Search

Abstract: Some previous evidence suggests that postural related syncope is associated with defective mechanisms of cerebrovascular (CB) and cardiovascular (CV) control. We characterized the information processing in short-term CB regulation, from the variability of mean cerebral blood flow velocity (CBFV) and mean arterial pressure (AP), and in CV regulation, from the variability of heart period (HP) and systolic AP (SAP), in ten young subjects developing orthostatic syncope in response to prolonged head-up tilt testing. We exploited a novel information-theoretic approach that decomposes the information associated with a variability series into three amounts: the information stored in the series, the information transferred to the series from another series, and the information unexplained by the knowledge of both series. With this approach we were able to show that, compared with the first minutes after head-up tilt, in the period preceding the syncope event (i) the information stored in CBFV variability decreased significantly while the information transferred to CBFV from AP variability increased significantly; (ii) the information storage of HP was kept high but the information transferred to HP from SAP variability decreased significantly. These patterns of information processing suggest that presyncope occurs with a loss both of CB regulation, described by the reduced ability of CBFV of buffering AP fluctuations, and of CV regulation, described by the reduced baroreflex modulation from SAP to HP. We believe that the utilization of tools from the field of information dynamics may give an integrated view of the mechanisms of CB and CV regulation in normal and diseased states, and also provide a deeper understanding of findings revealed by more traditional techniques. [Copyright &y& Elsevier]

Background: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.Methods: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.Findings: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).Interpretation: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

We present a framework for the linear parametric analysis of pairwise interactions in bivariate time series in the time and frequency domains, which allows the evaluation of total, causal and instantaneous interactions and connects time- and frequency-domain measures. The framework is applied to physiological time series to investigate the cerebrovascular regulation from the variability of mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP), and the cardiovascular regulation from the variability of heart period (HP) and systolic arterial pressure (SAP). We analyze time series acquired at rest and during the early and late phase of head-up tilt in subjects developing orthostatic syncope in response to prolonged postural stress, and in healthy controls. The spectral measures of total, causal and instantaneous coupling between HP and SAP, and between MAP and CBFV, are averaged in the low-frequency band of the spectrum to focus on specific rhythms, and over all frequencies to get time-domain measures. The analysis of cardiovascular interactions indicates that postural stress induces baroreflex involvement, and its prolongation induces baroreflex dysregulation in syncope subjects. The analysis of cerebrovascular interactions indicates that the postural stress enhances the total coupling between MAP and CBFV, and challenges cerebral autoregulation in syncope subjects, while the strong sympathetic activation elicited by prolonged postural stress in healthy controls may determine an increased coupling from CBFV to MAP during late tilt. These results document that the combination of time-domain and spectral measures allows us to obtain an integrated view of cardiovascular and cerebrovascular regulation in healthy and diseased subjects. [ABSTRACT FROM AUTHOR]

Techniques grounded on the simultaneous utilization of Tiecks' second order differential equations and spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV), recorded from middle cerebral arteries through a transcranial Doppler device, provide a characterization of cerebral autoregulation (CA) via the autoregulation index (ARI). These methods exploit two metrics for comparing the measured MCBFV series with the version predicted by Tiecks' model: normalized mean square prediction error (NMSPE) and normalized correlation ρ. The aim of this study is to assess the two metrics for ARI computation in 13 healthy subjects (age: 27 ± 8 yrs., 5 males) at rest in supine position (REST) and during 60° head-up tilt (HUT) and in 19 patients (age: 64 ± 8 yrs., all males), scheduled for coronary artery bypass grafting, before (PRE) and after (POST) propofol general anesthesia induction. Analyses were carried out over the original MAP and MCBFV pairs and surrogate unmatched couples built individually via time-shifting procedure. We found that: i) NMSPE and ρ metrics exhibited similar performances in passing individual surrogate test; ii) the two metrics could lead to different ARI estimates; iii) CA was not different during HUT or POST compared to baseline and this conclusion held regardless of the technique and metric for ARI estimation. Results suggest a limited impact of the sympathetic control on CA. • Two metrics for assessing autoregulation index (ARI) from spontaneous variations are tested. • The two metrics exhibited a similar performance in passing individual surrogate test. • ARIs estimated by the two metrics might be different. • Head-up tilt and propofol general anesthesia do not affect cerebral autoregulation • This conclusion holds regardless of metric utilized for ARI estimation. [ABSTRACT FROM AUTHOR]

Three approaches to the assessment of cerebrovascular autoregulation (CA) via the computation of the autoregulation index (ARI) from spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV) were applied: 1) a time domain method (TDM); 2) a nonparametric method (nonPM); 3) a parametric method (PM). Performances were tested over matched and surrogate unmatched pairs. Data were analyzed at supine resting (REST) and during the early phase of 60° head-up tilt (TILT) in 13 subjects with previous history of postural syncope (SYNC, age: 28 ± 9 yrs.; 5 males) and 13 control individuals (noSYNC, age: 27 ± 8 yrs.; 5 males). Analysis was completed by computing autonomic markers from heart period (HP) and systolic arterial pressure (SAP) variability series via spectral approach. HP and SAP spectral indexes suggested that noSYNC and SYNC groups exhibited different autonomic responses to TILT. ARI analysis indicated that: i) all methods have a sufficient statistical power to separate matched from unmatched pairs with the exception of nonPM applied to impulse response; ii) ARI estimates derived from different methods might be uncorrelated and, even when correlated, might exhibit a significant bias; iii) orthostatic stressor did not induce any evident ARI change in either noSYNC or SYNC individuals; iv) this conclusion held regardless of the method. Methods for the ARI estimation from spontaneous variability provide different ARIs but none indicate that noSYNC and SYNC subjects have different dynamic component of CA. • Three methods to autoregulation index (ARI) estimation from spontaneous variability were applied. • All methods for ARI estimation differentiated original and surrogate data. • Even when ARI estimates were correlated, a significant constant bias could be present. • Autonomic response to postural stressor was diverse in subjects with or without syncopal episodes. • ARI estimates were similar in subjects with or without syncopal episodes. [ABSTRACT FROM AUTHOR]

Abstract: Broad modifications of various positions of the minimal natural epitope recognized by the myelin-associated glycoprotein (MAG), a blocker of regeneration of neurite injuries, produced sialosides with nanomolar affinities. However, important pharmacokinetic issues, for example, the metabolic stability of these sialosides, remain to be addressed. For this reason, the novel non-carbohydrate mimic 3 was designed and synthesized from (−)-quinic acid. For the design of 3, previously identified beneficial modifications of side chains of Neu5Ac were combined with the replacement of the ring oxygen by a methylene group and the substitution of the C(4)-OH by an acetamide. Although docking experiments to a homology model of MAG revealed that mimic 3 forms all but one of the essential hydrogen bonds identified for the earlier reported lead 2, its affinity was substantially reduced. Extensive molecular-dynamics simulation disclosed that the missing hydrogen bond of the former C(8)-OH leads to a change of the orientation of the side chain. As a consequence, an important hydrophobic contact is compromised leading to a loss of affinity. [Copyright &y& Elsevier]