Reference Set Research Articles

Feasible Molecular Dynamics Simulation and Consistency of Critical Carbon Dioxide Thermophysical Properties.

A method of approaching goal values is proposed for the simulation parameter determination. An economic-scale particle system is built for critical carbon dioxide (CO2) system simulations. The approaching method is applied to a critical CO2 system by trial simulation. With the simulation converging to experimental values, the obtained parameter settings help simulation to make practical sense. The measured values of thermal conductivity and viscosity are taken as approaching goal values. A molecular dynamics simulation of these two thermophysical properties is performed. The parameter settings are obtained after approaching the simulation for thermal conductivity and viscosity. As a verification, diffusion of critical CO2 is simulated by the obtained settings. Parameters obtained from the approaching method give rise to diffusion simulation results with experimental agreement. The achieved parameters can directly be used to simulate thermophysical properties of the critical CO2 system, providing reference settings for the simulation of the critical CO2 system. The superiority of critical CO2 in thermal and physical aspects is theoretically confirmed.

Identification of genetic variants and individual genes associated with postpartum hypocalcemia in Holstein cows

Periparturient hypocalcemia is a complex metabolic disorder that occurs at the onset of lactation because of a sudden irreversible loss of Ca incorporated into colostrum and milk. Some cows are unable to quickly adapt to this demand and succumb to clinical hypocalcemia, commonly known as milk fever, whereas a larger proportion of cows develop subclinical hypocalcemia. The main goal of this study was to identify causative mutations and candidate genes affecting postpartum blood calcium concentration in Holstein cows. Data consisted of blood calcium concentration measured in 2513 Holstein cows on the first three days after parturition. All cows had genotypic information for 79 k SNP markers. Two consecutive rounds of imputation were performed: first, the 2513 Holstein cows were imputed from 79 k to 312 k SNP markers. This imputation was performed using a reference set of 17,131 proven Holstein bulls with 312 k SNP markers. Then, the 2513 Holstein cows were imputed from 312 k markers to whole-genome sequence data. This second round of imputation used 179 Holstein animals from the 1000 Bulls Genome Project as a reference set. Three alternative phenotypes were evaluated: (1) total calcium concentration in the first 24 h postpartum, (2) total calcium concentration in the first 72 h postpartum calculated as the area under the curve; and (3) the recovery of total calcium concentration calculated as the difference in total calcium concentration between 72 and 24 h. The identification of genetic variants associated with these traits was performed using a two-step mixed model-based approach implemented in the R package MixABEL. The most significant variants were located within or near genes involved in calcium homeostasis and vitamin D transport (GC), calcium and potassium channels (JPH3 and KCNK13), energy and lipid metabolism (CA5A, PRORP, and SREBP1), and immune response (IL12RB2 and CXCL8), among other functions. This work provides the foundation for the development of novel breeding and management tools for reducing the incidence of periparturient hypocalcemia in dairy cattle.

Thought and language: Effects of group-mindedness on young children's interpretation of exclusive we.

The current study investigated whether age-related changes in the conceptualization of social groups influences interpretation of the pronoun we. Sixty-four 2- and 4-year-olds (N = 29 female, 50 White-identifying) viewed scenarios in which it was ambiguous how many puppets performed an activity together. When asked who performed the activity, a speaker puppet responded, "We did!" In one condition, the speaker was near one and distant from another puppet, implying a dyadic interpretation of we. In another condition, the speaker was distant from both, thus pulling for a group interpretation. In the former condition, 2- and 4-year-olds favored the dyadic interpretation. In the latter condition, only 4-year-olds favored the group interpretation. Age-related conceptual development "expands" the set of conceivable plural person referents.

Optimal model-based control for automated robotized abrasive blasting system

In robotic abrasive blasting operations, achieving the required surface roughness and cleanliness relies heavily on manually pre-set operational parameters. These parameters, such as stand-off distance, blasting angle, inlet air pressure, abrasive flow rate, and particle size, are set based on operator experience. However, given that optimal values for these parameters vary depending on specific blasting conditions and surface requirements, the pre-set values often fail to deliver both the desired surface quality and productivity. To address these challenges, we propose a solution employing a set of proxy models and a model predictive control system to achieve optimal operational outputs. For energy efficiency and productivity maximization, we utilize computational fluid dynamics with a multiphase flow solver to determine the optimal stand-off and offset distances, thus controlling the blasting nozzle effectively. Additionally, we build a data-driven model to obtain the optimal reference set point of air pressure at the sensor location based on the desired surface roughness. Moreover, we develop a dynamic process model to link the inlet air pressure and abrasive flow rate to the air pressure at the sensor location, which facilitates the development of a model-based control system. By applying this comprehensive approach, we evaluate and optimize the control and operational parameters to achieve the desired surface roughness and productivity targets. To validate the effectiveness of our newly developed control system and models, extensive tests are conducted both virtually (in silico) and on-site. The results confirm the stability and accuracy of the control system. In on-site reliability tests, the automated blasting system successfully delivers the desired surface roughness with a relative error of less than 5 % and a remarkable 30–50 % improvement in productivity. Overall, our innovative control system and models offer a reliable and efficient solution for robotic abrasive blasting, ensuring consistent surface quality and productivity enhancements.

Exploring the effects of experimental parameters and data modeling approaches on in vitro transcriptomic point-of-departure estimates

Multiple new approach methods (NAMs) are being developed to rapidly screen large numbers of chemicals to aid in hazard evaluation and risk assessments. High-throughput transcriptomics (HTTr) in human cell lines has been proposed as a first-tier screening approach for determining the types of bioactivity a chemical can cause (activation of specific targets vs. generalized cell stress) and for calculating transcriptional points of departure (tPODs) based on changes in gene expression. In the present study, we examine a range of computational methods to calculate tPODs from HTTr data, using six data sets in which MCF7 cells cultured in two different media formulations were treated with a panel of 44 chemicals for 3 different exposure durations (6, 12, 24 hr). The tPOD calculation methods use data at the level of individual genes and gene set signatures, and compare data processed using the ToxCast Pipeline 2 (tcplfit2), BMDExpress and PLIER (Pathway Level Information ExtractoR). Methods were evaluated by comparing to in vitro PODs from a validated set of high-throughput screening (HTS) assays for a set of estrogenic compounds. Key findings include: (1) for a given chemical and set of experimental conditions, tPODs calculated by different methods can vary by several orders of magnitude; (2) tPODs are at least as sensitive to computational methods as to experimental conditions; (3) in comparison to an external reference set of PODs, some methods give generally higher values, principally PLIER and BMDExpress; and (4) the tPODs from HTTr in this one cell type are mostly higher than the overall PODs from a broad battery of targeted in vitro ToxCast assays, reflecting the need to test chemicals in multiple cell types and readout technologies for in vitro hazard screening.

Cross-efficiencyBasedonGeneralized-DEAandItsApplication

Traditional DEA selects automatically inner Decision-Making Units (DMUs) as the reference set. However, some applications might need specified units. Based on generalized DEA and cross-efficiency DEA, a cross-GDEA model is constructed in this paper, which not only considers any specified reference set in efficiency evaluation but also ranks distinguishably all DMUs. A numerical example and comparative analysis are given to illustrate the reasonableness of the cross-GDEA model. Comparative analysis with several established DEA models reveals the superior flexibility and generality of our method. Furthermore, an application aiming at measuring the multiple-factor carbon productivity of Western China is given to verify the applicability of the cross-GDEA model. Results show the proposed approach can contribute to advancing the theoretical and practical research of DEA.

The isoprene-responsive phosphoproteome provides new insights into the putative signalling pathways and novel roles of isoprene.

Many plants, especially trees, emit isoprene in a highly light- and temperature-dependent manner. The advantages for plants that emit, if any, have been difficult to determine. Direct effects on membranes have been disproven. New insights have been obtained by RNA sequencing, proteomic and metabolomic studies. We determined the responses of the phosphoproteome to exposure of Arabidopsis leaves to isoprene in the gas phase for either 1 or 5 h. Isoprene effects that were not apparent from RNA sequencing and other methods but were apparent in the phosphoproteome include effects on chloroplast movement proteins and membrane remodelling proteins. Several receptor kinases were found to have altered phosphorylation levels. To test whether potential isoprene receptors could be identified, we used molecular dynamics simulations to test for proteins that might have strong binding to isoprene and, therefore might act as receptors. Although many Arabidopsis proteins were found to have slightly higher binding affinities than a reference set of Homo sapiens proteins, no specific receptor kinase was found to have a very high binding affinity. The changes in chloroplast movement, photosynthesis capacity and so forth, found in this work, are consistent with isoprene responses being especially useful in the upper canopy of trees.

Detection of lung pathology using the fractal method

<span lang="EN-US">Currently, the detection of pathology of lung cavities and their digitalization is one of the urgent problems of the healthcare industry in Kazakhstan. In this paper, the method of fractal analysis was considered to solve the task set. Diagnosis of lung pathology based on fractal analysis is an actively developing area of medical research. Conducted experiments on a set of clinical data confirm the effectiveness of the proposed methodology. The results obtained show that fractal analysis can be a useful tool for early detection of lung pathologies. It allows you to detect even minor changes in the structure and texture of lung tissues, which may not be obvious during visual analysis. The article deals with images of pathology of the pulmonary cavity, taken from an open data source. Based on the analysis of fractal objects, they were pre-assembled. Software algorithms for the operation of the information system for screening diagnostics have been developed. Based on the information contained in the fractal image of the lungs, mathematical models have been developed to create a diagnostic rule. A reference set of information features has been created that allows you to create algorithms for diagnosing the lungs: healthy and with pathologies of tuberculosis. </span>

Inter‐network connectivity of early Aβ and tau‐seeded functional networks is associated with longitudinal tau accumulation in at‐risk cognitively normal older adults

AbstractBackgroundFunctional connectivity (FC) between networks may be related to Aβ and tau interactions in preclinical Alzheimer’s disease (AD). Here, we investigated associations between inter‐network FC of early Aβ and tau‐seeded networks, APOEe4, global Aβ, and longitudinal tau accumulation in cognitively healthy older adults (OA).MethodVoxel‐wise PiB‐PET and FTP‐PET OA images were ordered by increasing pathology burden and iteratively compared to a reference set of young adult (YA) PET images. Peak voxels of the earliest significant differences were matched to Brainnetome ROIs and used to construct separate Aβ and tau‐seeded networks within a group average YA FC matrix (Figure 1). Next, the average inter‐network FC between all node pairs between the networks was calculated in OA (n = 60; aged 77.6±5.5). Longitudinal FTP slopes of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) were estimated using linear mixed effects models. Linear regression was used to assess relationships between baseline inter‐network FC, APOEe4 status, baseline global PiB, and both a prior ROI and voxel‐wise FTP slopes.ResultIn all OA, inter‐network FC was not associated with baseline global PIB (t(58) = ‐0.23, p = 0.82), EC FTP slope (t(58) = 0.49, p = 0.63), or ITG FTP slope (t(58) = ‐1.45, p = 0.15). There was a significant interaction between baseline global PiB status and inter‐network FC where FC was negatively associated with ITG FTP slope in PiB+ participants (t(56) = ‐2.01, p = 0.04; Figure 2A). There was also a significant interaction between APOEe4 status and inter‐network FC in predicting ITG FTP slope with a negative relationship only in e4 carriers (t(56) = ‐3.19, p = 0.003; Figure 2B). Voxel‐wise analyses revealed significant negative relationships between inter‐network FC and FTP slope in the left fusiform gyrus and ITG in PiB+ participants and e4 carriers, respectively (Figure 2C‐D).ConclusionLower baseline inter‐network FC of early Aβ and tau‐seeded networks was associated with greater longitudinal tau accumulation outside of the medial temporal lobe (MTL) in cognitively normal OA with higher AD risk (i.e., elevated Aβ or APOEe4). Our results suggest that this network disruption is associated with faster rates of tau accumulation outside of the MTL, possibly reflecting a later stage in the preclinical progression to AD.

Range of chromatin accessibility configurations are permissive of GABAergic fate acquisition in developing mouse brain

In recent single-cell -omics studies, both the differential activity of transcription factors regulating cell fate determination and differential genome activation have been tested for utility as descriptors of cell types. Naturally, genome accessibility and gene expression are interlinked. To understand the variability in genomic feature activation in the GABAergic neurons of different spatial origins, we have mapped accessible chromatin regions and mRNA expression in single cells derived from the developing mouse central nervous system (CNS). We first defined a reference set of open chromatin regions for scATAC-seq read quantitation across samples, allowing comparison of chromatin accessibility between brain regions and cell types directly. Second, we integrated the scATAC-seq and scRNA-seq data to form a unified resource of transcriptome and chromatin accessibility landscape for the cell types in di- and telencephalon, midbrain and anterior hindbrain of E14.5 mouse embryo. Importantly, we implemented resolution optimization at the clustering, and automatized the cell typing step. We show high level of concordance between the cell clustering based on the chromatin accessibility and the transcriptome in analyzed neuronal lineages, indicating that both genome and transcriptome features can be used for cell type definition. Hierarchical clustering by the similarity in accessible chromatin reveals that the genomic feature activation correlates with neurotransmitter phenotype, selector gene expression, cell differentiation stage and neuromere origins.

Spatial Transcriptomics Unveils Novel Potential Mechanisms of Disease in a MI cγ1 Multiple Myeloma in vivo Model

Multiple Myeloma (MM) is a malignant plasma cell (PC) disorder characterized by a heterogeneous distribution of PCs in the bone marrow (BM) where the interactions between the PCs and the BM microenvironment guide the pathogenesis of the disease. The development of single cell technologies has contributed to understand the transcriptional heterogeneity of the disease both from the tumor and the microenvironment point of view, yet the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. To address the role of spatially resolved interactions in MM, we performed spatial transcriptomic analysis in BM from the MI cγ1mice strain (Larrayoz et al Nat Med. 2023) a recently described mouse model that recapitulates the characteristics of a MYC driven human MM disease using the Visium Spatial Gene Expression analysis (10x Genomics). Using formalin-fixed paraffin-embedded (FFPE) BM tissues from the femur of control mice, we first characterized the healthy BM. Considering that each spot contains an averaged transcriptomic profile of 3-10 cells, we generated a single-cell reference set that included the most prevalent cell types in the BM to identify the cell type contribution per spot. The relative proportions of the estimations are consistent with percentage estimations observed by previous works (Hongzhe et al, eLife. 2023). Next, using the “cell proportion estimations per spot” we identified four different clusters of spots. A deeper characterization of those clusters revealed a positive correlation between erythroblasts and B cells, and a negative correlation between both cell types and neutrophils. Additionally, we spatially defined clusters 1 and 2, those with larger proportion of erythroblasts, in the metaphysis trabecular regions of the bone marrow. We followed the same analysis framework to characterize the spatial configuration in the MI cγ1 mice BM with a developed MM. To this end, we incorporated the MM-derived single-cell PCs in the single-cell reference set. Importantly, the pathological PCs were identified and organized in large groups in the BM space. Cell proportion estimations in these samples revealed a distribution in 7 clusters, 4 of them concentrated in the periphery of the PC hot spots and 3 mirroring the PC gradient observed in previous analysis (Figure 1A). We next performed a targeted differential analysis to confirm previous observed markers identities of different MM processes as Cd44 (de Jong et al, Nat Immunol. 2021), a signature of dormant cells (Khoo et al, Blood. 2019), the 38 MM-associated surface-protein-encoding genes (Yao et al, Cancer Res. 2023), Mmp9 and different profiles of T cell exhaustion markers within the 3 clusters with higher PC concentration. These analyses allowed us to verify two different markers, Cd44 and Mmp9 localized in the periphery of the hot spots of PC which may explain an invasive mechanism of the cells localized in the outer areas of the MM combining an inflammatory environment, manifested by a Cd44 increment, with a degradative mechanism driven by Mmp9. Simultaneously, an untargeted differential analysis aimed to identify markers characterizing the clusters with high PC prevalence, revealed novel marker genes never described before in MM and not associated with PC proportion, as the Transmembrane Immune Signaling Adaptor ( Tyrobp) in the cluster 5 (peripheral cluster), which is predictive of a poor prognosis and high tumor immune infiltration in other described tumors (Lu et al BMC Cancer 2021) (Fig 1B). Finally, as a proof of principle of this technology potential in human samples, spatial transcriptomic was applied to FFPE samples from BM biopsies of 7 MM patients with different degrees of PC infiltration, providing a source for validation of the results obtained in the mouse model. In conclusion, our findings demonstrate that the application of spatial transcriptomics represents a useful tool for understanding the spatial architecture and niche specific interactions in human diseases, offering a systemic approach to dissect the role of the spatial interactions in the pathogenesis of MM.

2780. Factors associated with Staphylococcus aureus susceptibility to two lytic bacteriophages; Comparison of phage host susceptibility using a reference set of S. aureus

Abstract Background Timely access is a major concern when considering phage therapy. Using susceptible phage is critical for the outcomes of phage therapy. For timely access to susceptible phages, identifying factors associated with phage susceptibility and building a reference set (RS) to compare host ranges is needed. Methods Phage K, which was a well-documented lytic S. aureus phage, and phage PBSA02, which was a new S. aureus phage from the Korean phage biobank, were used. The efficiency of plating (EOP), the relative activity of phage against specific strain/host strain, and growth kinetics assays were used to determine phage susceptibility. The isolates with high lytic activity (HLA) were defined as susceptible (EOP > 1%). The phage PBSA02 and phage K susceptible groups were compared to the non-susceptible groups to determine the associating factors of phage susceptibility. Results We constructed a methicillin-resistant S. aureus (MRSA) RS using the Australian Group on Antimicrobial Resistance (AGAR) repository. We determined the predominant sequence types (ST) of MRSA in Australia in 2021; ST22 accounted for 90.1% of HA-MRSA and 5 STs for 67.9% of CA-MRSA (figure 1). Then, we randomly selected 39 AGAR MRSA isolates corresponding to each ST from each region in Australia (figure 1). Phage PBSA02 exhibited HLA against 56.4% of the 39 RS isolates, while phage K exhibited HLA against 30.8%. Phage PBSA02 showed HLA against 100% of ST93 and ST30 isolates following ST1 (62.5%), ST22 (37.5%), ST5 (20%) and ST45 (16.7%); phage K showed HLA against 100% of ST30 and 62.5% of ST22 isolates but against none of the ST93 isolates. Phage PBSA02 susceptibility correlated with the ST of MRSA isolates and ciprofloxacin susceptibility (table 1). Isolates from pneumonia/empyema tended to show phage PBSA02 susceptibility (table 1). Phage K susceptibility was also significantly associated with the ST (table 2). Conclusion Our study demonstrated that phage susceptibility was associated with the STs of MRSA, and the RS could be useful for a standardised comparison of the phage host range. Phage PBSA02 with broad susceptibility to the RS could be useful for phage therapy. Further work includes antibiotic synergy testing and resistance mechanism identification in these isolates. Disclosures All Authors: No reported disclosures

Development and validation of search filters to retrieve medication discontinuation articles in Medline and Embase.

Medication discontinuation studies explore the outcomes of stopping a medication compared to continuing it. Comprehensively identifying medication discontinuation articles in bibliographic databases remains challenging due to variability in terminology. To develop and validate search filters to retrieve medication discontinuation articles in Medline and Embase. We identified medication discontinuation articles in a convenience sample of systematic reviews. We used primary articles to create two reference sets for Medline and Embase, respectively. The reference sets were equally divided by randomization in development sets and validation sets. Terms relevant for discontinuation were identified by term frequency analysis in development sets and combined to develop two search filters that maximized relative recalls. The filters were validated against validation sets. Relative recalls were calculated with their 95% confidences intervals (95% CI). We included 316 articles for Medline and 407 articles for Embase, from 15 systematic reviews. The Medline optimized search filter combined 7 terms. The Embase optimized search filter combined 8 terms. The relative recalls were respectively 92% (95% CI: 87-96) and 91% (95% CI: 86-94). We developed two search filters for retrieving medication discontinuation articles in Medline and Embase. Further research is needed to estimate precision and specificity of the filters.

Explainable offline automatic signature verifier to support forensic handwriting examiners

Signature verification is a critical task in many applications, including forensic science, legal judgments, and financial markets. However, current signature verification systems are often difficult to explain, which can limit their acceptance in these applications. In this paper, we propose a novel explainable offline automatic signature verifier (ASV) to support forensic handwriting examiners. Our ASV is based on a universal background model (UBM) constructed from offline signature images. It allows us to assign a questioned signature to the UBM and to a reference set of known signatures using simple distance measures. This makes it possible to explain the verifier’s decision in a way that is understandable to non-experts. We evaluated our ASV on publicly available databases and found that it achieves competitive performance with state-of-the-art ASVs, even when challenging 1 versus 1 comparisons are considered. Our results demonstrate that it is possible to develop an explainable ASV that is also competitive in terms of performance. We believe that our ASV has the potential to improve the acceptance of signature verification in critical applications such as forensic science and legal judgments.

New insights into ancestry and health of Polynesians and New Zealand Māori

We are now moving towards the new era of personalised medicine. In prospect, a DNA-tailored healthcare system will utilise genomic information from patients and populations for the prevention and treatment of diseases. This near-future medicine recognises that there is already evidence of genetic disparity between people of different ethnicity. Our own previous genetic surveys of human genomes have demonstrated abundant genetic variation in New Zealanders. These now include extensive new work on immune system genes. We have produced a comprehensive reference set of genotypes for clinically relevant antigens in transplantation (human leukocyte antigen, major histocompatibility complex class I chain-related gene A and killer cell immunoglobulin-like receptor) and transfusion (blood group and human platelet antigens) medicine in Māori and Polynesians. This report sets these data in context and highlights allelic variations and their implications for ancestry and health. It is hoped that this information may help to resolve some of the present inequalities in Māori and Pacific health status.

The Patent and Literature Antibody Database (PLAbDab): an evolving reference set of functionally diverse, literature-annotated antibody sequences and structures.

Antibodies are key proteins of the adaptive immune system, and there exists a large body of academic literature and patents dedicated to their study and concomitant conversion into therapeutics, diagnostics, or reagents. These documents often contain extensive functional characterisations of the sets of antibodies they describe. However, leveraging these heterogeneous reports, for example to offer insights into the properties of query antibodies of interest, is currently challenging as there is no central repository through which this wide corpus can be mined by sequence or structure. Here, we present PLAbDab (the Patent and Literature Antibody Database), a self-updating repository containing over 150,000 paired antibody sequences and 3D structural models, of which over 65000 are unique. We describe the methods used to extract, filter, pair, and model the antibodies in PLAbDab, and showcase how PLAbDab can be searched by sequence, structure, or keyword. PLAbDab uses include annotating query antibodies with potential antigen information from similar entries, analysing structural models of existing antibodies to identify modifications that could improve their properties, and facilitating the compilation of bespoke datasets of antibody sequences/structures that bind to a specific antigen. PLAbDab is freely available via Github (https://github.com/oxpig/PLAbDab) and as a searchable webserver (https://opig.stats.ox.ac.uk/webapps/plabdab/).

Wide reference databases for typing Trypanosoma cruzi based on amplicon sequencing of the minicircle hypervariable region.

Trypanosoma cruzi, the etiological agent of Chagas Disease, exhibits remarkable genetic diversity and is classified into different Discrete Typing Units (DTUs). Strain typing techniques are crucial for studying T. cruzi, because their DTUs have significant biological differences from one another. However, there is currently no methodological strategy for the direct typing of biological materials that has sufficient sensitivity, specificity, and reproducibility. The high diversity and copy number of the minicircle hypervariable regions (mHVRs) makes it a viable target for typing. Approximately 24 million reads obtained by amplicon sequencing of the mHVR were analyzed for 62 strains belonging to the six main T. cruzi DTUs. To build reference databases of mHVR diversity for each DTU and to evaluate this target as a typing tool. Strains of the same DTU shared more mHVR clusters than strains of different DTUs, and clustered together. Different identity thresholds were used to build the reference sets of the mHVR sequences (85% and 95%, respectively). The 95% set had a higher specificity and was more suited for detecting co-infections, whereas the 85% set was excellent for identifying the primary DTU of a sample. The workflow's capacity for typing samples obtained from cultures, a set of whole-genome data, under various simulated PCR settings, in the presence of co-infecting lineages and for blood samples was also assessed. We present reference databases of mHVR sequences and an optimized typing workflow for T. cruzi including a simple online tool for deep amplicon sequencing analysis (https://ntomasini.github.io/cruzityping/). The results show that the workflow displays an equivalent resolution to that of the other typing methods. Owing to its specificity, sensitivity, relatively low cost, and simplicity, the proposed workflow could be an alternative for screening different types of samples.

Health State Utility Values for Children and Adolescents with Type 1 Diabetes: A Systematic Review and Meta-analysis.

Type 1 diabetes mellitus (T1DM) is one of the most burdensome chronic diseases in the world. Health utility values are an important tool for quantifying this disease burden and conducting cost-utility analyses. This review aimed to derive a reference set of health utility values for children and adolescents with T1DM. We searched MEDLINE and Embase from inception to March 2023 for health utility values of T1DM children and adolescents (aged ≤18 years) measured using direct and indirect preference elicitation approaches. Utility estimates were pooled by meta-analyses with subgroup analyses to evaluate differences by populations and elicitation approaches. Six studies involving 1276 participants were included in this study. Meta-analysis showed the overall utility value of children and adolescents with T1DM was 0.91 (95% CI 0.89-0.93). The utility value of T1DM children and adolescents with complications was 0.90 (95% CI 0.88-0.92), which was lower than those without complications (0.96, 95% CI 0.95-0.97). The utility value of children (aged <13 years) was higher than adolescents (aged 13-18 years) (0.90 vs. 0.85). The utility value measured by the EQ-5D-3L (0.91) was higher than the HUI3 (0.89), the SF-6Dv1 (0.83), and the time trade-off (0.81). The parent proxy-reported was similar to the patient self-reported (0.91 vs. 0.91). This study developed a reference set of pooled utility estimates for children and adolescents with T1DM, which is helpful for understanding the overall health status of T1DM and conducting economic evaluations. Further studies are needed to explore the utilities of T1DM with different types of complications.

Multi-environment screening of Linum germplasm collection for dissecting the potential of bud fly (Dasyneura lini Barnes) resistance and assembling a reference set for efficient utilization in genetic improvement

Linseed or flaxseed (Linum usitatissimum L.) is one of the most ancient industrial crops domesticated for oil and natural fiber. Bud fly (Dasyneura lini Barnes) susceptibility is serious biotic stress affecting its production both quantitatively and qualitatively. It has economic significance particularly in Asian countries, causing substantial crop damage leading to significant yield penalty and deterioration of seed quality. In the present study, a large collection of 2598 linseed germplasm accessions from the Indian National Genebank were screened for bud fly infestation at two natural hot-spot locations in India. The maximum bud fly incidence across all four environments ranged from 47.93% to 90.47%. Based on average bud fly infestation over the environments, a reference set comprising 195 accessions including 46 resistant, 94 moderately resistant and 55 moderately susceptible/susceptible germplasm was developed. Further, a selected subset of 26 accessions having a common reaction against linseed bud fly at both locations was validated for resistance over multi-location-year environments (four environments over two years) through GGE biplot analysis. The GGE biplot revealed that two accessions, G22 (EC0993391) and G23 (IC0633096) were highly resistant (<10% bud fly damage) and most stable over the tested environments against bud fly infestation. Additionally, two accessions namely G15 (IC0498795) and G24 (EC0099001) were considered resistant as they showed consistent performance and low bud fly infestation in comparison to the resistant check (Neela). Moreover, these accessions had a great buffering capacity to perceive environmental signals for developing adaptive capacities in a wide range of environments. The identified germplasm accessions may serve as potential donors for accelerating the resistance breeding programme to impart a long-lasting, broad-spectrum resistance against linseed bud fly.

Drug Response Profiling Informs Personalized Bridging to Cell Therapy for Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Introduction Treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL) remains challenging in spite of recent progress with immunotherapy and targeted small-molecule combinations. Growing awareness of the molecular complexity of the disease with subtype-specific cancer dependencies positions functional drug testing as a promising precision tool to improve the prediction of clinical drug efficacy and adapt treatment. We leverage automated, image-based Drug Response Profiling (DRP) and machine learning to deliver individualized therapeutic options in real time for ALL patients with urgent medical needs. Here we report on the DRP experience of 307 primary samples from 278 patients with BCP-ALL, T-ALL/T-LBL and mixed phenotypic acute leukemia (MPAL) registered from 2016 to 2022 in a non-interventional setting. Methods We have generated a reference set of 141 diagnostic samples from patients with high-risk (75%) or standard/medium-risk (25%) disease as defined by the clinical trial AIEOP-BFM ALL 2017, alongside 122 samples with first and 44 with more advanced relapse. We assayed cell viability at single-cell level from viably frozen bone marrow (BM) samples, co-cultured with hTERT-immortalized mesenchymal stromal cells (MSC) and following a 72h drug incubation with a library of up to 110 compounds. We quantified cell counts at five concentrations in duplicates by segmenting and classifying MSC, live and dead leukemia cells using a modular image processing pipeline deployed on cloud infrastructure. We longitudinally confirmed assay consistency with PDX models and monitored integrity of the stromal layer on a per-sample basis. In a subset of cases (15-20%), relevant stromal detachment or low leukemia survival led to samples not meeting all quality control standards. Drugs were ranked by the area under the dose response curve (AUC) and referenced to all previous samples. This patient-specific ex vivo drug fingerprint was reported to the treating physician with a typical turn-around time of less than two weeks. Results Dexamethasone sensitivities measured ex vivo in BM samples from pediatric front-line patients, who were treated on a one-week cytoreductive steroid pre-phase followed by a four-drug induction regimen, correlated significantly with clinical responses at d8 (PGR vs. PPR, p&amp;lt;0.001), d15 (flow MRD below 10%, p&amp;lt;0.001) and d33 (PCR MRD below E-2, p&amp;lt;0.001). By integrating dose-response profiles from all patients, we observed differential drug activities across cytogenetic groups and identified exceptional responders to Venetoclax in very high-risk subtypes including TCF3::HLF (5 patients, AUC percent rank: 0.03 - 0.19) as well as refractory T-ALL. In 77 r/r T-ALL patients from 12 different countries, DRP supported selection of a personalized bridging regimen prior to consolidation with cellular therapy. Top-scoring drug sensitivities (10th percentile of AUC) were found for a variety of agents including Imatinib, Dasatinib, Venetoclax, Bortezomib, Selinexor and different nucleoside analogs. Eleven T-ALL and 5 BCP-ALL patients received a DRP-guided bridging element involving compounds with high ex vivo drug efficacy and complemented by chemotherapy (Table 1). The other 66 r/r patients were treated according to physician's choice incorporating information on drug resistance detected by DRP in real time. Bridging strategies implementing DRP-guided therapy blocks stabilized or reduced disease burden in 15/16 patients allowing HSCT or infusion of CAR-T cells in 12 patients with 8 patients still being in remission at last follow-up. Conclusion We describe an array of pharmacological sensitivity and resistance patterns across a heterogeneous, high-risk cohort of BCP- and T-ALL patients. We identified individual susceptibilities to targeted agents of different classes including BH3-mimetics, proteasome, tyrosine kinase and exportin inhibitors as well as standard-of-care chemotherapeutics. Prospective recording of drug response profiles offers opportunities to systematically correlate ex vivo and clinical responses and inform personalized therapies. These data strongly advocate inclusion of DRP into randomized, early and late phase clinical trials for high-risk pediatric ALL, comprehensively integrating molecular and functional precision information to improve patient stratification and long-term outcome after HSCT and CAR-T.