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Abstract The ability to effectively exchange information and develop trusting, collaborative relationships across disciplinary boundaries is essential for 21st century scientists charged with solving complex and large‐scale societal and environmental challenges, yet these communication skills are rarely taught. Here, we describe an adaptable training program designed to increase the capacity of scientists to engage in information exchange and relationship development in team science settings. A pilot of the program, developed by a leader in ecological network science, the Global Lake Ecological Observatory Network (GLEON), indicates that the training program resulted in improvement in early career scientists’ confidence in team‐based network science collaborations within and outside of the program. Fellows in the program navigated human‐network challenges, expanded communication skills, and improved their ability to build professional relationships, all in the context of producing collaborative scientific outcomes. Here, we describe the rationale for key communication training elements and provide evidence that such training is effective in building essential team science skills.

Objectives: Cerebral artery critical closing pressure (CCP) is an estimated parameter with no single accepted method of calculation. Variation between methods could be significant. This study investigates two models to estimate CCP using arterial blood pressure (BP) and middle cerebral artery flow velocity (FV) waveforms, quantifying the difference between radial and aortic BP as the BP input signal. Methods: Suspected and untreated hypertensive subjects (n=445, 203 female, 50±10 years, range 21 to 73 years old), referred to Ruijin Hospital in Shanghai, China, for 24-hours BP monitoring, were recruited. Radial BP and FV waveforms were acquired by applanation tonometry and transcranial Doppler respectively. Aortic BP waveforms were synthesised from the radial waveform using a validated transfer function (SphygmoCor®). CCP was estimated using the relationship between BP and FV waveforms by both linear regression (LR), and the first harmonic (H1) in Fourier decomposition. The difference between the two models was quantified if the BP waveform input signal was radial or aortic and compared by Student’s paired t-test. Results: Use of aortic instead of radial BP resulted in a 29% increase in estimated CCP using the LR model, and 25% increase using the H1 model (Figure, p

Introduction: Modeling and mapping of soil organic carbon concentration and distribution at the pedon scale is a current knowledge gap that can be addressed by laboratory-based hyperspectral imaging and chemometric analysis of soil cores. Despite the advancements in soil organic carbon models based on hyperspectral images, it is not clear how these models will perform upon input with images at higher resolutions than those of their training sets. This study aims to measure the generalizability of a soil organic carbon model based on a test set with higher resolution hyperspectral images than that of its training set.Methods: Organic carbon contents were measured at 10 cm intervals on eight soil cores for use as the training set and at 1 cm intervals on a single core for use as the test set. Three regression models, namely, multilayer perceptron, partial least-squares, and support vector regressions, were trained and tested with the median of each hyperspectral image for each of these intervals as the training and test predictors. Permutation importance analysis was performed to explain the models.Results: The results show that although all three models had the same validation R2 of 0.92 for cross-validation on the 10 cm data, multilayer perceptron regression allowed the best generalization with a test R2 of 0.96 compared to the partial least-squares regression (0.81) and support vector regression (0.86). It was demonstrated that the multilayer perceptron model is more robust to soil surface anomalies and that it predicts soil organic carbon on the test set by learning the spectral features related to soil organic matter chromophore activity in the 950–1,150 nm region along with clay mineralogy derived from peaks at 1,400, 1,900, 2,200, 2,250, and 2,350 nm.Conclusions: This study shows that while the regression models based on hyperspectral images perform well at the 10-cm-resolution cross validation, multilayer perceptron regression shows superior generalization and robustness for a higher 1-cm-resolution test set without much loss of prediction power.

Abstract Social connection is important for long‐term care (LTC) residents' quality of life and care. However, there is a lack of consensus on how to measure it and this limits ability to find what improves and impairs social connection in LTC homes. We therefore aimed to systematically review and evaluate the measurement properties of existing measures of social connection for LTC residents, to identify which, if any, measures can be recommended. We searched eight electronic databases from inception to April 2022 for studies which reported on psychometric properties of a measure of any aspect(s) of social connection (including social networks, interaction, engagement, support, isolation, connectedness, and loneliness) for LTC residents. We used COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) guidelines to evaluate the measurement properties reported for each identified measure and make recommendations. We identified 62 studies reporting on 38 measures; 21 measured quality of life, well‐being or life satisfaction and included a social connection subscale or standalone items and 17 measures specifically targeted social connection. We found there was little high‐quality evidence on psychometric properties such as sufficient content validity (n = 0), structural validity (n = 3), internal consistency (n = 3), reliability (n = 1), measurement error (n = 0), construct validity (n = 4), criterion validity (n = 0) and responsiveness (n = 0). No measures demonstrated satisfactory psychometric properties on all these aspects, so none could be recommended for use. Thirty‐four measures have the potential to be recommended but require further research to assess their quality and the remaining four are not recommended for use. Our review therefore found that no existing measures have sufficient evidence to be recommended for assessment of social connection in residents of LTC homes. Further validation and reliability studies of existing instruments or the development of new measures are needed to enable accurate measurement of social connection in LTC residents for future observational and interventional studies. Highlights Social connection is fundamental to person‐centered care in long‐term care homes. There is insufficient evidence for the reliability and validity of existing measures. No current measures can be recommended for use based on existing evidence. A reliable and valid measure of social connection is needed for future research.

Abstract INTRODUCTION Social connection comprises distinct but interrelated aspects describing how individuals connect to each other. Various measures have assessed multiple aspects of social connection in long‐term care (LTC) home populations, but they use inconsistent terminology, making it unclear what aspects are measured. This scoping review describes how social connection is assessed by measures that have been used in LTC home residents. METHODS This review followed the Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) guidelines. Two systematic literature searches combining search terms for social connection AND LTC home residents AND measurement properties were conducted in eight electronic databases from inception to April 2022. Included studies reported the development or psychometric testing of measures which assessed social connection in LTC home residents. A content analysis with a deductive‐inductive approach was used to analyze the measures’ content and an adapted Framework Method was used for data management. Findings report each measure's items and the assessed aspects of social connection. Dementia and non‐dementia‐specific measures had content, administration, and scoring compared. RESULTS From 8753 records, 58 studies reporting on 14 dementia‐specific and 28 non‐dementia‐specific social connection measures were identified, including complete measures, subscales, and single items. These measures assessed social network (52.4%), social isolation (11.9%), social interaction (47.6%), social engagement (31.0%), social support (33.3%), social connectedness (21.4%), and loneliness (9.5%). A total of 27 (64.3%) of the measures included more than one aspect of social connection. Dementia‐specific measures most often assessed social interaction whereas non‐dementia‐specific measures most often assessed social network, social interaction, and social support. Dementia‐specific measures typically relied on a proxy response, whereas non‐dementia‐specific measures more often used self‐report. DISCUSSION Existing social connection measures in LTC home settings operationalize seven aspects of social connection and differ according to the target population (dementia or non‐dementia‐specific). These findings will inform future measure selection and development. Highlights Social connection is important to long‐term care (LTC) home residents’ quality of life. Social connection has been assessed by quantifying/describing relationships. Existing measures usually assess more than one aspect of social connection. These aspects cover several interlinked observed or experienced domains. Dementia and non‐dementia‐specific measures differ in assessing social connection.

Abstract Background Various measures have assessed social connection in long-term care (LTC) home residents. However, they use inconsistent terminology, conceptualizations, and operationalizations of social connection. In this systematic review protocol, we propose a study that will characterize measures that assess aspects of LTC home residents’ social connection using a unified conceptual model. The objectives are to (1) describe and analyze the measures and (2) evaluate their measurement properties. Methods A literature search was conducted in MEDLINE ALL (Ovid), Embase Classic and Embase (Ovid), Emcare Nursing (Ovid), APA PsycInfo (Ovid), Scopus, CINAHL Complete (EBSCOhost), AgeLine (EBSCOhost), and Sociological Abstracts (ProQuest). We will include primary research papers with no language limit, published from database inception. We will include studies of a measure of any aspect of social connection in LTC home residents that report at least one measurement property. Independently, two reviewers will screen titles and abstracts, review full-text articles against eligibility criteria, and extract data from included studies. In objective 1, we will analyze identified tools using an adapted framework method. In objective 2, we will evaluate each measure’s measurement properties using COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. We will engage experts and stakeholders to assist with interpreting results and translating knowledge. Discussion Our findings will inform the social connection in long-term care home residents (SONNET) study’s development of a novel, person-centered measure for social connection in LTC home settings. We will present our findings in academic and non-academic forums, including conferences, peer-reviewed journals, and other publications. Systemic review registration Prospero—“Systematic review of measures of social connection used in long-term care home research.” CRD42022303526 .

Abstract Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan–Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p

Abstract Background Maximizing quality of life (QoL) is a major goal of care for people with dementia in nursing homes (NHs). Social determinants are critical for residents' QoL. However, similar to the United States and other countries, most Canadian NHs routinely monitor and publicly report quality of care, but not resident QoL and its social determinants. Therefore, we lack robust, quantitative studies evaluating the association of multiple intersecting social determinants with NH residents’ QoL. The goal of this study is to address this critical knowledge gap. Methods We will recruit a random sample of 80 NHs from 5 Canadian provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario). We will stratify facilities by urban/rural location, for-profit/not-for-profit ownership, and size (above/below median number of beds among urban versus rural facilities in each province). In video-based structured interviews with care staff, we will complete QoL assessments for each of ~ 4,320 residents, using the DEMQOL-CH, a validated, feasible tool for this purpose. We will also assess resident’s social determinants of QoL, using items from validated Canadian population surveys. Health and quality of care data will come from routinely collected Resident Assessment Instrument – Minimum Data Set 2.0 records. Knowledge users (health system decision makers, Alzheimer Societies, NH managers, care staff, people with dementia and their family/friend caregivers) have been involved in the design of this study, and we will partner with them throughout the study. We will share and discuss study findings with knowledge users in web-based summits with embedded focus groups. This will provide much needed data on knowledge users' interpretations, usefulness and intended use of data on NH residents’ QoL and its health and social determinants. Discussion This large-scale, robust, quantitative study will address a major knowledge gap by assessing QoL and multiple intersecting social determinants of QoL among NH residents with dementia. We will also generate evidence on clusters of intersecting social determinants of QoL. This study will be a prerequisite for future studies to investigate in depth the mechanisms leading to QoL inequities in LTC, longitudinal studies to identify trajectories in QoL, and robust intervention studies aiming to reduce these inequities.

Abstract Background To develop and validate a prediction tool, or nomogram, for the risk of a decline in cognitive performance based on the interRAI Cognitive Performance Scale (CPS). Methods Retrospective, population-based, cohort study using Canadian Resident Assessment Instrument for Home Care (RAI-HC) data, collected between 2010 and 2018. Eligible home care clients, aged 18+, with at least two assessments were selected randomly for model derivation (75%) and validation (25%). All clients had a CPS score of zero (intact) or one (borderline intact) on intake into the home care program, out of a possible score of six. All individuals had to remain as home care recipients for the six months observation window in order to be included in the analysis. The primary outcome was any degree of worsening (i.e., increase) on the CPS score within six months. Using the derivation cohort, we developed a multivariable logistic regression model to predict the risk of a deterioration in the CPS score. Model performance was assessed on the validation cohort using discrimination and calibration plots. Results We identified 39,292 eligible home care clients, with a median age of 79.0 years, 62.3% were female, 38.8% were married and 38.6% lived alone. On average, 30.3% experienced a worsening on the CPS score within the six-month window (i.e., a change from 0 or 1 to 2, 3, 4, 5, or 6). The final model had good discrimination (c-statistic of 0.65), with excellent calibration. Conclusions The model accurately predicted the risk of deterioration on the CPS score over six months among home care clients. This type of predictive model may provide useful information to support decisions for home care clinicians who use interRAI data internationally.

Abstract Background Cancer disparities are a major public health concern in Canada, affecting racialized communities of Latin American and African descent, among others. This is evident in lower screening rates, lower access to curative, and palliative-intent treatments, higher rates of late cancer diagnoses and lower survival rates than the general Canadian population. We will develop an Access to Palliative Care Strategy informed by health equity and patient-oriented research principles to accelerate care improvements for patients with advanced cancer of African and Latin American descent. Methods This is a community-based participatory research study that will take place in two Canadian provinces. Patients and community members representatives have been engaged as partners in the planning and design of the study. We have formed a patient advisory council (PAC) with patient partners to guide the development of the Access to Palliative Care Strategy for people of African and Latin American descent. We will engage100 participants consisting of advanced cancer patients, families, and community members of African and Latin American descent, and health care providers. We will conduct in-depth interviews to delineate participants’ experiences of access to palliative care. We will explore the intersections of race, gender, socioeconomic status, language barriers, and other social categorizations to elucidate their role in diverse access experiences. These findings will inform the development of an action plan to increase access to palliative care that is tailored to our study population. We will then organize conversation series to examine together with community partners and healthcare providers the appropriateness, effectiveness, risks, requirements, and convenience of the strategy. At the end of the study, we will hold knowledge exchange gatherings to share findings with the community. Discussion This study will improve our understanding of how patients with advanced cancer from racialized communities in Canada access palliative care. Elements to address gaps in access to palliative care and reduce inequities in these communities will be identified. Based on the study findings a strategy to increase access to palliative care for this population will be developed. This study will inform ways to improve access to palliative care for racialized communities in other parts of Canada and globally.

Abstract Organoids are becoming increasingly relevant in biology and medicine for their physiological complexity and accuracy in modeling human disease. To fully assess their biological profile while preserving their spatial information, spatiotemporal imaging tools are warranted. While previously developed imaging techniques, such as four‐dimensional (4D) live imaging and light‐sheet imaging have yielded important clinical insights, these technologies lack the combination of cyclic and multiplexed analysis. To address these challenges, bioorthogonal click chemistry is applied to display the first demonstration of multiplexed cyclic imaging of live and fixed patient‐derived glioblastoma tumor organoids. This technology exploits bioorthogonal click chemistry to quench fluorescent signals from the surface and intracellular of labeled cells across multiple cycles, allowing for more accurate and efficient molecular profiling of their complex phenotypes. Herein, the versatility of this technology is demonstrated for the screening of glioblastoma markers in patient‐derived human glioblastoma organoids while conserving their viability. It is anticipated that the findings and applications of this work can be broadly translated into investigating physiological developments in other organoid systems.

With the COVID-19 pandemic halting all in-person research in March 2020, many researchers adopted virtual methods to continue their work amid this global crisis. As the pandemic persisted and the safety of participants and researchers remained a priority, virtual research grew in popularity for qualitative researchers. This in turn led to methodological insights on the application and advantages of conducting qualitative research using virtual methods. Virtual methods have been found to enhance participant comfort, facilitate open discussion of sensitive topics, alleviate fatigue in participants and researchers, and result in more engaging and focused interviews. While the body of evidence supporting virtual methods of data collection for nursing and other healthcare disciplines continues to grow, its application in the long-term care (LTC) setting remains underreported. In this paper, we discuss the virtual methods that we developed and implemented to successfully conduct a virtual qualitative single case study in a Canadian LTC home during the COVID-19 pandemic. Considerations from existing literature on virtual methods are discussed in parallel with strategies we implemented to successfully conduct a virtual study in LTC. This paper contributes to the growing body of literature on methodological insights into conducting virtual qualitative research in LTC. We provide evidence-based strategies for the virtual recruitment of study sites, study participants including residents, team members and families, and virtual data collection methods. These recommendations offer insights to overcome challenges and maximize the advantages of virtual methods, to enhance the quality and rigour of virtual qualitative research conducted within LTC settings.

HyperGUI is an intuitive R-based web application crafted to streamline the loading of raw hyperspectral images while offering essential processing functions for exploring hyperspectral data. Users can easily load, process, and visualize benchtop or aerial hyperspectral images, with the flexibility to export them to R, Python, MATLAB, or raster data frames for further analysis. HyperGUI’s source code is available on GitHub, and it is accessible online via shinyapps.io.

IntroductionInformal caregivers provide care to older adults but report lack of preparedness to enact the role. Intervention programs delivered by distance offer one alternative to support preparedness. Three review studies conducted to date have highlighted the benefits of distance interventions for enhancing preparedness among informal caregivers of older adults. However, these reviews have been limited in presenting and discussing how intervention components influenced outcomes. Additionally, they have not compared different distance delivery approaches for informal caregivers of older adults or assessed their varying impact on preparedness outcomes. These limitations make the effectiveness of diverse distance approaches unclear.AimTo evaluate the effects of distance interventions aimed at enhancing preparedness among informal caregivers of older adults.MethodsThis protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines and is guided by the Cochrane Handbook for Systematic Reviews of Interventions. It has been registered in PROSPERO (CRD42023400668). Databases used in the search will include CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, Scopus, and ProQuest Theses and Dissertations Global. The search will not be restricted by publication year to include all relevant studies. Studies published in English and Portuguese will be included. Study quality will be assessed using Downs and Black's checklist. If metanalysis is possible, it will be performed using the ReviewManager (RevMan) software.ConclusionsThe study will be the first of its type to systematically review and synthesize components and approaches of distance interventions aimed at supporting preparedness of informal caregivers of older adults.

Introduction Rapid population ageing is a demographic trend being experienced and documented worldwide. While increased health screening and assessment may help mitigate the burden of illness in older people, issues such as misdiagnosis may affect access to interventions. This study aims to elicit the values and preferences of evidence-informed older people living in the community on early screening for common health conditions (cardiovascular disease, diabetes, dementia and frailty). The study will proceed in three Phases: (1) generating recommendations of older people through a series of Citizens’ Juries; (2) obtaining feedback from a diverse range of stakeholder groups on the jury findings; and (3) co-designing a set of Knowledge Translation resources to facilitate implementation into research, policy and practice. Conditions were chosen to reflect common health conditions characterised by increasing prevalence with age, but which have been underexamined through a Citizens’ Jury methodology.Methods and analysis This study will be conducted in three Phases—(1) Citizens’ Juries, (2) Policy Roundtables and (3) Production of Knowledge Translation resources. First, older people aged 50+ (n=80), including those from traditionally hard-to-reach and diverse groups, will be purposively recruited to four Citizen Juries. Second, representatives from a range of key stakeholder groups, including consumers and carers, health and aged care policymakers, general practitioners, practice nurses, geriatricians, allied health practitioners, pharmaceutical companies, private health insurers and community and aged care providers (n=40) will be purposively recruited for two Policy Roundtables. Finally, two researchers and six purposively recruited consumers will co-design Knowledge Translation resources. Thematic analysis will be performed on documentation and transcripts.Ethics and dissemination Ethical approval has been obtained through the Torrens University Human Research Ethics Committee. Participants will give written informed consent. Findings will be disseminated through development of a policy brief and lay summary, peer-reviewed publications, conference presentations and seminars.

X-ray fluorescence (XRF) core scanners are commonly used for fine-scale geochemical analysis in sediment studies, but data are semi-quantitative and require calibration to convert geochemical element counts to concentrations. Application of XRF core scanning in soil science remains largely untapped. This study employed an ITRAX core scanner to scan grassland soil cores and developed a novel calibration method based on a chemometric approach to characterise soil geochemistry. As soil samples are collected based on depth sampling, this study investigated whether higher resolution element concentrations could be inferred from lower resolution reference samples and if regression models from multiple cores could apply to a new core at the same resolution. Reference concentrations were obtained for all cores at 10 cm intervals, with validation conducted at 1 cm for a single core. Two calibration curve types were proposed: one based on the single core’s 10 cm data to validate references at 1 cm intervals; and another using all cores, with each core serving as a test item after exclusion from the training set. Various preprocessing measures and feature selection techniques were tested. Results showed successful calibration for elements Ca, P, Zn, Sr, and S, with high R2 values of 0.94, 0.93, 0.93, 0.92 and 0.91, respectively. The study presents a novel method for calibrating XRF core scanning element counts, demonstrating its potential for high-resolution soil analysis.

Abstract Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTRasym values using PCs. Our predicted map correlated with MTRasym values with Spearman’s r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p

Abstract Serological testing to evaluate antigen-specific antibodies in plasma is generally performed by rapid lateral flow test strips that lack quantitative results or by high complexity immunoassays that are time- and labor-intensive but provide semi-quantitative results. Here, we describe a novel application of biolayer interferometry for the rapid detection of antigen-specific antibody levels in plasma samples, and demonstrate its utility for quantification of SARS-CoV-2 antibodies. Our biolayer interferometry immunosorbent assay (BLI-ISA) utilizes single-use biosensors in an automated “dip-and-read” format, providing real-time optical measurements of antigen loading, plasma antibody binding, and antibody isotype detection. Complete semi-quantitative results are obtained in less than 20 min. BLI-ISA meets or exceeds the performance of high complexity methods such as Enzyme-Linked Immunosorbent Assay (ELISA) and Chemiluminescent Immunoassay. Importantly, our method can be immediately implemented on existing BLI platforms for urgent COVID-19 studies, such as serosurveillance and the evaluation of vaccine candidates. In a broader sense, BLI-ISA can be developed as a novel diagnostic platform to evaluate antibodies and other biomolecules in clinical specimens.

Introduction The first clinical interaction most patients have in the emergency department occurs during triage. An unstructured narrative is generated during triage and is the first source of in-hospital documentation. These narratives capture the patient’s reported reason for the visit and the initial assessment and offer significantly more nuanced descriptions of the patient’s complaints than fixed field data. Previous research demonstrated these data are useful for predicting important clinical outcomes. Previous reviews examined these narratives in combination or isolation with other free-text sources, but used restricted searches and are becoming outdated. Furthermore, there are no reviews focused solely on nurses’ (the primary collectors of these data) narratives.Methods and analysis Using the Arksey and O’Malley scoping review framework and PRISMA-ScR reporting guidelines, we will perform structured searches of CINAHL, Ovid MEDLINE, ProQuest Central, Ovid Embase and Cochrane Library (via Wiley). Additionally, we will forward citation searches of all included studies. No geographical or study design exclusion criteria will be used. Studies examining disaster triage, published before 1990, and non-English language literature will be excluded. Data will be managed using online management tools; extracted data will be independently confirmed by a separate reviewer using prepiloted extraction forms. Cohen’s kappa will be used to examine inter-rater agreement on pilot and final screening. Quantitative data will be expressed using measures of range and central tendency, counts, proportions and percentages, as appropriate. Qualitative data will be narrative summaries of the authors’ primary findings.Patient and public involvement No patients involved.Ethics and dissemination No ethics approval is required. Findings will be submitted to peer-reviewed conferences and journals. Results will be disseminated using individual and institutional social media platforms.

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood–brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T-treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

Abstract River regulation or flow modification—the hydrological alteration of flow by dams and diversions—has been implicated as a cause of fundamental change to downstream aquatic ecosystems. Flow modification changes the patterns and functionality of the natural flow regime and has the potential to restrict population connectivity and gene flow in river‐dependent organisms. Since population connectivity and the maintenance of genetic diversity are fundamental drivers of long‐term persistence, understanding the extent flow modification impacts these critical attributes of genetic health is an important goal for long‐term conservation. Foothill yellow‐legged frogs (Rana boylii) were historically abundant throughout many western rivers but have declined since the onset of flow regulation. However, the extent to which R. boylii populations in rivers with altered flow regimes are maintaining connectivity and genetic diversity is unknown. Here, we use population genomics to investigate the impacts of flow alteration on R. boylii to explore their potential for long‐term persistence under continued flow modification. We found R. boylii in rivers with flow modification showed striking patterns of isolation and trajectories of genetic diversity loss relative to unregulated rivers. For example, flow modification explained the greatest amount of variance in population genetic differentiation compared with other covariates including geographic distance. Importantly, patterns of connectivity and genetic diversity loss were observed regardless of flow alteration level but were most prominent in locations with the greatest flow modification intensity. Although our results do not bode well for long‐term persistence of R. boylii populations under current flow regulation regimes, they do highlight the power of genetic monitoring for assessing population health in aquatic organisms.

Glioblastoma is the most common and lethal brain cancer globally. Clinically, this cancer has heterogenous molecular and clinical characteristics. Studies have shown that UBE2S is highly expressed in many cancers. But its expression profile in glioma, and the correlation with clinical outcomes is unknown. RNA sequencing data of glioma samples was downloaded from the Chinese Glioma Genome Atlas and The Cancer Genome Atlas. A total of 114 cases of glioma tissue samples (WHO grades II-IV) were used to conduct protein expression assays. The molecular and biological characteristics of UBE2S, and its prognostic value were analyzed. The results showed that high UBE2S expression was associated with a higher grade of glioma and PTEN mutations. In addition, UBE2S affected the degree of malignancy of glioma and the development of chemo-radiotherapy resistance. It was also found to be an independent predictor of worse survival of LGG patients. Furthermore, we identified five UBE2S ubiquitination sites and found that UBE2S was associated with Akt phosphorylation in malignant glioblastoma. The results also revealed that UBE2S expression was negatively correlated with 1p19q loss and IDH1 mutation; positively correlated with epidermal growth factor receptor amplification and PTEN mutation. This study demonstrates that UBE2S expression strongly correlates with glioma malignancy and resistance to chemo-radiotherapy. It is also a crucial biomarker of poor prognosis.

Autologous chimeric antigen receptor (CAR) T cells targeted to epidermal growth factor receptor variant III (CAR T-EGFRvIII) have been developed and administered experimentally to treat patients with IDH1 wildtype recurrent glioblastoma (rGBM) (NCT02209376). We report the case of a 59-year-old patient who received a single peripheral infusion of CAR T-EGFRvIII cells and survived 36 months after disease recurrence, exceeding expected survival for recurrent glioblastoma. Post-infusion histopathologic analysis of tissue obtained during a second stage surgical resection revealed immunosuppressive adaptive changes in the tumor tissue as well as reduced EGFRvIII expression. Serial brain imaging demonstrated a significant reduction in relative cerebral blood volume (rCBV), a measure strongly associated with tumor proliferative activity, at early time points following CAR T treatment. Notably, CAR T-EGFRvIII cells persisted in her peripheral circulation during 29 months of follow-up, the longest period of CAR T persistence reported in GBM trials to date. These findings in a long-term survivor show that peripherally administered CAR T-EGFRvIII cells can persist for years in the circulation and suggest that this cell therapy approach could be optimized to achieve broader efficacy in recurrent GBM patients.

Background: Personal contact interventions involve routine visits with a person or animal to address loneliness. Research supports the promise of these interventions to address loneliness among cognitively intact older adults, but little is known about their use with people with dementia. Objective: To assess the acceptability of personal contact interventions for use to address loneliness with older people with dementia, according to formal and informal care providers. Design: Cross-sectional, mixed methods complementarity design. Setting: Ontario, Canada Participants: A purposive sample of 25 family members, friends, and health care providers of people with dementia. Methods: Participants attended a face-to-face interview to discuss the acceptability of personal contact interventions. Participants completed questionnaires to rate acceptability (adapted Treatment Perception and Preference measure). A semi-structured interview followed to discuss the ratings and features of personal contact (with another person or animal) in more detail. The analysis involved descriptive statistics (quantitative data) and conventional content analysis (qualitative data). During the interpretation of the results, the qualitative findings were compared to the quantitative results to provide context and understand participants’ perceptions of intervention acceptability in more depth; these are presented together in the results to demonstrate their distinct and complementary contributions to the findings. Results: Personal contact with a person or animal was rated as effective, logical, suitable, and low risk to address loneliness by over 80% of participants. Participants’ willingness to engage in this type of contact, for example as a visitor or as a facilitator of animal contact, was 72%. Participants emphasized the benefits of personal contact. The findings highlight that individualized, flexible interventions that include appropriate facilitation are needed. Conclusions: Future studies to develop and test personal contact interventions should involve flexible delivery, assess the feasibility and acceptability of these interventions (as in a Phase 2 trial of a complex intervention), and focus on the experiences of people with dementia.Tweetable Abstract: Tailored, routine, and facilitated contact with a person or animal shows promise to address loneliness for people with dementia.What is already known about this topic:• Loneliness is emotionally painful and harms the health and quality of life of those that experience it.• Personal contact interventions refer to routine visits with another person or animal and have been found effective in addressing loneliness among cognitively intact older adults.What this paper adds:• Friends, family members and health care providers of people with dementia view personal contact interventions as logical, suitable and effective to address loneliness of older adults with dementia.• Personal contact interventions are not always easy to implement and do not automatically promote meaningful connection and prevent loneliness for people with dementia.• Strategies to tailor and facilitate personal contact interventions are needed to promote their effectiveness when used with people with dementia.

Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4+ T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4+ T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4+ T cells (CD4+CD25−) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration.

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells’ efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells. Keywords: glioblastoma, chimeric antigen receptor, CAR, IL-13Rα2, minibody, canine, immune checkpoint blockade, PD-1, CTLA-4, TIM-3

Resistance to anti-angiogenic therapies often occurs in patients. Here, the authors demonstrate the role of PDGF signaling in GBM resistance to anti-VEGF treatment via a mechanism that involves endothelial-mesenchymal transformation and transcriptional regulation of VEGFR-2.

Macrophages in the tumour microenvironment (TME) acquire tumour-promoting functions upon M2 polarization. Here the authors show, in a mouse model of glioblastoma, that endothelial cells in the TME induce macrophage M2 polarization via IL-6 and that depletion of endothelial IL-6 improves survival.

Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole-genome sequencing offers a culture-independent alternative to current bacterial identification methods, but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease–associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida) from dairy and beef cattle. One hundred genomically distinct assemblies were added to the NCBI database, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis. While computer-based analysis can identify antibiotic resistance genes within whole-genome sequences (genotype), it may not predict the actual antimicrobial resistance observed in a living organism (phenotype). Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001), showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory disease treatment and morbidity/mortality outcomes.

Glioblastoma, the most frequent primary malignant brain neoplasm, is genetically diverse and classified into four transcriptomic subtypes, i. e., classical, mesenchymal, proneural, and neural. Currently, detection of transcriptomic subtype is based on ex vivo analysis of tissue that does not capture the spatial tumor heterogeneity. In view of accumulative evidence of in vivo imaging signatures summarizing molecular features of cancer, this study seeks robust non-invasive radiographic markers of transcriptomic classification of glioblastoma, based solely on routine clinically-acquired imaging sequences. A pre-operative retrospective cohort of 112 pathology-proven de novo glioblastoma patients, having multi-parametric MRI (T1, T1-Gd, T2, T2-FLAIR), collected from the Hospital of the University of Pennsylvania were included. Following tumor segmentation into distinct radiographic sub-regions, diverse imaging features were extracted and support vector machines were employed to multivariately integrate these features and derive an imaging signature of transcriptomic subtype. Extracted features included intensity distributions, volume, morphology, statistics, tumors' anatomical location, and texture descriptors for each tumor sub-region. The derived signature was evaluated against the transcriptomic subtype of surgically-resected tissue specimens, using a 5-fold cross-validation method and a receiver-operating-characteristics analysis. The proposed model was 71% accurate in distinguishing among the four transcriptomic subtypes. The accuracy (sensitivity/specificity) for distinguishing each subtype (classical, mesenchymal, proneural, neural) from the rest was equal to 88.4% (71.4/92.3), 75.9% (83.9/72.8), 82.1% (73.1/84.9), and 75.9% (79.4/74.4), respectively. The findings were also replicated in The Cancer Genomic Atlas glioblastoma dataset. The obtained imaging signature for the classical subtype was dominated by associations with features related to edge sharpness, whereas for the mesenchymal subtype had more pronounced presence of higher T2 and T2-FLAIR signal in edema, and higher volume of enhancing tumor and edema. The proneural and neural subtypes were characterized by the lower T1-Gd signal in enhancing tumor and higher T2-FLAIR signal in edema, respectively. Our results indicate that quantitative multivariate analysis of features extracted from clinically-acquired MRI may provide a radiographic biomarker of the transcriptomic profile of glioblastoma. Importantly our findings can be influential in surgical decision-making, treatment planning, and assessment of inoperable tumors.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The EGFR gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated EGFR-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the EGFR mutations relevant in GBM.

Although it is now possible to produce recombinant HIV envelope glycoproteins (Envs) with epitopes recognized by the 5–6 major classes of broadly neutralizing antibodies (bNAbs), these have failed to consistently stimulate the formation of bNAbs in immunized animals or humans. In an effort to identify new immunogens better able to elicit bNAbs, we are studying Envs derived from rare individuals who possess bNAbs and are able to control their infection without the need for anti-retroviral drugs (elite supressors or ES), hypothesizing that in at least some people the antibodies may mediate durable virus control. Because virus evolution in people with the ES only phenotype was reported to be limited, we reasoned the Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. Using a phenotypic assay, we screened 25 controllers and identified two for more detailed investigation. In this study, we examined 20 clade B proviral sequences isolated from an African American woman, who had the rare bNAb/ES phenotype. Phylogenetic analysis of proviral envelope sequences demonstrated low genetic diversity. Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. In this report, we examine the impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization. These data suggest structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape.