Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.

BACKGROUND: Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. METHODS: This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. RESULTS: A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065-1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228-1:51 867] versus 1:164 504 [95% CI, 1:110 552-1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417-1:34 925] versus 1:74 581 [1:60 247-1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). CONCLUSIONS: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

Novel synthetic procedures for C2 substituted imidazoquinolines as ligands for the α/ß-interface of the GABAA-receptor.

A series of substituted imidazoquinolines, a structurally related chemotype to pyrazoloquinolinones, a well-known class of GABAA ligands, was prepared via two synthetic procedures and the efficiency of these procedures were compared. One method relies on classical heterocyclic synthesis, the other one aims at late-stage decoration of a truncated scaffold via direct C-H functionalization. A pharmacological evaluation disclosed that one of the synthesized derivatives showed interesting activity on a α1ß3 containing receptor subtype. Supplementary Information: The online version contains supplementary material available at 10.1007/s00706-022-02988-8.

Knee pain and injury: When is a surgical consult needed?

This review identifies clinical scenarios-such as unstable or displaced fractures, major tendon ruptures, and significant mechanical issues-that likely warrant surgical consultation.

Risk factors for immediate failure of outpatient surgery in gynecologic surgery.

OBJECTIVE: To describe the risk factors for immediate failure of gynecologic outpatient surgery. The secondary objective was to describe the risk factors for rehospitalization within 30 days after surgery. METHODS: This is a single-center retrospective cohort study conducted on all patients operated on in outpatient surgery in gynecology at the Lille University Hospital. The primary outcome was defined as any unanticipated admission to the inpatient postoperative care unit on the day of the operation. The secondary outcome was defined as any rehospitalization within 30 days following the intervention. Our statistical analysis included 916 patients operated on between January and July 2019. RESULTS: In our study, 84 patients (9.2%) had an immediate failure of outpatient surgery. The most frequent etiologies were surgical (58.3%). In multivariate analysis with logistic regression, the following variables were associated with an increased risk of immediate failure of outpatient surgery: urogynecologic surgery (P < 0.001), complex laparoscopy (P = 0.004), endometriosis surgery (P < 0.001), and a duration of intervention longer than 1 hour (P < 0.001). CONCLUSION: We find an increased risk of immediate failure of gynecologic outpatient surgery depending on the type of surgery as well as for surgeries lasting more than 1 hour.

Do 'pathologic' cardiac murmurs in adolescents identify structural heart disease? An evaluation of 15 141 active adolescents for conditions that put them at risk of sudden cardiac death.

OBJECTIVES: We assessed whether the presence and character of a cardiac murmur in adolescents were associated with structural heart disease that confers risk of sudden cardiac death (SCD). METHODS: We performed a retrospective analysis of 15 141 adolescents age 12-19 who underwent a heart screen with history, physical examination and ECG. Participants with any screening abnormality underwent an echocardiogram for the assessment of structural heart disease. Murmurs were classified as physiological or pathological according to standard clinical criteria, and participants with murmurs were compared with a comparison group without murmurs. The primary outcome was echocardiogram-detected structural heart disease associated with SCD. RESULTS: 905 participants with a cardiac murmur (mean age 15.8; 58% male) and 4333 participants without a murmur (comparison group; mean age 15.8; 55% male) had an echocardiogram to detect structural heart disease. 743 (82%) murmurs were described as physiological and 162 (18%) as pathological. Twenty-five (2.8%) participants with murmurs and 61 (1.4%) participants without murmurs had structural heart disease. Three (0.3%) participants in the murmur group were diagnosed with hypertrophic cardiomyopathy (HCM) which was the only identified condition associated with SCD. Two participants with HCM had physiological murmurs, one had a pathological murmur, and all three had an abnormal ECG. The most common minor structural heart disease was bicuspid aortic valve in both the murmur (7; 0.8%) and comparison (20; 0.5%) groups. The positive predictive value of physiological versus pathological murmurs for identifying any structural heart disease was 2.4% versus 4.3% (p=0.21), respectively. The positive predictive value of having any murmur versus no murmur for identifying structural heart disease was 2.8% versus 1.4% (p=0.003), respectively. CONCLUSIONS: In adolescents, the traditional classification of cardiac murmurs as 'physiologic' or 'pathologic' does not differentiate for structural heart disease that puts individuals at risk for SCD. We recommend ECG evaluation in all patients with a cardiac murmur found during preparticipation screening to increase detection of HCM.

Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study.

OBJECTIVE: To investigate the aetiology and incidence of sudden cardiac arrest and death (SCA/D) in US competitive athletes. METHODS: Prospective surveillance was conducted from 1 July 2014 to 30 June 2018 through the National Center for Catastrophic Sports Injury Research in collaboration with national sports organisations. Autopsy reports, death certificates, and medical records were reviewed by an expert panel to determine aetiology. Athlete participation statistics from the National Federation of State High School Associations and the National Collegiate Athletic Association (NCAA) were used to calculate incidence rates per athlete-years (AY). Comparisons of incidence rates were calculated using incidence rate ratios (IRR) with 95% CIs. RESULTS: 331 cases of confirmed SCA/D (158 survivors; 173 fatalities) were identified; 15.4% in middle school, 61.6% in high school and 16.6% in college and professional athletes. Average age was 16.7 (11-29) years, and the majority were in male (83.7%), basketball (28.7%) or American football (25.4%) athletes. Common causes included hypertrophic cardiomyopathy (20.6%), idiopathic left ventricular hypertrophy (13.4%), coronary artery anomalies (12.0%) and autopsy-negative sudden unexplained death (9.6%). Coronary anomalies were more common in middle school athletes (28%), while cardiomyopathies (hypertrophic, arrhythmogenic, dilated, non-compaction or restricted) accounted for 47% of cases in college and professional athletes. Incidence was higher in male versus female athletes at the high school (1:43 932 AY (95% CI 1:38 101 to 1:50 907) vs 1:203 786 AY (95% CI 1:145 251 to 1:293 794); IRR 4.6 (95% CI 3.1 to 7.2)) and NCAA (1:34 906 AY (95% CI 1:25 385 to 1:49 173) vs 1:123 278 AY (95% CI 1:66 078 to 1:249 853); IRR 3.5 (95% CI 1.5 to 9.5)) levels. African American male NCAA Division I basketball players had the highest annual incidence rate of SCA/D (1:2087 AY (95% CI 1:1073 to 1:4 450)). CONCLUSIONS: Cardiomyopathies account for nearly half of SCA/D cases in college and professional athletes, while coronary artery anomalies play a more prominent role than expected in middle school athletes. Over half of SCA cases in athletes result in sudden death, calling for improved prevention strategies.

Etiology of Sudden Cardiac Arrest and Death in US Competitive Athletes: A 2-Year Prospective Surveillance Study.

OBJECTIVE: To determine the etiology of sudden cardiac arrest and death (SCA/D) in competitive athletes through a prospective national surveillance program. DESIGN: Sudden cardiac arrest and death cases in middle school, high school, college, and professional athletes were identified from July 2014 to June 2016 through traditional and social media searches, reporting to the National Center for Catastrophic Sports Injury Research, communication with state and national high school associations, review of the Parent Heart Watch database, and search of student-athlete deaths on the NCAA Resolutions List. Autopsy reports and medical records were reviewed by a multidisciplinary panel to determine the underlying cause. SETTING AND PARTICIPANTS: US competitive athletes with SCA/D. MAIN OUTCOME MEASURES: Etiology of SCA/D. RESULTS: A total of 179 cases of SCA/D were identified (74 arrests with survival, 105 deaths): average age 16.6 years (range 11-29), 149 (83.2%) men, 94 (52.5%) whites, and 54 (30.2%) African American. One hundred seventeen (65.4%) had an adjudicated diagnosis, including 83 deaths and 34 survivors. The most common etiologies included hypertrophic cardiomyopathy (19, 16.2%), coronary artery anomalies (16, 13.7%), idiopathic left ventricular hypertrophy/possible cardiomyopathy (13, 11.1%), autopsy-negative sudden unexplained death (8, 6.8%), Wolff-Parkinson-White (8, 6.8%), and long QT syndrome (7, 6.0%). Hypertrophic cardiomyopathy was more common in male basketball (23.3%), football (25%), and African American athletes (30.3%). An estimated 56.4% of cases would likely demonstrate abnormalities on an electrocardiogram. CONCLUSIONS: The etiology of SCA/D in competitive athletes involves a wide range of clinical disorders. More robust reporting mechanisms, standardized autopsy protocols, and accurate etiology data are needed to better inform prevention strategies.

Sudden Death Associated With Sickle Cell Trait Before and After Mandatory Screening.

BACKGROUND: Sickle cell trait (SCT) has been associated with an increased risk of sudden death in athletes during strenuous exercise. In August 2010, the National Collegiate Athletic Association (NCAA) began requiring athletes to be screened for SCT, provide proof of SCT status, or sign a waiver and launched an educational campaign for athletes, coaches, and medical staff. The impact of this program is unknown. The purpose of this study was to determine the incidence of death associated with sickle cell trait (daSCT) in NCAA athletes before and after legislation. HYPOTHESIS: NCAA SCT legislation will decrease the incidence of daSCT. STUDY DESIGN: Observational study. LEVEL OF EVIDENCE: Level 2. METHODS: A database of NCAA athlete deaths from 2000 to 2019 was reviewed for daSCT. A total of 8,309,050 athlete-years (AY) were included. Incidence of death was calculated before and after legislation. RESULTS: The incidence of daSCT in Division I (DI) football athletes before legislation (n = 9) was 1:28,145 AY and after legislation (n = 1) was 1:250,468 AY (relative risk [RR], 0.112; 95% CI, 0.003-0.811; P = 0.022), an 89% reduction in risk after legislation was enacted. The incidence of daSCT in African American DI football athletes before legislation (n = 9) was 1:12,519 AY and after legislation (n = 1) was 1:118,464 AY (RR, 0.106; 95% CI, 0.002-0.763; P = 0.017), also an 89% risk reduction after legislation was enacted. For all NCAA athletes, the incidence of daSCT was 1:489,749 AY before legislation (n = 10) and 1:1,705,780 AY after legislation (n = 2) (RR, 0.288; 95% CI, 0.031-1.347; P = 0.146). CONCLUSION: The incidence of daSCT in DI football athletes has decreased significantly since legislation was enacted. Cases of daSCT outside of football are rare. It is unclear whether the decrease is related to screening for SCT, education, or both. CLINICAL RELEVANCE: This is the first evidence that NCAA SCT legislation may save lives.

Detection and Management of Heart Disease in Athletes.

Primary care clinicians fulfill critical roles of screening for, diagnosing, and managing cardiovascular disease. In young athletes, primary structural and electrical diseases are the focus. Coronary artery disease is the chief concern in older athletes. Sudden cardiac arrest may be the initial presentation of disease and is more common in young athletes than historically appreciated. The traditional preparticipation evaluation, or sports physical, is limited in its ability to accurately raise suspicion of underlying disease. The 12-lead electrocardiogram is a more accurate screening tool. Contemporary risk stratification and treatment protocols may allow for safe return to sport on a case-by-case basis.

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis.

The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure-activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising approach where simpler and fully synthetic intermediates of the natural product's biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.

Survival After Exercise-Related Sudden Cardiac Arrest in Young Athletes: Can We Do Better?

BACKGROUND:: Sudden cardiac arrest (SCA) is the leading cause of death in young athletes during sports. HYPOTHESIS:: Survival after SCA in young athletes is variable. STUDY DESIGN:: Prospective, active surveillance study. LEVEL OF EVIDENCE:: Level 3. METHODS:: From July 1, 2014, to June 30, 2016, exercise-related SCA in competitive young athletes was identified through a systematic search of traditional and social media sources, direct reporting to the National Center for Catastrophic Sports Injury Research, searching of the National Collegiate Athletic Association Resolutions List, regular communication with national and state high school athletic associations, and review of cases in the Parent Heart Watch database. RESULTS:: A total of 132 cases were identified during the 2-year study period (mean patient age, 16 years; age range, 11-27 years; 84% male; 51% white non-Hispanic/Latino, 30% black/African American, and 11% white Hispanic/Latino). High school athletes accounted for 78 (59%) cases, with 28 (21%) in middle school and 15 (11%) in college athletes. Overall survival was 48% (95% CI, 40%-57%; 64 survivors, 68 deaths). Survival was similar in male versus female athletes but higher in white non-Hispanic/Latino (40/67; 60%) versus black/African American (13/39; 33%) athletes (difference, 27%; 95% CI, 7%-45%; P = 0.008) and white non-Hispanic/Latino versus all minority (18/59; 31%) athletes (difference, 29%; 95% CI, 13%-46%; P = 0.001). Basketball accounted for 30% of cases, followed by football (25%), track/cross-country (12%), and soccer (11%). The majority (93%) of cases were witnessed. If a certified athletic trainer was on-site and involved in the resuscitation, 83% of athletes survived. If an on-site automated external defibrillator was used in the resuscitation, 89% of athletes survived. CONCLUSION:: Exercise-related SCA in young, competitive athletes is typically witnessed, providing an opportunity for rapid resuscitation. Additional research is needed to identify factors that affect survival in different athlete populations. CLINICAL RELEVANCE:: Public access defibrillator programs should be universal in schools and youth sporting venues and have the potential to increase survival after SCA in young athletes.

Engineered Flumazenil Recognition Site Provides Mechanistic Insight Governing Benzodiazepine Modulation in GABAA Receptors.

The anxiolytic, anticonvulsant, muscle-relaxant, and sedative-hypnotic effects of benzodiazepine site ligands are mainly elicited by allosteric modulation of GABAA receptors via their extracellular αx+/γ2- ( x = 1, 2, 3, 5) interfaces. In addition, a low affinity binding site at the homologous α+/ß- interfaces was reported for some benzodiazepine site ligands. Classical benzodiazepines and pyrazoloquinolinones have been used as molecular probes to develop structure-activity relationship models for benzodiazepine site activity. Considering all possible α+/ß- and α+/γ- interfaces, such ligands potentially interact with as many as 36 interfaces, giving rise to undesired side effects. Understanding the binding modes at their binding sites will enable rational strategies to design ligands with desired selectivity profiles. Here, we compared benzodiazepine site ligand interactions in the high affinity α1+/γ2- site with the homologous α1+/ß3- site using a successive mutational approach. We incorporated key amino acids known to contribute to high affinity benzodiazepine binding of the γ2- subunit into the ß3- subunit, resulting in a quadruple mutant ß3(4mut) with high affinity flumazenil (Ro 15-1788) binding properties. Intriguingly, some benzodiazepine site ligands displayed positive allosteric modulation in the tested recombinant α1ß3(4mut) constructs while diazepam remained inactive. Consequently, we performed in silico molecular docking in the wildtype receptor and the quadruple mutant. The results led to the conclusion that different benzodiazepine site ligands seem to use distinct binding modes, rather than a common binding mode. These findings provide structural hypotheses for the future optimization of both benzodiazepine site ligands, and ligands that interact with the homologous α+/ß- sites.

SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the α1+/γ2- Benzodiazepine Site.

The structural resolution of a bound ligand-receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure-activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABAA receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and γ2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the γ2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis.

The Use and Abuse of Human Growth Hormone in Sports.

CONTEXT: Recombinant human growth hormone (rHGH) has become a target of abuse in the sporting world. Conversely, sports medicine clinicians may encounter athletes using rHGH to achieve normalcy in the context of growth hormone (GH) deficiency. EVIDENCE ACQUISITION: Medline and PubMed databases were queried using the following keywords: GH, GH physiology, GH deficiency, acromegaly, GH athlete, GH sports, GH athletic performance, and GH deficiency concussion. Articles focusing on GH physiology, deficiency, excess, and its effects in both deficient and healthy patients were included. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: GH is a naturally occurring hormone with important roles in human physiology. Patients with GH deficiency (GHD) present variably, and GHD has numerous etiologies. rHGH treatment has substantial therapeutic benefits for patients with GHD. The benefits of rHGH treatment in otherwise-healthy adults are uncertain. GH excess may cause health problems such as acromegaly. Professional, collegiate, and international sports leagues and associations have banned rHGH use to maintain athlete health, safety, and fair play. Athletes misusing GH may face prolonged suspensions from competition. Implementing GH abuse testing is challenging, but new methods, such as the biomarker testing procedure, are being finalized. CONCLUSION: rHGH is not only an important therapeutic agent for GH-deficient patients but also a target of abuse in competitive athletics. Its benefits in a healthy, adult population are uncertain. A safe exercise and competition plan, developed with a physician knowledgeable of GH use, physiology, and abuse potential, should be of benefit to a longitudinal clinician-patient relationship.

Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors.

Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in α1ß3γ2-, α2ß3γ2-, α3ß3γ2-, and α5ß3γ2-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities, while for the other two chemotypes, a discrepancy in binding affinities of the different isomers was observed. Specifically, the R isomers displayed a loss of binding, whereas the S isomers remained active. These findings are in accordance with the results of our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to those of the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands interact via distinct binding modes rather than by using a common binding mode.

Sudden cardiac arrest on the field of play: turning tragedy into a survivable event.

Sudden cardiac arrest remains the leading cause of death in exercising athletes, and recent studies have shown that it occurs more frequently than historical estimates. While out-of-hospital cardiac arrest often proves fatal, advance preparation can improve outcomes and the chance of survival. First responders to a collapsed athlete on the field of play may include team medical personnel, coaches, other athletes, officials, venue staff, emergency medical services personnel, or lay bystanders. Prompt and accurate recognition of sudden cardiac arrest, a comprehensive and rehearsed emergency action plan, early cardiopulmonary resuscitation, and immediate access to and use of an automated external defibrillator are each pivotal links in the chain of survival. This review summarises the components of an effective emergency action plan, highlights the critical role of automated external defibrillators, and reviews the diagnosis and management of sudden cardiac arrest on the field of play.

Towards functional selectivity for α6ß3γ2 GABAA receptors: a series of novel pyrazoloquinolinones.

BACKGROUND AND PURPOSE: The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/ß- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL APPROACH: Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method. KEY RESULTS: We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6ß3γ2 GABAA receptors with nearly no residual activity at the other αxß3γ2 (x = 1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/ß- interfaces. CONCLUSION AND IMPLICATIONS: These results constitute a major step towards a potential selective positive modulation of certain α6-containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms.