To boldly go where no microRNAs have gone before: spaceflight impact on risk for small-for-gestational-age infants.

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.

Celebrating 30 years of access to NASA Space Life Sciences data.

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.

Early Electrophysiology in Suspected Acute Guillain-Barré Syndrome: A Prospective Study of Comprehensive Testing.

PURPOSE: Electrophysiologic changes in early Guillain-Barré Syndrome (GBS) can be nondiagnostic. Improved testing paradigms may improve hyperacute treatment. METHODS: This work prospectively evaluated consecutive patients admitted to a metropolitan teaching hospital in Melbourne, Australia, with suspected acute GBS. We performed extensive neurophysiology at three different time points. Novel tests, including cutaneous silent periods, long latency reflexes, and contraction-induced H reflexes, were assessed. RESULTS: Twenty-three participants were studied, including 13 cases of acute GBS. In total, 69% of acute cases of GBS were accurately diagnosed on the first nerve conduction study using published neurophysiologic criteria, with serial studies rarely altering the GBS subtype classification. Antidromic and orthodromic upper limb sensory studies were diagnostically equivalent. A sural sparing pattern was seen in 77% of cases of GBS at the first test. Long latency reflexes and contraction-induced H reflexes testing were abnormal in most participants but were limited by muscle weakness in some. Cutaneous silent periods testing was unobtainable in approximately 50% of cases because of weakness and did not discriminate from mimic disorders. CONCLUSIONS: Abnormalities of long latency reflexes and contraction-induced H reflexes may be helpful where initial electrophysiology is nondiagnostic but are nonspecific. Cutaneous silent periods testing seems of limited value. Comprehensive testing provides diagnostic certainty in most cases of GBS from the very first study.

The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

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 space1-6. 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 Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, 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.

Inspiration4 data access through the NASA Open Science Data Repository.

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.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

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.

NASA GeneLab derived microarray studies of Mus musculus and Homo sapiens organisms in altered gravitational conditions.

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.

Age and Sex Disparities in Cardiovascular Risk Factor Management prior to Stroke: Linked Registry and General Practice Data.

INTRODUCTION: There is limited evidence about the management of cardiovascular risk factors within 12 months before stroke or transient ischaemic attack (TIA) in Australian general practices. We evaluated whether age and sex disparities in cardiovascular risk factor management for primary prevention exist in general practice. METHODS: A retrospective cohort study using data from the Australian Stroke Clinical Registry (2014-2018) linked with general practice data from three Primary Health Networks in Victoria, Australia. We included adults who had ≥2 encounters with a general practitioner within 12 months immediately before the first stroke/TIA. Cardiovascular risk factor management within 12 months before stroke/TIA was evaluated in terms of: assessment of risk factors (blood pressure [BP], serum lipids, blood glucose, body weight); prescription of prevention medications (BP-lowering, lipid-lowering, glucose-lowering, antithrombotic agents); and attainment of risk factor targets. RESULTS: Of 2,880 patients included (median age 76.5 years, 48.4% women), 80.9% were assessed for BP, 49.9% serum lipids, 46.8% blood glucose, and 39.3% body weight. Compared to patients aged 65-84 years, those aged <65 or ≥85 years were less often assessed for risk factors, with women aged ≥85 years assessed for significantly fewer risk factors than their male counterparts. The most prescribed prevention medications were BP-lowering (64.9%) and lipid-lowering agents (42.0%). There were significant sex differences among those aged <65 years (34.7% women vs. 40.2% men) and ≥85 years (34.0% women vs. 44.3% men) for lipid-lowering agents. Risk factor target attainment was generally poorer in men than women, especially among those aged <65 years. CONCLUSION: Age-sex disparity exists in risk factor management for primary prevention in general practice, and this was more pronounced among younger patients and older women.

Explainable machine learning identifies multi-omics signatures of muscle response to spaceflight in mice.

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.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Stroke clinical coding education program in Australia and New Zealand.

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.

Case of Amaurosis Fugax in the Setting of a Persistent Primitive Hypoglossal Artery Requiring Carotid Endarterectomy with Regional Anesthesia.

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.

The scalable precision medicine open knowledge engine (SPOKE): a massive knowledge graph of biomedical information.

MOTIVATION: Knowledge graphs (KGs) are being adopted in industry, commerce and academia. Biomedical KG presents a challenge due to the complexity, size and heterogeneity of the underlying information. RESULTS: In this work, we present the Scalable Precision Medicine Open Knowledge Engine (SPOKE), a biomedical KG connecting millions of concepts via semantically meaningful relationships. SPOKE contains 27 million nodes of 21 different types and 53 million edges of 55 types downloaded from 41 databases. The graph is built on the framework of 11 ontologies that maintain its structure, enable mappings and facilitate navigation. SPOKE is built weekly by python scripts which download each resource, check for integrity and completeness, and then create a 'parent table' of nodes and edges. Graph queries are translated by a REST API and users can submit searches directly via an API or a graphical user interface. Conclusions/Significance: SPOKE enables the integration of seemingly disparate information to support precision medicine efforts. AVAILABILITY AND IMPLEMENTATION: The SPOKE neighborhood explorer is available at https://spoke.rbvi.ucsf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Machine learning multi-omics analysis reveals cancer driver dysregulation in pan-cancer cell lines compared to primary tumors.

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.

Validating Causal Diagrams of Human Health Risks for Spaceflight: An Example Using Bone Data from Rodents.

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.

Determining the sensitivity of emergency dispatcher and paramedic diagnosis of stroke: statewide registry linkage study.

Introduction: Correctly identifying people with suspected stroke is essential for ensuring rapid treatment. Our aims were to determine the sensitivity of emergency dispatcher and paramedic identification of patients with stroke, the factors associated with correct identification, and whether there were any implications for hospital arrival times. Methods: Observational study using patient-level data from the Australian Stroke Clinical Registry (2015-2017) linked with ambulance and emergency department records for the state of Victoria. The registry diagnosis was the reference standard to compare with the provisional diagnoses made by emergency services personnel classified as "suspected" and "not suspected" stroke/transient ischemic attack (TIA). Multivariable logistic and quintile regressions were used to determine factors associated with correct identification and timely arrival to hospital. Results: Overall, 4717 (64%) were matched to ambulance transport records (median age: 73 years, 43% female). Stroke/TIA was suspected in 56% of registrants by call-takers and 69% by paramedics. Older patients (75+ years) (adjusted odds ratio [aOR]: 0.61; 95% confidence interval [CI]: 0.49-0.75), females (aOR: 0.86; 95% CI: 0.75-0.99), those with severe stroke or intracerebral hemorrhage were less often suspected as stroke. Cases identified as stroke had a shorter arrival time to hospital (unadjusted median minutes: stroke, 54 [43, 72] vs not stroke, 66 [51, 89]). Conclusions: Emergency dispatchers and paramedics identified over half of patients with stroke in the prehospital setting. Important patient characteristics, such as being female and those having a severe stroke, were found that may enable refinement of prehospital ambulance protocols and dispatcher/paramedic education. Those correctly identified as stroke, arrived earlier to hospital optimizing their chances of receiving time-critical treatments.

Feedback of aggregate patient-reported outcomes (PROs) data to clinicians and hospital end users: findings from an Australian codesign workshop process.

OBJECTIVES: Patient-reported outcomes (PROs) are increasingly used to measure the patient's perspective of their outcomes following healthcare interventions. The aim of this study was to determine the preferred formats for reporting service-level PROs data to clinicians, researchers and managers to support greater utility of these data to improve healthcare and patient outcomes. SETTING: Healthcare professionals receiving PRO data feedback at the health service level. PARTICIPANTS: An interdisciplinary Project Working Group comprised of clinicians participated in three workshops to codesign reporting templates of summarised PRO data (modified Rankin Scale, EuroQol Five Dimension Descriptive System, EuroQol Visual Analogue Scale and Hospital Anxiety and Depression Scale) using a modified Delphi process. An electronic survey was then distributed to short list the preferred templates among a broad sample of clinical end users. A final workshop was undertaken with the Project Working Group to review results and reach consensus on the final templates. PRIMARY AND SECONDARY OUTCOME MEASURES: The recommendation of preferred PRO summary data feedback templates and guiding principles for reporting aggregate PRO data to clinicians was the primary outcome. A secondary outcome was the identification of perceived barriers and enablers to the use of PRO data in hospitals. For each outcome measure, quantitative and qualitative data were summarised. RESULTS: 31 Working Group members (19 stroke, 2 psychology, 1 pharmacy, 9 researchers) participated in the workshops, where 25/55 templates were shortlisted for wider assessment. The survey was completed by 114 end users. Strongest preferences were identified for bar charts (37/82 votes, 45%) and stacked bar charts (37/91 votes, 41%). At the final workshop, recommendations to enhance communication of PROs data for comparing health service performance were made including tailoring feedback to professional roles and use of case-mix adjustment to ensure fair comparisons. CONCLUSIONS: Our research provides guidance on PROs reporting for optimising data interpretation and comparing hospital performance.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

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.