Authors: Gillian Hotz PhD1, Jacob R. Griffin2, Hengyi Ke3, Raymond Crittenden IV2, Abraham Chileuitt MD4

1Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA

2KiDZ Neuroscience Center, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA

3Department of Public Health, Division of Biostatistics, University of Miami Miller School of Medicine, Miami, FL, USA

4Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

Corresponding Author:

Gillian Hotz, Ph.D.
1095 NW 14th Ter
Miami, FL 33136
ghotz@med.miami.edu
305-243-2074

Gillian A. Hotz, PhD is a research professor at the University of Miami Miller School of Medicine and a nationally recognized behavioral neuroscientist and expert in pediatric and adult neurotrauma, concussion management, and neurorehabilitation. Dr. Hotz is the director of the KiDZ Neuroscience Center, WalkSafe, and BikeSafe programs.

Return to Play and Learn: Findings from a Countywide High School Sports-Related Concussion Program

ABSTRACT

Purpose
To report return to play (RTP) and learn (RTL) findings of high school athletes with a sports-related concussion (SRC) from a 10-year injury surveillance system. The goal was also to explore differences between athletes who received and did not receive academic accommodations.

Methods

SRC data was entered into a REDCap database by certified athletic trainers (ATs) at 35 public high schools in Miami-Dade County (MDC). A required 6 Steps to Safe Play concussion protocol was implemented between 2012 to 2022. Concussion Clinic data was also reported for as well as symptom scores of post-injury ImPACT retesting.

Results

From review and analysis of the ImPACT retesting scores, the most common symptoms reported included; headache (54.0%), difficulty concentrating (35.0%), sensitivity to light (34.6%), and dizziness (30.5%). Overall, female athletes reported a higher symptom count and severity on post-injury ImPACT assessments than males (7 vs. 4 total symptoms score; p < 0.001), and all but 4 of the 22 reportable symptoms listed on the symptom inventory (vomiting, fatigue, numbness/tingling, and difficulty remembering) were significant (p < 0.05) between males and females. Despite experiencing a greater number of overall SRCs, athletes playing football had a smaller average (p < 0.001) ImPACT total symptom score than athletes playing other sports (10.9 vs. 14.2). Those seen in clinic and receiving academic accommodations were less likely to RTP, have a greater (p < 0.05) ImPACT total symptom score, more days between injury date and post-ImPACT testing, and a greater number of days until returning to play than athletes not academically accommodated.

Conclusions

It is important for concussion providers to identify and monitor symptoms post-SRC. Study findings report that high school female athletes report more symptoms following an SRC and that appropriate academic accommodations should be included when necessary to ensure athletes recover in a safe and timely manner. Understanding how SRC symptoms vary based on an athlete’s circumstances can help in managing SRC and making better RTL and RTL decisions.

Application In Sports

Academic accommodations, when appropriate, should be incorporated and implemented in an athlete’s recovery plan to help them safely return to the field and classroom after an SRC.

Key Words: Concussion, Adolescent, Accommodations, Symptoms

INTRODUCTION

Understanding factors that place certain groups at a higher risk of sports-related concussion (SRC) and post-SRC symptoms is useful in helping to navigate the difficulties of diagnosis and to better manage those most at risk. Historically, research has indicated that sex may be an important risk factor predicting SRC severity (1).More specifically, females have been found to have higher rates of SRC compared with males in sex-comparable sports and worse outcomes overall following SRC (1, 2).  One meta-analysis reported that out of 20 outcome variables measured after traumatic brain injury (TBI), females presented with worse outcomes for 17 (85%) of them, including post concussive symptoms, posttraumatic amnesia, and ability to return to work (3). Research also points to differences in the specific symptoms experienced between males and females. A study in 2011 (4) found that despite no difference in the number of symptoms reported, males reported more frequently amnesia and confusion/disorientation, while females instead were more likely to report drowsiness and sensitivity to noise.Additionally, researchers examining sex differences in symptoms reported that females experienced worse cognitive symptoms (poor concentration, forgetfulness) and somatic symptoms (headaches, dizziness,) than males after SRC (5).

The ImPACT neurocognitive screening test has been implemented and is part of the 6-step protocol of the University of Miami Miller School of Medicine’s Concussion Clinic in South Florida colloquially referred to as “UConcussion” (UCC). The UCC provides a comprehensive, interdisciplinary team approach to SRC management. In 2012, the UCC developed and implemented the Countywide Concussion Care Program (CCCP) to provide SRC management and treatment to the 35 public high schools in Miami Dade County (MDC) (6).ImPACT is a 20-minute online screening test that athletes playing contact sports in MDC public high schools complete on a computer prior to the sport season to establish a neurocognitive baseline (7, 8). A post-injury ImPACT retest is later completed by an athlete after a suspected SRC as it can provide a more comprehensive assessment of the severity of the injury and any issues athletes are experiencing.

The UCC and MDC school system consider the ImPACT testing process to be an important part of SRC management and treatment plan, and therefore, educational workshops are hosted by the UCC team on an annual basis to ensure MDC ATs know when and how to perform ImPACT tests so that results are as accurate and timely as possible. Funding for workshops and ImPACT tests for both MDC and Palm Beach County public high school athletes comes from The Miami Dolphins Foundation (6).Since reported symptoms, scores, and results from ImPACT tests are web based, they are easily accessed. UCC team member certified by ImPACT use the report during clinic visits to help make return to play (RTP) decisions.

ImPACT results are also used in the UCC clinical setting to determine the return to learn (RTL) timelines and to provide academic accommodations if appropriate. Historically, most of the advancement in education, policy, and research surrounding SRC has focused on RTP rather than RTL as evident by 50 states that have required RTP protocols since 2009. In comparison, only 8 states in 2016 had youth concussion laws that included RTL protocols (6, 9). Other states that have updated concussion laws since then to include RTL have mostly mandated for athletes only, which excludes the substantial number of concussions sustained in other settings such as recreational sports, non-sports falls, and car crashes (9).

To best ensure academic accommodations are granted and followed correctly, a collaborative approach has been recommended by the Concussion in Sport Group (CISG) 2017 consensus statement (6, 11). The UCC has implemented the CISG’s recommended approach within the CCCP by making available a multidisciplinary team of clinicians, neuropsychologists, and psychologists who can treat and manage the unique needs of athletes (6). In the annual workshops hosted by the UCC, ATs and athletic directors (ADs) are also reminded on the importance of academic accommodations and how to effectively coordinate needs with principals, counselors, and teachers. Continued education ensures responsible individuals understand the need for implementing the requested academic accommodations (12, 13). Due to a historical lack of awareness and importance of this necessity, there exists a need for more research regarding RTL management and academic accommodations (6, 11, 14).

The purpose of this study was to examine and report findings related to RTP and RTL of high school SRCs. Sex, sport, symptom, and academic accommodation differences were analyzed to determine their impact on RTP and RTL. Based on existing literature, it was hypothesized that females would report a greater number of and more severe symptoms, and those receiving academic accommodations would report a greater number of symptoms and have increased RTP days compared to those not receiving academic accommodations.

METHODS

Participants

This study included all MDC public high school SRCs that occurred in all sports’ practices or games between August 1st, 2012, and July 31st, 2022. Athletes that sustained an SRC outside of the study period were excluded as well as those with an SRC that did not occur during an MDC public high school sports practice or competition. Only athletes treated at the UCC are included in academic accommodation vs. no academic accommodation comparisons. Approval for this study was obtained from the Miami-Dade County Public School Department of Athletics and the University of Miami Institutional Review Board.

Protocol and Variables

Before every fall sports season starts, the UCC team provides ATs and ADs at MDC high schools with a training and educational workshop on SRC management and injury surveillance reporting. ATs are trained to immediately remove athletes exhibiting SRC symptoms from play or practice and manage athlete SRCs through the CCCP’s approved 6 Steps-to-Safe-Play return protocol (6).The first step of the protocol requires that athletes complete an ImPACT test prior to the season that serves as a baseline if a suspected SRC occurs. ATs use sideline assessment tests on athletes displaying signs or symptoms of an SRC to determine if the athlete should be removed from further play. Within 72 hours of injury, ATs should administer a post-injury ImPACT test and contact the UCC program director to share results and schedule an appointment for further clinical evaluation and treatment. Once at the UCC, athletes are seen by the program director and a neurologist trained in SRC. Neurotologists, neuropsychologists, and psychologists are also staffed and available if needed. During appointments, the program director and neurologist perform an extensive interview, neurological and vestibular evaluation, and if appropriate, a neurocognitive screening. ImPACT scores, athlete medical histories, and reported post SRC symptoms are reviewed as well.

Following the comprehensive assessment of an athlete, the UCC team provides recommendations regarding RTP to athletes, parents, coaches, and ATs. To clear an athlete to RTP, a Graduated Return to Play (GRTP) protocol is initiated and exertional actives are advanced as tolerated monitoring any symptoms. Athletes first begin with low levels of exertion and continually build to moderate and heavy exertion if they remain asymptomatic throughout. Athletes usually return to full contact practice and play activities within a three- to four-day period (6).

Academic accommodations are also recommended if the athlete is deemed to have any neurocognitive or psychological diagnoses that may affect school performance. The accommodation form is filled out by the UCC team and provided to ATs so that they can work in conjunction with parents, school principals, and athletic directors to ensure academic accommodations are implemented.

Once the athlete returns to play or a decision is made to retire the athlete, ATs at the 35 public MDC high schools are required to log into the UCC website and report every SRC using a Research Electronic Data Capture (REDCap) system (15).This database makes up the Concussion Injury Surveillance System (CISS). Trained UCC Research Assistants enter athlete’s data into a separate REDCap database if an individual is treated at the UCC. Reported variables include demographics, ImPACT testing scores, clinic dates, treatment plan, and completion of the academic accommodation and RTP forms. The amount, frequency, and type of academic accommodations are included in REDCap and reevaluated as well as updated with each additional clinic visit. SRC specific information is also reported and includes the sport played while injured, date of injury (DOI), days between DOI and clinic date (if treated at the UCC), and days between RTP and DOI (days withheld).

In this study, athletes who received any academic accommodation after a sustained SRC were grouped in the “accommodation” group while those did not were grouped in the “no accommodation” group. This classification was done to make comparisons between the groups. Additionally, since football accounted for over half of SRCs during the study period, post-SRC symptom comparisons between athletes who played football and those who did not play football were also examined.

Athlete ImPACT baseline testing and post-injury data from the ImPACT Test online database were included and were used to make comparisons between different populations. This data included self-reported symptoms and completion dates. A greater total symptom score on post-injury ImPACT assessments indicates more symptoms being reported.

Data Analysis

Data analysis was conducted using R software. The SRC symptoms data was selected from athletes who had a post-injury ImPACT retest between 2012 to 2022. The data were grouped by sex and accommodation status. For continuous data in the normal distribution, like “Total Symptom Score,” mean and standard deviation were reported. For categorical data, such as “Headache,” data were presented as frequency and percentage. Sample t-test was used to detect the significant difference for continuous data in the normal distribution. The Chi-Square test was used to detect significant differences for categorical data. Statistical significance was set at < 0.05.

RESULTS

Symptoms and Return to Play

Of the athletes who enrolled in this investigation over this 10-year period, 1,421 of 1,641 had a post-injury ImPACT retest.Of those who had a post-injury ImPACT retest, 1,070 of were completed by a male (75.3%) and 351 (24.7%) by a female. Female post-injury ImPACT total symptom scores were an average of 7 (SD: 6), which was significantly greater (p < 0.001) than the average of 4 (SD: 5) reported by males. From the 22 available symptom options included on ImPACT, the most reported symptoms overall were headache (54.0%), difficulty concentrating (35.0%), sensitivity to light (34.6%), and dizziness (30.5%). These symptoms were similarly the highest reported by males, while females reported the former 3 with the most frequency but included sensitivity to noise (37.9%) as opposed to dizziness (37.6%). Despite having less SRCs, a greater percentage of females reported experiencing each of the 22 symptoms than did males (e.g., 50.8% of males reported headache vs. 63.8% of females). Symptom differences between males and females were significant (p < 0.05) for each of the symptoms except for vomiting (p = 0.5), fatigue (p = 0.24), numbness or tingling (p = 0.47), and difficulty remembering (p = 0.1) (Table 1).

The relationship between total symptom score provided from post-injury ImPACT retests and RTP status was examined to determine if differences existed between those who did and did not RTP. Of the 1,430 athletes who did RTP, 1250 (87.4%) completed a post-injury ImPACT retest after the SRC event. The average symptom score for this group was 12 (SD: 16). 78 athletes did not RTP after injury over the 10 years, and 51 (65.4%) completed a post-injury ImPACT retest. Average symptom scores for this group were 20 (SD: 23). The difference between average symptom scores between those who did RTP and those who did not RTP was significant (p = 0.01) (Table 2).

Reported Post Concussion Symptoms

Symptoms reported by sport played during injury were reported to examine whether differences existed. Athletes whose sport was reported and had a post-injury ImPACT retest completed were classified into either the football or non-football group. The average total symptom score for the non-football group was significantly greater (p = 0.001) than the football group (14.2 vs. 10.9). Aside from vomiting, a greater percentage of the non-football group reported each of the symptoms than the football group, and this difference was significant for all but headache, fatigue, sleeping more than usual, sleeping less than usual, drowsiness, numbness/tingling, feeling slowed down, difficulty remembering, and visual problems (Table 3).

Accommodations

Differences in symptoms between UCC athletes receiving academic accommodations (A) and athletes not receiving academic accommodations (NA) groups were examined and reported to provide insight into post-injury symptom severity and its correlation to academic accommodation needs. The A group reported an average total symptom score of 25.8 (SD: 20.8), which was significantly greater (p < 0.001) than the NA group with an average of 11.5 (SD: 15.2). A greater percentage of the A group reported or experienced each of the 22 reportable symptoms included on ImPACT than the NA group (e.g., 80.8% of the A group reported headache vs. 56.1% of the NA group). This between group difference was found to be significant (p < 0.05) for every symptom except for vomiting (p = 0.37) (Table 4).

Also, SRC-specific variable differences, including RTP, days between DOI and post-injury ImPACT retest, days withheld, and days between DOI and clinic date, between A and NA groups were examined to determine if academic accommodation needs were related to and can be used to help predict any of these variables. A significantly (p < 0.001) greater percentage of the NA group did RTP compared to the A group (95.6% vs. 87.0%). There were also significant differences between the A and NA groups for days between DOI and post-injury ImPACT retest (p = 0.02) and days withheld (p < 0.001) as the average days for both was significantly greater for the A group. In contrast, the average days between DOI and clinic date were instead significantly (p = 0.004) greater for the NA group (10.0 vs. 13.1 days) than those in the A group (10 days) (Table 5).

DISCUSSION

RTL protocols oftentimes include academic accommodations to help reintegrate athletes back into the academic setting and ensuring recovery is not delayed by academic requirements and significant cognitive demand that can further cause symptoms and delay recovery (6). Consequently, understanding risk factors and symptoms contributing to delayed recovery is useful in predicting who may initially have difficulty transitioning back to class after an SRC. The CISS with REDCap database was analyzed and findings were reported. These findings provide further insight into how sex and sport may affect SRC symptoms, and subsequent RTP and RTL, but also how the need for academic accommodations may assist in predicting SRC outcomes.

Symptom Differences by Sex

As mentioned earlier, the need to clinically diagnose SRCs relies largely on the symptoms that athletes report (16).For CCCP surveillance data used in this study, symptom information was obtained via self-report by athletes completing post-injury ImPACT retests. Over the 10 years, average total symptom scores reported on ImPACT were higher for females than males (7 vs. 4). While consistent with some studies (3, 17),others have found no difference in the number of symptoms between these groups (4).This inconsistency may be the result of differences in populations studied or methods by which symptoms were reported. Additionally, with some of these studies being completed over a decade ago, the changing culture surrounding SRC may have contributed to reporting differences (18).

The most reported symptom was headache for both sexes (50.8% of males and 63.8% of females). Headache is one of the most commonly reported SRC symptoms (4,19). High school football players’ knowledge regarding signs and symptoms of SRC has been reported, with headache being the most common SRC symptom correctly identified by participants (20).This accuracy may be one factor contributing to prevalence of headache as it suggests that a majority of the study population (high school male football players) are aware that headache is a symptom of SRC and may be more likely to report it compared to other symptoms. It also emphasizes the importance of continued education to ensure that athletes understand the range of SRC symptoms so they can better detect and report what they experience.

The ImPACT test symptom inventory includes 22 symptoms that athletes can self-report (7, 8).In this study, a greater percentage of female athletes reported experiencing each of the symptoms than did males for all but 4 (vomiting, fatigue, numbness/tingling, and difficulty remembering) (see Table 1). There is still a need for increased information on how SRC symptoms differ between sexes, especially within the adolescent age group (4).These results give further insight into how SRC symptoms manifest differently based on sex and supplement existing literature(1, 2) that indicates females may have poorer outcomes following SRC and be at risk for prolonged RTP and RTL recovery.

Historically, a substantial amount of SRC research has focused solely on males, specifically football players (21). D’Lauro et al. (2022)reported that influential SRC consensus and position statements guiding clinical care of SRC relied on samples that were overall 80.1% male, with 40.4% of these studies including no female participants whatsoever (21).Medical professionals rely on these consensus and position statements to guide their treatment of SRC cases. Consequently, contemporary treatment of SRC may not be based on research that is representative of female athletes (21). This study’s data, along with other evidence (22), indicates females report significantly more symptoms and suggests high school female athletes are at greater risk for slower recovery. Females may benefit from additional research on sex differences in SRC. Results of future studies will lead to improved SRC guidelines, policies, and protocols that are the basis of more inclusive research with diverse populations, leaving no population disproportionately represented.

Return to Play

Research shows that one of the most consistent predictors of SRC recovery is the number and severity of symptoms (22, 23). While these studies have mostly focused on athletes who all did RTP at some point, the researchers wanted to see if this relationship held between athletes who RTP and those who did not RTP for various reasons (medically not cleared to return to play, quit sport, etc.). The average total symptom score (via ImPACT) for athletes who RTP was 12 and for those who did not RTP was 20 (see Table 2) which highlights the importance of ImPACT testing and why the CCCP and MDC consider the tool to be an important and useful step of SRC management. Following a suspected SRC, it is recommended that an athlete completes the post-injury ImPACT retest within 72 hours. Repeating the ImPACT test promptly after an SRC provides health professionals an additional tool to use in diagnosing whether an SRC has occurred, but as suggested by this study, may help in predicting whether an athlete will have prolonged RTP or is at risk of not returning at all.

Symptom Differences by Sport

Football is recognized as having one of the highest rates of SRC and injuries overall in the high school setting (24). For this study population, over half of the SRCs (56.4%) occurred in athletes who played football. Consequently, differences in symptoms were examined between athletes who played football vs. athletes playing other sports (non-football group) to determine whether football players are at an increased risk of severe symptoms that influence RTP and RTL following SRC. The opposite was found and reported as the non-football group average ImPACT total symptom score was greater than the average for the football group (see Table 3). Potential explanations include football players being less transparent in symptom reporting, less aware about SRC symptoms, and because non-football players may experience different types of symptoms. While several existing studies examine high school SRC rate variation by sport (24, 25), there is limited data that shows how outcomes and symptoms differ. Future research on this topic would be beneficial in helping to predict if athletes participating in a particular sport may be at greater risk for prolonged RTP and RTL.

Symptom Comparisons by Accommodation Status

Included in the UCC’s RTL protocol are academic accommodations individually designed to best reintegrate injured athletes into the school setting. Academic accommodations include short-term environmental adjustments; wearing sunglasses to reduce light exposure, and wearing blue light glasses for computer use. Accommodations may additionally include extra time for completion of assignments and exams, and modifications to educational plans that may become more permanent (26, 27). Athletes with an SRC are at risk for a wide range of symptoms that can negatively impact academic performance. Additionally, the cognitive demand required at school may further worsen symptoms and delay recovery from SRC, which has implications for both the on and off the field settings (28, 29). Therefore, academic accommodations are an important part of the RTL protocol that can help limit the extent of impairment and get athletes back to fully participating in the classroom and the field in a safe and timely manner.

The AT, along with the AD, principals, counselors, and teaching staff, should work in tandem with the athlete to ensure that all recommended academic accommodations are followed (11, 12, 13). Types of academic accommodations include environmental, physical, curriculum, and testing, with some of the most common ones for the UCC being rest breaks, limited screen-time, limited physical exertion, and extra time to complete assignments (6). For athletes with persisting symptoms, a 504 Plan may be implemented. A 504 Plan is part of the Rehabilitation Act of 1973 and is a formal process by which public schools must provide services or modifications to students with disabilities (29).These plans may be amended as symptoms worsen or instead if the athlete’s health improves.

Current literature suggests that the cognitive demand required at school can potentially further worsen symptoms and delay recovery (28, 29). In this study, those that had a greater number of symptoms were more likely to have academic accommodations. Using post-injury ImPACT retests, the A group reported a greater average total symptom score on post-injury ImPACT retesting than the NA group (see Table 4). A greater percentage of the A group reported each of the 22 symptoms than the NA group as well. These results demonstrate that ImPACT testing and symptom reporting may be beneficial in assisting medical professionals as this study indicates that those with a greater number of and more severe symptoms may be more likely to need academic accommodations included in their RTL and RTP plans. Athletes that delay reporting symptoms, “Playing Through It”(30), put themselves at risk for more severe injury but also minimize information medical professionals can use for providing RTL and RTP recommendations. When symptoms are reported in a timely manner, it assists medical providers with determining the severity of an SRC and the potential need for academic accommodations.

Concussion-Specific Variables by Accommodation Status

Previous literature(6) shows that athletes receiving academic accommodations for an SRC are likely to take longer to RTP. In this study, the NA group had a significantly greater RTP percentage than the A group (95.6% vs. 87.0%). The number of days for RTP (days withheld) was also longer for the A group than the NA group (see Table 5). These results suggest that athletes receiving academic accommodation may have had a more severe SRC that puts them at risk for a longer RTP timeline and potentially no RTP at all.

This study reported that the number of days between DOI and post-injury ImPACT retest was longer for the A group (9.5 vs. 7.8). Using a tool like ImPACT after a suspected SRC was beneficial because it indicated that a potential SRC had been identified and that the UCC’s 6-step protocol was being followed (6). Earlier initiation of clinical care following an SRC is associated with a shorter recovery time (31). In this study, the A group was on average treated in the clinic sooner than the NA group (see Table 5). These findings highlight the importance of having a well-defined SRC protocol and clinic management program so that athletes with an SRC can be identified and treated as soon as possible. 

Limitations

This study is not without limitations. All participants in this study were athletes that attended a public MDC high school. Results may not be generalizable to other playing levels, like youth, middle schools, and college, nor to public or private high schools in other counties. Additionally, while other counties may have their own SRC surveillance system, they may not have a program, such as the UConcussion program, that provides ATs with additional SRC training and encourages timely, accurate reporting. The ImPACT test itself also has limitations since athletes are self-reporting symptoms which may not be reportable with full disclosure in order to RTP sooner.

CONCLUSIONS

The overall goal of this study was to examine factors, including sex, sport, symptoms, and academic accommodation status, that may affect the return to play and learn of high school athletes who experience an SRC. Results showed that females, non-football athletes, and those athletes who did not RTP experienced significantly greater symptoms. Additionally, athletes in the A group had more symptoms and longer RTP. This study highlights the importance of providing a standardized SRC protocol and organized clinic management system for ensuring that high school SRC are identified and addressed appropriately. These protocols and systems can prevent further injury and allow athletes to return to play and the classroom in a safe but timely manner.

APPLICATIONS IN SPORT

Ensuring appropriate academic accommodations are implemented when an athlete is recovering from an SRC is important for helping the individual to reintegrate into the classroom and field (or court) safely. The accommodation form is also important to prevent worsening symptoms. School districts and athletic departments would benefit from a dedicated SRC program and protocol that helps them identify, treat, and manage athletes with an SRC.

Acknowledgements

The authors would like to thank: Dr. Kaplan and the UHealth Sports Medicine Clinic and Staff, the Division of Athletics and Activities for the Miami-Dade County Public Schools, all Miami-Dade County High School Certified Athletic Trainers, previous UConcussion team members, Dr Kester Nedd who served as medical director of the program from 2012 to 2019, current medical director Dr. Abraham Chileuitt, pediatric medical director Dr. Juan Solano, and other clinical staff including Dr. Mitchell Slugh and Dr. Jennifer Coto, and also The Miami Dolphin Foundation for supporting countywide ImPACT testing and educational workshops. The authors also want to thank David Goldstein and the Goldstein Family for the development of the Countywide Concussion Care Program and their initial and continued support. The work of Hengyi Ke was supported by the University of Miami Clinical and Translational Science Institute.

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