Citations

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Abstract High grade glioma (HGG) represents a group of devastating diseases with dismal prognosis. Surgical resection of the contrast enhancing (CE) region of HGG remains the mainstay of treatment, but recurrence inevitably arises from the unresected non-contrast enhancing (NE) region, surgically inaccessible due to cancer cell invasion into healthy brain tissue. Due to its critical role in recurrence, understanding of the NE region is central to the improvement of clinical outcomes. We reveal the biological characteristics of this region through image localized multi-regional sampling. We linked microenvironmental characteristics measured by multi-parametric MRI to genomic mutations and transcriptional phenotypes using mixed effect modeling which allowed us to control for individualized patient effects. We first confirmed that T2 is a significant indicator of IDH mutation status in the NE region, being the first description of such a relationship in a HGG cohort. We found the combination of EGFR amplification and CDKN2A homozygous loss was associated with a significantly lower mean diffusivity (MD) compared to double wild type tumors in the NE region, indicating the presence of greater cellular packing and proliferation in EGFR amplification/CDKN2A loss regions. Finally, using single cell pathway based tumor classifications, we showed that nK2, a DSC-MRI metric representing cell size heterogeneity, correlated positively with neuronal signature and negatively with glycolytic/plurimetabolic signature within the NE tumor, indicating that glycolytic/plurimetobolic tumors possessed a high amount of cell size heterogeneity compared to neuronal samples. This hypothesis was supported using digital reference object (DRO) modeling which confirmed that cell size and heterogeneity drove the differential nK2 signal between neuronal and glycolytic/plurimetabolic samples. We identified immune cell infiltrate as one possible mechanism of increased cell size heterogeneity using transcriptomic signature analysis which found more immune cell signatures within glycolytic/plurimetobolic tumors compared to neuronal. Collectively this study demonstrates the central role of multi-parametric MRI as a non-invasive measure of tumor biology and a tool for understanding the clinically critical NE region which can then inform new therapies targeting this region of HGG recurrence. Citation Format: Matthew Flick, Taylor Weiskittel, Kevin Meng-Lin, Fulvio D'Angelo, Francesca Caruso, Shannon Ensign, Mylan Blomquist, Luija Wang, Christopher Sereduk, Gustavo De Leon, Ashley Nespodzany, Javier Urcuyo, Ashlynn Gonzalez, Lee Curtin, Kyle Singleton, Aliya Anil, Natenael Simmineh, Erika Lewis, Teresa Noviello, Reyna Patel, Panwen Wang, Junwen Wang, Jennifer Eschbacher, Andrea Hawkins-Daarud, Pamela Jackson, Kris Smith, Peter Nakaji, Bernard Bendok, Richard Zimmerman, Chandan Krishna, Devi Patra, Naresh Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej Mrugala, Alyx Porter, Scott Beeman, Yuxiang Zhou, Leslie Baxter, Christopher Plaisier, Jing Li, Hu Li, Anna Lasorella, Chad Quarles, Kristin Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan Tran, Leland Hu. Multi-parametric MRI maps regional heterogeneity of high grade glioma phenotypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5621.

Background: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results: Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P =7.4×10 −14 ) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P =1.6×10 −14 ), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P =1.8×10 −6 with the secondary filter), while SERPINC1 did not (minimum P =4.4×10 −5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1 , became significant ( P =4.4×10 −7 using all missense variants with minor allele frequency <0.0005). Conclusions: Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

BACKGROUND: There are limited data regarding outcomes for patients with gastrointestinal (GI) primaries and brain metastases treated with stereotactic radiosurgery (SRS). OBJECTIVE: To examine clinical outcomes after SRS for patients with brain metastases from GI primaries and evaluate potential prognostic factors. METHODS: The International Radiosurgery Research Foundation centers were queried for patients with brain metastases from GI primaries managed with SRS. Primary outcomes were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used for univariate analysis (UVA) of prognostic factors. Factors significant on UVA were evaluated with a Cox multivariate analysis proportional hazards model. Logistic regressions were used to examine correlations with RN. RESULTS: We identified 263 eligible patients with 543 brain metastases. Common primary sites were rectal (31.2%), colon (31.2%), and esophagus (25.5%) with a median age of 61.6 years (range: 37-91.4 years) and a median Karnofsky performance status (KPS) of 90% (range: 40%-100%). One-year and 2-year LC rates were 83.5% (95% CI: 78.9%-87.1%) and 73.0% (95% CI: 66.4%-78.5%), respectively. On UVA, age >65 years ( P = .001), dose <20 Gy ( P = .006) for single-fraction plans, KPS <90% ( P < .001), and planning target volume ≥2cc ( P = .007) were associated with inferior LC. All factors other than dose were significant on multivariate analysis ( P ≤ .002). One-year and 2-year OS rates were 68.0% (95% CI: 61.5%-73.6%) and 31.2% (95% CI: 24.6%-37.9%), respectively. Age > 65 years ( P = .006), KPS <90% ( P = .005), and extracranial metastases ( P = .05) were associated with inferior OS. CONCLUSION: SRS resulted in comparable LC with common primaries. Age and KPS were associated with both LC and OS with planning target volume and extracranial metastases correlating with LC and OS, respectively. These factors should be considered in GI cancer patient selection for SRS.

Abstract Background Over the past decade, the use of technology‐enhanced simulation in emergency medicine (EM) education has grown, yet we still lack a clear understanding of its effectiveness. This systematic review aims to identify and synthesize studies evaluating the comparative effectiveness of technology‐enhanced simulation in EM. Methods We searched MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, Web of Science, and Scopus to identify EM simulation research that compares technology‐enhanced simulation with other instructional modalities. Two reviewers screened articles for inclusion and abstracted information on learners, clinical topics, instructional design features, outcomes, cost, and study quality. Standardized mean difference (SMD) effect sizes were pooled using random effects. Results We identified 60 studies, enrolling at least 5279 learners. Of these, 23 compared technology‐enhanced simulation with another instructional modality (e.g., living humans, lecture, small group), and 37 compared two forms of technology‐enhanced simulation. Compared to lecture or small groups, we found simulation to have nonsignificant differences for time skills (SMD 0.33, 95% confidence interval [CI] −0.23 to 0.89, n = 3), but a large, significant effect for non–time skills (SMD 0.82, 95% CI 0.18 to 1.46, n = 8). Comparison of alternative types of technology‐enhanced simulation found favorable associations with skills acquisition, of moderate magnitude, for computer‐assisted guidance (compared to no computer‐assisted guidance), for time skills (SMD 0.50, 95% CI −1.66 to 2.65, n = 2) and non–time skills (SMD 0.57, 95% CI 0.33 to 0.80, n = 6), and for more task repetitions (time skills SMD 1.01, 95% CI 0.16 to 1.86, n = 2) and active participation (compared to observation) for time skills (SMD 0.85, 95% CI 0.25 to 1.45, n = 2) and non–time skills (SMD 0.33 95% CI 0.08 to 0.58, n = 3). Conclusions Technology‐enhanced simulation is effective for EM learners for skills acquisition. Features such as computer‐assisted guidance, repetition, and active learning are associated with greater effectiveness.

Introduction: Hypertension in midlife, but not late life, is a robust predictor of subsequent dementia. However, the fraction of dementia attributable to hypertension might vary depending on the age of the population considered, and the age through which dementia onset occurs. Here, we investigated associations of hypertension assessed at various ages with incident dementia by age 80 or 90, then estimated population attributable fractions (PAF) for dementia from hypertension categories at each of these age groups. Hypothesis: Given hypertension prevalence increases with age but its relative risk for dementia tends to decrease, we had no prior expectation of the age at which the PAF’s would be highest. We hypothesized, however, that PAFs for incident dementia would be higher when hypertension is measured in midlife age groups versus late-life age groups. Methods: We leveraged 32 years of follow-up data from the Atherosclerosis Risk in Communities study (ARIC), a prospective, community-based cohort that enrolled participants aged 45-64 years from four US communities (Washington County, MD; Forsyth County, NC; Jackson, MS; and selected suburbs of Minneapolis, MI) at ARIC visit 1 (1987-1989). Participants were followed through 2018-2019. We used Cox proportional hazards models to estimate hazard ratios, then quantified PAFs, of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (ARIC visit 1), 55-64 (ARIC visits 1 and 4), 65-74 (ARIC visits 4 and 5), and 75-84 (ARIC visit 5). Results: Hypertension was assessed among 7,572 participants aged 45-54; 12,033 aged 55-64; and 6,561 aged 65-74. By age 80 the number identified as having incident dementia was 711, 910, and 372, respectively. Relative to normotension, hypertension in each age category was associated with hazard ratios (HRs) greater than 1.0 for dementia from hypertension by age 80. The PAF for dementia by age 80 from hypertension measured at age 45-54 was 15.3% (95% CI = 6.9, 22.3%), 19.1% (95% CI = 9.9, 26.9%) at ages 55-64, and 19.9% (95% CI = -4.4, 38.5%) at ages 65-74. By age 90, the number of incident dementia cases were 958; 2,302; and 1,327, respectively; and, among the 2,086 participants aged 75-84, 400 incident dementia cases. HRs were slightly smaller than those by age 80, while hypertension assessed in the 75-84 age group was not significant. The PAFs for dementia by age 90 from hypertension at age 45-54 was 13.8% (95% CI = 6.6, 20.0%), 12.9% (95% CI = 7.0, 18.2%) at ages 55-64, 10.9% (95% CI = 0.02, 21.0%) at ages 65-74, and non-significant at ages 75-84. Conclusions: Public health interventions targeting hypertension in midlife through early late-life might reduce a sizeable proportion of dementia cases.

Abstract Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

AbstractFocal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD.We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization.FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques.Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.