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Space biology and health data are critical for the success of deep space missions and sustainable human presence off-world. At the core of effectively managing biomedical risks is the commitment to open science principles, which ensure that data are findable, accessible, interoperable, reusable, reproducible and maximally open. The 2021 integration of the Ames Life Sciences Data Archive with GeneLab to establish the NASA Open Science Data Repository significantly enhanced access to a wide range of life sciences, biomedical-clinical and mission telemetry data alongside existing 'omics data from GeneLab. This paper describes the new database, its architecture and new data streams supporting diverse data types and enhancing data submission, retrieval and analysis. Features include the biological data management environment for improved data submission, a new user interface, controlled data access, an enhanced API and comprehensive public visualization tools for environmental telemetry, radiation dosimetry data and 'omics analyses. By fostering global collaboration through its analysis working groups and training programs, the open science data repository promotes widespread engagement in space biology, ensuring transparency and inclusivity in research. It supports the global scientific community in advancing our understanding of spaceflight's impact on biological systems, ensuring humans will thrive in future deep space missions., (Published by Oxford University Press on behalf of Nucleic Acids Research 2024.)

Objective: To evaluate the management in Victorian general practice of people who have been hospitalised with stroke or transient ischaemic attacks (TIA)., Study Design: Retrospective observational study; analysis of linked Australian Stroke Clinical Registry (AuSCR) and general practice data., Setting: 383 general practices in the Eastern Melbourne, South Eastern Melbourne, and Gippsland primary health networks (Victoria), 1 January 2014 - 31 December 2018., Participants: Adults who had been hospitalised with acute stroke or TIA and had at least two encounters with the same general practice during the observation period (7-18 months after the acute event)., Main Outcome Measures: Assessment of cardiometabolic risk factors (blood pressure, serum lipids, blood glucose, urinary protein); prescribing of guideline-recommended prevention medications (blood pressure-, lipid-, or glucose-lowering, antithrombotic agents); attainment of guideline targets for cardiometabolic risk factors at final assessment during observation period., Results: During 2014-2018, 3376 eligible AuSCR registrants (1465 women, 43.4%) had at least two encounters with one of the 383 general practices during the observation period; median age at stroke onset was 73.9 (interquartile range, 64.4-81.9) years, 737 events were TIAs (21.8%). Blood pressure was assessed in 2718 patients (80.5%), serum lipids in 1830 (54.2%), blood glucose in 1708 (50.6%). Prevention medications were prescribed for 2949 patients (87.4%), including lipid-lowering (2427, 71.9%) and blood pressure-lowering agents (2363, 70.0%). Blood glucose targets had been achieved by 1346 of 1708 patients assessed for this risk factor (78.8%), blood pressure targets by 1935 of 2717 (71.2%), and serum lipid targets by 765 of 1830 (41.8%). The incidence of having risk factors assessed was lower among patients aged 60 years or younger (incidence rate ratio [IRR], 0.97; 95% confidence interval [CI], 0.92-1.03) and those over 80 years of age (IRR, 0.92; 95% CI 0.88-0.97) than for those aged 61-80 years, and for women (IRR, 0.91; 95% CI, 0.87-0.95) and people with dementia (IRR, 0.89; 95% CI, 0.81-0.98). The likelihood of having classes of prevention medication prescribed was lower for patients aged 60 years or younger (IRR, 0.92; 95% CI, 0.88-0.97) and those over 80 years of age (IRR, 0.96; 95% CI, 0.92-0.997) than for patients aged 61-80 years, and for women (IRR, 0.95; 95% CI, 0.91-0.98) and people with dementia (IRR, 0.88; 95% CI, 0.78-0.98)., Conclusions: The general practice management of people who have been hospitalised with stroke or TIA could be improved. Effective monitoring of cardiometabolic risk factors will enable general practitioners to optimise care for people who need careful attention to prevent adverse secondary events., (© 2024 AMPCo Pty Ltd.)

Background: Cerebrovascular accident (CVA) is an outdated term for describing stroke as it implies stroke is an accident. We conducted an integrative review to determine use of CVA in terms of 1) frequency in major medical journals over time; 2) associated publication characteristics (e.g., number of authors, senior author country, topic); and 3) frequency in medical records., Methods: We searched Google Scholar for publications in leading neurology and vascular journals (Quartile 1) across two 5-year periods (1998-2002 and 2018-2022) using the terms "cerebrovascular accident" or "CVA." Two reviewers independently reviewed full-text publications and recorded the frequency of CVA use. Rates of use (per 1,000 articles/year) were calculated for each journal and time period. Associations of publication characteristics with CVA use were determined using multivariable logistic regression models. In addition, admission and discharge forms in the Auckland Regional Community Stroke Study (ARCOS V) were audited for frequency of use of the term CVA., Results: Of the 1,643 publications retrieved, 1,539 were reviewed in full. Of these, CVA was used ≥1 time in 676 publications, and ≥2 times in 276 publications (129 in 1998-2002; 147 in 2018-2022). The terms CVA and stroke both appeared in 57% of publications where CVA was used ≥2 times in 1998-2002, compared to 65% in 2018-2022. Majority of publications were on the topic of stroke (22% in 1998-2002; 20% in 2018-2022). There were no associations between publication characteristics and the use of CVA. The highest rate of CVA use in 2018-2022 was in Circulation, and increased over time from 1.3 uses per 1,000 publications in 1998-2002 to 1.8 uses per 1,000 publications in 2018-2022. The largest reduction the use of CVA was in Neuroepidemiology (2.0 uses per 1,000 publications in 1998-2002 to 0 uses in 2018-2022). The term CVA was identified in 0.2% of stroke admission and discharge forms audited (17/7808)., Conclusion: We found evidence of changes in the use of CVA in the scientific literature over the past two decades. Editors, authors and clinicians should avoid the use of the term CVA as it perpetuates the use of a non-specific, non-diagnostic, and non-scientific term., (The Author(s). Published by S. Karger AG, Basel.)

In the era of renewed space exploration, comprehending the effects of the space environment on human health, particularly for deep space missions, is crucial. While extensive research exists on the impacts of spaceflight, there is a gap regarding female reproductive risks. We hypothesize that space stressors could have enduring effects on female health, potentially increasing risks for future pregnancies upon return to Earth, particularly related to small-for-gestational-age (SGA) fetuses. To address this, we identify a shared microRNA (miRNA) signature between SGA and the space environment, conserved across humans and mice. These miRNAs target genes and pathways relevant to diseases and development. Employing a machine learning approach, we identify potential FDA-approved drugs to mitigate these risks, including estrogen and progesterone receptor antagonists, vitamin D receptor antagonists, and DNA polymerase inhibitors. This study underscores potential pregnancy-related health risks for female astronauts and proposes pharmaceutical interventions to counteract the impact of space travel on female health., (© 2024. The Author(s).)

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons., (© 2024. Springer Nature Limited.)

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space 1-6 . Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study 7 , JAXA CFE study 8,9 , SpaceX Inspiration4 crew 10-12 , Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions., (© 2024. The Author(s).)

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR., (© 2024. The Author(s).)

Background: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo., Methods: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete., Findings: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98])., Interpretation: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings., Funding: Australian Government Medical Research Future Fund., Competing Interests: Declaration of interests HZ is a board member of the Pre-hospital Stroke Treatment Organization. GCC has received honoraria from AstraZeneca for lectures and advisory board participation. HM has received honoraria for lectures from the Indonesia Stroke Society Meeting and is the co-chair of the scientific committee for the Asia Pacific Stroke Conference (2024). AM has received consulting fees and participated on an advisory board for Boehringer Ingelheim, and is a member of the board of the World Stroke Organisation. AR has received grants from the Health Research Council of New Zealand, New Zealand Ministry of Health, and Australian and New Zealand Association of Neurologists; participated in a Data Safety Monitoring Board for Argenica Therapeutics; is secretary of the Australia and New Zealand Stroke Organisation; and board member of the World Stroke Organisation and New Zealand Stroke Foundation. VT has received honoraria from Boehringer Ingelheim, Bayer, and Medtronic, and participated in a Data Safety Monitoring Board for EMVision and Itreas. BY has received institutional research grants and honoraria for lectures and conference attendance from Stryker and Medtronic. LMS has received honoraria for lectures and educational materials from Biogen, Pfizer, and AbbVie, and support for conference attendance from Abbott. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The increasing accessibility of commercial and private space travel necessitates a profound understanding of its impact on human health. The NASA Open Science Data Repository (OSDR) provides transparent and FAIR access to biological studies, notably the SpaceX Inspiration4 (I4) mission, which amassed extensive data from civilian astronauts. This dataset encompasses omics and clinical assays, facilitating comprehensive research on space-induced biological responses. These data allow for multi-modal, longitudinal assessments, bridging the gap between human and model organism studies. Crucially, community-driven data standards established by NASA's OSDR Analysis Working Groups empower artificial intelligence and machine learning to glean invaluable insights, guiding future mission planning and health risk mitigation. This article presents a concise guide to access and analyze I4 data in OSDR, including programmatic access through GLOpenAPI. This pioneering effort establishes a precedent for post-mission health monitoring programs within space agencies, propelling research in the burgeoning field of commercial space travel's impact on human physiology., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

One of the greatest challenges of humanity for deep space exploration is to fully understand how altered gravitational conditions affect human physiology. It is evident that the spaceflight environment causes multiple alterations to musculoskeletal, cardiovascular, immune and central nervous systems, to name a few known effects. To better characterize these biological effects, we compare gene expression datasets from microarray studies found in NASA GeneLab, part of the NASA Open Science Data Repository. In this review, we summarize these archived results for various tissues, emphasizing key genes which are highly reproducible in different mice or human experiments. Such exhaustive mining shows the potential of NASA Open Science data to identify and validate mechanisms taking place when mammalian organisms are exposed to microgravity or other spaceflight conditions. Our comparative meta-analysis findings highlight certain degrees of overlap and reproducibility in genes identified as differentially expressed within musculoskeletal tissues in each species across a variety of altered gravity conditions. However, the level of overlap between species was found to be significantly limited, partly attributed to the limited availability of human samples., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

NASA's space life sciences research programs established a decades-long legacy of enhancing our ability to safely explore the cosmos. From Skylab and the Space Shuttle Program to the NASA Balloon Program and the International Space Station National Lab, these programs generated priceless data that continue to paint a vibrant picture of life in space. These data are available to the scientific community in various data repositories, including the NASA Ames Life Sciences Data Archive (ALSDA) and NASA GeneLab. Here we recognize the 30-year anniversary of data access through ALSDA and the 10-year anniversary of GeneLab., (Published by Oxford University Press on behalf of GigaScience 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The adverse effects of microgravity exposure on mammalian physiology during spaceflight necessitate a deep understanding of the underlying mechanisms to develop effective countermeasures. One such concern is muscle atrophy, which is partly attributed to the dysregulation of calcium levels due to abnormalities in SERCA pump functioning. To identify potential biomarkers for this condition, multi-omics data and physiological data available on the NASA Open Science Data Repository (osdr.nasa.gov) were used, and machine learning methods were employed. Specifically, we used multi-omics (transcriptomic, proteomic, and DNA methylation) data and calcium reuptake data collected from C57BL/6 J mouse soleus and tibialis anterior tissues during several 30+ day-long missions on the international space station. The QLattice symbolic regression algorithm was introduced to generate highly explainable models that predict either experimental conditions or calcium reuptake levels based on multi-omics features. The list of candidate models established by QLattice was used to identify key features contributing to the predictive capability of these models, with Acyp1 and Rps7 proteins found to be the most predictive biomarkers related to the resilience of the tibialis anterior muscle in space. These findings could serve as targets for future interventions aiming to reduce the extent of muscle atrophy during space travel., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Accurate coded diagnostic data are important for epidemiological research of stroke., Objective: To develop, implement and evaluate an online education program for improving clinical coding of stroke., Method: The Australia and New Zealand Stroke Coding Working Group co-developed an education program comprising eight modules: rationale for coding of stroke; understanding stroke; management of stroke; national coding standards; coding trees; good clinical documentation; coding practices; and scenarios. Clinical coders and health information managers participated in the 90-minute education program. Pre- and post-education surveys were administered to assess knowledge of stroke and coding, and to obtain feedback. Descriptive analyses were used for quantitative data, inductive thematic analysis for open-text responses, with all results triangulated., Results: Of 615 participants, 404 (66%) completed both pre- and post-education assessments. Respondents had improved knowledge for 9/12 questions ( p  < 0.05), including knowledge of applicable coding standards, coding of intracerebral haemorrhage and the actions to take when coding stroke (all p  < 0.001). Majority of respondents agreed that information was pitched at an appropriate level; education materials were well organised; presenters had adequate knowledge; and that they would recommend the session to colleagues. In qualitative evaluations, the education program was beneficial for newly trained clinical coders, or as a knowledge refresher, and respondents valued clinical information from a stroke neurologist., Conclusion: Our education program was associated with increased knowledge for clinical coding of stroke. To continue to address the quality of coded stroke data through improved stroke documentation, the next stage will be to adapt the educational program for clinicians.

BACKGROUND A persistent primitive hypoglossal artery (PPHA) is a rare congenital anomaly leading to persistent carotid-basilar anastomosis. This is a report of an 83-year-old man with a PPHA presenting with amaurosis fugax of the left eye requiring carotid endarterectomy under regional anesthesia. CASE REPORT An 83-year-old man presented with 2 weeks of intermittent self-resolving visual disturbances, followed by an episode of left eye amaurosis fugax. The patient had been referred to the hospital for further investigation of symptoms 1 day following the amaurosis fugax event. Carotid Doppler ultrasound demonstrated a greater than 90% stenosis of the left internal carotid artery. Computed tomography carotid and Circle of Willis angiography confirmed a mixed, ulcerated plaque and revealed a persistent left hypoglossal artery originating from the left internal carotid artery and continuing as the basilar artery. On day 3 of admission, left carotid endarterectomy was performed under conscious sedation and regional anesthesia to permit continuous monitoring of neurological status and avoid the need for intraoperative shunting. "Permissive hypertension" by targeting a systolic blood pressure of 190 to 200 mmHg was sought for the duration of clamp time. There was no deterioration of neurological function during clamping of the carotid vessels. The patient recovered well and was discharged 2 days after surgery, with no residual neurology. CONCLUSIONS This report has presented a rare case of PPHA to highlight awareness of this congenital vascular anomaly when undertaking carotid endarterectomy.

Cancer cell lines have been widely used for decades to study biological processes driving cancer development, and to identify biomarkers of response to therapeutic agents. Advances in genomic sequencing have made possible large-scale genomic characterizations of collections of cancer cell lines and primary tumors, such as the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA). These studies allow for the first time a comprehensive evaluation of the comparability of cancer cell lines and primary tumors on the genomic and proteomic level. Here we employ bulk mRNA and micro-RNA sequencing data from thousands of samples in CCLE and TCGA, and proteomic data from partner studies in the MD Anderson Cell Line Project (MCLP) and The Cancer Proteome Atlas (TCPA), to characterize the extent to which cancer cell lines recapitulate tumors. We identify dysregulation of a long non-coding RNA and microRNA regulatory network in cancer cell lines, associated with differential expression between cell lines and primary tumors in four key cancer driver pathways: KRAS signaling, NFKB signaling, IL2/STAT5 signaling and TP53 signaling. Our results emphasize the necessity for careful interpretation of cancer cell line experiments, particularly with respect to therapeutic treatments targeting these important cancer pathways., (© 2022. The Author(s).)

As part of the risk management plan for human system risks at the US National Aeronautics and Space Administration (NASA), the NASA Human Systems Risk Board uses causal diagrams (in the form of directed, acyclic graphs, or DAGs) to communicate the complex web of events that leads from exposure to the spaceflight environment to performance and health outcomes. However, the use of DAGs in this way is relatively new at NASA, and thus far, no method has been articulated for testing their veracity using empirical data. In this paper, we demonstrate a set of procedures for doing so, using (a) a DAG related to the risk of bone fracture after exposure to spaceflight; and (b) four datasets originally generated to investigate this phenomenon in rodents. Tests of expected marginal correlation and conditional independencies derived from the DAG indicate that the rodent data largely agree with the structure of the diagram. Incongruencies between tests and the expected relationships in one of the datasets are likely explained by inadequate representation of a key DAG variable in the dataset. Future directions include greater tie-in with human data sources, including multiomics data, which may allow for more robust characterization and measurement of DAG variables.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cancer heterogeneity is a result of genetic mutations within the cancer cells. Their proliferation is not only driven by autocrine functions but also under the influence of cancer microenvironment, which consists of normal stromal cells such as infiltrating immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, vascular and lymphatic channels. The relationship between cancer cells and cancer microenvironment is a critical one and we are just on the verge to understand it on a molecular level. Cancer microenvironment may serve as a selective force to modulate cancer cells to allow them to evolve into more aggressive clones with ability to invade the lymphatic or vascular channels to spread to regional lymph nodes and distant sites. It is important to understand these steps of cancer evolution within the cancer microenvironment towards invasion so that therapeutic strategies can be developed to control or stop these processes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Diffuse midline gliomas with histone H3 K27M (H3K27M) mutations occur in early childhood and are marked by an invasive phenotype and global decrease in H3K27me3, an epigenetic mark that regulates differentiation and development. H3K27M mutation timing and effect on early embryonic brain development are not fully characterized., Results: We analyzed multiple publicly available RNA sequencing datasets to identify differentially expressed genes between H3K27M and non-K27M pediatric gliomas. We found that genes involved in the epithelial-mesenchymal transition (EMT) were significantly overrepresented among differentially expressed genes. Overall, the expression of pre-EMT genes was increased in the H3K27M tumors as compared to non-K27M tumors, while the expression of post-EMT genes was decreased. We hypothesized that H3K27M may contribute to gliomagenesis by stalling an EMT required for early brain development, and evaluated this hypothesis by using another publicly available dataset of single-cell and bulk RNA sequencing data from developing cerebral organoids. This analysis revealed similarities between H3K27M tumors and pre-EMT normal brain cells. Finally, a previously published single-cell RNA sequencing dataset of H3K27M and non-K27M gliomas revealed subgroups of cells at different stages of EMT. In particular, H3.1K27M tumors resemble a later EMT stage compared to H3.3K27M tumors., Conclusions: Our data analyses indicate that this mutation may be associated with a differentiation stall evident from the failure to proceed through the EMT-like developmental processes, and that H3K27M cells preferentially exist in a pre-EMT cell phenotype. This study demonstrates how novel biological insights could be derived from combined analysis of several previously published datasets, highlighting the importance of making genomic data available to the community in a timely manner., (© The Author(s) 2020. Published by Oxford University Press GigaScience.)

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Olena Vaske’s spouse has stock interests in NantHealth.

Background and Purpose- Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods- Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results- In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes ( P <0.001) for dispatch to hospital arrival and 15 minutes ( P <0.001) for hospital arrival to thrombolysis. The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes (95% CI, 36.0-49.0). In the same period, 41 MSU patients received EVT (mean age, 76 years; 61% men) with median dispatch-to-treatment time saving of 51 minutes ([95% CI, 30.1-71.9], P <0.001). This included a median time saving of 17 minutes ([95% CI, 7.6-26.4], P =0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions- The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.

Gliomatosis peritonei is a rare pathologic finding that is associated with ovarian teratomas and malignant mixed germ cell tumors. The occurrence of gliomatosis as a mature glial implant can impart an improved prognosis to patients with immature ovarian teratoma, making prompt and accurate diagnosis important. We describe a case of recurrent immature teratoma in a 10-yr-old female patient, in which comparative analysis of the RNA sequencing gene expression data from the patient's tumor was used effectively to aid in the diagnosis of gliomatosis peritonei., (© 2019 Sanders et al.; Published by Cold Spring Harbor Laboratory Press.)

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We previously demonstrated the safety and effectiveness of a nonadmission-based model for TIA care (Monash TIA Triaging Treatment [M3T]). In this microcosting study, we used a pre-post cohort design with multivariable uncertainty analyses to compare actual resource utilization costs between M3T (years 2004-2007) and the previous admission-based model (2003). Average total episode costs per patient were significantly less for M3T (Australian dollars [AUD] 1,927.00, 95% confidence interval [CI] AUD 1,829.00-1,037.00) compared with the admission-based model (AUD 4,841.00, 95% CI AUD 4,178.00-5,590.00). Nonadmission care in M3T was substantially cost-saving with a median 3 (95% uncertainty interval 0.7-6.0) additional strokes averted per 100 patients treated, based on an observed 90-day stroke rate of 1.50% (95% CI 0.73%-3.05%) and 4.67% (95% CI 2.28%-9.32%) in the admission-based model.

Background: There is a poor understanding of the interplay between cognitive and physiological functions in leading to falls. We hypothesized that poorer physiological function would modify the effect of poorer cognitive function on increased risk of falling in older people., Methods: A range of cognitive (executive function/attention, memory, processing speed, and visuospatial ability) and physiological functions (vision, proprioception, sway, leg strength, reaction time) were measured using standardized tests in 386 randomly selected adults aged 60-86. Incident falls were recorded over 12 months. Log-multinomial regression was used to model the relationships and test for interactions between cognition and physiological function in explaining the risk of single or multiple falls., Results: Overall, 94 people (24.4%) had a single fall, and 78 (20.2%) had multiple falls. No significant associations were observed between cognitive function and the risk of single falls. The risk of multiple falls was increased with poorer function in Stroop dot time (RR = 1.03, 95% CI [1.01, 1.05], p = .002) and Stroop word time (RR = 1.02 [1.01, 1.03], p = .001) and reduced with better function in Category Fluency (RR = 0.94 [0.91, 0.98], p = .001) and visuospatial function (RR = 0.95 [0.92, 0.98], p < .001). These associations were amplified by the presence of greater body sway, less ambulatory physical activity, slower reaction time and gait speed, weaker muscle strength, and poorer visual contrast (p for interactions <.05)., Conclusions: Preventing falls due to physiological impairments in community-dwelling older people may need to be tailored based on cognitive impairment, a key factor in their inability to compensate for physical decline.

Background: Gait impairments are associated with falls and loss of independence. The study of factors associated with poorer gait may assist in developing methods to preserve mobility in older people. The aim of this study was to examine the associations between a range of cognitive functions and gait and gait variability in a population-based sample of older people., Methods: Gait and intra-individual gait variability measures were obtained using the GAITRite walkway in a sample of older people, aged 60-85 years (N = 422), randomly selected from the Tasmanian electoral roll. Raw scores from a cognitive battery were subjected to principal component analyses deriving four summary domains: executive function/attention, processing speed, memory, and visuospatial ability. Multivariable linear regression was used to examine associations between cognitive domains and gait measures adjusting for age, sex, ambulatory activity, medication use, and mood., Results: The mean age of the sample was 72.0 years (SD = 7.0), with 238 men (56%). Poorer executive function was independently associated with poorer performance in most absolute gait measures and with greater variability in double support phase and step time. Processing speed was associated with absolute gait measures and double support phase variability. Visuospatial ability was only associated with greater double support phase variability, independently of executive function and processing speed. Memory was not independently associated with any gait measure., Conclusions: In community-dwelling older people, executive function/attention and processing speed were associated with many aspects of gait, whereas visuospatial ability may only play a role in double support phase variability.

Background and Purpose: Controversy surrounds the need for routine hospital admission for transient ischemic attack. The Monash Transient Ischemic Attack Triaging Treatment (M3T) model adopts rapid management in the emergency department followed by outpatient management prioritized by stroke mechanism. We compared safety and processes of care between M3T and the previous model of routine admission., Methods: Study cohorts consisted of patients managed with M3T (2004-2007) and the previous model (2003-2004). We determined 90-day stroke outcome using clinical and medical record review and data linkage to the population level state-wide hospital discharge morbidity database. We compared models of care using risk difference analysis, followed by logistic regression to adjust for previous indicators of risk. Secondary outcomes were proportions admitted, proportions undergoing carotid ultrasound, times to ultrasound and revascularization, and medication prescription., Results: In M3T (mean age, 64.7±14.7) 85/488 (17.4%) patients were admitted compared with 117/169 (62.9%) in the previous model (mean age, 72.5±13.9). With near-complete follow-up, 90-day stroke outcome was 1.50% (95% confidence interval, 0.73%-3.05%) in M3T and 4.67% (95% confidence interval, 2.28%-9.32%) in the previous model (P=0.03). Compared with the previous model, the adjusted odds ratio of stroke for M3T was 0.46 (95% confidence interval, 0.12-1.68; P=0.24). M3T was associated with greater proportions undergoing carotid ultrasound (P<0.001) and receiving antiplatelet therapy (P=0.005)., Conclusions: The M3T system was associated with low 90-day stroke outcome in transient ischemic attack patients, providing proof of concept that these patients may be managed safely without routine hospital admission using a closely supervised protocol in the emergency department.

Objective: To study the accuracy of the ABCD2 score in predicting early stroke risk following TIA and to model post-test probability of stroke for varying cutoff scores and baseline stroke risk., Methods: Medline, PubMed, Embase, conference proceedings, and manuscript references up to October 2010 were searched for studies reporting ABCD2 score and stroke outcome after TIA. Additional data were requested from authors. Meta-analysis, meta-regression, and post-test probability modeling were undertaken to assess prediction of stroke at 2, 7, and 90 days., Results: Of 44 eligible studies, data were available for 33 (16,070 patients): 26/33 reported stroke at 2 days (533 strokes), 32/33 at 7 days (781 strokes), and 28/33 at 90 days (1,028 strokes) after TIA. Using scores 0-3 ("low risk") and 4-7 ("high risk") for stroke at 7 days, pooled measures were sensitivity 0.89 (0.87-0.91), specificity 0.34 (0.33-0.35), positive predictive value 0.08 (0.07-0.09), negative predictive value 0.98 (0.98-0.98), positive likelihood ratio (PLR) 1.43 (1.33-1.54), negative likelihood ratio (NLR) 0.40 (0.33-0.50), and area under the curve (AUC) 0.70 (0.62-0.78). Results were similar at days 2 and 90. There was moderate heterogeneity while pooling PLR (p < 0.01, I(2) >50%), with stroke specialist TIA diagnosis associated with slightly higher PLR. At 5% baseline stroke risk, ABCD2 >3 indicated an absolute increase in 7-day stroke risk of only 2.0% while a score ≤3 indicated a 2.9% decrease in risk. Changes in risk were very small when baseline stroke risk was lower., Conclusions: The ABCD2 score leads to only small revisions of baseline stroke risk particularly in settings of very low baseline risk and when used by nonspecialists.

Background: it is uncertain as to which measures of gait best predict those who are likely to fall. Our aim was to investigate the associations of gait and gait variability measures with incident falls risk., Methods: individuals aged 60-86 years (n = 412) were randomly selected from the Tasmanian electoral roll. Average gait and gait variability measures were collected on a computerised walkway. Falls were recorded prospectively over 12 months. Log multinomial regression was used to estimate the relative risk of single and multiple falls associated with gait measures. Covariates included age, sex, sensorimotor and cognitive measures, mood and medications., Results: in this population-based study greater intra-individual variability in step length and double-support phase were linearly associated with increased risk of multiple falls (P = 0.04). Non-linear associations with multiple falls were found for gait speed P = 0.002, cadence P = 0.004 and step time variability P = 0.03. None of the gait measures predicted risk of single falls., Conclusion: there is an increased risk of multiple falls, but not single falls, in older people with poorer gait. Specific measures of gait and gait variability seem to confer this risk and may be amenable to interventions designed to reduce the risk of multiple falls in older people.

Objective: To determine the predictive value of the ABCD(2) score for early risk of stroke in Australian patients who have had transient ischaemic attack (TIA)., Design, Participants and Setting: Cohort study of 512 consecutive patients with suspected TIA referred by the emergency department to the acute stroke unit (in accordance with the TIA pathway) of an urban tertiary hospital in Melbourne, Victoria, between 1 June 2004 and 30 November 2007., Main Outcome Measures: Overall accuracy, estimated by the area under the curve (AUC) of receiver operating characteristic plots (of true positive rate v false positive rate), and sensitivity, specificity, predictive values and likelihood ratios at prespecified cut-off ABCD(2) scores for stroke within 2, 7 and 90 days., Results: 24 patients were excluded because their symptoms lasted more than 24 hours. All included patients were reviewed by a stroke physician; TIA was confirmed in 301/488 (61.7%). Most (289/301; 96.0%) had complete follow-up. Stroke occurred in 4/292 patients (1.37%; 95% CI, 0.37%-3.47%) within 2 days and 7/289 (2.42%; 95% CI, 0.98%-4.93%) within 90 days; no patient had a stroke between 2 and 7 days. The AUCs for stroke in patients with confirmed TIA were 0.80 (95% CI, 0.68-0.91) and 0.62 (95% CI, 0.40-0.83) for stroke within 2 days and 90 days, respectively. At a cut-off of ≥ 5, the ABCD(2) score had modest specificity for stroke within 2 days (0.58) and 90 days (0.58), but positive predictive values (2 days, 0.03; 90 days, 0.04) and positive likelihood ratios (2 days, 2.40; 90 days, 1.71) were both poor. The score performed similarly poorly at other prespecified cut-off scores., Conclusions: Given its poor predictive value, the use of the ABCD(2) score alone may not be dependable for guiding clinical treatment decisions or service organisation in an Australian tertiary setting. Validation in other Australian settings is recommended before it can be applied with confidence.