Coherent light scattering from a telecom C-band quantum dot.

Quantum networks have the potential to transform secure communication via quantum key distribution and enable novel concepts in distributed quantum computing and sensing. Coherent quantum light generation at telecom wavelengths is fundamental for fibre-based network implementations, but Fourier-limited emission and subnatural linewidth photons have so far only been reported from systems operating in the visible to near-infrared wavelength range. Here, we use InAs/InP quantum dots to demonstrate photons with coherence times much longer than the Fourier limit at telecom wavelength via elastic scattering of excitation laser photons. Further, we show that even the inelastically scattered photons have coherence times within the error bars of the Fourier limit. Finally, we make direct use of the minimal attenuation in fibre for these photons by measuring two-photon interference after 25 km of fibre, demonstrating finite interference visibility for photons emitted about 100,000 excitation cycles apart.

2D versus 3D comparison of angiographic imaging biomarkers using computational fluid dynamics simulations of contrast injections.

Quantitative angiography (QAngio) may provide hemodynamic information during neurointerventional procedures through imaging biomarkers related to contrast flow. The standard clinical implementation of QAngio is limited by projection imaging: analysis of contrast motion within complex 3D geometries is restricted to 1-2 projection views, truncating the potential wealth of imaging biomarkers related to disease progression or efficacy of treatment. To understand the limitations of 2D biomarkers, we propose the use of in-silico contrast distributions to investigate the potential benefits of 3D-QAngio within the context of neurovascular hemodynamics. Ground-truth in-silico contrast distributions were generated in two patient-specific intracranial aneurysm models, accounting for the physical interactions of contrast media and blood. A short bolus of contrast was utilized to obtain full a wash-in/ wash-out cycle within the aneurysm ROI. Simulated angiograms mimicking clinical cone-beam CT (CBCT) acquisitions were then generated, and volumetric contrast distributions were reconstructed to analyze bulk contrast flow. The ground-truth 3D-CFD, reconstructed 3D-CBCT-DSA, and 2D-DSA projections were used to extract QAngio parameters related to contrast time dilution curves, such as area under the curve (AUC), peak height (PH), mean-transit-time (MTT), time-to-peak (TTP), and time to arrival (TTA). An initial comparison of quantitative flow parameters in both 2D and 3D, in a smaller and larger aneurysm, indicated that 3D-QAngio can provide a good description of bulk flow characteristics (TTA, TTP, MTT), but recovery of integral parameters (PH, AUC) aneurysms is limited. Nonetheless, incorporation of 3D-QAngio methods may provide additional insight into our understanding of abnormal vascular flow patterns.

Multi-angled simultaneous biplane High-Speed Angiography (HSA) of patient-specific 3D-printed aneurysm phantoms using 1000 fps CdTe Photon-Counting Detectors (PCD's).

1000 fps HSA enables visualization of flow details, which may be important in accurately guiding interventional procedures; however, single-plane imaging may lack clear visualization of vessel geometry and flow detail. The previously presented high-speed orthogonal biplane imaging may overcome these limitations but may still result in foreshortening of vessel morphology. In certain morphologies, acquiring two non-orthogonal biplane projections at multiple angles can provide better flow detail rather than a standard orthogonal biplane acquisition. Flow studies of aneurysm models were performed, where simultaneous biplane acquisitions at various angles separating the two detector views allowed for better evaluation of morphology and flow. 3D-printed, patient-specific internal carotid artery aneurysm models were imaged with various non-orthogonal angles between the two high-speed photon-counting detectors (7.5 cm x 5 cm FOV) to provide frame-correlated simultaneous 1000-fps image sequences. Fluid dynamics were visualized in multi-angled planes of each model using automated injections of iodine contrast media. The resulting dual simultaneous frame-correlated 1000-fps acquisitions from multiple planes of each aneurysm model provided improved visualization of complex aneurysm geometries and flow streamlines. Multi-angled biplane acquisitions with frame correlation allows for further understanding of aneurysm morphology and flow details: additionally, the ability to recover fluid dynamics at depth enables accurate analysis of 3D flow streamlines, and it is expected that multiple-planar views will enable better volumetric flow visualization and quantification. Such better visualization has the potential to improve interventional procedures.

Comparison of pulsatile flow dynamics before and after endovascular intervention in 3D-printed patient-specific internal carotid artery aneurysm models using 1000 fps photon-counting detectors for Simultaneous Biplane High Speed Angiography (SB-HSA).

A significant challenge regarding the treatment of aneurysms is the variability in morphology and analysis of abnormal flow. With conventional DSA, low frame rates limit the flow information available to clinicians at the time of the vascular intervention. With 1000 fps High-Speed Angiography (HSA), high frame rates enable flow details to be better resolved for endovascular interventional guidance. The purpose of this work is to demonstrate how 1000 fps biplane-HSA can be used to differentiate flow features, such as vortex formation and endoleaks, amongst patient-specific internal carotid artery aneurysm phantoms pre- and post-endovascular intervention using an in-vitro flow setup. The aneurysm phantoms were attached to a flow loop configured to a carotid waveform, with automated injections of contrast media. Simultaneous Biplane High-Speed Angiographic (SB- HSA) acquisitions were obtained at 1000 fps using two photon-counting detectors with the respective aneurysm and inflow/ outflow vasculature in the FOV. After x-rays were turned on, the detector acquisitions occurred simultaneously, during which iodine contrast was injected at a continuous rate. A pipeline stent was then deployed to divert flow from the aneurysm, and image sequences were once again acquired using the same parameters. Optical Flow, an algorithm that calculates velocity based on spatial-temporal intensity changes between pixels, was used to derive velocity distributions from HSA image sequences. Both the image sequences and velocity distributions indicate detailed changes in flow features amongst the aneurysms before and after deployment of the interventional device. SB-HSA can provide detailed flow analysis, including streamline and velocity changes, which may be beneficial for interventional guidance.

Investigating Angiographic Injection Parameters for Cerebral Aneurysm Hemodynamic Characterization Using Patient-Specific Simulated Angiograms.

Cerebral aneurysm (CA) rupture is one of the major causes of hemorrhagic stroke. During endovascular therapy (ET), neurointerventionalists rely on qualitative image sequences and do not have access to crucial quantitative hemodynamic information. Quantifying angiographic image sequences can provide vital information, but it is not possible to perform this in a controlled manner in vivo. Computational fluid dynamics (CFD) is a valuable tool capable of providing high fidelity quantitative data by replicating the blood flow physics within the cerebrovasculature. In this work, we use simulated angiograms (SA) to quantify the hemodynamic interaction with a clinically utilized contrast agent. SA enables extraction of time density curves (TDC) within the desired region of interest to analyze hemodynamic parameters such as time to peak (TTP) and mean transit time (MTT) within the aneurysm. We present on the quantification of several hemodynamic parameters of interest for multiple, clinically-relevant scenarios such as variable contrast injection duration and bolus volumes for 7 patient-specific CA geometries. Results indicate that utilizing these analyses provides valuable hemodynamic information relating vascular and aneurysm morphology, contrast flow conditions and injection variability. The injected contrast circulates for multiple cardiac cycles within the aneurysmal region, especially for larger aneurysms and tortuous vasculature. The SA approach enables determination of angiographic parameters for each scenario. Together, these have the potential to overcome the existing barriers in quantifying angiographic procedures in vitro or in vivo, and can provide clinically valuable hemodynamic insights for CA treatment.

Determining 3D Distributions of Pulsatile Blood Flow Using Orthogonal Simultaneous Biplane High-Speed Angiography (SB-HSA) with 1000 fps CdTe Photon Counting Detectors for 3D X-ray Particle Image Velocimetry (3D-XPIV) compared to Results Using Computational Fluid Dynamics (CFD).

3D hemodynamic distributions are useful for the diagnosis and treatment of aneurysms. Detailed blood-flow patterns and derived velocity maps can be obtained using 1000 fps High Speed Angiography (HSA). The novel orthogonal Simultaneous Biplane High-Speed Angiography (SB-HSA) system enables flow information to be quantified in multiple planes, and with additional components of flow at depth, accurate 3D flow distributions are available. Computational Fluid Dynamics (CFD) is the current standard for derivation of volumetric flow distributions, but obtaining solution convergence is computationally expensive and time intensive. More importantly, matching in-vivo boundary conditions is non-trivial. Therefore, an experimentally derived 3D flow distribution method could offer realistic results with less computation time. Using SB-HSA image sequences, 3D X-Ray Particle Image Velocimetry (3D-XPIV) was explored as a new method for assessing 3D flow. 3D-XPIV was demonstrated using an in-vitro setup, where a patient-specific internal carotid artery aneurysm model was attached to a flow loop, and an automated injection of iodinated microspheres was used as a flow tracer. Two 1000 fps photon-counting detectors were placed orthogonally with the aneurysm model in the FOV of both planes. Frame-synchronization of the two detectors made correlation of single-particle velocity components at a given timepoint possible. With frame-rates of 1000 fps, small particle displacements between frames resolved realistic time varying flow, where accurate velocity distributions depended on near-instantaneous velocities. 3D-XPIV velocity distributions were compared to CFD velocity distributions, where the simulation boundary conditions matched the in-vitro setup. Results showed similar velocity distributions between CFD and 3D-XPIV.

Initial investigations of scatter cross-talk in simultaneous biplane high-speed 1000 frames per second neuro-angiography using Monte Carlo simulations.

The Aries photon counting detector (PCD) by Direct Conversion Inc. can image up to 1000 frames per second and is used to track contrast bolus in neuro-vasculature for hemodynamic calculations. For 3D tracking, synchronized biplane imaging with 1 ms acquisition times is used such that both imaging planes are exposed simultaneously. This leads to cross-scattered radiation being detected and a degradation of image quality compared to single-plane imaging. In this study, we utilize Monte Carlo (MC) methods to quantify the increase in scatter due to cross-talk without the use of a radiographic grid. EGSnrc biplane simulations were performed with the Zubal anthropomorphic head phantom. The total scatter plus primary and cross-scatter was calculated in the imaging planes for two orthogonal AP and lateral beams with a field size consistent with the 7.5×5 cm Aries detector, while the primary was determined with a 1×1 mm beam. The forward scatter was then determined from the difference between total and primary. The scatter is seen to increase by 4%-56% for AP projections and 48%-71% for lateral projections depending on detector orientation during simultaneous exposure. Scatter degradation from cross-talk can be reduced using an anti-scatter grid as well as the energy thresholding capabilities of the Aries PCD.

Use of 1000fps High Speed X-ray Angiography (HSAngio) to quantify differences in flow diversion effects of three stents with different coverage densities in a cerebral aneurysm invitro model.

High temporal resolution images acquired using 1000fps HSAngio can be used to visualize blood flow patterns and derive flow velocities during neurointerventional procedures. In this work we use this technology to quantify the changes in the blood flow velocities inside a cerebral aneurysm after treatment with three different stents with varying degrees of metal coverage density; stent A : <2%, stent B: 23% and stent C: 40%. A 3D printed in-vitro model of internal carotid artery aneurysm was connected to a flow loop (60% water, 40% glycerol solution used as circulation fluid, circulation flow rate 8 L/s). An automatic programmable injector (KD Scientific Legato 110) was used to inject iodine contrast agent at a rate of 88 mL/min in 3secs. 1000 fps HSAngio sequences of the contrast injection were acquired using an Aries single photon counting detector (Direct Conversion Inc., Stockholm). From these images blood flow velocities were calculated using an optical flow algorithm. As expected the biggest reduction in blood flow velocity inside the aneurysm was 32.4% after deployment of stent C. However, the velocity profile distribution indicated there was still a significant inflow jet into the aneurysm which could be caused by a endoluminal leak between the stent and the vessel wall. The average reduction was only 14% after placement of stent B and 3% after placement of stent A. Blood velocity distribution maps derived using 1000fps HSAngiography technology can be used to evaluate the quality of flow diversion within the aneurysm after placement of stent. Critical information such as endo luminal leakage which can cause treatment failure can also be detected.

Simultaneous Biplane High Speed 1000 fps X-ray Angiography (HSAngio).

High-speed 1000-fps x-ray Angiography (HSAngio) images can be used to visualize blood-flow patterns and derive flow velocities during neurointerventional procedures. In this work, we present for the very first-time, orthogonal views of contrast injection in an aneurysm model acquired simultaneously using biplane HSAngio imaging. 3-D printed in-vitro models A and B of two different internal carotid-artery aneurysms were connected to a flow loop (circulation fluid: 60% water, 40% glycerol solution, circulation flow rate: 8 L/s). An automatic programmable injector (KD Scientific Legato 110) injected iodine contrast agent at a rate of 88 mL/min for a duration of 3 sec. With an RQA5 spectrum, 1000 fps HSAngio sequences of the contrast injection were acquired simultaneously on the frontal plane using the Actaeon detector (Direct Conversion, Stockholm) and on the lateral plane using the Aries (Direct Conversion, Stockholm) detector. The start of contrast injection and simultaneous biplane x-ray exposures and detector image acquisitions were manually synchronized to capture the initial inflow of contrast into the aneurysm region. For model A the frontal plane images gave a better visualization of the flow streamlines in the parent artery in the inflow (average velocity 28 cm/s) and outflow (average velocity 24 cm/s) region of the aneurysm. The vortices within the aneurysm region especially within the aneurysm dome were better visualized in the lateral plane images (average velocity 27 cm/s). Biplane HSAngio imaging techniques can give more accurate representations of 3-D blood flow within the complex vascular pathology of the human brain, compared to single-plane imaging.

Comparison of quantitative imaging characteristics between a new, larger-FOV 1000 fps high-speed angiographic (HSA) photon-counting detector (Aries) with a smaller HSA detector (Actaeon).

High Speed Angiography (HSA) requires imaging detectors with both high-temporal and high-spatial resolution. Both the Aries and Acteon detectors by Direct Conversion (Stockholm, Sweden) are CdTe direct photon-counting detectors (PCD) that have acquisition frame rates of up to 1000-fps and a 100-micrometer pixel pitch; however, the new Aries detector offers a larger field of view (512 × 768 pixels) compared to the smaller Actaeon detector (256 × 256 pixels). An expanded field of view is required for imaging of larger vasculature, thus the Aries offers this advantage. Evaluations were performed of both detectors under Anti-Coincidence Circuitry (ACC-ON) mode, which corrects for charge sharing between pixels. Initial evaluations of instrumentation noise and detector energy-threshold calibration using Am-241 gamma spectroscopy were performed for the new Aries detector. Linearity was also evaluated for the Aries for each of the 12 individual modules that compose the detector field to check for homogeneity in response to exposure throughout the detector. Finally, Normalized Noise Power Spectrum (NNPS), Modulation Transfer Function (MTF) and Detective Quantum Efficiency (DQE) were then compared between the Aries and Actaeon detectors at two different exposures and detector energy thresholds. The detectors are linear up to approximately 1000 µR and have no instrumentation noise above a threshold of 15 keV. As expected, the MTF's and DQE's are similar between the Aries and Actaeon detectors, and there are thus no tradeoff's in image quality to achieve the larger FOV.

Initial evaluation of 2D and 3D simulated high-speed 1000 fps vascular contrast-flow image sequences using computational fluid dynamics (CFD).

Digital subtraction angiography (DSA) remains the clinical standard for detailed visualization of the neurovasculature due to its high-spatial resolution; however, detailed blood-flow quantification is impaired by its low-temporal resolution. Advances in photon-counting detector technology have led us to develop High-Speed Angiography (HSA), where x-ray images are acquired at 1000 fps for more accurate visualization and quantification of blood flow. We have implemented a physics-based optical flow method to extract such information from HSA, but validation of the angiography-derived velocity distributions is not straightforward. Computational fluid dynamics (CFD) is widely regarded as the benchmark for hemodynamic analysis, as it provides a multitude of quantitative flow parameters throughout the volume of interest. However, there are several limitations with this method related to over-simplification of boundary conditions and suboptimal meshing (spatial resolution), that make CFD simulation results an inexact criterion for validation. To overcome this issue for HSA validation, CFD was used to generate both simulated high-speed angiograms and the corresponding ground-truth 3D flow fields to better understand the relationship between the 3D volumetric-flow distribution and the 2D projected-flow distribution as is obtained with angiography, and the subsequent 2D approximation of flow velocity. Several geometries were investigated, ranging from simple pipe models to complex patient-specific aneurysms. Simulated datasets were analyzed with the optical flow algorithm, and the effects of flow divergence, quantum mottle, and intensity gradient on the calculation were evaluated. From these simulations, we can evaluate whether flow fields reconstructed from HSA are representative of significant flow patterns in the 3D vasculature.

Leveraging Patient-Specific Simulated Angiograms to Characterize Cerebral Aneurysm Hemodynamics using Computational Fluid Dynamics.

Cerebral aneurysms (CA) affect nearly 6% of the US population and its rupture is one of the major causes of hemorrhagic stroke. Neurointerventionalists performing endovascular therapy (ET) to treat CA rely on qualitative image sequences obtained under fluoroscopy guidance alone, and do not have access to crucial quantitative information regarding blood flow before, during and after treatment - partially contributing to a failure rate of up to 30%. Computational fluid dynamics (CFD) is a powerful tool that can provide a wealth of quantitative data; however, CFD has found limited utility in the clinic due to the challenges in obtaining hemodynamic boundary conditions for each patient. In this work, we present a novel CFD-based simulated angiogram approach (SAA) that resolves the blood flow physics and interaction between blood and injected contrast agent to extract quantitative hemodynamic parameters which can be used to design real-time parametric imaging analysis. The SAA enables correlating contrast agent transport to the underlying hemodynamic conditions via time-density curves (TDC) obtained at several points in the region of interest. The ability of the TDC and the SAA to provide critical hemodynamic parameters in and around CA anatomies, such as washout and local flow changes is explored and presented. This provides invaluable quantitative data to the clinician at the time of intervention, since it incorporates the physics of blood flow and correlates the contrast transport to hemodynamic parameters quantitatively - thereby enabling the clinician to take informed decisions that improve treatment outcomes.

Derivation of vascular wall shear stress from 1000 fps high-speed angiography (HSA) velocity distributions.

Pathological changes in blood flow lead to altered hemodynamic forces, which are responsible for a number of conditions related to the remodeling and regeneration of the vasculature. More specifically, wall shear stress (WSS) has been shown to be a significant hemodynamic parameter with respect to aneurysm growth and rupture, as well as plaque activation leading to increased risk of stroke. In-vivo measurement of shear stress is difficult due to the stringent requirements on spatial resolution near the wall boundaries, as well as the deviation from the commonly assumed parabolic flow behavior at the wall. In this work, we propose an experimental method of in-vitro WSS calculations from high-temporal resolution velocity distributions, which are derived from 1000 fps high-speed angiography (HSA). The high-spatial and temporal resolution of our HSA detector makes such high-resolution velocity gradient measurements feasible. Presented here is the methodology for calculation of WSS in the imaging plane, as well as initial results for a variety of vascular geometries at physiologically realistic flow rates. Further, the effect of spatial resolution on the gradient calculation is explored using CFD-derived velocity data. Such angiographic-based analysis with HSA has the potential to provide critical hemodynamic feedback in an interventional setting, with the overarching objective of supporting clinical decision-making and improving patient outcomes.

Combining tumor deposits with the number of lymph node metastases to improve the prognostic accuracy in stage III colon cancer: a post hoc analysis of the CALGB/SWOG 80702 phase III study (Alliance)☆.

BACKGROUND: In colon cancer, tumor deposits (TD) are considered in assigning prognosis and staging only in the absence of lymph node metastasis (i.e. stage III pN1c tumors). We aimed to evaluate the prognostic value of the presence and the number of TD in patients with stage III, node-positive colon cancer. PATIENTS AND METHODS: All participants from the CALGB/SWOG 80702 phase III trial were included in this post hoc analysis. Pathology reports were reviewed for the presence and the number of TD, lymphovascular and perineural invasion. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated by multivariable Cox models adjusting for sex, treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. RESULTS: Overall, 2028 patients were included with 524 (26%) TD-positive and 1504 (74%) TD-negative tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e. pN1c), 239 (46.1%) were pN1a/b (<4 positive lymph nodes) and 200 (38.5%) were pN2 (≥4 positive lymph nodes). The presence of TD was associated with poorer DFS [adjusted hazard ratio (aHR) = 1.63, 95% CI 1.33-1.98] and OS (aHR = 1.59, 95% CI 1.24-2.04). The negative effect of TD was observed for both pN1a/b and pN2 groups. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Combining TD and the number of lymph node metastases, 104 of 1470 (7.1%) pN1 patients were re-staged as pN2, with worse outcomes than patients confirmed as pN1 (3-year DFS rate: 65.4% versus 80.5%, P = 0.0003; 5-year OS rate: 87.9% versus 69.1%, P = <0.0001). DFS was not different between patients re-staged as pN2 and those initially staged as pN2 (3-year DFS rate: 65.4% versus 62.3%, P = 0.4895). CONCLUSION: Combining the number of TD and the number of lymph node metastases improved the prognostication accuracy of tumor-node-metastasis (TNM) staging.

COVID-19: Seroprevalence and Vaccine Responses in UK Dental Care Professionals.

Dental care professionals (DCPs) are thought to be at enhanced risk of occupational exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, robust data to support this from large-scale seroepidemiological studies are lacking. We report a longitudinal seroprevalence analysis of antibodies to SARS-CoV-2 spike glycoprotein, with baseline sampling prior to large-scale practice reopening in July 2020 and follow-up postimplementation of new public health guidance on infection prevention control (IPC) and enhanced personal protective equipment (PPE). In total, 1,507 West Midlands DCPs were recruited into this study in June 2020. Baseline seroprevalence was determined using a combined IgGAM enzyme-linked immunosorbent assay and the cohort followed longitudinally for 6 mo until January/February 2021 through the second wave of the coronavirus disease 2019 pandemic in the United Kingdom and vaccination commencement. Baseline seroprevalence was 16.3%, compared to estimates in the regional population of 6% to 7%. Seropositivity was retained in over 70% of participants at 3- and 6-mo follow-up and conferred a 75% reduced risk of infection. Nonwhite ethnicity and living in areas of greater deprivation were associated with increased baseline seroprevalence. During follow-up, no polymerase chain reaction-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 147.6 IU/ml with respect to the World Health Organization international standard 20-136. After vaccination, antibody responses were more rapid and of higher magnitude in those individuals who were seropositive at baseline. Natural infection with SARS-CoV-2 prior to enhanced PPE was significantly higher in DCPs than the regional population. Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 mo after initial sampling and 9 mo from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech 162b vaccine is associated with an antibody response indicative of immunological memory.

Evaluation of methods to derive blood flow velocity from 1000 fps high-speed angiographic sequences (HSA) using optical flow (OF) and computational fluid dynamics (CFD).

Digital Subtraction Angiography (DSA) is considered the gold standard for imaging and guiding treatment of neurovascular lesions, such as cerebral aneurysms and carotid stenoses. Though DSA can show high-resolution morphology, it remains difficult to extract temporal physiological information, because higher frame-rates are necessary to accurately quantify neurovascular flow details. Recent advances in photon-counting detector technology have led us to develop High-Speed Angiography (HSA), where X-ray images are acquired at 1000 fps for more accurate visualization and quantification of blood flow. Blood flow was imaged using HSA under constant flow conditions within various 3D printed patient-specific phantoms. Blood velocity was quantified using an open source Optical Flow algorithm, OpenOpticalFlow, to perform velocity estimation based on the spatio-temporal intensity changes of iodinated contrast wavefronts. The results of these algorithms are then compared with Computational Fluid Dynamics (CFD) simulations, using the same inlet boundary conditions and model geometries. The performance of these algorithms at lower temporal resolution was then also assessed by simulating lower frame rates from the acquired 1000 fps data. It is important to ascertain the hemodynamic effect of abnormal neurovascular conditions, as well as their effect on treatment of such conditions during the actual clinical interventional procedure. While theoretical CFD results requiring considerable computer capability are delayed for hours or more, it is expected that clinical results from multiple HSA sequences will be available almost immediately while the patient is still under treatment, and even right after flow conditions are changed beneficially by the intervention.

Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy.

BACKGROUND: The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. PATIENTS AND METHODS: Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. RESULTS: High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016). CONCLUSIONS: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.

Validation of a combined ELISA to detect IgG, IgA and IgM antibody responses to SARS-CoV-2 in mild or moderate non-hospitalised patients.

BACKGROUND: Frequently SARS-CoV-2 results in mild or moderate disease with potentially lower concentrations of antibodies compared to those that are hospitalised. Here, we validated an ELISA using SARS-CoV-2 trimeric spike glycoprotein, with targeted detection of IgG, IgA and IgM (IgGAM) using serum and dried blood spots (DBS) from adults with mild or moderate disease. METHODS: Targeting the SARS-CoV-2 trimeric spike, a combined anti-IgG, IgA and IgM serology ELISA assay was developed using 62 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 624 COVID-19 negative samples. The assay was validated using 73 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 359 COVID-19 negative serum samples with an additional 81 DBSs. The assay was further validated in 226 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 426 COVID-19 negative clinical samples. RESULTS: A sensitivity and specificity of 98.6% (95% CI, 92.6-100.0), 98.3% (95% CI, 96.4-99.4), respectively, was observed following validation of the SARS-CoV-2 ELISA. No cross-reactivities with endemic coronaviruses or other human viruses were observed, and no change in results were recorded for interfering substances. The assay was stable at temperature extremes and components were stable for 15 days once opened. A matrix comparison showed DBS to correlate with serum results. Clinical validation of the assay reported a sensitivity of 94.7% (95% CI, 90.9-97.2%) and a specificity of 98.4% (95% CI, 96.6-99.3%). CONCLUSIONS: The human anti-IgGAM SARS-CoV-2 ELISA provides accurate and sensitive detection of SARS-CoV-2 antibodies in non-hospitalised adults with mild or moderate disease. The use of dried blood spots makes the assay accessible to the wider community.

Characterization of velocity patterns produced by pulsatile and constant flows using 1000 fps high-speed angiography (HSA).

In order to accurately quantify rapidly changing blood flow velocities, as typically seen in the neurovasculature, high temporal resolution is necessary. Current methods to extract velocity data from angiographic image sequences are generally limited to 30 fps or less. High-speed angiography (HSA) with a maximal frame rate of 1000 fps can be used to evaluate time-dependent flow details normally averaged out with lower frame rates. For new HSA image sequences, two different quantitative methods were utilized to extract high-temporal resolution velocity changes: X-Ray Particle Image Velocimetry (X-PIV) and optical flow (OF). A variety of flow conditions were examined in a range of patient-specific 3D-printed phantoms. Both pulsatile and constant flow settings were investigated. X-PIV was performed using radiopaque sub-millimeter microspheres, which were tracked throughout the image sequence to provide accurate, but limited sampling of the velocity field within the 3D-printed models. Also, an open source optical flow algorithm, OpenOpticalFlow, was used to perform velocity estimation based on the spatio-temporal intensity changes of iodinated contrast wavefronts. Periodic changes in velocity within each phantom ROI can be illustrated throughout the pulsatile cycle capture by the high-speed detector. In the constant flow sequences, changes in velocity across the phantom geometry can be seen. The ability to accurately measure detailed velocity distributions and velocity changes throughout various flow conditions at high temporal resolution enables further insight into the evaluation and treatment of neurovascular disease states.