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Background Ultrafiltration to target weight during haemodialysis is complicated by intradialytic hypotension-associated adverse events (IHAAEs) in 10–30% of dialysis treatments. IHAAEs are caused by critical reductions in absolute blood volume (ABV), due to the interaction of ultrafiltration, refill and compensatory mechanisms. Non-randomised studies have suggested that ABV-guided treatment, using an indicator dilution technique employing the blood volume monitor on the dialysis machine, could reduce the incidence of IHAAEs. Methods We performed an open-label randomised controlled trial. Patients were randomly assigned to adjustment of target weight guided by ABV measurements or standard care. The primary outcome was the change in the incidence of IHAAEs from baseline, defined as the percentage of treatment episodes in a 4-week period where the patient had a systolic blood pressure <90 mmHg or symptoms of impending hypotension. ABV measurements were compared with anthropomorphometric estimation and the gold standard using isotope dilution. Results A total of 56 patients were randomised, of whom 29 were allocated to ABV-guided treatment and 27 to standard care. Overall baseline incidence of IHAAEs was 26.0%. ABV-guided treatment significantly reduced the incidence of IHAAEs compared with standard care, with a mean change from baseline of −9.6% [95% confidence interval (CI) −17.3 to −1.8) versus 2.4% (95% CI −2.3–7.2). The adjusted difference between the groups was 10.5% (95% CI 1.3–19.8; P  = .026). ABV measurement had moderate agreement with other methods to estimate blood volume. The sensitivity for the previously suggested threshold of a post-dialysis normalised blood volume of 65 ml/kg was observed to be 74% in this study. Conclusions ABV-guided volume management significantly reduced IHAAEs compared with standard care. The clinical relevance of the previously suggested threshold of 65 ml/kg cannot be firmly concluded on the basis of our results. If confirmed in a larger trial, this intervention could potentially change dialysis practice and impact patient care in a clinically meaningful way. [ABSTRACT FROM AUTHOR]

Background: External validation of prognostic models is necessary to assess the accuracy and generalizability of the model to new patients. If models are validated in a setting in which competing events occur, these competing risks should be accounted for when comparing predicted risks to observed outcomes.Methods: We discuss existing measures of calibration and discrimination that incorporate competing events for time-to-event models. These methods are illustrated using a clinical-data example concerning the prediction of kidney failure in a population with advanced chronic kidney disease (CKD), using the guideline-recommended Kidney Failure Risk Equation (KFRE). The KFRE was developed using Cox regression in a diverse population of CKD patients and has been proposed for use in patients with advanced CKD in whom death is a frequent competing event.Results: When validating the 5-year KFRE with methods that account for competing events, it becomes apparent that the 5-year KFRE considerably overestimates the real-world risk of kidney failure. The absolute overestimation was 10%age points on average and 29%age points in older high-risk patients.Conclusions: It is crucial that competing events are accounted for during external validation to provide a more reliable assessment the performance of a model in clinical settings in which competing risks occur. [ABSTRACT FROM AUTHOR]

Background: Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults. Methodology/Principal Findings: Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5- HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PCmax) and minimum (PCmin) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PCmax= 172 and PCmin = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations. Conclusion: In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall. [ABSTRACT FROM AUTHOR]

The pathogenesis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) remains unknown. Besides vasospasm, microthrombosis might have an important function. As in patients with thrombotic thrombocytopenic purpura an A Disintegrin And Metalloprotease with ThromboSpondin repeats-13 (ADAMTS13) deficiency leads to higher concentrations of large von Willebrand factor (vWF) multimers resulting in microthrombosis, our purpose was to compare ADAMTS13 and vWF in patients with and without DCI after aneurysmal SAH. We measured ADAMTS13 activity, vWF antigen, vWF propeptide, and vWF ristocetin cofactor activity in plasma at standard intervals. Thirty-one patients were included. Eleven patients (35%) developed DCI. No differences were observed in baseline characteristics between patients with and without DCI. Patients with DCI had a stronger decrease in ADAMTS13 activity, and a more profound increase in vWF antigen, vWF propeptide, and vWF activity in the first few days after the hemorrhage (P-values for difference in polynomial time trend 0.0001, 0.020, 0.004, and 0.188, respectively). No indication of correlation between vWF antigen and ADAMTS13 was found (r=−0.027, P=0.736). Our results suggest that microthrombosis has a role in the pathogenesis of DCI, as a result of decreased ADAMTS13 activity and endothelium dysfunction. [ABSTRACT FROM AUTHOR]

To ensure the safety of plasma-derived medicinal products, the Dutch Blood Supply Foundation (Sanquin) performs virus validation experiments. Data from these experiments are based on serial dilution assays. Regression analysis on assay data faces several problems: only a small number of data points are available, data contain censoring and are subject to sampling error. Furthermore, the process variability inherent to the experiments is not evident. In this paper we address these problems by introducing a regression model for serial dilution data and by analyzing how validation experiments and simulation techniques can help elucidate various sources of variability the experiments are subject to. These are then incorporated into the regression model. [ABSTRACT FROM AUTHOR]