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Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P

Connecting university methods courses and teacher daily practice is a persistent challenge in teacher education. Another challenge is preparing teachers to enact equitable instruction that meets the needs of an increasingly diverse student population. We take on these challenges by supporting practicing elementary teachers to design case-based teaching scenarios for preservice teachers that engage them with enacting culturally grounded mathematics and science instruction. We draw on data from workshops with teachers to illustrate how the design process elevates teachers' voices while also supporting their own learning. Workshop features that proved powerful for teachers included collaborating with colleagues, offering and receiving peer feedback, and working with a table describing key features of culturally grounded pedagogy in mathematics and science.

Abstract A suspected 443-486 kt of methane escaped from the Nord Stream pipelines in September 2022 at four explosion sites across three pipelines. Much of this methane rapidly escaped to the atmosphere, while an unknown amount was dissolved. We use sustained high-resolution observations of methane concentrations from autonomous gliders and an instrumented ship of opportunity to reveal the timing and spread of dissolved methane across different Baltic regions and marine protected areas. Estimates of methane spread and concentrations are essential to understand the ecosystem response, and for establishing accurate priors for atmospheric outgassing and transport models. A numerical model, initialized by engineering estimates and our observations, enables us to constrain the mass of locally dissolved Nord Stream methane (9.5-14.7 kt). We show that dissolved methane decreased rapidly through outgassing, however initial concentrations were so high that 14% of the Baltic Sea still experienced concentrations 5 times greater than average natural levels.

Increased ventilator use during the COVID-19 pandemic resurrected persistent questions regarding mechanical ventilation including the difference between physiological and artificial breathing induced by ventilators (i.e., positive- versus negative-pressure ventilation, PPV vs NPV). To address this controversy, we compare murine specimens subjected to PPV and NPV in ex vivo quasi-static loading and quantify pulmonary mechanics via measures of quasi-static and dynamic compliances, transpulmonary pressure, and energetics when varying inflation frequency and volume. Each investigated mechanical parameter yields instance(s) of significant variability between ventilation modes. Most notably, inflation compliance, percent relaxation, and peak pressure are found to be consistently dependent on the ventilation mode. Maximum inflation volume and frequency note varied dependencies contingent on the ventilation mode. Contradictory to limited previous clinical investigations of oxygenation and end-inspiratory measures, the mechanics-focused comprehensive findings presented here indicate lung properties are dependent on loading mode, and importantly, these dependencies differ between smaller versus larger mammalian species despite identical custom-designed PPV/NPV ventilator usage. Results indicate that past contradictory findings regarding ventilation mode comparisons in the field may be linked to the chosen animal model. Understanding the differing fundamental mechanics between PPV and NPV may provide insights for improving ventilation strategies and design to prevent associated lung injuries.

Objectives: Early detection and accurate diagnosis of lymph node metastasis (LNM) in head and neck cancer (HNC) are crucial for enhancing patient prognosis and survival rates. Current imaging methods have limitations, necessitating new evaluation of new diagnostic techniques. This study investigates the potential of combining pre-operative CT and intra-operative fluorescence lifetime imaging (FLIm) to enhance LNM prediction in HNC using primary tumor signatures. Methods: CT and FLIm data were collected from 46 HNC patients. A total of 42 FLIm features and 924 CT radiomic features were extracted from the primary tumor site and fused. A support vector machine (SVM) model with a radial basis function kernel was trained to predict LNM. Hyperparameter tuning was conducted using 10-fold nested cross-validation. Prediction performance was evaluated using balanced accuracy (bACC) and the area under the ROC curve (AUC). Results: The model, leveraging combined CT and FLIm features, demonstrated improved testing accuracy (bACC: 0.71, AUC: 0.79) over the CT-only (bACC: 0.58, AUC: 0.67) and FLIm-only (bACC: 0.61, AUC: 0.72) models. Feature selection identified that a subset of 10 FLIm and 10 CT features provided optimal predictive capability. Feature contribution analysis identified high-pass and low-pass wavelet-filtered CT images as well as Laguerre coefficients from FLIm as key predictors. Conclusions: Combining CT and FLIm of the primary tumor improves the prediction of HNC LNM compared to either modality alone. Significance: This study underscores the potential of combining pre-operative radiomics with intra-operative FLIm for more accurate LNM prediction in HNC, offering promise to enhance patient outcomes.

The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the mAbs cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity, as well as mediators of therapy resistance, though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted mAbs as well as antibody–drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers, as well as approaches to enhance the efficacy of current EREG- and AREG-targeted strategies.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

Background There is no clear evidence about how to support people with borderline personality disorder (BPD) during the perinatal period. Perinatal emotional skills groups (ESGs) may be helpful, but their efficacy has not been tested. Aims To test the feasibility of conducting a randomised controlled trial (RCT) of perinatal ESGs for women and birthing people with BPD. Method Two-arm parallel-group feasibility RCT. We recruited people from two centres, aged over 18 years, meeting DSM-5 diagnostic criteria for BPD, who were pregnant or within 12 months of a live birth. Eligible individuals were randomly allocated on a 1:1 ratio to ESGs + treatment as usual (TAU), or to TAU. Outcomes were assessed at 4 months post randomisation. Results A total of 100% of the pre-specified sample (n = 48) was recruited over 6 months, and we obtained 4-month outcome data on 92% of randomised participants. In all, 54% of participants allocated to perinatal ESGs attended 75% of the full group treatment (median number of sessions: 9 (interquartile range 6–11). At 4 months, levels of BPD symptoms (adjusted coefficient −2.0, 95% CI −6.2 to 2.1) and emotional distress (−2.4, 95% CI −6.2 to 1.5) were lower among those allocated to perinatal ESGs. The directionality of effect on well-being and social functioning also favoured the intervention. The cost of delivering perinatal ESGs was estimated to be £918 per person. Conclusions Perinatal ESGs may represent an effective intervention for perinatal women and birthing people with BPD. Their efficacy should be tested in a fully powered RCT, and this is a feasible undertaking. Trial registration ISRCTN80470632.

Abstract The importance of embedding participatory methods within youth mental health research is well accepted and often a funding prerequisite. However, we argue that there is a need to revisit the core values of the approach in order to ensure that participatory methods remain meaningful, effective and authentic. This should entail rigorously examining ‘why’ and ‘how’ to approach participatory methods ‐ not merely outlining the ‘what’ and ‘when’. We need to prioritise the naturalistic epistemic advantage youth can bring to our research, assigning them a unique collaborative role to reflect this rather than seeking to professionalise our participants. Similarly, we should explore innovative methods to empower youth to apply their lived experience and knowledge alongside the researcher. Equally, we must continue to reflect on our roles as researcher, ensuring we develop the skills necessary for participatory research with children and young people.

Summary: Plant roots grow in association with a community of microorganisms collectively known as the rhizosphere microbiome. Immune activation in response to elicitors like the flagellin-derived epitope flg22 restricts bacteria on plant roots but also inhibits plant growth. Some commensal root-associated bacteria are capable of suppressing the plant immune response to elicitors. In this study, we investigated the ability of 165 root-associated bacteria to suppress flg22-induced immune activation and growth restriction. We demonstrate that a type II secreted subtilase, which we term immunosuppressive subtilase A (IssA), from Dyella japonica strain MF79 cleaves the immune elicitor peptide flg22 and suppresses immune activation. IssA homologs are found in other plant-associated commensals, with particularly high conservation in the order Xanthomonadales. This represents a novel mechanism by which commensal microbes modulate flg22-induced immunity in the rhizosphere microbiome.

Antibodies are one of the most important reagents used in biomedical and fundamental research, used to identify, and quantify proteins, contribute to knowledge of disease mechanisms, and validate drug targets. Yet many antibodies used in research do not recognize their intended target, or recognize additional molecules, compromising the integrity of research findings and leading to waste of resources, lack of reproducibility, failure of research projects, and delays in drug development. Researchers frequently use antibodies without confirming that they perform as intended in their application of interest. Here we argue that the determinants of end-user antibody choice and use are critical, and under-addressed, behavioral drivers of this problem. This interacts with the batch-to-batch variability of these biological reagents, and the paucity of available characterization data for most antibodies, making it more difficult for researchers to choose high quality reagents and perform necessary validation experiments. The open-science company YCharOS works with major antibody manufacturers and knockout cell line producers to characterize antibodies, identifying high-performing renewable antibodies for many targets in neuroscience. This shows the progress that can be made by stakeholders working together. However, their work so far applies to only a tiny fraction of available antibodies. Where characterization data exists, end-users need help to find and use it appropriately. While progress has been made in the context of technical solutions and antibody characterization, we argue that initiatives to make best practice behaviors by researchers more feasible, easy, and rewarding are needed. Global cooperation and coordination between multiple partners and stakeholders will be crucial to address the technical, policy, behavioral, and open data sharing challenges. We offer potential solutions by describing our Only Good Antibodies initiative, a community of researchers and partner organizations working toward the necessary change. We conclude with an open invitation for stakeholders, including researchers, to join our cause.

Objective: Patient and public involvement (PPI) in health research is now well-established, whilst science, technology, engineering and mathematics (STEM) research has shifted from a focus on science communication alone to public engagement (PE) within its research processes. Despite frequently drawing on similar theoretical influences, and practical motivations, there is often a lack of dialogue between such settings meaning shared learning, practice and evidence from these two sectors are rarely pooled. Methods: In this article, we examine findings from a conceptual review of literature gathered between 1996 and 2019. Results: Analyzing 142 peer-reviewed articles, we ascertain shared definitions and concepts in patient and public involvement and public engagement, identifying key differences and similarities. Conclusion: The literature we review supports the notion that, in terms of origins, there are two distinct traditions, one based in science communication and one based in what we describe as public involvement in shared decision-making. Innovation: We find evidence that the two traditions are converging but our work also calls for the need for further conversations between these two settings, which are exploring intersecting issues but from parallel pathways.

Rural communities in forested regions across the United States are in the midst of a transformation driven by a complex mixture of economic, policy, and demographic dynamics. This research examines, through survey results, rural youth educational aspirations in two forest- dependent regions and the role that perceptions of the local school, perceptions of community, and views on economic trajectory play in shaping rural youths' aspirations. Although school perceptions, school and community engagement, grades, and identifying as a girl were positively related to educational aspirations, community perceptions were negatively related. These quantitative findings highlight the contradictory role that higher education may play for those who must choose between education and their families and home and reinforce similar findings from qualitative research on rural youth.

Rural schools in the United States serve more than 9.3 million students (Showalter et al., 2019), often possessing strengths and facing challenges that differ from their metropolitan and suburban counterparts. To attend to the unique context of rural schools and to encourage rural education research in key areas, the National Rural Education Association's (NREA) Research and Higher Education Committee presents the "National Rural Education Association Research Agenda--2022-2027." The central goal of this agenda is to present major priorities for current and future rural education research in order to support the efforts of rural education practitioners, administrators, and school board members as well as advise the policymakers, community leaders and activists, nonprofit organizations, and funding organizations who contribute to the vitality of rural schools and communities. A comprehensive research project that utilized surveys, interviews, and focus groups guided the direction of the agenda, from which spatial and educational equity emerged as the most common theme.