Baseline Sleep Characteristics in NCAA Division I Collegiate Athletes.

OBJECTIVE: The authors report no conflicts of interest.To determine baseline sleep characteristics of male/female student-athletes across multiple sports using objective and subjective measures. DESIGN: Prospective study. SETTING: Division I college. PARTICIPANTS: Eighty-two male and female Division I student-athletes. INTERVENTIONS: Participants completed 2 validated sleep questionnaires (Epworth Sleepiness Scale [ESS] and Single-Item Sleep Quality Scale [SISQS]) to assess subjective sleep. They also wore a validated sleep monitoring device (WHOOP 4.0 band) for at least 14 nights to collect objective data on total sleep time (TST) and sleep architecture. MAIN OUTCOME MEASURES: Overnight sleep variables, including TST, time spent awake in bed after falling asleep, time spent in light sleep, rapid eye movement (REM) sleep, and slow-wave sleep (SWS) cycles. Sleep quality and daytime sleepiness were also assessed. RESULTS: There were no statistical differences between male and female student-athletes in average TST, sleep architecture, sleep consistency, SISQS, and ESS scores. The average TST was 409.2 ± 36.3 minutes. Sleep architecture consisted of 25.6% REM, 19.9% SWS, and 54.4% light sleep. The average sleep consistency was 61.6% ± 8.9%. The average SISQS score was 6.48 ± 1.71, and the average ESS score was 7.57 ± 3.82. A significant difference was found in average wake time between males and females (55.0 vs 43.7 min, P = 0.020), with an overall average of 50.2 ± 16.2 minutes. CONCLUSIONS: College student-athletes do not typically obtain the recommended amount of sleep. Optimizing sleep can positively affect academic and athletic performance.

Should Adolescents Run Marathons?: Youth Marathon Training Injury Epidemiology and Risk Factors.

OBJECTIVE: Youth participation in distance running has increased, yet little data exist about the injury patterns and safety of such activity. This study seeks to determine the types and rates of injuries seen in an adolescent marathon training program. DESIGN: Observational prospective cohort study. SETTING: Community-based adolescent marathon training program. PARTICIPANTS: The study enrolled 1927 students from 50 high schools (HS) and 34 middle schools (MS) participating in the 2017 to 2018 Students Run Los Angeles marathon training program. ASSESSMENT OF RISK FACTORS: Weekly injury reports completed by running coaches. Data elements included participant demographics, weekly training distance, injury type, injury acuity, and missed training time. MAIN OUTCOME MEASURES: Epidemiology of self-reported injury in adolescent runners. RESULTS: A total of 583 injuries occurred in 18% of runners during the training program. High schools runners were more likely to be injured than MS runners (20.8% vs 14.2%, P < 0.001). Seventy-two percent of injuries were acute with a mean missed training time of 4.8 days (SD 4.8). The most frequent site of injury was the knee (33%). Overall, runners with injuries ran a significantly greater distance per week than uninjured runners (14.6 mi vs 12.0 mi, P < 0.001). Ninety-nine percent of marathon participants completed the race. CONCLUSIONS: During a 28-week marathon training program, 18% of adolescent participants reported an injury. More injuries occurred in HS students, were acute, and involved the knee. This study represents one of the largest descriptions of injury prevalence in adolescent distance running and highlights a lower injury rate than adults during marathon training.

Youth running consensus statement: minimising risk of injury and illness in youth runners.

Despite the worldwide popularity of running as a sport for children, relatively little is known about its impact on injury and illness. Available studies have focused on adolescent athletes, but these findings may not be applicable to preadolescent and pubescent athletes. To date, there are no evidence or consensus-based guidelines identifying risk factors for injury and illness in youth runners, and current recommendations regarding suitable running distances for youth runners at different ages are opinion based. The International Committee Consensus Work Group convened to evaluate the current science, identify knowledge gaps, categorise risk factors for injury/illness and provide recommendations regarding training, nutrition and participation for youth runners.

Nursing Monitoring of Microsurgical Free Flaps: Identifying and Addressing Knowledge Gaps.

BACKGROUND: Microsurgical free flaps require careful monitoring to detect early signs of compromise. At many hospitals, nursing staff provides the majority of postoperative monitoring of free flap patients and it lies within their responsibility to alert physicians of a failing free flap. The aim of this study is to identify knowledge gaps in the monitoring of microvascular free tissue transfer in both novice and experienced nurses and to provide appropriate education to address these gaps. METHODS: This was a pre- and postintervention study. An initial pilot survey was administered to identify knowledge deficiencies. A nursing educational session on free flap physiology and monitoring was then designed to address these deficiencies. An 18-question multiple choice quiz was administered before and after the educational session. Pre- and post-test scores were compared based on nursing experience. At 6 months, the participating nurses completed a survey rating their confidence with free flap patient care as a result of the educational session. RESULTS: A total of 72 nurses completed the in-service training course and quiz. The average quiz score increased from 61.9 to 89.3% after the in-service (p < 0.001). There was no correlation between precurriculum test scores and nursing experience as referenced by total number of years in the profession (r s = -0.038, p = 0.754). The follow-up survey showed that prior to the course 38% of respondents reported little or no confidence caring for free flap patients, decreasing to 6% after the course (p < 0.05). CONCLUSION: Based on the results of this study, nursing knowledge of capillary refill, venous congestion, and basic microsurgical free flap physiology is inadequate. With implementation of a teaching in-service curriculum highlighting these key areas of deficiencies, nurses improved both their understanding and confidence levels, regardless of their level of experience.

Ahead of the Curve: Tracking Progress in Novice Microsurgeons.

BACKGROUND: The purpose of this study was to evaluate learning curves for an existing microsurgical training model. We compared efficiency and amount of training needed to achieve proficiency between novice microsurgeons without operative experience versus those who had completed a surgical internship. METHODS: Ten novice microsurgeons anastomosed a silastic tube model. Time to perform each anastomosis, luminal diameter, and number of errors were recorded. RESULTS: First year residents improved up to a brief plateau at 10 repetitions, followed by continued improvement. Second year residents improved up to a plateau at 10 repetitions with no further improvement thereafter. There was no significant difference in luminal area or errors between groups. CONCLUSION: Residents with no operative experience can benefit from early exposure to microsurgical training. These interns continue to improve with additional repetitions while second year residents achieve proficiency with fewer repetitions.

Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts.

BACKGROUND: Knock-in mice provide useful models of congenital and age-related cataracts caused by α-crystallin mutations. R49C αA-crystallin and R120G αB-crystallin mutations are linked with hereditary cataracts. Knock-in αA-R49C+/- heterozygotes develop cataracts by 1-2months, whereas homozygote mice have cataracts at birth. The R49C mutation drastically reduces lens protein water solubility and causes cell death in knock-in mouse lenses. Mutant crystallin cannot function as a chaperone, which leads to protein aggregation and lens opacity. Protein aggregation disrupts the lens fiber cell structure and normal development and causes cell death in epithelial and fiber cells. We determined what aspects of the wild-type phenotype are age-dependently altered in the mutant lens. METHODS: Wild-type, heterozygote (αA-R49C+/-), and homozygote (αA-R49C+/+) mouse lenses were assessed pre- and postnatally for lens morphology (electron microscopy, immunohistochemistry), and autophagy or unfolded protein response markers (immunoblotting). RESULTS: Morphology was altered by embryonic day 17 in R49C+/+ lenses; R49C+/- lens morphology was unaffected at this stage. Active autophagy in the lens epithelium of mutant lenses was indicated by the presence of autophagosomes using electron microscopy. Protein p62 levels, which are degraded specifically by autophagy, increased in αA-R49C mutant versus wild-type lenses, suggesting autophagy inhibition in the mutant lenses. The unfolded protein response marker XBP-1 was upregulated in adult lenses of αB-R120G+/+ mice, suggesting its role in lens opacification. CONCLUSIONS: Mutated crystallins alter lens morphology, autophagy, and stress responses. GENERAL SIGNIFICANCE: Therapeutic modulation of autophagic pathways may improve protein degradation in cataractous lenses and reduce lens opacity. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Family Recall of and Response to Germline Pathologic Variants Found on Paired Tumor-Germline Sequencing in Pediatric Oncology.

PURPOSE: Paired tumor-germline sequencing can identify somatic variants for targeted therapy and germline pathogenic variants (GPVs) causative of hereditary cancer/tumor predisposition syndromes. It is unknown how patients/families in pediatric oncology use information about an identified GPV. We assessed recall of germline results and actions taken on the basis of findings. METHODS: We completed phone surveys with patients (and/or their parent) with GPVs identified via a single academic medical center's paired tumor-germline sequencing study. Seven hundred forty pediatric (aged 0-25 years) oncology patients were enrolled in this sequencing study between May 2012 and August 2021. Ninety-six participants (13.0%) had at least one GPV identified and were therefore eligible for this survey. The parent/guardian (for patients younger than 18 years or deceased patients) or patients themselves (if 18 years or older) were contacted. Survey topics included germline result recall, experience with genetic counseling, changes to patient's cancer treatment/screening, sharing of results with family members, and lifestyle changes. RESULTS: Fifty-three surveys (response rate, 55.2%) were completed between October 2021 and June 2022. Thirty-seven (69.8%) respondents correctly recalled the identified GPV. Discussing results with a genetic counselor (P = .0001), having a GPV related to the cancer/tumor diagnosis (P = .002), and non-Hispanic White race/ethnicity (P = .02) were associated with accurate recall. Twenty-five respondents (47.2%) reported a change in the child's cancer treatment and/or screening recommendations, 17 respondents (32.1%) made a lifestyle change on the basis of the results, and 44 respondents (83.0%) shared results with at least one family member. CONCLUSION: While most respondents remembered that a GPV was identified in the patient, some did not recall having a GPV found, and others recalled germline findings incorrectly. Future work may determine patient/family preferences for timing/method of result return to optimize patient recall and use of germline results.

Association of Premorbid Anxiety and Depression Symptoms in Concussion Recovery in Collegiate Student-Athletes.

BACKGROUND: Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and total symptom burden is unclear. OBJECTIVE: To examine the association of self-reported premorbid anxiety/depression symptoms in collegiate student-athletes with (1) recovery times until asymptomatic, (2) return-to-play, and (3) postconcussion symptom burden. STUDY DESIGN: Athletes in the Concussion Assessment, Research and Education Consortium completed baseline concussion assessments (Sport Concussion Assessment Tool [SCAT3] and Brief Symptom Inventory-18 [BSI-18]). Athletes were tested postinjury at <6 hours, 24 to 48 hours, time of asymptomatic and start of return-to-play protocol, unrestricted return-to-play, and 6 months after injury. Injured athletes were categorized into 4 groups based on BSI-18 scores: (1) B-ANX, elevated anxiety symptoms only; (2) B-DEP, elevated depression symptoms only; (3) B-ANX&DEP, elevated anxiety and depression symptoms; and (4) B-NEITHER, no elevated anxiety or depression symptoms. Relationship between age, sex, BSI-18 group, SCAT3 total symptom and severity scores, and time to asymptomatic status and return-to-play was assessed with Pearson's chi-squared test and robust analysis of variance. LEVEL OF EVIDENCE: Level 3. RESULTS: Among 1329 athletes with 1352 concussions, no respondents had a self-reported premorbid diagnosis of anxiety/depression. There was no difference in time until asymptomatic or time until return-to-play between BSI-18 groups (P = 0.15 and P = 0.11, respectively). B-ANX, B-DEP, and B-ANX&DEP groups did not have higher total symptom or severity scores postinjury compared with the B-NEITHER group. CONCLUSION: Baseline anxiety/depression symptoms in collegiate student-athletes without a mental health diagnosis are not associated with longer recovery times until asymptomatic, longer time to return-to-play, or higher postconcussion total symptom and severity scores compared with athletes without baseline symptoms. CLINICAL RELEVANCE: Anxiety and depression symptoms without a clear mental health diagnosis should be considered differently from other comorbidities when discussing prolonged recovery in collegiate student-athletes.

Mechanisms of Injury Leading to Concussions in Collegiate Soccer Players: A CARE Consortium Study.

BACKGROUND: Few previous studies have investigated how different injury mechanisms leading to sport-related concussion (SRC) in soccer may affect outcomes. PURPOSE: To describe injury mechanisms and evaluate injury mechanisms as predictors of symptom severity, return to play (RTP) initiation, and unrestricted RTP (URTP) in a cohort of collegiate soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The Concussion Assessment, Research and Education (CARE) Consortium database was used. The mechanism of injury was categorized into head-to-ball, head-to-head, head-to-body, and head-to-ground/equipment. Baseline/acute injury characteristics-including Sports Concussion Assessment Tool-3 total symptom severity (TSS), loss of consciousness (LOC), and altered mental status (AMS); descriptive data; and recovery (RTP and URTP)-were compared. Multivariable regression and Weibull models were used to assess the predictive value of the mechanism of injury on TSS and RTP/URTP, respectively. RESULTS: Among 391 soccer SRCs, 32.7% were attributed to a head-to-ball mechanism, 27.9% to a head-to-body mechanism, 21.7% to a head-to-head mechanism, and 17.6% to a head-to-ground/equipment mechanism. Event type was significantly associated with injury mechanism [χ2(3) = 63; P < .001), such that more head-to-ball concussions occurred in practice sessions (n = 92 [51.1%] vs n = 36 [17.1%]) and more head-to-head (n = 65 [30.8%] vs n = 20 [11.1]) and head-to-body (n = 76 [36%] vs n = 33 [18.3%]) concussions occurred in competition. The primary position was significantly associated with injury mechanism [χ2(3) = 24; P < .004], with goalkeepers having no SRCs from the head-to-head mechanism (n = 0 [0%]) and forward players having the least head-to-body mechanism (n = 15 [19.2%]). LOC was also associated with injury mechanism (P = .034), with LOC being most prevalent in head-to-ground/equipment. Finally, AMS was most prevalent in head-to-ball (n = 54 [34.2%]) and head-to-body (n = 48 [30.4%]) mechanisms [χ2(3) = 9; P = .029]. In our multivariable models, the mechanism was not a predictor of TSS or RTP; however, it was associated with URTP (P = .044), with head-to-equipment/ground injuries resulting in the shortest mean number of days (14 ± 9.1 days) to URTP and the head-to-ball mechanism the longest (18.6 ± 21.6 days). CONCLUSION: The mechanism of injury differed by event type and primary position, and LOC and AMS were different across mechanisms. Even though the mechanism of injury was not a significant predictor of acute symptom burden or time until RTP initiation, those with head-to-equipment/ground injuries spent the shortest time until URTP, and those with head-to-ball injuries had the longest time until URTP.

The Prevalence and Influence of New or Worsened Neck Pain After a Sport-Related Concussion in Collegiate Athletes: A Study From the CARE Consortium.

BACKGROUND: Neck pain in a concussion population is an emerging area of study that has been shown to have a negative influence on recovery. This effect has not yet been studied in collegiate athletes. HYPOTHESIS: New or worsened neck pain is common after a concussion (>30%), negatively influences recovery, and is associated with patient sex and level of contact in sport. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Varsity-level athletes from 29 National Collegiate Athletic Association member institutions as well as nonvarsity sport athletes at military service academies were eligible for enrollment. Participants completed a preseason baseline assessment and follow-up assessments at 6 and 24 to 48 hours after a concussion, when they were symptom-free, and when they returned to unrestricted play. Data collection occurred between January 2014 and September 2018. RESULTS: A total of 2163 injuries were studied. New or worsened neck pain was reported with 47.0% of injuries. New or worsened neck pain was associated with patient sex (higher in female athletes), an altered mental status after the injury, the mechanism of injury, and what the athlete collided with. The presence of new/worsened neck pain was associated with delayed recovery. Those with new or worsened neck pain had 11.1 days of symptoms versus 8.8 days in those without (P < .001). They were also less likely to have a resolution of self-reported symptoms in ≤7 days (P < .001). However, the mean duration of the return-to-play protocol was not significantly different for those with new or worsened neck pain (7.5 ± 7.7 days) than those without (7.4 ± 8.3 days) (P = .592). CONCLUSION: This novel study shows that neck pain was common in collegiate athletes sustaining a concussion, was influenced by many factors, and negatively affected recovery.

Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report.

The limited effects of current treatments of primary myelofibrosis (PM) led us to prospectively evaluate recombinant interferon-α (rIFNα) in "early" PM patients with residual hematopoiesis and only grade 1 or 2 myelofibrosis. Seventeen patients meeting World Health Organization PM diagnostic criteria received either rIFNα-2b 500 000 to 3 million units 3 times weekly, or pegylated rIFNα-2a 45 or 90 µg weekly. International Working Group for Myelofibrosis Research and Treatment criteria for prognosis and response were used. Eleven patients were women and 6 were men. Their median age at diagnosis was 57 years. Eleven patients were low risk and 6 were intermediate-1 risk. Two achieved complete remission, 7 partial, 1 clinical improvement, 4 stable disease, and 3 had progressive disease. Thus, more than 80% derived clinical benefit or stability. Improvement in marrow morphology occurred in 4. Toxicity was acceptable. These results, with documented marrow reversion because of interferon treatment, warrant expanded evaluation.

p62 expression and autophagy in αB-crystallin R120G mutant knock-in mouse model of hereditary cataract.

The formation of cataracts is associated with the accumulation of protein aggregates in the ocular lens, suggesting that defective protein degradation plays a role in cataract pathogenesis. Accumulation of the p62 protein has recently been identified as a marker for impaired autophagy in a variety of tissues; however, little information exists on its expression in the ocular lens and in cataracts. In the present study we examined the expression of p62 in the mouse lens and compared its expression in wild-type lenses with that in lenses from knock-in mice with an arginine to glycine mutation in αB-crystallin (αB-R120G) that is known to cause human hereditary cataract. Immunohistochemical, immunoblotting, and transmission electron microscopic analyses of wild type and αB-R120G mutant mice were performed. To assess the effect of increased protein aggregation on autophagy, immunohistochemical staining was performed with an anti-p62 antibody, revealing the presence of p62-positive punctate staining in a band of denucleated cortical fiber cells. The number and size of p62 puncta were significantly greater in αB-R120G homozygous mutant lenses than in wild type and heterozygous mutant lenses. p62 staining was also abundant in lens epithelial cells and was concentrated around the nuclear membrane. Double-membraned structures similar to autophagosomes containing cellular cytoplasmic content were detected in lens epithelial cells by transmission electron microscopy. The autophagosomes in lens epithelial cells from αB-R120G homozygous mutant mice were larger than those in wild type mice. Double-membraned structures that are probably autophagosomes were also detected in cortical fiber cells and were more abundant in the αB-R120G homozygous mutant lens than the wild type lens. This study demonstrates p62 distribution as speckles in the lens fiber cells, altered levels of p62 expression, and the presence of autophagosomes in the ocular lens of αB-R120G mutant mice. We propose that autophagy is inhibited in the αB-R120G mutant lenses because of a defect in protein degradation after autophagosome formation. Further work is necessary to determine the relationship between αB-crystallin function, autophagy, and cataract formation.

Clinical Evaluation of the Knee Arthritis Patient.

The evaluation of a patient with knee osteoarthritis (OA) has 3 main components: clinical history, physical examination, and radiographic imaging. The clinician should assess for inciting and aggravating factors for the knee pain as well as for the presence of any mechanical symptoms. A history of prior knee injury or surgery can suggest the development of early osteoarthritis. A thorough physical examination of the knee should be performed. Some features of OA include limited range of motion, crepitus in the patellofemoral compartment, and joint line tenderness. Depending on the severity of OA varus or valgus alignment can develop. Special tests such as the McMurray for meniscal tears may cause increased pain as patients with OA will often have degenerative meniscal tears. Weight bearing radiographs can confirm the diagnosis of OA. Several scales exist to grade the severity of OA with the Kellgren-Lawrence being one that is often used. Radiographic features of OA include joint space narrowing, osteophytes, sclerosis of bone and bone end deformities. If after the above evaluation the diagnosis is still unclear, advanced imaging or laboratory testing can be performed to evaluate for alternative diagnoses.

Role of Hashtags in Educating and Promoting the Field of Hand Surgery on Social Media.

Purpose: This study identifies the hand surgery content being posted on Instagram, how hashtags are being used, and those posting to determine what is reaching the public. Methods: Top hand surgery-related hashtags on Instagram from June 2020 to August 2020 were identified by searching "hand surgery" and sorting by relevance. Hashtags were quantified by number and qualitatively assessed. Posts without a clear relationship were excluded. Hashtags relevant to hand surgery were analyzed by educational merit, medical specialty, patient or nonpatient, and demographics. Results: The top 25 hashtags contained 325,400 posts. The 3 hashtags with the highest number of posts were #carpaltunnel (64,700), #handsurgery (50,500), and #handtherapy (48,300). Most posts were educational (53.2%). Nonsurgical fields (66.5%) posted the most, followed by orthopedic (25.9%), and plastic hand surgeons (7.7%). Nonpatients (68.8%) posted more than patients. The top 3 languages of the posts were English (67.7%), Russian (9.4%), and Spanish (7.1%). However, when looking at the hashtags with more than half of the posts being made by hand surgeons, we observed that most (62.9%) of the posts were noneducational in content. Conclusions: Instagram posts on hand surgery topics are largely posted by nonexperts and are educational in content. There is a major opportunity for hand surgeons to educate and market effectively using hand surgery-related hashtags. Given the number of hand surgeries performed annually, one would hope to see more representation by hand surgeons on social media. More active participation and provision of educational content by specialists is warranted. Clinical relevance: There is an opportunity for hand surgeons to educate those searching upper extremity conditions and seeking out expertise in a domain where information is largely driven by nonsurgeons and the quality of information is not vetted. This study identifies the need for more hand surgeon involvement to expand knowledge and communication efforts within the specialty and with the public through the evolving world of social media.

King-Devick Sensitivity and Specificity to Concussion in Collegiate Athletes.

CONTEXT: The King-Devick (K-D) test is used to identify oculomotor impairment after concussion. However, the diagnostic accuracy of the K-D test over time has not been evaluated. OBJECTIVES: To (1) examine the sensitivity and specificity of the K-D test at 0 to 6 hours postinjury, 24 to 48 hours postinjury, the beginning of a return-to-play (RTP) protocol (asymptomatic), unrestricted RTP, and 6 months postconcussion and (2) compare outcomes between athletes with and those without concussion across confounding factors (sex, age, sport contact level, academic year, learning disorder, attention-deficit/hyperactivity disorder, migraine history, concussion history, and test administration mode). DESIGN: Retrospective, cross-sectional design. SETTING: Multiple institutions in the Concussion Assessment, Research and Education Consortium. PATIENTS OR OTHER PARTICIPANTS: A total of 320 athletes with a concussion (162 men, 158 women; age = 19.80 ± 1.41 years) were compared with 1239 total collegiate athletes without a concussion (646 men, 593 women; age = 20.31 ± 1.18 years). MAIN OUTCOME MEASURE(S): We calculated the K-D test time difference (in seconds) by subtracting the baseline from the most recent time. Receiver operator characteristic (ROC) curve and area under the curve (AUC) analyses were used to determine the diagnostic accuracy across time points. We identified cutoff scores and corresponding specificity at both the 80% and 70% sensitivity levels. We repeated ROC with AUC analyses using confounding factors. RESULTS: The K-D test predicted positive results at the 0- to 6-hour (AUC = 0.724, P < .001), 24- to 48-hour (AUC = 0.701, P < .001), RTP (AUC = 0.640, P < .001), and 6-month postconcussion (AUC = 0.615, P < .001) tim points but not at the asymptomatic time point (AUC = 0.513, P = .497). The 0- to 6-hour and 24- to 48-hour time points yielded 80% sensitivity cutoff scores of -2.6 and -3.2 seconds (ie, faster), respectively, but 46% and 41% specificity, respectively. The K-D test had a better AUC when administered using an iPad (AUC = 0.800, 95% CI = 0.747, 0.854) compared with the spiral-bound card system (AUC = 0.646, 95% CI = 0.600, 0.692; P < .001). CONCLUSIONS: The diagnostic accuracy of the K-D test was greatest at 0 to 6 hours and 24 to 48 hours postconcussion but declined across subsequent postconcussion time points. The AUCs did not differentiate between groups across confounding factors. Our negative cutoff scores indicated that practice effects contributed to improved performance, requiring athletes to outperform their baseline scores.

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1+/- like B-ALL. SIGNIFICANCE: We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion: A Study of the NCAA-DoD CARE Consortium.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (ß = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (ß = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|ß|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (ßs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. DISCUSSION: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.

Optimizing Concussion Care Seeking: A Longitudinal Analysis of Recovery.

BACKGROUND: Approximately half of concussions go undisclosed and therefore undiagnosed. Among diagnosed concussions, 51% to 64% receive delayed medical care. Understanding the influence of undiagnosed concussions and delayed medical care would inform medical and education practices. PURPOSE: To compare postconcussion longitudinal clinical outcomes among (1) individuals with no concussion history, all previous concussions diagnosed, and ≥1 previous concussion undiagnosed, as well as (2) those who have delayed versus immediate symptom onset, symptom reporting, and removal from activity after concussion. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Participants included 2758 military academy cadets and intercollegiate athletes diagnosed with concussion in the CARE Consortium. We determined (1) each participant's previous concussion diagnosis status self-reported at baseline (no history, all diagnosed, ≥1 undiagnosed) and (2) whether the participant had delayed or immediate symptom onset, symptom reporting, and removal from activity. We compared symptom severities, cognition, balance, and recovery duration at baseline, 24 to 48 hours, date of asymptomatic status, and date of unrestricted return to activity using tests of parallel profiles. RESULTS: The ≥1 undiagnosed concussion group had higher baseline symptom burdens (P < .001) than the other 2 groups and poorer baseline verbal memory performance (P = .001) than the all diagnosed group; however, they became asymptomatic and returned to activity sooner than those with no history. Cadets/athletes who delayed symptom reporting had higher symptom burdens 24 to 48 hours after injury (mean ± SE; delayed, 28.8 ± 0.8; immediate, 20.6 ± 0.7), took a median difference of 2 days longer to become asymptomatic, and took 3 days longer to return to activity than those who had immediate symptom reporting. For every 30 minutes of continued participation after injury, days to asymptomatic status increased 8.1% (95% CI, 0.3%-16.4%). CONCLUSION: Clinicians should expect that cadets/athletes who delay reporting concussion symptoms will have acutely higher symptom burdens and take 2 days longer to become asymptomatic. Educational messaging should emphasize the clinical benefits of seeking immediate care for concussion-like symptoms.

Reducing Complications and Expanding Use of Robotic Rectus Abdominis Muscle Harvest for Pelvic Reconstruction.

SUMMARY: The rectus abdominis flap has long been a workhorse in perineal reconstruction. Although traditionally approached though an external incision, the morbid nature of the incision and subsequent violation of the anterior rectus sheath has encouraged innovation of minimally invasive approaches for harvest. In this study, we present our experience, evolution, and comparative outcomes of robotic rectus abdominis muscle harvest. A retrospective review of perineal reconstruction was performed for a 6-year period (2014 to 2019). Robotic rectus abdominis muscle flaps were compared to nonrobotic techniques performed during this time. Descriptive statistics and complication profiles were computed. The details of our surgical technique are also described. Thirty-six patients underwent perineal reconstruction. Sixteen were performed using the robotic rectus abdominis muscle and 20 with traditional repairs (12 vertical rectus abdominis myocutaneous flaps and eight gracilis flaps). Demographic profiles were similar between cohorts, including age, body mass index, smoking, diabetes, neoadjuvant radiation therapy, and need for vaginal wall repair. Six robotic patients underwent abdominal wall reinforcement with biological mesh. Length of stay, surgical times, and incidence of major complications were similar between cohorts with a trend toward increased minor complications in traditional reconstructions (55 percent versus 31 percent; p = 0.15). Robotic rectus abdominis muscle harvest is a powerful tool that continues to evolve the potential to mitigate common morbidities and complications of traditional repair and further enhance cosmetic outcomes. This study suggests that greater flexibility for reconstruction can be afforded with harvest of the posterior rectus sheath and complications avoided with prophylactic mesh reinforcement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.