Effect of nonsteroidal anti-inflammatory drugs on union, opioid utilization, and pain management for tibial fractures (NSAID Trial): a pragmatic randomized clinical trial protocol

Supplemental Digital Content is Available in the Text.

Abstract

Objectives:

The orthopaedic community has largely avoided the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the management of pain after fractures based on a combination of animal and clinical data, which suggest their association with impeded fracture healing. Given the significant deleterious effects of opiate analgesics, the use of NSAIDs for pain management in fracture care would be advantageous if potential concerns related to bone healing could be resolved. This study is designed to determine whether planned use of scheduled NSAIDs after fracture leads to a difference in fracture union rates, which in turn provides evidence regarding whether prohibition of NSAID use is justified.

Design:

This was a prospective, two-arm, pragmatic, randomized-controlled multicenter Phase III noninferiority trial.

Setting:

The study was conducted at 14 Level I trauma centers across the United States and Canada.

Patients:

Patients aged 18 to 80 years with open (Gustilo Type I, II, or IIIA) or closed tibia fractures treated with intramedullary nailing were included.

Intervention:

Patients received 600 milligrams of ibuprofen, 3 times daily, for up to 6 weeks.

Main Outcome Measurements:

Secondary surgery to achieve union within 12 months of definitive fixation was recorded.

1. Introduction

1.1. NSAIDs and the Risk of Nonunion

For over 50 years, research has been conducted to determine whether the use of oral or intravenous nonsteroidal anti-inflammatory drugs (NSAIDs) interferes with fracture healing in vivo.¹ Although the results of much of this inquiry have been either conflicting or inconclusive, the orthopaedic surgery community has largely adopted the policy that NSAIDs are a potential impediment to osseous union and has counseled patients with acute fractures and nonunions to abstain from using NSAID analgesics.^2–6

1.2. NSAIDs and Pain Control

NSAIDs have proven highly effective for treating the pain that accompanies musculoskeletal injury⁷ and as a component of perioperative analgesic regimens after elective nonfracture orthopaedic surgeries. The anti-inflammatory action of these medications provides an added benefit over other classes of analgesics, by reducing swelling and inflammation in addition to controlling pain. Current data leave little doubt that perioperative NSAIDs can reduce postoperative pain and postoperative opioid consumption across many types of surgery, including orthopaedic procedures.^7–9 A recent meta-analysis of 13 randomized trials confirmed previous findings that perioperative ketorolac is effective at reducing both pain and opioid consumption.⁸

Opioids are currently routinely administered during general and regional anesthesia as a component of the surgical anesthetic itself and as part of the postoperative analgesic therapy. Opioid-related side effects include nausea, vomiting, constipation, pruritus, miosis, sedation, and respiratory depression. All opioids depress respiratory drive, depending on the dose, patient comorbidities, and other drug therapies. Beyond these numerous side effects, opioids can also induce opioid tolerance and/or hyperalgesia.

Perhaps most importantly, however, opiates carry a high possibility for addiction and high risk of misuse. According to the 2015 National Survey on Drug Use, 12.5% (11.48 million) of US adults prescribed opioids misused them.¹⁰ A subsequent JAMA study demonstrated that 5% to 6% of previously unexposed patients introduced to opiate medicines at the time of both major and minor surgeries continued taking them more than 3 months after surgery.¹¹ One study of patients with orthopaedic trauma demonstrated that 20% of the cohort continued to take opiate pain medicine more than 3 months after their injury, despite only 15% having used any opiates in the 3 months before their injury.^12,13 Introduction to legitimate prescription opiates, as well as the subsequent unintended addiction, is one of the major drivers of the opiate overdose epidemic (42,000 deaths per year in the United States) and the subsequent resurgence of heroin use.¹⁴ Therefore, any analgesic pathway that minimizes opiate use would be of substantial benefit to society. The standard orthopaedic exclusion of NSAID use in the acute fracture setting eliminates an important pathway to effective nonopioid analgesia, and if this prohibition is not warranted or clinically impactful, a change in usage may open a new and effective method of pain control that reduces the use of more addictive analgesic options.

1.3. Knowledge Gap Regarding NSAIDs and Nonunion

Dating back to very early animal models of fracture healing and spinal fusion, NSAIDs have been implicated in the impairment of osteogenesis.^15,16 Similarly, animal studies with chronic ketorolac administration raise concerns regarding the integrity of healed wounds, with variable results for muscle and ligamentous injuries.¹⁷ Several clinical articles have demonstrated some association between NSAID use and delayed union or nonunion in long bone fractures, including observational studies linking NSAID exposure to elevated nonunion risk in humeral shaft fractures and retrospective cohort analyses of diaphyseal injuries.^3,18 However, these findings are limited by retrospective design, are confounded by indications, and include incomplete data on NSAID duration or dose. Multiple systematic reviews have identified substantial gaps in this work related to methodology, sample size, study population, nature of the intervention, and choice of outcomes.^19–25 Adequately powered, prospectively collected, and randomized data are lacking, particularly for modern short-course outpatient NSAID regimens after surgically treated fractures.²⁶ The NSAID trial addresses these evidence gaps directly.

1.4. Current Practice Guideline For use of NSAIDs in Fracture Care

Multiple previous reviews in the orthopaedic literature have found the case for NSAID inhibition of fracture healing compelling enough to recommend the routine exclusion of NSAIDs from acute fracture care analgesic treatment.^{5,23,24,27,28} However, in the past 6 years, clinical practice guidelines from the Orthopaedic Trauma Association and the Eastern Association for the Surgery of Trauma have revised these restrictions, acknowledging that NSAIDs may be permissible in the treatment of fracture-related pain, based on the weakness of the current evidence linking their use to risk of nonunion.^29,30 While these recent endorsements of the use of NSAIDs in fracture care may demonstrate some movement on the topic, the concerns regarding the role of NSAIDs in fracture nonunion remain highly influential in practice.²⁴

1.5. Study Objectives

The aim of this study was to determine whether the routine use of NSAIDs after intramedullary nailing for acute tibia fractures results in a noninferior rate of secondary surgery to achieve union within one year of definitive fixation surgery. If the proposed trial provides evidence of nondetrimental effects on osseous union and reoperation rates in patients with tibial fractures, then treating surgeons will have a powerful non-narcotic alternative for analgesia. NSAID use for postinjury pain control could potentially reduce patient exposure to dangerous opiate medicines without increasing the risk of negative clinical or functional impact on patients' recovery from skeletal injury. Quality prospective randomized data in a fracture type commonly associated with prolonged healing times and increased risk of nonunion (tibia fractures) could provide practicing orthopaedic surgeons with the evidence required to incorporate NSAIDs into their acute fracture analgesic regimen. Conversely, if the regular use of postoperative NSAIDs proves to have a deleterious effect on reoperation or union rates, then this clinically important information would allow clinicians to quantify the risk of nonunion and balance this concern with the potential advantages of NSAID use for analgesia.

2. Methods and Analysis

2.1. Trial Design and Setting

The NSAID trial is a multicenter two-arm, pragmatic, randomized, controlled Phase III noninferiority trial comparing the need for surgery to promote union within the 12 months after intramedullary nailing for acute tibial fractures between a group receiving scheduled NSAIDs and a group prohibited from using NSAIDs for the first 6 weeks after surgery. This trial is being conducted at 14 trauma centers across the United States and Canada (listed in Table 1).

Table 1.

NSAID trial participating centers.

University of Utah, Salt Lake City, UT

Allegheny General Hospital, Pittsburgh, PA

Calgary Foothills Medical Centre, Calgary, AB

Eskenazi Health, Indianapolis, IN

Harvard University Medical Center, Boston, MA

Hennepin County Medical Center, Minneapolis, MN

Indiana University Methodist Hospital, Indianapolis, IN

Inova Fairfax Hospital, Fairfax, VA

MetroHealth Medical Center, Cleveland, OH

University of Maryland Shock Trauma Center, Baltimore, MD

University of Mississippi Medical Center, Jackson, MS

University of Texas Health Science Center, Houston, TX

University of Wisconsin, Madison, WI

Vanderbilt University Medical Center, Nashville, TN

2.2. Patient Selection

2.2.1. Inclusion Criteria

1. Patients with open (Gustilo Type I, II, or IIIA) or closed tibia fractures treated with intramedullary nailing.

2. Patients aged 18 to 80 years, inclusive.

3. Patients able to be followed at a participating center for 12 months after definitive fixation surgery.

2.2.2. Exclusion Criteria

1. Patients or legally authorized representatives unable to provide informed consent.

2. Patients who are current intravenous drug users.

3. Patients with a history of allergy/intolerance to the trial drugs.

4. Patients unable to swallow oral medications or without a functioning gastrointestinal tract.

5. Patients with a history of gastrointestinal bleeds or gastric perforation.

6. Patients with a history of stroke or heart attack.

7. Patients requiring an aspirin or NSAID regimen except for low-dose aspirin (81 mg).

8. Patients with any known bleeding disorders.

9. Patients with severe renal failure [Glomerular Filtration Rate (GFR): <30]. Patients with moderate renal failure [GFR: 30–59] may participate in the trial at a modified dose.

10. Patients undergoing daily treatment with systemic glucocorticoids before surgery.

11. Patients likely to have significant problems maintaining follow-up, including those diagnosed with a severe psychiatric condition, those unable to follow up at a participating center, those who are incarcerated, and those who have unstable housing situations.

12. Patients with a Glasgow Coma Scale score <15 at the time of discharge.

13. Patients with a closed head injury that precludes NSAID prescription.

14. Patients who are pregnant or lactating at the time of screening.

15. Patients with a bone graft procedure planned for a future date at the time of initial tibial intramedullary nail surgery.

16. Patients who have not been enrolled within 48 hours after tibial intramedullary nail surgery.

17. Patients with prophylactic nailing of nondisplaced stress fractures and prophylactic nailing of impending pathologic fractures.

2.3. Patient Recruitment and Screening

All patients between the ages of 18 and 80 (inclusive) sustaining a tibia fracture treated with intramedullary nailing are screened for eligibility at each site by the local research coordinator in collaboration with the surgeon investigators. Research coordinators at each site identify potentially eligible patients for this study through daily monitoring of the orthopaedic trauma census. The research coordinators assess patients for study eligibility at one of the following points of enrollment: admission to the study hospital for acute care of their injury; transfer to the study hospital; prefixation assessment visit after discharge from the study hospital emergency department; or within 48 hours of the conclusion of tibial nailing surgery. The assessment includes a review of the medical records to ensure that none of the study exclusion criteria are met. The study is discussed with potentially eligible patients, and informed consent is obtained by institutional research staff when appropriate. A screening form is completed for every potentially eligible participant and entered into REDCap, the study coordinating center's electronic data capture system, to document screened patients and anonymously record information about enrolled participants.³¹ A study investigator is available to answer questions regarding study eligibility. An adjudication committee of 3 expert orthopaedic trauma surgeons not involved in the study reviews cases for participants who are enrolled and later removed by the site for any of the following reasons: inappropriate enrollment; late ineligible, late refusal; or withdrawn by physician. This independent review and blinded adjudication serves to prevent bias in the removal of participants from the study.³²

2.4. Study Interventions

Treatment patients are prescribed oral ibuprofen 600 mg 3 times a day for up to 6 weeks starting immediately after tibial IMN fixation or after randomization, whichever occurs later. Clinicians prescribing to this group may use any further analgesia they desire, excluding additional NSAIDs. Ibuprofen is prescribed on a standing basis for the first 3 weeks and on an as-needed basis for the subsequent 3 weeks. Current FDA-required warnings for ibuprofen list a potential increased risk of serious cardiovascular thrombotic events, MI and stroke, as well as gastrointestinal bleeding, ulceration, and perforation. The trial medication is FDA approved and marketed for over-the-counter pain management. In this study, the exclusion criteria have been defined to exclude patients at higher risk of the associated side effects of the treatment medication.

Control patients receive standard-of-care pain medication regimen and may not use NSAIDs for 6 weeks after definitive fixation surgery. Clinicians prescribing to this group may use any analgesia they desire, excluding NSAIDs.

2.5. Randomization

Randomization occurs immediately after enrollment. After meeting all inclusion criteria and none of the exclusion criteria during screening, informed consent is obtained and patients are randomized electronically using permuted blocks by an online data management system (REDCap) maintained by the study coordinating center. After randomization, patients are assessed for all baseline information. Initiation of the study intervention occurs after conclusion of the definitive surgery, or randomization, whichever is later. Because participants can be enrolled before or after definitive tibial IMN fixation, “time zero” for the purpose of initiating follow-up is defined as the conclusion of the definitive fixation surgery in patients who are enrolled preoperatively, and as the time of randomization in those patients enrolled postoperatively. Patients were considered eligible for enrollment if they received NSAIDs before randomization. Study participants and treating surgeons are not blinded to treatment allocation, but the adjudication committee is blinded.

2.6. Duration of Treatment

Patients in the treatment group are prescribed scheduled NSAIDs for 3 weeks, followed by an additional 3 weeks of NSAIDs to be taken as needed for pain. All participants in the intervention group will receive 3 weeks of standing NSAID coverage; if they experience continued discomfort, they may receive an additional prescription for a total of 6 weeks of NSAID coverage. The prohibition on NSAIDs in the control group extends to the 6-week follow-up. Medication use after the 6-week follow-up is not be tracked or recorded.

2.7. Outcome Ascertainment and Adjudication of Primary Outcome

The presence or absence of union is highly debatable even among orthopaedic trauma experts. Thus, the pragmatic primary outcome is the occurrence of secondary surgery to achieve union within the 12 months after the index surgery. If further surgery occurs on the injured limb in the 12 months after the definitive fixation surgery, 3 members of the adjudication committee review the records and rule on whether this was a surgery performed with the goal of promoting osseous union and they will have the final say on whether any secondary surgery was to promote union. When a fracture is declared radiographically healed at a given visit and this is agreed on by the adjudication committee, the healed status is “carried forward,” requiring no further radiograph review. However, all participants continue follow-up throughout 12 months to ensure that no further surgery to achieve union was performed.

2.8. Secondary Outcomes

Secondary outcome measures are patient-reported persistent pain, pain interference, physical functioning, and radiographic union based on the modified Radiographic Union Scale for Tibial fractures (mRUST) score between 3 and 12 months after definitive fixation surgery³³ and opioid utilization during the follow-up period. Pain intensity (as measured by the Brief Pain Inventory [BPI] pain intensity domain)³⁴ is assessed during hospitalization. Length of hospitalization is recorded, and functional outcomes and pain interference are assessed at 3, 6, and 12 months after definitive fixation surgery. Information is also collected on potential adverse effects and complications. Further descriptions of the outcomes included in this trial are as follows.

2.8.1. Opioid Utilization

Opioid utilization is recorded in 2 ways: Opiate pain medicine prescribed by the treating provider and self-reported opiate use by the study participants.

2.8.2. Adverse Effects and Complications

The study prospectively assesses for known perioperative adverse effects and complications of ibuprofen, as well as wound closure complications, bleeding complications, and pain treatment–related adverse effects. Further adverse effects include nausea, vomiting, dizziness, headaches, renal impairment, platelet inhibition, and angioedema. In addition, on July 9, 2015, the FDA released an announcement related to the risks of NSAIDs entitled, “FDA Drug Safety Communication: FDA strengthens warning that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes.”³⁵ Consequently, consent forms for this study include the required language, and participants are assessed for these cardiovascular complications.

2.8.3. Persistent Pain and Pain Inference

The BPI is a widely used, 15-item measure of pain intensity and interference with daily life and is assessed at baseline, 3, 6, and 12 months after definitive fixation surgery. It has been extensively validated in both English and Spanish and also includes questions about pain treatments and the effectiveness of these treatments.³⁴ The BPI pain intensity domain is compatible with the IMMPACT guidelines for assessing pain in clinical trials and with the FDA Guidance for Industry on the use of Patient-Reported Outcome Measures.³⁶ In addition to the BPI instrument, pain inference is collected using the Patient Report Outcomes Measurement Information System (PROMIS), as described further.³⁷

2.8.4. Physical and Psychosocial Function

Self-reported measures of physical and psychosocial function are assessed at baseline, 3, 6, and 12 months after definitive fixation surgery using the PROMIS Computer Adaptive Test (CAT) item banks. At any visit, if a CAT cannot be administered, respondents instead complete the appropriate short forms associated with the CAT measure. In this study, the following PROMIS domains are used: Physical Function, Depression, Anxiety, Pain Inference, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Psychosocial Illness Impact. In addition to the Anxiety PROMIS domain, 3 questions from the PTSD checklist are administered to further assess psychosocial function.³⁸

2.8.5. Assessment for Radiographic Union

Radiographic union based on the mRUST score between 3 and 12 months after definitive fixation surgery will be assessed as a secondary outcome. Radiographic examinations collected as standard of care during the routine follow-up will be collected at each time point, and an mRUST will be assigned based on final available radiographs.

2.9. Secondary Safety Outcomes

The trial monitors for and reports adverse events to ensure patient safety. Definitions and procedures for reporting adverse events are designed to satisfy 45 CFR Part 46, Subpart A, the “Common Rule,” shared by 17 Departments and Agencies, as well as 21 CFR 312, the FDA regulation for adverse events, including the use of written procedures and policies for ensuring reporting of “unanticipated problems” involving risks to participants to institutional review boards (IRBs), appropriate institutional officials, and the department or agency head.

The medical monitor (MM) is responsible for providing medical guidance and overseeing patient safety for the study. The MM participates in determining the course of action necessary to meet safety goals and objectives. This is achieved through the prospective review of serious adverse event (SAE) reports, resolution of safety issues, and interaction with principal investigators. SAE submission happens within 48 hours of occurrence by site, and MM reviews within 48 hours.

Each participating site is responsible for ensuring that the single IRB and local IRB reporting requirements for adverse events (both internal and external) are met.

2.10. Follow-Up

Participants return for follow-up visits at 3, 6, and 12 months after definitive fixation surgery or randomization. At each follow-up visit, participants undergo a clinical evaluation by the treating surgeon and are interviewed by the research coordinator. Patients may also submit self-reported data electronically through an individualized REDCap survey link, or outcomes may be assessed by the research coordinator through a phone call with the patient.

2.11. Final Study Visit

Participants complete the trial 12 months after enrollment. The final visit ideally occurs in the clinic and includes patient interviews and clinical assessments as identified above. Any ongoing SAEs are followed until resolution.

2.12. Early Termination Visit

Should a participant terminate the study prematurely, if possible, all procedures required at the 12-month visit are performed at the patient's final visit.

2.13. Maximizing Patient Retention

Every effort will be made to retain participants in the study. The study participants receive an honorarium in recognition of their time and effort spent at each study visit, regardless of whether the visit occurred in person, by phone, or through the online survey.

2.14. Medication Adherence

Medication adherence is defined on a daily basis for both inpatient and outpatient periods of care, recognizing that for most study participants, the majority of the days of medication coverage will occur in the outpatient setting. For the treatment group, inpatient adherence is defined as receiving a minimum of 2 of the 3 doses of ibuprofen for a given date. For the control group, inpatient adherence is defined as receiving 0 or one dose of NSAIDs (low-dose aspirin excluded) on a given date. On the outpatient side, this trial is designed to pragmatically assess delivery in the clinical setting. If a participant in the treatment cohort receives a prescription for ibuprofen at the time of discharge, they are considered adherent for the outpatient days through the 21-day mark. Conversely, if a patient in the control group is discharged with instruction to abstain from NSAIDs and without a prescription for NSAIDs, they are considered adherent for the outpatient days through the 21-day mark. Overall adherence is met if a patient is judged adherent to their assigned arm of the study for 80% (17 of 21 days) of the first 3 weeks of the study. The treatment patients may take as-needed ibuprofen for weeks 4 to 6, and the control patients are instructed to abstain. However, overall compliance with the treatment group is based on the 3 weeks during which scheduled ibuprofen is prescribed. Patients are provided an app or medication diaries for recording medication usage, but given the potential for variable use of these tools, the above mentioned definitions of compliance are used and the self-reported usage data are primarily to be used for exploratory analyses.

2.15. Data Management and Monitoring

All study forms, reports, and other records that are part of the study data collection materials are identified by a coded number and entered into the REDCap database maintained by the data coordinating center. Clinical information is not released without written permission of the patient, except as necessary for monitoring by the data coordinating center, IRB, Department of Defense (DOD), or the Data and Safety Monitoring Board (DSMB). Consent procedures and forms, as well as the communication, transmission, and storage of patient data, comply with individual site IRB and DOD requirements for compliance with the Health Insurance Portability and Accountability Act. After the trial is completed, all study data will be completely deidentified before analysis.

An independent DSMB is responsible for monitoring the accumulated interim data as the trial progresses to ensure patient safety and to review efficacy, evaluate recruitment, and assess overall data quality.

The DSMB is a multidisciplinary group with a written charge provided by the study coordinating center and DOD. The DSMB meets twice a year to review data or other issues and may request more frequent meetings, if necessary, to fulfill its mandate. It may also request additional safety reports on a more frequent basis.

At its first meeting, the DSMB reviewed definitions of all outcomes, adverse events and serious adverse events and revisions to the protocol were made as appropriate (Supplemental Content 1, http://links.lww.com/OTAI/A129). Summary data on adverse events (together with study outcomes) are monitored by the DSMB. These summaries include analyses comparing rates of adverse events, blinded by treatment group and clinic, or in other subgroups requested by the DSMB.

After each meeting, the DSMB issues a written summary of its review of the study data, including adverse events, for transmission to the IRBs at each of the study centers.

2.16. Statistical Analysis Plan and Power Calculations

The primary analysis will evaluate whether postoperative NSAID use is noninferior to standard care (NSAID avoidance) concerning the 12-month cumulative incidence of secondary surgery to promote union post definitive fixation surgery. The primary estimand is the risk difference at 12 months (NSAID - control), assessed using a Bayesian time-to-event model. Noninferiority will be declared if the upper bound of the 95% credible interval for the 12-month risk difference is <0.10 (less than 10 percentage points). Treatment effects will also be summarized using the posterior distribution of the hazard ratio from a Bayesian Cox model as a supportive measure and will not be used for the non-inferiority decision.

Bayesian simulation-based operating characteristics indicate that a sample size of approximately 650 participants (325 per arm) will provide at least 80% probability of declaring noninferiority, assuming a control arm event rate of 8.25% and treatment arm event rate up to 14%. All analyses will follow the intent-to-treat principle. A per-protocol sensitivity analysis will also be conducted if crossover exceeds 5%, using the same modeling approach.

Secondary outcomes, including persistent pain at 3 months, opioid utilization, and additional exploratory end points, will be analyzed using Bayesian regression models. Persistent pain (measured using the BPI) will be modeled using logistic regression, and opioid use (days of use) will be analyzed using Bayesian linear regression. All models will use weakly informative priors: N (0, 2) for logistic regression coefficients and N (0, 1) with inverse gamma (0.01, 0.01) prior for residual variance in linear regression. No formal hypothesis testing will be conducted for secondary outcomes; instead, treatment effects will be summarized using posterior distributions and 95% credible intervals. Additional secondary outcomes—including radiographic union, pain interference, and function—will be reported in subsequent publications.

Sensitivity analyses will include a per-protocol analysis to assess the robustness of the primary findings in the presence of nonadherence, and tipping point analyses to evaluate the impact of assumptions about missing data. Subgroup analyses will be conducted for the primary outcome by fracture type (open vs. closed), history of chronic pain, and tobacco or nicotine use, with treatment effects estimated using the same Bayesian modeling framework as the primary analysis.

2.17. Ethics and Dissemination

This study has been approved by the study coordinating center's single IRB, with reliance agreements executed with the local IRBs at each participating site. All participants provide written informed consent before enrollment. The study is conducted under the oversight of an independent DSMB, which reviews safety, efficacy, and data quality throughout the trial.

Results from this study will be disseminated through peer-reviewed publications and scientific conference presentations. Authorship criteria include (1) substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; (2) drafting the work or revising it critically for important intellectual content; (3) final approval of the version to be published; (4) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

A full deidentified data set and statistical code used in the primary analysis will be made publicly available on publication to promote transparency and reproducibility. A lay summary of results will be made available for the public at the conclusion of the trial.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Appendix 1. METRC Corporate Author

The following individuals meet ICMJE criteria for authorship. Site affiliations are as of the time of study unless otherwise noted.

Allegheny General Hospital: Daniel T. Altman, MD; Foothills Medical Centre: Prism S. Schneider, MD, PhD; Harvard University: Michael J. Weaver, MD; Derek S. Stenquist, MD; Nishant Suneja, MD; Thirushan Wignakumar, BA, BMBCh; Hennepin Healthcare: Nancy M. Luger, MD, FAAOS; Gudrun E. Mirick Mueller, MD; Andrew H. Schmidt, MD; Olutayo M. Alese, PhD; Indiana University - Eskenazi Health: Karl D. Shively, MD; Indiana University Health Methodist Hospital: Brian H. Mullis, MD; Yohan Jang, DO; Luke A. Lopas, MD; Roman M. Natoli, MD, PhD; Lauren C. Hill, BS, CCRC; Inova Fairfax Medical Campus: Greg Gaski, MD; Robert A. Hymes, MD; Abraham M. Goch, MD; Michael A. Holzman, MD; A. Stephen Malekzadeh, MD; Jeff E. Schulman, MD; Jonathan H. Wills, MD; McGovern Medical School at The University of Texas Health Science Center at Houston: Stephen J. Warner, MD, PhD; Timothy S. Achor, MD; Andrew Choo, MD; Patrick J. Kellam, MD; Sterling J. Boutte, BS; MetroHealth Medical Center: Nicholas M. Romeo, DO; Heather A. Vallier, MD (now affiliated with Cleveland Clinic); Anna C. Vergon, BS; R Adams Cowley Shock Trauma Center at the University of Maryland: Alice C. Bell, MD; Jason Nascone, MD; David Okhuereigbe, MD; Marcus F. Sciadini, MD; Gerard Slobogean, MD; Yasmin Degani, MPH; Asher Gruver-Williams, MS; Andrea L. Howe, MS; Heather Phipps, MPS; LaShann M. Selby, MPH; The University of Utah: Justin Haller, MD; Makoa Mau, MD; David Rothberg, MD; Derek Keeney, BS (no longer affiliated); University of Mississippi Medical Center: Patrick F. Bergin, MD; Matt L. Graves, MD; Peter N. Mittwede, MD, PhD; John Morellato, MBBS Hons; Priyanka V. Nehete, BDS, MPH; Tyranny A. Pryor, MS; Isaac J. Spears, BS; University of Wisconsin: Christopher Domes, MD; David C. Goodspeed, MD; Paul S. Whiting, MD; Vanderbilt University Medical Center: William Obremskey, MD, MPH; Phillip M. Mitchell, MD, MSCI; Andres Fidel Moreno-Diaz, MD; Lauren M. Tatman, MD; Juanita Velasco-Castro, MD; Joseph R. Cave, MPH; Karen M. Trochez, MA; METRC Coordinating Center at Johns Hopkins Bloomberg School of Public Health: Srinivasa N. Raja, MD; Anthony R. Carlini, MS; Shadae Chambers, BA (now affiliated with University of Maryland); Landon Katz; John A. Teague, BA; Elias Weston-Farber, BS; Elizabeth Wysocki, MS.