Do Measures of Real-World Physical Behavior Provide Insights Into the Well-Being and Physical Function of Cancer Survivors? Cross-Sectional Analysis.

BACKGROUND: As the number of cancer survivors increases, maintaining health-related quality of life in cancer survivorship is a priority. This necessitates accurate and reliable methods to assess how cancer survivors are feeling and functioning. Real-world digital measures derived from wearable sensors offer potential for monitoring well-being and physical function in cancer survivorship, but questions surrounding the clinical utility of these measures remain to be answered. OBJECTIVE: In this secondary analysis, we used 2 existing data sets to examine how measures of real-world physical behavior, captured with a wearable accelerometer, were related to aerobic fitness and self-reported well-being and physical function in a sample of individuals who had completed cancer treatment. METHODS: Overall, 86 disease-free cancer survivors aged 21-85 years completed self-report assessments of well-being and physical function, as well as a submaximal exercise test that was used to estimate their aerobic fitness, quantified as predicted submaximal oxygen uptake (VO2). A thigh-worn accelerometer was used to monitor participants' real-world physical behavior for 7 days. Accelerometry data were used to calculate average values of the following measures of physical behavior: sedentary time, step counts, time in light and moderate to vigorous physical activity, time and weighted median cadence in stepping bouts over 1 minute, and peak 30-second cadence. RESULTS: Spearman correlation analyses indicated that 6 (86%) of the 7 accelerometry-derived measures of real-world physical behavior were not significantly correlated with Functional Assessment of Cancer Therapy-General total well-being or linked Patient-Reported Outcomes Measurement Information System-Physical Function scores (Ps≥.08). In contrast, all but one of the physical behavior measures were significantly correlated with submaximal VO2 (Ps≤.03). Comparing these associations using likelihood ratio tests, we found that step counts, time in stepping bouts over 1 minute, and time in moderate to vigorous activity were more strongly associated with submaximal VO2 than with self-reported well-being or physical function (Ps≤.03). In contrast, cadence in stepping bouts over 1 minute and peak 30-second cadence were not more associated with submaximal VO2 than with the self-reported measures (Ps≥.08). CONCLUSIONS: In a sample of disease-free cancer survivors, we found that several measures of real-world physical behavior were more associated with aerobic fitness than with self-reported well-being and physical function. These results highlight the possibility that in individuals who have completed cancer treatment, measures of real-world physical behavior may provide additional information compared with self-reported and performance measures. To advance the appropriate use of digital measures in oncology clinical research, further research evaluating the clinical utility of real-world physical behavior over time in large, representative samples of cancer survivors is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT03781154; https://clinicaltrials.gov/ct2/show/NCT03781154.

Patient-centricity in digital measure development: co-evolution of best practice and regulatory guidance.

Digital health technologies (DHTs) have the potential to modernize drug development and clinical trial operations by remotely, passively, and continuously collecting ecologically valid evidence that is meaningful to patients' lived experiences. Such evidence holds potential for all drug development stakeholders, including regulatory agencies, as it will help create a stronger evidentiary link between approval of new therapeutics and the ultimate aim of improving patient lives. However, only a very small number of novel digital measures have matured from exploratory usage into regulatory qualification or efficacy endpoints. This shows that despite the clear potential, actually gaining regulatory agreement that a new measure is both fit-for-purpose and delivers value remains a serious challenge. One of the key stumbling blocks for developers has been the requirement to demonstrate that a digital measure is meaningful to patients. This viewpoint aims to examine the co-evolution of regulatory guidance in the United States (U.S.) and best practice for integration of DHTs into the development of clinical outcome assessments. Contextualizing guidance on meaningfulness within the larger shift towards a patient-centric drug development approach, this paper reviews the U.S. Food and Drug Administration (FDA) guidance and existing literature surrounding the development of meaningful digital measures and patient engagement, including the recent examples of rejections by the FDA that further emphasize patient-centricity in digital measures. Finally, this paper highlights remaining hurdles and provides insights into the established frameworks for development and adoption of digital measures in clinical research.

Measuring What Is Meaningful in Cancer Cachexia Clinical Trials: A Path Forward With Digital Measures of Real-World Physical Behavior.

PURPOSE: The burden of cancer cachexia on patients' health-related quality of life, specifically their physical functioning, is well documented, but clinical trials thus far have failed to show meaningful improvement in physical functioning. The purpose of this review is to summarize existing methods of assessing physical function in cancer cachexia, outline a path forward for measuring what is meaningful to patients using digital measures derived from digital health technologies (DHTs), and discuss the current landscape of digital measures from the clinical and regulatory standpoint. DESIGN: For this narrative review, peer-reviewed articles were searched on PubMed, clinical trials records were searched on clinicaltrials.gov, and records of digital measures submitted for regulatory qualification were searched on the US Food and Drug Administration's Drug Development Tool Qualification Program database. RESULTS: There are gaps in assessing aspects of physical function that matter to patients. Existing assessment methods such as patient-reported outcomes and objective performance outcomes have limitations, including their episodic nature and burden to patients. DHTs such as wearable sensors can capture real-world physical behavior continuously, passively, and remotely, and may provide a more comprehensive picture of patients' everyday functioning. Recent regulatory submissions showcase potential clinical implementation of digital measures in various therapeutic areas. CONCLUSION: Digital measures of real-world physical behavior present an opportunity to detect and demonstrate improvements in physical functioning in cancer cachexia, but evidence-based development is critical. For their use in clinical and regulatory decision making, studies demonstrating meaningfulness to patients as well as feasibility and validation are necessary.

Capturing Measures That Matter: The Potential Value of Digital Measures of Physical Behavior for Alzheimer's Disease Drug Development.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD's impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research.

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance.

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra-ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults in a randomized clinical trial.

As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.

Multimodal neuroimaging data from a 5-week heart rate variability biofeedback randomized clinical trial.

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy (1H MRS). During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO2) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests and ten questionnaires related to emotional well-being. A subset (N = 104) provided plasma samples pre- and post-intervention that were assayed for amyloid and tau. Data is publicly available via the OpenNeuro data sharing platform.

Isometric handgrip exercise speeds working memory responses in younger and older adults.

Physiological arousal affects attention and memory, sometimes enhancing and other times impairing what we attend to and remember. In the present study, we investigated how changes in physiological arousal-induced through short bursts of isometric handgrip exercise-affected subsequent working memory performance. A sample of 57 younger (ages 18-29) and 56 older (ages 65-85) participants performed blocks of isometric handgrip exercise in which they periodically squeezed a therapy ball, alternating with blocks of an auditory working memory task. We found that, compared with those in a control group, participants who performed isometric handgrip had faster reaction times on the working memory task. Handgrip-speeded responses were observed for both younger and older participants, across working memory loads. Analysis of multimodal physiological responses indicated that physiological arousal increased during handgrip. Our findings suggest that performing short bouts of isometric handgrip exercise can improve processing speed, and they offer testable possibilities for the mechanism underlying handgrip's effects on performance. The potential for acute isometric exercise to temporarily improve processing speed may be of particular relevance for older adults who show declines in processing speed and working memory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of a Randomised Trial of 5-Week Heart Rate Variability Biofeedback Intervention on Cognitive Function: Possible Benefits for Inhibitory Control.

Previous research suggests that higher heart rate variability (HRV) is associated with better cognitive function. However, since most previous findings on the relationship between HRV and cognitive function were correlational in nature, it is unclear whether individual differences in HRV play a causal role in cognitive performance. To investigate whether there are causal relationships, we used a simple breathing manipulation that increases HRV through a 5-week HRV biofeedback intervention and examined whether this manipulation improves cognitive performance in younger and older adults (N = 165). The 5-week HRV biofeedback intervention did not significantly improve inhibitory control, working memory and processing speed across age groups. However, improvement in the Flanker score (a measure of inhibition) was associated with the amplitude of heart rate oscillations during practice sessions in the younger and older intervention groups. Our results suggest that daily practice to increase heart rate oscillations may improve inhibitory control, but future studies using longer intervention periods are warranted to replicate the present finding.

Increasing coordination and responsivity of emotion-related brain regions with a heart rate variability biofeedback randomized trial.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also enhance brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression, or mood. These findings indicate that modulating heart rate oscillatory activity changes emotion network coordination in the brain.

Behavioral and fMRI evidence that arousal enhances bottom-up selectivity in young but not older adults.

The locus coeruleus-noradrenergic system integrates signals about arousal states throughout the brain and helps coordinate cognitive selectivity. However, age-related changes in this system may impact how arousal coordinates selectivity in older adults. To examine this, we compared how increases in emotional arousal modulates cognitive selectivity for images differing in perceptual salience in young and older adults. Using functional magnetic resonance imaging, we found that relative to older adults, hearing an arousing sound enhanced young adults' bottom-up processing and incidental memory for high versus low salience category-selective body images. We also examined how arousing sounds impacted a top-down goal to detect dot-probes that appeared immediately after high or low salience images. We found that young adults were slower to detect probes appearing after high salience body images on arousing trials, whereas older adults showed this pattern on non-arousing trials. Taken together, our findings show that arousal's effect on selectivity changes with age and differs across bottom-up and top-down processing.

Associations between locus coeruleus MRI contrast and physiological responses to acute stress in younger and older adults.

Acute stress activates the brain's locus coeruleus (LC)-noradrenaline system. Recent studies indicate that a magnetic resonance imaging (MRI)-based measure of LC structure is associated with better cognitive outcomes in later life. Yet despite the LC's documented role in promoting physiological arousal during acute stress, no studies have examined whether MRI-assessed LC structure is related to arousal responses to acute stress. In this study, 102 younger and 51 older adults completed an acute stress induction task while we assessed multiple measures of physiological arousal (heart rate, breathing rate, systolic and diastolic blood pressure, sympathetic tone, and heart rate variability, HRV). We used turbo spin echo MRI scans to quantify LC MRI contrast as a measure of LC structure. We applied univariate and multivariate approaches to assess how LC MRI contrast was associated with arousal at rest and during acute stress reactivity and recovery. In older participants, having higher caudal LC MRI contrast was associated with greater stress-related increases in systolic blood pressure and decreases in HRV, as well as lower HRV during recovery from acute stress. These results suggest that having higher caudal LC MRI contrast in older adulthood is associated with more pronounced physiological responses to acute stress. Further work is needed to confirm these patterns in larger samples of older adults.

Heart rate variability (HRV) changes and cortical volume changes in a randomized trial of five weeks of daily HRV biofeedback in younger and older adults.

Previous studies indicate that the structure and function of medial prefrontal cortex (PFC) and lateral orbitofrontal cortex (OFC) are associated with heart rate variability (HRV). Typically, this association is assumed to reflect the PFC's role in controlling HRV and emotion regulation, with better prefrontal structural integrity supporting greater HRV and better emotion regulation. However, as a control system, the PFC must monitor and respond to heart rate oscillatory activity. Thus, engaging in regulatory feedback during heart rate oscillatory activity may over time help shape PFC structure, as relevant circuits and connections are modified. In the current study with younger and older adults, we tested whether 5 weeks of daily sessions of biofeedback to increase heart rate oscillations (Osc+ condition) vs. to decrease heart rate oscillations (Osc- condition) affected cortical volume in left OFC and right OFC, two regions particularly associated with HRV in prior studies. The left OFC showed significant differences in volume change across conditions, with Osc+ increasing volume relative to Osc-. The volume changes in left OFC were significantly correlated with changes in mood disturbance. In addition, resting low frequency HRV increased more in the Osc+ than in the Osc- condition. These findings indicate that daily biofeedback sessions regulating heart rate oscillatory activity can shape both resting HRV and the brain circuits that help control HRV and regulate emotion.

Emotion Downregulation Targets Interoceptive Brain Regions While Emotion Upregulation Targets Other Affective Brain Regions.

Researchers generally agree that when upregulating and downregulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating brain areas. However, the "affective dial hypothesis" that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We tested this hypothesis by examining the overlap between the regions activated during upregulation and those deactivated during downregulation in 54 male and 51 female humans. We found that upregulation and downregulation both recruit regulatory regions, such as the inferior frontal gyrus and dorsal anterior cingulate gyrus, but act on distinct affect-generating regions. Upregulation increased activity in regions associated with emotional experience, such as the amygdala, anterior insula, striatum, and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity, such as periventricular white matter, while downregulation decreased activity in regions receiving interoceptive input, such as the posterior insula and postcentral gyrus. Nevertheless, participants' subjective sense of emotional intensity was associated with activity in overlapping brain regions (dorsal anterior cingulate, insula, thalamus, and frontal pole) across upregulation and downregulation. These findings indicate that upregulation and downregulation rely on overlapping brain regions to control and assess emotions but target different affect-generating brain regions.SIGNIFICANCE STATEMENT Many contexts require modulating one's own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: both emotion upregulation and downregulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation might differ more than previously appreciated for upregulation versus downregulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention.

Survival of the salient: Aversive learning rescues otherwise forgettable memories via neural reactivation and post-encoding hippocampal connectivity.

The effects of aversive events on memory are complex and go beyond the simple enhancement of threatening information. Negative experiences can also rescue related but otherwise forgettable details encoded close in time. Here, we used functional magnetic resonance imaging (fMRI) in healthy young adults to examine the brain mechanisms that support this retrograde memory effect. In a two-phase incidental encoding paradigm, participants viewed different pictures of tools and animals before and during Pavlovian fear conditioning. During Phase 1, these images were intermixed with neutral scenes, which provided a unique 'context tag' for this specific phase of encoding. A few minutes later, during Phase 2, new pictures from one category were paired with a mild shock (threat-conditioned stimulus; CS+), while pictures from the other category were not shocked. FMRI analyses revealed that, across-participants, individuals who showed aversive learning-related retroactive memory benefits for Phase 1 CS+ items were also more likely to exhibit three brain effects: first, greater spontaneous reinstatement of the Phase 1 context when participants viewed conceptually-related CS+ items in Phase 2; second, greater successful encoding-related VTA/SN and LC activation for Phase 2 CS+ items; and third, learning-dependent increases in post-encoding hippocampal functional coupling with CS+ category-selective cortex. These biases in hippocampal-cortical connectivity also mediated the relationship between VTA/SN aversive encoding effects and across-participant variability in the retroactive memory benefit. Collectively, our findings suggest that both online and offline brain mechanisms may enable threatening events to preserve memories that acquire new significance in the future.

Locus coeruleus MRI contrast is associated with cortical thickness in older adults.

There is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in 229 older and 67 younger adults. Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The FreeSurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.

Combining independent decisions increases diagnostic accuracy of reading lumbosacral radiographs and magnetic resonance imaging.

Diagnosing the causes of low back pain is a challenging task, prone to errors. A novel approach to increase diagnostic accuracy in medical decision making is collective intelligence, which refers to the ability of groups to outperform individual decision makers in solving problems. We investigated whether combining the independent ratings of chiropractors, chiropractic radiologists and medical radiologists can improve diagnostic accuracy when interpreting diagnostic images of the lumbosacral spine. Evaluations were obtained from two previously published studies: study 1 consisted of 13 raters independently rating 300 lumbosacral radiographs; study 2 consisted of 14 raters independently rating 100 lumbosacral magnetic resonance images. In both studies, raters evaluated the presence of "abnormalities", which are indicators of a serious health risk and warrant immediate further examination. We combined independent decisions of raters using a majority rule which takes as final diagnosis the decision of the majority of the group. We compared the performance of the majority rule to the performance of single raters. Our results show that with increasing group size (i.e., increasing the number of independent decisions) both sensitivity and specificity increased in both data-sets, with groups consistently outperforming single raters. These results were found for radiographs and MR image reading alike. Our findings suggest that combining independent ratings can improve the accuracy of lumbosacral diagnostic image reading.

Observed child restraint misuse in a large, urban community: Results from three years of inspection events.

PROBLEM: Child restraints (CRs) are vital for optimizing child passenger safety and reducing the risk of pediatric injury and fatality in motor vehicle crashes. However, most CRs are installed improperly. METHODS: This present study was an assessment of observed instances of CR misuse. Participants were recruited through advertisements for CR inspection events in Los Angeles County, California. Child Passenger Safety Technicians collected information about each child passenger, vehicle, and aspects of CR selection and installation. RESULTS: Of 693 CRs installed upon arrival, only 3.8% were used with no instances of misuse. The most common misuses were inappropriate use of the top tether and failure to secure the seatbelt in locked mode. CONCLUSIONS: The majority of observed CRs were installed with instances of misuse. CRs in newer vehicles were less likely to be installed in front of airbags and more likely to have the seatbelt routed inappropriately compared to those in older vehicles. Older children were more likely to be prematurely restrained in the front vehicle seat. PRACTICAL APPLICATIONS: The majority of CRs are installed improperly. We identified specific instances of CR misuse that are common in a large, urban community and present recommendations to improve child passenger safety practices and education.

Assessment of parental knowledge and attitudes toward pediatric sports-related concussions.

BACKGROUND: Parents of young athletes play a major role in the identification and management of sports-related concussions. However, they are often unaware of the consequences of concussions and recommended management techniques. HYPOTHESIS: This study quantitatively assessed parental understanding of concussions to identify specific populations in need of additional education. We predicted that parents with increased education and prior sports- and concussion-related experience would have more knowledge and safer attitudes toward concussions. STUDY DESIGN: Cross-sectional survey. LEVEL OF EVIDENCE: Level 5. METHODS: Participants were parents of children brought to a pediatric hospital and 4 satellite clinics for evaluation of orthopaedic injuries. Participants completed a validated questionnaire that assessed knowledge of concussion symptoms, attitudes regarding diagnosis and return-to-play guidelines, and previous sports- and concussion-related experience. RESULTS: Over 8 months, 214 parents completed surveys. Participants scored an average of 18.4 (possible, 0-25) on the Concussion Knowledge Index and 63.1 (possible, 15-75) on the Concussion Attitude Index. Attitudes were safest among white women, and knowledge increased with income and education levels. Previous sports experience did not affect knowledge or attitudes, but parents who reported experiencing an undiagnosed concussion had significantly better concussion knowledge than those who did not. CONCLUSION: Parents with low income and education levels may benefit from additional concussion-related education. CLINICAL RELEVANCE: There exist many opportunities for improvement in parental knowledge and attitudes about pediatric sports-related concussions. Ongoing efforts to understand parental knowledge of concussions will inform the development of a strategic and tailored approach to the prevention and management of pediatric concussions.