Swedish Ethical Review Authority Research Articles

Development of Humoral and Cellular Immunological Memory Against SARS-CoV-2 Despite B-Cell Depleting Treatment in Multiple Sclerosis

B-cell depleting therapies are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. The possible impact of B-cell depletion on development of humoral and cellular immunity to viruses and specifically SARS-CoV-2 has raised concerns with the COVID-19 pandemic. We here determined humoral and cellular responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs (COMBAT-MS; NCT03193866). Patients on B-cell depleting treatment, who previously had COVID-19-like symptoms, developed anti-SARS-CoV-2 antibodies and/or T-cell memory irrespective of their B-cell depletion status. Furthermore, antibody titers were similar to those observed with other treatments or controls, and anti-SARS-CoV-2 T-cells displayed functional similarity to controls producing IFN-γ and TNF. These results inform on the role of B- and T-cells in SARS-CoV-2 immunity and provide evidence that B-cell depleting therapy does not substantially abrogate SARS-CoV-2 immunological memory, in turn suggesting a low risk for reinfection and potentially responsiveness to vaccination.Funding: The COMBAT-MS study is funded through a Patient-Centered Outcomes Research Institute (PCORI) Award (MS-1511-33196), modified to include the sub-study reported herein. Additional funding was obtained from the Swedish Medical Research council (grant no. 2017-03054), Swedish Brain Foundation, NEURO Sweden, Tetra Laval, Region Stockholm, Knut and Alice Wallenberg foundation, Erling-Persson family foundation and Petrus och Augusta Hedlunds Stiftelse.Conflict of Interest: Tomas Olsson has received unrestricted grants for extended multiplesclerosis studies in relation to COVID-19 from Biogen and Merck. Not related to this manuscript, T. O. has received unrestricted grants, advisory board/ lectures from Biogen, Merck, Novartis, and Sanofi and F. P. has received research grants from Genzyme, Merck KGaA and UCB, and fees for serving as Chair of DMC in clinical trials with Parexel. All other authors declare no competing interests.Ethical Approval: Study procedures were conducted under the following ethical permits approved by the Swedish ethical review authority; COMBAT-MS: 2017/32-31/4; STOPMSII: 2009/2107-31/2; 2020 00052, with written informed consent from participants.

Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study

Background: Whether vaccine effectiveness against Coronavirus disease 2019 (Covid-19) lasts longer than 6 months is unclear.Methods: A retrospective cohort study was conducted using Swedish nationwide registries. The cohort comprised 842,974 pairs (N=1,684,958), including individuals vaccinated with 2 doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals. Cases of symptomatic infection and severe Covid-19 (hospitalization or 30-day mortality after confirmed infection) were collected from 12 January to 4 October 2021. Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, PInterpretation: Vaccine effectiveness against symptomatic Covid-19 infection wanes progressively over time across all subgroups, but at different rate according to type of vaccine, and faster for men and older frail individuals. The effectiveness against severe illness seems to remain high through 9 months, although not for men, older frail individuals, and individuals with comorbidities. This strengthens the evidence-based rationale for administration of a third booster dose.Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Swedish Ethical Review Authority (number 495/2021)

Rehabilitation Needs Following COVID-19: Five-Month Post-Discharge Clinical Follow-Up of Individuals With Concerning Self-Reported Symptoms

Background: This paper forms part of the Linköping COVID-19 Study (LinCoS) which includes all 745 individuals in Region Östergötland (RÖ) admitted to hospital for COVID-19 during March 1st – May 31st, 2020. This report aimed at describing and objectivizing the reported problems through clinical examination, and determining the required level of rehabilitation sevices according to rehabilitation complexity. Methods: In this ambidirectional cohort study, all 185 individuals who had reported concerning persisting symptoms were invited to a multi-professional clinical assessment of somatic, functional, affective, neuropsychological status and rehabilitation needs.Findings: A broad array of symptoms and signs attributable to COVID-19 involving respiratory, visual, auditory, motor, sensory and cognitive functions could be confirmed clinically at five months post-discharge in most patients. This translated into approximately 20% of survivors of the total regional cohort of hospitalised patients requiring further rehabilitative interventions at follow-up. Weakness in extremities was reported in 28·5%. On examination, clinically overt muscle weakness could be corroborated in 15 individuals (9·8%). 48% of cases reported cognitive symptoms, while the physician noted overt cognitive impairments in only 3%. Formal testing by a neuropsychologist showed that 39% performed 1.5 SD below the norm, indicating neurocognitive deficit. Fifty-five individuals (34·8%) reported new or aggravated pain. In three fourths of them, it exerted a ‘moderate’ detrimental effect or worse on their ability to work.Interpretation: Our study underscores the importance of providing extensive examination of cases with persisting problems after COVID-19, especially since symptoms such as fatigue and breathlessness are highly nonspecific, but may represent significant underlying functional impairments. Robust neurocognitive testing should be performed, as cognitive problems may easily be overlooked during routine medical consultation. Most rehabilitative interventions could be provided in a primary care setting. However, a substantial minority of patients should to be triaged to specialized rehabilitation services.Funding Information: The study was funded by the ALF grant and Region Östergötland.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: The Swedish Ethical Review Authority approved the study protocol (Dnr 2020-03029 and 2020-04443).

Fatigue after heart transplantation - a possible barrier to self-efficacy.

RationaleRecovery after heart transplantation is challenging and many heart recipients struggle with various transplant‐related symptoms, side‐effects of immunosuppressive medications and mental challenges. Fatigue has been reported to be one of the most common and distressing symptoms after heart transplantation and might therefore constitute a barrier to self‐efficacy, which acts as a moderator of self‐management.AimTo explore the prevalence of fatigue and its relationship to self‐efficacy among heart recipients 1–5 years after transplantation.Research methodAn explorative cross‐sectional design, including 79 heart recipients due for follow‐up 1–5 years after transplantation. Three different self‐assessment instruments were employed; The Multidimensional Fatigue Inventory‐19, Self‐efficacy for managing chronic disease 6‐Item Scale and The Postoperative Recovery Profile.Ethical approvalThe study was approved by the Regional Ethics Board of Lund (Dnr. 2014/670‐14/10) with supplementary approval from the Swedish Ethical Review Authority (Dnr. 2019‐02769).ResultsThe reported levels of fatigue for the whole group were moderate in all dimensions of the Multidimensional Fatigue Inventory‐19, with highest ratings in the General Fatigue sub‐scale. Those most fatigued were the groups younger than 50 years; pretransplant treatment with Mechanical Circulatory Support; not recovered or had not returned to work. Self‐efficacy was associated with the sub‐dimensions Mental Fatigue (ρ = −0·.649) and Reduced Motivation (ρ = −0·617), which explained 40·1% of the variance when controlled for age and gender.Study limitationsThe small sample size constitutes a limitation.ConclusionsThe moderate levels of fatigue reported indicate that it is not a widespread problem. However, for those suffering from severe fatigue it is a troublesome symptom that affects the recovery process and their ability to return to work. Efforts should be made to identify those troubled by fatigue to enable sufficient self‐management support.

Risk Factors for Mortality in Adult and Elderly COVID-19 Patients in a Swedish University Hospital

Background: The aim of this study was to investigate demographics, co-morbidities and death rate in hospitalized patients with confirmed COVID-19. In addition, we hypothesized that functional status, according to Clinical Frailty Scale (CFS), in patients aged 65 and older is a better predictor of poor outcome than age and co-morbidities. Methods: A total of 255 patients with COVID-19 admitted to a university hospital in Stockholm between 5th March and 28th April were randomly selected into the study and followed for 60 days. Patient data was extracted manually from the electronic health records using a standardized protocol with detailed instructions. Findings: The age of the study population ranged between 20 and 103 years, (mean age was 66 ± 17 years). Hypertension, diabetes mellitus and obesity were the three most prevalent co-morbidities. At the 60-day follow-up, 70 patients (27%) had died. In multivariate analyses, age, chronic kidney disease and previous stroke were significantly associated with death. Most fatal cases (90%) occurred in elderly patients. Among the elderly, CFS was the only predictor of death in multivariate analyses. Interpretation: This study shows that higher age, chronic kidney disease and previous stroke significantly contribute to a fatal outcome in hospitalized patients with COVID-19. In patients aged 65 years and older, the physical and functional status, as assessed by the Clinical Frailty Scale (CFS), was the strongest prognostic factor for mortality. Funding: No funding was received for this study.Declaration of Interests: The authors have no conflict of interest to report for this study.Ethics Approval Statement: The protocol of this trial was approved by the Swedish Ethical Review Authority (record number 2020-0177).

Study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT): a study protocol for a Swedish prospective multicentre cohort study.

IntroductionFirst-trimester pregnancy risk evaluation facilitates individualised antenatal care, as well as application of preventive strategies for pre-eclampsia or birth of a small for gestational age infant. A range of early intervention strategies in pregnancies identified as high risk at the end of the first trimester has been shown to decrease the risk of preterm pre-eclampsia (<37 gestational weeks). The aim of this project is to create the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) database; a nationwide database with individual patient data, including predictors recorded at the end of the first trimester and later pregnancy outcomes, to identify women at high risk of pre-eclampsia. A second aim is to link the IMPACT database to a biobank with first-trimester blood samples.Methods and analysisThis is a Swedish prospective multicentre cohort study. Women are included between the 11th and 14th weeks of pregnancy. At inclusion, pre-identified predictors are retrieved by interviews and medical examinations. Blood samples are collected and stored in a biobank. Additional predictors and pregnancy outcomes are retrieved from the Swedish Pregnancy Register. Inclusion in the study began in November 2018 with a targeted sample size of 45 000 pregnancies by end of 2021. Creation of a new risk prediction model will then be developed, validated and implemented. The database and biobank will enable future research on prediction of various pregnancy-related complications.Ethics and disseminationConfidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (Uppsala 2018-231) and national biobank approval at Uppsala Biobank (18237 2 2018 231). Results from the current as well as future studies using information from the IMPACT database will be published in peer-reviewed journals.Trial registration numberNCT03831490.

Study protocol: effects, costs and distributional impact of digital primary care for infectious diseases—an observational, registry-based study in Sweden

IntroductionThe ability to provide primary care with the help of a digital platform raises both opportunities and risks. While access to primary care improves, overuse of services and medication may...

Human ex vivo spinal cord slice culture as a useful model of neural development, lesion, and allogeneic neural cell therapy

BackgroundThere are multiple promising treatment strategies for central nervous system trauma and disease. However, to develop clinically potent and safe treatments, models of human-specific conditions are needed to complement in vitro and in vivo animal model-based studies.MethodsWe established human brain stem and spinal cord (cross- and longitudinal sections) organotypic cultures (hOCs) from first trimester tissues after informed consent by donor and ethical approval by the Regional Human Ethics Committee, Stockholm (lately referred to as Swedish Ethical Review Authority), and The National Board of Health and Welfare, Sweden. We evaluated the stability of hOCs with a semi-quantitative hOC score, immunohistochemistry, flow cytometry, Ca2+ signaling, and electrophysiological analysis. We also applied experimental allogeneic human neural cell therapy after injury in the ex vivo spinal cord slices.ResultsThe spinal cord hOCs presented relatively stable features during 7–21 days in vitro (DIV) (except a slightly increased cell proliferation and activated glial response). After contusion injury performed at 7 DIV, a significant reduction of the hOC score, increase of the activated caspase-3+ cell population, and activated microglial populations at 14 days postinjury compared to sham controls were observed. Such elevation in the activated caspase-3+ population and activated microglial population was not observed after allogeneic human neural cell therapy.ConclusionsWe conclude that human spinal cord slice cultures have potential for future structural and functional studies of human spinal cord development, injury, and treatment strategies.

Immediate parent-infant skin-to-skin study (IPISTOSS): study protocol of a randomised controlled trial on very preterm infants cared for in skin-to-skin contact immediately after birth and potential physiological, epigenetic, psychological and neurodevelopmental consequences

IntroductionIn Scandinavia, 6% of infants are born preterm, before 37 gestational weeks. Instead of continuing in the in-utero environment, maturation needs to occur in a neonatal unit with support of...

Effects of an automated digital brief prevention intervention targeting adolescents and young adults with risky alcohol and other substance use: study protocol for a randomised controlled trial

IntroductionAdolescence and young adulthood is a period in life when individuals may be especially vulnerable to harmful substance use. Several critical developmental processes are occurring in the brain, and substance...

Equal health at work? Protocol for an observational study of work organisation, workload and musculoskeletal complaints among women and men in grocery retail

IntroductionWomen generally report more work-related musculoskeletal complaints than men and have higher rates of sickness absence, even within occupations. One likely reason is that work tasks within the occupation are...

A prospective cohort study of self-reported computerised medical history taking for acute chest pain: protocol of the CLEOS-Chest Pain Danderyd Study (CLEOS-CPDS)

IntroductionManagement of acute chest pain focuses on diagnosis or safe rule-out of an acute coronary syndrome (ACS). We aim to determine the additional value of self-reported computerised history taking (CHT).Methods...

Fractures and Fall Injuries after Hospitalization for Seasonal Influenza&amp;nbsp;- A National Retrospective Cohort Study

Background: Fractures and fall injuries often lead to disability, increased morbidity and mortality. Older adults are at higher risk of influenza related complications such as pneumonia, cardiovascular events and deaths, but the risk of fractures and fall injuries is unclear. The primary objective of this study was to investigate the risk of fractures and fall injuries in older patients after admission with seasonal influenza. Methods: In this retrospective cohort study of 6604 older adults (≥65 years) admitted with seasonal influenza at Swedish hospitals (from December 1st 2015 to December 31st 2017) and 330200 age and sex matched controls from the general population and admitted for other reasons, the risk of fracture or fall injury was investigated. Findings: The mean (SD) age of the 6604 influenza patients was 80·9 (8·1) years and 50·1% were women. During the first year after hospital discharge, there were 680 (10·3%) fractures or fall injuries among the patients with influenza and 25807 (7·8%) among the controls, corresponding to incident rates of 141 (95% CI, 131-152) and 111 (95% CI, 110-112) fractures or fall injuries per 1000 person-years respectively, translating to a significantly increased risk of fracture or fall injury in a Cox regression model (hazard ratio 1·28 (95% CI, 1·19-1·38)). Interpretation: Older adults admitted with influenza diagnosis, have increased risk of fracture or fall injury during the first year after discharge, further supporting the need to prevent influenza by vaccination. Funding: The Swedish Research Council, ALF/LUA grants from the Sahlgrenska University Hospital. Declaration of Interests: Dr Axelsson has received lecture fees from Lilly, Meda/Mylan and Amgen. Prof Lorentzon has received lecture fees from Astellas, Amgen, Lilly, UCB Pharma, Radius Health, Meda/Mylan, GE-Lunar and Santax Medico/Hologic. Mr Litsne has no conflicts of interest. Ethics Approval Statement: The study was approved by the Swedish Ethical Review Authority.

Understanding the role of diabetes in the osteoarthritis disease and treatment process: a study protocol for the Swedish Osteoarthritis and Diabetes (SOAD) cohort

IntroductionOsteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. Metabolic comorbidities such as type II diabetes occur with a higher rate in people...

Patients’ experiences of early postoperative cognition and its relation to cognitive decline and inflammatory responses: a protocol for a mixed-methods study

IntroductionIn the early weeks after surgery, patients may experience cognitive changes and impaired memory and concentration—changes commonly referred to as postoperative cognitive decline. It is often the patient and/or a...