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An increased bleeding risk is reported for patients with end-stage renal disease. This study aims to analyze, whether bleeding risk can be assessed by global tests of hemostasis. Standard laboratory tests and an extended evaluation of hemostasis by rotational thromboelastometry, platelet function analyzer (PFA) and multiple electrode aggregometry as well as thrombin generation assays and measurement of fibrinolytic potential were performed in 20 patients on hemodialysis, 10 patients on peritoneal dialysis, 10 patients with chronic kidney disease stage G5 (CKD5) and in 10 healthy controls (HC). Hemoglobin was significantly lower in patients with end-stage renal disease versus HC (each p<0.01). Patients on peritoneal dialysis showed increased fibrinogen levels compared to HC (p<0.01), which were also reflected by FIBTEM results (each p<0.05). 41% of hemodialysis patients and 44% of CKD5 patients presented with prolonged PFA-ADP-test (p<0.05), while no patient on peritoneal dialysis and no HC offered this modification. Thrombin generating potential was significantly lower in patients on hemodialysis, while clot lysis time revealed a hypofibrinolytic state in patients on hemo- and peritoneal dialysis compared to HC (p<0.001). In conclusion, patients with end-stage renal disease have complex hemostatic changes with both hyper- and hypocoagulable features, which are dependent on use and type of dialysis. Hypercoagulable features include elevated fibrinogen levels and a hypofibrinolytic state, whereas hypocoagulable features include decreased thrombin generating capacity and platelet dysfunction. Our results may contribute to a more rational approach to hemostatic management in these patients.

Several factors, such as hypertension and diabetes mellitus, are known to influence the course of coronavirus disease 2019 (COVID-19). However, there is currently little information on genetic markers that influence the severity of COVID-19. In this study, we specifically investigated the single nucleotide polymorphism (SNP) rs4986790 in the gene to identify a universal marker for preclinical prediction of COVID-19 disease progression. We analyzed the influence of demographics, pre-existing conditions, inflammatory parameters at the time of hospitalization, and rs4986790 genotype on the outcome of COVID-19 in a comprehensive cohort (N = 1570). We performed multivariable analysis to investigate the impact of each factor. We confirmed that younger patient age and absence of pre-existing conditions were protective factors against disease progression. Furthermore, when comparing patients with mild SARS-CoV-2 infection with patients who required hospitalization or intensive care or even died due to COVID-19, the AG/GG genotype of rs4986790 was found to be a protective factor against COVID-19 disease progression (OR: 0.51, 95% CI: 0.34 - 0.77, = 0.001). In addition, we demonstrated that low levels of interleukin-6 (IL-6) and procalcitonin (PCT) had a favorable effect on COVID-19 disease severity. In the subsequent multivariable analysis, we confirmed the absence of cardiovascular disease, low levels of IL-6 and PCT, and rs4986790 AG/GG genotypes as independent predictors of potential hospitalization and reduction of severe or fatal disease course. In this study, we identified an additional genetic factor that may serve as an invariant predictor of COVID-19 outcome. The rs4986790 AG/GG genotype reduced by half the risk of COVID-19 patients requiring hospitalization, intensive care or to have a fatal outcome. In addition, we were able to confirm the influence of previously known factors such as pre-existing conditions and inflammatory markers upon the onset of disease on the course of COVID-19. Based on these observations, we hereby provide another prognostic biomarker that could be used in routine diagnostics as a predictive factor for the severity of COVID-19 prior to SARS-CoV-2 infection.

To investigate the outcomes of geriatric COVID-19 patients in a German academic setting during the pandemic. This study included 468 consecutive geriatric patients (≥ 70 years) who tested positive for SARS-CoV-2 and were treated at the University of Duisburg-Essen from 2/2020 to 3/2021. 74 patients were transferred to a geriatric hospital and a 12-month follow-up (prospective study) was performed in 51 patients. Clinical assessments evaluated depression (GDS), apathy (AES), cognitive status (MMST), mobility (TUG), health status (EQ-5D-5 L), and daily living activities (Barthel Index). Demographic and clinical data were also analyzed. Results showed that the mortality in this vulnerable group was 52% ( n  = 209). Long-term survival was higher in patients who received comprehensive geriatric treatment (74.3% vs. 51.8%). The duration of inpatient stay at the primary hospital was 13.3 ± 3.6 days, with 28.8% ( n  = 135) requiring intensive care. At the 12-month mark more patients with geriatric treatment lived in nursing homes. Barthel-Index/Timed-Up-and-Go-Test/MMST/AES/GDS, and EQ-5D-5 L indicated worse outcomes in the group who received geriatric treatment. Specialized geriatric care may improve survival in geriatric COVID-19 patients despite decreased long-term outcomes. Further research, including international studies like NAPKON, are encouraged to confirm these findings and explore potential interventions for improved outcomes in this vulnerable population.

Background Systemic inflammation triggers a wide range of sickness symptoms, including bodily discomfort and affective symptoms, which are relevant to numerous health conditions. While extensive research in the placebo field demonstrates that positive expectations can improve symptoms, it remains unclear if interventions designed to augment positive treatment expectations can alleviate sickness symptoms in the context of immunomodulatory drug therapies. Methods In this randomized, controlled, fully balanced 2 × 2 factorial placebo design, N  = 124 healthy volunteers received either active ibuprofen treatment (600 mg per os) or placebo, combined with either a positive or neutral labeling of the treatment by the physician. All participants were intravenously injected with lipopolysaccharide (LPS, 0.8 ng per kg of body weight) as a translational model of inflammation-induced sickness symptoms. Primary outcomes were bodily and affective symptoms, assessed at baseline and up to 6 h after injection, along with a range of inflammatory markers. Results Ibuprofen substantially alleviated inflammation-induced symptoms. Positive labeling also improved bodily and affective symptoms of sickness, even in placebo-treated groups. Notably, positive labeling enhanced ibuprofen’s efficacy for alleviating affective symptoms, supporting that expectations can boost the efficacy of a highly effective anti-inflammatory treatment. However, labeling did not influence changes in physiological markers of inflammation, suggesting that the effects of expectations primarily act through mechanisms distinct from direct modulation of peripheral immune responses. Conclusions Placebo mechanisms engaged by physician communication can independently alleviate inflammation-induced symptom burden and enhance the efficacy of an anti-inflammatory medication. Results underscore the critical role of healthcare provider communication and pave the way for improved treatment strategies for conditions characterized by inflammation-driven symptoms. Trial registration DRKS00023088, registration website German Clinical Trials Register (date registered: 10/22/2020).

Expression of the non-classical human leukocyte antigen-G (HLA-G) promotes cancer progression in various malignancies including epithelial ovarian cancer (EOC). As single nucleotide polymorphisms (SNPs) in the HLA-G 3′ untranslated region (UTR) regulate HLA-G expression, we investigated HLA-G 3′UTR haplotypes arranged by SNPs in healthy controls (n = 75) and primary EOC patients (n = 79) and determined soluble HLA-G (sHLA-G) levels. Results were related to the clinical status and outcome. Although haplotype frequencies were similar in patients and controls, (i) sHLA-G levels were increased in EOC independent of the haplotype, (ii) homozygosity for UTR-1 or UTR-2 genotypes were significantly associated with metastases formation and presence of circulating tumor cells before therapy, whereas (iii) the UTR-5 and UTR-7 haplotypes were significantly associated with a beneficial clinical outcome regarding negative nodal status, early FIGO staging, and improved overall survival. Lastly, (iv) the ambivalent impact on clinical EOC aspects could be deduced to specific SNPs in the HLA-G 3′UTR: +3187G, +3196G and +3035T alleles. Our results give evidence that even if the genetic background of the HLA-G 3′UTR is identical between patients and controls, certain SNPs have the potential to contribute to diametrical clinical status/outcome in EOC.

SARS-CoV-2 variants of concern (VOCs) can trigger severe endemic waves and vaccine breakthrough infections (VBI). We analyzed the cellular and humoral immune response in 8 patients infected with the alpha variant, resulting in moderate to fatal COVID-19 disease manifestation, after double mRNA-based anti-SARS-CoV-2 vaccination. In contrast to the uninfected vaccinated control cohort, the diseased individuals had no detectable high-avidity spike (S)-reactive CD4+ and CD8+ T cells against the alpha variant and wild type (WT) at disease onset, whereas a robust CD4+ T-cell response against the N- and M-proteins was generated. Furthermore, a delayed alpha S-reactive high-avidity CD4+ T-cell response was mounted during disease progression. Compared to the vaccinated control donors, these patients also had lower neutralizing antibody titers against the alpha variant at disease onset. The delayed development of alpha S-specific cellular and humoral immunity upon VBI indicates reduced immunogenicity against the S-protein of the alpha VOC, while there was a higher and earlier N- and M-reactive T-cell response. Our findings do not undermine the current vaccination strategies but underline a potential need for the inclusion of VBI patients in alternative vaccination strategies and additional antigenic targets in next-generation SARS-CoV-2 vaccines.

Background A high number of individuals report suffering from physical and psychological sequelae symptoms after COVID-19—the so-called post COVID-19 condition. Commonly reported complaints include physical symptoms such as fatigue, headache, attention and concentration deficits or dyspnea and anxiety, symptoms of post-traumatic stress, or depression. Evidence-based treatment recommendations are still lacking up to this point. Associations between physical and psychological symptoms in chronic diseases are known for a long time. Support in coping with the disease and improvement of self-efficacy can have a positive effect on the course of diseases. For this reason, we designed a randomized, controlled explorative intervention trial as a treatment of bodily distress disorder in COVID-19 recovered persons. Methods Patients with a post COVID-19 condition meeting to the criteria of the WHO, along with a bodily distress disorder, are randomized in an intervention and control arm (TAU). Randomization takes place after a diagnostic interview, screening, and informed consent. In total, 60 patients will be included in the trial (30 per group). The intervention group receives a cognitive behavioral therapy as a video-conference-based group therapy (6 weeks) and mobile, respiratory biofeedback treatment (for 4 weeks). At several time points, both groups are assessed in terms of psychological and physical health status, treatment expectation, and satisfaction with the intervention. Furthermore, they will get biofeedback examination appointments. The primary outcome is the change in self-efficacy; secondary outcomes include assessed parameters of mental health, somatic symptoms, and satisfaction with the intervention. Data will be analyzed primarily using R and SPSS. Discussion The randomized, controlled, explorative intervention trial POSITIV is one of the very first interventions for patients with post COVID-19 condition and psychological burden due to their different symptoms. The aim of the study is to generate new evidence and help patients to cope with the disease and thus, increase their quality of life and reduce symptomatology. We expect with a high probability that the patients’ self-efficacy and health status will improve as a result of the intervention. Trial registration German Clinical Trial Register (DRKS); DRKS-ID: DRKS00030565. Registered on December 22, 2022.

Background The complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs. Methods This multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab. Results Mean age (range) at ravulizumab initiation was 41 years (19–78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3–120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment. Conclusions This is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function.

HLA-G is a non-classical HLA class I molecule that promotes transplant tolerance. It engages the inhibitory receptor LILRB1 on immune effector cells, suppressing cytotoxic responses and inflammation, while promoting tolerogenic and regulatory immune phenotypes. Polymorphisms in the 3' untranslated region (3'UTR) modulate HLA-G expression levels, and promoter variants influence receptor expression. The combined effect on kidney transplant (KTx) rejection has not been systematically studied. Living donor-recipient pairs undergoing KTx were genotyped for nine variants in the 3'UTR region and two single nucleotide polymorphisms (SNPs) in the promoter (PROMO) regions. Haplotypes were arranged for both loci. Clinical endpoints were biopsy-proven T cell-mediated rejection (TCMR) within one year and antibody-mediated rejection (AMR) within five years post-transplant. Donor positivity for 3'UTR-1 or UTR-2 or negative for UTR-3 haplotype were associated with a significantly higher risk of TCMR in both univariate or multivariate analyses. Recipients lacking the -PROMO CG haplotype also had an increased TCMR risk. The combination of an 3'UTR-2 positive donor with a -PROMO CG haplotype negative recipient was found to be an independent predictor of TCMR. In contrast, HLA-G 3'UTR variants were not associated with AMR, while the presence of the recipient -PROMO CG haplotype emerged as an independent AMR risk factor. Donor 3'UTR and recipient -PROMO haplotypes define a functional immunogenetic axis that differentially influence TCMR and AMR. These results support the clinical potential of HLA-G/LILRB1 genetic profiling to improve donor selection in living KTx and to guide the development of novel rejection therapies.

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are increasingly observed in vaccinated individuals. Immune responses towards SARS-CoV-2 variants, particularly Omicron-BA.5, are poorly understood. We investigated the humoral and cellular immune responses of hospitalized COVID-19 patients during Delta and Omicron infection waves. The corresponding SARS-CoV-2 variant of the respective patients were identified by whole genome sequencing. Humoral immune responses were analyzed by ELISA and a cell culture-based neutralization assay against SARS-CoV-2 D614G isolate (wildtype), Alpha, Delta (AY.43) and Omicron (BA.1 and BA.5). Cellular immunity was evaluated with an IFN-γ ELISpot assay. On a cellular level, patients showed a minor IFN-γ response after stimulating PBMCs with mutated regions of SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced. Double-vaccinated patients with Delta breakthrough infection showed a significantly increased neutralizing antibody response against Delta compared to double-vaccinated uninfected controls (median complete neutralization titer (NT ) 640 versus 80, p<0.05). Omicron-BA.1 infection increased neutralization titers against BA.1 in double-vaccinated patients (median NT of 160 in patients versus 20 in controls, p=0.07) and patients that received booster vaccination (median NT of 50 in patients versus 20 in controls, p=0.68). For boosted patients with BA.5 breakthrough infection, we found no enhancing effect on humoral immunity against SARS-CoV-2 variants. Neutralizing antibody titers against Omicron-BA.1 and especially BA.5 were strongly reduced in SARS-CoV-2 breakthrough infections. Delta and Omicron-BA.1 but not Omicron-BA.5 infections boosted the humoral immunity in double-vaccinated patients and patients with booster vaccination. Despite BA.5 breakthrough infection, those patients may still be vulnerable for reinfections with BA.5 or other newly emerging variants of concern.