Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases.

Pro-inflammatory autoantigen-specific CD4+ T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional ex vivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory T cell (Treg) transcription factor. Auto-Th cells responded in vitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to T cell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4+ T cells to humoral autoimmune responses, with implications for therapeutic targeting.

Genetically- and spatially-defined basolateral amygdala neurons control food consumption and social interaction.

The basolateral amygdala (BLA) contains discrete neuronal circuits that integrate positive or negative emotional information and drive the appropriate innate and learned behaviors. Whether these circuits consist of genetically-identifiable and anatomically segregated neuron types, is poorly understood. Also, our understanding of the response patterns and behavioral spectra of genetically-identifiable BLA neurons is limited. Here, we classified 11 glutamatergic cell clusters in mouse BLA and found that several of them were anatomically segregated in lateral versus basal amygdala, and anterior versus posterior regions of the BLA. Two of these BLA subpopulations innately responded to valence-specific, whereas one responded to mixed - aversive and social - cues. Positive-valence BLA neurons promoted normal feeding, while mixed selectivity neurons promoted fear learning and social interactions. These findings enhance our understanding of cell type diversity and spatial organization of the BLA and the role of distinct BLA populations in representing valence-specific and mixed stimuli.

Patiromer to Reduce Albuminuria Through Increased Renin Angiotensin Aldosterone System Inhibition in Patients With CKD-A Feasibility Trial.

Introduction: We tested the feasibility of adding a potassium binder to enable increased renin angiotensin aldosterone system inhibition (RAASi) and reduce albuminuria in patients with chronic kidney disease (CKD). In a controlled trial design, a potassium binder was introduced exclusively in patients developing hyperkalemia after intensified RAASi, thereby mirroring clinical decision-making. Methods: We planned to include 140 patients aged 18 to 80 years with estimated glomerular filtration rate (eGFR) 25 to 60 ml/min per 1.73 m2, albuminuria, and a history of hyperkalemia to an open-label, randomized trial comparing treatment with or without patiromer alongside maximally tolerated RAASi. Patients were randomized only if developing a documented P-potassium >5.5 mmol/l during run-in with intensified RAASi (losartan/spironolactone). The primary end point was change in urine albumin-creatinine ratio (UACR). Results: Screening among 800,000 individuals with available laboratory results yielded just 317 candidates meeting major selection criteria during 18⅔ months, with 75 ultimately included. Among them, only 23 developed P-potassium >5.5 mmol/l, qualifying for randomization. Consequently, only 20 participants completed the study, falling short of the planned 98, precluding a significant effect on the primary outcome. Inclusion and randomization challenges stemmed from a limited pool of eligible patients for intensified RAASi at risk of hyperkalemia, along with a lower than expected incidence of hyperkalemia during run-in. Conclusion: Despite extensive screening efforts, few eligible patients were identified, and fewer developed hyperkalemia during run-in. Hence, a trial design limited to CKD patients at high hyperkalemia risk and including a run-in phase appears unlikely to provide evidence for a potential renal benefit from additional use of potassium binders.

Chemogenetic control of GABAergic activity within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype.

Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The habenulo-interpeduncular (Hb-IPN) circuit contains a high concentration of nAChRs and has been identified as a main circuit involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 and not the Epyc subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naïve mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective and somatic signs of withdrawal. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.

Voltage-Gated Ion Channels Are Transcriptional Targets of Sox10 during Oligodendrocyte Development.

The transcription factor Sox10 is an important determinant of oligodendroglial identity and influences oligodendroglial development and characteristics at various stages. Starting from RNA-seq data, we here show that the expression of several voltage-gated ion channels with known expression and important function in oligodendroglial cells depends upon Sox10. These include the Nav1.1, Cav2.2, Kv1.1, and Kir4.1 channels. For each of the four encoding genes, we found at least one regulatory region that is activated by Sox10 in vitro and at the same time bound by Sox10 in vivo. Cell-specific deletion of Sox10 in oligodendroglial cells furthermore led to a strong downregulation of all four ion channels in a mouse model and thus in vivo. Our study provides a clear functional link between voltage-gated ion channels and the transcriptional regulatory network in oligodendroglial cells. Furthermore, our study argues that Sox10 exerts at least some of its functions in oligodendrocyte progenitor cells, in myelinating oligodendrocytes, or throughout lineage development via these ion channels. By doing so, we present one way in which oligodendroglial development and properties can be linked to neuronal activity to ensure crosstalk between cell types during the development and function of the central nervous system.

Hemodynamic effects of low versus high dialysate bicarbonate concentration in hemodialysis patients.

INTRODUCTION: Hemodialysis treatment using standard dialysate bicarbonate concentrations cause transient metabolic alkalosis possibly associated with hemodynamic instability. The aim of this study was to perform a detailed comparison of high and low dialysate bicarbonate in terms of blood pressure, intradialytic hemodynamic parameters, orthostatic blood pressure, and electrolytes. METHODS: Fifteen hemodialysis patients were examined in a single-blind, randomized, controlled, crossover study. Participants underwent a 4-h hemodialysis session with dialysate bicarbonate concentration of 30 or 38 mmol/L with 1 week between interventions. Blood pressure was monitored throughout hemodialysis, while cardiac output, total peripheral resistance, stroke volume, and central blood volume were assessed with ultrasound dilution technique (Transonic). Orthostatic blood pressure was measured pre- and post-hemodialysis. FINDINGS: With similar ultrafiltration (UF) volume (2.6 L), systolic blood pressure (SBP) tended to decrease more during high dialysate bicarbonate compared to low dialysate bicarbonate; the mean (95% confidence interval) between treatment differences in SBP were: 8 (-4; 20) mmHg (end of hemodialysis) and 7 (0; 15) mmHg (post-hemodialysis). Stroke volume decreased whereas total peripheral resistance increased significantly more during high dialysate bicarbonate compared to low dialysate bicarbonate with mean between treatment differences: Stroke volume: 12 (1; 23) mL; Total peripheral resistance: -2.9 (-5.3; -0.5) mmHg/(L/min). Cardiac output tended to decrease more with high dialysate bicarbonate compared to low dialysate bicarbonate with mean between treatment difference 0.7 (0.0; 1.4) L/min. High dialysate bicarbonate caused alkalosis, hypocalcemia, and lower plasma potassium, whereas patients remained normocalcemic with normal pH during low dialysate bicarbonate. Orthostatic blood pressure response after dialysis did not differ significantly. DISCUSSION: The use of high dialysate bicarbonate compared to low dialysate bicarbonate was associated with hypocalcemia, alkalosis, and a more pronounced hypokalemia. During hemodialysis with UF, a better preservation of blood pressure, stroke volume, and cardiac output may be achieved with low dialysate bicarbonate compared to high dialysate bicarbonate.

Empowering γδ T-cell functionality with vitamin C.

Vitamin C (ascorbic acid) is a potent antioxidant and a cofactor for various enzymes including histone demethylases and methylcytosine dioxygenases. Vitamin C also exerts direct cytotoxicity toward selected tumor cells including colorectal carcinoma. Moreover, vitamin C has been shown to impact immune cell differentiation at various levels including maturation and/or functionality of T cells and their progenitors, dendritic cells, B cells, and NK cells. γδ T cells have recently attracted great interest as effector cells for cell-based cancer immunotherapy, due to their HLA-independent recognition of a large variety of tumor cells. While γδ T cells can thus be also applied as an allogeneic off-the-shelf product, it is obvious that the effector function of γδ T cells needs to be optimized to ensure the best possible clinical efficacy. Here we review the immunomodulatory mechanisms of vitamin C with a special focus on how vitamin C enhances the effector function of γδ T cells. We also discuss future directions of how vitamin C can be used in the clinical setting to boost the efficacy of adoptive cell therapies.

Nausea-induced suppression of feeding is mediated by central amygdala Dlk1-expressing neurons.

The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well understood. Pkcδ neurons in the lateral subdivision of the central amygdala (CeA) suppress feeding in response to satiety signals and nausea. Here, we characterized neurons enriched in the medial subdivision (CeM) of the CeA marked by expression of Dlk1. CeADlk1 neurons are activated by nausea, but not satiety, and specifically suppress feeding induced by nausea. Artificial activation of CeADlk1 neurons suppresses drinking and social interactions, suggesting a broader function in attenuating motivational behavior. CeADlk1 neurons form projections to many brain regions and exert their anorexigenic activity by inhibition of neurons of the parabrachial nucleus. CeADlk1 neurons are inhibited by appetitive CeA neurons, but also receive long-range monosynaptic inputs from multiple brain regions. Our results illustrate a CeA circuit that regulates nausea-induced feeding suppression.

Protocol for a randomised controlled trial comparing warfarin with no oral anticoagulation in patients with atrial fibrillation on chronic dialysis: the Danish Warfarin-Dialysis (DANWARD) trial.

INTRODUCTION: Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit. METHODS AND ANALYSIS: The DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0-3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient. ETHICS AND DISSEMINATION: The study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00.

Invasively Measured Aortic Systolic Blood Pressure and Office Systolic Blood Pressure in Cardiovascular Risk Assessment in CKD.

Introduction: Central aortic blood pressure (BP) could be a better risk predictor than brachial BP. This study examined whether invasively measured aortic systolic BP improved outcome prediction beyond risk prediction by conventional cuff-based office systolic BP in patients with and without chronic kidney disease (CKD). Methods: In a prospective, longitudinal cohort study, aortic and office systolic BPs were registered in patients undergoing elective coronary angiography (CAG). CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Multivariable Cox models were used to determine the association with incident myocardial infarction (MI), stroke, and death. Results: Aortic and office systolic BPs were available in 39,866 patients (mean age: 64 years; 58% males; 64% with hypertension) out of which 6605 (17%) had CKD. During a median follow-up of 7.2 years (interquartile range: 4.6-10.1 years), 1367 strokes (CKD: 353), 1858 MIs (CKD: 446), and 7551 deaths (CKD: 2515) occurred. CKD increased the risk of stroke, MI, and death significantly. Office and aortic systolic BP were both associated with stroke in non-CKD patients (adjusted hazard ratios with 95% confidence interval per 10 mm Hg: 1.08 [1.05-1.12] and 1.06 [1.03-1.09], respectively) and with MI in patients with CKD (adjusted hazard ratios: 1.08 [1.03-1.13] and 1.08 [1.04-1.12], respectively). There was no significant difference between prediction of outcome with office or aortic systolic BP when adjusted models were compared with C-statistics. Conclusion: Regardless of CKD status, invasively measured central aortic systolic BP does not improve the ability to predict outcome compared with brachial office BP measurement.

Synthesis of α3ß4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3ß4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3ß4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

Absence of Coronary Artery Disease is a Strong Negative Predictor of Major Adverse Cardiovascular Events in Patients with Chronic Kidney Disease.

Purpose: To investigate the interplay between chronic kidney disease (CKD) and coronary artery disease (CAD) on the incidence of cardiovascular events in patients with suspected chronic coronary syndrome (CCS). Patients and Methods: Patients with suspected CCS who underwent first-time coronary angiography in Western Denmark between 2003 and 2016 were included in this cohort study. Moreover, an age- and sex-matched general population cohort was established. Patients were stratified according to estimated glomerular filtration rate (eGFR). Presence of CAD was defined as ≥1 obstructive stenosis or non-obstructive diffuse disease. Major adverse cardiovascular events (MACE) were defined as a composite of myocardial infarction, ischemic stroke, and cardiac death. Results: A total of 42,611 patients were included with a median follow-up of 7.3 years. Patients without and with CAD had MACE rates per 100 person-years that were 0.52 and 1.67 for eGFR ≥90 mL/min/1.73 m2, 0.68 and 2.09 for eGFR 60-89 mL/min/1.73 m2, 1.27 and 3.85 for eGFR 30-59 mL/min/1.73 m2, and 2.27 and 6.92 for eGFR <30 mL/min/1.73 m2. Comparing to eGFR ≥90 mL/min/1.73 m2, the adjusted incidence rate ratios for MACE were 1.29 (1.10-1.51) for eGFR 60-89 mL/min/1.73 m2, 1.86 (1.49-2.33) for eGFR 30-59 mL/min/1.73 m2, and 3.57 (1.92-6.67) for eGFR <30 mL/min/1.73 m2 in patients without CAD, and 1.11 (1.03-1.20), 1.71 (1.55-1.90), and 2.46 (1.96-3.09) in patients with CAD. The inverse relationship between kidney function and risk of MACE was confirmed when comparing patients with and without CAD to matched individuals in the general population. Conclusion: Absence of CAD is a strong negative predictor of major adverse cardiovascular events in patients with CKD.

γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids.

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αß T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.

The unfolded protein response links ER stress to cancer-associated thrombosis.

Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.

Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.

The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic signatures of cell types and their links to function remain poorly understood. Using single-nucleus RNA sequencing, we describe nine CeA cell clusters, of which four are mostly associated with appetitive and two with aversive behaviors. To analyze the activation mechanism of appetitive CeA neurons, we characterized serotonin receptor 2a (Htr2a)-expressing neurons (CeAHtr2a) that comprise three appetitive clusters and were previously shown to promote feeding. In vivo calcium imaging revealed that CeAHtr2a neurons are activated by fasting, the hormone ghrelin, and the presence of food. Moreover, these neurons are required for the orexigenic effects of ghrelin. Appetitive CeA neurons responsive to fasting and ghrelin project to the parabrachial nucleus (PBN) causing inhibition of target PBN neurons. These results illustrate how the transcriptomic diversification of CeA neurons relates to fasting and hormone-regulated feeding behavior.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is a cytosolic sensor of microbial and host-derived DNA and plays a key role in innate immunity. Activation of STING by cyclic dinucleotide (CDN) ligands in human monocytes induces a type I interferon response and production of pro-inflammatory cytokines associated with the induction of massive cell death. In this study we have re-evaluated the effect of signal strength of STING activation on the cytokine plasticity of human monocytes. CDN (2'3'c-GAMP) and non-CDN (diABZI, MSA-2) STING ligands in the range of EC50 concentrations (15 µM 2'3'c-GAMP, 100 nM diABZI, 25 µM MSA-2) induced IFN-ß, IP-10, and large amounts of IL-1ß and TNF-α, but no IL-10 or IL-19. Interestingly, LPS-induced production of IL-10 and IL-19 was abolished in the presence of diABZI or MSA-2, whereas IL-1ß and TNF-α were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 µM) or 100-fold lower (diABZI, i.e. 1 nM) concentrations strongly stimulated secretion of anti-inflammatory IL-10 and IL-19, but little of IL-1ß and TNF-α. Induction of IL-10 was associated with up-regulation of PRDM1 (Blimp-1). While cytokine secretion stimulated by the higher concentrations was accompanied by apoptosis as shown by cleavage of caspase-3 and PARP-1, the low concentrations did not trigger overt cell death yet induced cleavage of gasdermin-D. Our results reveal a previously unrecognized plasticity of human monocytes in their signal strength-dependent production of pro- versus anti-inflammatory cytokines upon STING activation.

The use of non-vitamin K oral anticoagulants in dialysis patients-A systematic review.

Non-vitamin K oral anticoagulants (NOACs) are used for prevention of thromboembolic events, but their use in dialysis patients is debatable. This study investigated the available evidence for the use of NOACs in dialysis patients. Online databases were systematically searched for eligible studies including pharmacokinetic (PK) studies, cohort studies, and randomized control trials (RCTs) comparing NOAC with vitamin K antagonist (VKA) or no anticoagulant treatment. Newcastle Ottawa Scale and Cochrane Risk of bias tool were used for quality assessment. Twenty studies were identified (nine PK studies, two RCTs, and nine cohort studies). Most of the studies investigated apixaban or rivaroxaban. In dialysis patients, less accumulation was reported with apixaban and rivaroxaban compared to dabigatran and edoxaban. PK studies indicate that high dose apixaban or rivaroxaban should be avoided. The two RCTs (rivaroxaban/apixaban vs. VKA) were small and underpowered regarding stroke and bleeding outcomes. Most cohort studies found apixaban superior to VKA, whereas comparison of rivaroxaban with VKA yielded conflicting results. Cohort studies comparing apixaban high dose (5 mg) with low dose (2.5 mg) twice daily suggest a lower risk of stroke with high dose but also a higher risk of bleeding with high dose. Apixaban versus no anticoagulation was compared in one cohort study and did not lower the risk of stroke compared with non-treated regardless of apixaban dosage. Widespread use of NOACs in dialysis patients is limited by adequately sized RCTs. Available evidence suggests a potential for use of apixaban and rivaroxaban in reduced dose.

Estimated Pulse Wave Velocity Is Associated With All-Cause Mortality During 8.5 Years Follow-up in Patients Undergoing Elective Coronary Angiography.

Background Estimated pulse wave velocity (ePWV) calculated by equations using age and blood pressure has been suggested as a new marker of mortality and cardiovascular risk. However, the prognostic potential of ePWV during long-term follow-up in patients with symptoms of stable angina remains unknown. Methods and Results In this study, ePWV was calculated in 25 066 patients without diabetes, previous myocardial infarction (MI), stroke, heart failure, or valvular disease (mean age 63.7±10.5 years, 58% male) with stable angina pectoris undergoing elective coronary angiography during 2003 to 2016. Multivariable Cox models were used to assess the association with incident all-cause mortality, MI, and stroke. Discrimination was assessed using Harrell´s C-index. During a median follow-up period of 8.5 years (interquartile range 5.5-11.3 years), 779 strokes, 1233 MIs, and 4112 deaths were recorded. ePWV was associated with all-cause mortality (hazard ratio [HR] per 1 m/s, 1.13; 95% CI, 1.05-1.21) and MI (HR per 1 m/s 1.23, 95% CI, 1.09-1.39) after adjusting for age, systolic blood pressure, body mass index, smoking, estimated glomerular filtration rate, Charlson Comorbidity Index score, antihypertensive treatment, statins, aspirin, and number of diseased coronary arteries. Compared with traditional risk factors, the adjusted model with ePWV was associated with a minor but likely not clinically relevant increase in discrimination for mortality, 76.63% with ePWV versus 76.56% without ePWV, P<0.05. Conclusions In patients with stable angina pectoris, ePWV was associated with all-cause mortality and MI beyond traditional risk factors. However, the added prediction of mortality was not improved to a clinically relevant extent.