Introduction Respiratory syncytial virus (RSV) causes substantial morbidity in older adults. Patients receiving hemodialysis are particularly vulnerable due to impaired immunity and chronic health care exposure. Data on RSV vaccine immunogenicity in this population are lacking. Methods We conducted an observational study of 20 patients receiving hemodialysis (median age 78.4 years; 55% female; median dialysis duration 23 months) who received a single dose of the RSV vaccine Arexvy. Blood samples were obtained at baseline and at weeks two, five, eight, 16, and 32. RSV-specific IgG was quantified by ELISA, and cellular responses were assessed by multiparameter flow cytometry. Fifteen sex- and age-matched individuals with normal kidney function were included as a control group. Results At baseline, 14 of 20 patients were seropositive (IgG over 11 Standard Units (SU); median 12.6 SU). IgG titters remained stable through week 5, rose significantly at week eight (16.8 SU), peaked at week 16 (17.5 SU), and declined to 14.6 SU at week 32, remaining above baseline. In contrast, healthy control individuals, vaccinated with Arexvv, showed increasing RSV-IgG antibody levels already after two weeks. Antibody levels correlated negatively with dialysis duration, and patients with under one year of dialysis had significantly higher titers. RSV-specific CD4+ T cells increased at week two, with most producing IFN-γ, IL-2, or TNF, and returned to baseline by week eight. B cell responses included expansion of plasmablasts (weeks five-eight) and early increases in switched memory B cells. Cytokine profiling showed modest changes (IL-23, TNF and IL12p70 increased; IL-8 decreased). Conclusions Arexvy elicited robust humoral and cellular responses in patients receiving hemodialysis. Attenuated antibody responses with longer dialysis duration suggest dialysis vintage as a key determinant of vaccine efficacy in this high-risk population. The increase in anti-RSV IgG antibody levels was significantly delayed in patients receiving hemodialysis compared with control individuals.

Background:Atrial fibrillation (AF) is associated with systemic inflammation, endothelial dysfunction, and adverse cardiovascular outcomes. While there is robust evidence, that inflammation contributes to AF pathogenesis, the existence of a reverse relation - whether AF contributes to inflammation - remains elusive. This study therefore evaluates the impact of rhythm control on systemic inflammation and endothelial function. Methods:In this prospective observational study, 124 patients with persistent AF undergoing successful rhythm control therapy (electrical cardioversion or catheter ablation) were followed for nine months. Various Cytokines, high-sensitivity C-reactive protein (hsCRP), flow-mediated dilation (FMD) and additional inflammatory biomarkers were measured at baseline, 1 week, 1 month, 3 months, and 9 months. FMD was assessed by high-resolution brachial artery ultrasound. Patients with AF recurrence throughout the follow-up period were excluded from primary analysis. Results:In patients without AF recurrence, FMD improved significantly from 6.3 % (4.6-8.3) to 7.6 % (5.1-8.8) (p < 0.001). HsCRP, IL-8 and fibrinogen declined modestly (p = 0.002, p < 0.001 and p < 0.001, respectively), whereas IL-2, IP-10, IL-12p70, MCP-1 and TNF-α increased significantly over time (all p < 0.001). Elevated pre-treatment hsCRP was weakly associated with AF recurrence (r = 0.20, p = 0.023; AUC = 0.61). IL-6 showed temporal variation but no sustained change from baseline. Conclusion:Rhythm control therapy in persistent AF is associated with an improvement of endothelial function but not with a homogeneous improvement of systemic inflammatory serological profiles. Thus, the improvement in FMD appears to be mediated primarily by hemodynamic restoration rather than anti-inflammatory effects.

BACKGROUND:Chronic kidney disease-associated pruritus (CKD-aP) is associated with poor health-related quality of life (HRQoL). However, clarity on its prevalence is lacking. CENSUS-EU was a real-world, cross-sectional, non-interventional, multicentre study carried out in seven European countries to assess the prevalence of CKD-aP and its impact on HRQoL in patients receiving haemodialysis (HD). METHODS:Patients aged ≥18 years with CKD who were receiving in-centre HD for ≥3 months were eligible for enrolment. Medical records were used to gather baseline demographics and clinical characteristics. Patients completed patient-reported outcomes on pruritus severity (the Worst Itching Intensity Numerical Rating Scale) and HRQoL. They also completed a questionnaire on pruritus communication and treatment. Data were analysed by pruritus severity. RESULTS:Of 3095 enrolled patients, data concerning 2963 were available for analysis. Mean age was 66.2 years, and 62.7% were male. The prevalence of CKD-aP was 53.5%; 22.3% of patients experienced mild, 18.0% moderate, and 13.2% severe pruritus. Patients with moderate-to-severe pruritus experienced greater difficulty sleeping, higher depression scores, greater disability, and impact on daily activities compared with patients with no pruritus (P < .0001, all comparisons). Patients mainly reported pruritus to nephrologists (49%) or dialysis nurses (33.8%). However, 26.2% of patients experiencing pruritus did not report it to anyone, and 40.9% of patients with current or past severe itch were untreated at the time of study visit. CONCLUSIONS:In this study, over half of patients experienced CKD-aP, with 31.2% reporting moderate or severe symptoms. Many patients were untreated despite experiencing itch that impacted their HRQoL and day-to-day activities. Clinical Trial Registration This study was registered at ClinicalTrials.gov (Identifier: NCT05524467).

ABSTRACT Obstructive sleep apnea (OSA) is associated with increased cardiovascular risk and hypertension. While continuous positive airway pressure (CPAP) therapy reduces blood pressure (BP), its effect shows substantial interindividual variability. Hypoxic burden (HB) has been proposed as a potentially superior predictor of cardiovascular outcomes compared to the apnea–hypopnea index (AHI). In this retrospective study, 141 patients with OSA underwent in‐laboratory polysomnography and initiated CPAP therapy. Office BP and clinical parameters were assessed at baseline and follow‐up (median 200 days). Receiver operating characteristic (ROC), correlation, multiple linear and logistic regression analyses were performed to compare the predictive value of HB and AHI for BP reduction. CPAP therapy resulted in a modest, non‐significant reduction in systolic BP(−2.3 mmHg ±17.7,0.1237), while diastolic BP remained unchanged. Higher AHI and HB levels were associated with higher baseline systolic BP and numerically greater BP reductions, particularly in individuals with a higher than the median HB ≥57.5%min/h or median AHI ≥34.3/h. However, neither HB nor AHI predicted a systolic BP reduction ≥5 mmHg (AUC values≈0.5), and no relevant correlations between AHI, HB and blood pressure response were observed. HB is associated with OSA severity and higher baseline BP. However, it is not superior to AHI in the prediction of a CPAP‐associated reduction of BP in patients with OSA.

BackgroundThe Post-COVID syndrome is associated with the generation of autoantibodies to vasoregulative G-protein coupled receptors (GPCR). It remains elusive, however, whether these autoantibodies play a pathophysiological role in this disease. The present study investigates whether detection and concentration of GPCR autoantibodies are related to vascular function in patients with Post-COVID.Materials and methodsWe performed a cross-sectional study, enrolling 80 patients with Post-COVID and 54 individuals with a history of SARS-CoV-2 infection without persisting symptoms (control group). ELISA measurement of GPCR autoantibodies encompassed autoantibodies to Angiotensin-II-Receptor-1 (AGTR2), Beta-1 Adrenergic Receptor (ADRB1), Beta-2 Adrenergic Receptor (ADRB2), Endothelin Receptor (EDNRA), Muscarinergic Choline Receptor 3 (CHRM3), and Muscarinergic Choline Receptor 4 (CHRM4). Endothelium-dependent vasodilation was assessed by flow mediated dilation (FMD). Measurement of central aortic blood pressure and capillary nailfold capillary microscopy were performed as additional assessments of vasoregulatory function. Lipoprotein-associated phospholipase A2 (Lp-PLA2) served as markers of vascular inflammation.Results52 (65%) patients with Post-COVID had positive autoantibody findings above previously established cut-off values, the incidence was lower in the non-Post-COVID group (n = 12, 22.2%, p = 0.0001). The median concentrations for AGTR2, ADRB1, CHRM3 and CHRM4 autoantibodies were significantly higher in the symptomatic cohort (p < 0.05 each). Spearman correlation analysis showed a strong and significant negative correlation of several GPCR autoantibodies with aortic systolic blood pressure (AGTR2 p = 0.026, ADRB1 p = 0.001, ADRB2 p = 0.012) and aortic diastolic blood pressure (ADRB1 p = 0.005, CHRM4 p = 0.046) in Post-COVID. High EDNRA autoantibodies titers were associated with FMD (p = 0.038). There was no significant association of any GPCR autoantibody concentration with FMD or Lp-PLA2 in the control group.ConclusionGPCR autoantibodies were highly prevalent in this Post-COVID cohort. Several GPCR autoantibodies were associated with measures of vasorelaxation like lower systolic and diastolic aortic blood pressure and stronger endothelium-dependent vasodilation. However, given the absence of differences in microvascular and macrovascular function, the precise role of GPCR autoantibodies remains elusive.

Increasing evidence suggests that reactivation of latent EBV in patients with COVID-19 may be linked to the development of post-acute sequelae of COVID-19, colloquially known as Long COVID. However, the reason for this co-occurrence of primary infection and reactivation of latent viruses remains elusive. During the first wave of COVID-19, we assessed all major immune cell populations by flow cytometry in a cohort of 61 patients with moderate to critical COVID-19 at the time of hospitalization. Additional blood samples from these patients were biobanked for later analysis. Using these biobanked samples, we evaluated the co-occurrence of CMV, EBV, as well as HHV-6A and -6B by qPCR. EBV was found to be reactivated not only in patients with critical or severe COVID-19 (24/33 patients; 72.72

BACKGROUND:Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition effectively lowers low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but its pleiotropic effects remain insufficiently defined. This study examined whether PCSK9 inhibition influences vascular and systemic inflammation and high-density lipoprotein (HDL) antioxidant function. OBJECTIVE:To investigate the effects of PCSK9 inhibition on vascular inflammation, systemic inflammatory markers, and HDL antioxidant function in a real-world patient cohort. MATERIAL AND METHODS:In this monocentric, prospective study, blood samples from 89 patients were collected before and 3 to 6 months after initiation of PCSK9 inhibitor therapy. Lipoprotein-associated phospholipase A2 (LpPLA2) was measured as a marker of vascular inflammation. HDL antioxidant function was assessed by HDL lipid peroxide content (HDLox). Systemic inflammation was evaluated via high-sensitivity C-reactive protein (hsCRP) and a predefined cytokine panel. RESULTS:Seventy-three patients (82.0%) received alirocumab or evolocumab, and 16 (18.0%) received inclisiran. LDL-C decreased by 46.7% (120-64.5 mg/dL, P < .0001). LpPLA2 declined significantly (443.5-265.5 IU/L, P < .0001) and correlated with LDL-C reduction (R² = 0.58, P < .0001). HDLox did not change (1.190-1.210, P = .3438). Interferon gamma-induced protein (IP) 10 (P = .0141) and interleukin (IL)-2 (P = .0371) decreased, whereas hsCRP and other cytokines-including IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, tumor necrosis factor-α, monocyte chemotactic protein-1, interferon-γ, and free radicals-remained unchanged (all P > .05). CONCLUSION:PCSK9 inhibition reduces LpPLA2 and IP-10 without changing global inflammatory response or antioxidant function of HDL, which might indicate a decrease in chronic vascular inflammation without an undesired broad systemic immune alteration.

Abstract Inclisiran lowers LDL-cholesterol (LDL-C) by inhibiting hepatic PCSK9 synthesis. Whether concomitant statin therapy modifies the magnitude of inclisiran-associated LDL-C reduction in routine clinical practice remains uncertain. In this retrospective single-center observational study, 67 patients treated with inclisiran for at least 9 months were analyzed. Patients previously treated with PCSK9 monoclonal antibodies were excluded. LDL-C values were assessed longitudinally and stratified by concomitant statin therapy. Multivariable linear mixed-effects models were used to evaluate inclisiran-associated percentage LDL-C reduction over time. Thirty-seven patients received concomitant statin therapy and 30 patients did not. Median follow-up was 18 months (IQR 12.5–28). Median LDL-C reduction ranged from approximately − 25% to − 40% across follow-up visits. At 9 months, 10 of 59 patients (16.9%) achieved a ≥ 50% LDL-C reduction. In the primary multivariable longitudinal mixed-effects model, concomitant statin use was not significantly associated with percentage LDL-C reduction (β for no statin vs. statin: 33.1% points; 95% CI − 4.6 to 70.7; p = 0.085). Statin intensity was also not significantly associated with LDL-C reduction (β − 0.11 per percentage point of maximum approved dose; 95% CI − 0.60 to 0.37; p = 0.644). In an exploratory responder analysis, concomitant statin therapy was associated with higher odds of achieving ≥ 50% LDL-C reduction at 9 months (OR 7.69; 95% CI 1.28–45.45; p = 0.026). During follow-up, 18 patients (26.9%) discontinued inclisiran, predominantly due to insufficient LDL-C reduction. In routine clinical practice, neither concomitant statin use nor statin intensity was significantly associated with the magnitude of LDL-C reduction observed during inclisiran therapy. However, responder and attrition sensitivity analyses suggested a possible association between concomitant statin therapy and a more pronounced inclisiran-associated LDL-C response. These findings support the clinical use of inclisiran in heterogeneous real-world populations, while highlighting the potential benefit of maintaining concomitant statin therapy whenever tolerated.

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients' blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. 30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Reactivation of the BK virus (BKV) is a critical adverse event after kidney transplantation and can lead to graft loss. BKV-reactive T cell-mediated viral control can be facilitated by reducing immunosuppression. However, the exact mechanism underlying the T cell-mediated BKV clearance in the kidney transplant is not clear. Here, we used urine-derived renal tubular epithelial cells as a model system to investigate the immunomodulatory capacity of urine-derived renal tubular epithelial cells and their potential to induce T cell responses against BKV. Urine-derived renal tubular epithelial cells were generated by culturing urine-derived cell pellets. To assess the inflammatory potential of urine-derived renal tubular epithelial cells, the cells were treated with Poly I:C or TNFα/IFNγ. To investigate urine-derived renal tubular epithelial cell-induced T cell responses, autologous T cells, isolated from blood were co-cultured with urine-derived renal tubular epithelial cells, in the presence of BKV protein-derived peptides and PolyI:C or TNFα/IFNγ. BKV-reactive T cells, cytokine/chemokine secretion and expression of co-stimulatory molecules were evaluated using multiplex assays and multi-parameter flow cytometry. Urine-derived renal tubular epithelial cells phenotypically resemble renal tubular epithelial cells, as they express CD13, EPCAM, cytokeratin and the myo-inositol oxygenase. After stimulation with PolyI:C, urine-derived renal tubular epithelial cells showed increased levels of CD40 and HLA-ABC, whereas TNFα/IFNγ only induced HLA-DR/ABC expression. Poly I:C and TNFα/IFNγ stimulation of urine-derived renal tubular epithelial cells induced a district pattern of inflammatory cytokines and chemokines that facilitate the migration of certain immune cell subsets. Interestingly, urine-derived renal tubular epithelial cells can present BKV peptides, thereby inducing a functional BKV-reactive CD4 and CD8 T cell response. Urine-derived renal tubular epithelial cells express immunomodulatory molecules, and induce BKV-directed T cell reactivity, indicating that renal epithelial cells may serve as non-conventional antigen-presenting cells in the kidney and thereby help BKV clearance.

INTRODUCTION:Hyperuricemia is a frequent problem after renal transplantation. It is associated with an increased risk of cardiovascular events and graft loss. In the present study, we evaluated whether treatment of hyperuricemia is associated with intrarenal hemodynamic changes as measured by the resistance index (RI). METHODS:We performed a retrospective analysis of 402 patients who underwent renal transplants over a follow-up period of 120 months. The population was stratified into three groups based on examinations at month 12 after transplantation. Group 1 (normouricemia) had a serum uric acid (SUA) concentration <7 mg/dL and never received SUA-lowering therapy during follow-up. Group 2 (hyperuricemia, untreated) had a SUA≥7 mg/dL and never received SUA-lowering therapy. Group 3 (hyperuricemia, treated) received SUA-lowering therapy within the follow-up period. RESULTS:At 12 and 60 months, linear regression analysis was performed between RI and SUA concentrations showing a significant correlation for this group at month 12. The development of RI within the 10-year follow-up period differed among groups: At month 120, RI was significantly higher in subjects with hyperuricemia that was untreated (0.76 ± 0.06) than in the other groups (P < 0.05), although it started at a level even lower than the group of subjects with hyperuricemia that were treated at 12 months (0.70 ± 0.08 vs. 0.73 ± 0.08, P < 0.05). In cox regression analysis adjusted for age, eGFR, body mass index, and postmortal versus living donation, there was a trend to better survival in Group 3. CONCLUSION:SUA-lowering therapy is associated with a lower increase of RI over time and a trend to better survival of recipients of renal transplants in this retrospective analysis.

RESULTS. Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).CONCLUSION. HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS. TRIAL REGISTRATION. German Clinical Trials Register DRKS00014037. FUNDING. Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462. BACKGROUND. High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).METHODS. HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).