Clinical Utility and Analysis of the Run-Roll-Aim Task: Informing Return-to-Duty Readiness Decisions in Active-Duty Service Members

Introduction The Assessment of Military Multitasking Performance (AMMP1) consists of six dual-task and multitask military-relevant performance-based assessments which were developed to provide assistance in making return-to-duty decisions after concussion or mild traumatic brain injury (mTBI.) The Run-Roll-Aim (RRA) task, one component of the AMMP, was developed to target vulnerabilities following mTBI including attention, visual function, dynamic stability, rapid transition, and vestibular function. One aim of this study was to assess the known-group and construct validity of the RRA, and additionally to further explore reliability limitations reported previously. Materials and Methods A cross-sectional study consisting of 84 Active Duty service members in two groups (healthy control – HC and individuals experiencing persistent mTBI symptoms) completed neurocognitive tests and the RRA. The RRA task requires a high level of mobility and resembles military training activities in a maneuver that includes combat rolls, fast transitions, obstacle avoidance, and visual search. Observational and inertial sensor data were compared between groups and performance across four trial times was compared within groups. Correlations between RRA results and neurocognitive test scores were analyzed. Results Simple observational measures (time, errors) did not differ between groups. Spectral power analysis of the inertial sensor data showed significant differences in motor performance between groups. Within group one-way ANOVAs showed that in HC trial 1, time was significantly different than trials 2,3 and 4 (F(3,47) = 4.60, p < 0.01, Tukey HSD p < 0.05) while the mTBI group showed no significant difference in time between trials. During testing individuals with mTBI were less likely to complete the multiple test trials or required additional rest between trials than HCs (χ2 = 10.78, p < 0.01). Small but significant correlations were seen with two neurocognitive tests of attention and RRA performance time. Conclusion While observational scores were not sensitive to group differences, inertial sensor data showed motor performance on the forward run, combat roll, and backward run differed significantly between groups. The RRA task appeared challenging and provoked symptoms in the mTBI group, causing 8 of 33 mTBI participants to stop the task or require additional rest between trials while none of the HC participants had to stop. Individuals with mTBI demonstrated slower learning of the complex motor sequence compared to HCs who had significant improvement after one trial of RRA. Complex novel training maneuvers like RRA may aid clinicians in informing return to duty decisions

Military-Civilian Collaborations for mTBI Rehabilitation Research in an Active Duty Population: Lessons Learned From the Assessment of Military Multitasking Performance Project

This article describes lessons learned in the planning, development, and administration of a collaborative military-civilian research project, the Assessment of Military Multitasking Performance, which was designed to address a gap in clinical assessment for active duty service members with mild traumatic brain injury who wish to return to active duty. Our team worked over the course of multiple years to develop an assessment for military therapists to address this need. Insights gained through trial and error are shared to provide guidance for civilian researchers who may wish to collaborate with active duty researchers

Relative Burden of Cancer and Noncancer Mortality Among Long-Term Survivors of Breast, Prostate, and Colorectal Cancer in the US

IMPORTANCE: Improvements in cancer outcomes have led to a need to better understand long-term oncologic and nononcologic outcomes and quantify cancer-specific vs noncancer-specific mortality risks among long-term survivors. OBJECTIVE: To assess absolute and relative cancer-specific vs noncancer-specific mortality rates among long-term survivors of cancer, as well as associated risk factors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 627 702 patients in the Surveillance, Epidemiology, and End Results cancer registry with breast, prostate, or colorectal cancer who received a diagnosis between January 1, 2003, and December 31, 2014, who received definitive treatment for localized disease and who were alive 5 years after their initial diagnosis (ie, long-term survivors of cancer). Statistical analysis was conducted from November 2022 to January 2023. MAIN OUTCOMES AND MEASURES: Survival time ratios (TRs) were calculated using accelerated failure time models, and the primary outcome of interest examined was death from index cancer vs alternative (nonindex cancer) mortality across breast, prostate, colon, and rectal cancer cohorts. Secondary outcomes included subgroup mortality in cancer-specific risk groups, categorized based on prognostic factors, and proportion of deaths due to cancer-specific vs noncancer-specific causes. Independent variables included age, sex, race and ethnicity, income, residence, stage, grade, estrogen receptor status, progesterone receptor status, prostate-specific antigen level, and Gleason score. Follow-up ended in 2019. RESULTS: The study included 627 702 patients (mean [SD] age, 61.1 [12.3] years; 434 848 women [69.3%]): 364 230 with breast cancer, 118 839 with prostate cancer, and 144 633 with colorectal cancer who survived 5 years or more from an initial diagnosis of early-stage cancer. Factors associated with shorter median cancer-specific survival included stage III disease for breast cancer (TR, 0.54; 95% CI, 0.53-0.55) and colorectal cancer (colon: TR, 0.60; 95% CI, 0.58-0.62; rectal: TR, 0.71; 95% CI, 0.69-0.74), as well as a Gleason score of 8 or higher for prostate cancer (TR, 0.61; 95% CI, 0.58-0.63). For all cancer cohorts, patients at low risk had at least a 3-fold higher noncancer-specific mortality compared with cancer-specific mortality at 10 years of diagnosis. Patients at high risk had a higher cumulative incidence of cancer-specific mortality than noncancer-specific mortality in all cancer cohorts except prostate. CONCLUSIONS AND RELEVANCE: This study is the first to date to examine competing oncologic and nononcologic risks focusing on long-term adult survivors of cancer. Knowledge of the relative risks facing long-term survivors may help provide pragmatic guidance to patients and clinicians regarding the importance of ongoing primary and oncologic-focused care

Transcriptional Landscape of the Prenatal Human Brain

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Data from: Further development of the Assessment of Military Multitasking Performance: iterative reliability testing

The Assessment of Military Multitasking Performance (AMMP) is a battery of functional dual-tasks and multitasks based on military activities that target known sensorimotor, cognitive, and exertional vulnerabilities after concussion/mild traumatic brain injury (mTBI). The AMMP was developed to help address known limitations in post concussive return to duty assessment and decision making. Once validated, the AMMP is intended for use in combination with other metrics to inform duty-readiness decisions in Active Duty Service Members following concussion. This study used an iterative process of repeated interrater reliability testing and feasibility feedback to drive modifications to the 9 tasks of the original AMMP which resulted in a final version of 6 tasks with metrics that demonstrated clinically acceptable ICCs of > 0.92 (range of 0.92–1.0) for the 3 dual tasks and > 0.87 (range 0.87–1.0) for the metrics of the 3 multitasks. Three metrics involved in recording subject errors across 2 tasks did not achieve ICCs above 0.85 set apriori for multitasks (0.64) and above 0.90 set for dual-tasks (0.77 and 0.86) and were not used for further analysis. This iterative process involved 3 phases of testing with between 13 and 26 subjects, ages 18–42 years, tested in each phase from a combined cohort of healthy controls and Service Members with mTBI. Study findings support continued validation of this assessment tool to provide rehabilitation clinicians further return to duty assessment methods robust to ceiling effects with strong face validity to injured Warriors and their leaders

Further Development of the Assessment of Military Multitasking Performance: Iterative Reliability Testing.

The Assessment of Military Multitasking Performance (AMMP) is a battery of functional dual-tasks and multitasks based on military activities that target known sensorimotor, cognitive, and exertional vulnerabilities after concussion/mild traumatic brain injury (mTBI). The AMMP was developed to help address known limitations in post concussive return to duty assessment and decision making. Once validated, the AMMP is intended for use in combination with other metrics to inform duty-readiness decisions in Active Duty Service Members following concussion. This study used an iterative process of repeated interrater reliability testing and feasibility feedback to drive modifications to the 9 tasks of the original AMMP which resulted in a final version of 6 tasks with metrics that demonstrated clinically acceptable ICCs of > 0.92 (range of 0.92-1.0) for the 3 dual tasks and > 0.87 (range 0.87-1.0) for the metrics of the 3 multitasks. Three metrics involved in recording subject errors across 2 tasks did not achieve ICCs above 0.85 set apriori for multitasks (0.64) and above 0.90 set for dual-tasks (0.77 and 0.86) and were not used for further analysis. This iterative process involved 3 phases of testing with between 13 and 26 subjects, ages 18-42 years, tested in each phase from a combined cohort of healthy controls and Service Members with mTBI. Study findings support continued validation of this assessment tool to provide rehabilitation clinicians further return to duty assessment methods robust to ceiling effects with strong face validity to injured Warriors and their leaders