Loss of Y Chromosome and Cardiovascular Events in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease. METHODS: LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study, n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed. RESULTS: In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events. CONCLUSIONS: LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.

Graph-based association rule learning for context-based health monitoring to enable user-centered assistance.

In response to the demographic change and the accompanying challenges for effective healthcare, approaches to enable using advancements of digitalization and IoT infrastructures as well as AI methods to deliver results in the field of personalized health assistance are necessary. In our research, we aim at enabling user-centered assistance with the help of networked sensors and Health Assistance Systems as well as learning methods based on connected graph data that model the shared system, user, and environmental context. In particular, this paper demonstrates a graph-based dynamic context model for a medication assistance system and presents an association rule learning method using Apriori algorithm to learn correlations between user vitals, activities as well as medication intake behavior. An application scenario for context-based heart rate monitoring is consequently presented as proof of concept, where associated contextual elements from the modeled context relating surges in monitored heart rate to environmental and user activity are shown.

A Polyclonal Immune Function Assay Allows Dose-Dependent Characterization of Immunosuppressive Drug Effects but Has Limited Clinical Utility for Predicting Infection on an Individual Basis.

Dosage of immunosuppressive drugs after transplantation critically determines rejection and infection episodes. In this study, a global immune function assay was characterized among controls, dialysis-patients, and transplant-recipients to evaluate its utility for pharmacodynamic monitoring of immunosuppressive drugs and for predicting infections. Whole-blood samples were stimulated with anti-CD3/toll-like-receptor (TLR7/8)-agonist in the presence or absence of drugs and IFN-γ secretion was measured by ELISA. Additional stimulation-induced cytokines were characterized among T-, B-, and NK-cells using flow-cytometry. Cytokine-secretion was dominated by IFN-γ, and mainly observed in CD4, CD8, and NK-cells. Intra-assay variability was low (CV = 10.4 ± 6.2%), whereas variability over time was high, even in the absence of clinical events (CV = 65.0 ± 35.7%). Cyclosporine A, tacrolimus and steroids dose-dependently inhibited IFN-γ secretion, and reactivity was further reduced when calcineurin inhibitors were combined with steroids. Moreover, IFN-γ levels significantly differed between controls, dialysis-patients, and transplant-recipients, with lowest IFN-γ levels early after transplantation (p < 0.001). However, a single test had limited ability to predict infectious episodes. In conclusion, the assay may have potential for basic pharmacodynamic characterization of immunosuppressive drugs and their combinations, and for assessing loss of global immunocompetence after transplantation, but its application to guide drug-dosing and to predict infectious on an individual basis is limited.

A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors.

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.

Effect of uphill and downhill walking on walking performance in geriatric patients using a wheeled walker.

BACKGROUND: Wheeled walkers are recommended to improve walking performance in older persons and to encourage and assist participation in daily life. Nevertheless, using a wheeled walker can cause serious problems in the natural environment. This study aimed to compare uphill and downhill walking with walking level in geriatric patients using a wheeled walker. Furthermore, we investigated the effect of using a wheeled walker with respect to dual tasking when walking level. METHODS: A total of 20 geriatric patients (median age 84.5 years) walked 10 m at their habitual pace along a level surface, uphill and downhill, with and without a standard wheeled walker. Gait speed, stride length and cadence were assessed by wearable sensors and the walk ratio was calculated. RESULTS: When using a wheeled walker while walking level the walk ratio improved (0.58 m/[steps/min] versus 0.57 m/[steps/min], p = 0.023) but gait speed decreased (1.07 m/s versus 1.12 m/s, p = 0.020) when compared to not using a wheeled walker. With respect to the walk ratio, uphill and downhill walking with a wheeled walker decreased walking performance when compared to level walking (0.54 m/[steps/min] versus 0.58 m/[steps/min], p = 0.023 and 0.55 m/[steps/min] versus 0.58 m/[steps/min], p = 0.001, respectively). At the same time, gait speed decreased (0.079 m/s versus 1.07 m/s, p < 0.0001) or was unaffected. CONCLUSION: The use of a wheeled walker improved the quality of level walking but the performance of uphill and downhill walking was worse compared to walking level when using a wheeled walker.

Problems of older persons using a wheeled walker.

BACKGROUND: Wheeled walkers (WWs) are used to improve mobility and for fall prevention in older persons, but not all users are satisfied with the usability of WWs. Intelligent WWs are being developed to improve the usability. AIMS: The aim of this study was to support the development of intelligent WWs by investigating possible problems of using a WW. METHODS: This study investigated 22 geriatric in-patients (median age 82 years) with and without their WW while opening a door against the direction of walking and passing through. Other possible problems when using WWs were identified by interview. RESULTS: Walking through the door was faster without than with using the WW (8.71 versus 12.86 s, p < 0.001), while interference between door and WW was documented in 41 of 44 (93 %) cases. Backward walking performance was better when using a WW with regard to gait speed, step width and walk ratio (all p < 0.002). Most referred problems when using a WW were walking downhill (83 %) and uphill (77 %) and obstacle crossing in general (77 %). CONCLUSIONS: Problems with opening a door against the direction of walking and the optimization of downhill and uphill walking as well as obstacle crossing should be regarded when developing an intelligent WW.