolinska Institutet’s new university director from May 2019. She is currently the university director at Uppsala University. “We’re delighted that Katarina wants to return to Karolinska Institutet, where she once began her career,” says Karolinska Institutet’s president Ole Petter Ottersen. “She has great experience from the academic sector and the Ministry of Education and Research. She also has many years’ experience of management, which makes her well-suited to lead the University Administration and develop the support it provides to our core activities research and education.”  Katarina Bjelke was formally the deputy director-general of the research policy unit at the Ministry of Education and Research. Before that she was head of the Division of Research and Doctoral Education, the International Unit and the Grants Office at Karolinska Institutet. She took her degree in dentistry in 1989 and earned her PhD in neuroanatomy from Karolinska Institutet in 1997. "I look forward to my new assignment and to come to Karolinska Institutet," says Katarina Bjelke. Katarina Bjelke takes up office in May 2019, replacing university director Per Bengtsson, who is due to retire.

Academic researchers have examined raw data from a company-funded safety evaluation of the pesticide chlorpyrifos. They discovered an effect on the brain architecture of the exposed laboratory animals at all tested doses, which was not included in the reported conclusions. Karolinska Institutet in Sweden led this independent study, which is published in the scientific journal Environmental Health. All pesticides must be evaluated in terms of their safety and potential risks for human health before they can officially be approved. Normally the companies that manufacture the products cover the cost of such evaluations and commission test laboratories to perform the necessary animal tests. Assistant professor Axel Mie at Karolinska Institutet, Christina Rudén at Stockholm University and Philippe Grandjean at Harvard School of Public Health have examined a case in which independent research and company-funded tests deviated, at least in terms of the conclusions drawn in the industry-funded study. The company-funded animal test was performed to ascertain how neural development is affected by the pesticide chlorpyrifos, which is used on a wide variety of crops around the world, including some 20 EU countries (not, however, Sweden). The test laboratory concluded that there was no such effect, even at high doses. Several weak points “We have looked at the study design and raw data from the manufacturer-funded study and found several weak points,” says Axel Mie, assistant professor at Karolinska Institutet’s Department of Clinical Science and Education at the Stockholm South General (Söder) Hospital. “For instance, we observed a clear effect on the height of the cerebellum in young rats that were exposed to the substance while still at the fetal stage, even at the lowest tested dose. This was reported neither in the study’s summary nor in its conclusion.” Extensive independent research has also previously indicated that chlorpyrifos adversely affects brain development, including childhood IQ, even at the low doses that consumers are generally exposed to through food. “One conclusion we draw is that there is a risk that the results of industry-funded toxicity tests are not reported correctly,” says Dr Mie. “This makes it difficult for the authorities to evaluate the pesticides in a safe and valid way. We also conclude that independent academic research should be given a higher status in the evaluation of the safety of chemicals.” The researchers did not receive any external funding for the study. Publication “Safety of Safety Evaluation of Pesticides: Developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl” Axel Mie, Christina Rudén and Philippe Grandjean Environmental Health, online 16 November 2018, doi: 10.1186/s12940-018-0421-y

A multidisciplinary team of researchers led from Karolinska Institutet in Sweden have developed an anti-inflammatory drug molecule with a new mechanism of action. By inhibiting a certain protein, the researchers were able to reduce the signals that trigger an inflammation. The study is published in Science and was done in collaboration with the University of Texas Medical Branch, Uppsala University and Stockholm University. “We’ve developed a new drug molecule that inhibits inflammation,” says Professor Thomas Helleday, at the Department of Oncology-Pathology, Karolinska Institutet, Sweden, who co-led the study with Dr Torkild Visnes and Dr Armando Cázares-Körner. “It acts on a protein that we believe is a general mechanism for how inflammation arises in cells.” The discovery is the result of many years of research by Thomas Helleday’s group on how DNA is repaired by the body. One of the objectives has been to fight cancer by targeting damage to the tumour cells’ DNA. Several breakthroughs have already been reported, which have led, amongst other things, to a new treatment for congenital breast and ovarian cancer using so-called PARP inhibitors, which has been available for some years.  Trials on mice It was when developing a new molecule for inhibiting the enzyme that repairs oxygen damage to DNA that the researchers found, to their surprise, that it also dampened inflammation. It turned out that the enzyme OGG1, apart from repairing DNA, also triggers inflammation.  The inhibitor blocks the release of inflammatory proteins, such as TNF alpha. In trials on mice with acute pulmonary disease, the researchers succeeded in dampening the inflammation. “This discovery could give rise to a new treatment for a very serious condition,” says Professor Helleday. “We’ll now be developing our OGG1 inhibitor and examining whether it can lead to new treatments for inflammatory diseases in order to cure or relieve diseases such as sepsis, COPD and severe asthma.” The discovery was made in collaboration with Professor Istvan Boldogh from the University of Texas Medical Branch, USA. The repair pathway on which OGG1 operates was discovered by Tomas Lindahl at Karolinska Institutet in the 1970s, an achievement that earned him the Nobel Prize in Chemistry in 2015. Collaboration between several universities The study was a collaboration between Karolinska Institutet, Uppsala University and Stockholm University in Sweden and the University of Texas Medical Branch, USA. It was financed by grants from Vinnova, the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Pain Relief Foundation, the Torsten Söderberg Foundation, the National Institute of Allergic and Infectious Diseases (USA), the faculty of medicine and healthcare science at the Norwegian University of Science and Technology (NTNU), the Central Norway Regional Health Authority and the Svanhild and Arne Must Fund for Medical Research (Norway). Some of the authors, including Thomas Helleday, are listed as inventors on a US patent application for OGG1 inhibitors. The patent is owned by the Helleday Foundation, of which Thomas Helleday and co-author and KI researcher Ulrika Warpman Berglund are board members and through which they are involved in the development of OGG1 inhibitors for clinical application. Publication ”Small-molecule inhibitor of OGG1 suppresses pro-inflammatory gene expression and inflammation” Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elisée Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann-Sofie Jemth, Lang Pan3, Kumar Sanjiv, Stella Karsten, Camilla Gokturk, Maurice Grube, Evert J. Homan, Bishoy M.F. Hanna, Cynthia B. J. Paulin, Therese Pham, Azita Rasti, Ulrika Warpman Berglund, Catharina von Nicolai, Carlos Benitez-Buelga, Tobias Koolmeister, Dag Ivanic, Petar Iliev, Martin Scobie, Hans E. Krokan, Pawel Baranczewski, Per Artursson, Mikael Altun, Annika Jenmalm Jensen, Christina Kalderén, Xueqing Ba, Roman A. Zubarev, Pål Stenmark, Istvan Boldogh and Thomas Helleday. Science, online 15 November 2018.

Growing up with dogs is linked to a lower risk of asthma, especially if the dogs are female, a new study from Karolinska Institutet and Uppsala University in Sweden shows. However, the researchers found no relation between ‘allergy friendly’ breeds and a lower risk of asthma. The study is published in the journal Scientific Reports. Earlier studies have demonstrated a link between growing up with dogs and a lower risk of childhood asthma, but it has not been known whether this association is modified by dog characteristics. In this new study, the researchers have interrogated how variables such as sex, breed, number of dogs or size of dog are associated with the risk of asthma and allergy amongst children raised in a home with a dog during their first year of life. “The sex of the dog can affect the amount of allergens released, and we know that uncastrated male dogs express more of a particular allergen than castrated dogs and female dogs,” says Tove Fall, Senior Lecturer at the Department of Medical Sciences – Molecular Epidemiology at Uppsala University, who led the study with Professor Catarina Almqvist Malmros at Karolinska Institutet. “Moreover, some breeds are described anecdotally as ‘hypoallergenic’ or ‘allergy friendly’ and are said to be more suitable for people with allergies, but there is no scientific evidence for this.” Classified by different traits The study included all children born in Sweden from 1 January 2001 to 31 December 2004 who had a dog in their home for the first year of life (23,600 individuals). Data from the Swedish population and health data registries were linked anonymously to two dog-owner registries from the Swedish Board of Agriculture and the Swedish Kennel Club. The dogs were classified by sex, breed, number, size and alleged ‘hypoallergenicity’. The researchers then studied the relationship between the dogs’ characteristics and the risk of asthma and allergy diagnosis or the prescription of asthma or allergy drugs at the age of six. The statistical analyses controlled for all known confounders that could affect the risk of developing asthma or allergies, such as parental asthma/allergy, geographical location and number of siblings. Their results showed that the prevalence of asthma at age six was 5.4 per cent. Children with only female dogs at home had a 16 per cent lower risk of asthma than those raised with male dogs. However, living with a male dog did not correlate with a higher risk than living with no dog at all. Children living with two or more dogs had a 21 per cent lower risk of asthma than those who only lived with one dog. Hypoallergenic dogs linked to higher risk of allergy Children of parents with asthma/allergies more often had breeds described as ‘hypoallergenic’ than children of parents without asthma/allergies – 11.7 per cent versus 7.6 per cent. Exposure to these breeds was associated with a 27 per cent higher risk of allergy but no increased risk of asthma. “The likely explanation for this higher risk is that families with a history of allergy to furred pets more often choose these dogs, and also that ‘allergy friendly’ dogs do not in fact release less allergens,” says Catarina Almqvist Malmros, Professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and Consultant at Astrid Lindgren Children’s Hospital. “The finding should be treated with caution as we can say nothing about any actual causality,” she continues. “More studies are needed to monitor differences over time, measure the risk of allergies using biomarkers, and take account of the microflora.” The study was financed with grants from the Swedish Research Council, the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM), Agria, Forte, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), the Swedish Heart and Lung Foundation, Stockholm County Council (ALF funding) and the Strategic Research Programme in Epidemiology (SFO-epi) at Karolinska Institutet. Publication “Dog characteristics and future risk of asthma in children growing up with dogs” Tove Fall, Sara Ekberg, Cecilia Lundholm, Fang Fang and Catarina Almqvist Scientific Reports, online 15 November 2018, doi: 10.1038/s41598-018-35245-2.

The use of a new class of drugs in the treatment of type 2 diabetes, so called SGLT2 inhibitors, are linked to a twofold increased risk for lower-limb amputation as well as diabetic ketoacidosis, a serious diabetes complication. This is according to a Nordic study headed by researchers at Karolinska Institutet and published in the journal BMJ. Nearly every tenth person over the age of 18 across the world has diabetes and the number of patients is expected to increase in the next few decades. Patients with diabetes can develop several complications, such as diseases of the eyes, kidneys, heart and blood vessels as well as nerves. A new class of drugs for treatment of type 2 diabetes is SGLT2 inhibitors (sodium-glucose cotransporter 2). Use of the drugs has increased sharply during the past few years, especially since clinical trials have shown that they may reduce the risk of cardiovascular disease. At the same time, there has been uncertainty around some potential adverse effects. In the current study, a collaboration between researchers at Karolinska Institutet in Sweden, Statens Serum Institut in Denmark, NTNU in Norway and the Swedish National Diabetes Register, the researchers used several nationwide registers with information on prescription drug use, diseases and other data from roughly 34,000 patients in Sweden and Denmark from 2013-2016. The aim was to study the association between use of SGLT2 inhibitors (dapagliflozin, canagliflozin and empagliflozin) and seven potential adverse events that have been linked to the drug class. A group of patients who were prescribed a different drug class for treatment of type 2 diabetes (GLP1 receptor antagonists) were used as the comparator group. The analyses accounted for a large number of factors that may potentially affect the risk of the studied outcomes. The result showed that use of SGLT2 inhibitors was associated with two-fold increases in the risk of lower limb amputation and diabetic ketoacidosis, a serious diabetes complication, although absolute risk differences were small. There was no statistically significant association between use of SGLT2 inhibitors and the remaining five outcomes: bone fracture, acute kidney injury, serious urinary tract infection, venous thromboembolism (blood clot) or acute pancreatitis (inflammation of the pancreas). “In clinical trials, these drugs have shown a protective effect for cardiovascular disease. Patients with type 2 diabetes are at increased risk of cardiovascular disease, and the potential risk of adverse events should be weighed against the cardiovascular protection and other beneficial effects of the drugs.” says Peter Ueda, postdoctoral researcher at the Department of Medicine, Solna, Karolinska Institutet and first author of the study. The researchers behind this study also emphasise that this was an observational study. Therefore it is not certain that the associations observed in the study reflect the effect of SGLT2 inhibitors. “We have analysed national data from two countries. The study illustrates the strengths and possibilities offered by Nordic register data in answering important clinical questions, especially in the pharmaceutical area,” says the last author Björn Pasternak, senior researcher at the Department of Medicine, Solna, Karolinska Institutet, and affiliated with Statens Serum Institut. In addition to Peter Ueda and Björn Pasternak the study was also led by Henrik Svanström, senior statistician at the Department of Medicine, Solna, Karolinska Institutet. The results were presented earlier at a late-breaking clinical science session at the congress of the European Society of Cardiology (ESC) in Munich, August 2018. The study was conducted with support from the Heart and Lung Foundation, Swedish Society for Medical Research, Cancer Foundation, Nordic Cancer Union, Novo Nordisk Foundation, Swedish Research Council, the strategic research area in epidemiology at Karolinska Institutet and the Lundbeck Foundation. Publication “Sodium-glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study”. Peter Ueda, Henrik Svanström, Mads Melbye, Björn Eliasson, Ann-Marie Svensson, Stefan Franzén, Soffia Gudbjörnsdottir, Kristian Hveem, Christian Jonasson and Björn Pasternak. The BMJ, online 14 November 2018.

Inequality in children’s and young people’s health was in focus for the Pep Forum seminar, which was held at Karolinska Institute on 24 October. The day – which included research results and inspiring examples, as well as dancing – was organised by Generation Pep, an organisation founded by the Crown Princess and Prince. They participated together with Mai-Lis Hellénius and Marie Löf of Karolinska Institute, among others. We adults must ensure that all children have the opportunity to experience the pleasure of movement and to lay the foundation for a healthy and active life. So said Crown Princess Victoria when she opened the Pep Forum seminar, which was held in a packed Aula Medica yesterday. “The opportunity must be there, regardless of where you grow up and regardless of economic, social or physical conditions. It therefore feels important that we are able to meet here today to learn more and to be inspired by good, concrete examples of efforts for the health of children and young people,” Crown Princess Victoria continued. She was introduced by the day’s moderators – host David Hellenius and Carolina Klüft, former sports star and now project manager at Generation Pep. Motivating children and young people to get moving Pep Forum was organised by Generation Pep, an organisation founded by the Crown Princess and Prince in 2016. The aim is to give all children and young people the motivation and conditions to live an active and healthy life, and the idea is that to succeed, all parts of society must be included in the work - from local enthusiasts and movers to politicians and the powers that be. The purpose of the Pep Forum seminar day is to inform, inspire and get people together. This year, the focus for the day was inequality in children’s and young people’s health. The day’s first speaker, professor Mai-Lis Hellénius of the Department of Medicine in Solna, described the general health position of children and adults in Sweden. Among other things, she noted that cardiovascular disease - a major public health problem - is decreasing overall, but not among the young. “Among 35 to 44 year-olds, cases of stroke are increasing, and there is a difference between those with a short or long education,” says Mai-Lis Hellénius. Swedes are the most unhealthy Mai-Lis Hellenius explained that according to the latest Nordic survey of living habits, Swedes have the unhealthiest food habits and Swedish children are the most physically inactive. We now know that sitting increases the risk of ill health among adults, and that is still true even if we exercise three times a week between long periods of sitting every day. According to many studies, children too risk illnesses such as cardiovascular disease if they spend long periods sitting. But Mai-Lis Hellénius also said there was good news and referred to last spring’s international research compilation on physical activity and health. “We have very much underestimated the significance of a little movement - every day. Every step counts,” says Mai-Lis Hellenius. Project identifies risks for the heart and lungs Göran Bergström, professor at the University of Gothenburg, explained about the SCAPIS research project, which is to collect information about the heart and lung status of 30,000 randomly selected people aged 50 to 64. The idea is to follow these people over the course of time so as to be able to identify the risk of diseases such as stroke, COPD and heart attack and learn more about the incidence of the diseases. The project has recently recruited all the participants and Göran Bergström presented the first results of the nationwide surveys to Pep Forum. In the low socio-economic status group, one person in three, 30 per cent, was obese (BMI over 30). In the high socio-economic status group, the figure was 15 per cent. The same pattern can be seen for diabetes, high cholesterol, high blood pressure and smoking. The risk factors are much higher in the more vulnerable areas, compared to the socio-economically strong areas,” said Göran Bergström. National survey on physical activity Marie Löf, a researcher at the Department of Biosciences and Nutrition at Karolinska Institute, described an ongoing national survey of food and physical activity habits among children aged 4 to 17. The survey is an initiative from Generation Pep and is a collaboration between Karolinska Institute and the SOM Institute at the University of Gothenburg. “The advantage is partly that we are covering the entire age range from pre-school children to lower secondary pupils and partly that we plan to prepare the questions in such a way that we can see trends over time. We have no results yet, but the response rate is looking good in terms of quality,” she says. The day concluded with some inspiring examples from individuals, companies and organisations. Among other things, the “Activity Prevents” project in Ängelholm was presented. In this, school children have a mandatory extra period each week on sport and health, which is organised as a club. Vulnerable children are given extra opportunities to take part in club activities. Text: Sara Nilsson  

During a festive and solemn ceremony in the City Hall, Karolinska Institute's new doctors and jubilee doctors were celebrated on November 9th. President Ole Petter Ottersen stated in his speech that the doctors and their achieved knowledge are of great importance to society and the world.

Mapping of a certain group of cells, known as oligodendrocytes, in the central nervous system of a mouse model of multiple sclerosis (MS), shows that they might have a significant role in the development of the disease. The discovery can lead to new therapies targeted at other areas than just the immune system. The results are published in Nature Medicine by researchers at Karolinska Institutet in Sweden. 2.5 million people around the world live with MS, with approximately 18,000 people in Sweden, and about 1,000 new cases annually. MS develops when the immune system’s white blood cells attack the insulating fatty substance known as myelin that coats nerve fibres in the central nervous system. This interferes with the proper transmission of nerve electric signals and causes the symptoms of the disease. While it is unknown why the immune system attacks the myelin, a study by researchers at Karolinska Institutet shows that the cells that produce myelin, oligodendrocytes, might play an unexpected role. Oligodendrocytes are one of the most common types of cell in the brain and spinal cord. “Our study provides a new perspective on how multiple sclerosis might emerge and evolve” says Gonçalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. “Current treatments mainly focus on inhibiting the immune system. But we can now show that the target cells of the immune system in the brain and spinal cord, oligodendrocytes, acquire new properties during disease and might have a higher impact on the disease than previously thought.”  The researchers have shown that a subset of oligodendrocytes and their progenitor cells have much in common with the immune cells, in a mouse model of MS. Among other properties, they can take part in the clearing away of the myelin that is damaged by the disease, in a way that resembles how immune cells operate. Oligodendrocyte progenitor cells can also communicate with the immune cells and make them change their behaviour.  “We also see that some genes that have been identified as those that cause a susceptibility to MS are active (expressed) in oligodendrocytes and their progenitors,” says Ana Mendanha Falcão, joint first author of the study with David van Bruggen, both at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “All in all, this suggests that these cells have a significant role to play either in the onset of the disease or in the disease process,” says David van Bruggen. The study was conducted using the recently developed technique, single-cell RNA sequencing, which provides scientists with a snapshot of the genetic activity of single cells and therefore with a much more effective means of differentiating the properties of individual cells. This has made it possible for researchers to identify the various roles and functions of the different cells.  Although the study was largely conducted on mice, some of the results have also been observed in human samples. “We will now continue with further studies to ascertain the part played by the oligodendrocytes and their progenitor cells in MS,” says Gonçalo Castelo-Branco. “Further knowledge can eventually lead the way to the development of new treatments for the disease.” The research was financed by several funding bodies, including the European Union (European Research Council and Marie-Skłodowska Curie Actions), the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS), the Swedish Research Council, the Swedish Brain Foundation, the Ming Wai Lau Centre for Reparative Medicine, the Petrus and Augusta Hedlund Foundation and Karolinska Institutet.  Publication: “Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis”. Ana Mendanha Falcão, David van Bruggen, Sueli Marques, Mandy Meijer, Sarah Jäkel, Eneritz Agirre, Samudyata, Elisa M. Floriddia, Darya P. Vanichkina, Charles ffrench-Constant, Anna Williams, André Ortlieb Guerreiro-Cacais and Gonçalo Castelo-Branco. Nature Medicine, online 12 November 2018, doi: 10.1038/s41591-018-0236-y.   For more information, please contact: Gonçalo Castelo-Branco, associate professor Department of Medical Biochemistry and Biophysics, Karolinska Institutet Phone: +46 8 524 879 36 Mobile: +46 700 91 59 22 Email: Goncalo.Castelo-Branco@ki.se About Gonçalo Castelo-Branco Research Group