The relationship between self-perceived fatigue, muscle endurance, and circulating markers of inflammation in participants of the Copenhagen aging and Midlife Biobank (CAMB).

BACKGROUND: Fatigue, low muscle endurance, muscle weakness and low-grade inflammation are strongly related to frailty at higher age. When signs of self-perceived fatigue and low muscle endurance are interrelated with low-grade inflammation at midlife, they might be used as early markers for frailty. This study investigated whether the interrelationships among self-perceived fatigue, muscle endurance and inflammation can be observed at midlife. METHODS: A total of 965 participants of the Copenhagen Aging and Midlife Biobank (aged 52 ± 4 years, 536 males, 426 females) were assessed for self-perceived fatigue (20-item multidimensional fatigue inventory), muscle endurance (grip work), circulating markers of inflammation (hsCRP, IL-6, IL-10, TNF-alpha and IFN-γ), daily physical activity (PAS-2), body composition (%body fat assessed by bio-impedance) and self-reported health status. Participants were categorised (correcting for age and gender) according to high fatigue and/or low muscle endurance, differences in inflammatory profile between fatigue categories were assessed by ANCOVA (corrected for PAS-2, %body fat and presence of inflammatory conditions). RESULTS: Overall, muscle endurance, fatigue and inflammatory markers were significantly interrelated. Higher levels of hsCRP (p < 0.001), IL-6 (p < 0.001), IL-10 (p = 0.035) and TNF-alpha (p = 0.028) were observed in participants presenting both low muscle endurance and high fatigue. IFN-γ was highest in those with high fatigue but normal muscle endurance (p = 0.015). CONCLUSIONS: Middle-aged participants with higher fatigue in combination with low muscle endurance show higher levels of inflammation, independently from physical activity, body fat and inflammatory pathology. The underlying mechanisms should be identified and future studies should also investigate whether these individuals show early signs of reduced physiological reserve capacity, which in later life come to full expression by means of frailty.

Allogeneic mesenchymal stem cell therapy for dry eye disease in patients with Sjögren's syndrome: A randomized clinical trial.

PURPOSE: This double-blinded randomized clinical trial aimed to evaluate the efficacy of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) for the treatment of dry eye disease (DED) secondary to Sjögren's syndrome (SS). METHODS: Fifty-four participants with severe DED secondary to SS were included and allocated to either ASCs (n = 20), vehicle (n = 20), or a non-randomized observation group (n = 14). The intervention groups received a single injection of either ASCs or an active comparator (vehicle, Cryostor® CS10) into the LG in one eye, while the observation group received lubricating eye drops only. The primary outcome measure was changes in Ocular Surface Disease Index (OSDI) score and secondary outcome measures were non-invasive tear break-up time, tear meniscus height, Schirmer's test, and Oxford score within a 12-month follow-up. RESULTS: A significant reduction in OSDI score was observed in the ASCs and vehicle groups compared to the observation group. In addition, the ASCs group demonstrated a significant increase in non-invasive tear break-up time compared to the vehicle group at the 4-week follow-up and to the observation group at the 12-month follow-up. A significant improvement in ocular surface staining, tear osmolarity, and Schirmer test score from baseline was also observed in the ASCs group; however, these changes were not significant compared to the other groups. CONCLUSION: Improvement of subjective and objective signs and symptoms of DED was observed in both intervention groups following injection into the LG compared to the observation group. Future studies should investigate the mode-of-action of both injection treatments.

Identification of the novel HLA allele HLA-DRB1*03:201 by next-generation sequencing.

HLA-DRB1*03:201 differs from HLA-DRB1*03:01 in exon 3 at codon 178 resulting in a proline to serine substitution.

Scandiatransplant Exchange Program (STEP): Development and Results From an International Kidney Exchange Program.

Background: Kidney transplant candidates may be incompatible with their intended living donors because of the presence of antibodies against HLA and/or ABO. To increase the possibility of finding an acceptable kidney donor for these patients, the Scandiatransplant Exchange Program (STEP) program within Scandiatransplant was launched in 2019. Methods: This is a retrospective review of our experiences from the first 4 y of the STEP program, including details about the match runs, performed transplantations, and recipient outcomes within the program. Results: During 2019-2022, 11 match runs and 4 reruns were performed. In total, 114 pairs and 6 anonymous donors participated in these match runs. Fifty-one pairs (45%) participated in 1 match run, 31 pairs (27%) participated in 2 match runs, and 32 pairs (29%) participated in ≥3 match runs. Seventy-two individuals (63%) participated because of HLA incompatibility, 19 (17%) because of ABO incompatibility, and 7 (6%) because of both HLA and ABO incompatibility.Forty percent of the patients enrolled in the program underwent transplantation. In total, 49 transplantations have so far been performed within the program, and 46 (94%) of the recipients had a functioning kidney graft at follow-up in February 2023. Conclusions: The STEP program offers sensitized patients an enlarged pool of living donors and a chance of a compatible international living donor, resulting in an increased number of total transplantations. Currently, STEP is one of the largest transnational kidney exchange programs and has improved the situation for patients waiting for kidney transplantation in Scandiatransplant.

Herpes Virus Infections in Kidney Transplant Patients (HINT) - a prospective observational cohort study.

BACKGROUND: Kidney transplant recipients receive maintenance immunosuppressive therapy to avoid allograft rejection resulting in increased risk of infections and infection-related morbidity and mortality. Approximately 98% of adults are infected with varicella zoster virus, which upon reactivation causes herpes zoster. The incidence of herpes zoster is higher in kidney transplant recipients than in immunocompetent individuals, and kidney transplant recipients are at increased risk of severe herpes zoster-associated disease. Vaccination with adjuvanted recombinant glycoprotein E subunit herpes zoster vaccine (RZV) prevents herpes zoster in older adults with excellent efficacy (90%), and vaccination of kidney transplant candidates is recommended in Danish and international guidelines. However, the robustness and duration of immune responses after RZV vaccination, as well as the optimal timing of vaccination in relation to transplantation remain unanswered questions. Thus, the aim of this study is to characterize the immune response to RZV vaccination in kidney transplant candidates and recipients at different timepoints before and after transplantation. METHODS: The Herpes Virus Infections in Kidney Transplant Patients (HINT) study is a prospective observational cohort study. The study will include kidney transplant candidates on the waiting list for transplantation (n = 375) and kidney transplant recipients transplanted since January 1, 2019 (n = 500) from all Danish kidney transplant centers who are offered a RZV vaccine as routine care. Participants are followed with repeated blood sampling until 12 months after inclusion. In the case of transplantation or herpes zoster disease, additional blood samples will be collected until 12 months after transplantation. The immune response will be characterized by immunophenotyping and functional characterization of varicella zoster virus-specific T cells, by detection of anti-glycoprotein E antibodies, and by measuring cytokine profiles. DISCUSSION: The study will provide new knowledge on the immune response to RZV vaccination in kidney transplant candidates and recipients and the robustness and duration of the response, potentially enhancing preventive strategies against herpes zoster in a population at increased risk. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05604911).

Inflammatory human leucocyte antigen genotypes are not a risk factor in chronic subdural hematoma development.

BACKGROUND: Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH. METHODS: Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH. RESULTS: We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence. CONCLUSION: This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population.

Pretransplant serum levels of endothelial cell activation markers are associated with graft loss and mortality after kidney transplantation.

Long-term allograft survival remains a challenge in kidney transplantation. In this study, we aimed to identify biomarkers for potentially modifiable pathways involved in the outcome of kidney transplantation. We tested the hypothesis that a pre-existing systemic environment with endothelial cell activation in the recipient is associated with the outcome after kidney transplantation. In a retrospective study cohort of 611 kidney transplanted patients, we investigated associations between serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) before transplantation and delayed graft function, acute rejection, graft loss and mortality after transplantation. We adjusted associations for age, sex, preformed donor-specific antibodies (DSA), pretransplant diabetes, cardiovascular disease and dialysis. Additionally, we investigated if associations between endothelial cell activation markers and outcomes differed in recipients with and without preformed DSA. Serum levels of endothelial cell activation markers were associated with delayed graft function and mortality but not with rejection. Additionally, high levels of sICAM-1 were associated with graft loss. Associations were most pronounced in recipients without DSA, adjusted for potential confounders. Data suggest that endothelial cell activation at the time of transplantation is associated with graft loss and mortality after kidney transplantation, especially in transplant candidates without preformed DSA.

Detection of the novel HLA allele, HLA-DRB1*08:112, identified in a Danish family.

HLA-DRB1*08:112 differs from HLA-DRB1*08:01 in exon 2 at amino acid 62; asparagine to lysine substitution.

Physical activity paradox: could inflammation be a key factor?

OBJECTIVE: The aim of this study was to test the extent to which physical activity performed during work and leisure is associated with systemic inflammation. METHODS: Data regarding job history and high-sensitivity C reactive protein (hs-CRP) levels, as well as potential confounders, came from the Copenhagen Aging and Midlife Biobank. The participants' self-reported job history was combined with a job exposure matrix to give a more valid assessment of cumulated occupational physical activity compared with conventional self-reported activity. Occupational physical activity was measured as cumulative ton-years (lifting 1000 kg each day for a year). Current leisure time physical activity was self-reported into four different categories. We analysed the association between occupational physical activity, current leisure time physical activity and hs-CRP level in a multivariable linear regression model with adjustment for age, sex, smoking history, number of chronic diseases, body mass index and alcohol. RESULTS: In unadjusted analysis, higher occupational physical activity was associated with increased hs-CRP levels, while higher leisure time physical activity was associated with lower hs-CRP levels. In adjusted analysis, lower leisure time physical activity resulted in 12% higher hs-CRP levels while higher occupational physical activities showed a 6% increase in hs-CRP. When we analysed occupational and leisure time physical activity as continuous variables, only leisure time physical activity affected hs-CRP. CONCLUSION: This study indicates that the relationship between physical activity and hs-CRP depends on the setting of physical activity, with lower hs-CRP related to leisure time physical activity and higher hs-CRP related to occupational physical activity. The results suggest that systemic inflammation may explain the physical activity paradox.

Inflammatory Cytokine Profiles Do Not Differ Between Patients With Idiopathic Cytopenias of Undetermined Significance and Myelodysplastic Syndromes.

Immune dysregulation has been highlighted as a key player in the pathogenesis of myelodysplastic syndromes (MDS), but little is known about cytokine profiles in patients with unexplained cytopenia with or without mutations in MDS-associated genes (clonal cytopenias of undetermined significance [CCUS] and idiopathic cytopenias of undetermined significance [ICUS], respectively), which often precede MDS. Here, we study the cytokine profiles in 111 patients with ICUS (N = 41), CCUS (N = 30), lower-risk MDS (LR-MDS; N = 22) and higher-risk MDS (HR-MDS; N = 18), and in healthy elderly controls (N = 21). Twenty cytokines were examined in blood plasma at time of diagnosis using Luminex assays and enzyme linked immunosorbent assays. The cytokine levels were compared between patient groups, and in patients versus controls. Associations between cytokines and MDS-associated mutations were evaluated. An aberrant cytokine profile was observed in all patient groups relative to healthy elderly controls. Patients had significantly higher levels of IL-6 (P< 0 .001), tumor necrosis factor α (P < 0.001), IL-10 (P < 0.001), and C-X-C motif chemokine 10 (P < 0.001) and lower levels of transforming growth factor beta 1 (P < 0.001), CCL5/regulated on activation normal T-cell expressed and secreted (P < 0.001), and S100A4 (P < 0.001) compared with healthy controls. Survival was significantly shorter in CCUS and MDS patients with a high systemic inflammatory cytokine load (median overall survival [OS] 21 months) compared with those with low-moderate systemic inflammatory cytokine load (median OS 64 months; P < 0.0001). These data suggest that patients with ICUS and CCUS have cytokine levels as abnormal as in LR-MDS. Indeed, high cytokine levels are present before MDS is diagnosed and cytokine levels are elevated irrespective of the presence or size of the myeloid clones. Cytokines may have a prognostic impact at a very early premalignant stage of myeloid disorders.

Educational attainment in young adulthood and self-rated health in midlife - Does allostatic load mediate the association?

This study aimed to examine the extent to which allostatic load (AL), measured in midlife, mediates the association between educational attainment in young adulthood and self-rated health (SRH) in midlife among women and men. The study used data from the Copenhagen Aging and Midlife Biobank (CAMB; n = 5467 participants, aged 48-62 years, 31.5% women). Educational attainment was assessed as years of education. SRH was assessed with one item: 'In general, how would you say your health is?' with response options from "excellent" to "poor". AL mediated 31.7% and 19.7% of the association between educational attainment and SRH in women and men, respectively. We observed that higher educational attainment was associated with better SRH and lower AL in both women and men. Our study showed that AL partly mediates the association between educational attainment in young adulthood and SRH in adulthood among both men and women. This study indicates that educational attainment in young adulthood affects health throughout life. Such knowledge of a potential mediator may be important in breaking the social heritage.

Inflammatory markers and lung function in relation to indoor and ambient air pollution.

Ambient air pollution causes a range of adverse health effects, whereas effects of indoor sources of air pollution are not well described in high-income countries. We compared hazards of ambient air pollution and indoor sources with respect to important biomarkers of cardiorespiratory effects in terms of lung function and systemic inflammation in a middle-aged Danish cohort. Our cohort comprised 5199 men and women aged 49-63 years at the recruitment during April 2009 to March 2011, with information on exposure to second-hand smoke (SHS) and use of candles, wood stove, kerosene heater and gas cooker as well as relevant covariates. Ambient air pollution exposure was assessed as 2-year mean nitrogen dioxide (NO2) at the address (mean ± SD: 17.1 ± 9.9 µg/m3) and 4-day average levels of particulate matter with diameter <2.5 µm (PM2.5; mean ± SD: 12.5 ± 6.0 µg/m3) in urban background. Lung function was assessed as % predicted forced expiratory volume in the first second (FEV1) and inflammatory markers comprised interleukin-6 (IL-6), IL-10, IL-18, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hs-CRP). We used random-effect regression models controlling for potential confounders as well as models with further adjustment for self-reported health or for all other exposures. In models adjusted for confounders FEV1 was inversely associated with exposure to NO2, (-0,83% per 10 µg/m3; 95% CI: -1.26; -0.41%), SHS (-0.56% per 1 of 5 categories increment; 95% CI: -0.89; -0.23%), and gas cooker without hood (-0.89%; 95% CI: -1.62; -0.17%), whereas use of wood stove and candles showed positive associations, although these attenuated by mutual adjustment for all exposures or self-reported health. IL-6 showed positive associations with NO2 (6.30% increase in log-transformed values per 10 µg/m3; 95% CI: 3.54; 9.05%), PM2.5 (7.82% per 10 µg/m3; 95% CI: 3.35; 12.4%), SHS (4.38% per increase of 1 of 5 categories; 95% CI: 2.22; 6.54%) and use of kerosene (13.8%; 95% CI: 2.51; 25.1%), whereas the associations with use of wood stove and candles were inverse. PM2.5 and NO2 showed positive associations with IFN-γ and TNF-α, while PM2.5 further associated with IL-10 and IL-18. Hs-CRP was inversely associated with use of candles. These results suggest that the levels of exposure to ambient air pollution and SHS are more harmful than are the levels of exposure to indoor combustion sources from candles and wood stoves in a high-income setting.

Do partnership dissolutions and living alone affect systemic chronic inflammation? A cohort study of Danish adults.

BACKGROUND: Partnership breakups and living alone are associated with several adverse health outcomes. The aim of this study, carried out in Denmark, is to investigate whether accumulated numbers of divorces/partnership breakups or years lived alone across 26 years of adult life are associated with levels of inflammation, and if vulnerability with regards to gender or educational level can be identified. METHODS: 4835 participants from the Copenhagen Aging and Midlife Biobank (CAMB) aged 48-62 years were included. Data on accumulated numbers of partnership breakups and years living alone were retrieved from a national standardised annual register. Inflammatory markers interleukin 6 (IL-6) and high sensitivity C-reactive protein (hsCRP) were measured in blood samples. Multivariate linear regression analyses were adjusted for age, educational level, early major life events, body mass index, chronic diseases, medicinal intake affecting inflammation, acute inflammation and personality scores. RESULTS: For men, an association was found between an increasing number of partnership breakups or number of years living alone and higher levels of inflammatory markers. No such association was found for women, and no evidence of partnership breakups and educational level having a joint effect was found for either gender. CONCLUSION: The findings suggest a strong association between years lived alone or accumulated number of partnership breakups and low-grade inflammation for middle-aged men, but not for women. Among those of either sex with a lower level of education, no specific vulnerability to accumulated years lived alone or number of breakups was identified.

Detection of the novel HLA allele, HLA-DQA1*01:65, identified in a Danish donor.

HLA-DQA1*01:65 differs from HLA-DQA1*01:03 in exon 1 at amino acid -7 a valine to methionine substitution.

The HLA-DR4-DQ8 phenotype of the recipient is associated with increased mortality after kidney transplantation.

The importance of the human leukocyte antigen (HLA) system in kidney transplantation is well-known, but it remains unexplored if patient HLA antigens constitute independent risk factors in complications after transplantation. We hypothesized that specific HLA class II phenotypes associated with immune-mediated disease (HLA-IMD) predispose to immunological activity and/or complications after kidney transplantation. Based on the literature we defined HLA-DR2-DQ6; -DR3-DQ2 and -DR4-DQ8 as HLA-IMD phenotypes. We investigated associations between HLA-IMD phenotypes in patients, biomarkers of systemic chronic inflammation at the time of transplantation, and the outcome after kidney transplantation in a retrospective cohort study of 611 kidney transplanted patients. The HLA-IMD phenotypes were associated with higher levels of biomarkers of systemic inflammation. The HLA-DR4-DQ8 phenotype was associated with mortality after transplantation in Cox analyses with adjustments for confounders. Data support the hypothesis that specific HLA class II phenotypes affects immunological pathways that determine the midterm clinical outcome of kidney transplantation.

Identification of the novel HLA allele, HLA-DPA1*01:46, identified in a man of Serbian origin.

HLA-DPA1*01:46 differs from HLA-DPA1*01:03 in exon 2 at amino acid 85; Aspartate to Asparagine substitution.

Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease.

PURPOSE: To evaluate the safety and feasibility of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) as a treatment of aqueous deficient dry eye disease (ADDE). METHODS: In this open-label, 5-visit clinical trial (baseline, treatment and weeks 1, 4 and 16) seven subjects with ADDE received one transconjunctival injection of allogeneic ASCs into the LG in one eye. The ASC product contained 22 million ASCs/ml and the injected volume was maximally 50% of the LG volume as determined on magnetic resonance imaging (MRI). Treatment related adverse events (AEs) were assessed at each visit (primary endpoint). Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), corneal staining (Oxford grade) and Schirmer's I test were assessed at each timepoint. RESULTS: No AEs related to the study treatment were observed. Mean follow-up time was 126 days after treatment. The mean OSDI score decreased from 58.9 ± 20.6 at baseline to 34.1 ± 21.6 (p < 0.002). In the study eye mean tear osmolarity decreased from 312.9 ± 10.4 to 291.6 ± 10.9 mosm/l (p < 0.002), mean TBUT increased from 3.7 ± 1.5 to 7.1 ± 1.9 s (p < 0.002), mean Schirmer's I test increased from 4.6 ± 0.7 to 8.1 ± 3.1 mm/5 min (p < 0.03), while mean Oxford grade showed a trend towards a decrease from 2.4 ± 0.7 to 1.3 ± 1 (p < 0.10). CONCLUSION: Our trial suggests that injection of allogeneic ASCs into the LG is a safe and feasible treatment of severe ADDE. A randomized placebo-controlled trial aimed at elucidating the therapeutic effect of allogeneic ASCs in a larger patient cohort from our research group is currently underway.

Positive and negative aspects of social relations and low-grade inflammation in Copenhagen Aging and Midlife Biobank.

The association between social relations and health outcomes is well described, but pathways are relatively poorly understood. Inflammation has been suggested as a potential physiological pathway, linking social relations to adverse health outcomes. However, previous studies have shown ambiguous results and have for the vast majority been based on studies small in sample size. The aim of the present study is to examine the association between comprehensive measures of structural and positive as well as negative functional aspects of social relations, across four relational domains-partner/spouse, children, other family and friends, and the level of systemic low-grade inflammation in a large population-based middle-aged cohort and to examine variation by gender and socioeconomic position in these associations. The study comprised of 5576 participants in the Copenhagen Aging and Midlife Biobank. The inflammatory biomarkers collected in late midlife included C-reactive protein, Interleukin-6, and TNF-alpha. Multiple linear regression models were implemented to explore associations between social relations and inflammatory measures controlling for gender, age, socioeconomic position, marital status, early major lifeevents and morbidity. Results show weak and ambiguous associations in all analyses. There were no strong indications of interaction with socioeconomic position. Concluding cautiously, men appear to be more vulnerable toward living alone and low contact frequency with family compared to women as regards high level of low-grade inflammation. In conclusion, this large-scale population-based study among middle-aged men and women showed no association between social relations and low-grade inflammation.

[Donor search for haematopoietic stem cell transplantation].

Allogeneic haematopoietic stem cell transplantation is a clinical example of precision medicine, as one individual donor is selected for one individual patient based on genetic findings in the human leukocyte antigen (HLA) system. Unrelated donor search for Danish patients is based on an international collaboration between global registries hosting more than 37 million potential donors worldwide for patients in need. The implementation of next-generation sequencing technologies has been a revolution in donor registry typing due to more precise, detailed and cheaper HLA analyses, which is discussed in this review.