Signal Threshold Research Articles

Evaluation of deep learning-based reconstruction late gadolinium enhancement images for identifying patients with clinically unrecognized myocardial infarction

BackgroundThe presence of infarction in patients with unrecognized myocardial infarction (UMI) is a critical feature in predicting adverse cardiac events. This study aimed to compare the detection rate of UMI using conventional and deep learning reconstruction (DLR)-based late gadolinium enhancement (LGEO and LGEDL, respectively) and evaluate optimal quantification parameters to enhance diagnosis and management of suspected patients with UMI.MethodsThis prospective study included 98 patients (68 men; mean age: 55.8 ± 8.1 years) with suspected UMI treated at our hospital from April 2022 to August 2023. LGEO and LGEDL images were obtained using conventional and commercially available inline DLR algorithms. The myocardial signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and percentage of enhanced area (Parea) employing the signal threshold versus reference mean (STRM) approach, which correlates the signal intensity (SI) within areas of interest with the average SI of normal regions, were analyzed. Analysis was performed using the standard deviation (SD) threshold approach (2SD–5SD) and full width at half maximum (FWHM) method. The diagnostic efficacies based on LGEDL and LGEO images were calculated.ResultsThe SNRDL and CNRDL were two times better than the SNRO and CNRO, respectively (P < 0.05). Parea−DL was elevated compared to Parea−O using the threshold methods (P < 0.05); however, no intergroup difference was found based on the FWHM method (P > 0.05). The Parea−DL and Parea−O also differed except between the 2SD and 3SD and the 4SD/5SD and FWHM methods (P < 0.05). The receiver operating characteristic curve analysis revealed that each SD method exhibited good diagnostic efficacy for detecting UMI, with the Parea−DL having the best diagnostic efficacy based on the 5SD method (P < 0.05). Overall, the LGEDL images had better image quality. Strong diagnostic efficacy for UMI identification was achieved when the STRM was ≥ 4SD and ≥ 3SD for the LGEDL and LGEO, respectively.ConclusionsSTRM selection for LGEDL magnetic resonance images helps improve clinical decision-making in patients with UMI. This study underscored the importance of STRM selection for analyzing LGEDL images to enhance diagnostic accuracy and clinical decision-making for patients with UMI, further providing better cardiovascular care.

Disentangling the Physiological Responses of Sweet Orange Citrus Trees to Optimize the Design of Deficit Irrigation Strategies

Climate change scenarios and water restrictions are key challenges for Mediterranean citriculture, requiring sustainable deficit irrigation (DI) strategies to ensure sustainable yields. Further research on the physiological pathways that regulate crop responses to water stress is necessary. This work describes the physiological limitations induced under drought conditions in young Navelina orange trees, including the crop’s capability to recuperate its physiological status upon rewatering and after water withholding. A trial was conducted in two-year-old trees subjected to three irrigation treatments: a full irrigation treatment (FI) and two different DI strategies. The results show significant decreases in gas exchange rates for stem water potential (ΨStem) values below −1.5 MPa, evidencing diffusive limitations from drought stress. Additionally, there was evidence of increased osmolyte synthesis, a preventative response to oxidative damage. Significantly increased levels of proline (Pro) and malondialdehyde (MDA) were observed with higher levels of water stress (ΨStem &lt; −1.8 MPa), which leads us to assume that this threshold signals the presence of oxidative damage with no capacity for subsequent recovery, probably affecting the final yield.

The CD6 interactome orchestrates ligand-independent T cell inhibitory signaling

BackgroundT-cell membrane scaffold proteins are pivotal in T cell function, acting as versatile signaling hubs. While CD6 forms a large intracellular signalosome, it is distinguished from typical scaffolds like LAT or PAG by possessing a substantial ectodomain that binds CD166, a well-characterized ligand expressed on most antigen-presenting cells (APC), through the third domain (d3) of the extracellular region. Although the intact form of CD6 is the most abundant in T cells, an isoform lacking d3 (CD6∆d3) is transiently expressed on activated T cells. Still, the precise character of the signaling transduced by CD6, whether costimulatory or inhibitory, and the influence of its ectodomain on these activities are unclear.MethodsWe expressed CD6 variants with extracellular deletions or cytosolic mutations in Jurkat cells containing eGFP reporters for NF-κB and NF-AT transcription factor activation. Cell activation was assessed by eGFP flow cytometry following Jurkat cell engagement with superantigen-presenting Raji cells. Using imaging flow cytometry, we evaluated the impact of the CD6-CD166 pair on cell adhesiveness during the antigen-dependent and -independent priming of T cells. We also examined the role of extracellular or cytosolic sequences on CD6 translocation to the immunological synapse, using immunofluorescence-based imaging.ResultsOur investigation dissecting the functions of the extracellular and cytosolic regions of CD6 revealed that CD6 was trafficked to the immunological synapse and exerted tonic inhibition wholly dependent on its cytosolic tail. Surprisingly, however, translocation to the synapse occurred independently of the extracellular d3 and of engagement to CD166. On the other hand, CD6 binding to CD166 significantly increased T cell:APC adhesion. However, this activity was most evident in the absence of APC priming with superantigen, and thus, in the absence of TCR engagement.ConclusionsOur study identifies CD6 as a novel ‘on/off’ scaffold-receptor capable of modulating responsiveness in two ways. Firstly, and independently of ligand binding, it establishes signaling thresholds through tonic inhibition, functioning as a membrane-bound scaffold. Secondly, CD6 has the capacity for alternative splicing-dependent variable ligand engagement, modulating its checkpoint-like activity.

THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA

The current paradigm about the function of T cell immune checkpoints is that these receptors switch on inhibitory signals upon cognate ligand interaction. We here revisit this simple switch model and provide evidence that the T cell lineage protein THEMIS enhances the signaling threshold at which the immune checkpoint BTLA (B- and T-lymphocyte attenuator) represses T cell responses. THEMIS is recruited to the cytoplasmic domain of BTLA and blocks its signaling capacity by promoting/stabilizing the oxidation of the catalytic cysteine of the tyrosine phosphatase SHP-1. In contrast, THEMIS has no detectable effect on signaling pathways regulated by PD-1 (Programmed cell death protein 1), which depend mainly on the tyrosine phosphatase SHP-2. BTLA inhibitory signaling is tuned according to the THEMIS expression level, making CD8+ T cells more resistant to BTLA-mediated inhibition than CD4+ T cells. In the absence of THEMIS, the signaling capacity of BTLA is exacerbated, which results in the attenuation of signals driven by the T cell antigen receptor and by receptors for IL-2 and IL-15, consequently hampering thymocyte positive selection and peripheral CD8+ T cell maintenance. By characterizing the pivotal role of THEMIS in restricting the transmission of BTLA signals, our study suggests that immune checkpoint operability is conditioned by intracellular signal attenuators.

Safety of Ancestral Monovalent BNT162b2, mRNA-1273, and NVX-CoV2373 COVID-19 Vaccines in US Children Aged 6 Months to 17 Years

Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. To conduct near-real-time monitoring of health outcomes after COVID-19 vaccination in the US pediatric population. This cohort study evaluated 21 prespecified health outcomes after exposure before early 2023 to BNT162b2, mRNA-1273, or NVX-CoV2373 ancestral monovalent COVID-19 vaccines in children aged 6 months to 17 years by applying a near-real-time monitoring framework using health care data from 3 commercial claims databases in the US (Optum [through April 2023], Carelon Research [through March 2023], and CVS Health [through February 2023]). Increased rates of each outcome after vaccination were compared with annual historical rates from January 1 to December 31, 2019, and January 1 to December 31, 2020, as well as between April 1 and December 31, 2020. Receipt of an ancestral monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose identified through administrative claims data linked with Immunization Information Systems data. Twenty-one prespecified health outcomes, of which 15 underwent sequential testing and 6 were only monitored descriptively due to lack of historical rates. Among 4 102 016 vaccinated enrollees aged 6 months to 17 years, 2 058 142 (50.2%) were male and 3 901 370 (95.1%) lived in an urban area. Thirteen of 15 sequentially tested outcomes did not meet the threshold for a statistical signal. Statistical signals were detected for myocarditis or pericarditis after BNT162b2 vaccination in children aged 12 to 17 years and seizure after vaccination with BNT162b2 and mRNA-1273 in children aged 2 to 4 or 5 years. However, in post hoc sensitivity analyses, a statistical signal for seizure was observed only after mRNA-1273 when 2019 background rates were selected; no statistical signal was observed when 2022 rates were selected. In this cohort study of pediatric enrollees across 3 commercial health insurance databases, statistical signals detected for myocarditis or pericarditis after BNT162b2 (ages 12-17 years) were consistent with previous reports, and seizures after BNT162b2 (ages 2-4 years) and mRNA-1273 vaccinations (ages 2-5 years) should be further investigated in a robust epidemiologic study with confounding adjustment. The US Food and Drug Administration concludes that the known and potential benefits of COVID-19 vaccination outweigh the known and potential risks of COVID-19 infection.

P160 High levels of CD19 expression is a characteristic feature of age-associated B cells in ageing and autoimmunity

Abstract Background/Aims Recent evidence implicates an important role for age-associated B cells (ABCs), defined as CD19+IgD-CD27-T-bet+ B cells, in healthy ageing, following viral infection and in active SLE. We know that co-receptors of the B cell receptor (BCR) such as CD19 and other activating receptors can influence B cell activation through distinct pathways. Therefore, we compared the expression of CD19 in B cell subpopulations including ABCs in ageing and SLE. Methods Peripheral blood was obtained from six young (&amp;lt;45 years) healthy participants, seven elderly (&amp;gt;65 years) healthy participants and eight patients with SLE (25-65 years). We performed flow cytometry on peripheral blood mononuclear cells to analyse the expression of extracellular and intracellular markers. We performed statistical analysis using GraphPad Prism v7. Results CD19hi B cell frequency was at least 10-fold higher in T-bet+ cells as a whole and particularly enriched in IgD-CD27-T-bet+, ABCs, in all groups, p &amp;lt; 0.05. The geometric mean fluorescent intensity (gMFI, expression) of CD40 was significantly lower in IgD-CD27-T-bet+ subpopulations compared to IgD-CD27-T-bet- B cell subpopulations in all groups (Table). In all groups, in CD19+T-bet+ cells, compared to CD19+T-bet- cells, there was a significantly increased frequency of IFNγR+ cells, TLR4+ cells, TLR7+ cells and TLR9+ cells (p &amp;lt; 0.05 for all) with remarkable difference noted in SLE patients for TLR7 and TLR9, p &amp;lt; 0.01 (Table). In the switched memory IgD-CD27+ and ABCs, TLR7 expression was significantly higher (p &amp;lt; 0.01) in SLE patients (mean 43.8% and 18.5% respectively) compared to elderly participants (mean 13.5% compared to 4.3% respectively). Conclusion High levels of expression of CD19 is a characteristic feature of ABCs and CD19hiT-bet+ cells predominantly belong to the IgD-CD27-T-bet+ ABC subpopulation. CD19hi IgD-CD27-T-bet+ cells also had significantly lower expression of CD40 and higher expression of IFNγR and TLR7 and TLR9, suggesting that CD19 plays a significant role in moderating activation of ABCs triggered through T-independent, IFNγR-TLR-T-bet pathway. Taken together with the significant role of CD19 in regulating signalling threshold of B cell activation, and its stable expression across different B cell developmental stages, these data provide compelling mechanistic rationale for targeting CD19 to deplete B cells, including potentially pathogenic age-associated, in autoimmune disease such as SLE. Disclosure K. Shah: None. V. Poon: None. S.J. Taylor: None. C. Klein: Corporate appointments; CK is employed by Roche. Shareholder/stock ownership; CK has patents and stock ownership at Roche. F. Kollert: Corporate appointments; FK is employed by Roche. Shareholder/stock ownership; FK has stock ownership at Roche. F. Schuler: Corporate appointments; FS is employed by Roche. Shareholder/stock ownership; FS has patents and stock ownership at Roche. S. Mathur: None. M. Castelino: None. D. Sen: None. J. Cambridge: None. M. Cragg: None. M. Leandro: None. A. Akbar: None. V. Reddy: None.

Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds

The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.

Quantification of myocardial scar of different etiology using dark- and bright-blood late gadolinium enhancement cardiovascular magnetic resonance

Dark-blood late gadolinium enhancement (LGE) has been shown to improve the visualization and quantification of areas of ischemic scar compared to standard bright-blood LGE. Recently, the performance of various semi-automated quantification methods has been evaluated for the assessment of infarct size using both dark-blood LGE and conventional bright-blood LGE with histopathology as a reference standard. However, the impact of this sequence on different quantification strategies in vivo remains uncertain. In this study, various semi-automated scar quantification methods were evaluated for a range of different ischemic and non-ischemic pathologies encountered in clinical practice. A total of 62 patients referred for clinical cardiovascular magnetic resonance (CMR) were retrospectively included. All patients had a confirmed diagnosis of either ischemic heart disease (IHD; n = 21), dilated/non-ischemic cardiomyopathy (NICM; n = 21), or hypertrophic cardiomyopathy (HCM; n = 20) and underwent CMR on a 1.5 T scanner including both bright- and dark-blood LGE using a standard PSIR sequence. Both methods used identical sequence settings as per clinical protocol, apart from the inversion time parameter, which was set differently. All short-axis LGE images with scar were manually segmented for epicardial and endocardial borders. The extent of LGE was then measured visually by manual signal thresholding, and semi-automatically by signal thresholding using the standard deviation (SD) and the full width at half maximum (FWHM) methods. For all quantification methods in the IHD group, except the 6 SD method, dark-blood LGE detected significantly more enhancement compared to bright-blood LGE (p < 0.05 for all methods). For both bright-blood and dark-blood LGE, the 6 SD method correlated best with manual thresholding (16.9% vs. 17.1% and 20.1% vs. 20.4%, respectively). For the NICM group, no significant differences between LGE methods were found. For bright-blood LGE, the 5 SD method agreed best with manual thresholding (9.3% vs. 11.0%), while for dark-blood LGE the 4 SD method agreed best (12.6% vs. 11.5%). Similarly, for the HCM group no significant differences between LGE methods were found. For bright-blood LGE, the 6 SD method agreed best with manual thresholding (10.9% vs. 12.2%), while for dark-blood LGE the 5 SD method agreed best (13.2% vs. 11.5%). Semi-automated LGE quantification using dark-blood LGE images is feasible in both patients with ischemic and non-ischemic scar patterns. Given the advantage in detecting scar in patients with ischemic heart disease and no disadvantage in patients with non-ischemic scar, dark-blood LGE can be readily and widely adopted into clinical practice without compromising on quantification.

Subtle white matter intensity changes on fluid-attenuated inversion recovery imaging in patients with ischaemic stroke.

Leukoaraiosis is a neuroimaging marker of small-vessel disease that is characterized by high signal intensity on fluid-attenuated inversion recovery MRI. There is increasing evidence from pathology and neuroimaging suggesting that the structural abnormalities that characterize leukoaraiosis are actually present within regions of normal-appearing white matter, and that the underlying pathophysiology of white matter damage related to small-vessel disease involves blood-brain barrier damage. In this study, we aim to verify whether leukoaraiosis is associated with elevated signal intensity on fluid-attenuated inversion recovery imaging, a marker of brain tissue free-water accumulation, in normal-appearing white matter. We performed a cross-sectional study of adult patients admitted to our hospital with a diagnosis of acute ischaemic stroke or transient ischaemic attack. Leukoaraiosis was segmented using a semi-automated method involving manual outlining and signal thresholding. White matter regions were segmented based on the probabilistic tissue maps from the International Consortium for Brain Mapping 152 atlas. Also, normal-appearing white matter was further segmented based on voxel distance from leukoaraiosis borders, resulting in five normal-appearing white matter strata at increasing voxel distances from leukoaraiosis. The relationship between mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter and leukoaraiosis volume was studied in a multivariable statistical analysis using linear mixed modelling, having normal-appearing white matter strata as a clustering variable. One hundred consecutive patients meeting inclusion and exclusion criteria were selected for analysis (53% female, mean age 68 years). Mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was higher in the vicinity of leukoaraiosis and progressively lower at increasing distances from leukoaraiosis. In a multivariable analysis, the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter was positively associated with leukoaraiosis volume and age (B = 0.025 for each leukoaraiosis quartile increase; 95% confidence interval 0.019-0.030). This association was found similarly across normal-appearing white matter strata. Voxel maps of the mean normalized fluid-attenuated inversion recovery signal intensity on normal-appearing white matter showed an increase in signal intensity that was not adjacent to leukoaraiosis regions. Our results show that normal-appearing white matter exhibits subtle signal intensity changes on fluid-attenuated inversion recovery imaging that are related to leukoaraiosis burden. These results suggest that diffuse free-water accumulation is likely related to the aetiopathogenic processes underlying the development of white matter damage related to small-vessel disease.

Constant Fraction Discriminator for NA62 experiment at CERN

A new Constant Fraction Discriminator with additionalTime over Threshold measurement capabilities will be presented.It operates in a wide dynamic range of 1:150, with an excellent timeresolution of better than 70 psover one order of magnitude of the input signals.It is highly customizable for different signal shapes and thresholds,using remotely-programmableparameters for Detector Control System commands.Two outputs, each in the Nuclear Instrumentation Module and Low VoltageDifferentialSignaling standards,provide a precise signal arrival time and Time over Thresholdinformation with programmable thresholds.The technical specification and performance measured with cosmic rays and in thehigh-intensity NA62 experiment will be reported.

A New Method for the Analysis of Broadband Oscillation Mode of New Energy Stations

The accurate identification of the broadband oscillation mode is the premise of solving the resonance risk of new energy stations. Reviewing the traditional Prony algorithm, the problems of the high model order and poor noise immunity in broadband oscillation mode are identified. The accuracy and running time of the Variational mode decomposition (VMD) is a symmetric trade-off problem. An improved strategy based on VMD is proposed. Firstly, the optimal value of the number of modes and penalty factors obtained by a particle swarm optimization algorithm is input into VMD to decompose the signal into multiple modes. Then, combined with the energy threshold method, the denoising and signal reconstruction of each mode component after decomposition are carried out. Finally, the Prony algorithm is used to identify the oscillation mode of the original signal and the reconstructed signal, respectively. The Signal-to-noise ratio (SNR) and model order are compared and analyzed. Through the analysis of the example and simulation data, it is shown that the proposed method effectively solves the problem of poor engineering adaptability of the traditional Prony algorithm. It also can accurately obtain the time-domain characteristics of broadband oscillation, which has a promising future in the engineering application.

Dynamic sample rate acquisition system based on time-to-digital converter technology

In this paper, we propose a novel acquisition system, which can flexibly adjust the sampling rate according to different sampling requirements. First, we propose a sampling model and conduct feasibility verification experiments on it. The experimental results show that the sampling principle has excellent sampling function. Subsequently, we successfully implemented the system. The system combines the differential comparator of Field-Programmable Gate Array (FPGA) with the characteristics of Time-to-digital converter (TDC), which makes full use of the hardware resources of FPGA to realize efficient digital sampling and reconstruction of unknown signals. Among them, the TDC we designed has a time error of less than 100 ps at sampling rates lower than 50 MSps the sampled signal is transmitted via Ethernet, and the measured on-chip data link throughput rate reaches 600 Mbps the sampled information is decoded, fitted and reconstructed in the host computer. In addition, we have thoroughly studied the factors affecting the sampling quality in this acquisition method and summarized the sampling laws after acquiring multiple signals. To ensure the minimum distortion rate, we choose the threshold signal amplitude as 0–5 times of the highest amplitude of the sampled signal, and select the frequency as 10–30 times. Regarding the system resource consumption, the LUT utilization rate is 12.22%, the Slice utilization rate is 23.37%, and the overall design power consumption is 2.094 W. After a comprehensive evaluation of the performance and comparison with the literature (Kalisz et al 1997 IEEE Trans. Instrum. Meas. 46 51–55), it can be concluded that the system has the advantages of small error, high accuracy, and dynamic sampling function. Summarizing this paper, the system shows good engineering practicability and feasibility in the measurement field.

An open-sorce IP-Core for Multi-Voltage Thresholding signal acquisition with FPGAs

High-speed multichannel ADCs are costly and require complex FPGA or MCU firmware to communicate with them. The Multi-Voltage Thresholding (MVT) approach can replace to some extent an external ADC by harnessing the internal FPGA resources, thus reducing costs and complexity. The MVT approach needs only a few low-cost external components. The focus of the contribution is presenting an open-source IP-Core that implements the MVT approach and simplifies its implementation on a standard FPGA. The contribution also provides an overview of characterization measurements and specific calibration method. Our example application demonstrates the viability of the developed IP-Core for signal acquisition from multiple SiPMs.

DEVELOPMENT OF A LOCAL BIOMEDICAL SIGNAL COLLECTION NETWORK BASED ON ZIGBEE TECHNOLOGY

The article describes a methodology for developing a local network for remote monitoring of patient biomedical signals based on low-speed energy-saving ZigBee technology. The local network is based on two transmitters and one receiving module connected to the server. Transmitters transmit information from sensors about the condition of two patients (temperature, pulse, blood flow) to the on-site server. Information is displayed in a specially designed interface that is easy to visualize. In addition, audio elements are connected to the transmitting equipment to alert medical personnel if biomedical signal thresholds are exceeded. Thus, it is possible to monitor the condition of two or more patients (in one department, the number of transmitters can be in the dozens, thanks to the branched ZigBee topology). In the future, it is planned to increase the number of transmitting modules to create a large local monitoring network in a single medical institution. In addition, there is the prospect of collecting more biosignals, including ECG, body position, oxygen saturation of the patient’s blood, etc.

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma.

Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO ) sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long-term in situ resistance assay, most osimertinib-resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non-RTK-dependent epithelial-mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib-resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR-mutated LUAD.

Seeing or believing in hyperplexed spatial proteomics via antibodies: New and old biases for an image-based technology.

Hyperplexed in-situ targeted proteomics via antibody immunodetection (i.e., >15 markers) is changing how we classify cells and tissues. Differently from other high-dimensional single-cell assays (flow cytometry, single-cell RNA sequencing), the human eye is a necessary component in multiple procedural steps: image segmentation, signal thresholding, antibody validation, and iconographic rendering. Established methods complement the human image evaluation, but may carry undisclosed biases in such a new context, therefore we re-evaluate all the steps in hyperplexed proteomics. We found that the human eye can discriminate less than 64 out of 256 gray levels and has limitations in discriminating luminance levels in conventional histology images. Furthermore, only images containing visible signals are selected and eye-guided digital thresholding separates signal from noise. BRAQUE, a hyperplexed proteomic tool, can extract, in a marker-agnostic fashion, granular information from markers which have a very low signal-to-noise ratio and therefore are not visualized by traditional visual rendering. By analyzing a public human lymph node dataset, we also found unpredicted staining results by validated antibodies, which highlight the need to upgrade the definition of antibody specificity in hyperplexed immunostaining. Spatially hyperplexed methods upgrade and supplant traditional image-based analysis of tissue immunostaining, beyond the human eye contribution.

Comparison of Statistical Signal Detection Methods in Adverse Events Following Immunization - China, 2011-2015.

The current study aims to assess the performance of data mining techniques in detecting safety signals for adverse events following immunization (AEFI) using routinely obtained data in China. Four different methods for detecting vaccine safety signals were evaluated. The AEFI data from 2011 to 2015 was collected for our study. We analyzed the data using four different methods to detect signals: the proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). Each method was evaluated at 1-3 thresholds for positivity. To assess the performance of these methods, we used the published signal rates as gold standards to determine the sensitivity and specificity. The number of identified signals varied from 602 for PRR1 (with a threshold of 1) to 127 for MGPS1. When considering the common reactions as the reference standard, the sensitivity ranged from 0.9% for MGPS1/2 to 38.2% for PRR1/2, and the specificity ranged from 85.2% for PRR1 and ROR1 to 96.7% for MGPS1. When considering the rare reactions as the reference standard, PRR1, PRR2, ROR1, ROR2, and BCPNN exhibited the highest sensitivity (73.3%), while MGPS1 exhibited the highest specificity (96.9%). For common reactions, the sensitivities were modest and the specificities were high. For rare reactions, both the sensitivities and specificities were high. Our study provides valuable insights into the selection of signal detection methods and thresholds for AEFI data in China.

Significance of Physiological Signal Thresholds in the Early Diagnosis of Simulator Sickness

Significance of Physiological Signal Thresholds in the Early Diagnosis of Simulator Sickness

Accurate wavelet thresholding method for ECG signals

Current wavelet thresholding methods for cardiogram signals captured by flexible wearable sensors face a challenge in achieving both accurate thresholding and real-time signal denoising. This paper proposes a real-time accurate thresholding method based on signal estimation, specifically the normalized ACF, as an alternative to traditional noise estimation without the need for parameter fine-tuning and extensive data training. This method is experimentally validated using a variety of electrocardiogram (ECG) signals from different databases, each containing specific types of noise such as additive white Gaussian (AWG) noise, baseline wander noise, electrode motion noise, and muscle artifact noise. Although this method only slightly outperforms other methods in removing AWG noise in ECG signals, it far outperforms conventional methods in removing other real noise. This is attributed to the method’s ability to accurately distinguish not only AWG noise that is significantly different spectrum of the ECG signal, but also real noise with similar spectra. In contrast, the conventional methods are effective only for AWG noise. In additional, this method improves the denoising visualization of the measured ECG signals and can be used to optimize other parameters of other wavelet methods to enhancing the denoised periodic signals, thereby improving diagnostic accuracy.

Commissioning of Pixel Sensor Telescope for Monolithic Active Pixel Sensor Characterization

The Monolithic Active Pixel Sensors (MAPS) have been promisingly demonstrated as a core part of tracking detectors used in many experiments. In order to obtain decent particle tracks generated after high-energy particle collision, it is especially important that the detector must consist of high-performance MAPS. A pixel sensor telescope is a tool employed to investigate the properties of MAPS using high-energy particle test beams. At the Synchrotron Light Research Institute (SLRI), the pixel sensor telescope assembled with five layers of 50-µm thick pixel sensors has been commissioned and tested both in the laboratory with a radioactive source and by a high-energy electron test beam produced at the SLRI Beam Test Facility. With sensor signal threshold ranging from 9.73 to 10.15 DAC and noises between 0.62 and 0.87 DAC, each plane of the pixel sensor telescope can detect particles decaying from the radioactive source. Moreover, the test beam profiles have been measured to be 4.00 - 4.56 mm and 1.15 - 2.29 mm in horizontal and vertical axes, respectively. Correlations between each plane have been observed and confirm the proper operation of the pixel sensor telescope. Consequently, the pixel sensor telescope can be used to characterize the pixel sensor prototype.