Can a serious game-based cognitive training attenuate cognitive decline related to Alzheimer's disease? Protocol for a randomized controlled trial.

BACKGROUND Alzheimer's disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood. METHODS In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60-85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants' group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits. DISCUSSION The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings. TRIAL REGISTRATION This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864)

In silico trial of simulation-free hippocampal-avoidance whole brain adaptive radiotherapy

BACKGROUND AND PURPOSE: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) can be a time-consuming process compared to conventional whole brain techniques, thus potentially limiting widespread utilization. Therefore, we evaluated the MATERIALS AND METHODS: Ten patients previously treated for central nervous system cancers with cone-beam computed tomography (CBCT) imaging were included in this study. The CBCT was the adaptive image-of-the-day to simulate first fraction on-board imaging. Initial contours defined on the MRI were rigidly matched to the CBCT. Online ART was used to create treatment plans at first fraction. Dose-volume metrics of these simulation-free plans were compared to standard-workflow HA-WBRT plans on each patient CT simulation dataset. Timing data for the adaptive planning sessions were recorded. RESULTS: For all ten patients, simulation-free HA-WBRT plans were successfully created utilizing the online ART workflow and met all constraints. The median hippocampi D CONCLUSIONS: Simulation-free HA-WBRT, with commercially available systems, was clinically feasible via plan-quality metrics and timing

Intracranial stereotactic radiation therapy with a jawless ring gantry linear accelerator equipped with new dual layer multileaf collimator

Purpose: To test the feasibility of a simplified, robust, workflow for intracranial stereotactic radiation therapy (SRT) using a ring gantry linear accelerator (RGLA) equipped with a dual-layer stacked, staggered, and interdigitating multileaf collimator. Materials and Methods: Twenty recent clinical SRT cases treated using a radiosurgery c-arm linear accelerator were anonymized. From these data sets, a new planning workflow was developed and used to replan these cases, which then were compared to their clinical counterparts. Population-based dose-volume histograms were analyzed for target coverage and sparing of healthy brain. All plans underwent plan review and quality assurance and were delivered on an end-to-end verification phantom using image guidance to simulate treatment. Results: The RGLA plans were able to meet departmental standards for target coverage and organ-at-risk sparing and showed plan quality similar to the clinical plans. RGLA plans showed increases in the 50% isodose in the axial plane but decreases in the sagittal and coronal planes. There were no statistically significant differences in the homogeneity index or number of monitor units between the 2 systems. There were statistically significant increases in conformity and gradient indices, with median values of 1.09 versus 1.11 and 2.82 versus 3.13, respectively, for the c-arm versus RGLA plans. These differences were not believed to be clinically significant because they met clinical goals. The population-based dose-volume histograms showed target coverage and organ-at-risk sparing similar to that of the clinical plans. All plans were able to meet the departmental quality assurance requirements and were delivered under image guidance on an end-to-end phantom with measurements agreeing within 3% of the expected value. RGLA plans showed a median reduction in delivery time of ≈50%. Conclusions: This work describes a simplified and efficient workflow that could reduce treatment times and expand access to SRT to centers using an RGLA

Prospective in silico evaluation of cone-beam computed tomography-guided stereotactic adaptive radiation therapy (CT-STAR) for the ablative treatment of ultracentral thoracic disease

PURPOSE: We conducted a prospective, in silico study to evaluate the feasibility of cone-beam computed tomography (CBCT)-guided stereotactic adaptive radiation therapy (CT-STAR) for the treatment of ultracentral thoracic cancers (NCT04008537). We hypothesized that CT-STAR would reduce dose to organs at risk (OARs) compared with nonadaptive stereotactic body radiation therapy (SBRT) while maintaining adequate tumor coverage. METHODS AND MATERIALS: Patients who were already receiving radiation therapy for ultracentral thoracic malignancies underwent 5 additional daily CBCTs on the ETHOS system as part of a prospective imaging study. These were used to simulate CT-STAR, in silico RESULTS: Seven patients were accrued, 6 with intraparenchymal tumors and 1 with a subcarinal lymph node. CT-STAR was feasible in 34 of 35 simulated fractions. In total, 32 dose constraint violations occurred when the P CONCLUSIONS: CT-STAR widened the dosimetric therapeutic index of ultracentral thorax SBRT compared with nonadaptive SBRT. A phase 1 protocol is underway to evaluate the safety of this paradigm for patients with ultracentral early-stage NSCLC

Both helix topology and counterion distribution contribute to the more effective charge screening in dsRNA compared with dsDNA

The recent discovery of the RNA interference mechanism emphasizes the biological importance of short, isolated, double-stranded (ds) RNA helices and calls for a complete understanding of the biophysical properties of dsRNA. However, most previous studies of the electrostatics of nucleic acid duplexes have focused on DNA. Here, we present a comparative investigation of electrostatic effects in RNA and DNA. Using resonant (anomalous) and non-resonant small-angle X-ray scattering, we characterized the charge screening efficiency and counterion distribution around short (25 bp) dsDNA and RNA molecules of comparable sequence. Consistent with theoretical predictions, we find counterion mediated screening to be more efficient for dsRNA than dsDNA. Furthermore, the topology of the RNA A-form helix alters the spatial distribution of counterions relative to B-form DNA. The experimental results reported here agree well with ion-size-corrected non-linear Poisson–Boltzmann calculations. We propose that differences in electrostatic properties aid in selective recognition of different types of short nucleic acid helices by target binding partners

Genetically engineered zebrafish as models of skeletal development and regeneration.

Zebrafish (Danio rerio) are aquatic vertebrates with significant homology to their terrestrial counterparts. While zebrafish have a centuries-long track record in developmental and regenerative biology, their utility has grown exponentially with the onset of modern genetics. This is exemplified in studies focused on skeletal development and repair. Herein, the numerous contributions of zebrafish to our understanding of the basic science of cartilage, bone, tendon/ligament, and other skeletal tissues are described, with a particular focus on applications to development and regeneration. We summarize the genetic strengths that have made the zebrafish a powerful model to understand skeletal biology. We also highlight the large body of existing tools and techniques available to understand skeletal development and repair in the zebrafish and introduce emerging methods that will aid in novel discoveries in skeletal biology. Finally, we review the unique contributions of zebrafish to our understanding of regeneration and highlight diverse routes of repair in different contexts of injury. We conclude that zebrafish will continue to fill a niche of increasing breadth and depth in the study of basic cellular mechanisms of skeletal biology

AQuA: An

Abstract ⎯ Dependable distributed systems are difficult to build. This is particularly true if they have dependability requirements that change during the execution of an application, and are built with commercial off-the-shelf hardware. In that case, fault tolerance must be achieved using middleware software, and mechanisms must be provided to communicate the dependability requirements of a distributed application to the system and to adapt the system’s configuration to try to achieve the desired dependability. The AQuA architecture allows distributed applications to request a desired level of availability using the Quality Objects (QuO) framework and includes a dependability manager that attempts to meet requested availability levels by configuring the system in response to outside requests and changes in system resources due to faults. The AQuA architecture uses the QuO runtime to process and invoke availability requests, the Proteus dependability manager to configure the system in response to faults and availability requests, and the Ensemble protocol stack to provide group communication services. Furthermore, a CORBA interface is provided to application objects using the AQuA gateway. The gateway provides a mechanism to translate between process-level communication, as supported by Ensemble, and IIOP messages, understood by Object Request Brokers. Both active and passive replication are supported, and the replication type to use is chosen based on the performance and dependability requirements of particular distributed applications. 1