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NEWSLETTER N°4 / December 2024
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Welcome to the
4th Long COVID Newsletter!
We are pleased to present the 4th edition of our Long COVID EU project newsletter. The Long COVID project is a 4-year research project funded by the EU and coordinated by the Helsinki University Hospital (HUS). Since June 1, 2022, the consortium has been working together to understand the mechanisms of host-virus response underlying the long-term symptoms following SARS-CoV-2 infection.
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There has been a lot of research going on, and in this edition of the newsletter we look at recent research publications from the project, which provide valuable insights into the multifaceted nature of Long COVID.
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Recent Long COVID project publications
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Prognosis of patients with post-COVID-19 conditions: Prospective cohort cluster analysis at one year
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Authors: Helena Liira, Paul Garner, Antti Malmivaara, Mari Kanerva, Kirsi Kvarnström, Markku Sainio, Mikko Varonen, Mikko Venäläinen, Aki Vuokko, Jari Arokoski
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Affiliation: Clinic for Persistent Somatic Symptoms, Helsinki University Hospital, Helsinki, Finland
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Doi: 10.1016/j.jpsychores.2024.111808
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Published on 21 May 2024, Journal of Psychosomatic Research
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Methods
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A prospective, single-site cohort study consisting of administering questionnaires and clinical examinations was conducted. Patients enrolled were (i) aged≥ 18 years, (ii) referred to the Clinic for Long Term Effects of COVID-19 either from other hospital units or primary care, (iii) were diagnosed with COVID-19 ≥3 months earlier (confirmed by PCR or antigen testing), and (iv) willing to be enrolled in the study by signing the informed consent. In October 2023, the cohort had 409 patients enrolled, of whom 70.4% were women. Most (91.0%) had been treated in outpatient care during acute COVID-19, 45 (9.0%) had been hospitalised, and 18 (4.4%) had been in intensive care.
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Patient-reported outcome measures were assessed by:
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- Questionnaire on quality of life as measured by the European Health Interview Survey-Quality of Life (EUROHIS-8)
- Questionnaire on symptoms (based on the Danish Bodily Distress Syndrome (BDS) checklist)
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Patients were asked to complete the questionnaires within a week before or at their first clinic visit and then at 3, 6, and 12 months afterwards (consultations).
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At the consultation, the focus was on psychoeducation, which included giving information about the disease and its treatment and consulting the patient to empower them to overcome the disorder. This includes also the explanation of the infographic by Saunders et al. [1], presenting a biopsychosocial origin of Long COVID (LC). Furthermore, a multidisciplinary team supported the patient's treatment. All patients met with a physiotherapist, and a psychologist performed neuropsychological testing. Patients also could meet a social worker. The patients had an opportunity to attend group rehabilitation, which consisted of psychoeducation, relaxation exercises, and group discussions. For some patients, online therapies were suggested for managing insomnia, anxiety, or long-term physical symptoms, for example.
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With the collected data, a cluster analysis was performed. The aim was to identify both clusters of patients with similar symptom profiles as well as clusters of co-occurring symptoms (symptom clusters).
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Results
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This hierarchical cluster analysis divided the patients with LC into three clusters, with an average of 11 (Cluster-11), 17 (Cluster-17), or 25 (Cluster-25) symptoms of a list of 35 symptoms at baseline (before consultations took place). Fatigue and cognitive complaints were typical in all clusters. Female sex and more than one comorbidity were the significant determinants of belonging to the clusters with more symptoms, Cluster-17 and Cluster-25.
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In addition, four symptom-based clusters were defined:
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- Fatigue and cognitive complaints, lack of energy, headache, exhaustion from everyday activities, and memory problems
- Pain, trouble sleeping, palpitations, and other symptoms
- Gastrointestinal symptoms
- Emotion-related symptoms
For symptom clusters, in addition to female sex and comorbidities, anxiety, use of antidepressants, BMI, and smoking were among the determinants of the symptom clusters.
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--> In the one-year follow-up, the average number of symptoms decreased from 20.3 to 15.5, and the quality of life improved, regardless of the number of symptoms at baseline in this cohort of tertiary care patients with LC.
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Conclusion
Four patient clusters based on symptoms were identified in the LC cohort. Prognosis was favorable across all clusters, with symptom reduction and improved quality of life observed. Female sex, comorbidities, BMI, and mental-health related variables predicted higher symptom burden, suggesting multifactorial origins of LC.
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[1] C. Saunders, S. Sperling, E. Bendstrup, A new paradigm is needed to explain long COVID, Lancet Respir. Med. 11 (2) (2023) e12–e13. Epub 20230105, https://doi.org/10.1016/S2213-2600(22)00501-X.
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Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case
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Authors: Lee Tatham,1,2 Anja Kipar,3,4 Jo Sharp,1,2 Edyta Kijak,1,2 Joanne Herriott,1,2 Megan Neary,1,2 Helen Box,1,2 Eduardo Gallardo Toledo,1,2 Anthony Valentijn,1,2 Helen Cox,1,2 Henry Pertinez,1,2 Paul Curley,1,2 Usman Arshad,1,2 Rajith Kumar Reddy Rajoli,1,2 Steve Rannard,2,5 James P. Stewart,4 Andrew Owen1,2
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1 Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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2 Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, Liverpool, United Kingdom
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3 Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
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4 Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
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5 Department of Chemistry, University of Liverpool, Liverpool, United Kingdom
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Doi: 10.1128/spectrum.03916-23
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Published on 16 July 2024, Microbiology Spectrum
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Introduction
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Ronapreve (REGN-COV2) is a combination medicine used for the treatment and prevention of COVID-19 and is composed of two monoclonal antibodies. It was shown, among other monoclonal antibodies, to be effective against pre-Omicron SARS-CoV-2 variants in post-exposure prophylaxis, early treatment, and in the treatment of seronegative patients with severe COVID-19. However, with the successive emergence of Omicron sub-lineages, all approved monoclonal antibodies have lost or decreased efficiency. The purpose of this study was to investigate the ability of monoclonal antibody combinations to mitigate pulmonary and neurological manifestations of SARS-CoV-2 infection using Ronapreve and the Delta variant as a paradigm for activity against a susceptible variant.
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Methods
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This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies. Mice were randomly assigned into groups and infected with either the SARS-CoV-2 Delta variant or the Omicron variant. After 24 hours, mice from each group were treated with a single dose of either the saline control or Ronapreve. All animals were weighed and monitored daily throughout the experiment.
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At 4 and 6 days following infection, groups of mice were sacrificed. Lungs and nasal turbinants were collected for further analysis.
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In a separate study, utilising a comparable experimental design for infection with the SARS-CoV-2 Delta variant and the Ronapreve treatment approach, viral replication in mice lung and brain was quantified using qRT-PCR. Lungs and brains were collected for further analyses after the mice had been sacrificed.
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Results
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Effect of Ronapreve on viral replication
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qRT-PCR demonstrated that Ronapreve reduced viral replication in lung and nasal turbinates, 4 and 6 days post-infection (dpi), for the Delta variant but not the Omicron variant. In Delta-infected mice, Ronapreve also blocked viral replication in the brain and lung.
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Effect of Ronapreve on pulmonary changes and viral spread to the brain
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Productive viral infection and any associated pathological changes were determined in the nose turbinates and lungs of all mice at both 4 and 6 dpi and confirmed an identical spectrum of viral target cells in nasal mucosa and lung for both virus isolates. In Delta-infected mice treated with Ronapreve, viral presence was reduced in both nasal and lung tissues compared to the saline-treated group. Lung infection was limited to small, scattered patches with less severe histological changes, indicating Ronapreve's efficacy in limiting viral spread and tissue damage. Omicron-infected mice treated with Ronapreve displayed a pattern similar to untreated Omicron mice, with mild infection confined to limited areas of the lung and minimal nasal tissue infection.
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In saline-treated mice, Delta was found to spread to the brain, particularly in neurones and olfactory tissues, likely due to viral movement through the olfactory pathway. Brain infection was observed in most Delta-infected mice, often accompanied by mild inflammation. Omicron did not show the same capacity for brain infection, with no viral presence detected in olfactory or brain tissues. Ronapreve prevented brain infection in Delta-infected mice at both time points, with no viral antigen detected in the brain or olfactory tissues of Ronapreve-treated animals. This suggests Ronapreve's effectiveness in limiting Delta’s neuroinvasive capabilities, whereas Omicron did not demonstrate such a spread.
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Conclusion
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The current study made use of a reliable murine SARS-CoV-2 infection model to confirm and characterise the effect of Ronapreve on established infections with the Delta variant and confirm its ineffectiveness against Omicron. Indeed, it provides increased certainty in the absence of effect against Omicron, complementing in vitro neutralisation data for this variant. However, it also confirms efficacy for the Delta variant and provides evidence that monoclonal antibodies might limit the virus spread into the brain when deployed against susceptible variants.
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Furthermore, the results of this study suggest that Ronapreve treatment post-exposure inhibits viral spread into the brain of the Delta variant. Whether infection of the brain is completely blocked or only substantially reduced requires further investigations, particularly at the molecular level.
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Functioning of post-COVID-19 patients: a cross-sectional study at the outpatient clinic for long-term effects
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Authors: Sanna Stålnacke,1, Helena Liira,1, Velina Vangelova-Korpinen,1, Hélène Virrantaus,1, Mari Kanerva,1,2, Kirsi Kvarnström,1, Markku Sainio,1, Antti Malmivaara,3, Aki Vuokko,4, Mikko Varonen,1, Mikko Venäläinen,5 and Jari Arokoski,6
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1 Outpatient Clinic for Persistent Symptom Rehabilitation, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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2 Turku University Hospital and University, Turku, Finland
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3 Finnish Institute for Health and Welfare, Orton Orthopaedic Hospital, University of Helsinki, Helsinki, Finland
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4 Finnish Institute of Occupational Health, Helsinki, Finland
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5 Department of Medical Physics, University of Turku, Turku, Finland
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6 Department of Internal Medicine and Rehabilitation, Division of Rehabilitation, Helsinki University Hospital and Helsinki University, Helsinki, Finland
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Doi: 10.1080/02813432.2024.2410986
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Published on 03 October 2024, Scandinavian Journal of Primary Care
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Introduction
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Long COVID (LC) can affect people’s functioning in many ways. So far, descriptions of functioning in COVID-19 have mainly focused on patients after hospitalisation or intensive care.
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The current study aimed to evaluate patients after mild or moderate primary COVID-19 infection referred from primary healthcare to gain a deeper understanding of their needs and the challenges they face in terms of functioning and to derive insights that would guide their rehabilitation process. The functioning of LC patients was studied at Finland’s only LC clinic. Because patients with LC have experienced strong subjective symptoms and limitations in their functioning, it is hypothesised that they would exhibit significant reductions in physical functioning and Health-Related Quality of Life (HRQoL) compared with subjects without LC symptoms.
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Methods
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This cross-sectional study consisted of 442 patients with LC referred to rehabilitation at the HUS Outpatient Clinic for the Long-Term Effects of COVID-19 and 198 controls without LC. Functioning was assessed with a questionnaire including the World Health Organisation Disability Assessment Schedule 2.0 (WHODAS 2.0).
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Patients underwent physical testing, including a hand grip strength test (HGST) and a 6-minute walking test (6MWT). Lifestyle was assessed by questionnaire, and comorbidities were collected as ICD-10 codes.
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an assessment of patient-reported outcome measures by the questionnaire WHODAS 2.0. Data on comorbidities and depressive medications (yes/no) and confirmed hospitalisation and intensive care during acute COVID-19 (yes/no) were collected electronically from the patients’ healthcare data during the previous five years.
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a clinical evaluation, which was conducted by a physician. The physician evaluated whether symptoms could be explained by the patient’s known comorbidities. In addition, a physiotherapist measured the blood pressure.
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a physical function test. The testing was conducted under the supervision of the clinic’s physiotherapist and encompassed various assessments. These included measuring dominant hand grip strength test (HGST). The measuring of HGST was performed three times, and the value of the best effort was taken into the statistical analysis. In addition, a 6-minute walking test (6MWT) was conducted.
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Results
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When comparing the characteristics of individuals with LC to control subjects, there were no significant differences in terms of age, gender, height, mass, BMI, and systolic blood pressure. Further, the LC group had a lower employment rate and fewer participants engaging in weekly vigorous exercise. Living alone and smoking habits did not differ significantly between groups.
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The LC group had a higher mean number of comorbidities and greater use of depression medications. Hospitalisations and intensive care admissions during acute COVID-19 were more common among those with LC. Specific health conditions, including asthma, anxiety, hypertension, depression, migraine, and hypothyroidism, were more prevalent in the LC group.
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The LC group experienced significantly greater impairments across all domains of functionality, as measured by WHODAS 2.0. They reported moderate to severe limitations, particularly in life activities and participation. LC participants rated their functional ability at an average of 4.8 on a 0–10 scale, compared to 8.7 for controls, indicating substantial functional impairments.
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The LC group demonstrated a reduced walking distance in the 6MWT Test compared to controls, while no significant difference was observed in HGST between the groups.
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Conclusion
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Patients with LC had significantly reduced functioning based on WHODAS 2.0 scores and the 6MWT results. Comorbidities, anxiety, depression, and smoking were associated with moderate or severe limitations in functioning. Findings support that LC is multifactorial and requires a holistic approach to rehabilitation.
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Peer-reviewed scientific publications
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1. Stålnacke, S.; et al. Functioning of post-COVID-19 patients: a cross-sectional study at the outpatient clinic for long-term effects. Scand J Prim Health Care. 2024. doi: 10.1080/02813432.2024.2410986
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2. Tatham, L.; et al. Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case. Microbiol Spectr. 2024. doi: 10.1128/spectrum.03916-23
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4. Virrantaus, H.; et al. Prognosis of patients with long COVID symptoms: a protocol for a longitudinal cohort study at a primary care referred outpatient clinic in Helsinki, Finland. BMJ Open. 2023. doi: 10.1136/bmjopen-2023-072935
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5. De Neck, S.; et al. The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections. Viruses. 2023. doi: 10.3390/v15081637
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6. Kettunen, P.; et al. SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase. Journal of Virology. 2023. doi: 10.1128/jvi.00144-23
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These publications are also available in the Long COVID Community on Zenodo, a multi-disciplinary open repository maintained by CERN. Furthermore, they can be found on the Long COVID website as well.
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Introducing our Collaboration Partner Lifelines
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Lifelines is a unique biobank and large multi-generational cohort study based in the northern Netherlands, with 167,000 participants. It collects extensive health data, including genetic, biological, and lifestyle information, to support research on the prevention and treatment of multifactorial diseases. By offering rich, longitudinal data and biosamples, Lifelines enables researchers worldwide to study the underlying causes of diseases, especially those with complex interactions such as Long COVID. During the pandemic, Lifelines has set up a COVID-19 cohort to assess the psychological and societal impacts of the COVID-19 pandemic and investigate potential risk factors for COVID-19 within the Lifelines prospective population cohort. Thus, Lifelines has pre-infection data on symptom levels, which is a valuable contribution to the studies of the Long COVID EU project. In the EU project, pathophysiological mechanisms of the Long COVID syndrome are studied by using the data and biomaterials collected in the Lifelines COVID-19 cohort before and during the pandemic in repeated regular measurements.
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For more information see:
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In-person consortium meeting in Rovereto
In June 2024, the Long COVID consortium held its second biannual consortium meeting in Rovereto, Italy, hosted by the Long COVID partner Chino. The event took place over two days, allowing for comprehensive discussions and strengthening collaboration among the team members working across Europe.
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Day 1: Focus on scientific work
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The 10th of June marked the start of the hybrid session of the meeting. The day began with a warm welcome from the coordinator HUS and the host Chino, setting an enthusiastic tone for the day’s proceedings. The scientific presentations that followed highlighted the consortium’s progress on multiple fronts. WP2 and WP3 focused on the biomechanistic studies, whereas WP1 and WP4 presented their progress regarding the clinical cohort studies. After a well-deserved lunch break, the consortium reconvened for non-scientific presentations, such as data management, general project management, ethical issues, and dissemination & communication.
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The evening brought a change of pace, with the team enjoying a guided tour at the Marzadro Distillery and a fantastic dinner with Northern Italian food. This relaxed setting provided an opportunity for informal discussions, fostering stronger connections within the consortium.
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Day 2: Exploitation Workshop and next steps
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The second day began with an interactive exploitation workshop, exploring ways to share our results with the public and maximise the impact of our research. After a lunch break, the consortium discussed the next steps and future endeavours.
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At the end of the meeting, participants left with a renewed sense of purpose and commitment to the Long COVID mission. With these updates, the Long COVID project continues to make significant strides in advancing our understanding of Long COVID.
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1st Long COVID Webinar
On May 29, the Long COVID consortium hosted an insightful webinar titled “Unlocking the Mysteries of Long COVID: How EU Funding is Paving the Way for Recovery”. With 51 participants from different perspectives (company/institution, patient association/organisation, private/patient/relatives), the webinar offered a valuable opportunity to present the Long COVID research and to exchange.
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Does the COVID-19 virus infect our brain?
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The webinar started with a presentation from Giuseppe Balistreri (UH), who is a Long COVID project partner with his research team, half in Finland and half in Australia. Titled “Does the COVID-19 virus infect our brain?” Giuseppe Balistreri provided insights into his research to investigate if the COVID-19 virus can infect the human brain and, if so, if this is leading to the neurological symptoms of the LCS.
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What is the Long COVID project about?
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The second talk was given by the Long COVID Project coordinator, Helena Liira from HUS, with the title “What is the Long COVID Project about?”. She gave the audience a holistic overview of the project and gave insights into the Long COVID Project journey.
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Insights into the Finnish registry study
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The webinar concluded with a presentation by Velina Vangelova-Korpinen (HUS). Her talk, titled “Insights into the Finnish registry study”, gave exclusive insights into the Finnish registry study, which is part of the Long COVID project. She explained the study objectives, methods and presented preliminary results.
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With this webinar, the Long COVID consortium provided a dynamic platform for discussing cutting-edge research and clinical insights from the project.
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Upcoming Webinar: Transforming Healthcare: Insights into the Long COVID EU Project and the Role of AI in Patient Care
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On the 17th of December, the Long COVID consortium will host its 2nd webinar with the title "Transforming Healthcare: Insights into the Long COVID EU Project and the Role of AI in Patient Care". Thus, this webinar will focus on how artificial intelligence is transforming the health care sector.
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- Introduction into the LongCOVID project (Helena Liira, HUS)
- How could AI be used for personalised medicine? (Giampaolo Pileggi, NEC Laboraties)
- Trust in AI (Giampaolo Pileggi, NEC Laboraties)
- Impact of the AI Act on the healthcare sector (Francesca Carraro; CHINO)
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Call for Participants - Cohort Study with Digital Intervention in Basel, Switzerland
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Are you or someone you know affected by Long COVID? Are you or the person affected interested in participating in a study in Basel (Switzerland)?
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Our project partners from the University Hospital Basel (USB) are recruiting study participants. They have developed a digital treatment concept for Long COVID patients and are looking for study participants to evaluate its effectiveness. Specific topics of this treatment include energy management, sleep and stress management, but also physiotherapeutic instructions and mental health, acceptance and self-care. It is possible to participate entirely remote.
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Are you interested? Then contact our partner directly at dilcos@usb.ch.
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Project Coordinator
Helena Liira
Helsinki University Hospital
Helsinki, Finland
helena.liira@hus.fi
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Mari Kanerva (Clinical Studies)
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Helsinki University Hospital
Helsinki, Finland
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Giuseppe Balistreri (Mechanistic Studies)
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Project Coordinator-Support
Riikka Paasikivi
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Communication & Dissemination Leader
Lena Schleicher
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lena.schleicher@steinbeis-europa.de
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Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HaDEA). Neither the European Union nor HaDEA can be held responsible for them. This project has received funding from the European Union's Horizon Europe reserach and innovation programme under grand agreement No 101057553. This work was supported by the Swiss State for Education, Research and Innovation (SERI) under contract number 22.00094.
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