The Karolinska KI/K COVID-19 Immune Atlas: An open resource for immunological research and educational purposes.

The Karolinska KI/K COVID-19 Immune Atlas project was conceptualized in March 2020 as a part of the academic research response to the developing SARS-CoV-2 pandemic. The aim was to rapidly provide a curated dataset covering the acute immune response towards SARS-CoV-2 infection in humans, as it occurred during the first wave. The Immune Atlas was built as an open resource for broad research and educational purposes. It contains a presentation of the response evoked by different immune and inflammatory cells in defined naïve patient-groups as they presented with moderate and severe COVID-19 disease. The present Resource Article describes how the Karolinska KI/K COVID-19 Immune Atlas allow scientists, students, and other interested parties to freely explore the nature of the immune response towards human SARS-CoV-2 infection in an online setting.

Simultaneous Pancreas-Kidney Transplant From Donors After Brain Death vs Donors After Circulatory Death: A Single-Center Follow-up Study Over 3 Decades.

BACKGROUND: Despite an increase in the number of pancreas transplants in the Scandiatransplant region in the last decade, there continues to be a gap between demand and supply of transplantable organs. This imbalance has encouraged the transplant community to consider new sources of grafts, such as the reintroduction of donors after circulatory death (DCD) who were the standard donors in our center before 1988. MATERIAL AND METHODS: In this long-term follow-up study, we compare 44 consecutive, simultaneous pancreas kidney transplants performed at Karolinska University Hospital between 1986 and 1991: 21 patients received DCD grafts and 23 received grafts from donors after brain death. RESULTS: Both groups had similar donor and recipient characteristics, but cold ischemia times were significantly shorter in the DCD group. Warm ischemia times were very short compared with other studies on DCDs. Patient and graft survival rates were similar in both groups. CONCLUSION: This study suggests that controlled DCD pancreas and kidney grafts transplanted simultaneously can be a feasible option for reducing organ shortage without any negative impact on the long-term results.

Two for one? Effects of a couples intervention on partners of persons with Type 2 diabetes: a randomized controlled trial.

AIMS: To compare the outcomes of partners who participated in a telephone couples behavioural intervention to improve glycaemic control in persons with Type 2 diabetes with those of untreated partners of participants in an individual intervention or education; to explore 'ripple effects', i.e. positive behaviour changes seen in untreated partners. METHODS: The Diabetes Support Project was a three-arm randomized telephone intervention trial comparing outcomes of couples calls (CC), individual calls (IC) and diabetes education calls (DE). Couples included one partner with Type 2 diabetes and HbA1c ≥ 58 mmol/mol (7.5%). All arms received self-management education (two calls). CC and IC arms participated in 10 additional behaviour change calls. CC included partners, emphasizing partner communication, collaboration and support. Blinded assessments were performed at 4, 8 and 12 months. Partner outcomes were psychosocial (diabetes distress, relationship satisfaction, depressive symptoms), medical (BMI, blood pressure) and behavioural (fat intake, activity). RESULTS: Partners' (N = 268) mean age was 55.8 years, 64.6% were female and 29.9% were from minority ethnic groups. CC (vs. IC and DE) partners had greater reductions in diabetes distress, greater increases in marital satisfaction (4 and 8 months), and some improvements in diastolic BP. There were no consistent differences among arms in other outcomes. There was no evidence of a dietary or activity behaviour ripple effect on untreated partners, i.e. comparing partners in the IC and DE arms. CONCLUSIONS: A collaborative couples intervention resulted in significant improvements in partner diabetes distress and relationship satisfaction. There were no consistent effects on behavioural or medical partner outcomes, and no evidence of diet or activity behaviour ripple effects, suggesting that partners should be targeted directly to achieve these changes. (Clinical Trial Registry No: NCT01017523).

Cell-Mediated Immune Responses and Immunopathogenesis of Human Tick-Borne Encephalitis Virus-Infection.

Tick-borne encephalitis virus (TBEV) is a flavivirus that belongs to the Flaviviridae family. TBEV is transmitted to humans primarily from infected ticks. The virus causes tick-borne encephalitis (TBE), an acute viral disease that affects the central nervous system (CNS). Infection can lead to acute neurological symptoms of significant severity due to meningitis or meningo(myelo)encephalitis. TBE can cause long-term suffering and has been recognized as an increasing public health problem. TBEV-affected areas currently include large parts of central and northern Europe as well as northern Asia. Infection with TBEV triggers a humoral as well as a cell-mediated immune response. In contrast to the well-characterized humoral antibody-mediated response, the cell-mediated immune responses elicited to natural TBEV-infection have been poorly characterized until recently. Here, we review recent progress in our understanding of the cell-mediated immune response to human TBEV-infection. A particular emphasis is devoted to studies of the response mediated by natural killer (NK) cells and CD8 T cells. The studies described include results revealing the temporal dynamics of the T cell- as well as NK cell-responses in relation to disease state and functional characterization of these cells. Additionally, we discuss specific immunopathological aspects of TBEV-infection in the CNS.

Implementation of the integrated palliative care outcome scale in acute care settings - a feasibility study.

OBJECTIVE: Although hospitals have been described as inadequate place for end-of-life care, many deaths still occur in hospital settings. Although patient-reported outcome measures have shown positive effects for patients in need of palliative care, little is known about how to implement them. We aimed to explore the feasibility of a pilot version of an implementation strategy for the Integrated Palliative care Outcome Scale (IPOS) in acute care settings. METHOD: A strategy, including information, training, and facilitation to support the use of IPOS, was developed and carried out at three acute care units. For an even broader understanding of the strategy, it was also tested at a palliative care unit. A process evaluation was conducted including collecting quantitative data and performing interviews with healthcare professionals.ResultFactors related to the design and performance of the strategy and the context contributed to the results. The prevalence of completed IPOS in the patient's records varied from 6% to 44% in the acute care settings. At the palliative care unit, the prevalence in the inpatient unit was 53% and the specialized home care team 35%. The qualitative results showed opposing perspectives concerning the training provided: Related to everyday work at the acute care units and Nothing in it for us at the palliative care unit. In the acute care settings, A need for an improved culture regarding palliative care was identified. A context characterized by A constantly increasing workload, a feeling of Constantly on-going changes, and a feeling of Change fatigue were found at all units. Furthermore, the internal facilitators and the nurse managers' involvement in the implementation differed between the units.Significance of the resultsThe feasibility of the strategy in our study is considered to be questionable and the components need to be further explored to enhance the impact of the strategy and thereby improve the use of IPOS.

Implementation of national palliative care guidelines in Swedish acute care hospitals: A qualitative content analysis of stakeholders' perceptions.

In high-income countries a large proportion of all deaths occur in hospitals. A common way to translate knowledge into clinical practice is developing guidelines for different levels of health care organisations. During 2012, national clinical guidelines for palliative care were published in Sweden. Later, guidance for palliative care was issued by the National Board of Health and Welfare. The aim of this study was two-fold: to investigate perceptions regarding these guidelines and identify obstacles and opportunities for implementation of them in acute care hospitals. Interviews were conducted with local politicians, chief medical officers and health professionals at acute care hospitals. The Consolidated Framework for Implementation Research was used in a directed content analysis approach. The results showed little knowledge of the two documents at all levels of the health care organisation. Palliative care was primarily described as end of life care and only few of the participants talked about the opportunity to integrate palliative care early in a disease trajectory. The environment and culture at hospitals, characterised by quick decisions and actions, were perceived as obstacles to implementation. Health professionals' expressed need for palliative care training is an opportunity for implementation of clinical guidelines. There is a need for further implementation of palliative care in hospitals. One option for further research is to evaluate implementation strategies tailored to acute care.

Vitamin D treatment modulates immune activation in cystic fibrosis.

Persistent inflammatory response in cystic fibrosis (CF) airways is believed to play a central role in the progression of lung damage. Anti-inflammatory treatment may slow lung disease progression, but adverse side effects have limited its use. Vitamin D has immunoregulatory properties. We randomized 16 CF patients to receive vitamin D2, vitamin D3 or to serve as controls, and investigated the effect of vitamin D supplementation on soluble immunological parameters, myeloid dendritic cells (mDCs) and T cell activation. Three months of vitamin D treatment were followed by two washout months. Vitamin D status at baseline was correlated negatively with haptoglobin, erythrocyte sedimentation rate and immunoglobulin A concentration. Total vitamin D dose per kg bodyweight correlated with the down-modulation of the co-stimulatory receptor CD86 on mDCs. Vitamin D treatment was associated with reduced CD279 (PD-1) expression on CD4+ and CD8+ T cells, as well as decreased frequency of CD8+ T cells co-expressing the activation markers CD38 and human leucocyte antigen D-related (HLA-DR) in a dose-dependent manner. There was a trend towards decreased mucosal-associated invariant T cells (MAIT) cell frequency in patients receiving vitamin D and free serum 25-hydroxyvitamin D (free-s25OHD) correlated positively with CD38 expression by these cells. At the end of intervention, the change in free-s25OHD was correlated negatively with the change in CD279 (PD-1) expression on MAIT cells. Collectively, these data indicate that vitamin D has robust pleiotropic immunomodulatory effects in CF. Larger studies are needed to explore the immunomodulatory treatment potential of vitamin D in CF in more detail.

MAIT cells reside in the female genital mucosa and are biased towards IL-17 and IL-22 production in response to bacterial stimulation.

The female genital tract (FGT) mucosa is a critically important site for immune defense against microbes. Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population that recognizes microbial riboflavin metabolite antigens in an MR1-dependent manner. The role of MAIT cells in the FGT mucosa is unknown. Here, we found that MAIT cells and MR1+ antigen-presenting cells were present in the upper and lower FGT, with distinct tissue localization of MAIT cells in endometrium vs. cervix. The MAIT cells from the FGT and blood displayed a distinct phenotype with expression of interleukin (IL)-18Rα, CD127, α4ß7, PD-1, as well as the transcription factors promyelocytic leukemia zinc finger (PLZF), RORγt, Helios, Eomes, and T-bet. Their expression levels of PLZF and Eomes were lower in the FGT compared with blood. When stimulated with Escherichia coli, MAIT cells from the FGT displayed a bias towards IL-17 and IL-22 expression, whereas blood MAIT cells produced primarily IFN-γ, TNF, and Granzyme B. Furthermore, both FGT- and blood-derived MAIT cells were polyfunctional and contributed to the T-cell-mediated response to E. coli. Thus, MAIT cells in the genital mucosa have a distinct IL-17/IL-22 profile and may have an important role in the immunological homeostasis and control of microbes at this site.

Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial.

BACKGROUND/OBJECTIVES: Vitamin D insufficiency in cystic fibrosis is common. Vitamin D3 is currently preferred over D2. We aimed to study the efficacy of vitamin D2 and D3 at increasing serum 25-hydroxyvitamin D (s25OHD) concentrations and their effect on respiratory health in cystic fibrosis. SUBJECTS/METHODS: Sixteen CF patients were randomized to receive vitamin D2 or D3 or to serve as controls. The starting dose of 5000 IU (<16 years old) or 7143 IU/day (⩾16 years old) was further individually adjusted. Three months of intervention were followed by two of washout (ClinicalTrials.gov NCT01321905). RESULTS: To increase s25OHD, the mean daily dose of vitamin D2 and D3 had to be increased up to 15650 and 8184 IU, respectively. The combined group of vitamin D2 and D3 treated patients decreased plasma IL-8 (P<0.05). Patients provided vitamin D3 improved FVC at the end of the trial (P<0.05). Change in s25OHD was positively correlated with changes in the adult Quality-of-Life respiratory score at the end of supplementation (P=0.006, r=0.90), and with changes in FEV1 (P=0.042, r=0.62) and FVC (P=0.036, r=0.63) at one month of washout. CONCLUSIONS: Vitamin D supplementation may contribute to reduced inflammation and improved lung function in CF.

Invariant natural killer T cells developing in the human fetus accumulate and mature in the small intestine.

Invariant natural killer T (iNKT) cells are CD1d-restricted immunoregulatory lymphocytes that share characteristics of both the innate and adaptive immune systems. Although it has been reported that iNKT cells are present in the human fetal thymus, it is currently unknown how they distribute, differentiate, and function in fetal peripheral lymphoid and non-lymphoid organs. Here, we show that functional human fetal iNKT cells develop and differentiate in a tissue-specific manner during the second trimester. Fetal iNKT cells accumulated in the small intestine, where they gained a mature phenotype and mounted robust interferon (IFN)-γ responses. In contrast, iNKT cells in the spleen and mesenteric lymph nodes were less frequently detected, less differentiated, mounted poor IFN-γ responses, but proliferated vigorously upon stimulation with α-galactosylceramide. These data demonstrate that fetal iNKT cells can differentiate and acquire potent effector functions in utero before the establishment of the commensal microflora.

Insight into the sharing of medical images: physician, other health care providers, and staff experience in a variety of medical settings.

BACKGROUND: Scant knowledge exists describing health care providers' and staffs' experiences sharing imaging studies. Additional research is needed to determine the extent to which imaging studies are shared in diverse health care settings, and the extent to which provider or practice characteristics are associated with barriers to viewing external imaging studies on portable media. OBJECTIVE: This analysis uses qualitative data to 1) examine how providers and their staff accessed outside medical imaging studies, 2) examine whether use or the desire to use imaging studies conducted at outside facilities varied by provider specialty or location (urban, suburban, and small town) and 3) delineate difficulties experienced by providers or staff as they attempted to view and use imaging studies available on portable media. METHODS: Semi-structured interviews were conducted with 85 health care providers and medical facility staff from urban, suburban, and small town medical practices in North Carolina and Virginia. The interviews were audio recorded, transcribed, then systematically analyzed using ATLAS.ti. RESULTS: Physicians at family and pediatric medicine practices rely primarily on written reports for medical studies other than X-rays; and thus do not report difficulties accessing outside imaging studies. Subspecialists in urban, suburban, and small towns view imaging studies through internal communication systems, internet portals, or portable media. Many subspecialists and their staff report experiencing difficulty and time delays in accessing and using imaging studies on portable media. CONCLUSION: Subspecialists have distinct needs for viewing imaging studies that are not shared by typical primary care providers. As development and implementation of technical strategies to share medical records continue, this variation in need and use should be noted. The sharing and viewing of medical imaging studies on portable media is often inefficient and fails to meet the needs of many subspeciality physicians, and can lead to repeated imaging studies.

Challenges of immediate newborn care in maternity units in Lagos, Nigeria: an observational study.

Substandard newborn care has been identified as a major contributor to the estimated annual 4 million neonatal deaths and 1 million fresh stillbirths. Low-income countries, including Nigeria account for more than 95% of all cases. A cross-sectional comparative study utilising non-participant observation methods was used to study perinatal care at two maternity centres in Lagos, Nigeria. Data on 63 mother-baby pairs were included in the study. Two stillbirths and two early neonatal deaths occurred during the study period, equally divided between the two hospitals. The partograph, a crucial tool for monitoring progress of labour, was in use in 77.4% vs 50% of cases at the two centres. The only interventions utilised for the prevention of hypothermia were drying and covering newborns with towels. Hygiene routines were poor and caring procedures did not demonstrate adequate knowledge related to a newborn's health. An enabling environment and supportive supervision is urgently required.

NK cells and CD1d-restricted NKT cells respond in different ways with divergent kinetics to IL-2 treatment in primary HIV-1 infection.

Cytokine immunotherapy is being evaluated as adjunct treatment in infectious diseases. The effects on innate and adaptive immunity in vivo are insufficiently known. Here, we investigate whether combination treatment with antiretroviral therapy (ART) and Interleukin-2 (IL-2) of patients with primary HIV-1 infection induces sustained increases in circulating NKT cell and NK cell numbers and effector functions and investigate how changes are coordinated in the two compartments. Patients with primary HIV-1 infection starting ART were analyzed for numbers, phenotype and function of NKT cells, NK cells and dendritic cells (DC) in peripheral blood before, during and after IL-2 treatment. NKT cells expanded during IL-2 treatment as expected from previous studies. However, their response to α-galactosyl ceramide antigen were retained but not boosted. Myeloid DC did not change their numbers or CD1d-expression during treatment. In contrast, the NK cell compartment responded with rapid expansion of the CD56(dim) effector subset and enhanced IFNγ production. Expansions of NKT cells and NK cells retracted back towards baseline values at 12 months after IL-2 treatment ended. In summary, NKT cells and NK cells respond to IL-2 treatment with different kinetics. Effects on cellular function are distinct between the cell types and the effects appear not to be sustained after IL-2 treatment ends. These results improve our understanding of the effects of cytokine immunotherapy on innate cellular immunity in early HIV-1 infection.

Can ECOPATH with ECOSIM enhance models of radionuclide flows in food webs? An example for 14C in a coastal food web in the Baltic Sea.

In this study it was evaluated whether the ECOPATH with ECOSIM software could be used as a platform to facilitate the construction of models and study of transport and accumulation of radionuclides in aquatic food webs. The evaluation was based upon a food web model of carbon (C) and carbon-14 ((14)C) flow for a coastal area in the Baltic Sea, the ECOPATH, the ECOSIM and the ECOTRACE models. The original carbon flows and assumptions were easily incorporated into the ECOPATH and ECOSIM modelling environment. The new model was also well suited to drive a (14)C flow model (ECOTRACE) for each of the organisms included. ECOTRACE estimated steady-state concentrations of (14)C that were between 73 and 142% of the original flows. The results clearly show that there is great potential for a successful development of this approach for integrating scientific knowledge about food webs and radioecological models for aquatic systems.

ABO-incompatible kidney transplantation and rituximab.

We have designed a protocol for ABO-incompatible kidney transplantations based on antigen-specific immunoadsorption rather than plasmapheresis to remove anti-A or anti-B antibodies and with a Prograf/Cellcept/prednisolone protocol using rituximab rather than splenectomy to prevent rebound antibodies. Twelve patients have successfully received transplants with this protocol. The ABO-antibodies were readily removed by the antigen-specific immunoadsorption and maintained at a low-level posttransplantation. There were no side effects. All patients have normal renal transplant function with a follow-up of 1 to 34 months.

Metabolic assessment after simultaneous pancreas-kidney transplantation.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has become a standard therapy for patients with type 1 diabetes and end-stage renal disease. We analyzed metabolic data in this clinical setting under tacrolimus- versus cyclosporine microemulsion (ME)-based immunosuppressive therapy. PATIENTS AND METHODS: We analyzed 205 patients enrolled in the Euro-SPK001 study for fasting blood glucose, fasting C peptide, glycated hemoglobin (HbA(1c)), blood lipids (total cholesterol and triglycerides), and pancreatic enzymes at regular intervals during the study. We compared blood pressure values with target levels for diabetic patients published by the European Society for Hypertension. RESULTS: Throughout the study, HbA(1c) and fasting C peptide levels were within the normal range in the two groups. Fasting blood glucose was higher during the first 2 months posttransplant in the tacrolimus group than in the cyclosporine-ME group, but no differences were seen thereafter. From month 2 posttransplant, mean levels of total cholesterol were significantly lower among patients receiving tacrolimus than those in the cyclosporine-ME group. In addition, patients receiving cyclosporine-ME showed serologic features of mild pancreatitis with elevated blood amylase and lipase levels during the first 6 months posttransplant. The two regimens were comparable with respect to hypertension, but target levels were reached in only 50% of the patients. CONCLUSION: Except for lipid profiles, no major differences in metabolic effects or blood pressure control were observed among SPK transplant patients receiving immunosuppression based on tacrolimus versus cyclosporine-ME. In view of the potential risk of hypertension, antihypertensive strategies should be implemented for all patients.

Importance of the Gal alpha1-3 Gal antigen in discordant islet xenotransplantation: immunosuppression, which inhibits porcine islet xenograft rejection in ordinary mice, is equally effective in Gal-knockout mice.

BACKGROUND: Islet xenotransplantation will most likely be performed in diabetic patients treated with immunosuppressive drugs. The importance of the galactosyl alpha(1-3) galactose (Galalpha1-3Gal) antigen in immunosuppressed islet xenograft recipients has not been studied. METHODS: Fetal porcine islet-like cell clusters (ICCs) were transplanted into the renal subcapsular space of both Gal-knockout mice and ordinary mice. Transplantations were performed in untreated mice and mice immunosuppressed with cyclosporine A (CsA) plus 15-deoxyspergualin (DSG). Studies were also performed in immunosuppressed Gal-knockout mice that had been actively immunized against Galalpha1-3Gal. Evaluation was performed 12 days after transplantation using morphologic techniques. The levels of serum immunoglobulin (Ig)G and IgM to the Galalpha1-3Gal antigen or to the ICCs were determined. RESULTS: No difference in the morphologic appearance could be seen between ordinary mice and Gal-knockout mice. No deposits of IgG, IgM, or C3 could be detected. Almost no difference could be seen between immunosuppressed Gal-knockout mice and immunosuppressed ordinary mice. In immunosuppressed, immunized Gal-knockout mice, the results were similar. In ordinary mice treated with CsA+DSG, the levels of anti-Gal IgM were lower than they were in untreated mice, whereas the levels of anti-Gal IgG were similar. In Gal-knockout mice (including immunized animals) treated with CsA+DSG, the levels of anti-Gal IgG and IgM were lower than they were in untreated Gal-knockout mice. CONCLUSIONS: After renal subcapsular transplantation, antibodies against Galalpha1-3Gal have no major influence on islet xenograft rejection in the pig-to-mouse model. Immunosuppression, which inhibits rejection in the pig-to-mouse model, is equally effective when transplantation is performed across the Galalpha1-3Gal barrier.