KI News

Combining certain types of two antipsychotic agents in the maintenance treatment of schizophrenia is associated with a lower risk of relapse than using monotherapy. This is suggested in a paper published by researchers at Karolinska Institutet in the journal JAMA Psychiatry. The current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy, according to the researchers. The effectiveness of antipsychotic combination therapy in schizophrenia relapse prevention is controversial, and use of multiple agents is generally believed to impair physical well-being. But the evidence for this is weak and antipsychotic polypharmacy is widely used. Now researchers at Karolinska Institutet in Sweden have conducted a large registry based study to see if there is any difference in the risk of relapse in schizophrenia when patients use antipsychotic polypharmacy compared to monotherapy. Studied 62,000 patients The study was based on more than 62,000 patients; all persons with schizophrenia treated in the inpatient setting during 1972-2014 in Finland. The researchers then followed the patients to see to what extent they were rehospitalised for psychiatric care, which was used as a marker for relapse. The median follow-up time was 14.1 years and to avoid bias each patient was used as his or her own control (so called within-individual analysis). The results show that antipsychotic polypharmacy in general was associated with a slightly lower risk of psychiatric rehospitalisation than monotherapy. They do however not indicate that all types of polypharmacy are beneficial. Combining aripiprazole with clozapine was associated with the best outcome, with a 14-23 per cent lower risk of rehospitalisation compared to clozapine alone; which was the monotherapy associated with the best outcomes. Possible update of treatment guidelines Current treatment guidelines state that antipsychotic monotherapy should be preferred and polypharmacy should be avoided if possible. This study should change that view, according to first author of the study, Jari Tiihonen, specialist doctor and professor at Karolinska Institutet’s Department of Clinical Neuroscience. ”Our results indicate that the current treatment guidelines should tone down their categorical recommendations discouraging all antipsychotic polypharmacy. The evidence of superiority of polypharmacy might be sparse, and should be replicated in other countries, but there is no evidence at all on superiority of monotherapy over polypharmacy in the maintenance treatment of schizophrenia”, says Jari Tiihonen. Researchers affiliated to the University of Eastern Finland, Niuvanniemi Hospital, EPID research Oy, Hofstra Northwell School of Medicine, The Zucker Hillside Hospital, Charité Universitätsmedizin and National Institute for Health and Welfare, Finland, also contributed to the study. The study was funded by the Finnish Ministry of Social Affairs and the Academy of Finland. No company has financed this study, but several of the authors have previously received funding/fees from pharmaceutical companies in different contexts. Two of the authors are employed by the contract research organisation EPID Research. The scientific article provides more detailed information about potential conflicts of interest. Publication Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia Jari Tiihonen, Heidi Taipale, Juha Mehtälä, Pia Vattulainen, Christoph U. Correll and Antti Tanskanen JAMA Psychiatry, online Februari 20, 2019, doi:10.1001/jamapsychiatry.2018.4320

An international team of researchers from academia and the biopharma industry has published a Phase 1a/b study, showing the therapeutic potential of mRNA encoding for vascular endothelial growth factor A (VEGF-A) for regenerative angiogenesis in humans. The goal of this potential novel treatment is to generate new blood vessels and improve blood flow in tissues where it is otherwise restricted. Partners in this randomized, double blind, placebo-controlled study in men with type 2 diabetes were AstraZeneca, Moderna Inc., Karolinska Institutet, and the Sahlgrenska Academy of Gothenburg University. The findings have been published in the scientific journal Nature Communications. VEGF-A mRNA was delivered to the study participants in a saline solution and was administered by intradermal injection into forearm skin in single ascending doses. The trial met its primary objectives of describing safety and tolerability and secondary objectives of protein production and changes in local blood flow post injection. The study showed that the VEGF-A protein, post injection of mRNA, had increased. At each sampling time, mean VEGF­A protein levels, across all mRNA-treated sites from patients across all cohorts, were higher than that of placebo up to the 24-26 hour time point in the study. The bioactivity of the VEGF-A protein post injection was also observed by an increase in blood flow at injection sites, up to seven days following a single injection, and the treatment was overall well tolerated. An important milestone “I believe this an important milestone in the field of mRNA therapeutics as it starts to address many questions regarding delivery of mRNA to human tissues, the duration and level of the protein that can be expressed and the ability of the technology to have a physiologic, measurable function over a prolonged period of time”, said study co-author Dr. Kenneth Chien, a professor of Karolinska Institutet and scientific co-founder of Moderna, in a press release. “Based on these early data, this approach may provide benefit to patients where proper blood flow is compromised in areas such as heart disease and diabetes as well as for other vascular complications.” AstraZeneca is now leading a Phase 2a study with patients receiving epicardial injections of VEGF-A mRNA during coronary artery bypass grafting surgery. The recent study was funded by AstraZeneca. This news article is a re-write of a press release from Moderna, Inc., which is a Nasdaq listed company. Publication Intradermal Delivery of Modified mRNA Encoding VEGF-A is Well Tolerated and Transiently Enhances Basal Skin Blood Flow in Patients with Type 2 Diabetes Li-Ming Gan, Maria Lagerström-Fermér, Leif G Carlsson, Cecilia Arfvidsson, Ann-Charlotte Egnell, Anna Rudvik, Magnus Kjaer, Anna Collén, James D Thompson, John Joyal, Ligia Chialda, Thomas Koernicke, Rainard Fuhr, Kenneth R Chien, Regina Fritsche-Danielson Nature Communications, online 20 January 2019, doi: 10.1038/s41467-019-08852-4

Hello, Galit Andersson, who recently defended a doctoral thesis at the Department of Public Health Sciences, Karolinska Institutet. For your thesis you conducted large surveys of transgender people and people living with HIV in Sweden to assay their quality of life. What were your most interesting results? “People living with HIV generally rate their quality of life rather high. But many of them still feel that there’s a stigma related to negative attitudes towards people living with HIV, and that this creates a negative self-image that undermines their wellbeing. Mental health is an important health issue for many people and in our research we found high rates of hopelessness.” “In our study of transgender people, we found that quality of life and self-rated health were lower in those who’d encountered ignorance or prejudice when dealing with healthcare professionals. People who wanted to change legal gender but who, for whatever reason, hadn’t done so, also had poorer health and quality of life.” What surprised you? “That one in five participants of the HIV study had completely avoided sexual relations after their diagnosis out of fear of being rejected or shamed. This despite the fact that most of them had known about their HIV for 10 – 15 years and that over 95 per cent of all people living with known HIV-infection in Sweden are under very effective treatment and cannot transmit the virus.” What do you think should be done, given your results? “We must continue to inform the public about what it’s like to live with HIV today – that the treatment is so effective that people can generally live a long, quality life. This will help reduce the stigma that comes from ignorance and hopefully improve wellbeing among people living with HIV. It’s also important that the health services can meet the group’s need for psychological support and sexual health information.” “Since the number of people seeking change of legal gender or gender-affirming medical interventions has increased, the same holds true for transgender people. It’s vital that the public are well-informed and that medical staff treat them with respect. I also think that the possibility of making it easier to change legal gender should be looked into. At the moment the process is a long one and linked to which gender-affirming treatments someone is undergoing. Maybe it would help matters if it was a purely legal process.” How did you get into this research field? “Before becoming a doctoral student, I was a research assistant at KI, and that piqued my interest. The Global and Sexual Health research group was working with HIV and sexual health and I had the opportunity to work on a large survey of transgender people’s health. Both groups have seen many improvements, in terms of both policy and medical treatment, so I became interested in what their health looks like today and what factors influence it.” What will you do now? “I’m now an investigator at the Public Health Agency at a unit that works with HIV prevention and LGBT health. It’s great that I can continue with the same kind of issues that I did my thesis on.”

What happens in the brain when we feel discomfort? Researchers at Karolinska Institutet in Sweden are now one step closer to finding the answer. In a new study published in the journal Molecular Psychiatry they identify which pathways in the mouse brain control behaviour associated with aversion. Scientists have long been interested in how the brain creates signals associated with negative emotions in order to better understand how imbalances in the same system can lead to affective disorders such as depression and anxiety. The amygdala has long been the most commonly studied brain structure for understanding fear, whereas for rewards and positive signals the focus has been on the neurotransmitter dopamine. But when it comes to areas of the brain that control feelings of discomfort and aversion, much less is known. Brain structure controlling emotions In the past few years, research has indicated that a brain structure called the habenula controls positive and negative emotions in animal models. Moreover, clinical cases have been conducted with patients suffering from depression where deep brain stimulation of the habenula has been beneficial. The habenula controls both dopamine and the neurotransmitter serotonin, which is thought to play a significant part in the sense of wellbeing. However, it has not been known how the habenula is regulated. Researchers at Karolinska Institutet have now mapped which networks in the mouse brain control the habenula, and what role they play in aversion. “We’ve discovered a specific pathway that goes between the hypothalamus and the habenula, and that can be modulated using optogenetics to control the feeling of aversion,” says study leader docent Dinos Meletis at the Department of Neuroscience. “Our hope is that this can lead to the development of new treatments that can rebalance the brain’s networks in for example depression or anxiety disorders.” Using light to activate neurons Using optogenetics and other advanced methods, the group were able to identify the identity of the nerve cells and map their interconnections. Optogenetics is a method that uses light to activate specific neurons in order to study how the activation of different networks affects behaviour. “This methodological revolution in brain research has made it possible to functionally study how different types of nerve cell and pathways actually control different types of behaviour, something that was impossible to do only a decade ago,” says Dr Meletis. The study was supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Brain Foundation and Karolinska Institutet. Publication “A hypothalamus-habenula circuit controls aversion” Iakovos Lazaridis, Ourania Tzortzi, Moritz Weglage, Antje Märtin, Yang Xuan, Marc Parent, Yvonne Johansson, Janos Fuzik, Daniel Fürth, Lief E. Fenno, Charu Ramakrishnan, Gilad Silberberg, Karl Deisseroth, Marie Carlén, Konstantinos Meletis Molecular Psychiatry, online 12 February 2019, doi: 10.1038/s41380-019-0369-5

Learning what is dangerous by watching a video or being told (known as social learning) has just as strong an effect on our decision-making as first-hand experience of danger, researchers at Karolinska Institutet in Sweden report. The results of the study, which is published in the journal PNAS (Proceedings of the National Academy of Sciences), can help to explain why we take irrational decisions. It is easy nowadays to be exposed to unpleasant and threatening information, with accidents, terrorist attacks and natural disasters appearing, for instance, on TV, digital news sources and social media. Previous research has shown that individuals who have long exposure to news reports of a terrorist attack can develop psychological problems as serious as those afflicting people who experienced it first-hand. However, just how our actual behaviour is affected by such indirect learning of danger has remained unknown.  This has now been laboratory tested in a study conducted by researchers at Karolinska Institutet, University of Amsterdam and University of Zurich. The study shows that threat learning via video or orally can affect human behaviour just as strongly as personal experience. New study with 120 participants In the study, three groups of participants, totalling 120 individuals, initially learnt which of two neutral images was “dangerous”. The first group learnt through direct experience of an electric shock, the second by watching a film of someone receiving electric shock when looking at the image, and the third by being given oral instructions on which image to associate with an electric shock. In other words, the participants in the social learning groups (observation and oral instruction) suffered no actual physical discomfort. The participants were then asked to repeatedly choose between the two images. Their choice could result in an electric shock, their task being to receive as few shocks as possible. For half of the participants, the choice of image that was “dangerous” during the first part of the experiment entailed the highest risk of electric shock. This meant that their previous learning was relevant to their decisions. For the other half, the choice of image that was not “dangerous” in the initial stage entailed the highest risk of shock. This meant that their previous learning was wrong. Strong impact on decision-making What the researchers found was indirect social learning (watching a film and oral information) had just as strong an effect on the participants’ decisions as learning by first-hand experience. Participants who had learnt that a certain image was “dangerous” continued to avoid it, even though their choice resulted more often in an electric shock. “The study suggests that these social ways of obtaining information can strongly influence our decision-making, even to our own detriment”, says lead author Björn Lindström, researcher at Amsterdam University and the Department of Clinical Neuroscience, Karolinska Institutet. “The results can help us understand why people behave irrationally”, says research group leader Andreas Olsson, senior lecturer at the Department of Clinical Neuroscience, Karolinska Institutet. “They indicate that it can depend on something we’ve learnt by watching a video clip or listening to a rumour that’s misleading for the environment in which we find ourselves.” The researchers also used computational models to show that the two types of social learning influence behaviour through different learning mechanisms, possibly reflecting differences in underlying brain systems. Brain activity was not measured in the study, however. The study was financed by the Knut and Alice Wallenberg Foundation, the Bank of Sweden Tercentenary Foundation, the European Research Council, the Swedish Research Council for Health, Working Life and Welfare (Forte), the Swedish Research Council and the Swiss National Science Foundation. Publication ”Social threat learning transfers to decision-making in humans”. Björn Lindström, Armita Golkar, Simon Jangard, Philippe Tobler och Andreas Olsson PNAS, online 13 februari 2019, doi: 10.1073/pnas.1810180116

Knowledge of a newly discovered genetic disorder, which means that a person cannot produce the protein TXNIP (thioredoxin interacting protein) in their cells, can open for the development of new diabetes drugs. This is shown in a study from Karolinska Institutet published in the journal Diabetes. With modern techniques more and more previously unknown genetic diseases are being discovered, which can lead to new knowledge about human biology and contribute to the development of new drugs. Researchers at Karolinska Institutet have recently been using gene sequencing (genome analysis) to investigate a family in which three of the children had excessively high levels of lactate (lactic acid) and simultaneously low levels of the amino acid methionine in the blood, which is an unusual symptom picture. If left untreated, elevated lactate levels can cause tissue damage, respiratory effects and even fatal outcome, but the children are being given continuous medical treatment and are otherwise well. "We discovered that the children's symptoms were due to a mutation in the gene that encodes the protein TXNIP (thioredoxin interacting protein), which had never previously been described in humans. Based on the results in animal models, this protein has been suggested as a possible target for new diabetes drugs, since overexpressing TXNIP in mice induces diabetes, while a lack of TXNIP protects against diabetes,” says Anna Wedell, consultant and professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet and SciLifeLab. The cells thioredoxin system were analysed TXNIP is active in the thioredoxin system, which is found in all living cells. The system is of great importance in terms of the ability to make new DNA (genetic material) and to protect cells from reactive radicals. In the current study, the researchers examined cells from the children using more detailed methods and analyses of both the thioredoxin system and sugar metabolism. They also investigated how the mitochondria, which are the cells’ energy factories, functioned. "We found that the TXNIP protein was completely absent from the cells from these patients. The result is that the mitochondria are unable to use pyruvate resulting from the break-down of glucose, as is usually the case when cells use sugar to make energy. Instead, they only produced lactate from pyruvate. However, the cells were able to use another substance as fuel for the mitochondria - malate. This can explain much of the patients’ symptoms, and also shows that a complete absence of TXNIP is compatible with human life,” says Elias Arnér, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study together with Anna Wedell and Alfredo Giménez-Cassina at the Universidad Autónoma de Madrid. TXNIP potential target for drug treatment in diabetes It has not previously been known what happens in humans if TXNIP is absent. The results of the new study provide important insights into the significance of TXNIP and strengthen the hypothesis for TXNIP being a potential target for drug treatment in diabetes, provided that any high lactate levels as a result of such treatment can be managed. "Studying patients in whom this protein is entirely absent can give some idea of the potential effects of a drug that inhibits the protein, though more studies are needed because these children do not have diabetes," says Elias Arnér. The researchers now want to conduct further research in order to understand why the children also have low levels of methionine in their blood, and how the metabolism of methionine might be linked to sugar metabolism. The study was funded with the support of Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation, Region Stockholm, the Spanish Ministry of Economy and Competitiveness, the Ramón y Cajal Fellowship, the Swedish Diabetes Fund, the Alicia Koplowitz Foundation and the Ragnar Söderberg Foundation. Publication ”Absence of TXNIP in human gives lactic acidosis and low serum methionine linked to deficient respiration on pyruvate” Yurika Katsu-Jiménez, Carmela Vázquez-Calvo, Camilla Maffezzini, Maria Halldin, Xiaoxiao Peng, Christoph Freyer, Anna Wredenberg, Alfredo Giménez-Cassina, Anna Wedell and Elias S.J. Arnér. Diabetes, online 12 February, 2019, doi: 10.2337/db18-0557

Obesity or low physical fitness during adolescence is strongly associated with disability pension later in life. This is shown in a study of more than one million Swedish men, published in Annals of Internal Medicine by researchers at Karolinska Institutet. In many countries, disability pensions are granted to working-aged persons who are likely to never work full-time again because of a chronic disease or injury diagnosed by a physician.  In addition to serving as an important indicator of chronic disease, disability pensions are associated with high societal costs. Researchers from Karolinska Institutet in Sweden and University of Granada in Spain led a study assessing cardiorespiratory fitness and weight for more than 1 million men between the ages of 16 and 19. Data from the Swedish military service conscription registry was used. The researchers then reviewed who would later in life go on to receive a medical disability pension.  Over a median follow-up of 28.3 years, the data showed that low cardiorespiratory fitness was strongly associated with later receipt of a disability pension due to all causes. Obesity was also associated with a greater risk for disability pension, with the greatest risks observed for severe/morbid obesity.  Important marker regardless of body weight However, the researchers noted that compared with being unfit, being moderately or highly fit was associated with lower risk for disability, regardless of BMI. According to the researchers, this means that being physically fit is an important indicator of health irrespectively of body weight.  ”Our findings support the relevance of cardiorespiratory fitness and healthy body weight during adolescence as important markers of future health", said Pontus Henriksson, researcher at the Department of Biosciences and Nutrition, Karolinska Institutet, and first author of the study. This news article is based on a press release from Annals of Internal Medicine. The research was funded mainly by Karolinska Institutet, the Henning and Johan Throne-Holst Foundation, the Swedish Society of Medicine, Region Östergötland, National Institute on Aging, the European Union and the University of Granada. Publication ”Fitness and Body Mass Index During Adolescence and Disability Later in Life” Pontus Henriksson, Hanna Henriksson, Per Tynelius, Daniel Berglind, Marie Löf, I-Min Lee, Eric J. Shiroma and Francisco B. Ortega, Annals of Internal Medicine, online 12 February 2019, doi: 10.7326/M18-1861.

Using puzzle pieces from four different DNA analyses, researchers at Karolinska Institutet have been able to map three extremely complex chromosome aberrations. This has given families answers about the cause of their children’s serious symptoms. The study was published in the scientific journal PLOS Genetics and the goal is to produce a test to be used in the clinic. One in 500 people carries a balanced chromosome aberration. It means having all the genetic make-up but not in the right place. It does not necessarily cause any medical problems, depending on where the aberrations are located. However, healthy carriers may face fertility problems or an increased risk of having children with rare genetic disorders. Anna Lindstrand, clinically active researcher at Karolinska Institutet and Karolinska University Hospital, leads a research group specialised in studying the genetic background of rare diagnoses. This includes diseases caused by complex chromosome aberrations. For the past two years, she and her colleagues have used the latest technology to find genetic causes for the severe symptoms experienced by three persons since they were little. Neither studying the chromosomes under a microscope nor whole genome sequencing using the standard “short read” technique had been able to identify the exact cause of the problems. “We knew that they were carrying one or more irregular chromosomes, but we did not know what they looked like on a detailed level,” says Anna Lindstrand, Docent at the Department of Molecular Medicine and Surgery at Karolinska Institutet. The knowledge is important both in order to give the appropriate care, and to allow for prenatal screening in cases where parents want more children. The researchers chose to study the subjects’ genetic make-up with newer whole genome sequencing techniques. This allows them to study longer DNA molecules and also take high resolution images of the chromosomes. “Combining the results helped us solve the puzzle. We managed to piece together the complete altered chromosome in one patient and the chromosomes involved in the two other cases.” The results show that the chromosome aberrations in the three teenagers are each so rare that they can be considered unique. “It’s not even possible to calculate the probability that another person in the world would have the exact same 36 breakpoints on chromosome 1 that one of our patients had,” says Anna Lindstrand. She establishes that the message of the study is that there is a value in continuing with more whole genome sequencing when this type of deviation is found in clinical environments. “There is great clinical interest in developing better methods which allow us to describe in detail what is wrong.” Researchers now want to move on to studying the method on hundreds of people with different types of complicated chromosome aberrations. The goal is to create a test which can be used in clinics. “Perhaps in the future it will be possible to use this method directly when you have a sick child and don’t know why. I think this could be reality in just a couple of years. But today the method is more of a follow-up analysis.” The study was conducted in collaboration with researchers from KTH, Stockholm University and the Baylor College of Medicine in Houston, USA. The research project was funded by grants from SciLifeLab, the Swedish Research Council, the Swedish Society for Medical Research, Hjärnfonden, Riksbankens Jubileumsfond/Erik Rönnberg’s Donations and Stockholm County Council. Publication “Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements”. Jesper Eisfeldt, Maria Pettersson, Francesco Vezzi, Josephine Wincent, Max Käller, Joel Gruselius, Daniel Nilsson, Elisabeth Syk Lundberg, Claudia M.B. Carvalho, Anna Lindstrand. PLOS Genetics, online 8 February 2019, doi: 10.1371/journal.pgen.1007858

KI has now formalised its collaboration with the International Union of Basic and Clinical Pharmacology (IUPHAR) in the interests of promoting sustainable drug development and rational drug use. The agreement applies to both research and education. A memorandum of understanding was signed by Michael Spedding, secretary general of the IUPHAR and KI president Ole Petter Ottersen at the end of January. Two collaborative projects are already underway on enhancing the capacity of low and middle-income countries as regards academic drug development and rational drug use. From KI, the projects are being led by, respectively, Per Arvidsson and Lars L Gustafsson. The IUPHAR is a not-for-profit pharmacology organisation that was formed in 1959 and that works for greater international cooperation in the field. One of its main contributions is to provide access to information on drugs through pubic databases such as the Guide to Pharmacology. The memorandum was signed at a workshop organised by KI and the Swedish Institute for Drug Informatics, an organisation offering scientific and evidence-based information on drugs and drug therapies.

New research on how cancer mutations influence a certain type of receptor on the cell membrane opens the way for the development of tailored drugs for certain cancers, such as rectal cancer and lung cancer. This according to researchers at Karolinska Institutet and Uppsala University, who have been collaborating with researchers in the UK and USA. The results of their work, which concerns a group of G protein-coupled receptors called Class Frizzled (Class F), are published in the journal Nature Communications. “Class F receptor dysfunction can be linked to different forms of cancer,” says Gunnar Schulte, study leader and professor at Karolinska Institutet’s Department of Physiology and Pharmacology. “We can now describe in molecular detail how the receptors are activated and try to find drugs that stop this activation to prevent tumour growth.” The receptors on the cell membrane are activated by hormones or messenger molecules, which trigger a cascade of processes within. G protein-coupled receptors are one of the largest protein families in the body and are already an established drug target for a whole range of diseases. An important subgroup of G protein-coupled receptors are the so-called Class F receptors, but to date they have not constituted a therapeutic target to any great extent. In this present study, the researchers used newly developed methods to compare the mutation frequency of Class F receptors in tumours with the normal population. In linking cancer mutations to receptor function in this way, they claim to have opened up new opportunities for mechanism-based drug discovery. The study describes for the first time how regions of the Class F receptor act as a kind of switch for receptor activation, and how mutations in the receptor molecules can drive tumour development. Target individual receptors According to Professor Schulte, there are indications that other diseases, such as fibrosis, can also be linked to Class F receptor dysfunction. The researchers are currently working with the Swedish national research facility SciLifeLab to develop their ideas and explore potential new drugs. “Drugs targeting receptors in this group have been unspecific,” Professor Schulte says. “We hope that it will now be possible to develop more effective drugs that can target individual receptors, drugs for cancers such as rectal, cervical and lung cancer.” This publication is the product of five years’ work, in which Shane Wright and Pawel Kozielewicz from Professor Schulte’s research group also played a significant part. The other research leaders were Jens Carlsson (Uppsala University), M Madan Babu (MRC Laboratory of Molecular Biology, UK) and Nevin Lambert (Augusta University, USA).  The study was financed by several bodies, including Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Cancer Society, the Novo Nordisk Foundation, the Olle Engkvist Byggmästare Foundation, and the Emil and Wera Cornell Foundation. Publication A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection Shane C. Wright, Paweł Kozielewicz, Maria Kowalski-Jahn, Julian Petersen, Carl-Fredrik Bowin, Greg Slodkowicz, Maria Marti-Solano, David Rodríguez, Belma Hot, Najeah Okashah, Katerina Strakova, Jana Valnohova, M. Madan Babu, Nevin A. Lambert, Jens Carlsson and Gunnar Schulte Nature Communications, online 8 February 2019, doi: 10.1038/s41467-019-08630-2

The treatment of Hodgkin lymphoma is now so effective that young patients who do not have a relapse within two years of therapy have a life expectancy similar to that of their healthy peers. This according to a new study published in The Journal of Clinical Oncology by researchers at Karolinska Institutet and their colleagues at Aalborg University Hospital in Denmark and Radiumhospitalet in Oslo. Hodgkin lymphoma is a cancer of the lymph system that mainly affects people in their twenties. While the disease is fatal if left untreated, most sufferers are cured. The researchers behind the present study analysed data from over 2,500 patients in Sweden, Norway and Denmark between the ages of 18 and 49 to ascertain the magnitude of the relapse risk. At present, these patients are being monitored for up to five years after treatment. The results of the study show, however, that even after two years the patients have, on average, the same life expectancy as individuals of the same age and gender without Hodgkin lymphoma, and that the risk of relapse averages out at only about 4 per cent. “Bearing in mind the good survival rate and low risk of relapse after two years, the frequency of check-ups for detecting relapse could be greatly reduced after this time,” says joint last author Karin Ekström Smedby, researcher at Karolinska Institutet’s Department of Medicine in Solna. “That said, further checks are needed at a later stage to find and treat delayed adverse reactions to the treatment.” The study was financed by the Danish and Swedish cancer societies. Publication “Relapse risk and loss of lifetime after modern combined modality treatment for young Hodgkin lymphoma patients: A Nordic Lymphoma Epidemiology Group study”. Jorne Lionel Biccler, Ingrid Glimelius, Sandra Eloranta, Knut B. Smeland, Peter de Nully Brown, Lasse Hjort Jakobsen, Henrik Frederiksen, Mats Jerkeman, Alexander Fosså, Therese M.L. Andersson, Harald Holte, Martin Bøgsted, Tarec Christoffer El-Galaly and Karin E. Smedby. Journal of Clinical Oncology, online 6 February 2019, doi: 10.1200/JCO.18.01652.

Mai-Lis Hellénius, popularly known as Karolinska Institutet’s lifestyle professor, held her farewell lecture in Aula Medica, Solna, on 1 February. The lecture, How diet and exercise can prevent cardiovascular disease, attracted some 700 people. One of these was Prince Daniel. “I’m overwhelmed and stunned!” So said Mai-Lis Hellénius, professor at the Department of Medicine, Solna, her arms full of flowers after her farewell lecture in Karolinska Institutet’s Aula Medica. The lecture was held to mark Mai-Lis Hellénius’ retirement from her post as professor and senior physician. It attracted some 700 people. One of these was His Royal Highness Prince Daniel of Sweden. Welcoming Mai-Lis Hellénius to the stage at the start of the lecture, Cecilia Linde, professor at the Department of Medicine, Solna, used the word “megasuccess”. Cecilia Linde also spoke about the “lifestyle centre” started on Mai-Lis Hellénius’ initiative at the Cardiology Clinic, Karolinska University Hospital, Solna, in 2007. “This resulted in dissertations, scientific articles and the evidence necessary for lifestyle to make it onto the agenda and be included in the treatment guidelines for heart diseases,” commented Cecilia, who was the head of the Cardiology Clinic at that time. Squats and dancercise on the programme Focusing on diet and physical activity, the lecture highlighted the importance of lifestyle in preventing cardiovascular diseases. It included not only examples from Mai-Lis Hellénius’ own research in this area, but also international perspectives. “Time for a Kiruna! Stand up everyone!” As is only right when the speaker knows the importance of not sitting down for too long, Mai-Lis Hellénius interrupted her lecture for the squat series now known as a “Kiruna” (after the town of the female originator) and some dancercise. Mai-Lis Hellénius also gave details of a project she helped to start in Sollentuna in the middle of the 1980s. In this, healthcare centre visitors were offered free health checks and a prevention programme with individual lifestyle counselling, presentations and group activities. Now, over 20 years later, around 5,700 participants have been followed up and matched to reference people outside Sollentuna. These latter form a control group. “Those who have taken part in the programme are at less risk of having a heart attack and also show reduced all-cause mortality. Thanks to the programme, around 175 people have enjoyed longer lives. We’re very pleased with those results,” states Mai-Lis Hellénius. Popular educator and inspiration Mai-Lis additionally emphasised the importance of universities’ public and science outreach, i.e. sharing their knowledge. After a comprehensive thank you, she left the stage with a summary. “Take the risks of being sedentary seriously. However, remember that every movement counts. Trust the science-based advice about good diet and lifestyle. Furthermore, let everyone in on this knowledge.” Ole Petter Ottersen, president at Karolinska Institutet, thanked Mai-Lis Hellénius for her contributions as researcher, doctor and teacher. He stressed the importance of information from researchers being evidence-based and held out, not least, Mai-Lis Hellénius’ role as public educator and inspiration. “Your energy, your commitment and your know-how in communicating with the general public are exemplary. Thank you for your initiatives and your great impact.” Mai-Lis Hellénius is to continue as an affiliate of Karolinska Institutet.

Acute porphyria is a group of uncommon diseases that can cause severe, potentially life-threatening attacks of abdominal pain, nausea, vomiting and paralysis. Liver transplantation is currently the only effective treatment available for the most seriously afflicted patients. A clinical trial conducted in collaboration with researchers at Karolinska Institutet in Sweden now shows that a new drug candidate can prevent attacks in these patients. The study is published in The New England Journal of Medicine. Porphyria is caused by different inherited disorders in the synthesis of heme, the oxygen-binding component of red blood cells. Heme is also necessary for the metabolism of certain drugs and hormones by the liver. When the liver is unable to synthesise heme properly, toxic substances called porphyrin metabolites accumulate in the body, resulting in acute porphyria attacks. A small group of porphyria patients suffer recurrent acute attacks, which cause them chronic debilitating symptoms requiring constant hospital care. Acute intermittent porphyria (AIP) is the most common form of acute porphyria. Patients suffering from acute attacks are treated using an infusion containing a form of heme called hemin, which suppresses the formation of the toxic metabolites. “Hemin has saved the lives of many patients and will continue to be important, but it’s only for acute treatment,” says the study’s lead author Eliane Sardh, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and consultant at Karolinska University Hospital. “For patients with recurrent attacks, no other curative treatment is available than liver transplantation.” Reduced the number of acute attacks However, the new drug candidate givosiran, developed by Alnylam Pharmaceuticals, has shown promising results in a clinical phase I study in 40 patients. The study has been conducted in close, long-standing collaboration with Porphyria Centre Sweden, which has also provided the majority of the patients. The administration of givosiran reduced the number of acute attacks in the patients by up to 79 per cent, and the need for hemin decreased by up to 83 per cent. Most of the reported side effects were mild or moderate, and no clear link was observed between adverse reactions and dose. Severe adverse reactions were reported in six patients, including one death that was deemed unrelated to givosiran. The drug candidate is based on a natural method of inhibiting gene expression called RNA interference (RNAi). “Givosiran down-regulates ALAS1, the key regulator of the hepatic heme synthesis pathway, which reduces the toxic metabolites without the use of hemin,” says Dr Sardh. “It also has a lasting effect of at least one month, which gives us an effective means of preventing acute attacks in seriously afflicted porphyria patients who have limited treatment options.” Accelerated review process The drug candidate has been given PRIME and Breakthrough Designation by the European Medicines Agency and the U.S. Food and Drug Administration, which in speeding up the review process could mean that the drug may be available by early 2020. The patients that took part in the phase I study will remain on givosiran in a combined phase I/II study, and complete results from a phase III study in 94 patients from around the world are expected in the spring of 2019. The study design and study research was conducted by Karolinska University Hospital, Karolinska Institutet, Porphyria Centre Sweden, the Icahn School of Medicine at Mount Sinai (New York), King’s College Hospital (London), the University of California (San Francisco), the University of Utah (Salt Lake City), Wake Forest University (Winston-Salem), and the University of Texas Medical Branch (Galveston). It was financed by Alnylam Pharmaceuticals. Publication “Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria” Eliane Sardh, Pauline Harper, Manisha Balwani, Penelope Stein, David Rees, D. Montgomery Bissell, Robert Desnick, Charles Parker, John Phillips, Herbert L. Bonkovsky, Daphne Vassiliou, Craig Penz, Amy Chan-Daniels, Qiuling He, William Querbes, Kevin Fitzgerald, Jae B. Kim, Pushkal Garg, Akshay Vaishnaw, Amy R. Simon and Karl E. Anderson. The New England Journal of Medicine, online 6 February 2019, doi: 10.1056/NEJMoa1807838

For reasons that are unclear, schizophrenia patients have fewer connections between the neurons in the brain. Researchers at Karolinska Institutet, Sweden, and Massachusetts General Hospital, USA, have now succeeded in creating human cell models that show that there is an excessive degradation of connections in the brain of these patients, and they have been able to link this to a genetic risk variant for the disease. They have also been able to show that the antibiotic minocycline inhibits the degradation and that treatment in adolescence can be linked to a reduced risk of developing schizophrenia. The study is being published in the journal Nature Neuroscience. In the late teenage years, a normal extensive pruning of the number of connections between nerve cells, so-called synapses, takes place through microglia (the brain’s immune cells) selectively degrading less desirable connections. The process, referred to as synaptic pruning, is of great importance for the development of functional neural networks. Many individuals succumb to schizophrenia in their late teens, a period of intensive pruning in the brain. The researchers behind the study have created iPS cells (induced pluripotent stem cells) from schizophrenia patients and have reprogrammed them into neurons (brain cells). Using a proprietary method, they have then created a model of the microglia synaptic pruning in a test tube. Comparisons with matched control subjects indicated a clear increase in the pruning of synapses in schizophrenia patients. “We also conducted experiments where we combined nerve cells from healthy individuals and diseased microglia, and vice versa, and could conclude that the excessive pruning in the disease models was due to both a disrupted function of microglia and aberrations in the synapses,” says Jessica Gracias, doctoral student at the Department of Physiology and Pharmacology, Karolinska Institutet, and co-author of the study. Increased degradation of synapse The researchers also studied how different gene variants of the C4 gene (complement factor 4) affect the pruning. One variant of the complement factor proved to bind more strongly to synapses and result in the increased degradation of synapses. This is consistent with previous genetic findings indicating that this specific C4 risk variant increases the risk of schizophrenia. “The use of human cells from patients made it possible to study the risk variants directly because mice lack these specified variants of the C4 gene,” says Carl Sellgren Majkowitz, research group leader at the Department of Physiology and Pharmacology, Karolinska Institutet, and senior consultant at Region Stockholm, who led the research project together with Roy Perlis at Massachusetts General Hospital. Antibiotic proved to inhibit the synaptic pruning Finally, microglia in the cell models were also “treated” with an antibiotic, minocycline, which proved to inhibit the synaptic pruning. By then using electronic data records from more than 20,000 individuals who had received either minocycline or another antibiotic during adolescence, for treatment of acne, they were able to demonstrate a clear protective effect from minocycline treatment in relation to schizophrenia onset. The researchers hope that the findings will lead to more effective treatments for schizophrenia, which can then also be initiated early on in the event of an elevated genetic risk, for example. The research was conducted at Massachusetts General Hospital and Karolinska Institutet. The National Institute of Mental Health, the Marianne and Marcus Wallenberg Foundation and the Swedish Research Council contributed to fund the research. Publication “Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning” Carl M. Sellgren, Jessica Gracias, Bradley Watmuff, Jonathan D. Biag, Jessica M. Thanos, Paul B. Whittredge, Ting Fu, Kathleen Worringer, Hannah E. Brown, Jennifer Wang, Ajamete Kaykas, Rakesh Karmacharya, Carleton P. Goold, Steven D. Sheridan and Roy H. Perlis. Nature Neuroscience, online 4 February, 2019, doi: 10.1038/s41593-018-0334-7

At the end of January, KI hosted a national workshop on international and intercultural perspectives in teaching. Here, representatives from Swedish higher education institutions gathered under the leadership of international researchers. The organiser was SUHF, the Association of Swedish Higher Education Institutions. Eva Åkesson, Vice-Chancellor of Uppsala University and Chair of the expert group for internationalisation issues within SUHF, was among those started off the day’s proceedings. “The educational domain is becoming increasingly global and competition is intensifying. Maybe in the past internationalisation was viewed as a sideline activity, but that is no longer the case. Nowadays, it goes without saying that this is something that affects our entire organisation,” said Eva Åkesson. Among the invited members were vice-chancellors and deputy vice-chancellors with responsibility for internationalisation and pedagogical support, as well as students’ union representatives from all over the country. The reason for hosting the workshop at KI is explained by an ongoing development project, where five degree programmes participate with the aim of increasing the internationalisation of the teaching. “In the past we discussed internationalisation in terms of mobility and teaching in English. All with the intention of attracting more international students to Sweden. Today it is more a question of preparing our students for living and working in a globalised world,” says Jennifer Valcke, pedagogical developer within the Unit for Medical Education at the Department of Learning, Informatics, Management and Ethics, and the person responsible for the three-year development programme. When the development project reaches 2020, there should be guidelines, practice and experience in place that not only allows KI’s other degree programmes to be included, but also other Swedish universities. “This is also the reason why we are hosting today’s workshop. SUHF’s goal is to gather expertise within the field in order to build tighter networks and arenas at the national level for increased internationalisation,” says Jennifer Valcke. Both Jeanine Gregersen, Pro-Vice-Chancellor of Glasgow Caledonian University, and Betty Leask, Pro-Vice-Chancellor of La Trobe University, Melbourne, were present for the entire day. They are both international experts within the field and are also involved in the development project at KI. During her lecture, Betty Leask presented a rundown of methods and tools for increased internationalisation, and also highlighted several specific problems and obstacles. According to her, an important component is that the entire organisation must be involved for a successful outcome. “We must challenge our perception of what internationalisation means within all levels of our organisations, and focus on the staff as well as the students. How can we help our staff to develop the same skills as our students to strengthen internationalisation?” suggested Betty Leask. Among the other participants was also KI’s President Ole Petter Ottersen and European Parliamentarian Cecilia Wikström (L).

Transplanted pancreatic islets in diabetic animals can survive for a long period of time if the animals are treated with short anti-rejection therapy around the time of the transplant. This has been shown by researchers at Karolinska Institutet, Sweden, and the Diabetes Research Institute, University of Miami Miller School of Medicine, USA, in a new study published in the scientific journal Diabetologia. The results might have a significant impact on clinical islet transplantation in the treatment of type 1 diabetes. Transplantation of pancreatic islets with their insulin-secreting cells is a promising therapy in type 1 diabetes. However, one complication is that anti-rejection therapy, in the form of generalised immune suppression, is required to ensure the survival and function of the transplanted islets by preventing the immune system from attacking the transplants. It is well known that extended use of generalised immune suppression might have serious side effects that harm the transplanted patient. Moreover, immune attack against the transplanted islets can still occur despite continued immune suppression. Therefore, the transplantation field has been looking for new ways to ensure the long-term survival and function of transplanted islets with little or even no immune suppression. This new study demonstrates the potential for achieving long-term survival and function of transplanted pancreatic islets with short-term anti-rejection therapy around the time of the transplant. In transplanted mice and monkeys, this strategy resulted in immune tolerance that enabled survival of the transplanted islets long after the anti-rejection treatment was stopped. “These findings support the establishment of immune tolerance towards the transplanted islets and thereby their long-term protection from an immune attack in the transplanted patient after stopping the use of anti-rejection therapy,” says first author Dr Midhat H Abdulreda at the Diabetes Research Institute. Hope for effective treatment This new way of achieving immune tolerance might minimise the need for life-long immune suppression, which raises hope for an effective treatment of type 1 diabetes with fewer side effects. “If these findings are repeated in humans, this approach may serve as a game changer and positively impact on the success of islet transplantation for future treatment of type 1 diabetes,” says senior author Professor Per-Olof Berggren at the Department of Molecular Medicine and Surgery and Rolf Luft Research Center for Diabetes and Endocrinology at Karolinska Institutet. The research was supported by funds from the Diabetes Research Institute Foundation (DRIF) and the Diabetes Wellness Foundation and by grants from the Stanley J. Glaser Foundation Research Award, the NIH/NIDDK/NIAID, the Swedish Diabetes Association Fund, the Swedish Research Council, Novo Nordisk Foundation, the Family Erling-Persson Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2013-AdG 338936-BetaImage, the Knut and Alice Wallenberg Foundation, Skandia Insurance Company Ltd, the Diabetes and Wellness Foundation, the Berth von Kantzow Foundation, and the Stichting af Jochnick Foundation. Per-Olof Berggren is cofounder and CEO of Biocrine, an unlisted biotech company that is using the approach of cell transplant in the anterior chamber of the eye as a research tool. Midhat H Abdulreda is a consultant for the same company. More information about the technique can be found in the scientific article. Publication “Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate” Midhat H. Abdulreda, Dora M. Berman, Alexander Shishido, Christopher Martin, Maged Hossameldin, Ashley Tschiggfrie, Luis F. Hernandez, Ana Hernandez, Camillo Ricordi, Jean-Marie Parel, Ewa Jankowska-Gan, William J. Burlingham, Esdras A. Arrieta-Quintero, Victor L. Perez, Norma S. Kenyon, Per-Olof Berggren Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]), online 31 January 2019, doi: 10.1007/s00125-019-4814-4

Comments: Information in the media claims that the basic data for the external investigation of the so-called Macchiarini case at KI has disappeared or cannot be found. This information is also found in a newly published book by Harriet Wallberg and Kristina Appelqvist, När lögnen blir sanning (When the lie becomes truth).  KI comments on this information as follows. The investigation was external and was led by Sten Heckscher. None of the external investigators were an employee at KI. Thus, KI had no obligation to archive material in the investigation. This is confirmed in a decision by the Ombudsman (JO) on 17 February 2017 (JO serial number 299/2017, KI serial number 2-1259/2017) in connection with a JO notification by Harriet Wallberg. The information that the investigation material might have disappeared is not correct. All information that has been obtained from the KI archive is still available. The background to the external investigation was a decision by the Konsistoriet (the university’s board) and it was commissioned in 2016 by the board members at the time. The report Karolinska Institutet and the Macchiarini case (in Swedish) was presented on 5 September 2016. The investigators used information from KI's archives and records to review Karolinska Institutet's handling of the whole case – from the recruitment of Macchiarini in 2010 and onwards. This consisted of large quantities of decision records, e-mail messages etc. All the material that the investigators used in their work and which consists of public documents is archived at KI, but not collected under a single case heading. The external inquiry was also based on information that the investigators developed through conversations with KI employees and other sources. If any documentation of these conversations had been submitted to KI, it would have been registered. No such documentation has been received.

In a study published in Environment International researchers at Karolinska Institutet in Sweden show how PFAS industrial chemicals, which are used in many consumer products, pass through the placenta throughout pregnancy to accumulate in fetal tissue. Further research is now needed to ascertain the effect that highly persistent PFAS chemicals have on the fetus. The PFAS (perfluoroalkyl substances) group comprises thousands of human-made chemicals, which, thanks to their water- and grease-resistant properties, are used in everything from frying pans and food packaging to clothes, cleaning agents and firefighting foams. “We’ve focused on six of these PFAS substances and found that all appear to the same extent in fetal tissue as in the placenta,” says Richelle Duque Björvang, doctoral student at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. “So when the baby is born, it already has a build-up of these chemicals in the lungs, liver, brain, and elsewhere in the body.” High levels in the lung and liver PFAS levels were highest in the lung and liver tissue, in some cases as high as in adults, and lowest in the brain. The study included tissue samples from 78 embryos and fetuses aged 7 to 42 weeks, sourced from biobanks in Sweden and Denmark. Amongst the six PFAS substances studied were PFOS and PFOA, which are the best known. PFOS was banned by the EU in 2008, and at the start of the year the European Food Safety Authority sharpened its appraisal of PFOS and PFOA and lowered the tolerable daily intake thousandfold. “This shows how important it is for more research to be done on the health effects of different chemicals, especially in the longer term,” says Pauliina Damdimopoulou, senior researcher at the Department of Clinical Science, Intervention and Technology. “Today’s threshold values are based on an adult population rather than fetuses, which are much more susceptible.” The accumulation of PFAS substances was also higher in male fetuses than female. “We know that there are slight differences in the function of the placenta depending on the sex of the fetus, which is something we need to do more studies on in relation to impact on fetal chemical exposures,” says Dr Damdimopoulou. “We also need to find out what effects these substances have on different fetal organs.” Food is the main source PFAS substances have been used since the early 1900s and are ubiquitous in our environment. “The main source of PFAS substances today is food, in the form of fish, milk, meat and eggs, or in the drinking water, if you happen to live in a polluted area,” continues Dr Damdimopoulou. “We ingest them as a cocktail of substances that can also interact with each other. It would be in line with the precautionary principle in the restriction of chemical substances to make sure that all PFAS substances disappear from our society.” The study was conducted in collaboration with researchers from Copenhagen University and Rigshospitalet, and was financed by the EU ReproUnion project, the Novo Nordisk Foundation, Formas (the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning) and the Jane and Aatos Erkko Foundation. Publication  “Concentration of perfluoroalkyl substances (PFASs) in human embryonic and fetal organs from first, second, and third trimester pregnancies” Linn Salto Mamsen, Richelle D. Björvang, Daniel Mucs, Marie-Therese Vinnars, Nikos Papadogiannakise, Christian H. Lindh, Claus Yding Andersena and Pauliina Damdimopoulou Environment International, online 24 January 2019, doi: 10.1016/j.envint.2019.01.010

Scientists at Karolinska Institutet have experimented with a new adaptive treatment strategy for Internet-delivered cognitive behavioural therapy (ICBT) that identifies patients within the first month who face a major risk of treatment failure. Published in the scientific journal American Journal of Psychiatry, the results also suggest that such patients may nevertheless benefit if their treatment is adjusted to accommodate their specific needs and challenges. Internet-delivered CBT effectively addresses depression, panic and sleep disorders, and several other psychological issues. Many studies over the past 20 years have demonstrated benefits that are comparable with traditional face-to-face treatment, and clinical practice has adopted the approach throughout much of Sweden. As is the case with any method, not everyone benefits enough. Researchers have not yet found a way to prior to treatment separate those who are likely to benefit from those who are not. The adaptive treatment strategy evaluated by scientists at Karolinska Institutet permits such a classification within a few weeks into therapy. The study included 251 patients who were receiving Internet-delivered CBT for insomnia. “The findings indicate that an accurate assessment of patients who are likely and unlikely to benefit is possible by the fourth week of treatment. The strategy also reduces the risk of insufficient outcome since it enables additional support and adaptation for those who need it,” says Erik Forsell, psychologist and PhD student at the Department of Clinical Neuroscience, Karolinska Institutet. After four weeks of Internet-delivered CBT, the scientists performed a structured assessment of the individual risk of failure with a questionnaire and algorithm-based tool. Patients were then classified as either facing a low risk or high risk of failure, i.e., obtaining insufficient benefits. Those at high risk were randomly assigned to either continuing the treatment or receiving additional support and an adjusted treatment. High risk patients who continued with the standard treatment obtained less reduction in sleep problems, whereas those who received additional support and the adjusted treatment obtained similar benefits as those in the low-risk group. A first step in customising Internet-delivered CBT The scientists regard the study as a first step in customising Internet-delivered CBT, and ultimately traditional therapy as well, by constructing structured systems that identify and assist those who do not appear likely to benefit. “The strategy will help a greater number of patients and minimise the risk of extended therapies without desired benefits. The long-run consequences may be fewer failures and less time between diagnosis and effective treatment. The healthcare system would be less burdened and individual patients would suffer less,” says Viktor Kaldo, psychologist and associate professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the principal researcher, The study was financed by the Söderström-Königska sjukhemmet Foundation, the L.J. Boëthius Foundation, the Bror Gadelius Minnesfond Foundation, the Stockholm County Council, the Erling-Persson Family Foundation and the Swedish Research Council. Publication ”Proof of concept for an Adaptive Treatment Strategy to prevent failures in Internet-delivered Cognitive Behavior Therapy: a single-blind Randomized Clinical Trial with insomnia patients” Forsell, E., Jernelöv, S., Blom, K., Kraepelien, M., Svanborg, C., Andersson, G., Lindefors, N. & Kaldo, V. American Journal of Psychiatry, online 30 January, 2019, doi: 10.1176/appi.ajp.2018.18060699

A new EU project on the theme of HIV, hepatitis C and tuberculosis is a door opener for collaboration between researchers from EU countries and Russia. One of the project’s initiators is Anders Sönnerborg, Professor of Clinical Virology and Infectious Diseases at KI’s Departments of Laboratory Medicine, and Medicine Huddinge. The project Common Actions Against HIV/TBC/HCV Across the Regions of Europe (CARE) will mainly focus on the spread of the infections and resistance to treatment. Tell us more about the research you’ll be doing. “It’s generally about understanding and preventing the spread of HIV, hepatitis C and tuberculosis in Europe and Russia, with emphasis on counteracting development of multi-resistance to TB and HIV. There’s a high rate of treatment-resistant tuberculosis in Russia and we are afraid that a similar scenario may arise also for HIV. We’ll compare data from different patient groups in EU and Russia to learn from each other as well as developing methods for the identification of mechanisms of drug resistance. The long-term goal is to describe approaches for optimal treatment in all three areas and also to establish a research infrastructure which allows a continuation of research collaboration between EU and Russia after the project end.” What are your and KI’s roles in the project? “We’re in charge of the HIV part and will be studying how the virus spreads and what the different viral strains look like. There’s also the issue of resistance when it comes to HIV, too. The virus is constantly mutating and we want to compare the different strains circulating in Europe and Russia. The WHO now recommends a triple therapy in which a new drug, integrase inhibitors, is added. We want to see how any resistance can emerge to this drug and the consequences thereof.” You were one of the project’s initiators. What difference might this make further down the line? “Our project scored maximum points at the reviews of both EU and the Russian Ministry of Science and Education which is promising for the long-term sustainability. The idea is to set up a common infrastructure and contacts and networks for future research. The aim is to establish a research partnership between the EU and Russia for the field that can continue after this initial project phase. The project we’re now running is scheduled to last two years, forming a platform for continuing knowledge-exchange and data comparison and I am convinced that KI will play a role.” Can you say more about the background and how the new collaboration is structured? “Presently Russia can only exceptionally be a partner in EU-sponsored projects. This new innovative call is structured along two parallel processes. The EU and the Russian ministry of science and education are in charge of and finance their respective parts. These parts are combined into one project, so we’re mutually dependent on each other in our research. The project also involves researchers from Georgia, Moldavia and Ukraine, as well as from EU countries. Why study these issues now? “We need to know about how these three infections spread and to avoid resistance problems in the future. Not only do they spread quickly, but more people are travelling more often between countries.” More about Professor Sönnerborg Many new EU projects at KI this spring KI is involved in many EU projects starting this spring. In 19 new collaborations, which span a wide range of fields, KI is either the coordinator or a partner. “There are, for instance, infrastructure projects and technology-development projects, as well as projects aimed at developing new methods for studying toxicity; examining the effects of exercise on cancer treatment; analysing cyber risks in hospitals; or investigating the relationship between the microbiome and cancer,” says Carolina Kristell, coordinator for some of the EU grants at KI’s Grants Office. The number of new projects changes over the years. “It naturally varies depending on how well the EU Commission’s calls fit with the research being done at KI that particular year,” she says. “But it’s still nice to see that KI has more new projects on the go than in the past few years.” Most EU projects last 4 or 5 years. These 19 new projects represent a total of approximately 9,500,000 Euro in grants for KI. “But the form of collaboration and the sums for the individual projects vary, since each call is specific,” she says. Dr Kristell identifies a clear trend in the EU’s framework programmes for research. In the past few years, the Commission has emphasised that researchers applying for grants must describe their work from a societal perspective and show how it helps to bring about improvements. KI’s grants come from many different EU funding programmes. The collaborative project CARE, for example, is funded by a grant from Health, demographic change and wellbeing, a funding scheme within the EU’s Societal Challenges programme. In total there are currently close to 200 ongoing EU projects at KI. Besides collaborative projects, KI also takes part in individual projects like Marie Sklodowska Curie (MSCA) individual fellowships and grants from the European Research Council (ERC). The figures for this year’s new programmes do not include the MSCA or the ERC programmes.