Measurement Of Transit Time Research Articles

Intensity- and time-based strategies for micro/nano-sizing via single-particle ICP-mass spectrometry: A comparative assessment using Au and SiO2 as model particles

BackgroundSingle-particle ICP-mass spectrometry (SP-ICP-MS) is a powerful method for micro/nano-particle (MNP) sizing. Despite the outstanding evolution of the technique in the last decade, most studies still rely on traditional approaches based on (1) the use of integrated intensity as the analytical signal and (2) the calculation of the transport efficiency (TE). However, the increasing availability of MNP standards and advancements in hardware and software have unveiled new venues for MNP sizing, including TE-independent and time-based approaches. This work systematically examines these different methodologies to identify and summarize their strengths and weaknesses, thus helping to determine their preferred application areas. ResultsDifferent SP-ICP-MS methods for MNP sizing were assessed using AuNPs (20–70 nm) and SiO2MNPs (100–1000 nm). Among TE-dependent approaches, the particle frequency method was characterized by larger uncertainties than the particle size method. The results of the latter were dependent on the appropriate selection of the reference MNP, making the use of multiple reference MNPs recommended. TE-independent methods were based on external (linear and polynomial) calibrations and a relative approach. These methods exhibited the lowest uncertainties of all the strategies evaluated. External calibrations benefited from simpler calculations, but their application could be hindered by a lack of reference MNPs within the desired size range or by the need for interpolations outside the calibration range. Finally, transit time signals are directly proportional to the MNP size rather than its mass. The time-based method demonstrated adequate performance for sizing AuNPs but failed when sizing the largest SiO2MNPs (1000 nm). Significance and noveltyThis work provides further insights into the application of different SP-ICP-MS methodologies for MNP sizing. Both TE-independent approaches and the monitoring of the transit time as the analytical signal are underused strategies; in this context, a Python script was developed for accurate transit time measurement. After 20 years of development, a quantitative comparison of the different methodologies, including the most novel approaches, is deemed necessary for further growth on solid theoretical ground.

New Transit Timing Observations of WASP-12b from TESS Sectors 71 and 72

I present new transit and occultation timing measurements for the hot Jupiter WASP-12b using data from TESS Sectors 71 and 72, observed in 2023. Using full-phase curve fitting for the first time, I precisely locate both transits and occultations. I report 34 new transit times and sector-specific occultation times, updating the orbital decay rate to −26.310 ± 0.901 ms yr−1. My analysis strongly favors the orbital decay model over constant period and apsidal precession models.

Signal Quality Classification of Impedance Plethysmogram and Ballistocardiogram for Pulse Transit Time Measurement

Signal Quality Classification of Impedance Plethysmogram and Ballistocardiogram for Pulse Transit Time Measurement

O58 CONTINUOUS MEASUREMENT OF BLOOD PRESSURE DURING NIGHT - INSIGHTS INTO THE GENESIS OF THE NOCTURNAL BLOOD PRESSURE FLUCTUATIONS

Background and Objective: Nighttime blood pressure (BP) is a strongly predictive marker for overall cardiovascular risk. Traditional cuff-based BP measurements methods provide only discrete BP data. Short-term BP fluctuations are not detectable with such methods. Therefore, we applied two independent and continuously measuring methods with the aim to characterize systolic nocturnal blood pressure fluctuations (NBPF) related to sleep apnoea or periodic leg movements (PLM). Methods: BP fluctuations were analysed in patients with suspected sleep disturbances. The Portapres™ device (Penaz method) and a system based on the measurement of the pulse transit time (SOMNOscreen®) were used to measure the BP in addition to a polysomnography performed under the conditions of a clinical sleep laboratory. The calculation of the BP by the SOMNOscreen® was performed using a BP-pulse wave velocity (PWV) transfer function. Results: We saw BP fluctuations which occurred in connection with obstructive apnoeic events as well as in connection with PLM. Both methods recorded the same apnoea related NBPF. The amplitudes of these NBPF accounted for 24.7 mmHg and 22.8 mmHg (Portapres™ and SOMNOscreen®, respectively, 11 patients, number of events: n=695). PLM related PB fluctuations (in 5 of 11 patients, n=317) amounted to 18.4 mmHg (Portapres™ and 16.9 mmHg (SOMNOscreen®). Most of the patients did not show BP dipping when comparing awake with sleep time periods and they had a moderate to severe apnoea/hypopnoea index. Conclusions: The study demonstrates a strong relation between apnoeic events/PLM and NPBF. The NBPF were similarly detected by two different BP measuring methods suggesting that the more indirect method of BP determination using the PWV provides a reliable measurement of NBPF. The results suggest that OSA and PLM related NBPF strongly contribute to non- or reverse dipping of patients with these sleep disorders.

Evaluation of right ventricular function in patients with Behcet's disease by four-dimensional echocardiography.

Behcet's disease (BD) is a systemic disorder characterized by vasculitis, resulting in thickened vascular walls that reduce elasticity and impair function. BD can involve the cardiovascular system in three ways: cardiac, arterial, and venous. In this study, our objective was to evaluate the efficacy of pulmonary arterial stiffness (PAS) and pulmonary pulse transit time (PPTT) measures in demonstrating right ventricular functions in asymptomatic BD patients. We aimed to objectively evaluate right ventricular function in patients with BD using four-dimensional echocardiography (4DE). This study included 40 patients diagnosed with BD and 40 healthy subjects. Demographic, clinical, laboratory, and echocardiographic parameters were compared. In addition to standard transthoracic echocardiographic evaluation, right ventricle quantification (RVQ) by using the 4DE and 2D-speckle tracking echocardiography were performed. The sPAP, 4D RVQ, and right ventricular strain values exhibited significant differences between the BD and control groups. Right ventricular end-diastolic diameter (RVDD), right ventricular end-systolic diameter (RVSD), right atrium (RA) area, right ventricular myocardial performance index (RVMPI), and PAS were increased in BD patients compared to the control group. Right ventricular ejection fraction (RVEF), right ventricular fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), Tricuspid S', and PPTT were decreased in BD patients compared to control subjects. PPTT correlated with right ventricular free wall strain (RV-FWS) and PAS. In a multivariate linear regression analysis, PAS and RVFAC were found to be independent predictors of RVFWS. In addition, RVFAC and TAPSE are independent predictors for PPTT. Patients with BD may have elevated pulmonary arterial stiffness (PAS) in correlation with decreased PPTT. To ascertain the prognosis for these individuals, right ventricular (RV) functions must be evaluated. Measurements of RVFAC and RVEF via 4DE and deformation imaging techniques may be more useful in identifying subclinical impairment of RV. Individuals with BD, PAS, and PPTT may suggest a link between early pulmonary vascular remodeling and RV subclinical impairment.

Development and study of ultrasonic pulse velocity measurement system using wave analysis and two-point detection approach

Abstract This article focuses on the development and analysis of an Ultrasonic Pulse Velocity (UPV) measurement system used for the evaluation of concrete and Reinforced Cement Concrete (RCC) in civil construction. The UPV tester is essential for on-site assessments of structures, as it is used to measure the velocity of ultrasonic waves within the material, directly correlating with its strength. UPV testing is affected by the attenuation of ultrasonic waves in concrete, particularly due to the interfacial transition zone. Excess ultrasonic attenuation results in the reduction in the received signal amplitude which may also results in the omission of the initial pulses due to threshold comparison at the receiver. The study highlights the impact of receiver gain on threshold error and discusses the limitations associated with ADC sampling rate and amplitude resolution. UPV measurement, including counter or data acquisition approach, have error contributions associated with threshold voltage comparison. The error due to threshold amplitude selection is quantified, emphasizing the importance of accurate signal analysis, particularly in highly attenuating medium. The article presents the design and development of a PC-based UPV tester with automatic threshold error compensation. The system includes a transmitter, receiver, 32-bit microcontroller, and a Graphical User Interface (GUI) for data analysis. The article introduces a two-point linear detection logic to minimize errors caused by selected signal amplitude and omission of initial pulses in transit time measurements. The proposed method provides effective resolution of 10 ns through software, even at low sampling rate of 2 MS/s. The experimental results demonstrate the effectiveness of the developed UPV tester, with comparisons to a reference calibration facility at CSIR-NPL. The standard deviation in the ultrasonic transit time measurement by the developed UPV device, with threshold error correction, was ±70 ns.

The use of pulse transit time in diagnostics of sleep-disordered breathing in children

<b><br>Introduction:</b> Sleep is the physiological state of the body where proper morphology and duration are indispensable for human functions throughout both, physical and mental spheres. Disordered breathing during sleep impairs its morphology and results in major disorders in any age group. Adverse effects of Obstructive Sleep Apnea Syndrome in children and poor availability of centers offering children’s polysomnography call for a reliable and easily accessible screening method.</br> <b><br>Aim:</b> The aim of the study were to evaluate the usefulness of pulse transit time in the diagnostics of disordered sleep breathing in children and to attempt to employ the parameter in screening tests. Pulse transit time is a physiological parameter determining the time needed for the pulse wave to travel between two measurement points.</br> <b><br>Material and methods:</b> Enrolled in the retrospective study were 153 patients (100 boys and 53 girls) suspected of obstructive sleep apnea syndrome who underwent polysomnography at I. Mościcki ENT Hospital in Chorzów.</br> <b><br>Results:</b> Statistically significant relations between apnea/hypopnea index and pulse transit time were observed in both, individual age groups and all of the patients. Pulse transit time results proved a negative correlation with apnea/hypopnea index values commonly accepted as a parameter concluding the polysomnography procedures.</br> <b><br>Conclusions:</b> The results of the study indicate that pulse transit time measurements may find application in screening tests of sleep-disordered breathing in children.</br>

Doppler-derived pulmonary pulse transit time measurements in chronic obstructive pulmonary disease: Reproducibility and cardiopulmonary function.

Doppler-derived pulmonary pulse transit time (pPTT) is an auspicious hemodynamic marker in chronic pulmonary diseases. The aim is to compare four distinct pPTT measurements and its relation to right cardiac and pulmonary function. Prospectively, 25 chronic obstructive pulmonary disease (COPD) patients (four patients excluded) and 32 healthy subjects underwent repeated distinct pPTT measurements, standard echocardiography, and pulmonary function testing on the same day. pPTT was defined as the interval from the R or Q-wave in the electrocardiogram to the corresponding pulse wave Doppler peak late systolic (S) 2 or diastolic (D) pulmonary vein flow velocity (pPTT R-S, Q-S, R-D, Q-D). Reproducibility was assessed using Bland-Altman analysis, coefficient of variation (COV), intraclass correlation coefficient (ICC), and power calculations. Associations with right ventricular RV tissue and pulse wave Doppler velocities (RV E', RV S', RV A', RV E, RV A, RV E/E', RV E/A), TAPSE, right ventricular fractional area change, left ventricular systolic and diastolic function (LV ejection fraction, E, A, E/A, E/E', septal E', lateral E'), LA diameters, as well as forced expiratory volume in 1 s, forced vital capacity (FVC) predicted (%), and in liters were analyzed. There was no significant difference and no bias between pPTT measures (p range:.1-.9). COV was in COPD 1.2%-2.3%, in healthy subjects 1.0%-3.1%. ICC ranged from.92 (COPD) to.96 (healthy subjects). In COPD significant correlations were found for pPTT R-S, Q-S and R-D with RV E`, (all>ρ:.49,<p=.0364), pPTT R-S, Q-S with RV E/E` (both>ρ:.49,<p=.0291), pPTT Q-S with RV S´ (ρ:.58, p=.0134), RV A (ρ:.59, p=.0339) and heart rate>ρ: -.39,<p=.0297). pPTT R-S, R-D showed significant correlations with FVC predicted (%) (ρ:.48 p=.0224) and FVC (l) (ρ:.47 p=.0347). All pPTT measures exhibited high reproducibility. In COPD patients pPTT measures correlate with diastolic right ventricular function. Defining Q as starting point seems clinically advantageous considering electromechanical desynchrony in patients with conduction disorders.

Generalized channel separation algorithms for accurate camera-based multi-wavelength PTT and BP estimation

Single-site multi-wavelength (MW) pulse transit time (PTT) measurement was recently proposed using contact sensors with sequential illumination. It leverages different penetration depths of light to measure the traversal of a cardiac pulse between skin layers. This enabled continuous single-site MW blood pressure (BP) monitoring, but faces challenges like subtle skin compression, which importantly influences the PPG morphology and subsequent PTT. We extended this idea to contact-free camera-based sensing and identified the major challenge of color channel overlap, which causes the signals obtained from a consumer RGB camera to be a mixture of responses in different wavelengths, thus not allowing for meaningful PTT measurement. To address this, we propose novel camera-independent data-driven channel separation algorithms based on constrained genetic algorithms. We systematically validated the algorithms on camera recordings of palms and corresponding ground-truth BP measurements of 13 subjects in two different scenarios, rest and activity. We compared the proposed algorithms against established blind source separation methods and against previous camera-specific physics-based method, showing good performance in both PTT reconstruction and BP estimation using a Random Forest regressor. The best-performing algorithm achieved mean absolute errors (MAEs) of 3.48 and 2.61 mmHg for systolic and diastolic BP in a leave-one-subject-out experiment with personalization, solidifying the proposed algorithms as enablers of novel contact-free MW PTT and BP estimation.

Pulmonary Transit Time Assessment by CEUS in Healthy Rabbits: Feasibility, and the Effects of UCAs Dilution Concentration.

To evaluate the inter-observer variability and the intra-observer repeatability of pulmonary transit time (PTT) measurement using contrast-enhanced ultrasound (CEUS) in healthy rabbits, and assess the effects of dilution concentration of ultrasound contrast agents (UCAs) on PTT. Thirteen healthy rabbits were selected, and five concentrations UCAs of 1:200, 1:100, 1:50, 1:10, and 1:1 were injected into the right ear vein. Five digital loops were obtained from the apical 4-chamber view. Four sonographers obtained PTT by plotting the TIC of right atrium (RA) and left atrium (LA) at two time points (T1 and T2). The frame counts of the first appearance of UCAs in RA and LA had excellent inter-observer agreement, with intra-class correlations (ICC) of 0.996, 0.988, respectively. The agreement of PTT among four observers was all good at five different concentrations, with an ICC of 0.758-0.873. The reproducibility of PTT obtained by four observers at T1 and T2 was performed well, with ICC of 0.888-0.961. The median inter-observer variability across 13 rabbits was 6.5% and the median variability within 14 days for 4 observers was 1.9%, 1.7%, 2.2%, 1.9%, respectively; The PTT of 13 healthy rabbits is 1.01 ± 0.18 second. The difference of PTT between five concentrations is statistically significant. The PTT obtained by a concentration of 1:200 and 1:100 were higher than that of 1:1, while there were no significantly differences in PTT of a concentration of 1:1, 1:10, and 1:50. PTT measured by CEUS in rabbits is feasible, with excellent inter-observer and intra-observer reliability and reproducibility, and dilution concentration of UCAs influences PTT results.

Measurement of colonic transit time in patients with refractory chronic constipation referred to a tertiary center

BackgroundMeasurement of colonic transit time (CTT) of different colon segments can help to find the subtype of constipation and the appropriate treatment. This study aimed to estimate the segmental and total CTT in patients with refractory chronic constipation who attended gastrointestinal clinics. MethodsA cross-sectional study was done in patients with refractory chronic constipation according to ROME IV criteria with normal colonoscopy. Patients with underlying diseases, including diabetes, hypoparathyroidism, hypothyroidism, anemia, past intestinal surgery, metabolic disorders, and recent medication use with constipation complications, were excluded. Every patient took a gelatin capsule containing ten 1–3 ​mm angiographic catheters for six consecutive days. On the seventh day, an upright abdominal x-ray was performed. The remaining markers were counted in three divided colonic segments, and the total CTT using radio-opaque markers was measured subsequently. Results40 patients were eventually included in this study. Twenty-eight were female (70%), and 55% of patients had standard body mass index (BMI). The mean age of patients was 43 years with a standard deviation of 18 years, while the mean total CTT was 37.05 ​h with a standard deviation of 24 ​h. Additionally, 60% had a normal CTT (≤45 ​h), and 40% had abnormal and prolonged CTT. ConclusionConstipation as a complaint is more common in women than men. Total CTT is slightly higher in men than women, but there is no significant difference. CTT may be normal in patients with refractory constipation despite all investigations. Additionally, there was no correlation between BMI and prolonged total CTT.

Effect of a Gluten-Free Diet on Whole Gut Transit Time in Celiac Disease (CD) and Non-Celiac Gluten Sensitivity (NCGS) Patients: A Study Using the Wireless Motility Capsule (WMC).

Background: This study explores the impact of a gluten-free diet (GFD) on regional gastrointestinal (GI) transit times in individuals with celiac disease (CD) and non-celiac gluten sensitivity (NCGS). While a GFD is established for managing CD and wheat allergy, its effects on NCGS remain controversial due to inconclusive evidence. Methods: Utilizing a wireless motility and pH capsule (WMC) to assess regional (measurements of gastric, small bowel, and colonic transit times) and whole gut transit, newly diagnosed CD (n = 12) and NCGS (n = 12) patients underwent evaluations at baseline and 4 weeks after having a GFD. Results: At baseline conditions, individuals diagnosed with CD exhibited prolonged colonic and intestinal transit times when compared to those with NCGS (p < 0.05). Following a 4-week GFD, CD patients experienced significant reductions in both intestinal and colonic transit times, along with enhanced small intestine contractility. NCGS individuals showed improvements in intestinal transit time and contractility with a GFD, although the colon exhibited no discernible effect. The GFD did not significantly impact intragastric, intestinal, or colonic pH. Conclusions: This study, employing WMC for the first time, provides novel insights into the positive effects of a GFD on intestinal and colonic transit, as well as contractility, in CD patients, and to a lesser extent, in those with NCGS.

MRI Assessment of Cerebral White Matter Microvascular Hemodynamics Across the Adult Lifespan.

Changes in cerebral hemodynamics with aging are important for understanding age-related variation in neuronal health. While many prior studies have focused on gray matter, less is known regarding white matter due in part to measurement challenges related to the lower vascular density in white matter. To investigate the impact of age and sex on white matter hemodynamics in a Human Connectome Project in Aging (HCP-A) cohort using tract-based spatial statistics (TBSS). Retrospective cross-sectional. Six hundred seventy-eight typically aging individuals (381 female), aged 36-100 years. Multi-delay pseudo-continuous arterial spin labeling (ASL) and diffusion-weighted pulsed-gradient spin-echo echo planar imaging sequences at 3.0 T. A skeleton of mean fractional anisotropy (FA) was produced using TBSS. This skeleton was used to project ASL-derived cerebral blood flow (CBF) and arterial transit time (ATT) measures onto white matter tracts. General linear models were applied to white matter FA, CBF, and ATT maps, while covarying for age and sex. Threshold-free cluster enhancement multiple comparisons correction was performed for the effects of age and sex, thresholded at PFWE < 0.05. CBF, ATT, and FA were compared between sex for each tract using analysis of covariance, with multiple comparisons correction for the number of tracts at PFDR < 0.05. Significantly lower white matter CBF and significantly prolonged white matter ATTs were associated with older age. These effects were widespread across tracts for ATT. Significant (PFDR < 0.05) sex differences in ATT were observed across all tracts, and significant sex differences in CBF were observed in all tracts except the bilateral uncinate fasciculus. Females demonstrated significantly higher CBF compared to males across the lifespan. Few tracts demonstrated significant sex differences in FA. This study identified significant sex- and age-associated differences in white matter hemodynamics across tracts. 3 TECHNICAL EFFICACY: Stage 3.

A dual-mode wearable sensor with electrophysiological and pressure sensing for cuffless blood pressure monitoring

A wearable dual-mode sensor is created by integrating liquid metal into an ionogel. It can simultaneously monitor both the electrocardiogram and arterial pulse to simplify the measurement of the pulse transit time and thus the blood pressure.

Orbital Decay of Hot Jupiters due to Weakly Nonlinear Tidal Dissipation

We study tidal dissipation in hot Jupiter host stars due to the nonlinear damping of tidally driven g-modes, extending the calculations of Essick & Weinberg to a wide variety of stellar host types. This process causes the planet’s orbit to decay and has potentially important consequences for the evolution and fate of hot Jupiters. Previous studies either only accounted for linear dissipation processes or assumed that the resonantly excited primary mode becomes strongly nonlinear and breaks as it approaches the stellar center. However, the great majority of hot Jupiter systems are in the weakly nonlinear regime in which the primary mode does not break but instead excites a sea of secondary modes via three-mode interactions. We simulate these nonlinear interactions and calculate the net mode dissipation for stars that range in mass from 0.5M ⊙ ≤ M ⋆ ≤ 2.0M ⊙ and in age from the early main sequence to the subgiant phase. We find that the nonlinearly excited secondary modes can enhance the tidal dissipation by orders of magnitude compared to linear dissipation processes. For the stars with M ⋆ ≲ 1.0M ⊙ of nearly any age, we find that the orbital decay time is ≲100 Myr for orbital periods P orb ≲ 1 day. For M ⋆ ≳ 1.2M ⊙, the orbital decay time only becomes short on the subgiant branch, where it can be ≲10 Myr for P orb ≲ 2 days and result in significant transit time shifts. We discuss these results in the context of known hot Jupiter systems and examine the prospects for detecting their orbital decay with transit timing measurements.

Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAβKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodsContrast‐enhanced PWI MRI (9.4T) was undertaken from hAβKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultsCompared to WT mice at 18mo of age, hAβKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p&lt;0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAβKI only mice.ConclusionsThe 18mo hAβKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aß Knock‐In (hAßKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAßKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodContrast‐enhanced PWI MRI (9.4T) was undertaken from hAßKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultCompared to WT mice at 18mo of age, hAßKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p&lt;0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAßKI only mice.ConclusionThe 18mo hAßKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

The influence of the digital pulse wave reference point on the pulse transit time measurement and variability

By measuring pulse wave velocity (PWV) via an arterial route, one can determine the stiffness of the artery. The duration between the ECG R-wave climax and a reference point on the digital pulse wave (DPW) in the same cardiac cycle must be determined in order to determine the pulse transit time (PTT). The time it takes for a pulse wave to travel from the heart to a peripheral artery location is known as the PTT. To find out the best reference point on the DPW that is associated with the least beat-beat coefficient of variation (CV) of PWV. The study was carried out on 10 healthy young males aged 19 years. A two-minute recording of the left middle fingertip DPW signals (through piezoelectric Finger Pulse Transducer) and lead II ECG (through three surface electrodes) were carried out. PTT was calculated as follows: from the climax of the electrocardiogram R wave to the onset (foot) of the DPW (PTT1); from the apex to the onset points of the DPW at 10% of its amplitude (PTT2); and from the apex to the onset points of the DPW at 50% of its amplitude (PTT3). PTT1, PTT, and PTT3 were measured on each volunteer and on the same cardiac cycles.

Free Energy Simulations of Receptor-Binding Domain Opening of the SARS-CoV-2 Spike Indicate a Barrierless Transition with Slow Conformational Motions.

Infection by sarbecoviruses begins with the attachment of the homotrimeric viral "spike" protein to the angiotensin-converting enzyme 2 receptor on the surface of mammalian cells. This requires one or more receptor-binding domains (RBDs) to be in the open (up) position. Here, we present the results of long molecular dynamics simulations with umbrella sampling (US) to compute a one-dimensional free energy profile of RBD opening/closing and the associated transition times. After ≃3.58μs of simulation time per US window (∼229 μs in total), which was required to approach trajectory decorrelation, the computed free energy profile was found to be without large barriers. This suggests that the RBD diffuses between the open and closed positions without significant energetic hindrance. This interpretation appears consistent with experiments but is at odds with some previous simulations. Modeling the RBD motion as diffusive dynamics along the computed free energy profile, we find that the overall time required for the transition is only about 2 μs, which is 5 orders of magnitude shorter than experimentally measured transition times. We speculate that the most likely reason for the transition time mismatch is our use of very short glycans, which was required to make the simulations performed here feasible. Despite the long simulation times, the final free energy profile is not fully converged with statistical errors of ≃1.16 kcal/mol, which were found to be consistent with the slow time decay in the autocorrelation of the conformational motions of the protein. The simulation lengths that would be required to obtain fully converged results remain unknown, but the present calculations would benefit from at least an order-of-magnitude extension.

Personalised simulation of hemodynamics in cerebrovascular disease: lessons learned from a study of diagnostic accuracy.

Intracranial atherosclerotic disease (ICAD) poses a significant risk of subsequent stroke but current prevention strategies are limited. Mechanistic simulations of brain hemodynamics offer an alternative precision medicine approach by utilising individual patient characteristics. For clinical use, however, current simulation frameworks have insufficient validation. In this study, we performed the first quantitative validation of a simulation-based precision medicine framework to assess cerebral hemodynamics in patients with ICAD against clinical standard perfusion imaging. In a retrospective analysis, we used a 0-dimensional simulation model to detect brain areas that are hemodynamically vulnerable to subsequent stroke. The main outcome measures were sensitivity, specificity, and area under the receiver operating characteristics curve (ROC AUC) of the simulation to identify brain areas vulnerable to subsequent stroke as defined by quantitative measurements of relative mean transit time (relMTT) from dynamic susceptibility contrast MRI (DSC-MRI). In 68 subjects with unilateral stenosis >70% of the internal carotid artery (ICA) or middle cerebral artery (MCA), the sensitivity and specificity of the simulation were 0.65 and 0.67, respectively. The ROC AUC was 0.68. The low-to-moderate accuracy of the simulation may be attributed to assumptions of Newtonian blood flow, rigid vessel walls, and the use of time-of-flight MRI for geometric representation of subject vasculature. Future simulation approaches should focus on integrating additional patient data, increasing accessibility of precision medicine tools to clinicians, addressing disease burden disparities amongst different populations, and quantifying patient benefit. Our results underscore the need for further improvement of mechanistic simulations of brain hemodynamics to foster the translation of the technology to clinical practice.