Alterations of cerebrovascular reactivity following pediatric mild traumatic brain injury are independent of neurodevelopmental changes.

Cerebrovascular dysfunction following mild traumatic brain injury (mTBI) is understudied relative to other microstructural injuries, especially during neurodevelopment. The blood-oxygen level dependent response was used to investigate cerebrovascular reactivity (CVR) in response to hypercapnia following pediatric mTBI (pmTBI; ages 8-18 years), as well as pseudocontinuous arterial spin labeling to measure cerebral blood flow (CBF). Data were collected ∼1-week (N = 107) and 4 months (N = 73) post-injury. Sex- and age-matched healthy controls (HC) underwent identical examinations at comparable time points (N = 110 and N = 91). Subtle clinical and cognitive deficits existed at ∼1 week that resolved for some, but not all domains at 4 months post-injury. At both visits, pmTBI showed an increased maximal fit between end-tidal CO2 regressor and the cerebrovascular response across multiple regions (primarily fronto-temporal), as well as increased latency to maximal fit in independent regions (primarily posterior). Hypoperfusion was also noted within the bilateral cerebellum. A biphasic relationship existed between CVR amplitude and age (i.e., positive until 14.5 years, negative thereafter) in both gray and white matter, but these neurodevelopment effects did not moderate injury effects. CVR metrics were not associated with post-concussive symptoms or cognitive deficits. In conclusion, cerebrovascular dysfunction may persist for up to four months following pmTBI.

PECARN prediction rule for cervical spine imaging of children presenting to the emergency department with blunt trauma: a multicentre prospective observational study.

BACKGROUND: Cervical spine injuries in children are uncommon but potentially devastating; however, indiscriminate neck imaging after trauma unnecessarily exposes children to ionising radiation. The aim of this study was to derive and validate a paediatric clinical prediction rule that can be incorporated into an algorithm to guide radiographic screening for cervical spine injury among children in the emergency department. METHODS: In this prospective observational cohort study, we screened children aged 0-17 years presenting with known or suspected blunt trauma at 18 specialised children's emergency departments in hospitals in the USA affiliated with the Pediatric Emergency Care Applied Research Network (PECARN). Injured children were eligible for enrolment into derivation or validation cohorts by fulfilling one of the following criteria: transported from the scene of injury to the emergency department by emergency medical services; evaluated by a trauma team; and undergone neck imaging for concern for cervical spine injury either at or before arriving at the PECARN-affiliated emergency department. Children presenting with solely penetrating trauma were excluded. Before viewing an enrolled child's neck imaging results, the attending emergency department clinician completed a clinical examination and prospectively documented cervical spine injury risk factors in an electronic questionnaire. Cervical spine injuries were determined by imaging reports and telephone follow-up with guardians within 21-28 days of the emergency room encounter, and cervical spine injury was confirmed by a paediatric neurosurgeon. Factors associated with a high risk of cervical spine injury (>10%) were identified by bivariable Poisson regression with robust error estimates, and factors associated with non-negligible risk were identified by classification and regression tree (CART) analysis. Variables were combined in the cervical spine injury prediction rule. The primary outcome of interest was cervical spine injury within 28 days of initial trauma warranting inpatient observation or surgical intervention. Rule performance measures were calculated for both derivation and validation cohorts. A clinical care algorithm for determining which risk factors warrant radiographic screening for cervical spine injury after blunt trauma was applied to the study population to estimate the potential effect on reducing CT and x-ray use in the paediatric emergency department. This study is registered with ClinicalTrials.gov, NCT05049330. FINDINGS: Nine emergency departments participated in the derivation cohort, and nine participated in the validation cohort. In total, 22 430 children presenting with known or suspected blunt trauma were enrolled (11 857 children in the derivation cohort; 10 573 in the validation cohort). 433 (1·9%) of the total population had confirmed cervical spine injuries. The following factors were associated with a high risk of cervical spine injury: altered mental status (Glasgow Coma Scale [GCS] score of 3-8 or unresponsive on the Alert, Verbal, Pain, Unresponsive scale [AVPU] of consciousness); abnormal airway, breathing, or circulation findings; and focal neurological deficits including paresthesia, numbness, or weakness. Of 928 in the derivation cohort presenting with at least one of these risk factors, 118 (12·7%) had cervical spine injury (risk ratio 8·9 [95% CI 7·1-11·2]). The following factors were associated with non-negligible risk of cervical spine injury by CART analysis: neck pain; altered mental status (GCS score of 9-14; verbal or pain on the AVPU; or other signs of altered mental status); substantial head injury; substantial torso injury; and midline neck tenderness. The high-risk and CART-derived factors combined and applied to the validation cohort performed with 94·3% (95% CI 90·7-97·9) sensitivity, 60·4% (59·4-61·3) specificity, and 99·9% (99·8-100·0) negative predictive value. Had the algorithm been applied to all participants to guide the use of imaging, we estimated the number of children having CT might have decreased from 3856 (17·2%) to 1549 (6·9%) of 22 430 children without increasing the number of children getting plain x-rays. INTERPRETATION: Incorporated into a clinical algorithm, the cervical spine injury prediction rule showed strong potential for aiding clinicians in determining which children arriving in the emergency department after blunt trauma should undergo radiographic neck imaging for potential cervical spine injury. Implementation of the clinical algorithm could decrease use of unnecessary radiographic testing in the emergency department and eliminate high-risk radiation exposure. Future work should validate the prediction rule and care algorithm in more general settings such as community emergency departments. FUNDING: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Health Resources and Services Administration of the US Department of Health and Human Services in the Maternal and Child Health Bureau under the Emergency Medical Services for Children programme.

Sex- and Age-Related Differences in Post-Concussive Symptom Reporting Among Children and Their Parents.

Pediatric mild traumatic brain injury (pmTBI) has received increased public attention over the past decade, especially for children who experience persistent post-concussive symptoms (PCS). Common methods for obtaining pediatric PCS rely on both self- and parental report, exhibit moderate test-retest reliability, and variable child-parent agreement, and may yield high false positives. The current study investigated the impact of age and biological sex on PCS reporting (Post-Concussion Symptom Inventory) in patients with pmTBI (n = 286) at retrospective, 1 week, 4 months, and 1 year post-injury time points, as well as reported symptoms in healthy controls (HC; n = 218) at equivalent assessment times. HC and their parents reported higher PCS for their retrospective rating relative to the other three other study visits. Child-parent agreement was highest for female adolescents, but only approached acceptable ranges (≥ 0.75) immediately post-injury. Poor-to-fair child/parental agreement was observed for most other study visits for pmTBI and at all visits for HC. Parents rated female adolescents as being more symptomatic than their male counterparts in spite of small (pmTBI) or no (HC) sex-related differences in self-reported ratings, suggestive of a potential cultural bias in parental ratings. Test-retest reliability for self-report was typically below acceptable ranges for both pmTBI and HC groups, with reliability decreasing for HC and increasing for pmTBI as a function of time between visits. Parental test-retest reliability was higher for females. Although continued research is needed, current results support the use of child self-report over parental ratings for estimating PCS burden. Results also highlight the perils of relying on symptom self-report for diagnostic and prognostic purposes.

Dynamic Functional Connectivity in Pediatric Mild Traumatic Brain Injury.

Resting-state fMRI can be used to identify recurrent oscillatory patterns of functional connectivity within the human brain, also known as dynamic brain states. Alterations in dynamic brain states are highly likely to occur following pediatric mild traumatic brain injury (pmTBI) due to the active developmental changes. The current study used resting-state fMRI to investigate dynamic brain states in 200 patients with pmTBI (ages 8-18 years, median = 14 years) at the subacute (∼1-week post-injury) and early chronic (∼ 4 months post-injury) stages, and in 179 age- and sex-matched healthy controls (HC). A k-means clustering analysis was applied to the dominant time-varying phase coherence patterns to obtain dynamic brain states. In addition, correlations between brain signals were computed as measures of static functional connectivity. Dynamic connectivity analyses showed that patients with pmTBI spend less time in a frontotemporal default mode/limbic brain state, with no evidence of change as a function of recovery post-injury. Consistent with models showing traumatic strain convergence in deep grey matter and midline regions, static interhemispheric connectivity was affected between the left and right precuneus and thalamus, and between the right supplementary motor area and contralateral cerebellum. Changes in static or dynamic connectivity were not related to symptom burden or injury severity measures, such as loss of consciousness and post-traumatic amnesia. In aggregate, our study shows that brain dynamics are altered up to 4 months after pmTBI, in brain areas that are known to be vulnerable to TBI. Future longitudinal studies are warranted to examine the significance of our findings in terms of long-term neurodevelopment.

Multifaceted neural and vascular pathologies after pediatric mild traumatic brain injury.

Dynamic changes in neurodevelopment and cognitive functioning occur during adolescence, including a switch from reactive to more proactive forms of cognitive control, including response inhibition. Pediatric mild traumatic brain injury (pmTBI) affects these cognitions immediately post-injury, but the role of vascular versus neural injury in cognitive dysfunction remains debated. This study consecutively recruited 214 sub-acute pmTBI (8-18 years) and age/sex-matched healthy controls (HC; N = 186), with high retention rates (>80%) at four months post-injury. Multimodal imaging (functional MRI during response inhibition, cerebral blood flow and cerebrovascular reactivity) assessed for pathologies within the neurovascular unit. Patients exhibited increased errors of commission and hypoactivation of motor circuitry during processing of probes. Evidence of increased/delayed cerebrovascular reactivity within motor circuitry during hypercapnia was present along with normal perfusion. Neither age-at-injury nor post-concussive symptom load were strongly associated with imaging abnormalities. Collectively, mild cognitive impairments and clinical symptoms may continue up to four months post-injury. Prolonged dysfunction within the neurovascular unit was observed during proactive response inhibition, with preliminary evidence that neural and pure vascular trauma are statistically independent. These findings suggest pmTBI is characterized by multifaceted pathologies during the sub-acute injury stage that persist several months post-injury.

Neural correlates of cognitive control deficits in pediatric mild traumatic brain injury.

There is a growing body of research showing that cerebral pathophysiological processes triggered by pediatric mild traumatic brain injury (pmTBI) may extend beyond the usual clinical recovery timeline. It is paramount to further unravel these processes, because the possible long-term cognitive effects resulting from ongoing secondary injury in the developing brain are not known. In the current fMRI study, neural processes related to cognitive control were studied in 181 patients with pmTBI at sub-acute (SA; ~1 week) and early chronic (EC; ~4 months) stages post-injury. Additionally, a group of 162 age- and sex-matched healthy controls (HC) were recruited at equivalent time points. Proactive (post-cue) and reactive (post-probe) cognitive control were examined using a multimodal attention fMRI paradigm for either congruent or incongruent stimuli. To study brain network function, the triple-network model was used, consisting of the executive and salience networks (collectively known as the cognitive control network), and the default mode network. Additionally, whole-brain voxel-wise analyses were performed. Decreased deactivation was found within the default mode network at the EC stage following pmTBI during both proactive and reactive control. Voxel-wise analyses revealed sub-acute hypoactivation of a frontal area of the cognitive control network (left pre-supplementary motor area) during proactive control, with a reversed effect at the EC stage after pmTBI. Similar effects were observed in areas outside of the triple-network during reactive control. Group differences in activation during proactive control were limited to the visual domain, whereas for reactive control findings were more pronounced during the attendance of auditory stimuli. No significant correlations were present between task-related activations and (persistent) post-concussive symptoms. In aggregate, current results show alterations in neural functioning during cognitive control in pmTBI up to 4 months post-injury, regardless of clinical recovery. We propose that subacute decreases in activity reflect a general state of hypo-excitability due to the injury, while early chronic hyperactivation represents a compensatory mechanism to prevent default mode interference and to retain cognitive control.

Applying holistic review practices to a Combined Baccalaureate/Medical Degree Program: Reflections on lessons learned.

PROBLEM: Despite the implementation of holistic review in the medical school application process, there is little information about how this can be utilized in Combined Baccalaureate/Medical Degree pipeline programs, especially since many programs offer reserved spots to their students in the medical school. Implementing holistic review in a Combined Baccalaureate/Medical Degree program and intentionally structuring it to align with the medical school mission and admissions practices and processes, can improve the diversification of the physician workforce, contribute to more primary care doctors, and promote in-state practice. INTERVENTION: Utilizing the medical school admissions by-laws, committee structure, shared training, and educational processes, we successfully engrained in our committee members the values and mission alignment to select the best applicants to fulfill the medical school mission using holistic review. To our knowledge, no other program has written about how holistic review is used in Combined Baccalaureate/Medical Degree programs and how it contributes to program outcomes. CONTEXT: The Combined Baccalaureate/Medical Degree Program is a partnership between the undergraduate College of Arts and Sciences and the School of Medicine. The Combined Baccalaureate/Medical Degree admissions committee is a subcommittee of the School of Medicine admissions committee but has a separate membership. Hence, the holistic admissions process for the program mirrors the School of Medicine admissions process. To determine the outcome of this process, we analyzed practice specialty, practice location, gender, race and ethnicity of program alumni. IMPACT: To date, the Combined Baccalaureate/Medical Degree holistic admissions processes have supported the medical school mission, "…To meet the physician workforce needs of the state by selection of students who are likely to train in specialty areas of need and to remain in or return to the areas of our state needing physicians." This implementation has resulted in 75% (37/49) of our practicing alumni selecting a primary care specialty, and 69% (34/49) practicing in the state. In addition, 55% (27/49) identify as Underrepresented in Medicine. LESSONS LEARNED: We observed that having an intentional structured alignment in place allowed for implementation of holistic practices in the Combined Baccalaureate/Medical Degree admissions process. The high retention rates and specialty of graduates from the Combined Baccalaureate/Medical Degree Program support our intentional efforts to diversify our admissions committees and align the Combined Baccalaureate/Medical Degree program's holistic review admissions process with our School of Medicine mission and admissions practices and processes, as key strategies to reach our diversity-related goals.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic time course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months postinjury, which would be inversely associated with age at injury. METHODS: Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). RESULTS: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d = -0.49) and hippocampal volumes (d = -0.24) observed for pmTBI, but not associated with age at injury. Hippocampal volume recovery was mediated by loss of consciousness/posttraumatic amnesia. Significantly greater postconcussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). DISCUSSION: Current findings indicate that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury.

The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicates that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion MRI data in consecutively recruited patients (n = 203; 8-18 years old) and age and sex-matched healthy controls (n = 170) in a prospective cohort design. Patients were evaluated subacutely (1-11 days post-injury) as well as at 4 months post-injury (early chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at 4 months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to 4 months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when ∼70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients versus controls) by ∼10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also indicate that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury and even criteria for diagnoses. Finally, current results indicate ongoing clinical and physiological recovery at 4 months post-injury.

A Cross-Sectional Geographic Information Systems Study of a Pediatric Emergency Department Child Restraint System Distribution Program.

INTRODUCTION: A pediatric ED program sought to promote injury prevention through distribution of child restraint systems. Program funds are paid for child passenger safety technician certification of all personnel. Pediatric emergency nurses distributed child restraint systems at hospital discharge and dedicated technicians at fitting stations. Researchers described program characteristics, developed a baseline understanding of program outreach using geographic information systems, and evaluated adherence to manufacturer guidelines with a sensitivity analysis. METHODS: This retrospective cross-sectional study used distribution forms linked to hospital records from 2013 to 2016. Testing for differences used nonparametric methods. Median values and interquartile ranges for weight and height of children were compared with manufacturer guidelines. Geographic information systems visualized recipients' street addresses and motor vehicle crashes on an underlying base map. RESULTS: There were 312 child restraint systems distributed: of which 179 (57.4%) at the hospital, 126 (40.4%) at fitting stations, and 7 (2.2%) missing a location. Among those on Medicaid, 64.4% received a child restraint system at the hospital compared with 35.6% at fitting stations (χ2 = 5.40, P < .02). Fitting stations had limited outreach to rural residents. Finally, results from the sensitivity analysis showed that devices were issued according to manufacturer guidelines. DISCUSSION: Despite the workplace pressures of clinical care, pediatric emergency nurses delivered educational information and demonstrated hands-on installation at similar rates to dedicated technicians. Distribution of child restraint systems through the hospital reached a uniquely underserved population. Further research should investigate methods to improve fitting station outreach among Medicaid recipients.