BACKGROUND AND RATIONALE
There are 2 common approaches to transtibial amputation. The standard Burgess approach involves the creation of a long posterior muscle flap that is wrapped over the ends of the residual tibia and secured by sutures.1 The modified Ertl procedure joins the cut ends of the tibia and fibula with a bone bridge synostosis.2,3 The Ertl procedure has gained popularity in treating trauma sustained in combat and may offer some advantages over the Burgess procedure for amputation in young, active, and healthy patients.4–7 Proponents of the Ertl procedure argue that the bone bridge provides a more stable platform for prosthetic weight bearing resulting in better residual limb health and improved prosthetic fit. This, in turn, may lead to a faster recovery and higher levels of function. However, the Ertl procedure is technically more complex, requires more operative time, and may result in complications unique to the bone bridge including delayed union or nonunion of the tibiofibular synostosis, bone bridge dislocation, and other implant-related complications.8,9 Currently, there is little high-quality evidence to inform which amputation approach is better for treatment of lower limb trauma.
The few studies comparing Ertl versus the Burgess procedures are small, conducted mainly in military patient populations, and retrospective in design. An early study of veterans treated during the Vietnam war with a transtibial amputation compared scores on the Short Form (SF)-36 between patients treated with an Ertl (n = 42) versus Burgess (n = 30) procedure. Patients with the Ertl procedure reported consistently higher scores on average in each domain of the SF-3610; however, the differences were not statistically significant.11 A study by Pinzur found that patients from a single center treated with a unilateral Ertl amputation (n = 32) reported higher scores on several subscales of the Prosthetic Evaluation Questionnaire (PEQ)12 indicating better quality of life and higher level of function compared with those treated with a Burgess amputation (n = 17).13 However, these results were not replicated in a follow-up study which showed worse scores on the PEQ in patients with an Ertl amputation (n = 8) compared with scores from the earlier cohorts.14 The discrepancy in results is likely due to demographic differences in the patient populations, the reason for amputation (ie, dysvascular disease vs. infection) and the timing of the assessment relative to the procedure. A more recent study found no difference in self-reported function using the SF-36 or PEQ 18 months after amputation among military patients receiving the Ertl (n = 27) versus the Burgess (n = 38) procedure.15 Although not statistically significant, the study found that compared with patients treated with a Burgess amputation, patients receiving the Ertl procedure reported more consecutive miles run on a weekly basis (5 vs. 3.4 miles) and slightly longer wear time of the prosthesis (14.4 vs. 13.8 h/d). Plucknette et al also found some trends toward better outcomes among those undergoing the Ertl versus Burgess procedure, but as with previous studies, differences were not statistically significant. Among 478 military patients treated with a transtibial amputation (72 of whom underwent the Ertl procedure), 13% of patients treated with an Ertl procedure were able to deploy compared with 7% of patients treated with a Burgess procedure; the percentages determined fit for active duty based on the Physical Evaluation Board Liaison Office (PEBLO) evaluation criteria were 32% versus 18% for those undergoing Ertl and Burgess procedures, respectively.16
While these studies suggest that patients treated with an Ertl procedure may experience better function after amputation, the results are inconsistent and inconclusive because of relatively small sample sizes and retrospective designs. Large, prospective, randomized studies are needed to address the potential for selection bias introduced in observational (OBS) studies. Furthermore, these studies should include both patient-reported and performance-based measures of function. It is possible that measures of physical performance are more sensitive than patient-reported outcomes in determining important differences between the approaches, particularly for high-functioning individuals. For example, one small study looking at 3-dimensional gait parameters showed that patients treated with an Ertl amputation exerted greater forces while walking at a fast pace compared with those treated with a Burgess amputation.17 These results suggest that the bone bridge may provide better loading support during vigorous activity. However, given the paucity of data that currently exists, it is unclear whether improvements in function are significant and whether they outweigh the complications associated with the Ertl procedure.
The purpose of the Transtibial Amputation Outcomes Study (TAOS) was to compare 18-month outcomes after transtibial amputation with and without a bone bridge synostosis in a prospective, multicenter randomized controlled trial (RCT). It is hypothesized that fewer patients receiving the Burgess procedure will require surgery for complications compared with patients receiving the Ertl procedure, but patient-reported health and function will be better for patients receiving an Ertl versus Burgess procedure. This study also compares physical performance and overall treatment cost between the groups. It is hypothesized that patients receiving the Ertl procedure will perform better on tests of physical performance compared with those receiving the Burgess, but overall treatment costs will be lower for patients receiving the Burgess procedure.
The quality of prosthetic fit and alignment may significantly affect these outcomes. However, there are no validated quantitative measures that can be used in the research setting—especially in the context of a large, multicenter trial. Thus, an exploratory aim of TAOS is to compare fit and alignment of the prosthesis using an objective assessment tool developed by orthopaedic trauma surgeons in collaboration with a panel of Certified Prosthetist–Orthotists (CPOs) and prosthetic engineers. The assessment tool was developed and validated as part of an ancillary study supported by the Department of Defense (DoD) through the Peer Reviewed Orthopaedic Research Program (PRORP).
METHODS: TRIAL DESIGN, PARTICIPANT SELECTION, AND INTERVENTION
Overview of Trial Design and Randomization
The study was initiated at 23 US trauma centers participating in the Major Extremity Trauma Research Consortium (METRC).18 The list of participating centers can be found in Appendix 1. The study protocol, including written informed consent, was approved by the Johns Hopkins Bloomberg School of Public Health (location of the METRC Coordinating Center), the DoD Human Research Protection Office (HRPO) (study sponsor), and the local institutional review boards at each participating center. Furthermore, each site was required to obtain DoD HRPO approval of local institutional review board documents and certification by the Coordinating Center to ensure proper training on study procedures and data collection before the initiation of the study.
The population consists of patients aged 18 to 60 undergoing a unilateral transtibial amputation after major limb trauma regardless of when the injury occurred. Eligible patients who provide informed consent are randomized in permuted blocks stratified by clinical center and administered centrally by the Coordinating Center. Randomization is administered centrally by the Coordinating Center using REDCap, the web-based distributed data collection system used for all METRC projects.19 Patients are randomized before definitive amputation (ie, final soft tissue closure) in variable permuted blocks, stratified by clinical center. Patients who refuse randomization are offered the opportunity to enroll in an OBS cohort study. Treatment for these OBS study patients is based on patient preference. The intent of including an OBS study is to address concerns about patient willingness to randomize, provide an opportunity to evaluate the generalizability of the RCT results, and provide further information about prosthetic fit and alignment which is evaluated as an exploratory aim of the study. All enrolled patients are followed for 18 months after amputation.
Participants meeting the study criteria described in Table 1 are approached for informed consent during the initial hospitalization for amputation. METRC has adopted a comprehensive informed consent process for all of its studies that involve the treating surgeon, the clinical site research coordinator, and material and resources for patients and family members to facilitate informed decision making about participation (see Figure 1, Supplemental Digital Content 1, http://links.lww.com/BOT/A905). In this study, patients and their family members view a brief video that provides a standardized description of the 2 amputation procedures. If patients refuse randomization, the research team is instructed to wait 24 hours before approaching the patient again for enrollment into the OBS study. This delay in consent for the OBS study helps ensure that priority is given to the randomized study and discourages preferential enrollment into the OBS study. A legally authorized representative is permitted to consent on behalf of patients who are unable to do so before definitive amputation.
The sample size calculation for the RCT is based on testing the primary hypotheses associated with surgical complications and patient-reported function. It is assumed that 30% of patients in the Burgess arm will require surgical treatment for complications within 18 months after amputation.20 Using a 2-sided 0.05 level test of the null hypothesis of no treatment difference, 101 patients are required per arm to provide 80% power to detect an absolute increase in the surgical treatment for complications of 20% for the Ertl arm. With one interim analysis (after 50% of patients have reached 18 months of follow-up) using an O'Brien–Fleming stopping boundary, the number of patients is inflated by 1% to preserve the overall type I error. Accounting for 5% missing data, the required sample size for the randomized study is 107 per arm.
Regarding patient-reported health and function, the planned sample size provides 88% power of establishing superiority of the Ertl procedure if the true effect size is 0.47 (assuming 15% missing data). For the Short Musculoskeletal Function Assessment, this effect translates into a difference in treatment-specific means of 7 with a common SD of 15.
Given the transition in the beginning of the enrollment period into a low-volume casualty flow period, fewer than expected amputations have been treated at the military treatment facilities. Thus, it is unlikely that sample size requirements for the RCT will be met within the enrollment period of 5 years. Given the enrollment experience to date, the expected enrollment between both the randomized and OBS studies is 250 (138 in the RCT and 112 in the OBS), with one-half of the patients in the RCT assigned to receive the Ertl procedure and 30% of OBS patients choosing the Ertl procedure. To address this issue, novel methods for combining data from the randomized and OBS components of the study will be used to estimate the treatment effect in the RCT.21 Simulations suggest that the effective sample size contribution of OBS patients is one-third of that for randomized patients. Thus, the effective number of Ertl and Burgess patients in the RCT is 80 and 95, respectively. These effective sample sizes yield 72% and 80% power for addressing surgical treatment for a complication and self-reported function, respectively.
TREATMENT ARMS: BURGESS AND ERTL AMPUTATION PROCEDURES
Both amputation techniques are well described.1,3,6 Although standard approaches are used to perform both the Burgess and the Ertl amputations, the details of the procedures for this study are determined by the treating surgeon. Patients randomized to the Ertl amputation receive a distal tibiofibular synostosis. The synostosis can be achieved by a variety of techniques, including use of a cortical screw, tightrope, or nonabsorbable suture to secure the bone bridge, and maintaining blood supply to the fibular strut or transposing a sleeve of periosteum with attached bone chips from the tibia to fibula.22 Soft tissue closure is conducted according to surgeon preference, which may or may not include a myocutaneous flap.
Specifics regarding soft issue closure for patients randomized to the Burgess amputation are left to the discretion of the surgeon, but typically a conventional long posterior myocutaneous flap is sutured over the end of the residual tibia.23 Although not required for this study, myodesis of the gastrocnemius tendon to reinforce proximal tibial periosteum and anterior compartment fascia is generally performed as part of this technique.
METHODS: DATA COLLECTION AND OUTCOME MEASURES
Baseline Assessment and Frequency of Follow-up Assessments
Data collected at baseline (during the hospitalization for amputation) are summarized in Supplemental Digital Content 2 (see Table 1, http://links.lww.com/BOT/A909) and include patient characteristics and preinjury health, classification of the study injury, and details of the amputation procedure.
Participants return for follow-up study visits at 3, 6, 12, and 18 months after amputation. Study visits involve a clinical examination and an interview with the patient. At the final study visit, participants are asked to complete a series of physical performance tests and given a StepWatch Activity Monitor24 to monitor daily activity at home. Photographs, x-rays, and videos are also taken of the participant with and without the prosthesis for evaluation of prosthetic fit and alignment. In addition to the scheduled study visits, all hospital readmissions and same day surgeries (ie, outpatient procedures) related to the amputation are prospectively recorded for 18 months after the amputation. To estimate treatment cost, sites are asked to provide medical bills for the initial hospital stay, readmissions, and outpatient surgeries related to the amputation.
The primary outcomes include reoperation for an amputation-related complication and patient-reported function 18 months after the procedure. Reoperation for a complication is defined as either (1) a revision to the residual limb that either reduces, eliminates, or adjusts the position of the coverage and/or shortens the bone or (2) a reoperation after definitive soft tissue closure for one of the following complications: any infection, necrosis, wound dehiscence, exostosis, neuroma, heterotopic ossification, or pain. Patient-reported function is measured by the Short Musculoskeletal Function Assessment, a validated 46-item questionnaire consisting of 2 main indices. The dysfunction index includes 34 items assessing function in 4 domains: daily activities, arm and hand function, mobility, and emotional status. The bother index includes 12 items designed to detect how much patients are bothered by functional deficits.25
Secondary outcomes of interest include clinical and patient-reported outcomes, collected according to the data standards adopted by the consortium.26 The timing of data collection is summarized in Supplemental Digital Content 2 (see Table 1, http://links.lww.com/BOT/A909).
Physical performance and overall activity are objectively evaluated using measures of performance in tests of agility, strength/power, speed, endurance, and balance as described in Supplemental Digital Content 3 (see Figure 2, http://links.lww.com/BOT/A906). The performance tests were selected by an expert panel of physical therapists and orthopaedic surgeons and include those which can easily be conducted in a standard orthopaedic outpatient office by a trained Research Coordinator. Tests were also selected based on their ability to measure performance at different levels of difficulty to evaluate both low- and high-functioning individuals. Overall activity is estimated using the StepWatch Activity Monitor, worn by participants for 2 weeks after the 18-month study visit.24
Pain is measured using a visual analog scale and the Brief Pain Inventory (BPI) questionnaire, a widely used, 15-item measure of pain intensity and interference with daily life.27
Overall treatment costs (initial amputation through the 18-month follow-up) are derived using standard approaches developed for all METRC studies. Case report forms document the initial admission and subsequent readmission, including data on inpatient length of stay, intensive care unit stay, number and type of surgeries, and reason for admission. Also, captured are data on outpatient surgeries and outpatient visits (including physical and occupational therapies). Hospital bills (UB04) are obtained for admissions to METRC facilities. Billed charges are converted to costs based on Medicare cost-to-charge ratios. Costs of inpatient care at METRC facilities will be modeled as a function of patient demographics and characteristics of the hospital episode and used to estimate costs of inpatient care at non-METRC hospitals (for which bills were not obtained). Outpatient care costs are estimated by applying a medical service unit cost to patient-reported use of outpatient care services (eg, physician visit, physical therapy). The medical service unit cost is derived by matching TAOS patients to a sample in a large national insurance claims database (Truven MarketScan) using clinical and patient characteristics, and then calculating the sample's unit cost for various medical care services. Costs attributable to the value of lost productivity will also be estimated using standard human capital approaches.
Exploratory Outcome: Prosthetic Fit and Alignment
The prosthetic fit and alignment assessments are based on a series of quantifiable observations using x-rays, photographs, and videos taken on all study participants at the 18-month study visit.
Seven photographs are taken of the participant without the prosthesis in axial, medial, posterior, and anterior views, as well as in lateral neutral, flexion, and extension positions. Five videos are taken of the participant while wearing the prosthetic in posterior, anterior, and sagittal views and while walking. A total of 4 x-rays are taken—2 while wearing the prosthesis and weight bearing and 2 without the prosthesis and non–weight bearing. Images are uploaded to an on-line program designed specifically for the study and evaluated independently by a pair of CPOs using the 39-item prosthetic fit and alignment tool (ProFit). The images are evaluated for skin quality (3 items), static and dynamic alignments (31 items), and radiographic characteristics (5 items). Based on the data and the ratings provided on individual items, CPOs also provide an overall rating of fit and alignment on a 1–10 scale. Consent is obtained from a subset of participants to collect these data at the 6-month visit (in addition to the 18-month visit). For this subgroup of participants, CPOs fit the prosthesis with a Smart Pyramid device which quantifies alignment by measuring forces on the prosthetic limb while walking.28,29 These data allow further validation of the ProFit assessment tool using an objective measure of alignment and an evaluation of the responsiveness of the assessment tool over time.
Monitoring and Quality Assurance
Details of the METRC-wide standard operative procedures for monitoring can be found in the on-line supplement material (see Figure 3, Supplemental Digital Content 4, http://links.lww.com/BOT/A907). The monitoring plan is designed to verify site compliance with the protocol and with study-specific standard operative procedures on the data collection and procedures. The plan facilitates compliance with good clinical practice guidelines (5.18.1). An independent Data Safety Monitoring Board (DSMB) reviews study progress; all reported complications and serious adverse events during meetings held twice each year. The chair of the DSMB serves as the Medical Monitor who reviews each serious adverse event as it is reported in real time.
METHODS: DATA MANAGEMENT AND ANALYSIS
Data are collected by site Research Coordinators and clinical investigators using paper case report forms designed specifically for this study and then entered into REDCap. Details about data handling and data management can be found in the on-line supplemental material (see Figure 4, Supplemental Digital Content 5, http://links.lww.com/BOT/A908).
Analysis for Main Study Aims
The main hypotheses will be addressed using 2-sample testing procedures at the 5% type-error level; estimates of the treatment effects will be reported along with 95% 2-sided confidence intervals. The surgical complication outcome will be analyzed as both a binary (any surgery for complications) and a count (number of surgeries for complications) variable. To the extent possible, statistical procedures that use baseline covariates that are moderately or strongly predictive of outcomes (eg, age, obesity, preinjury function, time from injury to amputation, ipsilateral injuries) will be used to increase statistical precision (ie, power).30 Because it is unlikely that RCT enrollment goals will be met, a newly developed procedure that uses data from OBS patients will be applied to construct a more precise estimator of the treatment effect in the RCT.21 If necessary, secondary analyses will also be performed to address treatment crossovers. Multiple imputation will be used to handle missing baseline covariates. Missing outcomes will not be imputed. Sensitivity analyses will be performed to evaluate the robustness of the trial results to various untestable assumptions about the missing outcome mechanism.
Analysis for Exploratory Aim
Standard statistical approaches will be used to test the reliability, validity, and responsiveness of the ProFit assessment. Interrater reliability and internal consistency between CPO evaluators will be assessed using kappa statistics and Cronbach's alpha. Validity will be tested by examining the association of ProFit with outcomes, including patient-reported pain and function, objective measures of physical performance, and an objective assessment of fit using the Smart Pyramid. Responsiveness will be tested by calculating the effect size observed from the 6- to 18-month study visit. Based on these findings, the ProFit assessment will be refined by removing items that demonstrate poor interrater agreement, weak relationships with clinical and patient-reported outcomes, and strong ceiling or floor effects.
This is the first large, multicenter trial of trauma-related transtibial amputation comparing clinical and functional outcomes of patients with and without a bone bridge synostosis. Building on the work of earlier studies, TAOS includes both patient-reported and performance-based measures of function. Although self-reported function may be similar between the 2 groups, performance measures may delineate important differences among higher functioning individuals. Advocates of the Ertl procedure suggest that the bone bridge creates a stable platform with a larger distal surface area, allowing for improvements in load transfer while walking.7 Although there is some evidence that supports this advantage during vigorous exercise,17 the interface between the residual limb and the prosthesis is complex, and it is unclear whether improvements are due to residual limb length and advancements in prosthetic limb componentry rather than the bone bridge itself.31 A concern with the Burgess procedure is that loading at the distal end of the residual limb results in residual limb breakdown and wounds that can be painful. However, most modern transtibial prostheses are designed to bear weight through the tibial metaphyseal flare. Weight-bearing studies of prosthetic users show that few “bottom out” during the stance phase.31 Given advancements in prosthetic care, there may be no additional value in the synostosis procedure, especially in light of the added surgical time and complications related to the bone bridge which have been reported in retrospective studies to occur in 32%–62% of patients receiving an Ertl amputation.8,9 TAOS will prospectively track readmission for amputation-related complications, including amputation revision.
In addition to comparing clinical and functional outcomes, this study is designed to evaluate the mechanisms by which differences might occur. Prosthetic fit and alignment may have significant impact on amputation outcomes, yet there are no objective means for quantifying the effect. This study will account for fit and alignment using a quantitative assessment that can be replicated in future studies. Moreover, imaging data such as weight-bearing and non–weight-bearing radiographs will allow improved assessment of end bearing. Taken together, assessments of prosthetic fit and alignment, and physical performance (including data from a StepWatch Activity Monitor) will provide important insight into how the synostosis affects stance, mobility, and function. These assessments are conducted 18 months after the procedure, a time when most patients should have achieved maximum medical improvement.20,32
There are 3 notable challenges to this study. One of these challenges is overall low enrollment. When designing the study, military treatment facilities were performing 75–80 transtibial amputations per year. However, since the initiation of the study, military facilities are performing far fewer amputations (less than 10 per year) as a result of the drawdown in combat activity. Enrollment may also be low as a result of fairly stringent eligibility criteria related to the residual limb. Approximately 55% of ineligible patients do not meet inclusion criteria because the residual limb is not stabilized, there is significant soft tissue damage, or the residual limb will be too short. An unstabilized proximal tibiofibular joint or a very short residual limb would theoretically eliminate any potential advantage conveyed by the Ertl procedure, thus introducing bias relative to the subgroup of patients with normal residual limb length and proximal stability. Significant soft tissue damage would theoretically increase the risk of soft tissue complications with the synostosis procedure, thus introducing bias into the analysis of complication risks for the Ertl versus the Burgess, at least in comparison with the group of patients without such soft tissue damage.
In addition to low enrollment overall, consenting patients into the RCT rather than the OBS study is a challenge. Currently, only 54% of enrolled TAOS patients have agreed to be randomized. Similar trends are seen in other orthopaedic trials that include an OBS arm which speaks to the challenge of conducting large randomized trials in orthopaedic surgery.33 Recognizing that meeting the target sample size in the RCT is unlikely, the analysis will use novel methods to gain statistical power by combining data from the OBS and RCT studies. Although this will not produce level I evidence equivalent to that associated with adequately powered RCTs, it will be better than the evidence produced by an OBS study alone.
Another challenge to this study is accounting for surgeon expertise with the Ertl procedure. Clinical sites are required to have equipoise to participate. Some centers may identify 1 or 2 “expert” surgeons to conduct all Ertl procedures for patients randomized to this treatment. Other centers may take an approach where all surgeons, if they are willing, conduct the procedures regardless of their experience. To examine the potential of this effect in the primary analysis, surgeons are surveyed about the number of amputations (both Burgess and Ertl) they conducted before the start of the study. This information will be used in subgroup analyses to determine the impact on results. It is also possible that certain techniques to obtain the synostosis are associated with more complications. The study was not designed to test for differences across the various approaches, but in theory, these effects should be minimized through randomization. However, details of the amputation procedure are collected and will be evaluated in subgroup analyses to illuminate trends that may exist.
Despite these challenges, TAOS represents the largest prospective amputation study to date. Results should provide important information regarding the 2 different amputation approaches which will inform future treatment guidelines. Moreover, the study will validate and refine a measure of prosthetic fit and alignment that can be used in future amputation research.
APPENDIX 1. CORPORATE AUTHORS
Participating Centers: Barnes-Jewish Hospital at Washington University: William M. Ricci, MD, Amanda Spraggs-Hughes, MA, Christopher M. McAndrew, MD MSc, Anna N. Miller, MD, FACS; Carolinas Medical Center: Michael J Bosse, MD, Stephen H Sims, MD, Madhav A. Karunakar, MD, Joseph R. Hsu, MD, Christine Churchill, MA, Rachel B. Seymour, PhD; Emory University: Thomas Moore Jr., MD, Mara L. Schenker, MD, William M. Reisman, MD, Patricia A. Bush, EdD; Florida Orthopaedic Institute: Hassan R. Mir, MD, MBA, FACS, Anjan R. Shah, MD, Barbara Steverson, RN, MHA; Grant Medical Center: Benjamin C. Taylor; Hennepin County Medical Center: Andrew H. Schmidt, MD, Gudrun E Mirick, MD, Jerald R. Westberg, BA, Patrick Yoon, MD; MetroHealth Medical Center: Heather A. Vallier, MD, Mary A. Breslin, BA; Penn State University: J. Spence Reid, MD, Andrea H. Horne, CCRP; Rhode Island Hospital, Brown University: Roman A. Hayda, MD, Mary Jean H. Crisco, RN; San Antonio Military Medical Center: Daniel J. Stinner, MD, Patrick M. Osborn, MD, Michelle Norton, MPH, MBA, Jason M. Wilken, PT, PhD; Saint Louis University Hospital: Lisa K. Cannada, MD, Sarah A. Dawson, BSN; Stanford University Medical Center: Michael J. Gardner, MD; The University of Texas Health Science Center at Houston: Joshua L. Gary MD, William H. Harvin, MD, Danielle H. Melton, MD, Matthew C. Galpin, CCRC; University of California San Francisco: Saam Morshed, MD PhD, Theodore Miclau, MD, Tigist Belaye, MS; University of Iowa Hospitals and Clinics: Michael Willey, MD; University of Maryland R Adams Cowley Shock Trauma Center: Robert V. O'Toole, MD, Theodore Manson, MD, Gerard P. Slobogean, MD, MPH, FRCSC, Andrea L. Howe, BS, Marcus F. Sciadini, MD; University of Miami Ryder Trauma Center: James J Hutson Jr, MD; University of Mississippi Medical Center: Patrick F. Bergin, MD, Clay A. Spitler, MD, Josie Hydrick, BS, Matt L. Graves, MD, George V. Russell, MD; University of Oklahoma Medical Center: Zachary V Roberts, MD, David C. Teague, MD, William J. J. Ertl, MD; University of Pittsburgh: Ivan S. Tarkin, MD; University of Washington/Harborview Medical Center: Reza Firoozabadi, MD, MA; Vanderbilt University Medical Center: William T. Obremskey, MD, MPH, MMHC, Manish K. Sethi, MD, A. Alex Jahangir, MD, MMHC, Vamshi Gajari, MBBS, Eduardo J. Burgos, MD, Andres Rodriguez-Buitrago, Kristin R. Archer, PhD, DPT; Walter Reed National Military Medical Center: Wade T Gordon, MD, Xochitl Ceniceros, PhD, RN, Sandra Waggoner, BA; Wake Forest Baptist Medical Center: Eben A Carroll, MD, Jason J. Halvorson, MD, J. Brett Goodman, MBA, Martha B. Holden, AAS, AA; Other Corporate Authors: Naval Medical Center San Diego: James E. Toledano, MD CAPT, MC, USN (protocol committee member). METRC Coordinating Center at Johns Hopkins Bloomberg School of Public Health: Lauren E. Allen, MA, Jeromie M. Ballreich, MHS, Anthony R. Carlini, MS, Renan C. Castillo, PhD, Gregory deLissovoy, PhD, MPH, Jason Luly, MS, Rachel Kirk, BS, Ellen J. MacKenzie, PhD, Christina D. Owens, BS, Lisa Reider, PhD, Daniel O. Scharfstein, ScD.
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