Sport-related concussion (SRC) is a highly prevalent injury predominantly affecting millions of youth through high school athletes every year. In recent years, SRC has received a significant amount of attention due to potential for long-term neurologic sequelae. However, the acute symptoms and possibility of prolonged recovery account for the vast majority of morbidity from SRC. Modifying factors have been identified and may allow for improved prediction of a protracted course. Potential novel modifying factors may include genetic determinants of recovery, as well as radiographic biomarkers, which represent burgeoning subfields in SRC research. Helmet design and understanding the biomechanical stressors on the brain that lead to concussion also represent active areas of research. This narrative review provides a general synopsis of SRC, including relevant definitions, current treatment paradigms, and modifying factors for recovery, in addition to novel areas of research and future directions for SRC research.
BACKGROUND
Although many clinical risk factors of spastic cerebral palsy (CP) have been identified, the genetic basis of spastic CP is largely unknown. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU) with replication in the UK Biobank and FinnGen, we perform the first genome-wide association study (GWAS) for spastic CP.
OBJECTIVE
To define the genetic basis of spastic CP.
METHODS
Whole-genome data were obtained using the multi-ethnic genotyping array (MEGA) genotyping array capturing single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) > 0.01, and imputation quality score (r2) > 0.3, imputed based on the 1000 genomes phase 3 reference panel. Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (P < 5.0 × 10–8). Replication analysis (defined as P < .05) was performed in the UK Biobank and FinnGen.
RESULTS
We identify 1 SNP (rs78686911) reaching genome-wide significance with spastic CP. Expression quantitative trait loci (eQTL) analysis suggests that rs78686911 decreases expression of GRIK4, a gene that encodes a high-affinity kainate glutamatergic receptor of largely unknown function. Replication analysis in the UK Biobank and FinnGen reveals additional SNPs in the GRIK4 loci associated with CP.
CONCLUSION
To our knowledge, we perform the first GWAS of spastic CP. Our study indicates that genetic variation contributes to CP risk.
Objective: To identify risk factors and generate hypotheses for pediatric persistent postconcussion symptoms (PPCS). Setting: A regional healthcare system in the Southeastern United States. Participants: An electronic health recordbased algorithm was developed and validated to identify PPCS cases and controls from an institutional database of more than 2.8 million patients. PPCS cases (n = 274) were patients aged 5 to 18 years with PPCS-related diagnostic codes or with PPCS key words identified by natural language processing of clinical notes. Age, sex, and year of index event-matched controls (n = 1096) were patients with mild traumatic brain injury codes only. Patients with moderate or severe traumatic brain injury were excluded. All patients used our healthcare system at least 3 times 180 days before their injury. Design: Case-control study. Main Measures: The outcome was algorithmic classification of PPCS. Exposures were all preinjury medical diagnoses assigned at least 180 days before the injury. Results: Cases and controls both had a mean of more than 9 years of healthcare system use preinjury. Of 221 preinjury medical diagnoses, headache disorder was associated with PPCS after accounting for multiple testing (odds ratio [OR] = 2.9; 95% confidence interval [CI]: 1.6-5.0; P = 2.1e-4). Six diagnoses were associated with PPCS at a suggestive threshold for statistical significance (false discovery rate P < .10): gastritis/duodenitis (OR = 2.8; 95% CI: 1.6-5.1; P = 5.0e-4), sleep disorders (OR = 2.3; 95% CI: 1.4-3.7; P = 7.4e-4), abdominal pain (OR = 1.6; 95% CI: 1.2-2.2; P = 9.2e-4), chronic sinusitis (OR = 2.8; 95% CI: 1.5-5.2; P = 1.3e-3), congenital anomalies of the skin (OR = 2.9; 95% CI: 1.5-5.5; P = 1.9e-3), and chronic pharyngitis/nasopharyngitis (OR = 2.4; 95% CI: 1.4-4.3; P = 2.5e-3). Conclusions: These results support the strong association of preinjury headache disorders with PPCS. An
Objective: To identify risk factors and generate hypotheses for pediatric post-concussion syndrome (PCS) using a phenome-wide association study (PheWAS).
Methods: A PheWAS (case-control) was conducted following the development and validation of a novel electronic health record-based algorithm that identified PCS cases and controls from an institutional database of >2.8 million patients. Cases were patients ages 5-18 with PCS codes or keywords identified by natural language processing of clinical notes. Controls were patients with mild traumatic brain injury (mTBI) codes only. Patients with moderate or severe brain injury were excluded. All patients used our healthcare system at least three times 180 days before their injury. Exposures included all pre-injury medical diagnoses assigned at least 180 days prior.
Results: The algorithm identified 274 pediatric PCS cases (156 females) and 1,096 controls that were age and sex matched to cases. Cases and controls both had a mean of >8 years of healthcare system use pre-injury. Of 202 pre-injury medical, four were associated with PCS after controlling for multiple testing: headache disorders (OR=5.3; 95%CI 2.8-10.1;P=3.8e-7), sleep disorders (OR=3.1; 95%CI 1.8-5.2; P=2.6e-5), gastritis/duodenitis (OR=3.6, 95%CI 1.8-7.0;P=2.1e-4), and chronic pharyngitis (OR=3.3; 95%CI 1.8-6.3;P=2.2e-4).
Conclusions: These results confirm the strong association of pre-injury headache disorders with PCS and provides evidence for the association of pre-injury sleep disorders with PCS. An association of PCS with prior chronic gastritis/duodenitis and pharyngitis was seen that suggests a role for chronic inflammation in PCS pathophysiology and risk. These factors should be considered during the management of pediatric mTBI cases.
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