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In the past decade, scientific research in the area of Nephrology has focused on evaluating the clinical utility and performance of various biomarkers for diagnosis, risk stratification and prognosis. Before implementing a biomarker in everyday clinical practice for screening a specific disease context, specific statistic measures are necessary to evaluate the diagnostic accuracy and performance of this biomarker. Receiver Operating Characteristic (ROC) Curve analysis is an important statistical method used to estimate the discriminatory performance of a novel diagnostic test, identify the optimal cut-off value for a test that maximizes sensitivity and specificity, and evaluate the predictive value of a certain biomarker or risk, prediction score. Herein, through practical examples, we aim to present a simple methodological approach to explain in detail the principles and applications of ROC curve analysis in the field of nephrology pertaining diagnosis and prognosis., (© 2024. The Author(s).)

Background: Neuropeptide Y (NPY) is a neurotransmitter expressed in both the central and peripheral nervous systems, which is involved in regulating a multitude of physiological processes ranging from arterial pressure, energy balance, the immune response and inflammation and renal electrolyte transport. In a cohort of chronic kidney disease (CKD) patients, we recently showed that high plasma NPY levels predict renal disease progression independently of hypertension and other risk factors but the causal nature of this association remains unproven., Methods: In the same cohort of the previous study, we tested the relationship of NPY gene variability, as assessed by five single nucleotide polymorphisms (SNPs) that explained the whole gene variability, with the incidence rate of a predefined combined renal endpoint (dialysis/transplantation/estimated glomerular filtration rate reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months) in 735 ethnically homogeneous patients with stage 2-5 CKD., Results: Two variants [rs16131 (recessive model for the T risk allele: TT, n  = 563; CT + CC, n  = 172) and rs16140 (dominant model for the G risk allele: GG + CG, n  = 413; CC, n  = 322)] were coherently associated with the incidence rate of renal events [hazard ratio (HR) ranging from 1.39 to 1.57, P  ≤ 0.015] and this was also true when the two SNPs were jointly introduced into the same Cox model ( P  ≤ 0.043). The analysis of the biological interaction showed a significant synergism between the NPY rs16131 and rs16140 variants. Indeed, patients harboring NPY rs16131 TT and NPY rs16140 GG + CG risk genotypes had a much higher HR of renal events [HR: 1.80, 95% confidence interval (CI):1.16-2.79, P  = 0.009] than that expected in the absence of biological interaction under both the additive and multiplicative models and the attributable proportion due to interaction (AP) was 25% and 38% on crude and adjusted analyses, respectively., Conclusion: This study, based on the Mendelian randomization approach and using NPY gene variants as instrumental variables to test the link between NPY and CKD progression, is in line with findings indicating that high plasma NPY levels predict an increased risk for renal events and lend support to the hypothesis that NPY is causally involved in renal disease progression., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Exosomes mediate near and long-distance intercellular communication by transferring their molecular cargo to recipient cells, altering their biological response. Milk exosomes (MEx) are internalized by immune cells and exert immunomodulatory functions in vitro. Porcine MEx can accumulate in the small intestine, rich in macrophages. No information is available on the immunomodulatory ability of porcine MEx on porcine monocytes, which are known precursors of gut macrophages. Therefore, this study aims at (1) assessing the in vitro uptake of porcine MEx by porcine monocytes (CD14+), and (2) evaluating the in vitro impact of porcine MEx on porcine monocytes immune functions. MEx were purified by ultracentrifugation and size exclusion chromatography. The monocytes' internalization of PKH26-labeled MEx was examined using fluorescence microscopy. Monocytes were incubated with increasing exosome concentrations and their apoptosis and viability were measured. Lastly, the ability of MEx to modulate the cells' immune activities was evaluated by measuring monocytes' phagocytosis, the capacity of killing bacteria, chemotaxis, and reactive oxygen species (ROS) production. MEx were internalized by porcine monocytes in vitro. They also decreased their chemotaxis and phagocytosis, and increased ROS production. Altogether, this study provides insights into the role that MEx might play in pigs' immunity by demonstrating that MEx are internalized by porcine monocytes in vitro and exert immunomodulatory effects on inflammatory functions., (© 2023. The Author(s).)

In this paper, we present a mechanical hand-tracking system with tactile feedback designed for fine manipulation in teleoperation scenarios. Alternative tracking methods based on artificial vision and data gloves have become an asset for virtual reality interaction. Yet, occlusions, lack of precision, and the absence of effective haptic feedback beyond vibrotactile still appear as a limit for teleoperation applications. In this work, we propose a methodology to design a linkage mechanism for hand pose tracking purposes, preserving complete finger mobility. Presentation of the method is followed by design and implementation of a working prototype, and by evaluation of the tracking accuracy using optical markers. Moreover, a teleoperation experiment involving a dexterous robotic arm and hand was proposed to ten participants. It investigated the effectiveness and repeatability of the hand tracking with combined haptic feedback during a proposed pick and place manipulation tasks.

Background: Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point., Methods: We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2-5 CKD were included in the analysis., Results: The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category., Conclusion: The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression., Competing Interests: C.Z. is a member of the CKJ editorial board. No conflicts of interest are related to this paper as for the remaining co-authors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Sex differences for cardiovascular (CV) risk and outcomes in chronic kidney disease (CKD) patients not on dialysis have been scarcely or never investigated. We therefore studied this important aspect in a cohort of CKD stage 2-5 in the south of Italy., Methods: We tested the relationship between sex and fatal and non-fatal major CV events in a cohort of 759 stage 2-5 CKD patients followed up for a median time of 36 months., Results: Out of 759 patients, 455 were males (60%) and the remaining 304 patients were females (40%). During the follow-up, 42 patients died, and 118 had fatal and non-fatal CV events. On univariate Cox regression analyses, the male sex failed to be associated with all-cause mortality but was strongly related to the incidence rate of fatal and non-fatal major CV events [hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.18-2.60, P  = .006]. Data adjustment for a series of major potential confounders did not materially affect the strength of this relationship (HR 1.78, 95% CI 1.03-3.09). Further analysis testing the effect of age on major CV outcomes by sex showed an effect modification by this risk factor on the same outcome ( P  = .037) because the HR of male versus female CV events increased progressively with aging., Conclusion: Male patients in stage G2-5 CKD had a higher risk for CV events compared with female patients. Age was shown to be a risk modifier for the association between sex and CV events and this risk increased linearly across a wide age spectrum in CKD patients., Competing Interests: C.Z. and F.M. are members of the CKJ editorial board., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

We present a novel soft exoskeleton providing active support for hand closing and opening. The main novelty is a different tendon routing, folded laterally on both sides of the hand, and adding clenching forces when the exoskeleton is activated. It improves the stability of the glove, diminishing slippage and detachment of tendons from the hand palm toward the grasping workspace. The clenching effect is released when the hand is relaxed, thus enhancing the user's comfort. The alternative routing allowed embedding a single actuator on the hand dorsum, resulting more compact with no remote cable transmission. Enhanced adaptation to the hand is introduced by the modular design of the soft polymer open rings. FEM simulations were performed to understand the interaction between soft modules and fingers. Different experiments assessed the desired effect of the proposed routing in terms of stability and deformation of the glove, evaluated the inter-finger compliance for non-cylindrical grasping, and characterized the output grasping force. Experiments with subjects explored the grasping performance of the soft exoskeleton with different hand sizes. A preliminary evaluation with Spinal Cord Injury patients was useful to highlight the strengths and limitations of the device when applied to the target scenario.

Background: Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested., Methods: We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction >30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up., Results: In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P < .001)] and this was also true for repeated measurements of serum phosphate [HR (1 mg/dl) 1.3924 (range 1.1459-1.6918), P = .001], serum calcium [HR (1 mg/dl) 0.7487 (range 0.5843-0.9593), P = .022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P = .045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P = .006]., Conclusion: Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Endothelial dysfunction (ED) starts early in chronic kidney disease (CKD) and is the hallmark of atherosclerosis in these patients. During recent years, numerous markers have emerged, aiming to predict the onset of ED in CKD patients. Therefore, there is a need to evaluate and assess the discriminatory ability (or diagnostic accuracy) of such a marker (i.e., the ability to correctly classify individuals as having a given disease or not) and identify the optimal cut-off value. A receiver operating characteristic (ROC) curve analysis has been used in the majority of the research papers evaluating the predictive ability of a marker of ED. It is a graphical plot combining pairs of sensitivity (true positive rate) on the y axis and the complement of specificity (1-specificity, false positive rate) in the x axis, corresponding to several of the cut-off values covering the complete range of possible values that this test/marker might take. Herein, using a series of practical examples derived from clinical studies on ED in the special population of CKD, we address the principles, fundamentals, advantages and limitations regarding the interpretation of the ROC analysis.

Objective: The purpose of the current study is to use 3D technology to measure in-vehicle belt fit both with and without booster seats across different vehicles among a large, diverse sample of children and to compare belt fit with and without a booster., Methods: Lap and shoulder belt fit were measured for 108 children ages 6-12 years sitting in the second-row, outboard seats of three vehicles from October 2017 to March 2018. Each child was measured with no booster, a backless booster, and a high-back (HB) booster in three different vehicles. Alternative high-back (HB HW) and backless boosters that could accommodate higher weights were used for children who were too large to fit in the standard boosters. Lap and torso belt scores were computed based on the belt location relative to skeletal landmarks., Results: Both lap and torso belt fit scores were significantly different across vehicles when using the vehicle belt alone (no booster). In all vehicles, lap belt fit improved when using boosters compared with no booster among children ages 6-12 years in rear seats-with one exception of the HB HW booster in the minivan. Torso belt fit improved when using boosters compared with no booster in the sedan, and torso belt fit improved in the minivan and SUV with the use of HB and HB HW boosters when compared with no booster., Conclusions: Lap and torso belt fit for children ages 6-12 years in rear seats was substantially improved by using boosters. Parents and caregivers should continue to have their children use booster seats until vehicle seat belts fit properly which likely does not occur until children are 9-12 years old. Decision makers can consider strengthening child passenger restraint laws with booster seat provisions that require children who have outgrown car seats to use booster seats until at least age 9 to improve belt fit and reduce crash injuries and deaths.

Objective: Teen drivers experience elevated crash risk compared with experienced adult drivers. Active parental oversight can improve teen driving safety, and several manufacturers have released teen-focused safety features over the past decade. Still, parents don't always use these systems and often don't even know their vehicle is equipped. A recent survey found that parents who do know about such systems on their vehicle first learned of them from a salesperson at a dealership. The current study examined how salespeople discuss and sell teen-specific safety systems on vehicles to parents shopping for a new teen driver., Methods: The study focused on four vehicle brands. Two researchers posed as the parents of a new teen driver who were shopping for a vehicle for their teen. They entered dealerships and conducted semistructured interviews with the salesperson that approached them, using prompts of increasing specificity about their teen driver and their interest in safety, and tracking at what point each salesperson mentioned their brand's teen-specific systems, what features they mentioned, and how accurate those mentions were., Results: Thirty of the 40 participating salespeople were able to mention their brand's teen-specific system at some point during the procedure. Hyundai salespeople most consistently brought up their brand's teen features, and Chevy salespeople mentioned the most features while Ford salespeople mentioned the fewest. Salespeople often mentioned speed-related features, although the most commonly mentioned features varied by brand. No participating salespeople reported receiving training specifically about their brand's teen features., Discussion: Most salespeople approached did mention their brand's teen-focused safety systems, but did not usually do so until they had received more targeted prompts. Information these salespeople did share was often vague and general. Salespeople are a key source of information about a vehicle's specific and relevant safety features, and parents without at least some vague preexisting knowledge about the systems or features that could be available on a vehicle of interest are not likely to leave a dealership with a clear idea of all available features that could aid their efforts to keep their teen drivers safe.

The Cox model is a regression technique for performing survival analyses in epidemiological and clinical research. This model estimates the hazard ratio (HR) of a given endpoint associated with a specific risk factor, which can be either a continuous variable like age and C-reactive protein level or a categorical variable like gender and diabetes mellitus. When the risk factor is a continuous variable, the Cox model provides the HR of the study endpoint associated with a predefined unit of increase in the independent variable (e.g., for every 1-year increase in age, 2 mg/L increase in C-reactive protein). A fundamental assumption underlying the application of the Cox model is proportional hazards; in other words, the effects of different variables on survival are constant over time and additive over a particular scale. The Cox regression model, when applied to etiological studies, also allows an adjustment for potential confounders; in an exposure-outcome pathway, a confounder is a variable which is associated with the exposure, is not an effect of the exposure, does not lie in the causal pathway between the exposure and the outcome, and represents a risk factor for the outcome., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Samar Abd ElHafeez et al.)

Hyperkalemia is a potential life-threatening condition among chronic kidney disease (CKD) patients. Available estimates of the burden of this alteration in CKD are mainly derived from large administrative databases. Since K measurements in patients in these databases are often dictated by clinical reasons, longitudinal studies including pre-planned measurements of potassium independently of clinical complication/symptoms may produce more reliable estimates of the frequency and the risk factors underlying hyperkalemia in CKD patients. We estimated the prevalence and the incidence of hyperkalemia in a longitudinal study in 752 stages 2-5 CKD patients lasting 3 years and including up to seven pre-planned assessment of key biochemical measurements including K. At baseline, 203 out of 752 patients (27%) had serum K > 5.0 mM/L and 33% had acidosis (HCO 3  ≤ 22 mmol/L). Among those without hyperkalemia at baseline (n = 549), 284 patients developed this alteration across the 3-year follow-up. The point prevalence of hyperkalemia rose from 27% (baseline) to 30% (last visit) (P = 0.001). In a multivariate model, hyperkalemia at baseline [odds ratio (OR):7.29, 95% CI 5.65-9.41, P < 0.001], venous bicarbonate levels [OR (1 mmol/l): 0.92, 0.89-0.96, P < 0.001], eGFR [OR (1 ml/min/1.73m 2 ): 0.98, 0.97-0.99, P < 0.001], use of ACE inhibitors (OR: 1.68, 1.28-2.19, P < 0.001) and angiotensin II antagonists (OR: 1.30, 1.01-1.68, P = 0.045) were related to hyperkalemia over time. Of note, venous bicarbonate levels emerged as an independent risk factor of hyperkalemia over time also in a separate analysis of patients with and without hyperkalemia at baseline. In a cohort of CKD patients including pre-planned measurements of K, 27% of patients had hyperkalemia. Metabolic acidosis and the use of drugs interfering with renin-angiotensin system were the strongest modifiable risk factors for this potentially life-threatening alteration in CKD in longitudinal analyses in the whole study cohort and in patients developing de novo hyperkalemia over time., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Studies performed in the field of oxidative medicine and cellular longevity frequently focus on the association between biomarkers of cellular and molecular mechanisms of oxidative stress as well as of aging, immune function, and vascular biology with specific time to event data, such as mortality and organ failure. Indeed, time-to-event analysis is one of the most important methodologies used in clinical and epidemiological research to address etiological and prognostic hypotheses. Survival data require adequate methods of analyses. Among these, the Kaplan-Meier analysis is the most used one in both observational and interventional studies. In this paper, we describe the mathematical background of this technique and the concept of censoring (right censoring, interval censoring, and left censoring) and report some examples demonstrating how to construct a Kaplan-Meier survival curve and how to apply this method to provide an answer to specific research questions., Competing Interests: No conflict of interest is related to this manuscript., (Copyright © 2021 Graziella D'Arrigo et al.)

Background: Italy was the second country in the world, after China, to be hit by SARS-CoV-2 pandemic. Italy's experience teaches that steps to limit people's movement by imposing 'red zones' need to be put in place early by carefully identifying the cities to be included within these areas of quarantine. The assessment of the relationship between the distance from an established outbreak of SARS-CoV-2 infection with transmission-linked cases and mortality observed in other sites could provide useful information to identify the optimal radius of red zones., Methods: We investigated the relationship between SARS-CoV-2 cases and the distance of each Italian province from the first outbreak of SARS-CoV-2 epidemic in Italy (the city of Lodi placed in the Lombardia region). In 38 provinces of Lombardia and neighboring regions, we performed a breakpoint analysis to identify the radius of the red zone around Lodi minimizing epidemic spread and mortality in neighboring cities., Results: In all Italian provinces, a non-linear relationship was found between SARS-CoV-2 cases and distance from Lodi. In an analysis including the provinces of Lombardia and neighboring regions, SARS-CoV-2 cases and mortality increased when the distance from Lodi reduced below 92 and 140 km, respectively, and such relationships were amplified by ozone (O3) pollution., Conclusions: The breakpoint analysis identifies the radius around the outbreak of Lodi minimizing the public health consequences of SARS-CoV-2 in neighboring cities. Such an approach can be useful to identify the red zones in future epidemics due to highly infective pathogens similar to SARS-CoV-2., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: The past decade has seen the emergence of rehabilitation treatments using virtual reality. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. The aim of this study is to determine the efficacy of immersive Virtual Environments and weaRable hAptic devices (VERA) for rehabilitation of upper limb in children with Cerebral Palsy (CP) and Developmental Dyspraxia (DD)., Methods: A two period cross-over design was adopted for determining the differences between the proposed therapy and a conventional treatment. Eight children were randomized into two groups: one group received the VERA treatment in the first period and the manual therapy in the second period, and viceversa for the other group. Children were assessed at the beginning and the end of each period through both the Nine Hole Peg Test (9-HPT, primary outcome) and Kinesiological Measurements obtained during the performing of similar tasks in a real setting scenario (secondary outcomes)., Results: All subjects, not depending from which group they come from, significantly improved in both the performance of the 9-HPT and in the parameters of the kinesiological measurements (movement error and smoothness). No statistically significant differences have been found between the two groups., Conclusions: These findings suggest that immersive VE and wearable haptic devices is a viable alternative to conventional therapy for improving upper extremity function in children with neuromotor impairments. Trial registration ClinicalTrials, NCT03353623. Registered 27 November 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03353623.

Background: Human sensorimotor control of dexterous manipulation relies on afferent sensory signals. Explicit tactile feedback is generally not available to prosthetic hand users, who have to rely on incidental information sources to partly close the control loop, resulting in suboptimal performance and manipulation difficulty. Recent studies on non-invasive supplementary sensory feedback indicated that time-discrete vibrational feedback delivered upon relevant mechanical events outperforms continuous tactile feedback. However, we hypothesize that continuous tactile feedback can be more effective in non-routine manipulation tasks (i.e., tasks where the grip force is modified reactively in response to the sensory feedback due to the unpredictable behavior of the manipulated object, such as picking and holding a virtual fragile object) if delivered to highly sensitive areas. We further hypothesize that this continuous tactile feedback is not necessary during all the duration of the manipulation task, since adaptation occurs., Methods: We investigated the effectiveness of continuous tactile feedback in precision manipulation, together with a new sensory feedback policy, where the continuous tactile feedback is gradually removed when the grasp reaches a steady state (namely, transient tactile feedback). We carried out an experiment in a virtual-reality setting with custom tactile feedback devices, which can apply continuous pressure and vibrations, attached to the thumb and index finger. We enrolled 24 healthy participants and instructed them to pick and hold a fragile virtual cube without breaking it. We compared their manipulation performance when using four different sensory feedback methods, i.e., no tactile feedback, discrete vibrations, continuous tactile feedback, and transient tactile feedback. The latter consisted of gradually removing the continuous feedback in the static phase of the grasp., Results: Continuous tactile feedback leads to a significantly larger number of successful trials than discrete vibrational cues and no feedback conditions, yet the gradual removal of the continuous feedback yields to comparable outcomes. Moreover, the participants preferred the continuous stimuli over the vibrational cues and the removal in the static phase did not significantly impact their appreciation of the continuous tactile feedback., Conclusions: These results advocate for the use of continuous supplementary tactile feedback for fine manipulation control and indicate that it can seamlessly be removed in the static phase of the grasp, possibly due to the mechanism of sensory adaptation. This encourages the development of energy-efficient supplementary feedback devices for prosthetic and telemanipulation applications, where encumbrance and power consumption are burdensome constraints.

Background: Neuropeptide Y (NPY) is a multifaceted sympathetic neurotransmitter regulating reflex cardiovascular control, myocardial cell growth, inflammation and innate immunity. Circulating NPY levels predict cardiovascular mortality in patients with end stage kidney disease on dialysis but this relationship has never been tested in predialysis chronic kidney disease (CKD) patients., Methods: We investigated the relationship between circulating NPY and the risk for cardiovascular events (Fine & Gray competing risks model) in a cohort of 753 stages 2-5 CKD patients over a median follow-up of 36 months., Results: Independently of other risk factors, plasma NPY was directly related with the glomerular filtration rate (β = -0.19, P < 0.001) but was independent of systemic inflammation as quantified by serum IL6 and C reactive protein. Over follow-up 112 patients had cardiovascular events and 12 died. In analyses fully adjusted for traditional risk factors and a large series of CKD-specific risk factors and considering death as a competing event (Fine and Gray model) a 0.25 μmol/l increase in NPY robustly predicted the incident risk for cardiovascular events (subdistribution hazard ratio: 1.25; 95% confidence interval: 1.09-1.44; P = 0.002). Furthermore, the fully adjusted NPY - cardiovascular outcomes relationship was modified by age (P = 0.012) being quite strong in young patients but weaker in the old ones., Conclusion: NPY is an independent, robust predictor of cardiovascular events in predialysis CKD patients and the risk for such events is age-dependent being maximal in young patients. These findings suggest that NPY may play a role in the high risk of cardiovascular disease in this population.

The use of robotic devices to provide active motor support and sensory feedback of ongoing motor intention, by means of a Brain Computer Interface (BCI), has received growing support by recent literature, with particular focus on neurorehabilitation therapies. At the same time, performance in the use of the BCI has become a more critical factor, since it directly influences congruency and consistency of the provided sensory feedback. As motor imagery is the mental simulation of a given movement without depending on residual function, training of patients in the use of motor imagery BCI can be extended beyond each rehabilitation session, and practiced by using simpler devices than rehabilitation robots available in the hospital. In this work, we investigated the use of haptic stimulation provided by vibrating electromagnetic motors to enhance BCI system training. The BCI is based on motor imagery of hand grasping and designed to operate a hand exoskeleton. We investigated whether haptic stimulation at fingerpads proves to be more effective than stimulation at wrist, already experimented in literature, due to the higher density of mechano-receptors. Our results did not show significant differences between the two body locations in BCI performance, yet a wider and more stable event-relateddesynchronization appeared for the finger-located stimulation. Future investigations will put in relation training with haptic feedback at fingerpads with BCI performance using the handexoskeleton, in grasping tasks that naturally involve haptic feedback at fingerpads.

Erythroferrone (ERFE) is a hepcidin inhibitor whose synthesis is stimulated by erythropoietin, which increases iron absorption and mobilization. We studied the association between serum ERFE and mortality and non-fatal cardiovascular (CV) events in a cohort of 1123 hemodialysis patients and in a cohort of 745 stage 1-5 chronic kidney disease (CKD) patients. Erythroferrone was measured by a validated enzyme-linked immunosorbent assay (ELISA). In the hemodialysis cohort, serum ERFE associated directly with erythropoiesis stimulating agents (ESA) dose ( p < 0.001) and inversely with serum iron and ferritin ( p < 0.001). Erythroferrone associated with the combined outcome in an analysis adjusting for traditional risk factors, factors peculiar to end-stage kidney disease, serum ferritin, inflammation, and nutritional status (HR, hazard ratio, (5 ng/mL increase: 1.04, 95% confidence interval, CI: 1.01-1.08, p = 0.005). Furthermore, treatment with ESA modified the relationship between ERFE and the combined end-point in adjusted analyses ( p for the effect modification = 0.018). Similarly, in CKD patients there was a linear increase in the risk for the same outcome in adjusted analyses (HR (2 ng/mL increase): 1.04, 95% CI: 1.0-1.07, p = 0.015). Serum ERFE is associated with mortality and CV events in CKD and in HD patients, and treatment by ESA amplifies the risk for this combined end-point in HD patients., Competing Interests: Conflict of Interest: The authors B.S., P.P., C.T., G.T., F.M., and C.Z. declare no conflict of interest. R.K., L.L., and M.D. are all employees of Corvidia Therapeutics. Corvidia is interested in the mechanisms of EPO-linked CV risk and whether reducing EPO exposure may reduce that risk but has no interest in ERFE as a commercial entity.

Background: Neuropeptide Y (NPY) is a sympathetic neurotransmitter that has been implicated in various disorders including obesity, gastrointestinal and cardiovascular diseases., Methods: We investigated the relationship between circulating NPY and the progression of the glomerular filtration rate (GFR) and proteinuria and the risk for a combined renal endpoint (>30% GFR loss, dialysis/transplantation) in two European chronic kidney disease (CKD) cohorts including follow-up of 753 and 576 patients for 36 and 57 months, respectively., Results: Average plasma NPY was 104 ± 32 pmol/L in the first CKD cohort and 119 ± 41 pmol/L in the second one. In separate analyses of the two cohorts, NPY associated with the progression of the estimated GFR (eGFR) and proteinuria over time in both unadjusted and adjusted {eGFR: -3.60 mL/min/1.73 m2 [95% confidence interval (CI): -4.46 to - 2.74] P < 0.001 and -0.83 mL/min/1.73 m2 (-1.41 to - 0.25, P = 0.005); proteinuria: 0.18 g/24 h (0.11-0.25) P < 0.001 and 0.07 g/24 h (0.005-0.14) P = 0.033} analyses by the mixed linear model. Accordingly, in a combined analysis of the two cohorts accounting for the competitive risk of death (Fine and Gray model), NPY predicted (P = 0.005) the renal endpoint [sub-distribution hazard ratio (SHR): 1.09; 95% CI: 1.03-1.16; P = 0.005] and the SHR in the first cohort (1.14, 95% CI: 1.04-1.25) did not differ (P = 0.25) from that in the second cohort (1.06, 95% CI: 0.98-1.15)., Conclusions: NPY associates with proteinuria and faster CKD progression as well as with a higher risk of kidney failure. These findings suggest that the sympathetic system and/or properties intrinsic to the NPY molecule may play a role in CKD progression.

The past decade has seen the emergence of rehabilitation treatments using virtual reality (VR) environments although translation into clinical practice has been limited so far. In this paper, an immersive VR rehabilitation training system endowed with wearable haptics is proposed for children with neuromotor impairments: it aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises and to benefit from the flexibility of VR in adapting exercises to the patient's need. An experimental rehabilitation session conducted with children with cerebral palsy (CP) and developmental dyspraxia (DD) has been performed to evaluate the usability of the system and proof of concept trial of the proposed approach. We compared CP/DD performance with both typically developing children and adult control group. Results show the system was compliant with different levels of motor skills and allowed patients to complete the experimental rehabilitation session, with performance varying according to the expected motor abilities of different groups. Moreover, a kinematic assessmentbased on the presented system has been designed. Obtained results reflected different motor abilities of patients and participants, suggesting suitability of the proposed kinematic assessment as a motor function outcome.

Objectives: Hypertension is a risk factor for renal function loss in kidney transplant patients but there are still no longitudinal studies focusing on the relationship between ambulatory blood pressure (BP) monitoring (ABPM) and the glomerular filtration rate (GFR) evolution over time in these patients., Methods: In a cohort of 260 renal transplant patients, we investigated the longitudinal relationship between repeated office BP measurements and simultaneous GFR measurements (on average 35 paired measurements per patient) and the relationship between baseline ABPM with the same outcome measure (by linear mixed models). Furthermore, we tested the prediction power of baseline ABPM and standardized BP measurements for a combined renal end point (GFR loss >30%, end-stage kidney disease or death) over a 3.7 years follow-up., Results: Longitudinal office BP measurements were inversely related with simultaneous GFR measurements and the same was true both for baseline daytime and night-time BP. (all P < 0.001). Baseline 24-h ABPM [hazard ratio (5 mmHg):1.11; 95% confidence interval 1.03-1.19] and night-time SBP [hazard ratio (5 mmHg):1.10; 95% confidence interval 1.03-1.17] predicted the combined renal end point and the predictive model based on night-time SBP provided a data-fit superior than that by daytime SBP., Conclusion: In renal transplant patients, daytime and night-time SBP predict the risk of GFR loss overtime, and among the various BP metrics, night-time BP is the strongest indicator of the risk of renal function loss. Optimization of BP control and interventions targeting night-time BP may afford renal benefits in transplant patients, a hypothesis that remains to be tested in a clinical trial.

Background and Objectives: Feedback plays a crucial role for using brain computer interface systems. This paper proposes the use of vibration-evoked kinaesthetic illusions as part of a novel multisensory feedback for a motor imagery (MI)-based BCI and investigates its contributions in terms of BCI performance and electroencephalographic (EEG) correlates., Methods: sixteen subjects performed two different right arm MI-BCI sessions: with the visual feedback only and with both visual and vibration-evoked kinaesthetic feedback, conveyed by the stimulation of the biceps brachi tendon. In both conditions, the sensory feedback was driven by the MI-BCI. The rich and more natural multisensory feedback was expected to facilitate the execution of MI, and thus to improve the performance of the BCI. The EEG correlates of the proposed feedback were also investigated with and without the performing of MI., Results and Conclusions: the contribution of vibration-evoked kinaesthetic feedback led to statistically higher BCI performance (Anova, F (1,14) = 18.1, p < .01) and more stable EEG event-related-desynchronization. Obtained results suggest promising application of the proposed method in neuro-rehabilitation scenarios: the advantage of an improved usability could make the MI-BCIs more applicable for those patients having difficulties in performing kinaesthetic imagery.

The development of technological applications that allow people to control and embody external devices within social interaction settings represents a major goal for current and future brain-computer interface (BCI) systems. Prior research has suggested that embodied systems may ameliorate BCI end-user's experience and accuracy in controlling external devices. Along these lines, we developed an immersive P300-based BCI application with a head-mounted display for virtual-local and robotic-remote social interactions and explored in a group of healthy participants the role of proprioceptive feedback in the control of a virtual surrogate (Study 1). Moreover, we compared the performance of a small group of people with spinal cord injury (SCI) to a control group of healthy subjects during virtual and robotic social interactions (Study 2), where both groups received a proprioceptive stimulation. Our attempt to combine immersive environments, BCI technologies and neuroscience of body ownership suggests that providing realistic multisensory feedback still represents a challenge. Results have shown that healthy and people living with SCI used the BCI within the immersive scenarios with good levels of performance (as indexed by task accuracy, optimizations calls and Information Transfer Rate) and perceived control of the surrogates. Proprioceptive feedback did not contribute to alter performance measures and body ownership sensations. Further studies are necessary to test whether sensorimotor experience represents an opportunity to improve the use of future embodied BCI applications.

A novel wearable haptic device for modulating contact forces at the fingertip is presented. Rendering of forces by skin deformation in three degrees of freedom (DoF), with contact-no contact capabilities, was implemented through rigid parallel kinematics. The novel asymmetrical three revolute-spherical-revolute (3-RSR) configuration allowed compact dimensions with minimum encumbrance of the hand workspace. The device was designed to render constant to low frequency deformation of the fingerpad in three DoF, combining light weight with relatively high output forces. A differential method for solving the non-trivial inverse kinematics is proposed and implemented in real time for controlling the device. The first experimental activity evaluated discrimination of different fingerpad stretch directions in a group of five subjects. The second experiment, enrolling 19 subjects, evaluated cutaneous feedback provided in a virtual pick-and-place manipulation task. Stiffness of the fingerpad plus device was measured and used to calibrate the physics of the virtual environment. The third experiment with 10 subjects evaluated interaction forces in a virtual lift-and-hold task. Although with different performance in the two manipulation experiments, overall results show that participants better controlled interaction forces when the cutaneous feedback was active, with significant differences between the visual and visuo-haptic experimental conditions.

The past decade has seen the emergence of rehabilitation treatments using virtual reality environments. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. In this work, we propose a novel Neuro Rehabilitation System for children with movement disorders, that is based on serious games in immersive virtual reality with haptic feedback. The system design aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises, and to benefit from the flexibility of virtual reality in adapting exercises to the patient's needs. We present a feasibility study of the method conducted through an experimental rehabilitation session in a group of 4 children with Cerebral Palsy and Developmental Dyspraxia, 4 Typically Developing children and 4 healthy adults. Subjects and patients were able to accomplish the proposed rehabilitation session and average performance of the motor exercises in patients were lower, although comparable, to healthy subjects. Together with positive comments reported by children after the rehabilitation session, results are encouraging for application of the method in a prolonged rehabilitation treatment.

Background: The clinical relevance of ambulatory blood pressure monitoring (ABPM) for risk stratification in renal transplant patients still remains poorly defined., Methods: We investigated the association between clinic and ABPM with an established biomarker of atherosclerosis (intima-media thickness [IMT] by echo-color Doppler) in a large, inclusive survey (n = 172) in renal transplant patients at a single institution., Results: Forty-two patients (24%) were classified as hypertensive by ABPM criteria and 29 (17%) by clinic blood pressure (BP) criteria. Average daytime and nighttime BP was 126 ± 12/78 ± 9 mm Hg and 123 ± 13/74 ± 10 mm Hg, respectively. Forty-five patients (26%) were classified as hypertensive by the daytime criterion (>135/85 mm Hg) and a much higher proportion (n = 119, 69%) by the nighttime criterion (>120/70 mm Hg). Sixty-two patients (36%) had a night-day ratio of 1 or greater, indicating clear-cut nondipping. The average nighttime systolic BP (r = 0.24, P = 0.001) and the night-day systolic BP ratio (r = 0.23, P = 0.002) were directly related to IMT, and these associations were much more robust than the 24-hour systolic BP-IMT relationship (r = 0.16, P = 0.04). Average daytime BP and clinic B were unrelated to IMT. In a multiple regression analysis adjusting for confounders, the night-day systolic BP ratio maintained an independent association with IMT (β = 0.14, P = 0.04)., Conclusions: In renal transplant patients, the prevalence of nocturnal hypertension by far exceeds the prevalence of hypertension as assessed by clinic, daytime, and 24-hour ABPM. Nighttime systolic BP and the night-day ratio but no other BP metrics are independently associated with IMT. Blood pressure during nighttime may provide unique information for the assessment of cardiovascular risk attributable to BP burden in renal transplant patients.

Objective: Oxidative stress is considered a major pathway conducive to cardiovascular disease in chronic kidney disease (CKD) patients. However, observational studies and clinical trials testing this relationship are controversial. The Nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) system is a major system regulating antioxidant mechanisms in living organisms. Owing to the fact that genes are transmitted randomly (Mendelian randomization), genetic variants may provide unconfounded assessment of putative causal risk factors., Methods: We have therefore explored the association of eight polymorphisms in the Nrf2 gene and three polymorphisms in the Keap1 gene (capturing over 80% of the genetic variance in the same genes) with cardiovascular events in a multicenter cohort study of 758 CKD patients., Results: During the follow-up period, 117 patients had fatal and nonfatal cardiovascular events and 42 died. The hazard rate of fatal and nonfatal cardiovascular outcomes was about twice higher in patients with the AA or the CA genotype (dominant model) in the rs110857735 polymorphism of the Keap1 gene (hazard rate: 1.85, 95% CI: 1.20-2.84, P = 0.005) than in those with the CC genotype. Further analyses adjusting for Framingham risk factors and CKD-specific risk factors and a bootstrapping validation analysis did not modify the strength of this association. No association was registered between other Keap1 and Nrf2 polymorphisms and cardiovascular disease in the same cohort., Conclusion: In this exploratory study a gene-variant in Keap1, a major gene regulating the antioxidant response, predicts incident cardiovascular events in CKD patients. This finding is in keeping with the hypothesis implicating oxidative stress in cardiovascular disease in this population.

Objectives: to describe the performance and the impact on the population coverage of a population-based organised screening programme with primary HPV-DNA test., Design: population-based cohort study., Setting and Participants: organised screening programme for women aged 30-64 years., Main Outcome Measures: coverage of the target population with Pap test and HPV-DNA test, compliance to invitation, positivity at HPV-DNA testing, proportion of positive Pap test (squamous cells of undetermined significance or more severe, ASC-US+), referral for colposcopy, positive predictive value (PPV) of the cytology triage for grade-2 or more severe intraepithelial neoplasia (CIN2+), detection rate of CIN2+. Regarding coverage, seasonally adjusted trends of the PASSI surveillance from 2008 to 2014 were analysed. To evaluate performance, data of the information screening system were used., Results: from December 2011 to December 2014, 48,852 women were invited for screening and 22,991 participated (48.4%); in addition, 968 women spontaneously participated in the programme, achieving a total of 23,959 screened women. The HPV test resulted positive for 2,000 women (8.4%). After triage 1,049 women were referred for colposcopy because of ASC-US+ (No. 968) or inadequate result (No. 81). The compliance at 12 months retesting among women with positive HPV test and negative triage was 79.3%, and the HPV positive rate was 60.4%. In the whole, 1,322 women were referred for colposcopy (5.5%) and 1,221 were actually tested. The overall detection rate for CIN2+ was 6.2/1,000. From 2011 to 2014, spontaneous Pap tests passed from 7,461/year to 2,491/year; the test coverage achieved a positive trend and it settles in recent years to 83%, including 43% of HPV-DNA., Conclusions: compliance to screening of invited women was satisfactory compared to previous experiences in Liguria Region (Northern Italy). Performance indicators confirm what was observed in other Italian experiences.

Chronic Kidney Disease (CKD) regression is considered as an infrequent renal outcome, limited to early stages, and associated with higher mortality. However, prevalence, prognosis and the clinical correlates of CKD regression remain undefined in the setting of nephrology care. This is a multicenter prospective study in 1418 patients with established CKD (eGFR: 60-15 ml/min/1.73m²) under nephrology care in 47 outpatient clinics in Italy from a least one year. We defined CKD regressors as a ΔGFR ≥0 ml/min/1.73 m2/year. ΔGFR was estimated as the absolute difference between eGFR measured at baseline and at follow up visit after 18-24 months, respectively. Outcomes were End Stage Renal Disease (ESRD) and overall-causes Mortality.391 patients (27.6%) were identified as regressors as they showed an eGFR increase between the baseline visit in the renal clinic and the follow up visit. In multivariate regression analyses the regressor status was not associated with CKD stage. Low proteinuria was the main factor associated with CKD regression, accounting per se for 48% of the likelihood of this outcome. Lower systolic blood pressure, higher BMI and absence of autosomal polycystic disease (PKD) were additional predictors of CKD regression. In regressors, ESRD risk was 72% lower (HR: 0.28; 95% CI 0.14-0.57; p<0.0001) while mortality risk did not differ from that in non-regressors (HR: 1.16; 95% CI 0.73-1.83; p = 0.540). Spline models showed that the reduction of ESRD risk associated with positive ΔGFR was attenuated in advanced CKD stage. CKD regression occurs in about one-fourth patients receiving renal care in nephrology units and correlates with low proteinuria, BP and the absence of PKD. This condition portends better renal prognosis, mostly in earlier CKD stages, with no excess risk for mortality.

High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2-4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04-1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03-1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68-4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05-2.91). High ePASP is relatively common in patients with stage 2-4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.

Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR±SD, 36±13 ml/min per 1.73 m(2)) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64±39 ml/min per 1.73 m(2)). In the first cohort, 214 patients had renal events (decrease in eGFR of >30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P<0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P<0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P<0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression., (Copyright © 2015 by the American Society of Nephrology.)

This paper presents a novel electromyography (EMG)-driven hand exoskeleton for bilateral rehabilitation of grasping in stroke. The developed hand exoskeleton was designed with two distinctive features: (a) kinematics with intrinsic adaptability to patient's hand size, and (b) free-palm and free-fingertip design, preserving the residual sensory perceptual capability of touch during assistance in grasping of real objects. In the envisaged bilateral training strategy, the patient's non paretic hand acted as guidance for the paretic hand in grasping tasks. Grasping force exerted by the non paretic hand was estimated in real-time from EMG signals, and then replicated as robotic assistance for the paretic hand by means of the hand-exoskeleton. Estimation of the grasping force through EMG allowed to perform rehabilitation exercises with any, non sensorized, graspable objects. This paper presents the system design, development, and experimental evaluation. Experiments were performed within a group of six healthy subjects and two chronic stroke patients, executing robotic-assisted grasping tasks. Results related to performance in estimation and modulation of the robotic assistance, and to the outcomes of the pilot rehabilitation sessions with stroke patients, positively support validity of the proposed approach for application in stroke rehabilitation.

Background and Objectives: High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature., Design, Setting, Participants, & Measurements: In a cohort of 755 patients with stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up±SD, 31±10 months) and used the functional polymorphism (-174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal., Results: In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P<0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the -174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes., Conclusions: In patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the -174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population., (Copyright © 2015 by the American Society of Nephrology.)

Frequency-specific vibratory stimulation of peripheral tendons induces an illusion of limb movement that may be useful for restoring proprioceptive information in people with sensorimotor disability. This potential application may be limited by inter- and intra-subject variability in the susceptibility to such an illusion, which may depend on a variety of factors. To explore the influence of stimulation parameters and participants' handedness on the movement illusion, we vibrated the right and left tendon of the biceps brachii in a group of right- and left-handed people with five stimulation frequencies (from 40 to 120 Hz in step of 20 Hz). We found that all participants reported the expected illusion of elbow extension, especially after 40 and 60 Hz. Left-handers exhibited less variability in reporting the illusion compared to right-handers across the different stimulation frequencies. Moreover, the stimulation of the non-dominant arm elicited a more vivid illusion with faster onset relative to the stimulation of the dominant arm, an effect that was independent from participants' handedness. Overall, our data show that stimulation frequency, handedness and arm dominance influence the tendon vibration movement illusion. The results are discussed in reference to their relevance in linking motor awareness, improving current devices for motor ability recovery after brain or spinal damage and developing prosthetics and virtual embodiment systems.

Background: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis., Study Design: Cross-sectional study., Setting & Participants: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy., Factor: Serum uric acid level, rs734553 allele, and age., Outcome: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV)., Results: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (β=0.33; P=0.01), whereas no such relationship was found for internal diameter (β=-0.15; P=0.3) or PWV (β=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (β=0.40 [P<0.001] and β=0.48 [P=0.003], respectively) analyses., Limitations: This is a hypothesis-generating study., Conclusions: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Hyperuricemia associates with hypertension, but it is uncertain whether this relationship is causal in nature. Glucose transporter 9 (GLUT9) gene is a major genetic determinant of plasma uric acid levels in humans. Since polymorphisms are randomly distributed at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and hypertension., Methods: We tested the association between uric acid, the rs734553 polymorphism of the GLUT9 gene and arterial pressure in a family-based study including 449 individuals in a genetically homogenous population in Southern Italy., Results: Serum uric acid levels were strongly associated (P < 0.001) with all components of clinic and 24-h ambulatory blood pressures (BPs). However, only clinic SBP and the white-coat effect (the difference in clinic systolic and daytime systolic ambulatory blood pressure monitoring) associations remained significant after adjustment for classical risk factor and the estimated glomerular filtration rate. Serum uric acid was strongly associated with the risk allele (T) of the rs734553 polymorphism (P < 0.001). Furthermore, TT individuals showed higher clinic SBP (129 + SEM 1 mmHg) than GT (125 + 1 mmHg) and GG individuals (122 + 3 mmHg), as well as a higher white-coat effect (P = 0.02), confirming that the association between uric acid and these BP components is unconfounded by environmental risk factors., Conclusion: Results in this family-based study are compatible with the hypothesis that uric acid is a causal risk factor for hypertension. Trials testing uric acid-lowering interventions are needed to definitively establish the causal implication of hyperuricemia in human hypertension. [Corrected]

Background and Objectives: Hyperuricemia predicts a high risk for CKD progression but there is no large clinical trial in humans indicating that this relationship is causal in nature. The rs734553 single-nucleotide polymorphism (SNP) of the GLUT9 urate transporter gene was strongly associated with uric acid (UA) levels in a large meta-analysis., Design, Setting, Participants, & Measurements: This prospective study adopted the Mendelian randomization approach. The rs734553 SNP was used as an instrumental variable to investigate the relationship between UA and renal outcomes in a cohort of 755 patients with CKD who were enrolled between October 18, 2005, and October 2, 2008. The association between the polymorphism and UA was preliminary confirmed in a series of 211 healthy volunteers enrolled between January 1, 2001, and July 12, 2011, from the same geographic area as the patients with CKD. The study end point was a composite renal-end point (i.e., >30% decrease in the GFR, dialysis, or transplantation). Patients were followed up for a median of 36 months., Results: In healthy individuals, serum UA levels were highest in homozygotes for the T allele (risk allele), intermediate in heterozygotes for the same allele, and lowest in those without the risk allele (P<0.001), but no such relationship was found in patients with CKD. In the CKD cohort, homozygotes (TT) and heterozygotes (GT) for the risk allele had a 2.35 times higher risk (hazard ratio, 2.35; 95% confidence interval, 1.25 to 4.42; P=0.008) of CKD progression. The risk for CKD progression by rs734553 remained unmodified in analyses adjusting for proteinuria, GFR, and other classical and CKD-peculiar risk factors., Conclusions: A GLUT9 polymorphism, which is strongly associated with serum UA levels in healthy individuals of the general population with normal renal function, holds a strong predictive power for CKD progression. These findings are compatible with the hypothesis that the link between UA and CKD progression is causal in nature., (Copyright © 2014 by the American Society of Nephrology.)

Long-term visit-to-visit blood pressure (BP) variability predicts a high risk for cardiovascular events in patients with essential hypertension. Whether long-term visit-to-visit BP variability holds the same predictive power in predialysis patients with chronic kidney disease (CKD) is unknown. Here we tested the relationship between long-term visit-to-visit office BP variability and a composite end point (death and incident cardiovascular events) in a cohort of 1618 patients with stage 2-5 CKD. Visit-to-visit systolic BP variability was significantly and independently related to baseline office, maximal, and average systolic BPs, age, glucose, estimated glomerular filtration rate, and albumin, and to the number of visits during the follow-up. Both the standard deviation of systolic BP (hazard ratio: 1.11, 95% confidence interval: 1.01-1.20) and the coefficient of variation of systolic BP (hazard ratio: 1.15, 95% confidence interval: 1.02-1.29) were significant predictors of the combined end point independent of peak and average systolic BP, cardiovascular comorbidities, Framingham risk factors, and CKD-related risk factors. Antihypertensive treatment (β-blockers and sympatholytic drugs) significantly abrogated the excess risk associated with high systolic BP variability. Thus, large visit-to-visit systolic BP variability in patients with CKD predicts a higher risk of death and nonfatal cardiovascular events independent of underlying BP levels.

Objectives: Inflammation is considered as a major effector of arterial damage brought about by salt excess in animal models. In a randomized, single masked, cross-over study in 32 uncomplicated essential hypertensive patients, we assessed the effect of a short-term low-salt diet on biomarkers of innate immunity [procalcitonin (PCT), interleukin-6, C-reactive protein, and tumor necrosis factor-α (TNF-α)], adiponectin (ADPN, an anti-inflammatory cytokine), and leptin., Methods: Patients were randomized to either a 10-20 mmol sodium diet and sodium tablets (180 mEq/day) to achieve a 200 mmol intake per day or the same diet and identical placebo tablets, each for 2 weeks. At the end of each of these periods, all patients underwent a 24-h urine collection, a fasting blood sampling, and a 24 h ambulatory blood pressure monitoring., Results: In parallel with expected increase in plasma renin activity and aldosterone (P<0.001), both PCT (+33%) and TNF-α (9%) rose at low salt intake (P≤0.007) while ADPN underwent an opposite change (- 17%, P<0.001). In a linear regression analysis for repeated measurements, PCT was significantly and inversely related to urinary salt (weighted r=-0.27, P=0.03). Changes in inflammation biomarkers did not differ in salt-sensitive (n=7) and salt-resistant (n=25) patients., Conclusion: In essential hypertensive patients, a very low salt diet generates a pro-inflammatory phenotype characterized by an increase in PCT and TNF-α and an opposite effect on an anti-inflammatory cytokine like ADPN.

Background: In this study, we compare the effects of enamel matrix derivative (EMD) associated with a hydroxyapatite and β-tricalcium phosphate (HA/β-TCP) implant to EMD alone and to open-flap debridement (OFD) when surgically treating 1- to 2-wall intrabony defects., Methods: Thirty-four patients, exhibiting ≥3 intraosseous defects in different quadrants, were each treated by OFD, EMD, or EMD + HA/β-TCP in each defect. At baseline and 12 and 24 months, a complete clinical and radiographic examination was done. Pre-therapy and post-therapy clinical (probing depth [PD], clinical attachment level [CAL], and gingival recession [GR]) and radiographic (defect bone level [DBL] and radiographic bone gain [RBG]) parameters for the different treatments were compared., Results: After 12 and 24 months, almost all the clinical and radiographic parameters showed significant changes from baseline within each group (P <0.001). Differences in PD, CAL, and DBL scores were also seen among the three groups at the 12- and 24-month visits (P <0.001). At 12 and 24 months after treatment, the EMD + HA/β-TCP group showed significantly greater PD reduction (4.00 ± 0.42 mm; 4.25 ± 0.63 mm), CAL gain (3.47 ± 0.65 mm; 3.63 ± 0.91 mm), and RBG (3.17 ± 0.69 mm; 3.35 ± 0.80 mm) and less GR increase (0.56 ± 0.37 mm; 0.63 ± 0.42 mm) compared with the OFD and EMD groups (P <0.05)., Conclusion: Our data support the hypothesis that the adjunct of an HA/β-TCP composite implant with EMD may improve the clinical and radiographic outcomes of the surgical treatment of unfavorable intrabony defects.

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.