Orthopedics

Review Article 

Accelerated Growth of Cellular Therapy Trials in Musculoskeletal Disorders: An Analysis of the NIH Clinical Trials Data Bank

Nicolas S. Piuzzi, MD; Mitchell Ng, BA; Morad Chughtai, MD; Anton Khlopas, MD; Prem N. Ramkumar, MD, MBA; Steven F. Harwin, MD; Michael A. Mont, MD; Thomas W. Bauer, MD, PhD; George F. Muschler, MD

Abstract

The purpose of this study was to (1) determine the growth rate and the trends of musculoskeletal cellular therapy trials in the National Institutes of Health Clinical Trials Data Bank; (2) analyze the study design and characteristics; and (3) assess which cellular therapies and disease conditions are studied. A systematic review of musculoskeletal clinical trials from 2005 to 2016 using cell-based therapies as the primary intervention was performed through ClinicalTrials.gov. The number of musculoskeletal cell-based clinical trials is increasing, with most being early stage, phase I/II, and using autologous cells harvested mostly from bone marrow to target cartilage-related diseases. Among the 282 clinical trials identified, only 99 (35.1%) were completed; 62 of the 99 (62.6%) did not list any related publications. [Orthopedics. 2019; 42(2):e144–e150.]

Abstract

The purpose of this study was to (1) determine the growth rate and the trends of musculoskeletal cellular therapy trials in the National Institutes of Health Clinical Trials Data Bank; (2) analyze the study design and characteristics; and (3) assess which cellular therapies and disease conditions are studied. A systematic review of musculoskeletal clinical trials from 2005 to 2016 using cell-based therapies as the primary intervention was performed through ClinicalTrials.gov. The number of musculoskeletal cell-based clinical trials is increasing, with most being early stage, phase I/II, and using autologous cells harvested mostly from bone marrow to target cartilage-related diseases. Among the 282 clinical trials identified, only 99 (35.1%) were completed; 62 of the 99 (62.6%) did not list any related publications. [Orthopedics. 2019; 42(2):e144–e150.]

In the past decade, there has been marked interest in the development of regenerative therapies that preserve, repair, regenerate, or replace lost or damaged tissues. A large fraction of this research is dedicated to the development of cell-based therapies.1 This interest is evident by a doubling of the number of articles about cell-based therapies across all fields of medicine published during the past 10 years in PubMed.

The awareness and discussion around cell therapies has created a large demand for information and services. In the United States during the past 2 decades, this has fueled a burgeoning direct-to-consumer Internet-based marketplace offering “stem cell” therapies.2 Turner and Knoepfler2 found 351 US businesses engaged in the marketing of stem cell interventions, with orthopedic/musculoskeletal applications being the most frequent.3 However, much of the recent growth in clinical offerings of cell therapies has preceded the publication of objective evidence of efficacy.4 This fact elevates the importance of understanding the current landscape of clinical trials and the pipeline of ongoing clinical trials that may fill this gap. There are numerous publications analyzing the use of cell-based therapies, but few have analyzed the clinical pipeline and the nature of ongoing research.4–6

To ensure patient safety, convey generalizable knowledge of treatment efficacy, and minimize bias in reporting, access to information concerning clinical trials and their results is critical to all fields of medicine. Underreporting clinical trials has been recognized as a form of scientific misconduct that can lead health care providers to make inappropriate treatment decisions.7 Completed trials that remain unpublished and therefore unavailable can have important negative consequences.8 In 1997, US law mandated that trials of investigational new drugs for serious or life-threatening diseases be registered beginning February 2000.9,10 The web-based registry National Institutes of Health (NIH) Clinical Trials Data Bank, usually referred to as ClinicalTrials.gov ( http://clinicaltrials.gov), is operated at the NIH by the National Library of Medicine and constitutes a publicly accessible online database featuring more than 230,000 studies with locations in 194 countries. Since 2005, the International Committee of Medical Journal Editors has established that, as a condition for publication, prospective clinical trials must be registered prior to initiating patient enrollment.11–13 Furthermore, prospective trial registration has become a requirement under US law for multiple interventional clinical trials due to the release of the US Food and Drug Administration Amendments Act of 2007.14 In September 2016, the Department of Health and Human Services and the NIH added a new legislation and policy (The Final Rule [Department of Health and Human Services, NIH new policy]) for ClinicalTrials.gov to expand and to ensure compliance with the reporting requirements in registration and results submission.15,16

In some settings, clinical trials are not required before clinical introduction. For example, class I devices, such as centrifuge devices using density separation in various forms, are considered to represent minimal risk and are not life threatening by nature. Therefore, clinical trials are not required before the introduction of therapies using density separation processing. The same is true for products regulated under the 510k classification as “substantially equivalent to existing products” (eg, bone graft substitute materials). In these cases, the data available to clinicians regarding relative efficacy are limited to clinical series, occasional post-marketing studies, and perhaps collaborative registries. Regardless, human clinical trials remain the primary pathway for establishing clinical safety and efficacy.

Several reviews have analyzed the available evidence for the use of cellular therapies in different areas of musculoskeletal medicine.4,17–23 However, no study has systematically assessed the overall status of the clinical trials that represent the pipeline for future information. Therefore, the authors systematically reviewed the clinical trials for musculoskeletal applications using the NIH Clinical Trials Data Bank. They had the dual goals of (1) understanding the current state of clinical research related to cellular therapies and (2) exploring and proposing methods that can be used to track progress in this area going forward. The authors specifically asked 3 questions. First, what is the growth rate and what are the trends in musculoskeletal cellular therapy trials relative to those for all clinical research featured in the NIH Clinical Trials Data Bank? Second, what are the study design and characteristics of the registered musculoskeletal clinical trials? Third, which cellular therapies and disease conditions are being studied?

Materials and Methods

A systematic review of the clinical trials registered on the use of cell-based therapy for musculoskeletal applications was performed by 2 of the authors (N.S.P., M.N.) using the NIH Clinical Trials Data Bank. The queries were performed on February 12, 2017, and evaluated the time period from January 1, 2005, to August 31, 2016. Due to the large scope of topics pertinent to the use of cell-based therapies, the following search strategy was used to ensure that relevant trials relating to the most common musculoskeletal diagnoses would not be overlooked. Relevant trials were identified by using the following electronic search terms and their respective combinations: “orthopaedics”; “musculoskeletal”; “stem-cells”; “cell-therapy”; “osteonecrosis”; “tendon”; “meniscus”; “ligament”; “spine”; “intervertebral-disc”; “osteoarthritis”; and “cartilage” (Figure 1). Clinical trials were excluded from analysis if they (1) were unrelated to orthopedic/musculoskeletal conditions, (2) did not feature cell therapy as a treatment, and (3) were in a language other than English. Discrepancies in the search results were resolved by discussion among investigators involving reassessing the inclusion and exclusion criteria. The search yielded 1071 individual studies, of which 635 were unique. A total of 282 clinical trials met the inclusion and exclusion criteria.

Flow diagram of the systematic review process used in this study.

Figure 1:

Flow diagram of the systematic review process used in this study.

To assess the growth rate and the trends of musculoskeletal cellular therapy trials relative to those for all clinical research featured in the NIH Clinical Trials Data Bank, the numbers of trials initiated and completed each calendar year were plotted, as well as the time since registration for those clinical trials that had not yet been completed and/or published. For completed trials, the mean time from registration to closure was calculated along with its respective standard deviation and 95% confidence interval, to estimate the proportion of studies expected to be completed up to that point. The fates of the included clinical trials were recorded from 2005 to 2016. Of the studies that reported completion, further searches were included to identify associated publications to provide some basis for measuring trial quality. After quantification of the numbers of clinical trials started per year for orthopedic cell-based therapy and for the entire NIH clinical database, best-fit linear/polynomial/exponential lines were made and regression analyses (R2 values) were performed to characterize the growth rate of musculoskeletal cell-based trials.

To assess the study design and characteristics of the registered clinical trials on the use of cell-based therapy in orthopedics, the following data were obtained for analysis: (1) allocation (randomized vs nonrandomized); (2) intervention model (single group, parallel, not listed/other); (3) masking (single blind, double blind); (4) funding sources; (5) clinical phase of the study24; (6) projected patient enrollment; (7) geographic location; (8) registration status (completed, recruiting participants, ongoing, suspended/terminated, not yet open, unknown); (9) start date; (10) end date (if completed or closed); and (11) from the clinical trials identified as completed, associated listed publications in ClinicalTrials.gov.25

To assess the cellular therapies and disease conditions most frequently studied, the authors extracted the following information: (1) clinical indication; (2) cell source; and (3) autologous or allogeneic source.

Results

Growth of Musculoskeletal Cell-Based Clinical Research Is Greater Than the Overall Growth in Clinical Research Registered in the NIH Database

There were 282 musculoskeletal cell-based therapy clinical trials registered; a mean of approximately 24 new clinical trials per year were registered from 2005 to 2016 (Figure 2A). For the period from 2010 to 2016, the mean rate at which musculoskeletal trials were registered rose exponentially to approximately 33 new trials per year (Figure 2B). The quadratic best-fitting curve shown provided an R2 value of 0.99702. In contrast, the overall rate at which studies have been added to the NIH clinical database has been linear (Figure 2C), at 18,293 per year with an R2 value of 0.99142. Although musculoskeletal cell therapy trials represent a small fraction of the total (0.001%), the growth rate of musculoskeletal cell-based clinical research is close to twice that of the overall clinical research featured in the NIH database.

Orthopedic cell-based clinical research grows exponentially relative to that of the entire National Institutes of Health database, which grows at a constant rate. Increase in the number of cell-based therapy clinical trials started, by year (2005–2016). Accelerated growth of cell-based therapies in orthopedics vs overall constant growth of all clinical trials (2005–2016) (A). Total number of cell-based clinical trials in orthopedics with polynomial regression (B). Total number of studies registered to the National Institutes of Health clinical database with linear regression. Best-fit curves and R2 values included (C).

Figure 2:

Orthopedic cell-based clinical research grows exponentially relative to that of the entire National Institutes of Health database, which grows at a constant rate. Increase in the number of cell-based therapy clinical trials started, by year (2005–2016). Accelerated growth of cell-based therapies in orthopedics vs overall constant growth of all clinical trials (2005–2016) (A). Total number of cell-based clinical trials in orthopedics with polynomial regression (B). Total number of studies registered to the National Institutes of Health clinical database with linear regression. Best-fit curves and R2 values included (C).

Clinical Trials Design and Characteristics

Clinical Phase (Phases I–IV). The clinical phase of musculoskeletal cell-based clinical trials from 2005 to the present was quantified and appropriately stratified (Figure 3A), with an emphasis on comparing the number of completed and uncompleted trials. The overall trial breakdown was as follows: 3 (1%) phase 0; 62 (23%) phase I; 77 (27%) phase I/II; 54 (19%) phase II; 13 (5%) phase II/III; 18 (6%) phase III; 4 (1%) phase IV; and 51 (18%) not listed. Overall, 85% (196 of 231) of all studies were early-stage safety/efficacy trials (phase I/II). The completed trials had a similar clinical phase distribution.

Data on clinical phase distribution, funding sources, and patient enrollment. Bar graph showing completed relative to total musculoskeletal cell-based clinical trials, separated by clinical phase (2005–2016), stratified by completion status (A). Pie chart showing distribution of funding sources (B). Histogram showing patient enrollment distribution of musculoskeletal cell therapy clinical trials (C).

Figure 3:

Data on clinical phase distribution, funding sources, and patient enrollment. Bar graph showing completed relative to total musculoskeletal cell-based clinical trials, separated by clinical phase (2005–2016), stratified by completion status (A). Pie chart showing distribution of funding sources (B). Histogram showing patient enrollment distribution of musculoskeletal cell therapy clinical trials (C).

Funding Sources. Funding sources were collected and shown as a pie chart (Figure 3B). Most of the trials, 158 of 282 (56%) were funded by academic, hospital, and other institutions. In contrast, 90 (32%) trials were funded solely by industry, and 34 (12%) trials were funded by both industry and academic institutions.

Patient Enrollment. The distribution of planned patient enrollment is shown by histogram plot (Figure 3C). Most of the trials (190 of 282 clinical trials) included fewer than 50 patients. Half had enrollment between 11 and 50 patients (141 of 282 clinical trials). Excluding only 5 trials with patient enrollments exceeding 1000 as outliers, the mean enrollment for musculoskeletal cell-based clinical trials was 55 patients.

Clinical Trial Allocation, Intervention Model, and Masking. Most of the trials, 174 (61.7%), were randomized, whereas 32 (11.3%) were identified as nonrandomized and 76 (27.0%) were unlisted (Table 1). A total of 148 (52.5%) trials were identified as parallel assignments (2 or more groups of participants receive different interventions), 119 (42.2%) as single group, and 15 (5.3%) as not listed/other. Most of the trials, 164 (58.2%), were open label, whereas 65 (23.0%) were double blind, 37 (13.1%) were single blind regarding the subject, and 16 (5.7%) were not listed/other.

Study Design of Clinical Trials Registered to ClinicalTrials.gov on the Use of Cell-Based Therapies for Musculoskeletal Conditions

Table 1:

Study Design of Clinical Trials Registered to ClinicalTrials.gov on the Use of Cell-Based Therapies for Musculoskeletal Conditions

Clinical Trial Status. The number of studies opened and closed over time for each year from January 2005 to August 2016 was quantified and plotted. Among the 282 clinical trials identified, 99 (35%) were completed, 76 (26%) were recruiting participants, 51 (18%) were ongoing, 12 (4%) were suspended/terminated, 13 (5%) were not yet open, and the status of 34 (12%) was unknown. The mean time from registration to closure for completed trials was 49.9 months (SD, 30.9 months; 95% confidence interval, 43.6–56.2). Of the 183 uncompleted trials, 31 (17%) fell outside this range (ie, past 56.2 months), suggesting a skew in the data. However, it was not possible to determine from the available data whether these studies with extended time lines had been completed or abandoned but not updated regarding status in the database.

Geographic Distribution of Musculoskeletal Cell-Based Trials. The United States was the country with the most clinical trials—28% (79 of 282) (Figure 4A). The following 8 countries conducted almost half of all trials: Korea, 33 (12%); China, 26 (9%); Spain, 26 (9%); Iran, 22 (8%); France, 10 (3%); Belgium, 8 (3%); Germany, 5 (2%); and the United Kingdom, 6 (2%). The geographic distribution for musculoskeletal cell-based clinical trials was consistent with the distribution of all studies registered to the NIH database, with 37% (84,495 of 231,169 studies) conducted in the United States.

Characteristics of musculoskeletal cell-based therapy clinical trials. Geographic distribution of clinical trials for cell-based therapies (2005–2016) (A). Distribution of musculoskeletal disease conditions studied by total number of cell-based therapy clinical trials (B). Distribution of disease conditions of interest in completed cell-based therapy clinical trials (C). Abbreviations: FCD, focal cartilage defect; OA, osteoarthritis; ON, osteonecrosis; UK, United Kingdom; US, United States.

Figure 4:

Characteristics of musculoskeletal cell-based therapy clinical trials. Geographic distribution of clinical trials for cell-based therapies (2005–2016) (A). Distribution of musculoskeletal disease conditions studied by total number of cell-based therapy clinical trials (B). Distribution of disease conditions of interest in completed cell-based therapy clinical trials (C). Abbreviations: FCD, focal cartilage defect; OA, osteoarthritis; ON, osteonecrosis; UK, United Kingdom; US, United States.

Listed Publications. Of the 99 trials that were completed, 62 (62.6%) did not list any related publications in the NIH Clinical Trials Data Bank or in the National Center for Biotechnology Information. From the 37 clinical trials that had at least 1 associated publication, there were a total of 68 publications (mean, 2.1 per completed trial; range, 1–8).

Primary Disease Conditions of Interest

Most of the musculoskeletal cell-based therapy clinical trials were aimed at the treatment of osteoarthritis, focal cartilage defects, spondylitis, and osteonecrosis. These combined constituted 79% of all studies. From 2005 to the present, the distribution of clinical trials studying musculoskeletal disease conditions of interest was as follows: osteoarthritis, 136 (48%); focal cartilage defects, 38 (13%); spondylosis, 29 (10%); osteonecrosis, 22 (8%); rotator cuff tear, 7 (3%); bone fracture, 9 (3%); and miscellaneous/other, 34 (12%) (Figures 4B–C).

Cellular Therapies Used in Clinical Trials for the Treatment of Musculoskeletal Conditions. Autologous cells were used in most of the studies (71.3%) relative to allogeneic cells. Bone marrow was the dominant source chosen to obtain cells (49%), followed by cartilage and adipose tissue. Overall, cell sourcing involved bone marrow (139 studies, 50%), adipose (72 studies, 13%), cartilage (37 studies, 25%), amniotic tissues (5 studies, 1.5%)/umbilical cord cells (27 studies, 9.5%), and other sources (2 studies, 0.8%) (Figure 5).

Treatment sources in cell-based therapy clinical trials (2005–2016). Bar graph showing relative distribution of treatment sources in musculoskeletal cell-based therapy clinical trials (A). Summary of cell-based therapies studied by included clinical trials, sorted by treatment source and autologous vs allogeneic cell source (B). Abbreviation: BM, bone marrow.

Figure 5:

Treatment sources in cell-based therapy clinical trials (2005–2016). Bar graph showing relative distribution of treatment sources in musculoskeletal cell-based therapy clinical trials (A). Summary of cell-based therapies studied by included clinical trials, sorted by treatment source and autologous vs allogeneic cell source (B). Abbreviation: BM, bone marrow.

Discussion

Stem cell therapies have garnered great interest and excitement; however, evidence regarding their safety and efficacy has been slow to evolve.26–29 Despite the limited evidence, the combination of clinical demand and business opportunity has induced some physicians to forge ahead, and in the United States, musculoskeletal applications of cell-based therapies seem to be rising.2,3 The widening gap between evidence and use risks a breach of faith with patients and compromise of the field.

This study systematically assessed the overall status of the clinical trials that represent the pipeline for future information in the field; however, it had several limitations. First, the authors did not include other registries such as the World Health Organization International Clinical Trials Registry Platform. It is possible that the use of more search terms would have identified additional trials. Future studies may refine these methodologies for systematic inclusion of registered clinical trials. Second, the authors only reported on the presence or absence of publications listed in the NIH Clinical Trials Data Bank and did not perform a search in other databases (eg, EMBASE, PubMed). Third, the authors did not attempt to assess if there is any bias regarding the publication of positive or negative clinical trial results in the field of cell-based therapies.

The rate at which cell-based clinical trials for musculoskeletal indications are being registered has risen exponentially, faster than the relatively linear rise in the number of overall registered trials across all indications. This is an appropriate reflection of the level of need for and interest in regenerative therapies and the promise that has been generated in the domain of cellular therapies through ongoing advances in connective tissue stem cell biology.

The analysis appraising the study design showed that selection bias was being addressed by randomization in most of the studies (62%); however, performance and detection bias might be a challenge, as only 23% of the studies were double blind and 13% were single blind (subject). The assessment of trial study phase indicated that musculoskeletal cell-based therapy research remains in an early stage of development. Most of the trials (85%) involving musculoskeletal cellular therapies were early-stage, phase I/II, safety-efficacy studies. In resemblance, historical trends in the more established drug development industry suggest that approximately 10% of therapies examined in phase I will advance to Food and Drug Administration approval and that this path is slow, generally taking 5 to 10 years.30

Starting a clinical trial is one thing, but completing it is another. Although the completion rate that the authors found for cell-based therapy trials in musculoskeletal medicine was low (35%), it was similar to the overall completion rate reported for clinical trials for all interventions: 29.9% for the period from October 2007 to September 2010.31 In February 2013, a cross-sectional study of the NIH Clinical Trials Data Bank evaluated all terminated trials, reporting that most of them failed due to an inability to recruit patients.32 However, the currently available information does not define the reason for suspension or termination of a trial. Although recruitment may have been a limiting factor in the studies analyzed, the authors cannot exclude other causes, such as closure due to adverse events, lack of evidence of efficacy, loss of funding, or changes in research or business focus, or simple failure to update status in the registry.

The lag between completion of a clinical trial and publication of the results is a concern. There are few legitimate reasons for failure to publish. Even if the results of a trial are disappointing or inconclusive, publication is an obligation. Negative findings are a valuable component of the scientific literature. They force physicians to critically evaluate their current thinking, enable them to avoid unnecessary waste of resources on rediscovery of ineffective strategies, and generate new hypotheses that move physicians forward.33 Of the 99 trials that were completed, a large proportion (62.6%) did not list related publications in the NIH Clinical Trials Data Bank. Although it is possible that some of those trials may be in the process of publication, or that publications have been generated and are not listed in ClinicalTrials.gov, there is currently no efficient way to link registered trials to publications. However, the 35% publication rate for cell-based therapies is similar to the 39% publication rate reported for spine-related studies, the 23% publication rate reported for arthroplasty trials, and the 43% publication rate reported for orthopedic trauma trials.34 A previous cross-sectional study analyzing the entire ClinicalTrials.gov database determined that, overall, less than half of all trials resulted in publications.35 Although consistent with the rest of medicine, this low publication rate for completed trials is not reassuring.

Data collected in this study corroborate that osteoarthritis is the primary disease condition for which cell-based therapies are being studied and accounts for almost half (48%) of all trials. This is expected because osteoarthritis constitutes a leading cause of disability with an increasing prevalence.36,37 It is also no great surprise that trials favor the use of autologous cell sources (71.3% of trials) without in vitro culture, particularly autologous bone marrow–derived cells (49% of trials).

Recent systematic reviews of the use of cellular therapies in clinical trials in orthopedics have shown that there is deficiency in the reporting and characterization of the cell populations.4,27 Editorial boards are increasingly aware of the need for more rigorous characterization of the cell source, harvest method, processing methods, and composition of the cell populations. With the accelerated growth of cell-based clinical trials, the expectation is that increasing numbers of studies will be focused on comparison of alternative cell sources with defined critical quality attributes. Currently, databases such as ClinicalTrials. gov include only superficial information regarding cell source and attribute. This is another opportunity to improve granularity in the available data that would be valuable for ongoing tracking and communication.

Conclusion

Musculoskeletal cell-based clinical trials are being registered at a faster rate than the overall research registered to the NIH clinical database. This acceleration reflects the large burden of musculoskeletal disease and an increasing interest in regenerative cell-based therapies from the perspective of patients, clinicians, and industry. Overall, most of the clinical trials have targeted the treatment of cartilage-related diseases using autologous cells harvested mostly from bone marrow. These data reflect the relative complexity, time line, and risk associated with completion of high-quality studies in this rapidly evolving clinical space. Despite its limitations, ClinicalTrials.gov provides a valuable window into the process and dynamics of musculoskeletal clinical trials that can be used to track progress in critically assessing cell-based therapies research.

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Study Design of Clinical Trials Registered to ClinicalTrials.gov on the Use of Cell-Based Therapies for Musculoskeletal Conditions

Design ElementNo. of Clinical Trials (%)
Allocation
  Randomized174 (61.7)
  Nonrandomized32 (11.3)
  Other/not listed/not applicable76 (27.0)
  Total282 (100)
Intervention model
  Single group119 (42.2)
  Parallel148 (52.5)
  Crossover0 (0)
  Factorial0 (0)
  Sequential0 (0)
  Not listed/other15 (5.3)
  Total282 (100)
Masking
  Double blind65 (23.0)
  Single blind (subject)37 (13.1)
  Open label164 (58.2)
  Participant, care provider, investigator, outcomes assessor0 (0)
  Not listed/other16 (5.7)
  Total282 (100)
Authors

The authors are from the Department of Orthopaedics (NSP, MN, MC, AK, PNR, MAM, GFM), Cleveland Clinic, Cleveland, Ohio; and the Department of Orthopaedic Surgery (SFH), Mount Sinai West Hospital, the Department of Orthopaedic Surgery (MAM), Lenox Hill Hospital, and the Hospital for Special Surgery (TWB), New York, New York.

Dr. Harwin was not involved in the peer review of this manuscript.

Dr Piuzzi, Mr Ng, Dr Chughtai, Dr Khlopas, Dr Ramkumar, Dr Bauer, and Dr Muschler have no relevant financial relationships to disclose. Dr Harwin is a paid consultant for, is on the speaker's bureau of, and holds stock in Stryker. Dr Mont is a paid consultant for Stryker, DJO Global, Sage Products, TissueGene, OnGoing Care Solutions, Orthosensor, Johnson & Johnson, Pacira Pharmaceuticals, Cymedica, and Performance Dynamics Inc; has received research support from Stryker, DJO Global, TissueGene, OnGoing Care Solutions, Orthosensor, and Johnson & Johnson; receives royalties from MicroPort; and holds stock in Peerwell.

Correspondence should be addressed to: Nicolas S. Piuzzi, MD, Department of Orthopaedics, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 ( piuzzin@ccf.org).

Received: January 10, 2018
Accepted: April 23, 2018
Posted Online: January 31, 2019

10.3928/01477447-20190118-04

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