Aerobic exercise facilitates postconcussion symptom resolution at the group level, but patient-level characteristics may affect the likelihood of treatment efficacy.
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.
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.
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.
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.
Reaction time (RT) is a critical element of return to participation (RTP), and impairments have been linked to subsequent injury after a concussion. Current RT assessments have limitations in ...clinical feasibility and in the identification of subtle deficits after concussion symptom resolution.
To examine the utility of RT measurements (clinical drop stick, simple stimulus-response, single-task Stroop, and dual-task Stroop) to differentiate between adolescents with concussion and uninjured control individuals at initial assessment and RTP.
Prospective cohort study.
A pediatric sports medicine center associated with a regional tertiary care hospital.
Twenty-seven adolescents with a concussion (mean age = 14.8 ± 2.1 years; 52% female; tested 7.0 ± 3.3 days postconcussion) and 21 uninjured control individuals (mean age = 15.5 ± 1.6 years; 48% female).
Participants completed the Post-Concussion Symptoms Inventory (PCSI) and a battery of RT tests: clinical drop stick, simple stimulus-response, single-task Stroop, and dual-task Stroop.
The concussion group demonstrated slower clinical drop stick (β = 58.8; 95% CI = 29.2, 88.3; P < .001) and dual-task Stroop (β = 464.2; 95% CI = 318.4, 610.0; P < .001) RT measures at the initial assessment than the uninjured control group. At 1-month follow up, the concussion group displayed slower clinical drop stick (238.9 ± 25.9 versus 188.1 ± 21.7 milliseconds; P < .001; d = 2.10), single-task Stroop (1527.8 ± 204.5 versus 1319.8 ± 133.5 milliseconds; P = .001; d = 1.20), and dual-task Stroop (1549.9 ± 264.7 versus 1341.5 ± 114.7 milliseconds; P = .002; d = 1.04) RT than the control group, respectively, while symptom severity was similar between groups (7.4 ± 11.2 versus 5.3 ± 6.5; P = .44; d = 0.24). Classification accuracy and area under the curve (AUC) values were highest for the clinical drop stick (85.1% accuracy, AUC = 0.86, P < .001) and dual-task Stroop (87.2% accuracy, AUC = 0.92, P < .002) RT variables at initial evaluation.
Adolescents recovering from concussion may have initial RT deficits that persist despite symptom recovery. The clinical drop stick and dual-task Stroop RT measures demonstrated high clinical utility given high classification accuracy, sensitivity, and specificity to detect postconcussion RT deficits and may be considered for initial and RTP assessment.
This study aimed to examine how moderate-to-vigorous physical activity (MVPA) during concussion recovery influences self-reported anxiety symptoms at follow-up assessment. We hypothesized that more ...MVPA after concussion would be associated with lower anxiety rating at follow-up.
We performed a prospective study of participants aged 13-18 yr initially assessed within 14 d of diagnosed concussion. Participants rated concussion symptoms using the Post-Concussion Symptom Inventory and were provided a wrist-worn actigraphy device to track activity for 1 wk after assessment. At follow-up assessment, participants rated anxiety symptoms using the four-question Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety subscale. Each question ranged from 1 (never) to 5 (almost always), with an overall score range of 4-20. For univariable analysis, we calculated correlation coefficients between MVPA and PROMIS anxiety subscale scores. We then created a multiple linear regression model with follow-up PROMIS anxiety subscale score as the outcome and MVPA, sex, initial symptom severity, and preconcussion anxiety as predictors.
We enrolled and initially tested 55 participants, and 48 were included in the final analysis (age, 14.6±2.7 yr; 56% female; initial assessment, 7.3± 3.1 d; follow-up assessment, 42.0±29.7 d). We observed an inverse and low correlation between MVPA and follow-up PROMIS anxiety subscale T-scores ( r = -0.30, P = 0.04). Multivariable regression results indicated that MVPA ( β = -5.30; 95% confidence interval (CI), -10.58 to -0.01), initial Post-Concussion Symptom Inventory score ( β = 0.11; 95% CI, 0.03 to 0.19), and preconcussion anxiety ( β = 5.56; 95% CI, 0.12 to 11.0), but not sex ( β = -2.60; 95% CI, -7.14, to 1.94), were associated with follow-up PROMIS anxiety subscale T-scores.
After adjusting for covariates, more MVPA early after concussion predicted lower PROMIS anxiety subscale scores at follow-up. Although initial concussion symptom severity and preconcussion anxiety were also associated with follow-up PROMIS anxiety subscale score, MVPA represents a modifiable factor that may contribute to lower anxiety symptoms.
Combination chemotherapy, either modified FOLFIRINOX (mFFX) or gemcitabine-nabpaclitaxel, are used in the treatment of most patients with advanced pancreatic ductal adenocarcinoma (PDAC), yet robust ...biomarkers of outcome are currently lacking to guide regimen selection. Here, we tested GATA6 immunohistochemistry (IHC) as a putative biomarker in advanced PDAC. GATA6 is a transcription factor in normal pancreas development. Two pathologists, blinded to clinical and molecular data, independently assessed GATA6 IHC in biopsy specimens of 130 patients with advanced PDAC, in 2 distinct phases (without and with computer assistance using the open source software QuPath). Low GATA6 IHC expression was associated with shorter overall survival median OS 6.2 months for patients with GATA6 low tumors vs. 11.5 months for patients with GATA6 high tumors, HR 1.66 (95% CI 1.15-2.40), P = 0.007. Progression appears to be higher in GATA6-low tumors compared to GATA6-high tumors in patients treated with mFFX (P = 0.024) but not in patients treated with gemcitabine regimens. GATA6 IHC expression was significantly associated with molecular subtypes (P = 0.0003). Digital assistance markedly improved interrater concordance (Cohen's kappa scores of 0.32 vs. 0.95). Our results provide strong evidence that GATA6 IHC can be used as a single biomarker in the clinic to predict clinical outcome in advanced PDAC, warranting further investigation in prospective clinical trials. These results provide the basis for an improved classification of PDAC and future biomarker design using digital pathology workflow.
Persistent gait alterations can occur after concussion and may underlie future musculoskeletal injury risk. We compared dual-task gait stability measures among adolescents who did/did not sustain a ...subsequent injury post-concussion, and uninjured controls. Forty-seven athletes completed a dual-task gait evaluation. One year later, they reported sport-related injuries and sport participation volumes. There were three groups: concussion participants who sustained a sport-related injury (n = 8; age =15.4 ± 3.5 years; 63% female), concussion participants who did not sustain a sport-related injury (n = 24; 14.0 ± 2.6 years; 46% female), and controls (n = 15; 14.2 ± 1.9 years; 53% female). Using cross-recurrence quantification, we quantified dual-task gait stability using diagonal line length, trapping time, percent determinism, and laminarity. The three groups reported similar levels of sports participation (11.8 ± 5.8 vs. 8.6 ± 4.4 vs. 10.9 ± 4.3 hours/week;
= 0.37). The concussion/subsequent injury group walked slower (0.76 ± 0.14 vs. 0.65 ± 0.13 m/s;
= 0.008) and demonstrated higher diagonal line length (0.67 ± 0.08 vs. 0.58 ± 0.05;
= 0.02) and trapping time (5.3 ± 1.5 vs. 3.8 ± 0.6;
= 0.006) than uninjured controls. Dual-task diagonal line length (hazard ratio =1.95, 95% CI = 1.05-3.60), trapping time (hazard ratio = 1.66, 95% CI = 1.09-2.52), and walking speed (hazard ratio = 0.01, 95% CI = 0.00-0.51) were associated with subsequent injury. Dual-task gait stability measures can identify altered movement that persists despite clinical concussion recovery and is associated with future injury risk.
Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance ...of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1‐4) receptor expression without affecting the levels of NMDA (GRIN) or GABAA receptors. Ubiquitin over‐expression also negatively impacted hippocampus‐dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3‐CA1 synapses. These changes occurred in a dose‐dependent manner in that mice with the highest levels of ubiquitin over‐expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress‐induced changes observed in neurological disorders.
Changes in ubiquitin pools have been reported in several chronic neurological disorders, and a variety of cell stressors can up‐regulate ubiquitin levels. As ubiquitin is critical for protein degradation, elevated ubiquitin pools may directly contribute to increased protein turnover and the onset of neurological disease. In this study, we find that over‐expression of ubiquitin in neurons is sufficient to reduce GRIA receptor levels, decrease baseline excitability and synaptic plasticity of hippocampal neurons, and impair hippocampal‐dependent learning and memory. Enhanced ubiquitin expression induced by cell stress may therefore play an important role in the progression of neurological disease.
Background:
Existing data suggest that after concussion, athletes experience an increased risk of subsequent injury. Exploring methods that may reduce injury risk after successful postconcussion ...return to play may lead to new treatment approaches.
Purpose:
To examine the efficacy of a neuromuscular training (NMT) intervention on acute sports-related time-loss injury over the subsequent year relative to standard of care.
Study Design:
Randomized clinical trial; Level of evidence, 1.
Methods:
A total of 27 youth athletes were assessed initially postconcussion (median, 7 days postconcussion; interquartile range IQR, 5-10) and after return-to-play clearance (median, 40 days postconcussion; IQR, 15-52). After return-to-play clearance, they were randomly assigned to NMT intervention (n = 11; mean ± SD age, 14.7 ± 1.7 years; 36% female) or standard of care (n = 16; mean ± SD age, 15.3 ± 1.8 years; 44% female). The intervention (duration, 8 weeks; frequency, 2 times per week) included guided strength exercises with landing stabilization focus. Standard of care received no recommendations. For the subsequent year, athletes prospectively completed a monthly log of sports-related injuries and organized sports competitions.
Results:
During the first year after postconcussion return-to-play clearance, sports-related time-loss injuries were more common among standard of care relative to NMT intervention (75% 95% CI, 48%-93% vs 36% 95% CI, 11%-69%). After adjusting for age and sex, the hazard of subsequent injury in the standard-of-care group was 3.56 times (95% CI, 1.11-11.49; P = .0334) that of the NMT intervention group. Sports participation was similar between NMT intervention and standard of care during the year-long monitoring period (hours of organized sports per month; median, 12 IQR, 2.6-32.1 vs 15.6 IQR, 3.5-105.9; P = .55). The age- and sex-adjusted incidence of injuries was 10.2 per 1000 competitive exposures (95% CI, 3.7-28.4) in the standard-of-care group as opposed to 3.4 per 1000 (95% CI, 0.9-13.4) in the NMT intervention group. After adjusting for age and sex, incidence of injuries was higher for standard of care vs NMT intervention (rate ratio, 2.96 95% CI, 0.89-9.85; P = .076).
Conclusion:
Although preliminary, our findings suggest that an NMT intervention initiated after return-to-play clearance may significantly reduce sports-related time-loss injuries over the subsequent year.
Registration:
NCT03917290 (ClinicalTrials.gov identifier).
To identify differential expression of shorter non-coding RNA (ncRNA) genes associated with autism spectrum disorders (ASD).
ncRNA are functional molecules that derive from non-translated DNA ...sequence. The HUGO Gene Nomenclature Committee (HGNC) have approved ncRNA gene classes with alignment to the reference human genome. One subset is microRNA (miRNA), which are highly conserved, short RNA molecules that regulate gene expression by direct post-transcriptional repression of messenger RNA. Several miRNA genes are implicated in the development and regulation of the nervous system. Expression of miRNA genes in ASD cohorts have been examined by multiple research groups. Other shorter classes of ncRNA have been examined less. A comprehensive systematic review examining expression of shorter ncRNA gene classes in ASD is timely to inform the direction of research.
We extracted data from studies examining ncRNA gene expression in ASD compared with non-ASD controls. We included studies on miRNA, piwi-interacting RNA (piRNA), small NF90 (ILF3) associated RNA (snaR), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), transfer RNA (tRNA), vault RNA (vtRNA) and Y RNA. The following electronic databases were searched: Cochrane Library, EMBASE, PubMed, Web of Science, PsycINFO, ERIC, AMED and CINAHL for papers published from January 2000 to May 2022. Studies were screened by two independent investigators with a third resolving discrepancies. Data was extracted from eligible papers.
Forty-eight eligible studies were included in our systematic review with the majority examining miRNA gene expression alone. Sixty-four miRNA genes had differential expression in ASD compared to controls as reported in two or more studies, but often in opposing directions. Four miRNA genes had differential expression in the same direction in the same tissue type in at least 3 separate studies. Increased expression was reported in miR-106b-5p, miR-155-5p and miR-146a-5p in blood, post-mortem brain, and across several tissue types, respectively. Decreased expression was reported in miR-328-3p in bloods samples. Seven studies examined differential expression from other classes of ncRNA, including piRNA, snRNA, snoRNA and Y RNA. No individual ncRNA genes were reported in more than one study. Six studies reported differentially expressed snoRNA genes in ASD. A meta-analysis was not possible because of inconsistent methodologies, disparate tissue types examined, and varying forms of data presented.
There is limited but promising evidence associating the expression of certain miRNA genes and ASD, although the studies are of variable methodological quality and the results are largely inconsistent. There is emerging evidence associating differential expression of snoRNA genes in ASD. It is not currently possible to say whether the reports of differential expression in ncRNA may relate to ASD aetiology, a response to shared environmental factors linked to ASD such as sleep and nutrition, other molecular functions, human diversity, or chance findings. To improve our understanding of any potential association, we recommend improved and standardised methodologies and reporting of raw data. Further high-quality research is required to shine a light on possible associations, which may yet yield important information.
Collagen peptides are analyzed using a low-cost, high-throughput method for assessing deamidation using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). For each chosen ...peptide, the theoretical distribution is calculated and the measured distribution for each sample compared with this to determine the extent of glutamine deamidation. The deamidation of glutamine (Q) to glutamic acid (E) results in a mass shift of +0.984 Da. Thus, from the resolution of our data, the second peak in the isotope distribution for a peptide containing one glutamine residue coincides with the first peak of the isotope distribution for the peptide in which the residue is deamidated. A genetic algorithm is used to determine the extent of deamidation that gives the best fit to the measured distribution. The method can be extended to peptides containing more than one glutamine residue. The extent of protein degradation assessed in this way could be used, for example, to assess the damage of collagen, and screen samples for radiocarbon dating and DNA analysis.
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