Simultaneous determination of wave speed and arrival time of reflected waves using the pressure-velocity loop

This is the post print version of the article. The official published version can be found at the link below.In a previous paper we demonstrated that the linear portion of the pressure–velocity loop (PU-loop) corresponding to early systole could be used to calculate the local wave speed. In this paper we extend this work to show that determination of the time at which the PU-loop first deviates from linearity provides a convenient way to determine the arrival time of reflected waves (Tr). We also present a new technique using the PU-loop that allows for the determination of wave speed and Tr simultaneously. We measured pressure and flow in elastic tubes of different diameters, where a strong reflection site existed at known distances away form the measurement site. We also measured pressure and flow in the ascending aorta of 11 anaesthetised dogs where a strong reflection site was produced through total arterial occlusion at four different sites. Wave speed was determined from the initial slope of the PU-loop and Tr was determined using a new algorithm that detects the sampling point at which the initial linear part of the PU-loop deviates from linearity. The results of the new technique for detecting Tr were comparable to those determined using the foot-to-foot and wave intensity analysis methods. In elastic tubes Tr detected using the new algorithm was almost identical to that detected using wave intensity analysis and foot-to-foot methods with a maximum difference of 2%. Tr detected using the PU-loop in vivo highly correlated with that detected using wave intensity analysis (r 2 = 0.83, P < 0.001). We conclude that the new technique described in this paper offers a convenient and objective method for detecting Tr, and allows for the dynamic determination of wave speed and Tr, simultaneously

Cohort Analysis of the Association of Delirium Severity With Cerebrospinal Fluid Amyloid-Tau-Neurodegeneration Pathologies

Delirium is associated with cognitive decline and subsequent dementia, and rises in plasma total Tau (tTau) and neurofilament light (NfL), providing links to Amyloid-Tau-Neurodegeneration (ATN) pathophysiology. We investigated whether changes in delirium severity after surgery correlated with changes in cerebrospinal fluid (CSF) ATN biomarkers. Thirty-two thoracic vascular surgical patients were recruited into a prospective biomarker cohort study with assessment of delirium severity and incidence (NCT02926417). CSF (n = 54) and plasma (n = 118) samples were sent for biomarker analysis for tTau, phosphorylated tau-181 (pTau) (plasma n = 53), NfL, and amyloid-β 42/40 ratio (Ab42/40-ratio). The primary outcome was the correlation of preoperative to postoperative change in ATN biomarkers with the highest postoperative Delirium Rating Scale-98 score. CSF and plasma biomarkers all increased postoperatively (all P < .05, n = 13 paired preoperative-postoperative samples). Delirium severity was associated with peak changes in CSF tTau (P = .007, r = 0.710) and pTau (P = .01, r = 0.667) but not NfL (P = .09, rho = 0.491) or Ab42/40-ratio (P = 0.18, rho = 0.394). Sensitivity analysis with exclusion of subjects with putative spinal cord ischaemia shifted the NfL result to significance (P < .001, rho = .847). Our data show that changes in tau and biomarkers of neurodegeneration in the CSF are associated with delirium severity. These data should be considered hypothesis generating and future studies should identify if these changes are robust to confounding

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

&lt;p&gt;Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.&lt;/p&gt; &lt;p&gt;Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).&lt;/p&gt; &lt;p&gt;Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.&lt;/p&gt

Postoperative troponin increases after noncardiac surgery are associated with raised neurofilament light: a prospective observational cohort study

Background: Myocardial and neuronal injury occur commonly after noncardiac surgery. We examined whether patients who had perioperative myocardial injury (PMI) also incurred neuronal injury, and whether myocardial and neuronal injury were associated with similar changes in inflammatory markers or overlapping clinical predictors. / Methods: A total of 114 individuals >65 yr old were recruited from two ongoing perioperative cohort studies (NCT02926417; NCT03124303). Plasma samples were collected before and daily after surgery to process assays for troponin I (PMI), neurofilament light (NfL; neuronal injury) and multiplexed plasma cytokines (inflammation). The primary outcome was the change in NfL in individuals with PMI (>40 pg ml−1 increase in troponin above preoperative values). We conducted logistic regression to identify if there were shared clinical predictors for myocardial and neuronal injury. / Results: Ninety-six patients had paired NfL and troponin data. Twenty-three of 94 subjects (24%) with PMI had greater increases in NfL (median [inter-quartile range, IQR]: 29 pg ml−1 [3–95 pg ml−1]; 2.8-fold increase) compared with subjects with no troponin increase (8 pg ml−1 [3–20]; 1.3-fold increase; P=0.008). PMI was associated with increased interleukin (IL)-1ra (P=0.005), IL-2 (P=0.045), IL-8 (P=0.002), and IL-10 (P<0.001). Logistic regression showed that intraoperative hypotension was associated with PMI (P=0.043). Preoperative stroke (P=0.041) and blood loss (P=0.002), but not intraoperative hypotension, were associated with increased NfL. / Conclusions: Postoperative troponin increases were associated with changes in NfL and inflammatory cytokines. Increases in troponin, but not NfL, were associated with intraoperative hypotension, suggesting differences in the mechanisms contributing to neuronal and myocardial injury

A model of top-down gain control in the auditory system

To evaluate a model of top-down gain control in the auditory system, 6 participants were asked to identify 1-kHz pure tones differing only in intensity. There were three 20-session conditions: (1) four soft tones (25, 30, 35, and 40 dB SPL) in the set; (2) those four soft tones plus a 50-dB SPL tone; and (3) the four soft tones plus an 80-dB SPL tone. The results were well described by a top-down, nonlinear gain-control system in which the amplifier’s gain depended on the highest intensity in the stimulus set. Individual participants’ identification judgments were generally compatible with an equal-variance signal-detection model in which the mean locations of the distribution of effects along the decision axis were determined by the operation of this nonlinear amplification system

Automatic correction of hand pointing in stereoscopic depth

In order to examine whether stereoscopic depth information could drive fast automatic correction of hand pointing, an experiment was designed in a 3D visual environment in which participants were asked to point to a target at different stereoscopic depths as quickly and accurately as possible within a limited time window (≤300 ms). The experiment consisted of two tasks: "depthGO" in which participants were asked to point to the new target position if the target jumped, and "depthSTOP" in which participants were instructed to abort their ongoing movements after the target jumped. The depth jump was designed to occur in 20% of the trials in both tasks. Results showed that fast automatic correction of hand movements could be driven by stereoscopic depth to occur in as early as 190 ms.This work was supported by the Grants from the National Natural Science Foundation of China (60970062 and 61173116) and the Doctoral Fund of Ministry of Education of China (20110072110014)

Positron kinetics in an idealized PET environment

The kinetic theory of non-relativistic positrons in an idealized positron emission tomography PET environment is developed by solving the Boltzmann equation, allowing for coherent and incoherent elastic, inelastic, ionizing and annihilating collisions through positronium formation. An analytic expression is obtained for the positronium formation rate, as a function of distance from a spherical source, in terms of the solutions of the general kinetic eigenvalue problem. Numerical estimates of the positron range - a fundamental limitation on the accuracy of PET, are given for positrons in a model of liquid water, a surrogate for human tissue. Comparisons are made with the 'gas-phase' assumption used in current models in which coherent scattering is suppressed. Our results show that this assumption leads to an error of the order of a factor of approximately 2, emphasizing the need to accurately account for the structure of the medium in PET simulations

Solar-type dynamo behaviour in fully convective stars without a tachocline

In solar-type stars (with radiative cores and convective envelopes), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in Sun-like stars. As the X-ray activity - rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone.Comment: 6 pages, 1 figure. Accepted for publication in Nature (28 July 2016). Author's version, including Method

Cohort study of electroencephalography markers of amyloid-tau-neurodegeneration pathology

Electroencephalography signatures of amyloid-β, tau and neurodegenerative pathologies would aid in screening for, tracking progression of, and critically, understanding the pathogenesis of dementia. We hypothesized that slowing of the alpha peak frequency, as a signature of hyperpolarization-activated cyclic nucleotide gated ‘pacemaker’ channel activity, would correlate with amyloid and tau pathology burden measured by amyloid (Pittsburgh Compound B) and tau (MK-6240) positron emission tomography or CSF biomarkers. We also hypothesized that EEG power would be associated with neurodegeneration (CSF neurofilament light and hippocampal volume). Wakeful high-density EEG data were collected from 53 subjects. Both amyloid-β and tau pathology were associated with slowing in the alpha peak frequency [Pittsburgh Compound B (+) vs. Pittsburgh Compound B (−) subjects, P = 0.039 and MK-6240 (+) vs. MK-6240 (−) subjects, P = 0.019]. Furthermore, slowing in the peak alpha frequency correlated with CSF Aβ42/40 ratio (r2 = 0.270; P = 0.003), phosphoTau (pTau181, r2 = 0.290; P = 0.001) and pTau181/Aβ42 (r2 = 0.343; P < 0.001). Alpha peak frequency was not associated with neurodegeneration. Higher CSF neurofilament light was associated with lower total EEG power (r2 = 0.136; P = 0.018), theta power (r2 = 0.148; P = 0.014) and beta power (r2 = 0.216; P = 0.002); the latter was also associated with normalized hippocampal volume (r2 = 0.196; P = 0.002). Amyloid-tau and neurodegenerative pathologies are associated with distinct electrophysiological signatures that may be useful as mechanistic tools and diagnostic/treatment effect biomarkers in clinical trials

Association between plasma tau and postoperative delirium incidence and severity: a prospective observational study

BACKGROUND: Postoperative delirium is associated with increases in the neuronal injury biomarker, neurofilament light (NfL). Here we tested whether two other biomarkers, glial fibrillary acidic protein (GFAP) and tau, are associated with postoperative delirium. METHODS: A total of 114 surgical patients were recruited into two prospective biomarker cohort studies with assessment of delirium severity and incidence. Plasma samples were sent for biomarker analysis including tau, NfL, and GFAP, and a panel of 10 cytokines. We determined a priori to adjust for interleukin-8 (IL-8), a marker of inflammation, when assessing associations between biomarkers and delirium incidence and severity. RESULTS: GFAP concentrations showed no relationship to delirium. The change in tau from preoperative concentrations to postoperative Day 1 was greater in patients with postoperative delirium (P<0.001) and correlated with delirium severity (ρ=0.39, P<0.001). The change in tau correlated with increases in IL-8 (P<0.001) and IL-10 (P=0.0029). Linear regression showed that the relevant clinical predictors of tau changes were age (P=0.037), prior stroke/transient ischaemic attack (P=0.001), and surgical blood loss (P<0.001). After adjusting for age, sex, preoperative cognition, and change in IL-8, tau remained significantly associated with delirium severity (P=0.026). Using linear mixed effect models, only tau (not NfL or IL-8) predicted recovery from delirium (P<0.001). CONCLUSIONS: The change in plasma tau was associated with delirium incidence and severity, and resolved over time in parallel with delirium features. The impact of this putative perioperative neuronal injury biomarker on long-term cognition merits further investigation. CLINICAL TRIAL REGISTRATION: NCT02926417 and NCT03124303