Methodology and Implementation of a Randomized Controlled Trial (RCT) for Early Post-concussion Rehabilitation: The Active Rehab Study

Background: Sports-related concussion (SRC) is a complex injury with heterogeneous presentation and management. There are few studies that provide guidance on the most effective and feasible strategies for recovery and return to sports participation. Furthermore, there have been no randomized studies of the feasibility, safety, and efficacy of early rehabilitation strategies across multiple sports and age groups. This international cluster-randomized pragmatic trial evaluates the effectiveness of early multi-dimensional rehabilitation integrated with the current return to sport strategy vs. the current return to sport strategy alone. Methods: The study is a cluster-randomized pragmatic trial enrolling male and female athletes from 28 sites. The sites span three countries, and include multiple sports, levels of play (high school, college, and professional), and levels of contact. The two study arms are Enhanced Graded Exertion (EGE) and Multidimensional Rehabilitation (MDR). The EGE arm follows the current return to sport strategy and the MDR arm integrates early, MDR strategies in the context of the current return to sport strategy. Each arm employs a post-injury protocol that applies to all athletes from that site in the event they sustain a concussion during their study enrollment. Participants are enrolled at pre-season baseline. Assessment timepoints include pre-season baseline, time of injury (concussion), 24–48 h post-injury, asymptomatic, and 1-month post-injury. Symptoms and activity levels are tracked post injury through the return to play process and beyond. Injury and recovery characteristics are obtained for all participants. Primary endpoints include time to medical clearance for full return to sport and time to become asymptomatic. Secondary endpoints include symptom, neurocognitive, mental status, balance, convergence insufficiency, psychological distress, and quality of life trajectories post-injury. Discussion: Outputs from the trial are expected to inform both research and clinical practice in post-concussion rehabilitation across all levels of sport and extend beyond civilian medicine to care for military personnel. Ethics and Dissemination: The study is approved by the data coordinating center Institutional Review Board and registered at clinicaltrials.gov. Dissemination will include peer-reviewed publications, presentation to patients and public groups, as well as dissemination in other healthcare and public venues of interest. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02988596 Trial Funding: National Football League

TRY plant trait database – enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Genetics of disease, diagnosis and treatmen

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource