Large Screening Research Articles

Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib

IntroductionSCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial. MethodsA total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening. ResultsOn the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22–2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26–1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial. ConclusionsMolecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.

S458 Impact of Personalized Patient Outreach on Multi-Target Stool DNA Test Adherence in a Large Colorectal Cancer Screening Population

S458 Impact of Personalized Patient Outreach on Multi-Target Stool DNA Test Adherence in a Large Colorectal Cancer Screening Population

Texting while driving is a visual problem influenced by phone viewing angle and working distance in young individuals

PurposeTo investigate the impact of smartphone viewing distance and angle on reaction times. DesignA prospective, self-controlled, single-center study. MethodsParticipants engaged in a driving simulation facing a large screen with a simulated brake pedal. They were tasked to stop the simulation once recognizing the deceleration of upcoming traffic. Tests were conducted without distraction and with a standardized distraction simulating texting while driving (TWD). Smartphone positions varied at distances of 30 cm and 60 cm, and at angles parallel to and 30° below the road plane. Reaction times were measured from the onset of simulated closure to detection. Stopping distances were extrapolated using data from the National Highway Traffic Safety Administration. ResultsNinety-four participants were included with a mean age of 24 ± 2.7 years. The control reaction time was 11.5 ± 4.1 s. Reaction times significantly decreased with smartphone placement at a closer distance of 30 cm parallel (17.0 ± 3.3 s) vs 60 cm parallel (15.4 ± 3.8 s), P < 0.001. A 30-degree downward placement at 30 cm (18.6 ± 4.0 s) and 60 cm (17.9 ± 3.6 s), further decreased reaction time compared to parallel phone positioning, P < 0.001. Extrapolating to stopping distances based on real-world data, smartphone distractions placed at 30 cm 30° below the dashboard had the greatest effect, resulting in a 3 times increase of stopping distance compared to the control, 1201 vs 394 ft respectively, P < 0.001. ConclusionTWD significantly delays reaction time in young participants. Both the distance and viewing angle of a smartphone significantly influences reaction times during driving simulations. The greatest delays are observed when the smartphone is positioned closer to the user and at a 30-degree angle which we hypothesize is due to vision blur from increased accommodation, loss of stereopsis, and fixation with the peripheral retina.

Large scale screening and quantification of micropollutants in fish from the coastal waters of Cochin, India: Analytical method development and health risk assessment

Urban estuarine and coastal water receive several micropollutants through industrial and agricultural influxes. The bioaccumulation of these micropollutants in fish and their entry into the coastal population's food chain raises significant food safety concerns. Hence, a comprehensive analytical method was developed for ultra-trace level quantification of 345 micropollutants in fish. The optimized sample preparation method could extract compounds suitable for both GC–MS/MS and LC-MS/MS analysis simultaneously. The target list of contaminants included 278 agricultural pesticides and also 102 endocrine disruptors covering polyaromatic hydrocarbons, polychlorinated biphenyls, organochlorines, and endocrine-disrupting pesticides. The GC–MS/MS with large volume injection (LVI) technique, and LC-MS/MS operating in MRM mode, achieved an LOQ of <2.00 ng/g for most of the analytes. The extraction strategy involved tri-phase partitioning between water, acidified acetonitrile, and hexane, followed by salting out. Dispersive solid phase cleanup (dSPE) with C18, Z-Sep+, CaCl2, and MgSO4 was able to reduce the matrix influence, and the method achieved satisfactory recovery in the range of 70.0–120.0 % for all the target analytes. The repeatability and reproducibility relative standard deviation values of the measured analytes were <20.0 %, and the Horwitz ratio values were well below 2. The method was used to accurately measure the target micropollutants in fish from the Cochin estuary, the highly urbanized portion of the Vembanad Lake, and an important Ramsar site. At least one or more of the 41 different micropollutants were identified and quantified in about 90.7 % of the 108 samples analyzed. The importance of large-scale screening and trace-level quantification methods in environmental monitoring and risk assessment is underscored by the results. The risk assessment showed a moderate risk of exposure to the nearby coastal population through the food chain.

Kinetic characterization of amino acid activation by aminoacyl-tRNA synthetases using radiolabelled γ-[32P]ATP.

Aminoacyl-tRNA synthetases (AARSs) are fundamental enzymes that pair amino acids and tRNAs for protein synthesis. Aminoacylation occurs in two discrete steps. The amino acid is first activated by ATP, leading to an aminoacyl-adenylate intermediate and pyrophosphate (PPi) formation. In a subsequent step, the aminoacyl moiety is transferred to the tRNA. Kinetic assays were developed to follow each of these steps independently, as well as cumulative two-step aminoacylation. The main advantage of following the activation step over two-step aminoacylation is that most AARSs can activate amino acids in the absence of the tRNA, the production of which is laborious. Hence, the activation step is often tested first in the kinetic analysis, including large screens exploring AARS-targeting inhibitors. Since the 1960s, the activation reaction has been routinely followed by the standard ATP/[32P]PPi exchange assay, which relies on the equilibrium exchange of radiolabel between PPi and ATP using [32P]PPi as a labelled compound. However, this method became much less convenient when [32P]PPi was discontinued in 2022. As a solution, we developed a modified assay that uses easily attainable γ-[32P]ATP as a labelled compound in the equilibrium-based assay. Using this assay, herein named the [32P]ATP/PPi assay, we followed the activation step of several AARSs. The obtained data are in good agreement with the previously published kinetic constants obtained with the standard ATP/[32P]PPi exchange assay.

Flagging Frailty in the Emergency Department: A System to Identify and Visualise Frailty

Abstract Background Older adults with frailty who present to the Emergency Department (ED) are at increased risk of hospitalisation, prolonged length of stay, deconditioning and loss of independence.1 Early identification of frailty using a validated tool, such as the Clinical Frailty Scale (CFS), is widely recommended to inform clinical decisions, identify the best pathway of care for older adults with frailty, and for potential use as a predictor or an outcome.2 We aimed to develop and implement a system of frailty identification which is highly visible, digitised and integrated with routine ED processes. Methods In the ED of a large teaching hospital, an expanded interdisciplinary Acute Frailty Team (AFT) commenced work in the ED in February 2024. The AFT aimed to screen all over 70s presenting within working hours for frailty using CFS. ED consultants collaborated with software developers through iterative design stages to create a ‘Frailty Flag’ for the ED Whiteboard with the requirements that it is highly visible, easy to use and highlights patients with higher frailty scores. Results In April 2024, a ‘Frailty Flag’ was launched on the ED Whiteboard, prominently displaying the CFS and using traffic light colouring to highlight those with higher CFS scores. As part of standard work, the AFT populate the CFS on the ED Whiteboard, which is viewed by all staff in ED on large wall-mounted screens. Feedback from ED and inpatient staff indicate that a highly visible frailty score is a valuable addition to the ED Whiteboard which allows them to prioritise care and supports decision making regarding suitability for geriatric care pathways. Conclusion A Frailty Flag on the ED Whiteboard allows for easy, accessible communication of frailty scores to the ED multi-disciplinary team. Next steps involve integrating the Frailty Flag with in-patient systems and developing standard work for out of hours use of the system.

Temperature mapping of milling by dual centrifugation: A systematic investigation

Using low quantities of drug compounds is often favorable in the early stages of drug development, especially for what require a large screening investigation to define the final formulation composition, such as nano- and microsuspensions. For that reason, the dual centrifugation approach has in the recent years been used due to its reproducible and fast-milling capacity with 40 samples in 2 mL vials simultaneously without the addition of cooling breaks due to a built-in cooling system. Nonetheless, heat can be dissipated into the samples during high-intensity milling, resulting in increased sample temperatures that potentially can affect thermolabile compounds and potential influence the obtained suspensions in the screening experiments if the used stabilizer has temperature dependent variations in the performance. Hence, a systematic investigation of the influence of different process parameters on the heat dissipation in samples during milling by the dual centrifugation approach was performed in the present study. It was found that the milling speed had the highest impact on the final sample temperature, but also other parameters, such as the bead loading, bead size, and placement in the centrifuge during milling had significantly influenced the final mean temperature of the milling media. Higher temperatures were obtained with higher bead loadings, i.e., 3000 mg milling beads/mL and milling speeds (1500 rpm), and when smaller milling beads, i.e., 0.1 mm, were used during production. The study further showed that higher temperatures were measured for samples located on the bottom disk during milling, and also when located on the outer placement on the sample disk. Upscale investigations showed immensely increased sample temperatures (almost up to boiling point) when samples were prepared under similar formulation parameters and milling speed as small-volume vials. Furthermore, the study indicated that the addition of drug compounds during suspension preparation decreased the final sample temperature compared to samples that only contained purified water due to energy absorption of the drug compound.

MEPO-ML: a robust graph attention network model for rapid generation of partial atomic charges in metal-organic frameworks

Accurate computation of the gas adsorption properties of MOFs is usually bottlenecked by the DFT calculations required to generate partial atomic charges. Therefore, large virtual screenings of MOFs often use the QEq method which is rapid, but of limited accuracy. Recently, machine learning (ML) models have been trained to generate charges in much better agreement with DFT-derived charges compared to the QEq models. Previous ML charge models for MOFs have all used training sets with less than 3000 MOFs obtained from the CoRE MOF database, which has recently been shown to have high structural error rates. In this work, we developed a graph attention network model for predicting DFT-derived charges in MOFs where the model was developed with the ARC-MOF database that contains 279,632 MOFs and over 40 million charges. This model, which we call MEPO-ML, predicts charges with a mean absolute error of 0.025e on our test set of over 27 K MOFs. Other ML models reported in the literature were also trained using the same dataset and descriptors, and MEPO-ML was shown to give the lowest errors. The gas adsorption properties evaluated using MEPO-ML charges are found to be in significantly better agreement with the reference DFT-derived charges compared to the empirical charges, for both polar and non-polar gases. Using only a single CPU core on our benchmark computer, MEPO-ML charges can be generated in less than two seconds on average (including all computations required to apply the model) for MOFs in the test set of 27 K MOFs.

Fully Flexible All‐in‐One Electronic Display Skin with Seamless Integration of MicroLED and Hydrogel Battery

AbstractVisualization is a cornerstone in human–computer interaction, evolving from large screens to mobile devices and now to wearable display technology. However, conventional batteries and displays lack the softness and stretchability inherent to human skin. Here, a fully flexible, all‐in‐one electronic display skin by integrating a flexible microLED display, a stretchable circuit, and a Zn|PAM|V2O5 hydrogel battery pack is developed. Vapor‐phase bulk transfer is used to efficiently and accurately transfer 10 000 microLEDs onto a flexible substrate, ensuring high flexibility and ultra‐thin (240 µm). The flexible hydrogel battery pack provides sustainable energy, with a high specific capacity of 331.3 mAh g−1. Additionally, a transparent stretchable circuit board (maximum stretch 40%) is made by 3D printing technology. The skin display exhibited exceptional stretchability and biocompatibility, conforming to movements while maintaining high‐resolution dynamic visual outputs. These innovations pave the way for advanced skin‐implanted displays, promising transformative applications in information interaction, healthcare, and artificial intelligence.

Can people determine object distance from its visual size and position in a correctly scaled 2D scene displayed on a large screen with aligned ground plane?

Can people determine object distance from its visual size and position in a correctly scaled 2D scene displayed on a large screen with aligned ground plane?

Two different visual stimuli that cause axial eye shortening have no additive effect

Previous studies identified two visual stimuli that can shorten the human eye by thickening the choroid after short-term visual stimulation, potentially inhibiting myopia: (1) watching digitally filtered movies where the red plane has full spatial resolution while green and blue are low-pass filtered according to the human longitudinal chromatic aberration (LCA) function (the “red in focus” filter), and (2) reading text with inverted contrast. This study aimed to determine whether combining these two stimuli would have an additive effect on axial length. Twenty-two emmetropic subjects were recruited to read text (standard and inverted contrast) for 30 min from a large screen, 2 m away, either unfiltered or filtered with the “red in focus” filter. Axial length was measured before and after each reading episode using low-coherence interferometry (Lenstar LS 900, Haag Streit). Reading text with conventional contrast polarity (dark letters on a bright background) resulted in no significant axial length change. Adding the “red in focus” filter did not alter the outcome. Consistent with previous findings, reading inverted contrast text made emmetropic eyes shorter. Surprisingly, when the text was combined with the “red in focus” filter, eyes became longer rather than shorter. A possible explanation for this contradictory result is that, for the text stimulus, the “red in focus” filter removes spatial information in the blue channel needed by the retina to use LCA analysis to thicken the choroid.

The French hypertrophic cardiomyopathy gene register: A systematic large gene screening for hypertrophic cardiomyopathy

BackgroundAlthough the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. AimsThe performance of this approach was tested in GEREMY, a HCM prospective observational French register. MethodsScreening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17–80 gene panels of were used. ResultsA 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis. ConclusionsSystematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach.

Nineteen years of radiographic screening: Impact of sepsis and evolution of osteochondrosis dissecans prevalence in Walloon sport horses born between 2004 and 2022.

Osteochondrosis dissecans is a particularly common developmental orthopaedic disorder in equines. Among its causes, the hereditary component is no longer a matter of debate, and, for several decades, the various studbooks for sport horses have been selecting stallions in order to limit the prevalence of this condition in the population. However, to our knowledge, no study has evaluated changes in the prevalence of osteochondrosis dissecans over time through longitudinal monitoring of a population of sport horses. The study presented here is part of a large screening programme for developmental orthopaedic pathologies in Wallonia (Belgium) and assessed the presence of these lesions over a period of 19 years in the Walloon sport horse population according to constant and standardised sampling and diagnostic criteria. The effects of breeding conditions and infection in foals were also assessed by means of questionnaires. The results showed no significant change in the prevalence of osteochondrosis dissecans in a population of 1099 individuals born between 2004 and 2022. Furthermore, individuals who had suffered from sepsis during their growing period were very significantly predisposed (p < 0.001) to the development of osteochondrosis dissecans compared to a control group, with respectively 14/21 (67%) and 103/364 (28%) of individuals affected. This study suggests that the selection programmes applied to the population studied are not sufficiently strong or adapted to reduce the prevalence of osteochondrosis dissecans in the population over a period of 19 years. Moreover, this study confirms that foals with sepsis and concurrent osteochondrosis dissecans lesions should not necessarily be excluded from breeding programmes on this basis.

Gaze behavior in open-angle glaucoma patients during visuo-cognitive-motor tasks: a cross-sectional study

This study investigated gaze behavior during visuo-cognitive-motor tasks with a change of movement direction in glaucoma patients and healthy controls. Nineteen glaucoma patients (10 females, 9 males) and 30 healthy sighted controls (17 females, 13 males) participated in this cross-sectional study. Participants performed two visuo-cognitive-motor tasks with a change of movement direction: (i) the “Speed-Court-Test” that involved stepping on different sensors in response to a visual sign displayed on either a large or small screen (165″ and 55″, respectively); (ii) the “Trail-Walking-Test” that required walking to 15 cones labeled with numbers (1–8) or letters (A-G) in an alternately ascending order. During these tasks, the time needed for completing each task was determined and the gaze behavior (e.g., saccade duration, fixation duration) was recorded via eye tracking. Data were analyzed with repeated measures analyses of covariance (ANCOVA; GROUP × SCREEN) and one-way ANCOVA. No differences between groups were found for the time needed to complete the tasks. However, during the “Trail-Walking-Test”, the fixation duration was longer for glaucoma patients than for controls (p = 0.016, ηp2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\upeta }_{\ ext{p}}^{2}$$\\end{document} = 0.131). Furthermore, during the “Speed-Court-Test”, there was a screen size effect. Irrespective of group, saccade amplitudes were lower (p < 0.001, ηp2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\upeta }_{\ ext{p}}^{2}$$\\end{document} = 0.242) and fixation durations were higher (p = 0.021, ηp2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\upeta }_{\ ext{p}}^{2}$$\\end{document} = 0.125) for the small screen. Fixation durations were longer in glaucoma patients during the cognitively demanding “Trail-Walking-Test”, which might indicate a strategy to compensate for their visual impairment.

Methodology for Design of Hydrogen Robot for Medical Needs

The paper examines the concept of creating a Collaborative Service Robot powered by a Hydrogen Fuel Cell designed to assist in medical facilities. The characteristics of this robot are analyzed and its advantages are highlighted, from the point of view of ecological operation and long life during the patient service activities in a hospital facility. Some key features and benefits of Hydrogen Fuel Cell-powered robots are compared to battery-powered robots and the positives in this comparison are shown. The advantages of modern Collaborative Robots used as Service Robots in inpatient service processes in a hospital are presented. It shows the possibility, based on the competence and expertise of the authors in the field of Service Mobile Collaborative Robots, to create and implement one for the needs of human service in medical facilities, which will be powered by a hydrogen fuel cell. The main characteristics of the created mobile collaborative service robots of the ``AnRI'' series (Anthropomorphic Robot with Intelligence) are briefly indicated, where ``AnRI-1'' is equipped with a manipulator with a three-finger gripper, and ``AnRI-2'' is an information robot equipped with a large screen on top. The article analyzes the process of creating these collaborative robots, realizing several important elements of the control system, such as its development with elements of Artificial Intelligence. The advantages of hydrogen power and increased reliability of the general complex of systems in these Collaborative Mobile Robots and their possibility to be used effectively in the realization of medical care are emphasized.

Synthesis at the Interface of Chemistry and Biology.

ConspectusChemical synthesis as a tool to control the structure and properties of matter is at the heart of chemistry─from the synthesis of fine chemicals and polymers to drugs and solid-state materials. But as the field evolves to tackle larger and larger molecules and molecular complexes, the traditional tools of synthetic chemistry become limiting. In contrast, Mother Nature has developed very different strategies to create the macromolecules and molecular systems that make up the living cell. Our focus has been to ask whether we can use the synthetic strategies and machinery of Mother Nature, together with modern chemical tools, to create new macromolecules, and even whole organisms with properties not existing in nature. One such example involves reprogramming the complex, multicomponent machinery of ribosomal protein synthesis to add new building blocks to the genetic code, overcoming a billion-year constraint on the chemical nature of proteins. This methodology exploits the concept of bioorthogonality to add unique codons, tRNAs and aminoacyl-tRNA synthetases to cells to encode amino acids with physical, chemical and biological properties not found in nature. As a result, we can make precise changes to the structures of proteins, much like those made by chemists to small molecules and beyond those possible by biological approaches alone. This technology has made it possible to probe protein structure and function in vitro and in vivo in ways heretofore not possible, and to make therapeutic proteins with enhanced pharmacology. A second example involves exploiting the molecular diversity of the humoral immune system together with synthetic transition state analogues to make catalytic antibodies, and then expanding this diversity-based strategy (new to chemists at the time) to drug discovery and materials science. This work ushered in a new nature-inspired synthetic strategy in which large libraries of natural or synthetic molecules are designed and then rationally selected or screened for new function, increasing the efficiency by which we can explore chemical space for new physical, chemical and biological properties. A final example is the use of large chemical libraries, robotics and high throughput phenotypic cellular screens to identify small synthetic molecules that can be used to probe and manipulate the complex biology of the cell, exemplified by druglike molecules that control cell fate. This approach provides new insights into complex biology that complements genomic approaches and can lead to new drugs that act by novel mechanisms of action, for example to selectively regenerate tissues. These and other advances have been made possible by using our knowledge of molecular structure and reactivity hand in hand with our understanding of and ability to manipulate the complex machinery of living cells, opening a new frontier in synthesis. This Account overviews the work in my lab and with our collaborators, from our early days to the present, that revolves around this central theme.

Developing probabilistic ensemble machine learning models for home-based sleep apnea screening using overnight SpO2 data at varying data granularity.

This study aims to develop sleep apnea screening models with overnight SpO2 data, and to investigate the impact of the SpO2 data granularity on model performance. A total of 7,718 SpO2 recordings from the SHHS and MESA datasets were used. Probabilistic ensemble machine learning was employed to predict sleep apnea status at three AHI cutoff points: ≥ 5, ≥ 15, and ≥ 30 events/hour. To investigate the impact of data granularity, SpO2 data were aggregated at 30, 60, and 300s. Our models demonstrated good to excellent performance on internal test, with average area under the curve (AUC) values of 0.91, 0.93, and 0.96 for cutoffs ≥ 5, ≥ 15, and ≥ 30 at data granularity of 1s, respectively. Both sensitivity (0.76, 0.84, 0.89) and specificity (0.87, 0.86, 0.90) ranged from good to excellent across three cutoffs. Positive predictive values (PPV) ranged from excellent to fair (0.97, 0.83, 0.66), and negative predictive values (NPV) ranged from low to excellent (0.43, 0.87, 0.98). Model performance on external test slightly dropped compared to internal test, but still achieved good to excellent AUC above 0.80 across all data granularity and all the three cutoffs. Data granularity of 300s led to a reduction in performance metrics across all cutoffs. Our models demonstrated superior performance across all three AHI cutoff thresholds compared to existing large sleep apnea screening models, even when considering varying SpO2 data granularity. However, lower data granularity was associated with decreased screening performance, indicating a need for further research in this area.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody-Based Therapy in ERBB2-Amplified Metastatic Colorectal Cancer.

HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Simultaneous screening for selective SARS-CoV-2, Lassa, and Machupo virus entry inhibitors

Emerging highly pathogenic viruses can pose profound impacts on global health, the economy, and society. To meet that challenge, the National Institute of Allergy and Infectious Diseases (NIAID) established nine Antiviral Drug Discovery (AViDD) centers for early-stage identification and validation of novel antiviral drug candidates against viruses with pandemic potential. As part of this initiative, we established paired entry assays that simultaneously screen for inhibitors specifically targeting SARS-CoV-2 (SARS2), Lassa virus (LASV) and Machupo virus (MACV) entry. To do so we employed a dual pseudotyped virus (PV) infection system allowing us to screen ∼650,000 compounds efficiently and cost-effectively. Adaptation of these paired assays into 1536 well-plate format for ultra-high throughput screening (uHTS) resulted in the largest screening ever conducted in our facility, with over 2.4 million wells completed. The paired infection system allowed us to detect two PV infections simultaneously: LASV + MACV, MACV + SARS2, and SARS2 + LASV. Each PV contains a different luciferase reporter gene which enabled us to measure the infection of each PV exclusively, albeit in the same well. Each PV was screened at least twice utilizing different reporters, which allowed us to select the inhibitors specific to a particular PV and to exclude those that hit off targets, including cellular components or the reporter proteins. All assays were robust with an average Z’ value ranging from 0.5 to 0.8. The primary screening of ∼650,000 compounds resulted in 1812, 1506, and 2586 unique hits for LASV, MACV, and SARS2, respectively. The confirmation screening narrowed this list further to 60, 40, and 90 compounds that are unique to LASV, MACV, and SARS2, respectively. Of these compounds, 8, 35, and 50 compounds showed IC50 value < 10 μM, some of which have much greater potency and excellent antiviral activity profiles specific to LASV, MACV, and SARS2, and none are cytotoxic. These selected compounds are currently being studied for their mechanism of action and to improve their specificity and potency through chemical modification.

Accuracy of daily extreme air temperatures under natural variations in thermometer screen ventilation

AbstractAccurate air temperatures underpin environmental research. Most professional meteorological air temperature measurements still expose thermometers within traditional, naturally ventilated screens. Their representation of true air temperature depends on screen airflow, and therefore local winds. Accuracies of daily maximum (Tmax) and minimum (Tmin) air temperatures are assessed by comparison between a naturally ventilated large conventional screen and a co‐located aspirated reference screen. In over 1200 days' data, the naturally ventilated Tmin and Tmax both showed small (median &lt; 0.06°C) cold bias, but, in 1% of cases, warm Tmax bias and cold Tmin bias &gt;|1°C|. The Tmin cold bias is associated with calm clear nights, and the Tmax warm bias events with calm winter days at low sun angles, allowing solar heating of the screen. The prevalence of poor natural ventilation, potentially affecting Tmin and Tmax, is estimated across European sites. Poor ventilation occurred at Tmin for 12% of values, and at Tmax for 4%. Climatological averaging will reduce these effects, but, without corroborating wind data, statistical changes in Tmin or Tmax, including identifying “Tropical Nights” (Tmin &gt; 20°C) or occurrences of winter extremes, may have limited value. Wider adoption of aspirated thermometer screens, with an initial overlap period, will largely eliminate these effects.