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.

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.

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.

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.

Treatment with Multiple Therapeutic Classes of Medication Is Associated with Survival after Stroke.

INTRODUCTION: Treatment with several therapeutic classes of medication is recommended for secondary prevention of stroke. We analyzed the associations between the number of classes of prevention medications supplied within 90 days after discharge for ischemic stroke (IS)/transient ischemic attack (TIA) and survival. METHODS: This is a retrospective cohort study of adults with first-ever IS/TIA (2010-2014) from the Australian Stroke Clinical Registry individually linked with data from national pharmaceutical and Medicare claims. Exposure was the number of classes of recommended medications, i.e., blood pressure-lowering, antithrombotic, or lipid-lowering agents, supplied to patients within 90 days after discharge for IS/TIA. The longitudinal association between the number of classes of medications and survival was evaluated with Cox proportional hazards regression models using the landmark approach. A landmark date of 90 days after hospital discharge was used to separate exposure and outcome periods, and only patients who survived until this date were included. RESULTS: Of 8,429 patients (43% female, median age 74 years, 80% IS), 607 (7%) died in the year following 90 days after discharge. Overall, 56% of patients were supplied all 3 classes of medications, 28% 2 classes of medications, 11% 1 class of medications, and 5% no class of medications. Compared to patients supplied all 3 medication classes, adjusted hazard ratios for all-cause mortality ranged from 1.43 (95% confidence interval [CI]: 1.18-1.72) in those supplied 2 medication classes to 2.04 (95% CI: 1.44-2.88) in those supplied with no medication class. DISCUSSION/CONCLUSION: Treatment with all 3 classes of guideline-recommended medications within 90 days after discharge was associated with better survival. Ongoing efforts are required to ensure optimal pharmacological intervention for secondary prevention of stroke.

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

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.

Melbourne Mobile Stroke Unit and Reperfusion Therapy: Greater Clinical Impact of Thrombectomy Than Thrombolysis.

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.

Performance of claims-based algorithms for identifying incident thyroid cancer in commercial health plan enrollees receiving antidiabetic drug therapies.

BACKGROUND: Thyroid cancer incidence is increasing in the United States (US) and many other countries. The objective of this study was to develop and evaluate algorithms using administrative medical claims data for identification of incident thyroid cancer. METHODS: This effort was part of a prospective cohort study of adults initiating therapy on antidiabetic drugs and used administrative data from a large commercial health insurer in the US. Patients had at least 6 months of continuous enrollment prior to initiation during 2009-2013, with follow-up through March, 2014 or until disenrollment. Potential incident thyroid cancers were identified using International Classification of Diseases, 9th Revision (ICD-9) diagnosis code 193 (malignant neoplasm of the thyroid gland). Medical records were adjudicated by a thyroid cancer specialist. Several clinical variables (e.g., hospitalization, treatments) were considered as predictors of case status. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated to evaluate the performance of two primary algorithms. RESULTS: Charts were requested for 170 patients, 150 (88%) were received and 141 (80%) had sufficient information to adjudicate. Of the 141 potential cases identified using ≥1 ICD-9 diagnosis code 193, 72 were confirmed as incident thyroid cancer (PPV of 51% (95% CI 43-60%)). Adding the requirement for thyroid surgery increased the PPV to 68% (95% CI 58-77%); including the presence of other therapies (chemotherapy, radio-iodine therapy) had no impact. When cases were required to have thyroid surgery during follow-up and ≥2 ICD-9 193 codes within 90 days of this surgery, the PPV was 91% (95% CI 81-96%); 62 (82%) of the true cases were identified and 63 (91%) of the non-cases were removed from consideration by the algorithm as potential cases. CONCLUSIONS: These findings suggest a significant degree of misclassification results from relying only on ICD-9 diagnosis codes to detect thyroid cancer. An administrative claims-based algorithm was developed that performed well to identify true incident thyroid cancer cases.

Abdominal Incision Selection for Cesarean Delivery of Women with Class III Obesity.

Objective The objective of this study was to evaluate cesarean outcomes, stratified by abdominal incision type, in women with class III obesity. Study Design We performed a retrospective cohort study of patients with class III obesity undergoing cesarean at our institution from 2010 to 2013 with singletons ≥ 34 weeks. Outcomes were compared between patients with transverse subpannicular and vertical abdominal incisions. The primary outcome was a wound composite (cellulitis, abscess, hematoma, seroma, or dehiscence). Other outcomes included transfusion, vertical hysterotomy, 5-minute Apgar < 7, and umbilical artery pH < 7.10. Results Of 423 patients, 364 had subpannicular transverse, 57 had vertical, and 2 had periumbilical transverse incisions (not analyzed). Although vertical incisions were associated with more wound complications (26.3 vs. 14.8%; p = 0.03), the difference became null after adjustment (adjusted odds ratios [aOR], 1.7; 95% confidence interval [CI], 0.7, 4.1). Vertical incisions were associated with increased risk of vertical hysterotomy (aOR 4.8; 95% CI, 2.2, 10.4), decreased risk of 5-minute Apgar < 7 (aOR, 0.06; 95% CI, 0.004, 0.9), and not statistically significantly associated with transfusion (aOR, 4.2; 95% CI, 0.9, 19.0) or umbilical artery pH < 7.1 (aOR, 0.42; 95% CI, 0.11, 1.7). Conclusions In women with class III obesity cesarean delivery via vertical abdominal incisions is associated with more maternal but less immediate neonatal complications.