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Hand Transplantation

Scott M. Tintle, MD » Upper extremity limb loss is catastrophic. It affects nearly every Benjamin K. Potter, MD activity of daily living, leaving patients with substantial disability. River M. Elliott, MD » Despite high rates of rejection of upper extremity prostheses, hand transplantation remains controversial. L. Scott Levin, MD » The indications for hand transplantation remain relatively ill defined.

» The American Society for Reconstructive Transplantation (ASRT) and Investigation performed at the University of Pennsylvania, the International Registry on Hand and Composite Tissue Transplan- Philadelphia, Pennsylvania tation (IRHCTT) have been founded to advance the science, to educate, to report outcomes, and to define the indications for vascularized composite .

pper extremity loss repre- Pioneers of hand transplantation rec- sents a life-changing, often ognized that prosthetic devices probably devastating event, affecting would never completely satisfy the upper nearly every activity of daily extremity amputee for these very reasons. livingU and subsequently leaving a patient Even if the prehensile function and dex- with substantial disability1,2. The potential terity of the human hand could be restored, immediate dependency and despair result- these would do little to restore patient ing from the loss of one or both hands body image or hand sensibility, both traits cannot be overstated. Promising techno- coveted by amputees. Rather, they postu- logical advances in upper extremity pros- lated that these could only be replaced with theses include improved neural-control “like” human tissue14. The field of vascu- interfaces, multiple-degrees-of-freedom larized composite allotransplantation has terminal devices, and prototype haptic grown from this basic desire to fully feedback mechanisms3,4. However, the restore both the functional and emotional available literature still demonstrates high aspects of the human hand, building on the prosthesis rejection rates for upper ex- foundations developed by solid organ tremity amputees5-12, suggesting that transplantation, hand surgery, and recon- prostheses continue to inadequately repli- structive microsurgery. cate the complex, prehensile functions of The concept of using composite tissue the native hand and arm. The most com- allograft was first suggested in 1960 by monly cited reasons for upper extremity Peacock, when he utilized cadaveric flexor prosthesis rejection remain limited useful- tendons along with their synovial sheaths ness, weight, and residual limb in order to reconstruct end-stage tendon discomfort5,13. incarcerations that otherwise would have

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

COPYRIGHT © 2014 BY THE Disclaimer: The opinions and assertions contained herein are the private views of the authors and are JOURNAL OF BONE AND JOINT not to be construed as official or as reflecting the views of the United States Army, United States SURGERY, INCORPORATED Navy, Department of Defense, or the US Government.

JBJS REVIEWS 2014;2(1):e1 · http://dx.doi.org/10.2106/JBJS.RVW.M.00063 1 | Hand Transplantation

required amputation15-18. Shortly after Indications for Transplantation and reconstructive and transplant surgery. this early success with composite tissue Ethical Considerations Last year, the ASRT published guide- allografts, and likely inspired by the “Primum non nocere”—“first do no lines for medical necessity determina- rapid growth of the solid organ trans- harm”—remains a paramount principle tion for transplantation of the hand and/ plantation community, the world’s first as the field of vascularized composite or upper extremity (Fig. 1). hand transplantation was performed in allotransplantation progresses. In the South America in 19641,19,20. Unfor- 2002 position statement of the Ameri- Psychological Screening tunately, probably because of the rela- can Society for Surgery of the Hand, The majority of amputee patients are tively primitive immunosuppression Cooney and Hentz echoed this senti- afflicted by a psychological disorder33. as well as a lack of basic-science prepa- ment when they recommended “great This consideration complicates hand ration, acute rejection predictably caution and a measured approach to the transplantation in that the outcome of occurred and the transplanted limb patient requesting a limb transplant.”28 a hand transplantation is very much was amputated about three weeks This caution, along with appropriate dependent on the participation, coop- later15,21. Perhaps reflecting the scien- ethical considerations, have tempered eration, and compliance of a patient tific hazards of reaching too far, too the growth of vascularized composite with hand therapy, medications, and fast, the next attempt at hand trans- allotransplantation as compared with follow-up screening appointments. plantation did not occur until thirty- solid . Hand A kidney, liver, or heart transplant four years later in Lyon, France, in transplantation is very different from depends only on compliance with 199815,22,23. Technically, this second most solid organ transplantations in medications, and even still there are procedure succeeded; however, this that the candidate for hand transplan- relatively high rates of medication non- success was not functionally realized tation is not faced with a life-or-death compliance in this population34,35.In and sustained because the patient did decision29. For this reason, developing a combined heart and heart/lung trans- not adapt psychologically to the new widely accepted indications for subject- plant population, it was found that hand and discontinued the use of ing a physiologically healthy person to the only risk factor for loss between immunosuppressive medications. The the risks of life-long immunosuppres- six and twelve months was being transplanted limb was eventually sion remains a challenge for the allo- unmarried or not living in a stable amputated1. The first hand transplan- transplantation community30. relationship34,35. It is therefore impera- tation in the United States was per- In 2009, Hollenbeck et al. indi- tive that all patients who are to be formed the following year in Louisville, cated that there were no current, well- considered for hand transplantation Kentucky. At the time of writing, this defined indications for vascularized undergo extensive psychological and third patient still had the transplanted composite allotransplantation of the psychiatric screening prior to selection hand, nearly fourteen years later15,24. hand or face14. Unfortunately, this for hand transplantation. In addition, The early success of hand trans- remains the case today31,32—the indi- the social support for an individual plantation in the late 1990s was made cations remain open to interpretation candidate must be identified, and a possible by advances in solid organ by individual vascularized composite transplantation should not occur if transplantation. Specifically, the devel- allotransplantation centers. While this the surgeon is not comfortable with opment of new medications such autonomy to develop indications to the patient’s support system. as cyclosporine, tacrolimus, and accompany slightly different approaches mycophenolate mofetil made the is ostensibly important in a developing Immunosuppression avoidance of rejection possible. In ad- field, the vascularized composite allo- Conventional Immunosuppression dition, animal models of vascularized transplantation community is attempt- Aside from the ethical issues surround- composite allotransplantation provided ing to develop universally accepted ing hand transplantation, perhaps the the basic and translational science evi- indications for hand transplantation most critical reason that vascularized dence that successful composite tissue based on the evidence available. Having composite allotransplantation has lag- allotransplantation without rejection recognized the need for defined and ged behind solid organ transplantation was possible with use of these accepted indications for hand trans- is the skin. Skin is the most antigenic medications15,25-27. Since that time, the plantation, the allotransplantation tissue of the composite tissues that field of vascularized composite allo- community founded the American constitute a hand transplant, and pre- transplantation has grown dramatically. Society for Reconstructive Transplan- venting the immune system from Eighty-nine hand transplantations tation (ASRT) in 2008. The goal rejecting the skin was necessary prior to have been performed worldwide to date, of the ASRT is to provide a platform successful hand transplantation1,36-38. and there are at least seven centers in for the advancement of education, sci- In the 1990s, the aforementioned the United States at which hand trans- ence, and the practice of composite pharmacologic discoveries and subse- plantation has been performed. tissue allotransplantation as relevant to quent animal testing provided evidence

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Fig. 1 ASRT Guidelines for Medical Necessity Determination for Transplantation of the Hand and/or Upper Extremity. (Reproduced with permission from the American Society for Reconstructive Transplantation.) that skin rejection could be overcome recipients undergo induction therapy at lymphocytes in order to minimize the with acceptable, often minimal, side the time of hand transplantation with initial host immune response to the effects25,39. use of either polyclonal antibody prep- newly transplanted hand. Following The International Registry on arations (antithymocyte globulins induction therapy, the most frequently Hand and Composite Tissue Trans- [ATG]) or monoclonal antibody prep- utilized conventional immunosuppres- plantation (IRHCTT)40 indicates arations (e.g., alemtuzumab, basilix- sive regimen is triple-drug therapy that the majority of hand transplant imab) targeted against the recipient’s similar to the medications that renal

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TABLE I Immunosuppression Complications

Complication No. of Patients

Serum sickness 1 Opportunistic infections 29 Post-transplant lymphoproliferative disorder 1 Basal cell carcinoma of the nose 1 Metabolic complications 23 Hyperglycemia 9 (not reversible in 3 patients, who needed hypoglycemic medications) Elevated creatinine 5 End-stage renal disease 1 (8 years after transplantation) Arterial hypertension 5 Cushing syndrome 1 Osteonecrosis of the hip 1 Hyperparathyroidism 1

transplantation patients receive, gener- syndrome, osteonecrosis, and im- transplantation45. This point is clearly ally consisting of tacrolimus, mycophe- paired renal function30,40. Two low- controversial; however, less-toxic, nolate mofetil, and prednisone30,41. grade malignant lesions also have minimal immunosuppressive regimens While conventional, this immu- been reported as a result of immuno- that could produce equivalent long- notherapy has been extremely effective suppression in patients managed term functional outcomes after trans- in the field of hand transplantation: no with vascularized composite allotrans- plantation could lead to both a more hand transplant has been lost because plantation, but both were treated widely accepted risk-benefit ratio and of acute rejection when conventional successfully (Table I). Finally, one expanded indications for vascularized triple-drug immunosuppression has confirmed case of lymphoproliferative composite allotransplantation. been used30. This 100% rate of graft disorder leading to a central nervous This ambition is the impetus for survival at one year after transplantation system lymphoma was recently diag- the development of novel protocols hasnotbeenachieved todateinanyother nosed in a patient who was managed that aspire to shift the paradigm from field of transplantation30. Despite this with bilateral lower extremity trans- one of immunosuppression to one of impressive statistic, however, 85% to plantation43.Thispatienthad immunoregulation and graft toler- 90% of these twenty-four transplanted removal of the transplanted extremi- ance45. Some unique features of vascu- extremities were associated at least one ties, with immediate cessation of larized composite allotransplantation episode of acute rejection within the first immunosuppression. make this field particularly amenable to year following transplantation30,40,41. the potential for decreased immuno- The side effects of these medica- Immunomodulation suppression. The highly antigenic skin tions are well documented in the solid Despite the fact that few life-threatening is visible and represents a distinct organ transplantation literature and complications have developed in advantage for vascularized composite have been further reported by the patients managed with conventional allotransplantation monitoring. Acute IRHCTT following vascularized therapy, standard immunosuppression rejection is easily and quickly detected composite allotransplantation40,42. may not represent an acceptable risk because of the maculopapular skin The most common side effects reported for patients managed with vascularized changes that rapidly develop. Immediate by the IRHCTT include both oppor- composite allotransplantation given medication changes can be made, and tunistic infections and metabolic the evolving indications and the pre- serum markers of rejection are therefore abnormalities. Infections have in- transplantation health of appropriate generally not necessary to detect rejec- cluded cytomegalovirus, clostridium candidates44. That is, because the tion. In addition, topical medications difficile enteritis, herpes simplex, absence of one or both hands does not sometimes can be utilized to treat acute cutaneous mucosis, and osteomyelitis. lead to death, many have argued that cutaneous rejection, reversing or pre- The metabolic complications include the acceptable risks of surgery and venting rejection episodes with minimal hyperglycemia, diabetes, hyperlipid- immunosuppression ostensibly should systemic effects40,45,46. This benefit in emia, hyperparathyroidism, Cushing be lower than those of solid organ terms of both monitoring and treatment

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represents an advantage that cannot and, unfortunately, tolerance to skin was patient was managed in France and currently be exploited in the field of solid not achieved. underwent bilateral hand transplanta- organ transplantation. Schneeberger et al.47 reported on tion as well as face transplantation. This Attempts to minimize immuno- their cell-based protocol to minimize patient sustained cerebral anoxia as a suppression following solid-organ immunosuppression in human trials result of an obstructed airway and died transplantation by infusing bone involving five patients. All patients had on the sixty-fifth postoperative day. marrow from donors into recipients successful hand/arm transplantation Two additional deaths have now been have successfully led to decreased with use of tacrolimus monotherapy reported in Turkey57-59. These two immunosuppressive medication for maintenance immunosuppression. deaths represent substantial concern requirements47-51. The goal of such an Two patients had three episodes of in that they occurred following triple and infusion is to create chimerism, in which rejection each, whereas the other three quadruple limb transplantations. These the host does not attack the graft and, patients had one episode each. All epi- questionably indicated lower extremity vice versa, there is no graft-versus-host sodes were treated with steroid bolus transplantations are reminiscent of the disease52-54. Studies have demonstrated therapy and/or topical tacrolimus and first hand transplantation that was per- that as little as 1% “microchimerism” clobetasol. These episodes of rejection formed in 1964 with poor indications and has been sufficient to allow for the are consistent with the world experience little or no basic-science preparation. development of tolerance55,56. The with hand transplantation40. Donor- In China, at least seven grafts resulting chimerism, as well as the use of specific alloantibodies were detected have been removed. The indications cell-based therapies, may lead to host in four of the five patients and were for graft removal in these patients tolerance for the grafted hand, resulting associated with skin rejection in most included noncompliance with medica- in potentially lower immunosuppressive instances. However, the authors dem- tions, a lack of appropriate immuno- requirements and subsequently fewer onstrated that their protocol involving suppressive therapy, the long distance treatment-related morbidities and tacrolimus monotherapy following from the patient homes to the transplant sequelae. bone-marrow-cell infusion was suc- centers, and/or unreported episodes Since 2009, one group in the cessful for maintaining viability of a of rejection that were discovered on United States has been utilizing a hand/arm transplant. They concluded eventual follow-up. In Western countries, bone-marrow-cell-based treatment pro- that larger and/or randomized con- therehavebeenthreepublishedreportsof tocol (the so-called Pittsburgh protocol) trolled trials with long-term follow-up graft losses. One patient with bilateral in efforts to minimize maintenance were needed to confirm their early involvement lost one hand transplant immunosuppression47. This protocol findings47. forty-five days postoperatively as a result includes standard induction followed of infection, one patient lost a graft 275 by tacrolimus monotherapy. On the Outcomes days postoperatively because of intimal fourteenth day after transplantation, The IRHCTT was founded in May hyperplasia (potentially representing the patients receive an infusion of 200240, with the aim of the registry chronic rejection), and one patient lost the donor bone-marrow cells isolated from being to combine international clinical transplanted limb twenty-nine months nine vertebral bodies of the donor experiences so that state-of-the-art postoperatively as a result of noncompli- patient47. The authors had performed knowledge can be shared among those ance with immunosuppressive medica- a successful trial of a similar regimen in already working in or approaching tions and poor function. a swine model prior to implementing the field of composite tissue allotrans- To date, 85% of the thirty-three this method in humans44,47. In this plantation. According to the IRHCTT patients in the registry have experienced at miniature swine model of hindlimb itself, one of the main limitations that least one episode of acute rejection, and allotransplantation across a major currently exists with the registry is that many have had multiple episodes (Table histocompatibility complex barrier, the some international and even some United II). These rejection events frequently authors were able to induce tolerance States vascularized composite allotrans- correlated with short-term noncompli- to the musculoskeletal elements of the plantation programs had not submitted ance with medications and/or a decrease transplanted hindlimb in two of three their patients’ data at the time of the last in immunosuppression as ordered by the swine treated with bone marrow cells publication from the IRHCTT 40. vascularized composite allotransplanta- along with enteral cyclosporine for The IRHCTT reported on thirty- tion team for various reasons. However, monotherapy immunosuppression. three patients who had undergone upper all episodes of rejection were reversed with The third animal died early (on the extremity transplantation in 201040. short-term increases in medication dos- forty-second day after transplantation) One death has been reported among the ing, the use of topical agents, and/or in- as a result of an upper gastrointestinal patients from the registry who were travenous steroid boluses. bleed44. The authors did not demon- managed with vascularized composite While no definite chronic rejection strate chimerism in the animal recipients allotransplantation of the hand. The has been reported to our knowledge, the

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psychological outcome, social behavior, TABLE II Acute Rejection Episodes in Registry Patients work status, subjective satisfaction, body No. of Patients No. of Acute Rejection Episodes image, and well-being of the patient. The registry indicates that quality of life 15 1 improved in .75% of patients, and 72a return to work has been a consistent 33feature for a majority. While pre- 24transplantation HTSS scores were not 15reported, the average score was 52 at one year following transplantation and was 88 at ten years (maximum score, patient who required graft removal at in a majority of the patients despite often 100). Similarly, the mean DASH score 275 days postoperatively for myointimal high-level nerve coaptation. In several was 38 at one year and 16 at ten years proliferation had experienced four un- hands, recovery of intrinsic function has (best score, 0)40. Moving forward, treated episodes of acute rejection. In been confirmed with use of electromy- it will be imperative to gather these addition, all patients from the Louisville ography. The composite recovery of same data on upper extremity ampu- program now have evidence of graft vas- extrinsic and intrinsic motor function as tees successfully utilizing modern culopathy, a concern that is being closely well as functional sensibility has allowed prostheses in order to make valid followed and potentially will become the recipients to independently perform comparisons. focus of frequent monitoring in vascu- most activities of daily living, including larized composite allotransplantation eating, driving, grasping objects, riding Economics of Hand Transplantation programs worldwide60. Importantly, a motorcycle or bicycle, using the tele- The economics of vascularized com- no evidence of graft-versus-host disease phone, and writing40. As expected, posite allotransplantation have become has been reported from any program, the more distal transplants have dem- an important issue and may even begin to our knowledge. onstrated relatively greater motor and to dictate the future of many vascular- sensory function as the nerves have to ized composite allotransplantation Functional Results regenerate over shorter distances; how- programs, especially in light of both Thirty-one of the thirty-three recipients ever, good results have been obtained their experimental, generally funded from the registry were included in the even with proximal-level amputations nature as well as the changing healthcare functional assessment as they had as high as the deltoid61,62. Despite these economic environment in the United more than one year of follow-up at the overall good results, detailed functional States31,63,64. Fifteen years ago, prior to time of data analysis. Despite concerns assessments involving comparisons the first successful hand transplantation, regarding relatively high rates of with highly trained prosthetic users as McCabe et al.64 performed a decision immunosuppression-related side effects, well as comparisons based on the levels analysis in order to attempt to guide acute rejection, and composite graft loss, transplanted are necessary in order to decision-making with regard to the cost themotor andsensoryrecoveryfollowing truly narrow and refine the indications effectiveness of hand transplantation. composite tissue allotransplantation has for hand transplantation. Understanding decision analysis is im- been better than expected. Importantly, portant in order to interpret both this registry data demonstrate that motor and Quality of Life initial study as well as a subsequent study sensory improvements may continue for The quality-of-life assessment of pa- by Chung et al.31 on the economics of as long as five years following transplan- tients managed with transplantation is hand transplantation. tation40. All patients developed protec- one of the most important parameters In the study by McCabe et al., tive sensation, thirty developed tactile of success of vascularized composite twenty-two young adult volunteers were sensibility, and twenty-eight developed allotransplantation, but such assess- interviewed about limb loss. The pa- discriminative sensibility40. ments have not been adequately re- tients were allowed to choose to remain Motor recovery following upper ported or captured by the literature to in a defined state of poor health or to extremity transplantation has been bet- date. The IRHCTT has utilized the trade future years of life for an improved ter than what would be expected fol- Hand Transplantation Score System health state. The volunteers’ willingness lowing similar-level nerve repairs, with (HTSS) and the Disabilities of the Arm, to trade corresponded with the value the return of extrinsic muscle function Shoulder and Hand (DASH) score to placed on the various states of health64. first allowing pinch and grip activities. evaluate outcomes following transplan- McCabe et al. found, on the basis of the This has been followed by unusual in- tation. The HTSS score evaluates decision analysis, that unilateral hand trinsic muscle function at nine to fifteen both the cosmetic and functional re- transplantation was not economically months after the time of transplantation sults of transplantation, including the recommended.

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In the similar study recently per- progressive vasculopathy, patient non- the change in these factors after trans- formed by Chung et al.31, 100 medical compliance with immunosuppression, plantation will need to be closely scru- student volunteers were utilized to as- failure of functional recovery despite tinized in order for the risk-benefit ratio sign utilities. The investigators found a living transplant, and substantial psy- to be defined accurately. In addition, that, in the setting of unilateral hand chiatric pathology adversely affecting objective sensory and motor testing with amputation, prosthesis use was favored functional outcomes40. In addition, two breakdown by the level of transplanta- over hand transplantation. They found cases of perioperative failure resulting tion as well as the use of accepted func- that bilateral hand transplantation was in reamputation have occurred in the tional assessments (e.g., the Carroll test) favored over prosthesis use in the setting United States. Even more concerning, need to be embraced and widely utilized. of bilateral limb loss; however, the however, are the reports of perioperative Last, rapid and transparent reporting incremental cost-utility ratio of bilateral mortality that have occurred following of complications to the IRHCTT is transplantation was $381,961 per questionably indicated and undoubt- necessary in order to both quantify and quality-adjusted life year (QALY), edly aggressive triple and quadruple qualify both failures and successes. which greatly exceeds the traditionally limb performed Only then can an accurate assessment accepted cost-effectiveness threshold outside of the United States57. Similarly, of the risk-benefit ratio be performed, of $50,000 per QALY31. Nonetheless, potentially premature implementation indications be refined, immunosup- the authors concluded that prosthesis of lower extremity vascularized com- pression and immunomodulation regi- adoption was the dominant strategy posite allotransplantation has led some mens be adjusted, and candidate for unilateral hand amputation and to conclude that “just because you can, patients be appropriately screened and that bilateral hand transplantation does not mean that you should.”65 counseled. As physicians and surgeons, exceeds the societal acceptable threshold Rather than accelerating the advance- we can accept nothing less for our for general adoption. ment and acceptance of composite tissue patients, and doing so ostensibly may Despite the importance of viewing allotransplantation, ill-advised and po- jeopardize the entire field of composite the success and feasibility of an inter- tentially reckless utilization of the tech- tissue allotransplantation. vention financially, there are inherent nique threatens to endanger the field. While the field remains in its in- flaws in decision analysis, which both The risk-benefit ratio guides us as fancy, hand transplantation has dem- McCabe et al.64 and Chung et al.31 surgeons and influences our decision to onstrated many successes, and the future brought to light in their discussions. offer various procedures. This is no dif- appears promising for this restorative Perhaps the biggest problem with such ferent in the case of hand transplanta- treatment. We believe that it is now time decision analysis lies in the fact that the tion, except that the risks and benefits of to step back and reevaluate what has and assigning of utilities will vary among the procedure have yet to be clearly de- has not worked and to reassess the different populations of people and fined29. However, the intermediate risks current public and medical field accep- critically affects the outcome of the of hand transplantation are relatively tance of allotransplantation. Many analysis64. While assessing the general well defined in the literature40, and the obstacles remain, among them contin- public is important to determine the long-term risks of immunosuppression ued funding, immunology, candidate societal perspective, surrogate patients can be extrapolated from the data on selection, and long-term assessment from the general public and even medi- solid-organ transplantation. We now of outcomes, in addition to the contin- cal students may not be able to truly have evidence that a patient who has had ued refinement of indications. We assess the benefit of a transplanted a leg transplantation will likely die of an should approach the future with cau- hand or to comprehend the complica- immunosuppression-related central tious optimism and continue to evaluate tions associated with long-term nervous system tumor in the near future. all that we do with bench science, peer immunosuppression29,31. It is critical to the future of this field review of both favorable and unfavorable that appropriate indications for trans- clinical outcomes, and ethical treatment Future of Hand Transplantation plantation are established and that our of our patients. Video 1 demonstrates Reconstructive surgeons have made patients are counseled about the com- hand function following bilateral prox- considerable progress over the last fifteen plications of immunosuppression, in- imal forearm transplantation with years and can now offer functional cluding potential death. complete flexor-pronator and extensor restorative surgery to patients with up- Moving forward, it is imperative muscle transfers with coaptation of the per extremity limb loss that cannot be that the physical and mental benefits radial, median, and ulnar nerves at the treated with conventional techniques. of hand transplantation are carefully elbow. The lingering question at this point is reported and evaluated66. In this regard, whether this trend can and will con- attempts to better understand the social Source of Funding tinue. Recent reports have described and psychological impact of upper ex- No external funding was received for the limb loss after transplantation due to tremity limb loss and then to document present study.

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