Age-Dependent Differences in Blood Levels of Glial Fibrillary Acidic Protein but Not Ubiquitin Carboxy-Terminal Hydrolase L1 in Children.

OBJECTIVES: Despite the growing evidence of the clinical utility of blood-brain biomarkers in adults with traumatic brain injury (TBI), less is known about the performance of these biomarkers in children. We characterize age-dependent differences in levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in children without TBI. METHODS: Plasma biobank specimens from children and adolescents aged 0-<19 years without TBI were obtained, and UCH-L1 and GFAP levels were quantified. The relationship between age and biomarker expression was determined using previously defined aged epochs (<3.5 years, 3.5 years to <11 years, 11 years and older), then biomarker levels were compared with established thresholds for ruling out the need for a head CT in adults with a mild TBI (mTBI) (UCH-L1 400 pg/mL, GFAP 35 pg/mL). RESULTS: The age range of the 366 control patients was 3 months-18 years. There was a significant negative association between age and GFAP but not UCH-L1. Only 1.4% of samples exceeded the UCH-L1 cutoff; however, 20% of samples exceeded the GFAP cutoff and 100% children younger than 3.5 years had values that exceeded the cutoff. DISCUSSION: Age seems to modify physiologic plasma GFAP levels. Diagnostic cutoffs for TBI based on GFAP but not UCH-L1 and may need to be adjusted in children younger than 11 years.

Adolescents With a High Burden of New-Onset Mood Symptoms After Sport-Related Concussion Benefit From Prescribed Aerobic Exercise, a Secondary Analysis of 2 Randomized Controlled Trials.

OBJECTIVE: Approximately 20% of students with sport-related concussion (SRC) report new symptoms of anxiety and depression which may be associated with delayed recovery and increased risk for developing a mood disorder. Early prescribed aerobic exercise facilitates recovery in athletes with concussion-related exercise intolerance. We studied the effect of aerobic exercise treatment on new mood symptoms early after SRC. DESIGN: Exploratory secondary analysis of 2 randomized controlled trials (RCT). SETTING: Sports medicine clinics associated with UB (Buffalo, NY), CHOP (Philadelphia, PA), and Boston Children's Hospital (Boston, MA). PARTICIPANTS: Male and female adolescents (aged 13-18 years) diagnosed with SRC (2-10 days since injury). INTERVENTIONS: Participants were randomized to individualized targeted heart rate aerobic exercise (n = 102) or to a placebo intervention designed to mimic relative rest (n = 96). MAIN OUTCOME MEASURES: Incidence of Persisting Post-Concussive Symptoms (PPCS, symptoms ≥28 days). RESULTS: First RCT recruited from 2016 to 2018 and the second from 2018 to 2020. Of 198 adolescents, 156 (79%) reported a low burden (mean 1.2 ± 1.65/24) while 42 (21%) reported a high burden (mean 9.74 ± 3.70/24) of emotional symptoms before randomization. Intervention hazard ratio for developing PPCS for low burden was 0.767 (95% CI, 0.546-1.079; P = 0.128; ß = 0.085) and for high burden was 0.290 (95% CI, 0.123-0.683; P = 0.005; ß = 0.732). CONCLUSIONS: High burden of mood symptoms early after injury increases risk for PPCS, but the sports medicine model of providing early targeted aerobic exercise treatment reduces it. Nonsports medicine clinicians who treat patients with a high burden of new mood symptoms after concussion should consider prescribing aerobic exercise treatment to reduce the risk of PPCS and a mood disorder.

Research Letter: Concussion-Related General Startle Suppression in Adolescent Athletes.

OBJECTIVES: We investigated the acoustic startle reflex in recently concussed adolescent athletes compared to healthy controls and those with concussion history (>1 year prior) but no current symptoms. We hypothesized that individuals with recent concussion would have a suppressed startle response compared to healthy controls. METHODS: We conducted a cross-sectional study on 49 adolescent athletes with a recent concussion (n = 20; age: 14.6 ± 1.6 years; 60% female), a concussion history > 1 year prior (n = 16; age: 14.8 ± 2.0 years; 44% female), and healthy controls (n = 13; age: 13.3 ± 2.8 years; 54% female). We measured the eyeblink of the general startle reflex via electromyography activity of the orbicularis oculi muscle using electrodes placed under the right eye. Measurement sessions included twelve 103 decibel acoustic startle probes ~50 milliseconds in duration delivered ~15-25 seconds apart. The primary dependent variable was mean startle magnitude (µV), and group was the primary independent variable. We used a one-way analysis of variance followed by a Tukey post hoc test to compare mean startle magnitude between groups. RESULTS: Mean startle magnitude significantly differed (F = 5.49, P = .007) among the groups. Mean startle magnitude was significantly suppressed for the concussion (P = .01) and concussion history groups (P = .02) compared to healthy controls. There was no significant difference between the recent concussion and concussion history groups (P = 1.00). CONCLUSION: Our results provide novel evidence for startle suppression in adolescent athletes following concussion. The concussion history group had an attenuated startle response beyond resolution of their recovery, suggesting there may be lingering physiological dysfunction.

Emergency Department Evaluation of Young Infants With Head Injury.

OBJECTIVES: We compared the emergency department (ED) evaluation and outcomes of young head-injured infants to older children. METHODS: Using the Pediatric Health Information Systems database, we performed a retrospective, cross-sectional analysis of children <2 years old with isolated head injuries (International Classification of Diseases, 10th Revision, diagnoses) at one of 47 EDs from 2015 to 2019. Our primary outcome was utilization of diagnostic cranial imaging. Secondary outcomes were diagnosis of traumatic brain injury (TBI), clinically important TBI, and mortality. We compared outcomes between the youngest infants (<3 months old) and children 3 to 24 months old. RESULTS: We identified 112 885 ED visits for children <2 years old with isolated head injuries. A total of 62 129 (55%) were by males, and 10 325 (9.1%) were by infants <3 months of age. Compared with older children (12-23 months old), the youngest infants were more likely to: Undergo any diagnostic cranial imaging (50.3% vs 18.3%; difference 31.9%, 95% confidence interval [CI] 35.0-28.9%), be diagnosed with a TBI (17.5% vs 2.7%; difference 14.8%, 95% CI 16.4%-13.2%) or clinically important TBI (4.6% vs 0.5%; difference 4.1%, 95% CI 3.8%-4.5%), and to die (0.3% vs 0.1%; difference 0.2%, 95% CI 0.3%-0.1%). Among those undergoing computed tomography or MRI, TBIs were significantly more common in the youngest infants (26.4% vs 8.8%, difference 17.6%, 95% CI 16.3%-19.0%). CONCLUSIONS: The youngest infants with head injuries are significantly more likely to undergo cranial imaging, be diagnosed with brain injuries, and die, highlighting the need for a specialized approach for this vulnerable population.

Longitudinal Characterization of Pain Interference and Influential Factors in Former National Football League (NFL) Players Over a 19-Year Period: An NFL-LONG Study.

Previous studies on pain experiences in retired contract sport athletes have been cross-sectional, leaving gaps in our understanding of the evolution of pain interference (PI) and factors that influence trajectories decades after sport discontinuation. This study investigated the longitudinal course of PI in former male National Football League (NFL) players over a 19-year period following sport discontinuation and examined factors influencing overall levels and trajectories of PI. Former NFL players completed health surveys in 2001, 2010, and 2019, with PI ratings measured using the 36-Item Short Form Health Survey (2001 and 2010) and the Patient-Reported Outcomes Measurement Information System (2019). Unconditional latent growth curve models analyzed overall PI severity and trajectories. Conditional latent growth curve models explored the influence of musculoskeletal injuries, osteoarthritis (OA), and depression diagnosis on PI. Over 19 years (N = 338; mean age = 48.96 ± 9.35), PI significantly increased (slope = .179, P < .001; mean Patient-Reported Outcomes Measurement Information System PI t-scores 2001 = 54.19, 2010 = 54.64, 2019 = 57.38). Cumulative musculoskeletal injuries (B = .092, P < .001) and baseline depression diagnosis (B = 4.463, P < .001) were associated with overall PI levels but not change over time. OA was significantly associated with overall PI levels (B = 6.536, P < .001) and trajectory (B = -.253, P < .001); those endorsing OA in 2001 had lower PI increases over 19 years. The body region of injury and level of play during injuries mirrored overall injury effects. PI mildly increased over 19 years, with multiple factors independently influencing overall PI levels. Enhancing former contact sport athletes' daily functionality may be achieved through holistic biopsychosocial interventions addressing musculoskeletal injuries, OA, and depression. Future research should identify factors influencing elevated trajectories of long-term PI post-sport discontinuation. PERSPECTIVE: This study assessed PI in former NFL athletes over 2 decades, revealing notable interindividual variability in trajectories over time. Musculoskeletal injuries, depression, and OA correlated with overall PI. Prevention and intervention in these 3 areas present the potential to improve disruptions in daily living due to pain in former athletes.

A Pilot Study Investigating the Use of Serum Glial Fibrillary Acidic Protein to Monitor Changes in Brain White Matter Integrity After Repetitive Head Hits During a Single Collegiate Football Game.

Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurological outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after nonconcussive RHHs during a single sporting contest, raising the possibility that they could be used in real time to monitor the brain's early response to repeated asymptomatic head hits. To test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 min (T2) after a single collegiate football game in 30 athletes. Glial fibrillary acidic protein (GFAP) changes were correlated with three measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 h before (T1) to 48 h after (T3) the game. To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5 ± 1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs. 91.95 pg/mL, p = 0.008) and from T0 to T2 (mean 79.69 vs. 99.21 pg/mL, p < 0.001). WM integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% confidence interval [CI]: -2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus and with increased MD in the right fornix (r-values ranged from 0.59 to 0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69 to 0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurological response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Owing to the small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.

Time-Dependent Long-Term Effect of Memantine following Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (rmTBI, e.g., sports concussions) may be associated with both acute and chronic symptoms and neurological changes. Despite the common occurrence of these injuries, therapeutic strategies are limited. One potentially promising approach is N-methyl-D-aspartate receptor (NMDAR) blockade to alleviate the effects of post-injury glutamatergic excitotoxicity. Initial pre-clinical work using the NMDAR antagonist, memantine, suggests that immediate treatment following rmTBI improves a variety of acute outcomes. It remains unclear (1) whether acute memantine treatment has long-term benefits and (2) whether delayed treatment following rmTBI is beneficial, which are both clinically relevant concerns. To test this, animals were subjected to rmTBI via a weight drop model with rotational acceleration (five hits in 5 days) and randomized to memantine treatment immediately, 3 months, or 6 months post-injury, with a treatment duration of one month. Behavioral outcomes were assessed at 1, 4, and 7 months post-injury. Neuropathological outcomes were characterized at 7 months post-injury. We observed chronic changes in behavior (anxiety-like behavior, motor coordination, spatial learning, and memory), as well as neuroinflammation (microglia, astrocytes) and tau phosphorylation (T231). Memantine treatment, either immediately or 6 months post-injury, appears to confer greater rescue of neuroinflammatory changes (microglia) than vehicle or treatment at the 3-month time point. Although memantine is already being prescribed chronically to address persistent symptoms associated with rmTBI, this study represents the first evidence of which we are aware to suggest a small but durable effect of memantine treatment in mild, concussive injuries. This effect suggests that memantine, although potentially beneficial, is insufficient to treat all aspects of rmTBI alone and should be combined with other therapeutic agents in a multi-therapy approach, with attention given to the timing of treatment.

Effectiveness of biomedical interventions on the chronic stage of traumatic brain injury: a systematic review of randomized controlled trials.

Traumatic brain injury (TBI), in any form and severity, can pose risks for developing chronic symptoms that can profoundly hinder patients' work/academic, social, and personal lives. In the past 3 decades, a multitude of pharmacological, stimulation, and exercise-based interventions have been proposed to ameliorate symptoms, memory impairment, mental fatigue, and/or sleep disturbances. However, most research is preliminary, thus limited influence on clinical practice. This review aims to systematically appraise the evidence derived from randomized controlled trials (RCT) regarding the effectiveness of pharmacological, stimulation, and exercise-based interventions in treating chronic symptoms due to TBI. Our search results indicate that despite the largest volume of literature, pharmacological interventions, especially using neurostimulant medications to treat physical, cognitive, and mental fatigue, as well as daytime sleepiness, have yielded inconsistent results, such that some studies found improvements in fatigue (e.g., Modafinil, Armodafinil) while others failed to yield the improvements after the intervention. Conversely, brain stimulation techniques (e.g., transcranial magnetic stimulation, blue light therapy) and exercise interventions were effective in ameliorating mental health symptoms and cognition. However, given that most RCTs are equipped with small sample sizes, more high-quality, larger-scale RCTs is needed.

Visual Impairment in Pre-Clinical Models of Mild Traumatic Brain Injury.

Impairment in visual function is common after traumatic brain injury (TBI) in the clinical setting, a phenomenon that translates to pre-clinical animal models as well. In Morris et al. (2021), we reported histological changes following weight-drop-induced TBI in a rodent model including retinal ganglion cell (RGC) loss, decreased electroretinogram (ERG) evoked potential, optic nerve diameter reduction, induced inflammation and gliosis, and loss of myelin accompanied by markedly impaired visual acuity. In this review, we will describe several pre-clinical TBI models that result in injuries to the visual system, indicating that visual function may be impaired following brain injury induced by a number of different injury modalities. This underscores the importance of understanding the role of the visual system and the potential detrimental sequelae to this sensory modality post-TBI. Given that most commonly employed behavioral tests such as the Elevated Plus Maze and Morris Water Maze rely on an intact visual system, interpretation of functional deficits in diffuse models may be confounded by off- target effects on the visual system.

Exposure to potentially lethal weapons and drugs among U.S. adolescents with recent depressive symptoms or suicidality in the Adolescent Behaviors and Experiences Survey.

The scope of lethal means exposure (i.e. guns, intravenous drugs, prescription drugs) relative to depressive symptoms and suicidality in adolescents is not well described. Using the Adolescent Behaviors and Experiences Survey (ABES), we found lethal means exposure increased in a dose dependent manner with increasing depressive symptoms, adjusting for age, sex, race, and ethnicity. Adolescent males were more than 6 times more likely to have exposure to guns and intravenous drugs compared to adolescent females.

Pediatric ECG-Based Deep Learning to Predict Left Ventricular Dysfunction and Remodeling.

BACKGROUND: Artificial intelligence-enhanced ECG analysis shows promise to detect ventricular dysfunction and remodeling in adult populations. However, its application to pediatric populations remains underexplored. METHODS: A convolutional neural network was trained on paired ECG-echocardiograms (≤2 days apart) from patients ≤18 years of age without major congenital heart disease to detect human expert-classified greater than mild left ventricular (LV) dysfunction, hypertrophy, and dilation (individually and as a composite outcome). Model performance was evaluated on single ECG-echocardiogram pairs per patient at Boston Children's Hospital and externally at Mount Sinai Hospital using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS: The training cohort comprised 92 377 ECG-echocardiogram pairs (46 261 patients; median age, 8.2 years). Test groups included internal testing (12 631 patients; median age, 8.8 years; 4.6% composite outcomes), emergency department (2830 patients; median age, 7.7 years; 10.0% composite outcomes), and external validation (5088 patients; median age, 4.3 years; 6.1% composite outcomes) cohorts. Model performance was similar on internal test and emergency department cohorts, with model predictions of LV hypertrophy outperforming the pediatric cardiologist expert benchmark. Adding age and sex to the model added no benefit to model performance. When using quantitative outcome cutoffs, model performance was similar between internal testing (composite outcome: AUROC, 0.88, AUPRC, 0.43; LV dysfunction: AUROC, 0.92, AUPRC, 0.23; LV hypertrophy: AUROC, 0.88, AUPRC, 0.28; LV dilation: AUROC, 0.91, AUPRC, 0.47) and external validation (composite outcome: AUROC, 0.86, AUPRC, 0.39; LV dysfunction: AUROC, 0.94, AUPRC, 0.32; LV hypertrophy: AUROC, 0.84, AUPRC, 0.25; LV dilation: AUROC, 0.87, AUPRC, 0.33), with composite outcome negative predictive values of 99.0% and 99.2%, respectively. Saliency mapping highlighted ECG components that influenced model predictions (precordial QRS complexes for all outcomes; T waves for LV dysfunction). High-risk ECG features include lateral T-wave inversion (LV dysfunction), deep S waves in V1 and V2 and tall R waves in V6 (LV hypertrophy), and tall R waves in V4 through V6 (LV dilation). CONCLUSIONS: This externally validated algorithm shows promise to inexpensively screen for LV dysfunction and remodeling in children, which may facilitate improved access to care by democratizing the expertise of pediatric cardiologists.

Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs.

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.

Concussion Symptoms and Neurocognitive Performance of Children and Adolescents on Antidepressants.

INTRODUCTION/PURPOSE: There is a well-established association between preexisting depression/anxiety and greater postconcussion symptom burden, but the potential impact of antidepressant medications has not been fully explored. The primary objective of this study was to compare preinjury/baseline and postinjury concussion symptom scores and neurocognitive performance of athletes on antidepressant medications, both with healthy controls and with those with depression/anxiety not on antidepressants. METHODS: This is a cross-sectional study using data collected from 49,270 junior and high school athletes from computerized neurocognitive assessments (Immediate Post-Concussion Assessment and Cognitive Test [ImPACT]) administered between 2009 and 2018 held by the Massachusetts Concussion Management Coalition. The main outcome measures were symptom scores and neurocognitive performance measures, all of which were assessed both at baseline and postinjury. Statistical analysis included analysis of variance and Tukey pairwise comparisons for continuous variables and Fisher's exact test for categorical variables. Multivariate regression models were used to adjust for potential confounding variables. RESULTS: Both at baseline and postinjury, athletes with depression/anxiety had mean total symptom scores that were more than double that of healthy controls regardless of antidepressant use. Although there were no significant differences in neurocognitive performance at baseline, depression/anxiety was associated with small but significant decreases in postinjury visual memory and visual motor scores. CONCLUSIONS: Both at baseline and after sustaining a concussion, young athletes with depression/anxiety experience significantly greater symptom burden compared with healthy controls regardless of antidepressant use.

The Longitudinal Relationship Between Concussion History, Years of American Football Participation, and Alcohol Use Among Former National Football League Players: an NFL-LONG Study.

OBJECTIVE: Investigate the relationships between concussion history and years of football participation (repetitive head impact proxy) with alcohol use across multiple decades in former professional football players. METHODS: Participants (n = 348; mean age = 49.0 ± 9.4) completed health questionnaires in 2001 and 2019, which included self-reported concussion history and years of participation. Alcohol use frequency and amount per occasion were reported for three timepoints: during professional career, 2001, and 2019. Ordinal logistic regression models were fit to test associations of concussion history and years of participation with alcohol use at each timepoint. RESULTS: There were no significant associations between either concussion history or years of football participation with alcohol use (frequency and amount per occasion) at any timepoint. Effect estimates for concussion history and years of football participation with alcohol use were generally comparable across timepoints. CONCLUSIONS: Later life alcohol use by former American football players is not associated with concussion history or years of exposure to football.

Non-invasive fluid biomarkers in the diagnosis of mild traumatic brain injury (mTBI): a systematic review.

BACKGROUND: Despite approximately 55.9 million annual mild traumatic brain injuries (mTBIs) worldwide, the accurate diagnosis of mTBI continues to challenge clinicians due to symptom ambiguity, reliance on subjective report and presentation variability. Non-invasive fluid biomarkers of mTBI offer a biological measure to diagnose and monitor mTBI without the need for blood draws or neuroimaging. The objective of this study is to systematically review the utility of such biomarkers to diagnose mTBI and predict disease progression. METHODS: A systematic review performed in PubMed, Scopus, Cochrane and Web of Science followed by a manual search of references without a specified timeframe. Search strings were generated and run (27 June 2022) by a research librarian. Studies were included if they: (1) included human mTBI subjects, (2) assessed utility of a non-invasive biomarker and (3) published in English. Exclusion criteria were (1) non-mTBI subjects, (2) mTBI not assessed separately from moderate/severe TBI, (3) required intracranial haemorrhage or (4) solely assesses genetic susceptibility to mTBI. RESULTS: A total of 29 studies from 27 subject populations (1268 mTBI subjects) passed the inclusion and exclusion criteria. Twelve biomarkers were studied. Salivary RNAs, including microRNA, were assessed in 11 studies. Cortisol and melatonin were assessed in four and three studies, respectively. Eight salivary and two urinary biomarkers contained diagnostic or disease monitoring capability. DISCUSSION: This systematic review identified several salivary and urinary biomarkers that demonstrate the potential to be used as a diagnostic, prognostic and monitoring tool for mTBI. Further research should examine miRNA-based models for diagnostic and predictive utility in patients with mTBI. PROSPERO REGISTRATION NUMBER: CRD42022329293.

Patterns and Predictors of Health Care Utilization After Pediatric Concussion: A Retrospective Cohort Study.

OBJECTIVE: To characterize types, duration, and intensity of health care utilization following pediatric concussion and to identify risk factors for increased post-concussion utilization. METHODS: A retrospective cohort study of children 5 to 17 years old diagnosed with acute concussion at a quaternary center pediatric emergency department or network of associated primary care clinics. Index concussion visits were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. We analyzed patterns of health care visits 6 months before and after the index visit using interrupted time-series analyses. The primary outcome was prolonged concussion-related utilization, defined as having ≥1 follow-up visits with a concussion diagnosis more than 28 days after the index visit. We used logistic regressions to identify predictors of prolonged concussion-related utilization. RESULTS: Eight hundred nineteen index visits (median [interquartile range] age, 14 [11-16] years; 395 [48.2%] female) were included. There was a spike in utilization during the first 28 days after the index visit compared to the pre-injury period. Premorbid headache/migraine disorder (adjusted odds ratio (aOR) 2.05, 95% confidence interval [CI] 1.09-3.89) and top quartile pre-injury utilization (aOR 1.90, 95% CI 1.02-3.52) predicted prolonged concussion-related utilization. Premorbid depression/anxiety (aOR 1.55, 95% CI 1.31-1.83) and top quartile pre-injury utilization (aOR 2.29, 95% CI 1.95-2.69) predicted increased utilization intensity. CONCLUSIONS: Health care utilization is increased during the first 28 days after pediatric concussion. Children with premorbid headache/migraine disorders, premorbid depression/anxiety, and high baseline utilization are more likely to have increased post-injury health care utilization. This study will inform patient-centered treatment but may be limited by incomplete capture of post-injury utilization and generalizability.

Addressing State-Based Differences in Suicide Fatalities Among Children and Adolescents-Finding Another Way.

This Viewpoint uses state-based data obtained from the National Center for Health Statistics' Web-Based Injury Statistics Query and Reporting System to discuss the importance of legislatively addressing firearm-related suicide fatalities among children and adolescents in the US.

Abortion Restrictiveness and Infant Mortality: An Ecologic Study, 2014-2018.

INTRODUCTION: The U.S. has the highest infant mortality rate among peer countries. Restrictive abortion laws may contribute to poor infant health outcomes. This ecological study investigated the association between county-level infant mortality and state-level abortion access legislation in the U.S. from 2014 to 2018. METHODS: A multivariable regression analysis with the outcome of county-level infant mortality rates, controlling for the primary exposure of state-level abortion laws, and county-level factors, county-level distance to an abortion facility, and state Medicaid expansion status was performed. Incidence rate ratios and 95% CIs were reported. Analyses were conducted in 2022-2023. RESULTS: There were 113,397 infant deaths among 19,559,660 live births (infant mortality rate=5.79 deaths/1,000 live births; 95% CI=5.75, 5.82). Black infant mortality rate (10.69/1,000) was more than twice the White infant mortality rate (4.87/1,000). In the multivariable model, increased infant mortality rates were seen in states with ≥8 restrictive laws, with the most restrictive (11-12 laws) having a 16% increased infant mortality level (adjusted incidence rate ratios=1.162; 95% CI=1.103, 1.224). Increased infant mortality rates were associated with increased county-level Black race individuals (adjusted incidence rate ratios=1.031; 95% CI=1.026, 1.037), high school education (adjusted incidence rate ratios=1.018; 95% CI=1.008, 1.029), maternal smoking (adjusted incidence rate ratios=1.025; 95% CI=1.018, 1.033), and inadequate prenatal care (adjusted incidence rate ratios=1.045; 95% CI=1.036, 1.055). CONCLUSIONS: State-level abortion law restrictiveness is associated with higher county-level infant mortality rates. The Supreme Court decision on Dobbs versus Jackson and changes in state laws limiting abortion may affect future infant mortality.

Factors Associated with Symptom Resolution after Aerobic Exercise Intervention in Adolescent and Young Adults with Concussion.

BACKGROUND: Aerobic exercise facilitates postconcussion symptom resolution at the group level, but patient-level characteristics may affect the likelihood of treatment efficacy. PURPOSE: This study aimed to investigate demographic and clinical characteristics, which differentiate postconcussion aerobic exercise treatment efficacy from nonefficacy in the intervention arm of a randomized clinical trial. METHODS: Adolescent and young adult participants initiated a standardized aerobic exercise intervention within 14 d of concussion, consisting of self-selected exercise for 100 min·wk -1 at an individualized heart rate (80% of heart rate induced symptom exacerbation during graded exercise testing). Treatment efficacy was defined as symptom resolution within 28-d postconcussion. Treatment efficacy and nonefficacy groups were compared on demographics, clinical characteristics, intervention adherence, and persistent symptom risk using the Predicting Persistent Postconcussive Problems in Pediatrics (5P) clinical risk score. RESULTS: A total of 27 participants (16.1 ± 2.3 yr old; range, 11-21 yr; 52% female) began the intervention, with a mean of 9.5 ± 3.7 d after concussion; half ( n = 13; 48%) demonstrated treatment efficacy (symptom resolution within 28 d postconcussion). Those whose symptoms resolved within 28 d had significantly lower preintervention postconcussion symptom inventory scores (21.2 ± 13.2 vs 41.4 ± 22.2; P < 0.01), greater adherence to the intervention (77% vs 36%; P = 0.05), and longer average exercise duration (median [interquartile range], 49.7 [36.8-68.6] vs 30.4 [20.7-34.7] min; P < 0.01) than those whose symptoms lasted more than 28 d. Groups were similar in age, sex, timing of intervention, and preintervention 5P risk score. CONCLUSIONS: A standardized aerobic exercise intervention initiated within 14 d of concussion demonstrated efficacy for approximately half of participants, according to our definition of treatment efficacy. This multisite aerobic exercise intervention suggests that lower symptom severity, higher intervention adherence, and greater exercise duration are factors that increase the likelihood of symptoms resolving within 28 d of concussion.