Mimicking Clinical Rejection Patterns in a Rat Osteomyocutaneous Flap Model of Vascularized Composite Allotransplantation.

INTRODUCTION: Graft loss in vascularized composite allotransplantation (VCA) is more often associated with vasculopathy and chronic rejection (CR) than acute cellular rejection (ACR). We present a rat osteomyocutaneous flap model using titrated tacrolimus administration that mimics the graft rejection patterns in our clinical hand transplant program. Comparison of outcomes in these models support a role for ischemia reperfusion injury (IRI) and microvascular changes in CR of skin and large-vessel vasculopathy. The potential of the surgical models for investigating mechanisms of rejection and vasculopathy in VCA and treatment interventions is presented. MATERIALS AND METHODS: Four rodent groups were evaluated: syngeneic controls (Group 1), allogeneic transient immunosuppression (Group 2), allogeneic suboptimal immunosuppression (Group 3), and allogeneic standard immunosuppression (Group 4). Animals were monitored for ACR, vasculopathy, and CR of the skin. RESULTS: Transient immunosuppression resulted in severe ACR within 2 wk of tacrolimus discontinuation. Standard immunosuppression resulted in minimal rejection but subclinical microvascular changes, including capillary thrombosis and luminal narrowing in arterioles in the donor skin. Further reduction in tacrolimus dose led to femoral vasculopathy and CR of the skin. Surprisingly, femoral vasculopathy was also observed in the syngeneic control group. CONCLUSIONS: Titration of tacrolimus in the allogeneic VCA model resulted in presentations of rejection and vasculopathy similar to those in patients and suggests vasculopathy starts at the microvascular level. This adjustable experimental model will allow the study of variables and interventions, such as external trauma or complement blockade, that may initiate or mitigate vasculopathy and CR in VCA.

Identifying Health-Related Quality of Life Domains After Upper Extremity Transplantation.

OBJECTIVE: To identify the most important health-related quality of life (HRQOL) domains and patient-reported outcomes after upper extremity transplantation (UET) in individuals with upper extremity amputation. DESIGN: Verbatim audio-recordings of individual interviews and focus groups were analyzed using qualitative, grounded theory-based methods to identify important domains of HRQOL and provide guidance for outcomes measurement after UET. SETTING: Individual interviews were conducted by phone. Focus groups were conducted at 5 upper extremity vascularized composite allotransplantation (VCA) centers in the US and at an international conference of VCA experts. PARTICIPANTS: Individual phone interviews were conducted with 5 individuals with lived experience of UET. Thirteen focus groups were conducted with a total of 59 clinical professionals involved in UET. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Twenty-eight key HRQOL domains were identified, including physical functioning and medical complications, positive and negative emotional functioning, and social participation, relations, and independence. We identified key constructs for use in evaluation of the potentially substantial physical, medical, social, and emotional effects of UET. CONCLUSIONS: This study provides an overview of the most important issues affecting HRQOL after UET, including several topics that are unique to individuals with UET. This information will be used to establish systematic, comprehensive, and longitudinal measurement of post-UET HRQOL outcomes.

Grasping with a new hand: Improved performance and normalized grasp-selective brain responses despite persistent functional changes in primary motor cortex and low-level sensory and motor impairments.

Hand loss can now be reversed through surgical transplantation years or decades after amputation. Remarkably, these patients come to use their new hand to skilfully grasp and manipulate objects. The brain mechanisms that make this possible are unknown. Here we test the hypothesis that the anterior intraparietal cortex (aIPC) - a multimodal region implicated in hand preshaping and error correction during grasping - plays a key role in this compensatory grasp control. Motion capture and fMRI are used to characterize hand kinematics and brain responses during visually guided grasping with a transplanted hand at 26 and 41 months post-transplant in patient DR, a former hand amputee of 13 years. Compared with matched controls, DR shows increasingly normal grasp kinematics paralleled by increasingly robust grasp-selective fMRI responses within the very same brain areas that show grasp-selectivity in controls, including the aIPC, premotor and cerebellar cortices. Paradoxically, over this same time DR exhibits significant limitations in basic sensory and motor functions, and persistent amputation-related functional reorganization of primary motor cortex. Movements of the non-transplanted hand positively activate the ipsilateral primary motor hand area - a functional marker of persistent interhemispheric amputation-related reorganization. Our data demonstrate for the first time that even after more than a decade of living as an amputee the normative functional brain organization governing the control of grasping can be restored. We propose that the aIPC and interconnected premotor and cerebellar cortices enable grasp normalization by compensating for the functional impact of reorganizational changes in primary sensorimotor cortex and targeting errors in regenerating peripheral nerves.

Microstructural integrity of corticospinal and medial lemniscus tracts: insights from diffusion tensor tractography of right-hand amputees.

Reductions in sensory and motor activity following unilateral upper limb amputation during adulthood are associated with widespread, activity-dependent reorganization of the gray matter and white matter through the central nervous system. Likewise, in cases of congenital limb absence there is evidence that limited afferent or efferent activity affects the structural integrity of white matter pathways serving the affected side. Evidence that the structural integrity of mature sensory and motor tracts controlling the lost upper limb exhibits similar activity dependence is, however, sparse and inconsistent. Here we used diffusion tensor tractography to test whether amputation of the dominant right hand during adulthood (n = 16) alters the microstructural integrity of the major sensory (medial lemniscus, ML) and motor (corticospinal tract, CST) pathways controlling missing hand function. Consistent with prior findings, healthy control subjects (n = 27) exhibited higher fractional anisotropy (FA), an index of white matter microstructural integrity, within dominant left CST and nondominant right ML. Critically, in contrast to what might be expected if the microstructural organization of these tracts is activity dependent, these asymmetries persisted in amputees. Moreover, we failed to detect any differences in dominant left ML or CST between healthy control subjects and amputees. Our results are consistent with these white matter tracts being robust to changes in activity once mature or that continued use of the residual limb (in a compensatory fashion or with prosthesis) provides stimulation sufficient to maintain tract integrity. NEW & NOTEWORTHY We report that unilateral hand amputation in adults has no significant effects on the structure of major sensory or motor pathways contralateral to the amputation. Our results are consistent with the organization of these white matter tracts being robust to changes in activity once mature or that continued use of the residual limb (with or without a prosthesis) provides stimulation sufficient to maintain tract integrity.

Magnetic resonance spectroscopy of current hand amputees reveals evidence for neuronal-level changes in former sensorimotor cortex.

Deafferentation is accompanied by large-scale functional reorganization of maps in the primary sensory and motor areas of the hemisphere contralateral to injury. Animal models of deafferentation suggest a variety of cellular-level changes including depression of neuronal metabolism and even neuronal death. Whether similar neuronal changes contribute to patterns of reorganization within the contralateral sensorimotor cortex of chronic human amputees is uncertain. We used functional MRI-guided proton magnetic resonance spectroscopy to test the hypothesis that unilateral deafferentation is associated with lower levels of N-acetylaspartate (NAA, a putative marker of neuronal integrity) in the sensorimotor hand territory located contralateral to the missing hand in chronic amputees (n = 19) compared with the analogous hand territory of age- and sex-matched healthy controls (n = 28). We also tested whether former amputees [i.e., recipients of replanted (n = 3) or transplanted (n = 2) hands] exhibit NAA levels that are indistinguishable from controls, possible evidence for reversal of the effects of deafferentation. As predicted, relative to controls, current amputees exhibited lower levels of NAA that were negatively and significantly correlated with the time after amputation. Contrary to our prediction, NAA levels in both replanted and transplanted patients fell within the range of the current amputees. We suggest that lower levels of NAA in current amputees reflects altered neuronal integrity consequent to chronic deafferentation. Thus local changes in NAA levels may provide a means of assessing neuroplastic changes in deafferented cortex. Results from former amputees suggest that these changes may not be readily reversible through reafferentation.NEW & NOTEWORTHY This study is the first to use functional magnetic resonance-guided magnetic resonance spectroscopy to examine neurochemical mechanisms underlying functional reorganization in the primary somatosensory and motor cortices consequent to upper extremity amputation and its potential reversal through hand replantation or transplantation. We provide evidence for selective alteration of cortical neuronal integrity associated with amputation-related deafferentation that may not be reversible.

Accommodation and related conditions in vascularized composite allografts.

PURPOSE OF REVIEW: The outcome of vascularized composite allografts (VCA) often appear unrelated to the presence of donor-specific antibodies (DSA) in blood of the recipient or deposition of complement in the graft. The attenuation of injury and the absence of rejection in other types of grafts despite manifest donor-specific immunity have been explained by accommodation (acquired resistance to immune-mediated injury), adaptation (loss of graft antigen) and/or enhancement (antibody-mediated antigen blockade). Whether and how accommodation, adaptation and/or enhancement impact on the outcome of VCA is unknown. Here we consider how recent observations concerning accommodation in organ transplants might advance understanding and resolve uncertainties about the clinical course of VCA. RECENT FINDINGS: Investigation of the mechanisms through which kidney allografts avert antibody-mediated injury and rejection provide insights potentially applicable to VCA. Interaction of DSA can facilitate replacement of donor by recipient endothelial cells, modulate or decrease synthesis of antigen, mobilize antigen that in turn blocks further immune recognition and limit the amount of bound antibody, allowing accommodation to ensue. These processes also can explain the apparent dissociation between the presence and levels of DSA in blood, deposition of C4d in grafts and antibody-mediated rejection. Over time the processes might also explain the inception of chronic graft changes. SUMMARY: The disrupted tissue in VCA and potential for repopulation by endothelial cells of the recipient establish conditions that potentially decrease susceptibility to acute antibody-mediated rejection. These conditions include clonal suppression of donor-specific B cells, and adaptation, enhancement and accommodation. This setting also potentially highlights heretofore unrecognized interactions between these 'protective' processes.

Adipose-derived cellular therapies in solid organ and vascularized-composite allotransplantation.

PURPOSE OF REVIEW: Controlling acute allograft rejection following vascularized composite allotransplantation requires strict adherence to courses of systemic immunosuppression. Discovering new methods to modulate the alloreactive immune response is essential for widespread application of vascularized composite allotransplantation. Here, we discuss how adipose-derived cellular therapies represent novel treatment options for immune modulation and tolerance induction in vascularized composite allotransplantation. RECENT FINDINGS: Adipose-derived mesenchymal stromal cells are cultured from autologous or allogeneic adipose tissue and possess immunomodulatory qualities capable of prolonging allograft survival in animal models of vascularized composite allotransplantation. Similar immunosuppressive and immunomodulatory effects have been observed with noncultured adipose stromal-vascular-fraction-derived therapies, albeit publication of in-vivo stromal vascular fraction cell modulation in transplantation models is lacking. However, both stromal vascular fraction and adipose derived mesenchymal stem cell therapies have the potential to effectively modulate acute allograft rejection via recruitment and induction of regulatory immune cells. SUMMARY: To date, most reports focus on adipose derived mesenchymal stem cells for immune modulation in transplantation despite their phenotypic plasticity and reliance upon culture expansion. Along with the capacity for immune modulation, the supplemental wound healing and vasculogenic properties of stromal vascular fraction, which are not shared by adipose derived mesenchymal stem cells, hint at the profound therapeutic impact stromal vascular fraction-derived treatments could have on controlling acute allograft rejection and tolerance induction in vascularized composite allotransplantation. Ongoing projects in the next few years will help design the best applications of these well tolerated and effective treatments that should reduce the risk/benefit ratio and allow more patients access to vascularized composite allotransplantation therapy.

Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice.

UNLABELLED: The Na(+) -taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane of hepatocytes. It has recently been recognized as the receptor mediating hepatocyte-specific entry of hepatitis B virus and hepatitis delta virus. Myrcludex B, a peptide inhibitor of hepatitis B virus entry, is assumed to specifically target NTCP. Here, we investigated BA transport and Myrcludex B binding in the first Slc10a1-knockout mouse model (Slc10a1 encodes NTCP). Primary Slc10a1(-/-) hepatocytes showed absence of sodium-dependent taurocholic acid uptake, whereas sodium-independent taurocholic acid uptake was unchanged. In vivo, this was manifested as a decreased serum BA clearance in all knockout mice. In a subset of mice, NTCP deficiency resulted in markedly elevated total serum BA concentrations, mainly composed of conjugated BAs. The hypercholanemic phenotype was rapidly triggered by a diet supplemented with ursodeoxycholic acid. Biliary BA output remained intact, while fecal BA excretion was reduced in hypercholanemic Slc10a1(-/-) mice, explained by increased Asbt and Ostα/ß expression. These mice further showed reduced Asbt expression in the kidney and increased renal BA excretion. Hepatic uptake of conjugated BAs was potentially affected by down-regulation of OATP1A1 and up-regulation of OATP1A4. Furthermore, sodium-dependent taurocholic acid uptake was inhibited by Myrcludex B in wild-type hepatocytes, while Slc10a1(-/-) hepatocytes were insensitive to Myrcludex B. Finally, positron emission tomography showed a complete abrogation of hepatic binding of labeled Myrcludex B in Slc10a1(-/-) mice. CONCLUSION: The Slc10a1-knockout mouse model supports the central role of NTCP in hepatic uptake of conjugated BAs and hepatitis B virus preS1/Myrcludex B binding in vivo; the NTCP-independent hepatic BA uptake machinery maintains a (slower) enterohepatic circulation of BAs, although it is occasionally insufficient to clear BAs from the circulation.

Renal Targeting: Peptide-Based Drug Delivery to Proximal Tubule Cells.

Kidney-specific drug targeting is an attractive strategy to reduce unwanted side effects and to enhance drug efficacy within the renal tissue. For this purpose a novel kidney-specific drug carrier was developed. The peptide sequence (KKEEE)3K triggers exceptional renal specificity at high accumulation rates. Micro-PET imaging studies of megalin-deficient mice indicate that the cellular endocytosis of this carrier is mediated by megalin. This assumption is supported by immunohistochemical analysis of FITC-labeled carrier peptide, which exclusively accumulated at the apical side of proximal tubule cells within the renal cortex. Scintigraphic studies of modified ciprofloxacin conjugated to (KKEEE)3K confirmed the excellent drug targeting potential of the peptide carrier. The conjugate accumulated entirely in the kidneys, revealing flawless redirection of ciprofloxacin, a compound that is mainly excreted by the liver. In conclusion, these results suggest the potential of (KKEEE)3K as a promising candidate for kidney-targeted drug delivery to proximal tubule cells.

Immunobiology in VCA.

Transplantation of vascularized composite tissue is a relatively new field that is an amalgamation of experience in solid organ transplantation and reconstructive plastic and orthopedic surgery. What is novel about the immunobiology of VCA is the addition of tissues with unique immunologic characteristics such as skin and vascularized bone, and the nature of VCA grafts, with direct exposure to the environment, and external forces of trauma. VCAs are distinguished from solid organ transplants by the requirement of rigorous physical therapy for optimal outcomes and the fact that these procedures are not lifesaving in most cases. In this review, we will discuss the immunobiology of these systems and how the interplay can result in pathology unique to VCA as well as provide potential targets for therapy.

Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.

BACKGROUND & AIMS: Hepatitis B and D viruses (HBV and HDV) are human pathogens with restricted host ranges and high selectivity for hepatocytes; the HBV L-envelope protein interacts specifically with a receptor on these cells. We aimed to identify this receptor and analyze whether it is the recently described sodium-taurocholate co-transporter polypeptide (NTCP), encoded by the SLC10A1 gene. METHODS: To identify receptor candidates, we compared gene expression patterns between differentiated HepaRG cells, which express the receptor, and naïve cells, which do not. Receptor candidates were evaluated by small hairpin RNA silencing in HepaRG cells; the ability of receptor expression to confer binding and infection were tested in transduced hepatoma cell lines. We used interspecies domain swapping to identify motifs for receptor-mediated host discrimination of HBV and HDV binding and infection. RESULTS: Bioinformatic analyses of comparative expression arrays confirmed that NTCP, which was previously identified through a biochemical approach is a bona fide receptor for HBV and HDV. NTCPs from rat, mouse, and human bound Myrcludex B, a peptide ligand derived from the HBV L-protein. Myrcludex B blocked NTCP transport of bile salts; small hairpin RNA-mediated knockdown of NTCP in HepaRG cells prevented their infection by HBV or HDV. Expression of human but not mouse NTCP in HepG2 and HuH7 cells conferred a limited cell-type-related and virus-dependent susceptibility to infection; these limitations were overcome when cells were cultured with dimethyl sulfoxide. We identified 2 short-sequence motifs in human NTCP that were required for species-specific binding and infection by HBV and HDV. CONCLUSIONS: Human NTCP is a specific receptor for HBV and HDV. NTCP-expressing cell lines can be efficiently infected with these viruses, and might be used in basic research and high-throughput screening studies. Mapping of motifs in NTCPs have increased our understanding of the species specificities of HBV and HDV, and could lead to small animal models for studies of viral infection and replication.

Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.

BACKGROUND & AIMS: Chronic hepatitis B and hepatitis D are global health problems caused by the human hepatitis B and hepatitis D virus. The myristoylated preS1 domain of the large envelope protein mediates specific binding to hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP). NTCP is a bile salt transporter known to be inhibited by cyclosporin A. This study aimed to characterize the effect of cyclosporin A on HBV/HDV infection. METHODS: HepaRG cells, primary human hepatocytes, and susceptible NTCP-expressing hepatoma cell lines were applied for infection experiments. The mode of action of cyclosporin A was studied by comparing the effect of different inhibitors, cyclophilin A/B/C-silenced cell lines as well as NTCP variants and mutants. Bile salt transporter and HBV receptor functions were investigated by taurocholate uptake and quantification of HBVpreS binding. RESULTS: Cyclosporin A inhibited hepatitis B and D virus infections during and--less pronounced--prior to virus inoculation. Binding of HBVpreS to NTCP was blocked by cyclosporin A concentrations at 8 µM. An NTCP variant deficient in HBVpreS binding but competent for bile salt transport showed resistance to cyclosporin A. Silencing of cyclophilins A/B/C did not abrogate transporter and receptor inhibition. In contrast, tacrolimus, a cyclophilin-independent calcineurin inhibitor, was inactive. CONCLUSIONS: HBV and HDV entry via sodium taurocholate co-transporting polypeptide is inhibited by cyclosporin A. The interaction between the drug and the viral receptor is direct and overlaps with a functional binding site of the preS1 domain, which mediates viral entry.

LEMD2-associated progeroid syndrome: Expanding the phenotype of the nuclear envelopathy caused by a defect in LEMD2 gene.

Nuclear envelopathies are rare genetic diseases that compromise the integrity of the nuclear envelope. Patients with a defect in LEM domain nuclear envelope protein 2 (LEMD2) leading to LEMD2-associated progeroid syndrome are exceedingly scarce in number, yet they exhibit shared clinical features including skeletal abnormalities and a prematurely-aged appearance. Our study broadens the understanding of LEMD2-associated progeroid syndrome by detailing its phenotypic and molecular characteristics in the first female and fourth reported case, highlighting a distinct impact on metabolic functions. The patient's history revealed growth delay, facial and skeletal abnormalities, and recurrent abdominal pain crises caused by hepatomegaly. Comparisons with the previously documented cases emphasized similarities in skeletal and facial features while showcasing unique variations, notably in cardiac and hepatic manifestations. In vitro experiments conducted on patient-derived peripheral blood and urinary epithelial cells and LEMD2-downregulated HepG2 cells confirmed abnormalities in the structure of the nuclear envelope in all three tissue-types. Overall, our work offers a comprehensive profile of a patient with LEMD2-related syndrome, emphasizing the hepatic involvement in the disease and broadening our understanding of clinical and molecular implications. This study not only contributes specific insights into LEMD2-related conditions but also underscores potential therapeutic paths for disorders affecting nuclear envelope dynamics.

Response of dupuytren fibroblasts to different oxygen environments.

PURPOSE: It is thought that local ischemia and oxygen radicals are responsible for fibroblast-to-myofibroblast cell transformation and proliferation. We hypothesized that hypoxia could differentially activate the contractility of fibroblasts from normal human palmar fascia and from fibroblasts-myofibroblasts of Dupuytren cords. METHODS: Normal palmar fascia from 5 patients with carpal tunnel syndrome and Dupuytren cords from 5 patients were harvested. Cells were cultured from all tissue samples, and collagen lattices were prepared containing these cells. Oxygen treatment subgroups were created and incubated under hypoxic (1% O(2), 5% CO(2), and 94% N(2)), normoxic (21% O(2), 5% CO(2), and 74% N(2)), and hyperoxic (100% oxygen using 2.4 atm pressure twice a day for 7 d) conditions. After 7 days, each subgroup was photographed, and lattices were released from dishes. Postrelease photographs were taken immediately, 5 minutes after release, and after 1 hour. Areas of the lattices at each time point were calculated using MetaMorph software. Actin staining and live/dead cell analysis was performed. Linear repeated measures analysis of variance was used for data analysis given that contraction levels were measured over 3 distinct time points. RESULTS: We found a statistically significant difference between normal samples and Dupuytren samples in mean contraction levels over time. There was no statistically significant difference between tissue groups over the 3 time periods based on the oxygen treatment received. CONCLUSIONS: Our results showed a greater degree of contractility in Dupuytren disease cells than normal fibroblasts. However, the contraction in either group was not affected by oxygen level. Future in vivo research is needed to better understand the nature of pathophysiology of Dupuytren disease.

Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.

Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.

Monitoring and long-term outcomes in vascularized composite allotransplantation.

PURPOSE OF REVIEW: The field of vascularized composite allotransplantation (VCA) is young, with less than 150 transplants worldwide. However, we now possess as much as 14 years of clinical follow-up. There are similarities and distinct differences between solid-organ transplantation (SOT) and VCA. This review will summarize how VCA recipients are monitored, outcomes observed, and what aspects are unique to VCA. RECENT FINDINGS: Of about 90 documented cases, 10% of VCA recipients are out more than 10 years and 14% are out 5 or more years. There have been both graft losses and patient mortality. In most cases, these losses have been acute, most within the first year, and all within 3 years. Unlike SOT, VCA grafts function well during severe rejection. Chronic rejection-like sequelae are less frequent than in SOT, but do appear. Immunosuppression ranges from standard protocols to novel trials aimed at immunosuppression minimization. Patient selection greatly affects the outcome. Graft loss after year 1 is associated with compliance issues. SUMMARY: Functional outcomes have exceeded expectations. VCA recipients enjoy a quality of life not achievable with conventional reconstruction. Outstanding long-term results of more than a decade have been achieved. Monitoring of VCA patients will require new strategies to incorporate external visualization and effects of environment on rejection. Graft loss has occurred early, suggesting we focus improvement on this time period. More follow-up is needed to determine the rates and targets of chronic rejection, and the characteristics of VCA unique to face vs. hand transplantation.

Greater and More Natural Use of the Upper Limbs During Everyday Life by Former Amputees Versus Prosthesis Users.

Hand loss profoundly impacts daily functioning. Reversal of amputation through hand replantation or transplantation offers an alternative to prosthetics for some. Whether recipients exhibit more extensive and natural limb use during everyday life than prosthesis users is, however, unknown.We asked unilateral, below-elbow amputees (N = 22), hand graft recipients (transplants N = 4; replants N = 2), and healthy matched controls (N = 20) to wear wireless accelerometers distally on their forearms/prostheses and proximally on their upper arms. These units captured limb activity over 3 days within participants' natural environments.Graft recipients exhibited heavier reliance on their affected hands compared to amputees' reliance on their prostheses, P < .001. Likewise, reliance on the injured side upper arm was also greater for hand graft recipients than amputees, regardless of whether they were wearing their prostheses, P < .05 in both cases. Hand graft recipients, like healthy controls, also relied more on forearm vs upper arm movements when controlling their limbs, P < .001.Compared with conventional prosthesis users, graft recipients exhibited more extensive and natural functioning of the upper limbs during everyday activities. This information is an important addition to other considerations when evaluating risk-benefit of these treatment alternatives.

Corrigendum: Changes in primary somatosensory cortex following allogeneic hand transplantation or autogenic hand replantation.

[This corrects the article DOI: 10.3389/fnimg.2022.919694.].

Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages.

As clinical experience with surgical techniques and immunosuppression in vascularized composite allotransplantation recipients has accumulated, vascularized composite allotransplantation for hand and face have become standard of care in some countries for select patients who have experienced catastrophic tissue loss. Experience to date suggests that clinical vascularized composite allotransplantation grafts undergo the same processes of allograft rejection as solid organ grafts. Nonetheless, there are some distinct differences, especially with respect to the immunologic influence of the skin and how the graft is affected by environmental and traumatic insults. Understanding the mechanisms around these similarities and differences has the potential to not only improve vascularized composite allotransplantation outcomes but also outcomes for all types of transplants and to contribute to our understanding of how complex systems of immunity and function work together. A distinct disadvantage in the study of upper extremity vascularized composite allotransplantation recipients is the low number of clinical transplants performed each year. As upper extremity transplantation is a quality of life rather than a lifesaving transplant, these numbers are not likely to increase significantly until the risks of systemic immunosuppression can be reduced. As such, experimental models of vascularized composite allotransplantation are essential to test hypotheses regarding unique characteristics of graft rejection and acceptance of vascularized composite allotransplantation allografts. Rat hind limb vascularized composite allotransplantation models have been widely used to address these questions and provide essential proof-of-concept findings which can then be extended to other experimental models, including mice and large animal models, as new concepts are translated to the clinic. Here, we review the large body of rat hind limb vascularized composite allotransplantation models in the literature, with a focus on the various surgical models that have been developed, contrasting the characteristics of the specific model and how they have been applied. We hope that this review will assist other researchers in choosing the most appropriate rat hind limb transplantation model for their scientific interests.

Psychosocial factors and medication adherence among recipients of vascularized composite allografts.

OBJECTIVES: Psychosocial factors are important predictors of medication adherence, and subsequently graft survival, in solid organ transplantation. Early experiences suggest this may also be the case in vascularized composite allotransplantation. METHODS: Using validated tools, we surveyed upper extremity transplant recipients at two centers to assess depression (Patient Health Questionnaire-9), personality (Ten-Item Personality Inventory), anxiety (Generalized Anxiety Disorder 7-Item Scale), post-traumatic stress disorder (Primary Care Post-Traumatic Stress Disorder Screen for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), and social support (Multidimensional Scale of Perceived Social Support). Medication adherence among vascularized composite allotransplantation recipients at two centers was assessed by a member of the clinical research team using the recipients' medical records. RESULTS: Medication adherence was reported for 12 vascularized composite allotransplantation recipients, and 9 vascularized composite allotransplantation recipients completed psychosocial assessments. Most recipients were believed to be adherent to their immunosuppression, however, three recipients were believed to be non-adherent and a member of the clinical team had discussed non-adherence at least once with five recipients. Results from the psychosocial assessment (n = 9) indicated that eight participants had high levels of social support, and eight demonstrated high levels of conscientiousness which have been associated with better medication adherence in solid organ transplantation. However, three participants demonstrated mild anxiety, two demonstrated minimal symptoms of depression, and one demonstrated post-traumatic stress disorder which have been associated with worse medication adherence in solid organ transplantation. CONCLUSION: These findings lay the groundwork for future assessments of the role psychosocial factors play in facilitating medication adherence and broader transplant outcomes.