High RIPK3 expression is associated with a higher risk of early kidney transplant failure.

Renal ischemia-reperfusion injury (IRI) is associated with reduced allograft survival, and each additional hour of cold ischemia time increases the risk of graft failure and mortality following renal transplantation. Receptor-interacting protein kinase 3 (RIPK3) is a key effector of necroptosis, a regulated form of cell death. Here, we evaluate the first-in-human RIPK3 expression dataset following IRI in kidney transplantation. The primary analysis included 374 baseline biopsy samples obtained from renal allografts 10 minutes after onset of reperfusion. RIPK3 was primarily detected in proximal tubular cells and distal tubular cells, both of which are affected by IRI. Time-to-event analysis revealed that high RIPK3 expression is associated with a significantly higher risk of one-year transplant failure and prognostic for one-year (death-censored) transplant failure independent of donor and recipient associated risk factors in multivariable analyses. The RIPK3 score also correlated with deceased donation, cold ischemia time and the extent of tubular injury.

Immunophenotypic Characterization of Citrate-Containing A Concentrates in Maintenance Hemodialysis: A Pre-Post Study.

Introduction: Due to chronic inflammation, maintenance hemodialysis (MHD) patients continue to show excess mortality. Acetate-free citrate-buffered A concentrates could be a way to improve the biocompatibility of the procedure, reduce chronic inflammation, and thus in the long term improve the prognosis of patients. Methods: Using a pre-post design (3 months of acetate followed by 3 months of citrate-acidified A concentrates in standard bicarbonate-based dialysate hemodialysis, CiaHD) and linear mixed model analysis in 61 stable HD patients, we assessed the impact of CiaHD on counts and phenotypes of peripheral T cells and monocytes by flow cytometry. Results: Switching to CiaHD left C-reactive protein (CRP) levels and leucocyte counts unaffected. However, CiaHD increased lymphocyte counts ex vivo. Furthermore, we found a decrease in total CD3+CD4+CD69+ ((109/L), mean ± SD: acetate, 0.04 ± 1.0 versus citrate, 0.02 ± 0.01; P = 0.02) activated cells, while the number of CD28+ T cells remained stable. No differences were noted regarding T-cell exhaustion marker expression, CD14+CD16+ monocyte counts, and PMN-MDSCs. Conclusion: Compared with acetate, CiaHD has a minor impact on lymphocyte counts and CD4+T-cell activation, which was independent of systemic CRP and ionized magnesium, calcium levels, and other dialysis prescription modalities.

Automatic ECG-based detection of left ventricular hypertrophy and its predictive value in haemodialysis patients.

Objective.Left ventricular hypertrophy (LVH) is one of the most severe risk factors in patients with end-stage kidney disease (ESKD) regarding all-cause and cardiovascular mortality. It contributes to the risk of sudden cardiac death which accounts for approximately 25% of deaths in ESKD patients. Electrocardiography (ECG) is the least expensive way to assess whether a patient has LVH, but manual annotation is cumbersome. Thus, an automated approach has been developed to derive ECG-based LVH parameters. The aim of the current study is to compare automatic to manual measurements and to investigate their predictive value for cardiovascular and all-cause mortality.Approach.From the 12-lead 24 h ECG measurements of 301 ESKD patients undergoing haemodialysis, three different LVH parameters were calculated. Peguero-Lo Presti voltage, Cornell voltage, and Sokolow-Lyon voltage were automatically derived and compared to the manual annotations. To determine the agreement between manual and automatic measurements and their predictive value, Bland-Altman plots were created and Cox regression analysis for cardiovascular and all-cause mortality was performed.Main results.The median values for the automatic assessment were: Peguero-Lo Presti voltage 1.76 mV (IQR 1.29-2.55), Cornell voltage 1.14 mV (IQR 0.721-1.66), and Sokolow-Lyon voltage 1.66 mV (IQR 1.08-2.23). The mean differences when compared to the manual measurements were -0.027 mV (0.21 SD), 0.027 mV (0.13 SD) and -0.025 mV (0.24 SD) for Peguero-Lo Presti, Cornell, and Sokolow-Lyon voltage, respectively. The categorial LVH detection based on pre-defined thresholds differed in only 13 cases for all indices between manual and automatic assessment. Proportional hazard ratios only differed slightly in categorial LVH detection between manually and automatically determined LVH parameters; no differences could be found for continuous parameters.Significance.This study provides evidence that automatic algorithms can be as reliable in LVH parameter assessment and risk prediction as manual measurements in ESKD patients undergoing haemodialysis.

Ethnic diversity fosters the social integration of refugee students.

Forced migration has become a global megatrend, and many refugees are school aged. As social integration is key to their wellbeing and success, it is pivotal to determine factors that promote the social integration of refugee youth within schools. Here, using a large, nationally representative social network dataset from Germany, we examine the relationships of refugee adolescents with their peers (304 classrooms, 6,390 adolescents and 487 refugees). We find that refugee adolescents have fewer friends and are more often rejected as desk mates than their classmates. Crucially, however, they are less rejected in more diverse classrooms. This results from two basic processes: (1) more opportunities to meet other ethnic minority peers, who are more accepting of refugees in general and (2) higher acceptance of refugee adolescents by ethnic majority peers in more diverse settings. Our results can help promote the social adjustment of young refugees in school and mitigate the negative consequences of prejudice.

Evaluation of corneal biomechanical properties using the ocular response analyzer and the dynamic Scheimpflug-Analyzer Corvis ST in high pressure and normal pressure open-angle glaucoma patients.

PURPOSE: To characterize differences in corneal biomechanics in high (HPG) and normal pressure (NPG) primary open-angle glaucoma, and its association to disease severity. METHODS: Corneal biomechanical properties were measured using the Ocular Response Analyzer (ORA) and the dynamic Scheimpflug-Analyzer Corvis ST (CST). Disease severity was functionally assessed by automated perimetry (Humphrey field analyzer) and structurally with the Heidelberg Retina Tomograph. To avoid a possible falsification by intraocular pressure, central corneal thickness and age, which strongly influence ORA and CST measurements, group matching was performed. Linear mixed models and generalized estimating equations were used to consider inter-eye correlation. RESULTS: Following group matching, 60 eyes of 38 HPG and 103 eyes of 60 NPG patients were included. ORA measurement revealed a higher CRF in HPG than in NPG (P < 0.001). Additionally, the CST parameter integrated radius (P < 0.001) was significantly different between HPG and NPG. The parameter SSI (P < 0.001) representing corneal stiffness was higher in HPG than in NPG. Furthermore, regression analysis revealed associations between biomechanical parameters and indicators of disease severity. In HPG, SSI correlated to RNFL thickness. In NPG, dependencies between biomechanical readings and rim area, MD, and PSD were shown. CONCLUSION: Significant differences in corneal biomechanical properties were detectable between HPG and NPG patients which might indicate different pathophysiological mechanisms underlying in both entities. Moreover, biomechanical parameters correlated to functional and structural indices of diseases severity. A reduced corneal deformation measured by dynamic methods was associated to advanced glaucomatous damage.

A randomized prospective cross over study on the effects of medium cut-off membranes on T cellular and serologic immune phenotypes in hemodialysis.

Extended cut-off filtration by medium cut-off membranes (MCO) has been shown to be safe in maintenance hemodialysis (HD). The notion of using them for the control of chronic low-grade inflammation and positively influencing cellular immune aberrations seems tempting. We conducted an open label, multicenter, randomized, 90 day 2-phase cross over clinical trial (MCO- vs. high flux-HD). 46 patients underwent randomization of which 34 completed the study. Dialysate- or pre- and post-dialysis serum inflammatory mediators were assayed for each study visit. Ex vivo T cell activation was assessed from cryopreserved leucocytes by flow cytometry. Linear mixed models were used to compare treatment modalities, with difference in pre-dialysis serum MCP-1 levels after 3 months as the predefined primary endpoint. Filtration/dialysate concentrations of most mediators, including MCP-1 (mean ± SD: 10.5 ± 5.9 vs. 5.1 ± 3.8 pg/ml, P < 0.001) were significantly increased during MCO- versus high flux-HD. However, except for the largest mediator studied, i.e., YKL-40, this did not confer any advantages for single session elimination kinetics (post-HD mean ± SD: 360 ± 334 vs. 564 ± 422 pg/ml, P < 0.001). No sustained reduction of any of the studied mediators was found neither. Still, the long-term reduction of CD69+ (P = 0.01) and PD1+ (P = 0.02) activated CD4+ T cells was striking. Thus, MCO-HD does not induce reduction of a broad range of inflammatory mediators studied here. Long-term reduction over a 3-month period was not possible. Increased single session filtration, as evidenced by increased dialysate concentrations of inflammatory mediators during MCO-HD, might eventually be compensated for by compartment redistribution or increased production during dialysis session. Nevertheless, lasting effects on the T-cell phenotype were seen, which deserves further investigation.

Mortality prediction of retinal vessel diameters and function in a long-term follow-up of haemodialysis patients.

AIM: Retinal vessel diameters are candidate biomarkers of mortality prediction in large population-based studies. We aimed to investigate the predictive value of retinal vessel diameters and flicker-induced retinal arteriolar and venular dilation on all-cause mortality in long-term follow-up of haemodialysis patients. METHODS AND RESULTS: Retinal vessel diameters as well as maximum arteriolar (aMax) and venular dilation (vMax) were investigated in 275 and 214 haemodialysis patients, respectively. Patients were observed in a long-term follow-up for a median period of 73 months. About 36% (76/214) and 41% (113/275) of patients died. Arteriolar and venular diameters were 175 ± 19 and 208 ± 20 µm, respectively. Median aMax and vMax were 1.6 (0.3-3.3) and 3.2 (2.0-5.1)%. Patients within the lowest tertile of vMax showed lower 5-year survival rates compared with the highest tertile (50.6 vs. 82.1%) and also exhibited a higher incidence of infection-related deaths (21.7 vs. 4.0%). Univariate hazard ratio (HR) per standard deviation increase of vMax for all-cause mortality was 0.69 (0.54-0.88) and was even more pronounced for infection-related mortality [HR 0.53 (0.33-0.83)]. Regarding all-cause mortality, multivariate adjustment for eight non-retinal mortality predictors including interleukin-6 did not attenuate the HR relevantly [0.73 (0.54-0.98)]. Arteriolar and venular diameters did not predict all-cause nor cardiovascular and infection-related mortality. CONCLUSIONS: Long-term follow-up of patients on haemodialysis demonstrated the potential of retinal venular dilation capacity for mortality prediction, which was most pronounced for infection-related mortality. In the same cohort, retinal arteriolar and venular diameters showed no predictive value for hard endpoints. Retinal venular dilation but not arteriolar and venular diameters is a valuable diagnostic biomarker for risk prediction in patients with end-stage renal disease and should be considered for monitoring of critically ill patients.

Social comparison effects on academic self-concepts-Which peers matter most?

Social comparisons with peers are important sources of self-development during adolescence. Many previous studies showed that students' academic self-concepts (ASC) form by contrasting one's own achievement with the average of one's class or school (the Big-Fish-Little-Pond Effect [BFLPE]). Based on social comparison theory, however, we would expect some peers to be more likely social comparison targets than other peers, for example, because they are more visible or students perceive them as similar to themselves. In this study, we used sociometric data to analyze which peers play the most important role for social comparison effects on ASC. We examined how the average achievement of friends, study partners, peers perceived as popular by the student, as well as same-gender and same-ethnic peers affect the general ASC and how these effects compare to the effect of the classroom's average achievement. The study was based on a German longitudinal sample of 2,438 students (44% no recent immigrant background, 19% Turkish immigrant background, 10% Eastern European immigrant background, 27% other immigrant background) from 117 school classes that were followed from grade 9 to 10. Results from longitudinal social network analysis do not confirm substantial incremental effects of specific types of peers, while class average achievement showed a stable negative effect (confirming the BFLPE). In addition, we could provide evidence for social selection effects based on ASC. We conclude that classrooms provide a specific setting that imposes social comparisons with the "generalized peer" rather than with specific subgroups of peers. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus.

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-ß superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6lpr/lpr) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15-/- C57BL/6 and lupus-prone C57BL/6lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system.

Cognitive impairment and microvascular function in end-stage renal disease.

OBJECTIVE: Hemodialysis patients show an approximately threefold higher prevalence of cognitive impairment compared to the age-matched general population. Impaired microcirculatory function is one of the assumed causes. Dynamic retinal vessel analysis is a quantitative method for measuring neurovascular coupling and microvascular endothelial function. We hypothesize that cognitive impairment is associated with altered microcirculation of retinal vessels. METHODS: 152 chronic hemodialysis patients underwent cognitive testing using the Montreal Cognitive Assessment. Retinal microcirculation was assessed by Dynamic Retinal Vessel Analysis, which carries out an examination recording retinal vessels' reaction to a flicker light stimulus under standardized conditions. RESULTS: In unadjusted as well as in adjusted linear regression analyses a significant association between the visuospatial executive function domain score of the Montreal Cognitive Assessment and the maximum arteriolar dilation as response of retinal arterioles to the flicker light stimulation was obtained. CONCLUSION: This is the first study determining retinal microvascular function as surrogate for cerebral microvascular function and cognition in hemodialysis patients. The relationship between impairment in executive function and reduced arteriolar reaction to flicker light stimulation supports the involvement of cerebral small vessel disease as contributing factor for the development of cognitive impairment in this patient population and might be a target for noninvasive disease monitoring and therapeutic intervention.

Electrocardiographic parameters of left ventricular hypertrophy and prediction of mortality in hemodialysis patients.

BACKGROUND: In hemodialysis patients, left ventricular hypertrophy (LVH) contributes to high cardiovascular mortality. We examined cardiovascular mortality prediction by the recently proposed Peguero-Lo Presti voltage since it identifies more patients with electrocardiographic (ECG) LVH than Cornell or Sokolow-Lyon voltages. METHODS: A total of 308 patients on hemodialysis underwent 24 h ECG recordings. LVH parameters were measured before and after dialysis. The primary endpoint of cardiovascular mortality was recorded during a median 3-year follow up. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score. RESULTS: The Peguero-Lo Presti voltage identified with 21% the most patients with positive LVH criteria. All voltages significantly increased during dialysis. Factors such as ultrafiltration rate, Kt/V, body mass index, sex, and phosphate were the most relevant for these changes. During follow-up, 26 cardiovascular deaths occurred. Post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages were independently associated with cardiovascular mortality in unadjusted and adjusted analysis. The Sokolow-Lyon voltage was not significantly associated with mortality. An optimal cut-off for the prediction of cardiovascular mortality was estimated at 1.38 mV for the Peguero-Lo Presti. CONCLUSIONS: The post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages allowed independent risk prediction of cardiovascular mortality in hemodialysis patients. Measuring the ECG LVH parameters after dialysis might allow a standardized interpretation as dialysis-specific factors influence the voltages.

U-Shaped Association of the Heart Rate Variability Triangular Index and Mortality in Hemodialysis Patients With Atrial Fibrillation.

Background: Atrial fibrillation (AF) is common in hemodialysis patients and contributes to increased mortality. We aimed to examine heart rate variability triangular index (HRVI) in hemodialysis patients with AF as it has recently been reported to predict mortality in AF patients without kidney disease. Methods: A total of 88 patients on hemodialysis with a medical history of AF or newly diagnosed AF underwent 24-h electrocardiography recordings. The primary endpoint of cardiovascular mortality was recorded during a median follow up of 3.0 years. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score. Results: Median age was 76 years, median dialysis vintage was 27 months. Altogether, 22 and 44 patients died due to cardiovascular and non-cardiovascular causes. In 55% of patients AF was present during the recording. Kaplan-Meier plots of HRVI quartiles suggested a non-linear association between HRVI, cardiovascular, and all-cause mortality which was confirmed in non-linear Cox regression analysis. Adjusted linear Cox regression revealed a hazard ratio of 6.2 (95% CI: 2.1-17.7, p = 0.001) and 2.2 (95% CI: 1.3-3.8, p = 0.002) for the outer quartiles (combined first and fourth quartile) for cardiovascular and all-cause mortality, respectively. Patients in the first quartile were more likely to have sinus rhythm whereas patients in the fourth quartile were more likely to have AF. Conclusions: We found a U-shaped association between HRVI and mortality in hemodialysis AF patients. The results might contribute to risk stratification independent of known risk scores in hemodialysis AF patients.

Clinico-genetic findings in 509 frontotemporal dementia patients.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Application of regularized regression to identify novel predictors of mortality in a cohort of hemodialysis patients.

Cohort studies often provide a large array of data on study participants. The techniques of statistical learning can allow an efficient way to analyze large datasets in order to uncover previously unknown, clinically relevant predictors of morbidity or mortality. We applied a combination of elastic net penalized Cox regression and stability selection with the aim of identifying novel predictors of mortality in a cohort of prevalent hemodialysis patients. In our analysis we included 475 patients from the "rISk strAtification in end-stage Renal disease" (ISAR) study, who we split into derivation and confirmation cohorts. A wide array of examinations was available for study participants, resulting in over a hundred potential predictors. In the selection approach many of the well established predictors were retrieved in the derivation cohort. Additionally, the serum levels of IL-12p70 and AST were selected as mortality predictors and confirmed in the withheld subgroup. High IL-12p70 levels were specifically prognostic of infection-related mortality. In summary, we demonstrate an approach how statistical learning can be applied to a cohort study to derive novel hypotheses in a data-driven way. Our results suggest a novel role of IL-12p70 in infection-related mortality, while AST is a promising additional biomarker in patients undergoing hemodialysis.

Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.

Myeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

Extracorporeal multiorgan support including CO2-removal with the ADVanced Organ Support (ADVOS) system for COVID-19: A case report.

A substantial part of COVID-19-patients suffers from multi-organ failure (MOF). We report on an 80-year old patient with pulmonary, renal, circulatory, and hepatic failure. We decided against the use of extracorporeal membrane oxygenation (ECMO) due to old age and a SOFA-score of 13. However, the patient was continuously treated with the extracorporeal multi-organ- "ADVanced Organ Support" (ADVOS) device (ADVITOS GmbH, Munich, Germany). During eight 24h-treatment-sessions blood flow (100-300 mL/min), dialysate flow (160-320 mL/min) and dialysate pH (7.6-9.0) were adapted to optimize arterial PaCO2 and pH. Effective CO2 removal and correction of acidosis could be demonstrated by mean arterial- versus post-dialyzer values of pCO2 (68.7 ± 13.8 vs. 26.9 ± 11.6 mmHg; p < 0.001). The CO2-elimination rate was 48 ± 23mL/min. The initial vasopressor requirement could be reduced in parallel to pH-normalization. Interruptions of ADVOS-treatment repeatedly resulted in reversible deteriorations of paCO2 and pH. After 95 h of continuous extracorporeal decarboxylating therapy the patient had markedly improved circulatory parameters compared to baseline. In the context of secondary pulmonary infection and progressive liver failure, the patient had a sudden cardiac arrest. In accordance with the presumed patient will, we decided against mechanical resuscitation. Irrespective of the outcome we conclude that extracorporeal CO2 removal and multiorgan-support were feasible in this COVID-19-patient. Combined and less invasive approaches such as ADVOS might be considered in old-age-COVID-19 patients with MOF.

Impact of Janus Kinase Inhibition on the Treatment of Axial Spondyloarthropathies.

Many immune cells and effector molecules (e.g. cytokines, Interferons, growth factors) utilize different combinations of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules to transduce signals from the cell surface to the nucleus, where they regulate transcription. This pathway is basically involved in almost all inflammatory diseases and also in the interleukin (IL)-23/IL-17 cascade, which is an essential part of the pathogenesis of spondyloarthropathies (SpA). Upon evidence from in vitro and in vivo experiments indicating disease-modifying effects of JAK inhibition in inflammatory joint disease, numerous inhibitors of the JAK/STAT pathway (= JAKinibs) with different selectivity against the four members of the JAK family [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] were developed. Trials in rheumatoid arthritis were successful with respect to efficacy and safety, and currently, three JAKinibs are approved for the treatment of rheumatoid arthritis in the European Union. Although new treatment options (anti-IL-23, anti-IL-17, and phosphodiesterase 4 inhibitors) have become available for spondyloarthritis and especially psoriatic arthritis (PsA) within the last years, most of them are biologics and do not address all disease manifestations equally. Therefore, multiple trials were initiated to evaluate JAKinibs in PsA and axial spondyloarthritis (axSpA). A trial of Tofacitinib (OPAL) was successful in PsA and has led to the inclusion of JAKinibs into the treatment algorithm. Currently many trials with JAKinibs are ongoing for PsA and axSpA, with one phase III trial of upadacitinib (selective JAK1 inhibitor) showing good therapeutic response in active radiographic axSpA.

Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients.

Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

Heart Failure and Atrial Fibrillation Modify the Associations of Nocturnal Blood Pressure Dipping Pattern With Mortality in Hemodialysis Patients.

Heart failure (HF), hypertension, and abnormal nocturnal blood pressure dipping are highly prevalent in hemodialysis patients. Atrial fibrillation (AF) and HF might be important mediators for the association of abnormal dipping patterns with worse prognosis. Thus, the aim of this study is to investigate the association of dipping with mortality in hemodialysis patients and to assess the influence of AF and HF. In total, 525 hemodialysis patients underwent 24-hour ambulatory blood pressure monitoring. All-cause and cardiovascular mortality served as end points. Patients were categorized according to their systolic dipping pattern (dipper, nondipper, and reverse dipper). Cox regression analysis was performed to determine the association between dipping pattern and study end points with dipping as reference. Subgroup analysis was performed for patients with and without AF or HF. In total, 185 patients with AF or HF and 340 patients without AF or HF were included. During a median follow-up of 37.8 months, 177 patients died; 81 from cardiovascular causes. Nondipping and reverse dipping were significantly associated with all-cause mortality in the whole cohort (nondipper: hazard ratio, 1.95 [1.22-3.14]; P=0.006; reverse dipper: hazard ratio, 2.31 [1.42-3.76]; P<0.001) and in patients without AF or HF (nondipper: hazard ratio, 2.78 [1.16-6.66]; P=0.02; reverse dipper: hazard ratio, 4.48 [1.87-10.71]; P<0.001) but not in patients with AF or HF. For cardiovascular mortality, associations were again significant in patients without AF or HF and in the whole cohort. The observed associations remained significant after adjustment for possible confounders. This study provides well-powered evidence for the association between abnormal dipping patterns and mortality in hemodialysis patients and suggests that HF or AF modifies this association.