Upper Esophageal Sphincter Response to Laryngeal Adductor Reflex Elicitation in Humans

Objective: The laryngeal adductor reflex (LAR) is an important mechanism to secure the airways from potential foreign body aspiration. An involvement of the upper esophageal sphincter (UES) in terms of a laryngo-UES contractile reflex has been identified after laryngeal mucosa stimulation. However, the LAR–UES relationship has not yet been fully explained. This study aimed to determine the magnitude, latency, and occurrence rate of the UES pressure response when the LAR is triggered in order to elucidate the functional relationship between the larynx and the UES. Methods: This prospective study included seven healthy volunteers (5 female, 2 male, age 22–34 years). Laryngeal penetration was simulated by eliciting the LAR 20 times in each individual by applying water-based microdroplets onto the laryngeal mucosa. UES pressures were measured simultaneously using high-resolution manometry. Results: Two distinct pressure phases (P1, P2) associated with the LAR were identified. P1 corresponded with a short-term UES pressure decrease in two subjects and a pressure increase in five subjects occurring 200 to 500 ms after the stimulus. In P2, all subjects experienced an increase in UES pressure with a latency time of approximately 800 to 1700 ms and an average of 40 to 90 mmHg above the UES resting tone. Conclusion: Foreign bodies penetrating the laryngeal inlet lead to a reflex contraction of the UES. Phase P1 could be a result of vocal fold activity caused by the LAR, leading to pressure changes in the UES. The constriction during P2 could strengthen the barrier function of the UES in preparation to a subsequent cough that may be triggered to clear the airways. Level of Evidence: 4 Laryngoscope, 2020. © 2020 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA)

Effect of MLC tracking latency on conformal volumetric modulated arc therapy (VMAT) plans in 4D stereotactic lung treatment

AbstractBackground and purposeThe latency of a multileaf collimator (MLC) tracking system used to overcome respiratory motion causes misalignment of the treatment beam with respect to the gross tumour volume, which may result in reduced target coverage. This study investigates the magnitude of this effect.Material and methodsSimulated superior–inferior breathing motion was used to construct histograms of isocentre offset with respect to the gross tumour volume (GTV) for a variety of tracking latencies. Dose distributions for conformal volumetric modulated arc therapy (VMAT) arcs were then calculated at a range of offsets and summed according to these displacement histograms. The results were verified by delivering the plans to a Delta4 phantom on a motion platform.ResultsIn the absence of an internal target margin, a tracking latency of 150ms reduces the GTV D95% by approximately 2%. With a margin of 2mm, the same drop in dose occurs for a tracking latency of 450ms. Lung V13Gy is unaffected by a range of latencies. These results are supported by the phantom measurements.ConclusionsAssuming that internal motion can be modelled by a rigid translation of the patient, MLC tracking of conformal VMAT can be effectively accomplished in the absence of an internal target margin for substantial breathing motion (4s period and 20mm peak–peak amplitude) so long as the system latency is less than 150ms

Effectiveness of visual biofeedback-guided respiratory-correlated 4D-MRI for radiotherapy guidance on the MR-linac

Purpose: Respiratory-correlated 4D-MRI may provide motion characteristics for radiotherapy but is susceptible to irregular breathing. This study investigated the effectiveness of visual biofeedback (VBF) guidance for breathing regularization during 4D-MRI acquisitions on an MR-linac. Methods: A simultaneous multislice-accelerated 4D-MRI sequence was interleaved with a one-dimensional respiratory navigator (1D-RNAV) in 10 healthy volunteers on a 1.5T Unity MR-linac (Elekta AB, Stockholm, Sweden). Volunteer-specific breathing amplitudes and periods were derived from the 1D-RNAV signal obtained during unguided 4D-MRI acquisitions. These were used for the guidance waveform, while the 1D-RNAV positions were overlayed as VBF. VBF effectiveness was quantified by calculating the change in coefficient of variation ((Formula presented.)) for the breathing amplitude and period, the position SD of end-exhale, end-inhale and midposition locations, and the agreement between the 1D-RNAV signals and guidance waveforms. The 4D-MRI quality was assessed by quantifying amounts of missing data. Results: VBF had an average latency of 520 ± 2 ms. VBF reduced median breathing variations by 18% to 35% (amplitude) and 29% to 57% (period). Median position SD reductions ranged from −3% to 35% (end-exhale), 29% to 38% (end-inhale), and 25% to 37% (midposition). Average differences between guidance waveforms and 1D-RNAV signals were 0.0 s (period) and +1.7 mm (amplitude). VBF also decreased the median amount of missing data by 11% and 29%. Conclusion: A VBF system was successfully implemented, and all volunteers were able to adapt to the guidance waveform. VBF during 4D-MRI acquisitions drastically reduced breathing variability but had limited effect on missing data in respiratory-correlated 4D-MRI

Real-time myocardial landmark tracking for MRI-guided cardiac radio-ablation using Gaussian Processes

The high speed of cardiorespiratory motion introduces a unique challenge for cardiac stereotactic radio-ablation (STAR) treatments with the MR-linac. Such treatments require tracking myocardial landmarks with a maximum latency of 100 ms, which includes the acquisition of the required data. The aim of this study is to present a new method that allows to track myocardial landmarks from few readouts of MRI data, thereby achieving a latency sufficient for STAR treatments. We present a tracking framework that requires only few readouts of k-space data as input, which can be acquired at least an order of magnitude faster than MR-images. Combined with the real-time tracking speed of a probabilistic machine learning framework called Gaussian Processes, this allows to track myocardial landmarks with a sufficiently low latency for cardiac STAR guidance, including both the acquisition of required data, and the tracking inference. The framework is demonstrated in 2D on a motion phantom, and in vivo on volunteers and a ventricular tachycardia (arrhythmia) patient. Moreover, the feasibility of an extension to 3D was demonstrated by in silico 3D experiments with a digital motion phantom. The framework was compared with template matching - a reference, image-based, method - and linear regression methods. Results indicate an order of magnitude lower total latency (<10 ms) for the proposed framework in comparison with alternative methods. The root-mean-square-distances and mean end-point-distance with the reference tracking method was less than 0.8 mm for all experiments, showing excellent (sub-voxel) agreement. The high accuracy in combination with a total latency of less than 10 ms - including data acquisition and processing - make the proposed method a suitable candidate for tracking during STAR treatments

Stereo Laryngoscopic Impact Site Prediction for Droplet-Based Stimulation of the Laryngeal Adductor Reflex

The laryngeal adductor reflex (LAR) is a vital reflex of the human larynx. LAR malfunctions may cause life-threatening aspiration events. An objective, noninvasive, and reproducible method for LAR assessment is still lacking. Stimulation of the larynx by droplet impact, termed Microdroplet Impulse Testing of the LAR (MIT-LAR), may remedy this situation. However, droplet instability and imprecise stimulus application thus far prevented MIT-LAR from gaining clinical relevance. We present a system comprising two alternative, custom-built stereo laryngoscopes, each offering a distinct set of properties, a droplet applicator module, and image/point cloud processing algorithms to enable a targeted, droplet-based LAR stimulation. Droplet impact site prediction (ISP) is achieved by droplet trajectory identification and spatial target reconstruction. The reconstruction and ISP accuracies were experimentally evaluated. Global spatial reconstruction errors at the glottal area of (0.3±0.3) mm and (0.4±0.3) mm and global ISP errors of (0.9±0.6) mm and (1.3±0.8) mm were found for a rod lens-based and an alternative, fiberoptic laryngoscope, respectively. In the case of the rod lens-based system, 96% of all observed ISP error values are inferior to 2 mm; a value of 80% was found with the fiberoptic assembly. This contribution represents an important step towards introducing a reproducible and objective LAR screening method into the clinical routine

The lipids of the common house cricket,Acheta domesticus L. I. Lipid classes and fatty acid distribution

The lipids of the common house cricket,Acheta domesticus L., have been examined with the following results. The fatty acids associated with the lipid extracts do not change significantly from the third through the eleventh week of the crickets’ postembryonic life. The major fatty acids are linoleic (30–40%), oleic (23–27%), palmitic (24–30%), and stearic acids (7–11%). There are smaller amounts of palmitoleic (3–4%), myristic (∼1%), and linolenic acids (<1%). The fatty acid composition of the cricket lipids reflects but is not identical to the fatty acids of the dietary lipids: linoleic (53%), oleic (24%), palmitic (15%), stearic (3%), myristic (2%), and linolenic acid (2%).The amount of triglycerides present in the crickets increases steadily from the second through the seventh or eighth week of postembryonic life, then drops sharply. Other lipid classes, such as hydrocarbons, simple esters, diglycerides, monoglycerides, sterols, and free fatty acids remain about constant. The composition of the fatty acids associated with the tri‐, di‐, and monoglycerides and the free fatty acid fraction are all about the same. The fatty acids associated with the simple esters are high in stearic acid.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142007/1/lipd0247.pd

Human Immune Responses to \u3cem\u3eH. pylori\u3c/em\u3e HLA Class II Epitopes Identified by Immunoinformatic Methods

H. pylori persists in the human stomach over decades and promotes several adverse clinical sequelae including gastritis, peptic ulcers and gastric cancer that are linked to the induction and subsequent evasion of chronic gastric inflammation. Emerging evidence indicates that H. pylori infection may also protect against asthma and some other immune-mediated conditions through regulatory T cell effects outside the stomach. To characterize the complexity of the CD4+ T cell response generated during H. pylori infection, computational methods were previously used to generate a panel of 90 predicted epitopes conserved among H. pylori genomes that broadly cover HLA Class II diversity for maximum population coverage. Here, these sequences were tested individually for their ability to induce in vitro responses in peripheral blood mononuclear cells by interferon-γ ELISpot assay. The average number of spot-forming cells/million PBMCs was significantly elevated in H. pylori-infected subjects over uninfected persons. Ten of the 90 peptides stimulated IFN-γ secretion in the H. pylori-infected group only, whereas two out of the 90 peptides elicited a detectable IFN-γ response in the H. pylori-uninfected subjects but no response in the H. pylori-infected group. Cytokine ELISA measurements performed using in vitro PBMC culture supernatants demonstrated significantly higher levels of TNF-α, IL-2, IL-4, IL-6, IL-10, and TGF-β1 in the H. pylori-infected subjects, whereas IL-17A expression was not related to the subjects H. pylori-infection status. Our results indicate that the human T cell responses to these 90 peptides are generally increased in actively H. pylori-infected, compared with H. pylori-naïve, subjects. This information will improve understanding of the complex immune response to H. pylori, aiding rational epitope-driven vaccine design as well as helping identify other H. pylori epitopes with potentially immunoregulatory effects

A hybrid 2D/4D-MRI methodology using simultaneous multi-slice imaging for radiotherapy guidance

Purpose: Respiratory motion management is important in abdominothoracic radiotherapy. Fast imaging of the tumor can facilitate multileaf collimator (MLC) tracking that allows for smaller treatment margins, while repeatedly imaging the full field-of-view is necessary for 4D dose accumulation. This study introduces a hybrid 2D/4D-MRI methodology that can be used for simultaneous MLC tracking and dose accumulation on a 1.5 T Unity MR-linac (Elekta AB, Stockholm, Sweden). Methods: We developed a hybrid 2D/4D-MRI methodology that uses a simultaneous multislice (SMS) accelerated MRI sequence, which acquires two coronal slices simultaneously and repeatedly cycles through slice positions over the image volume. As a result, the fast 2D imaging can be used prospectively for MLC tracking and the SMS slices can be sorted retrospectively into respiratory-correlated 4D-MRIs for dose accumulation. Data were acquired in five healthy volunteers with an SMS-bTFE and SMS-TSE MRI sequence. For each sequence, a prebeam dataset and a beam-on dataset were acquired simulating the two phases of MR-linac treatments. Prebeam data were used to generate a 4D-based motion model and a reference mid-position volume, while beam-on data were used for real-time motion extraction and reconstruction of beam-on 4D-MRIs. In addition, an in-silico computational phantom was used for validation of the hybrid 2D/4D-MRI methodology. MLC tracking experiments were performed with the developed methodology, for which real-time SMS data reconstruction was enabled on the scanner. A 15-beam 8× 7.5 Gy intensity-modulated radiotherapy plan for lung stereotactic body radiotherapy with isotropic 3 mm GTV-to-PTV margins was created. Dosimetry experiments were performed using a 4D motion phantom. The latency between target motion and updating the radiation beam was determined and compensated. Local gamma analyses were performed to quantify dose differences compared to a static reference delivery, and dose area histograms (DAHs) were used to quantify the GTV and PTV coverage. Results: In-vivo data acquisition and MLC tracking experiments were successfully performed with the developed hybrid 2D/4D-MRI methodology. Real-time liver–lung interface motion estimation had a Pearson's correlation of 0.996 (in-vivo) and 0.998 (in-silico). A median (5th–95th percentile) error of 0.0 (−0.9 to 0.7) mm and 0.0 (−0.2 to 0.2) mm was found for real-time motion estimation for in-vivo and in-silico, respectively. Target motion prediction beyond the liver–lung interface had a median root mean square error of 1.6 mm (in-vivo) and 0.5 mm (in-silico). Beam-on 4D MRI reconstruction required a median amount of data equal to an acquisition time of 2:21–3:17 min, which was 20% less data compared to the prebeam-derived 4D-MRI. System latency was reduced from 501 ± 12 ms to −1 ± 3 ms (SMS-TSE) and from 398 ± 10 ms to −10 ± 4 ms (SMS-bTFE) by a linear regression prediction filter. The local gamma analysis agreed within (Formula presented.) to 3.3% (SMS-bTFE) and (Formula presented.) to 10% (SMS-TSE) with a reference MRI sequence. The DAHs revealed a relative D 98% GTV coverage between 97% and 100% (SMS-bTFE) and 100% and 101% (SMS-TSE) compared to the static reference. Conclusions: The presented 2D/4D-MRI methodology demonstrated the potential for accurately extracting real-time motion for MLC tracking in abdominothoracic radiotherapy, while simultaneously reconstructing contiguous respiratory-correlated 4D-MRIs for dose accumulation

Dosimetric evaluation of MRI-guided multi-leaf collimator tracking and trailing for lung stereotactic body radiation therapy

Purpose: The treatment margins for lung stereotactic body radiotherapy (SBRT) are often large to cover the tumor excursions resulting from respiration, such that underdosage of the tumor can be avoided. Magnetic resonance imaging (MRI)-guided multi-leaf collimator (MLC) tracking can potentially reduce the influence of respiration to allow for smaller treatment margins. However, tracking is accompanied by system latency that may induce residual tracking errors. Alternatively, a simpler mid-position delivery combined with trailing can be used. Trailing reduces influences of respiration by compensating for baseline motion, to potentially improve target coverage. In this study, we aim to show the feasibility of MRI-guided tracking and trailing to reduce influences of respiration during lung SBRT. Methods: We implemented MRI-guided tracking on the MR-linac using an Elekta research tracking interface to track tumor motion during intensity modulated radiotherapy (IMRT). A Quasar (Formula presented.) phantom was used to generate Lujan motion ((Formula presented.), 4 s period, 20 mm peak-to-peak amplitude) with and without 1.0 mm/min cranial drift. Phantom tumor positions were estimated from sagittal 2D cine-MRI (4 or 8 Hz) using cross-correlation-based template matching. To compensate the anticipated system latency, a linear ridge regression predictor was optimized for online MRI by comparing two predictor training approaches: training on multiple traces and training on a single trace. We created 15-beam clinical-grade lung SBRT plans for central targets (8 × 7.5 Gy) and peripheral targets (3 × 18 Gy) with different PTV margins for mid-position based motion management (3–5 mm) and for MLC tracking (3 mm). We used a film insert with a 3 cm spherical target to measure the spatial distribution and quantity of the delivered dose. A 1%/1 mm local gamma-analysis quantified dose differences between motion management strategies and reference cases. Additionally, a dose area histogram (DAH) revealed the target coverage relative to the reference scenario. Results: The prediction filter gain was on average 25% when trained on multiple traces and 44% when trained on a single trace. The filter reduced system latency from 313 ± 2 ms to 0 ± 5 ms for 4 Hz imaging and from 215 ± 3 ms to 3 ± 3 ms for 8 Hz. The local gamma analysis for the central delivery showed that tracking improved the gamma pass-rate from 23% to 96% for periodic motion and from 14% to 93% when baseline drift was applied. For the peripheral delivery during periodic motion, delivery pass-rates improved from 22% to 93%. Comparing mid-position delivery to trailing for periodic+drift motion increased the local gamma pass rate from 15% to 98% for a central delivery and from 8% to 98% for a peripheral delivery. Furthermore, the DAHs revealed a relative (Formula presented.) GTV coverage of 101% and 97% compared to the reference scenario for, respectively, central and peripheral tracking of periodic+drift motion. For trailing, a relative (Formula presented.) of 99% for central and 98% for peripheral trailing was found. Conclusions: We provided a first experimental demonstration of the technical feasibility of MRI-guided MLC tracking and trailing for central and peripheral lung SBRT. Tracking maximizes the sparing of healthy tissue, while trailing is highly effective in mitigating baseline motion