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Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice ( P = 3.4 × 10 −8 ). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications. Genet Med 17 10, 774–781.

Background Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. Objective The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. Methods We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. Results Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. Conclusions Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

Impostor phenomenon (IP) is the psychological construct used to describe potentially debilitating feelings of fraud and fear of being exposed as a phony in individuals who are actually high achieving and successful. The purpose of this study was to investigate the IP feelings of music education graduate students. A total of 130 master’s and doctoral students completed a survey that included the Clance IP Scale, the Graduate Music Student Scale, and demographic items. Results indicated that impostor feelings were present in a substantial percentage of the participants. Full-time student status was associated with stronger IP responses than part-time status, as was working on the degree face-to-face versus hybrid. More frequent and intense impostor feelings were experienced by females versus males, participants ages 26 to 35, students who were not married or in a committed relationship, and those who were the first in their family to attend graduate school. Master’s and doctoral students’ IP responses were not different, but successive year in the graduate program was associated with stronger impostor feelings. Based on the possible detrimental effects of strong impostor feelings, the findings should raise concern for students, their instructors, and their mentors.

Students who aim to become practicing physicians in the United States are required to demonstrate their competence with a variety of assessments during medical school, including those required to obtain a license to practice medicine. The specific challenges and stressors associated with the preparation for successful completion of licensure assessments is not well understood. To better understand students’ experiences in preparation for United States Medical Licensing Examination (USMLE) Step 1, as part of the Re-examining Exams: NBME Effort on Wellness (RENEW) research initiative, a series of eight focus groups were conducted with 33 medical school students who took the exam and received their score. The results provide a retrospective understanding of the lived experiences of aspiring medical professionals and their perceptions of the impact of a high-stakes licensure examination.

Objectives Women are under-represented in the sports literature despite increasing rates of sports participation. Our objective was to investigate the risks and benefits of an elite women’s soccer career in five health domains: general, musculoskeletal, reproductive endocrinology, post-concussion, and mental. Methods An online survey was distributed to retired US college, semi-professional, professional, and national team soccer players using personal networks, email, and social media. Short validated questionnaires were used to evaluate the health domains, including the Patient-Reported Outcomes Measurement Information System (PROMIS), Single Assessment Numerical Evaluation (SANE), Post-Concussion Symptom Scale (PCSS), and Patient Health Questionnaire (PHQ). Results A total of 560 eligible players responded to the survey over a 1-year period. The highest competitive levels were 73% college, 16% semi-professional, 8% professional, and 4% national team. The mean number of years since retirement was 12 (SD = 9), and 17.0% retired for involuntary reasons. The mean SANE scores (0–100 scale as percentage of normal) were knee = 75% (SD = 23), hip = 83% (SD = 23), and shoulder = 87% (SD = 21). The majority (63%) reported that their current activity level included participation in impact sports. A substantial proportion of players reported menstrual irregularities during their careers: 40% had fewer periods with increasing exercise and 22% had no periods for ≥ 3 months. The players ( n  = 44) who felt that post-concussion symptoms were due to soccer reported more time-loss concussions (F[2] = 6.80, p  = 0.002) and symptom severity (F[2] = 30.26, p  < 0.0001). Players who recently retired (0–5 years) reported the highest anxiety/depression scores and lowest satisfaction rates compared with those who retired 19+ years ago. Conclusion Health concerns include musculoskeletal injuries, post-concussion symptoms, and lower mental health in the early years following retirement. This comprehensive survey provides initial results that will lay the foundation for further analyses and prioritize research studies that can help all female athletes.

Background Sport-related concussion is recognized as a significant injury with variable recovery rates. Objective This study defined the acute natural history of sport concussion in male and female collegiate athletes participating in a broad array of sports. Methods We conducted a prospective, longitudinal investigation among collegiate student athletes ( n  = 34,709) from 30 academic institutions. Primary outcomes included the time (days) from injury until initiation of a return to participation (RTP) protocol and time from injury until medical clearance for unrestricted RTP. Results Concussed athletes ( n  = 1751, 19.2 years, 63.2% male) participating in 22 different sports began the RTP protocol in a median 6.4 (IQR 3.7–11.8) days. Time to initiate the RTP protocol was lengthened by less frequent post-injury assessments, greater initial post-injury symptom severity, limited contact sports participation, practice/training injuries, and three or more prior concussions. The median total RTP duration was 12.8 (IQR 8.7–20.1) days. Total RTP duration was shorter with ADHD medication usage, males, and greater assessment frequency; while greater initial post-injury symptom severity, practice-/training-related injuries, and three or more prior concussions had longer recoveries. Conclusion Although median recovery times are consistent with previous guidelines, it was not until 1 month post-injury that a preponderance of collegiate athletes were cleared to begin the RTP protocol (92%) or cleared for unrestricted sport participation (85%). Intrinsic and extrinsic factors had a small effect, altering recovery trajectories by up to 2 days, suggesting a largely unified approach to post-injury monitoring and management across all athletes. These data represent a shift from previous classification parameters of normal clinical recovery.

Background Reducing the energetic cost of running seems the most feasible path to a sub-2-hour marathon. Footwear mass, cushioning, and bending stiffness each affect the energetic cost of running. Recently, prototype running shoes were developed that combine a new highly compliant and resilient midsole material with a stiff embedded plate. Objective The aim of this study was to determine if, and to what extent, these newly developed running shoes reduce the energetic cost of running compared with established marathon racing shoes. Methods 18 high-caliber athletes ran six 5-min trials (three shoes × two replicates) in prototype shoes (NP), and two established marathon shoes (NS and AB) during three separate sessions: 14, 16, and 18 km/h. We measured submaximal oxygen uptake and carbon dioxide production during minutes 3–5 and averaged energetic cost (W/kg) for the two trials in each shoe model. Results Compared with the established racing shoes, the new shoes reduced the energetic cost of running in all 18 subjects tested. Averaged across all three velocities, the energetic cost for running in the NP shoes (16.45 ± 0.89 W/kg; mean ± SD) was 4.16 and 4.01% lower than in the NS and AB shoes, when shoe mass was matched (17.16 ± 0.92 and 17.14 ± 0.97 W/kg, respectively, both p  < 0.001). The observed percent changes were independent of running velocity (14–18 km/h). Conclusion The prototype shoes lowered the energetic cost of running by 4% on average. We predict that with these shoes, top athletes could run substantially faster and achieve the first sub-2-hour marathon.

Background and Objective Metabolomics studies of recreational and elite athletes have been so far limited to venipuncture-dependent blood sample collection in the setting of controlled training and medical facilities. However, limited to no information is currently available to determine if findings in laboratory settings are translatable to a real-world scenario in elite competitions. The goal of this study was to define molecular signatures of exertion under controlled exercise conditions and use these signatures as a framework for assessing cycling performance in a World Tour competition. Methods To characterize molecular profiles of exertion in elite athletes during cycling, we performed metabolomics analyses on blood isolated from 28 international-level, elite, World Tour professional male athletes from a Union Cycliste Internationale World Team taken before and after a graded exercise test to volitional exhaustion and before and after a long aerobic training session. Moreover, established signatures were then used to characterize the metabolic physiology of five of these cyclists who were selected to represent the same Union Cycliste Internationale World Team during a seven-stage elite World Tour race. Results Using dried blood spot collection to circumvent logistical hurdles associated with field sampling, these studies defined metabolite signatures and fold change ranges of anaerobic or aerobic exertion in elite cyclists, respectively. Blood profiles of lactate, carboxylic acids, fatty acids, and acylcarnitines differed between exercise modes. The graded exercise test elicited significant two- to three-fold accumulations in lactate and succinate, in addition to significant elevations in free fatty acids and acylcarnitines. Conversely, the long aerobic training session elicited a larger magnitude of increase in fatty acids and acylcarnitines without appreciable increases in lactate or succinate. Comparable signatures were revealed after sprinting and climbing stages, respectively, in a World Tour race. In addition, signatures of elevated fatty acid oxidation capacity correlated with competitive performance. Conclusions Collectively, these studies provide a unique view of alterations in the blood metabolome of elite athletes during competition and at the peak of their performance capabilities. Furthermore, they demonstrate the utility of dried blood sampling for omics analysis, thereby enabling molecular monitoring of athletic performance in the field during training and competition.

Background Sport-related concussions (SRCs) affect millions of adolescents and young adults annually in the USA; however, current SRC consensus statements provide limited guidance on academic support for students within higher education. Objective To generate consensus on appropriate academic recommendations for clinicians, students, and academic stakeholders to support university students during their recovery. Methods Panelists participated in three stages of a modified Delphi procedure: the first stage included a series of open-ended questions after reviewing a literature review on post-SRC return-to-learn (RTL) in higher education; the second stage asked panelists to anonymously rate the recommendations developed through the first Delphi stage using a 9-point scale; and the final stage offered panelists the opportunity to change their responses and/or provide feedback based on the group’s overall ratings. Results Twenty-two panelists including clinicians, concussion researchers, and academic stakeholders (54.5% female) from 15 institutions and/or healthcare systems participated in a modified Delphi procedure. A total of 42 statements were developed after round one. Following the next two rounds, 27 statements achieved consensus amongst the panel resulting in the four-stage Post-Concussion Collegiate RTL Protocol . Conclusion There are several unique challenges when assisting university students back to the classroom after SRC. Explicit guidelines on when to seek additional medical care (e.g., if they are experiencing worsening or persistent symptoms) and how to approach their instructor(s) regarding academic support may help the student self-advocate. Findings from the present study address barriers and provide a framework for universities to facilitate a multidisciplinary approach amongst medical and academic stakeholders.