Evaluation of a Preparticipation Cardiovascular Screening Program Among 1,686 National Collegiate Athletic Association Division I Athletes: Comparison of the Seattle, Refined, and International Electrocardiogram Screening Criteria.

OBJECTIVES: To: (1) analyze the results of 5 years of preparticipation cardiac screening including 12-lead electrocardiogram (ECG) of National Collegiate Athletic Association (NCAA) Division I athletes; and (2) assess the rates of ECG screening abnormalities and false-positive rates among 3 ECG screening criteria. DESIGN: Retrospective chart review. SETTING: National Collegiate Athletic Association Division I University. PARTICIPANTS: One thousand six hundred eighty-six first-year athletes presenting for their preparticipation examination including 12-lead resting ECG. INTERVENTIONS: At the completion of the study period, all ECGs were retrospectively reviewed using the Seattle, Refined, and International Criteria. MAIN OUTCOME MEASURES: (1) Prevalence of pathologic cardiac conditions identified by screening; and (2) number of ECG screening abnormalities by criteria. RESULTS: Three athletes (0.2%) were found to have conditions that are associated with sudden cardiac death. Retrospective review of ECGs using Seattle, Refined, and International criteria revealed an abnormal ECG rate of 3.0%, 2.1%, and 1.8%, respectively. International criteria [odds ratios (OR), 0.58; P = 0.02] demonstrated a lower false-positive rate compared with the Seattle criteria. There was no significant difference in false-positive rates between the Seattle and Refined (OR, 0.68; P = 0.09) or the International and Refined criteria (OR, 0.85; P = 0.5). CONCLUSIONS: There was a low rate of significant cardiac pathology in this population, and no athletes were permanently restricted from play as a result of screening. Our results suggest that the International criteria have the lowest false-positive rate of athlete-specific ECG criteria, and thus, it is the preferred method for preparticipation ECG screening in NCAA athletes.

Time Out of Play Due to Illness in Major and Minor League Baseball.

OBJECTIVE: To generate a summative report on the most commonly diagnosed illnesses in Major League Baseball (MLB) and Minor League Baseball (MiLB) athletes with specific attention to their impact based on time out of play. DESIGN: Retrospective analysis. SETTING: Injury and illness data from the MLB Health and Injury Tracking System. PARTICIPANTS: All MLB and MiLB athletes active between 2011 and 2016. ASSESSMENT OF RISK FACTORS: Illnesses were defined as atraumatic medical diagnoses that occurred during the MLB or MiLB season and resulted in at least 1 day out of play. MAIN OUTCOME MEASURES: Incidence of illness diagnoses and resulting time out play. RESULTS: Eight thousand eight hundred thirty-four illnesses were reported, representing 14.7% of all diagnoses resulting in time out of play. Total days missed (DM) due to illness were 39 614, with a mean of 4.6 (SD 9.9 days) and median 2 DM per diagnosis. The annual incidence of illness per season was 20.3 per 100 athletes. The most common diagnosis was nonspecific viral illness (15.3%), followed by gastroenteritis (13.6%), other gastrointestinal illness (8.3%), influenza (7.0%), and upper respiratory infection (6.2%). Appendicitis (15.2%) and Epstein-Barr virus/cytomegalovirus (9.1%) were the most common season-ending diagnoses. CONCLUSIONS: Illnesses represent a significant cause of time out of play in MLB and MiLB. Prevention efforts should focus on limiting the spread of communicable viral, respiratory, and gastrointestinal disease among players, as the majority of diagnoses fell into these categories. This work may be used to guide future research into illness treatment and prevention in professional baseball.

Preparticipation Cardiovascular Screening: An Infrastructure Assessment in Collegiate Athletics.

OBJECTIVE: To assess the available infrastructure for secondary testing after preparticipation cardiovascular screening of collegiate athletes. DESIGN: Cross-sectional study. SETTING: National Collegiate Athletic Association (NCAA) athletic programs PARTICIPANTS:: Team physicians. INTERVENTIONS: Online survey distributed by the NCAA and American Medical Society for Sports Medicine. MAIN OUTCOME MEASURES: Availability of secondary cardiovascular diagnostic testing and services. RESULTS: Team physicians from 235 schools completed the assessment, representing 21% of all NCAA schools. Ninety (38.3%) NCAA team physicians reported screening athletes using electrocardiogram (ECG). Division I schools were more likely than Division II and III schools to perform both screening ECG (RR, 2.38, P < 0.0001) and echocardiogram (RR, 2.83, P = 0.01). More than 97% of schools had access to resting echocardiogram, stress ECG/echocardiogram, and Holter monitoring within 25 miles with no significant variability between divisions, regions, or size of undergraduate student body. Cardiac magnetic resonance imaging and electrophysiology studies were available within 25 miles of more than 80% of schools, and genetics testing was available within 25 miles for 64.8%. CONCLUSIONS: Secondary testing for cardiovascular abnormalities seems to be readily available for NCAA athletes, regardless of division, region, or school size.

Long-Range Ordering of Blunt-Ended DNA Tiles on Supported Lipid Bilayers.

Long-range ordering of DNA crossover tiles with blunt ends on lipid bilayers is investigated using atomic force microscopy. "Blunt-ended" tiles do not have single-stranded complementary ends, and thus instead of assembling via base-pairing, they can interact by π-stacking of their duplex ends. This work demonstrates that the balance of base π-stacking interactions between the ends of DNA duplexes, cholesterol-mediated DNA anchoring, and electrostatic DNA binding to supported lipid bilayers (SLBs) presents an opportunity to build dynamic materials with long-range order on a soft support. The tiles are shown to organize into novel tunable surface packing morphologies on the micrometer scale. This work focuses on three-point star (3PS) tiles that are either unmodified or modified with a cholesterol unit and investigates their interactions on supported lipid bilayers. On fluid bilayers, the cholesterol tiles form extended hexagonal arrays with few defects, while the unmodified tiles do not bind. In contrast, both modified and unmodified tiles bind to gel-phase bilayers and produce arrays of new organized morphologies. With increasing tile concentration, we observe a range of motifs, that progressively favor tile-tile packing over duplex-end π-stacking. These structures can selectively pattern domains of phase-separated lipid bilayers, and the patterning is also observed for four-arm cross-tiles. Dynamic blunt end contacts promote error correction and network reconfiguration to maximize favorable interactions with the substrate and are required for the observed tile organization. These results suggest that small blunt-ended tiles can be used as a platform to organize oligonucleotides, nanoparticles, and proteins into extensive networks at the interface with biologically relevant membrane systems or other soft surface materials for applications in cellular recognition, plasmonics, light harvesting, model systems for membrane protein assemblies, or analytical devices.

Development and characterization of gene silencing DNA cages.

RNA interference (RNAi) is a powerful therapeutic strategy that induces gene silencing by targeting disease-causing mRNA and can lead to their removal through degradation pathways. The potential of RNAi is especially relevant in cancer therapy, as it can be designed to regulate the expression of genes involved in all stages of tumor development (initiation, growth, and metastasis). We have generated gene silencing 3D DNA prisms that integrate antisense oligonucleotide therapeutics at 1, 2, 4, and 6 positions. Synthesis of these structures is readily achieved and leads to the assembly of highly monodisperse and well-characterized structures. We have shown that antisense strands scaffolded on DNA cages can readily induce gene silencing in mammalian cells and maintain gene knockdown levels more effectively than single and double stranded controls through increased stability of bound antisense units.

Serial Ultrasonography for the Assessment of Healing of Lower Extremity Bone Stress Injury and Correlation With Return to Sport/Exercise.

BACKGROUND: Lower extremity bone stress injuries (BSIs) are common among athletes who participate in high-impact activities. Conventional imaging is limited in assessing healing of BSIs. HYPOTHESIS: Serial ultrasonography (US) can identify changes in appearance of lower extremity BSIs over time that can be correlated with symptoms and return to exercise/sport. STUDY DESIGN: Cohort observational study. LEVEL OF EVIDENCE: Level 3. METHODS: Adults 18 to 50 years old with a recent exercise-associated BSI of distal tibia/fibula or metatarsals diagnosed by magnetic resonance imaging (MRI) were enrolled. US was performed every 2 weeks for 12 weeks. The sonographic appearance (soft tissue edema, periosteal reaction, hyperemia on power Doppler, callus) was correlated with the numerical rating scale (NRS) for pain and ability to return to sport/exercise. RESULTS: A total of 30 patients were enrolled (mean age, 35.3 ± 7.7 years; 21 [70.0%] female). The tibia was most frequently affected (n = 15, 50.0%), followed by metatarsals (n = 14, 46.7%) and fibula (n = 1, 3.3%). At week 4, 25 of 30 (83.3%) had at least 1 US finding associated with the BSI. The degree of hyperemia was correlated with NRS at weeks 4 and 6 (Spearman correlations [ρ] 0.45 [0.09, 0.69] and 0.42 [0.07, 0.67], respectively), as well as return to sport/exercise at week 6 (ρ -0.45 [-0.68, -0.09]). US soft tissue edema was also correlated with NRS at week 6 (ρ 0.38 [0.02, 0.65]). CONCLUSION: Serial US of lower extremity BSIs can provide objective measures of healing. US findings were correlated with clinical outcomes at multiple timepoints. CLINICAL RELEVANCE: US may have advantages over conventional imaging for monitoring healing of lower extremity BSIs. Further research is needed to better understand the prognostic value of these sonographic indicators of BSI healing and role in assessing readiness for return to sport/exercise.

Three-dimensional organization of block copolymers on "DNA-minimal" scaffolds.

Here, we introduce a 3D-DNA construction method that assembles a minimum number of DNA strands in quantitative yield, to give a scaffold with a large number of single-stranded arms. This DNA frame is used as a core structure to organize other functional materials in 3D as the shell. We use the ring-opening metathesis polymerization (ROMP) to generate block copolymers that are covalently attached to DNA strands. Site-specific hybridization of these DNA-polymer chains on the single-stranded arms of the 3D-DNA scaffold gives efficient access to DNA-block copolymer cages. These biohybrid cages possess polymer chains that are programmably positioned in three dimensions on a DNA core and display increased nuclease resistance as compared to unfunctionalized DNA cages.

Changes in objectively measured physical activity (performance) after epidural steroid injection for lumbar spinal stenosis.

OBJECTIVE: To examine changes in objectively measured physical activity (performance) at 1 week following epidural steroid injection for lumbar spinal stenosis. DESIGN: Prospective cohort. SETTING: University spine program. PARTICIPANTS: Individuals (N=17) who were undergoing fluoroscopically guided epidural steroid injection for symptomatic lumbar spinal stenosis (mean age ± SD, 70.1±6.7; 47% women). INTERVENTION: Fluoroscopically guided epidural injection. MAIN OUTCOME MEASURE(S): The 2 primary outcomes, measured with accelerometers, were total activity (performance) measured over 7 days and maximum continuous activity (capacity). Walking capacity was also assessed with the Self-Paced Walking Test, and subjects completed the Oswestry Disability Index, Swiss Spinal Stenosis Questionnaire, Medical Outcomes Study 36-Item Short-Form Health Survey, visual analog pain scales, and body diagrams. RESULTS: At 1 week postinjection, 58.8% of the subjects demonstrated increased total activity and 53% had increased maximum continuous activity, although neither change was statistically significant. Significant improvements were observed in a number of the self-report instruments, including the Physical Function Scale of the Swiss Spinal Stenosis Questionnaire, general health (Medical Outcomes Study 36-Item Short-Form Health Survey), role-limitation emotional (Medical Outcomes Study 36-Item Short-Form Health Survey), leg pain intensity (visual analog pain scales), and presence of leg weakness. CONCLUSIONS: While patients perceived improvements in pain and function following injection, these improvements were not reflected in significant changes in performance or capacity. Future studies will continue to find value in subjective measures of pain and quality of life. However, with modern technology, performance is no longer a subjective variable. Use of activity monitors to objectively measure performance can result in more rigorous validation of treatment effects, while simultaneously highlighting the potential need for additional postinjection rehabilitation aimed at improving performance.

Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice.

The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer's disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer's disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.

The effect of modular tapered fluted stems on proximal stress shielding in the human femur.

The purpose of this study was to show a change in proximal femur surface strains following total hip arthroplasty and after the addition of BoneSource hydroxyapatite bone cement in the proximal region of an instrumented femur and to measure the surface strain on the proximal body. Seven third-generation composite femurs (Pacific Research Laboratories, Vashon, Wash) were instrumented with 12 uniaxial strain gages, 6 gages on the anterior face, and 6 gages on the posterior face of each femur. All femurs exhibited stress shielding since the strains in the proximal region were drastically reduced. There was a large decrease in strain in the mid-shaft region and small changes in strain in the distal region. The surface strains on the modular implant were relatively low.

Using Clinical Decision Support Within the Electronic Health Record to Reduce Incorrect Prescribing for Acute Sinusitis.

PURPOSE: Acute sinusitis has viral etiology in more than 90% of cases, but antibiotics are prescribed for more than 80% of adults in the United States. While applications of computer-assisted guidelines have been found effective in reducing inaccurate prescribing for acute respiratory infections, there is a paucity of research focused specifically on the utilization of electronic best practice alerts (BPA) in improving treatment for acute sinusitis. METHODS: This observational cohort study examined prescribing behavior for sinusitis at a single Federally Qualified Health Center 1 year prior and during the first year of implementation of a BPA in the electronic health record (EHR) reminding providers of the recommended treatment of sinusitis. The advisory included a link to national guidelines and a note template was installed to assist providers in documentation. The BPA appeared on the providers' screen when an ICD-9 code of acute or bacterial sinusitis was entered during the patient visit. RESULTS: After adjusting for select patient and provider factors, the computer-assisted guidelines effectively reduced the overall antibiotic prescribing among these patients by 31% (relative risk: 0.69, 95% confidence interval: 0.51-0.95) and reduced incorrect prescribing from 88.5% to 78.7% (P=0.02). CONCLUSIONS: Clinical reminders within the EHR can be an effective tool to reduce inappropriate antibiotic use and improve providers' decisions regarding the correct antibiotic choices for patients with acute sinusitis.

Prevalence of Inadequate Immunity to Measles, Mumps, Rubella, and Varicella in MLB and NBA Athletes.

BACKGROUND: Multiple outbreaks of vaccine-preventable viral diseases have occurred in professional sports in recent years. Currently, there is no established protocol for vaccination or immunity screening for professional athletes. HYPOTHESIS: There are significant differences in the prevalence of inadequate immunity dependent on age, sport, country of birth, and participation in collegiate sports. STUDY DESIGN: Cross-sectional cohort study. LEVEL OF EVIDENCE: Level 4. METHODS: A sample of Major League Baseball (MLB) and National Basketball Association (NBA) players were screened for serologic evidence of immunity to measles, mumps, rubella, and varicella prior to the 2015 and 2016 seasons. The results were designated as adequate (immune) or inadequate (equivocal or nonimmune) based on laboratory criteria. Comparison with an age-matched control group was performed using data from the National Health and Nutrition Examination Survey (NHANES). RESULTS: A total of 98 athletes (62 MLB, 36 NBA) were screened. The prevalence of inadequate immunity for any virus was 35.5% in MLB players and 33.3% in NBA players. There was a significantly greater risk of inadequate immunity to rubella (risk ratio, 6.38; P < 0.01) and varicella (risk ratio, 4.21; P < 0.01) in athletes compared with the age-matched NHANES population. Our analysis did not reveal differences in rates of immunity based on sport, country of birth (US born vs international), or participation in college athletics. There was a lower rate of inadequate immunity to varicella with increasing age (odds ratio, 0.72; P = 0.05). CONCLUSION: One-third of athletes studied had inadequate immunity to 1 of the 4 viruses tested. Younger players had a significantly greater risk of inadequate immunity to varicella. Birth outside the US and lack of participation in college athletics were not found to influence immunity rates. CLINICAL RELEVANCE: These results can inform the development of future screening programs to prevent outbreaks of viral infections in professional athletes.

Summative Report on Time Out of Play for Major and Minor League Baseball: An Analysis of 49,955 Injuries From 2011 Through 2016.

BACKGROUND: Recent epidemiologic reports have demonstrated rising injury rates in Major League Baseball (MLB) and Minor League Baseball (MiLB). Although several studies have recently been published on specific injuries, the majority of injuries have not yet been formally studied. PURPOSE: The purpose of this study is to (1) generate a summative analysis of all injuries that occur in MLB and MiLB, (2) identify the 50 most common injuries, and (3) generate focused reports and fact sheets on the characteristics of each of those diagnoses. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The MLB Health and Injury Tracking System was used to identify injuries occurring in MLB and MiLB players from 2011 to 2016. Injuries were defined as those that occurred during normal baseball activity and resulted in at least 1 day out of play. A multitude of player and injury characteristics were analyzed, and detailed reports of the 50 most commonly occurring injuries were generated. RESULTS: A total of 49,955 injuries occurred during the study period; 45,123 were non-season ending, and they resulted in 722,176 days out of play. The mean (median) days missed per injury was 16 (6) days. Overall, 39.1% of all injuries occurred in pitchers. The upper extremity was involved in 39% of injuries, while 35% occurred in the hip/groin/lower extremity. Surgery was required in 6.5% of cases, and 9.7% of injuries were season ending. Hamstring strains were the most common injury (n = 3337), followed by rotator cuff strain/tear (n = 1874), paralumbar muscle strain (n = 1313), biceps tendinitis (n = 1264), oblique strain (n = 1249), and elbow ulnar collateral ligament injury (n = 1191). The diagnoses that were most likely to end a player's season were elbow ulnar collateral ligament injury (60% season ending) and superior labrum anterior and posterior tear (50.9% season ending). CONCLUSION: Contrary to prior reports relying on disabled list data, the annual number of injuries in professional baseball remained steady from 2011 to 2016. Similar trends were noted for the annual number of days missed and mean days missed per injury. Although the mean days missed per injury was high (16), the median was much lower at 6 days.

Correction: Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown.

Correction for 'Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown' by Johans J. Fakhoury, et al., Nanoscale, 2015, 7, 20625-20634.

Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown.

Therapeutic nucleic acids are powerful molecules for shutting down protein expression. However, their cellular uptake is poor and requires transport vectors, such as cationic polymers. Of these, poly(ethylenimine) (PEI) has been shown to be an efficient vehicle for nucleic acid transport into cells. However, cytotoxicity has been a major hurdle in the development of PEI-DNA complexes as clinically viable therapeutics. We have synthesized antisense-polymer conjugates, where the polymeric block is completely monodisperse and sequence-controlled. Depending on the polymer sequence, these can self-assemble to produce micelles of very low polydispersity. The introduction of linear poly(ethylenimine) to these micelles leads to aggregation into size-defined PEI-mediated superstructures. Subsequently, both cellular uptake and gene silencing are greatly enhanced over extended periods compared to antisense alone, while at the same time cellular cytotoxicity remains very low. In contrast, gene silencing is not enhanced with antisense polymer conjugates that are not able to self-assemble into micelles. Thus, using antisense precision micelles, we are able to achieve significant transfection and knockdown with minimal cytotoxicity at much lower concentrations of linear PEI then previously reported. Consequently, a conceptual solution to the problem of antisense or siRNA delivery is to self-assemble these molecules into 'gene-like' micelles with high local charge and increased stability, thus reducing the amount of transfection agent needed for effective gene silencing.

DNA nanostructure serum stability: greater than the sum of its parts.

Simple chemical modifications to oligonucleotide ends with hexaethylene glycol and hexanediol are shown to significantly increase nuclease resistance under serum conditions. The modified oligonucleotides were used to construct DNA prismatic cages in a single step and in quantitative yield. These cages further stabilize their strands towards nucleases, with lifetimes of 62 hours in serum. The cages contain a large number of single-stranded regions for functionalization, illustrating their versatility for biological applications.

Walking assessment in people with lumbar spinal stenosis: capacity, performance, and self-report measures.

BACKGROUND CONTEXT: Ambulation limitation is the hallmark of impairment in lumbar spinal stenosis (LSS). Capacity and performance have been defined as two distinct aspects of disability. Previous literature suggests that a person's walking capacity may not be reflected in their daily walking performance. PURPOSE: To examine the relationship between survey instruments, tested walking capacity, and daily ambulatory performance in people diagnosed with LSS. STUDY DESIGN/SETTING: Prospective laboratory and clinical observational study at a tertiary care spine clinic. PATIENT SAMPLE: Twelve subjects with LSS significant enough to be scheduled for epidural injection. OUTCOME MEASURES: Questionnaire (including the Swiss Spinal Stenosis Questionnaire, Pain Disability Index, Oswestry Disability Index, Quebec Back Pain Disability Scale, and 36-Item Short Form Health Survey), laboratory walk testing (walking capacity), and activity monitors (community ambulation). METHODS: Subjects filled out functional questionnaires, performed a Self-Paced Walking Test (SPWT) of up to 30 minutes, and wore an Actigraph activity monitor during walking hours for 7 days. RESULTS: There was no statistically significant relationship between walking capacity (SPWT) and community ambulation per day (activity monitors), however, the maximum time of continuous activity during community ambulation had a strong relationship (r=0.63) with the SPWT. Fifteen self-report measures of ambulation were significantly correlated with the SPWT, activity monitor, or both. Of these, 13 (87%) were more highly correlated to the SPWT than the activity monitor. The SPWT had a strong relationship (r>0.60, p<.05) with global function scales but community ambulation did not. CONCLUSIONS: Walking capacity and walking performance in LSS appear to be different constructs. Survey instruments appear to reflect capacity rather than performance. This dissociation between walking capacity and walking performance has implications for the clinical management and outcomes assessment of people with LSS.