Tremor Induced by Focal Peripheral Nerve Entrapment: A Case Series.

Little is known about tremors caused by peripheral nerve entrapment. We report two cases of tremors caused by peripheral nerve compressions. Two patients presented with intentional tremors combined with peripheral nerve compression symptoms on their affected hand. Based on the clinical findings and evaluations, the first patient was diagnosed with double-crush compression of the ulnar nerve at the cubital tunnel and Guyon canal, and the second patient was diagnosed with lacertus syndrome. The first patient underwent surgical release of the cubital tunnel and Guyon canal in two stages. The second patient underwent release of the lacertus fibrosus. At the 1-month follow-up after surgery, the tremors had completely resolved, and neurological symptoms improved. Peripheral nerve entrapment should be considered a potential cause of tremors in patients with tremors combined with symptoms of peripheral neuropathy. Surgical release can be curative.

Normothermic Ex Situ Machine Perfusion of Vascularized Composite Allografts with Oxygen Microcarriers for 12 Hours Using Real-Time Mitochondrial Redox Quantification.

BACKGROUND: Normothermic ex situ perfusion of vascularized composite allografts (VCAs) necessitates high oxygen demand and, thus, increased metabolic activity, which, in turn, requires the use of blood-based perfusion solutions. However, blood-derived perfusates, in turn, constitute an antigenic load. To circumvent this immunogenic problem, we used a perfusate enriched with acellular dextrane oxygen microcarriers to perfuse rat hindlimbs. METHODS: Rat hindlimbs (n = 11) were perfused with either (non-), oxygenated dextrane-enriched Phoxilium, or Phoxilium enriched with dextrane oxygen microcarriers (MO2) for 12 h at 37 °C or stored on ice. Oxygenation of the skeletal muscle was assessed with Raman spectroscopy, tissue pO2-probes, and analysis of the perfusate. Transmission electronic microscopy was utilized to assess the ultrastructure of mitochondria of the skeletal muscle. RESULTS: For all evaluated conditions, ischemia time until perfusion was comparable (22.91 ± 1.64 min; p = 0.1559). After 12 h, limb weight increased significantly by at least 81%, up to 124% in the perfusion groups, and by 27% in the static cold storage (SCS) group. Raman spectroscopy signals of skeletal muscle did not differ substantially among the groups during either perfusion or static cold storage across the duration of the experiment. While the total number of skeletal muscle mitochondria decreased significantly compared to baseline, mitochondrial diameter increased in the perfusion groups and the static cold storage group. CONCLUSION: The use of oxygen microcarriers in ex situ perfusion of VCA with acellular perfusates under normothermic conditions for 12 h facilitates the maintenance of mitochondrial structure, as well as a subsequent recovery of mitochondrial redox status over time, while markers of muscle injury were lower compared to conventional oxygenated acellular perfusates.

A systematic review of immunomodulatory strategies used in skin-containing preclinical vascularized composite allotransplant models.

BACKGROUND: Acute rejection remains a vexing problem in vascularized composite allotransplantation (VCA). Available immunosuppressive regimens are successful at minimizing alloimmune response and allowing VCA in humans. However, repeated rejection episodes are common, and systemic side effects of the current standard regimen (Tacrolimus, MMF, Prednisone) are dose limiting. Novel immunomodulatory approaches to improve allograft acceptance and minimize systemic toxicity are continuously explored in preclinical models. We aimed to systematically summarize past and current approaches to help guide future research in this complex field. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed databases. For inclusion, articles had to primarily investigate the effect of a therapeutic approach on prolonging the survival of a skin-containing preclinical VCA model. Non-VCA studies, human trials, anatomical and feasibility studies, and articles written in a language other than English were excluded. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: The search retrieved 980 articles of which 112 articles were ultimately included. The majority of investigations used a rat model. An orthotopic hind limb VCA model was used in 53% of the studies. Cell and drug-based approaches were investigated 58 and 52 times, respectively. We provide a comprehensive review of immunomodulatory strategies used in VCA preclinical research over a timeframe of 44 years. CONCLUSION: We identify a transition from anatomically non-specific to anatomical models mimicking clinical needs. As limb transplants have been most frequently performed, preclinical research focused on using the hind limb model. We also identify a transition from drug-based suppression therapies to cell-based immunomodulation strategies.

Donor and Recipient Matching in Facial Vascularized Composite Allotransplantation: A Closer Look at the Donor Pool.

BACKGROUND: Identifying a donor for facial vascularized composite allotransplant recipients can be a lengthy, emotionally challenging process. Little is known about the relative distribution of key donor characteristics among potential donors. Data on actual wait times of patients are limited, making it difficult to estimate wait times for future recipients. METHODS: The authors retrospectively reviewed charts of nine facial vascularized composite allotransplant patients and provide data on transplant wait times and patient characteristics. In addition, they analyzed the United Network for Organ Sharing database of dead organ donors. After excluding donors with high-risk characteristics (e.g., active cancer or risk factors for blood-borne disease transmission), the authors calculated the distribution of relevant donor-recipient matching criteria (i.e., ethnicity, body mass index, age, ABO blood group, cytomegalovirus, Epstein-Barr virus, hepatitis C virus) among 65,201 potential donors. RESULTS: The median wait time for a transplant was 4 months (range, 1 day to 17 months). The large majority of United Network for Organ Sharing-recorded deaths from disease were white (63 percent) and male (58 percent). Female donors of black, Hispanic, or Asian descent are underrepresented, with 7, 5, and 1 percent of all recorded deaths from disease, respectively. Potential donors show cytomegalovirus and Epstein-Barr virus seropositivity of 65 and 95 percent, respectively. The number of annual hepatitis C-positive donors increased over time. CONCLUSIONS: Actual facial vascularized composite allotransplant wait times vary considerably. Although most patients experience acceptable wait times, some with underrepresented characteristics exceed acceptable levels. Cytomegalovirus-seropositive donors present a large portion of the donor pool, and exclusion for seronegative patients may increase wait time. Hepatitis C-seropositive donors may constitute a donor pool for underrepresented patient groups in the future.

Dynamic Maxillary Sinus Changes of Facial Vascularized Composite Allotransplants.

SUMMARY: Skin is one of the target tissues of rejection in face transplants and, because of its easy accessibility, has become the gold standard in the diagnosis of rejection. The allograft contains deeper tissues where rejection can occur, but samples cannot be obtained because of difficult access. Deep tissue changes were monitored on computed tomographic scans of the midface in six face transplant recipients with the help of image segmentation. The maxillary sinus was identified as a dynamic anatomical compartment. Observed changes in volume of the aeration relative to the opacification (aeration coefficient) of the maxillary sinus were quantified with the help of image segmentation. Changes in the aeration coefficient as a surrogate of mucosal swelling were quantified and related to time, treatment, and skin rejection grade. Lower aeration coefficients were found only in patients with transplanted maxillary sinus mucosa. Pathologic changes were not observed in face transplant recipients with a native maxillary sinus. The data show that the aeration coefficient was significantly lower at the time of biopsy-proven allograft rejection. Neither mechanical, nor infectious, nor medication side effects sufficiently explain the findings presented herein. The authors' findings are important to consider for clinical management of face transplant patients who receive parts of the sinonasal tract. The authors identify a potential radiologic biomarker of deep tissue allograft rejection. In the future, the proposed methodology might prove useful in monitoring deeper dynamic tissue changes in vascularized composite allografts and might help in designing patient-specific, individualized treatment strategies.

Pathologies of oral and sinonasal mucosa following facial vascularized composite allotransplantation.

BACKGROUND: Cutaneous changes of facial vascularized composite allotransplants (fVCAs) are extensively described in the literature. Parts of the nose, nasal, and oral cavities are included in most fVCAs. Distinctively, the nose and mouth are lined by mucosa. Little is known about the histopathology and complications of the mucosa involved in fVCA patients. METHODS: The study constitutes a retrospective cohort study of nine fVCA patients. Medical records were reviewed for information about changes of oral and nasal mucous membranes. Types of mucosal lesions were recorded and analyzed. Uni- and multivariate generalized estimating equation (GEE) models were used to assess the odds of developing mucosal inflammation in the presence of clinico-pathologic variables. RESULTS: A total of 186 clinical encounters with examination of oral and nasal mucous membranes were included. Membranes were devoid of clinical pathology in 101 instances (53% of all clinical assessments). Ulcerations/erosions (27%), edema (18%), and erythema (14%) were the most common lesions. Oral lesions affected the lips (58%), buccal mucosa (38%), and palate (5%). Sinonasal processes predominantly affected nasal vestibules and septae. In univariate analysis, sirolimus, skin rejection, and skin Banff grade were associated with the presence of an acute inflammatory mucosal lesion (p<0.05). In multivariate analysis, skin Banff grade and sirolimus were independent predictors of mucosal inflammation. CONCLUSION: Pathologies of fVCA mucous membranes are more common than previously reported. Mucosal assessment plays an important role in the pleomorphic allograft rejection process evaluation rather than diagnosis and treatment based on cutaneous pathology.  A closer look at the pathophysiology of fVCA mucosal rejection and inflammation is warranted.

Long-term Outcomes After Facial Allotransplantation: Systematic Review of the Literature.

BACKGROUND: Facial vascularized composite allotransplantation (fVCA) represents a reconstructive approach that enables superior improvements in functional and esthetic restoration compared with conventional craniomaxillofacial reconstruction. Outcome reports of fVCA are usually limited to short-term follow-up or single-center experiences. We merge scientific literature on reported long-term outcome data to better define the risks and benefits of fVCA. METHODS: We conducted a systematic review of PubMed/MEDLINE databases in accordance with PRISMA guidelines. English full-text articles providing data on at least 1 unique fVCA patient, with ≥3 years follow-up, were included. RESULTS: The search yielded 1812 articles, of which 28 were ultimately included. We retrieved data on 23 fVCA patients with mean follow-up of 5.3 years. More than half of the patients showed improved quality of life, eating, speech, and motor and sensory function following fVCA. On average, the patients had 1 acute cell-mediated rejection and infectious episode per year. The incidence rates of acute rejection and infectious complications were high within first-year posttransplant but declined thereafter. Sixty-five percent of the patients developed at least 1 neoplastic or metabolic complication after transplantation. Chronic vascular rejection was confirmed in 2 patients, leading to allograft loss after 8 and 9 years. Two patient deaths occurred 3.5 and 10.5 years after transplant due to suicide and lung cancer, respectively. CONCLUSIONS: Allograft functionality and improvements in quality of life suggest a positive risk-benefit ratio for fVCA. Recurrent acute rejection episodes, chronic rejection, immunosuppression-related complications, and heterogeneity in outcome reporting present ongoing challenges in this field.

Local immunosuppression in vascularized composite allotransplantation (VCA): A systematic review.

BACKGROUND: Local immunosuppression in vascularized composite allotransplantation (VCA) aims to minimize immunosuppressant-related toxic and malignant side effects. Promising allograft survival data have been published by multiple workgroups. In this systematic review, we examine preclinical animal studies that investigated local immunosuppression in VCA. MATERIAL AND METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed database concerning preclinical VCA models. Papers included had to be available as full-text and written in English. Non-VCA studies, human trials, and studies using cell-based therapy strategies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Literature research retrieved 980 articles. Ten studies published between 2010 and 2019 met the inclusion and exclusion criteria. Seven out of ten articles demonstrated a significant prolongation of allograft survival by using local immunosuppression. Five articles employed tacrolimus (TAC) as the main immunosuppressive agent. Seven studies performed hind-limb VCA in a rat model. CONCLUSION: The easily accessible location of skin containing VCAs makes it an ideal candidate for local immunosuppression. Published preclinical data are very promising in terms of improved allograft survival and reduced systemic toxicity.

Comparison of Acellular Solutions for Ex-situ Perfusion of Amputated Limbs.

INTRODUCTION: Hypothermic ex-situ machine perfusion (MP) has been shown to be a promising alternative to static cold storage (SCS) for preservation of solid organs for transplantation and vascularized composite allotransplantation. Perfusion with blood-based perfusion solutions in austere environments is problematic due to their need for appropriate storage and short shelf life, making it impractical for military and emergency use. Acellular perfusion has been shown to be effective, but the ideal perfusate solution for MP of amputated limbs is yet to be determined. The purpose of this study is to evaluate the efficacy of alternative perfusate solutions, such as dextran-enriched Phoxilium, Steen, and Phoxilium in ex-vivo hypothermic MP of amputated limbs in a porcine model. MATERIALS AND METHODS: Amputated forelimbs from Yorkshire pigs (n = 8) were preserved either in SCS (n = 2) at 4°C for 12 hours or machine-perfused at 10°C for 12 hours with oxygenated perfusion solutions (n = 6) at a constant flow rate. The perfusates used include modified Steen-solution, Phoxilium (PHOX), or Phoxilium enriched with dextran-40 (PHODEX). The perfusate was exchanged after 1 and 6 hours of perfusion. Machine data were recorded continuously. Perfusate samples for clinical chemistry, blood gas analysis, and muscle biopsies were procured at specific timepoints and subsequently analyzed. In this semi in-vivo study, limb replantation has not been performed. RESULTS: After amputation, every limb was successfully transferred and connected to our perfusion device. The mean total ischemia time was 77.5 ± 5.24 minutes. The temperature of the perfusion solution was maintained at 10.18 ± 2.01°C, and perfusion pressure at 24.48 ± 10.72 mmHg. Limb weight increased by 3% in the SCS group, 36% in the PHODEX group, 25% in the Steen group, and 58% in the PHOX group after 12 hours. This increase was significant in the PHOX group compared with the SCS group. All perfusion groups showed a pressure increase of 10.99 mmHg over time due to edema. The levels of HIF-1a decreased over time in all groups except the Steen and the PHODEX group. The biomarkers of muscle injury in the perfusate samples, such as creatine kinase and lactate-dehydrogenase, showed a significant difference between groups, with highest values in the PHODEX group. No significant differences were found in the results of the blood gas analysis. CONCLUSION: With the exception of significantly higher levels of creatine kinase and lactate dehydrogenase, MP with dextran-enriched Phoxilium provides similar results as that of the commercially available perfusates such as Steen, without the need for cold storage, and at circa 5% of the cost of the Steen solution. Further large-scale replantation studies are necessary to evaluate the efficacy of dextran-enriched Phoxilium as an alternate perfusate solution.

Partial Loss of Nasal Tissue in a Facial Vascularized Composite Allograft Patient.

Supplemental Digital Content is available in the text.

Mucosa and Rejection in Facial Vascularized Composite Allotransplantation: A Systematic Review.

BACKGROUND: Facial vascularized composite allotransplantation (fVCA) presents an established approach to restore form and function of patients with catastrophic facial defects. Skin is one of the target tissues of the rejection process, and due to its easy accessibility has become the gold standard in the diagnosis of rejection. Mucosal rejection frequently occurs; however, the added value of mucosal rejection assessment for patient management is unknown. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE/PubMed and GoogleScholar databases to identify articles that provide data on mucosal rejection following fVCA. For inclusion, papers had to be available as full-text and written in English. Non-VCA studies and animal studies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We included 17 articles that described changes in allotransplanted mucosa of fVCAs. These articles yielded data on 168 BANFF graded biopsies of corresponding skin and mucosa biopsies. Rejection grades were consistently higher in mucosal biopsies. Concordance between allograft skin and mucosa biopsy grades increased with an increasing skin-BANFF grade. Mucosa rejection grades were on average lower in the early stages of the posttransplant period (postoperative mo 12). CONCLUSIONS: The mucosa of facial allotransplants is one of the primary targets of rejection. The data indicates that higher-grade skin rejection does not occur in absence of mucosal rejection. Further investigations are needed to elucidate the exact role of mucosal biopsies for fVCA patient management.

Implementation of a contingency approach for people with co-occurring substance use and psychiatric disorders: Acceptability and feasibility pilot study.

INTRODUCTION: The prevalence of co-occurrent substance use and psychiatric disorders is high. Contingency-based interventions have been shown to be effective in promoting adherence to treatment for people with substance use disorders but are among the least used evidence-based interventions for clients with comorbid psychiatric disorders, related to acceptability issues. OBJECTIVE: The present implementation study aims to evaluate the acceptability and feasibility of a contingency approach in co-occurring disorders specialized treatment services. METHODOLOGY: Focus groups were conducted with health professionals and service users recruited from a specialized co-occurring disorder program (COD). Pre-intervention focus groups were conducted to select preferred modalities to implement the program. Post-intervention focus groups were conducted to document the satisfaction and benefits of the intervention. Throughout the study, program monitoring was conducted systematically to determine the gaps between planned and actual interventions. RESULTS: Both health professionals consulted and service users agreed that the contingency approach could be integrated within usual co-occurring disorders treatment. In general, patients more readily accepted the contingency approach than health professionals. The higher functioning level group reported several benefits from the approach and implementation in its group sessions went as planned. Contingency approach was described by all participants as consistent with general treatment goals and led to patient's awareness about their group attendance. CONCLUSION: This study highlights several challenges related to the implementation of a contingency approach. It also suggests that implementation of this approach could benefit from taking into account the needs and perspectives of service users.

Use of bilaminar grafts as life-saving interventions for severe burns: A single-center experience.

BACKGROUND: Skin coverage remains a significant hurdle in large-sized burns. Recent advances have allowed to grow Bilaminar Cultured Skin Autografts (BCSGs) from patients' own donor sites. The aim of this study was to report long-term outcomes in patients with large-sized burns having received BCSGs. METHODS: Nine patients received BCSGs from January 2010 to May 2015. Except one patient who died during hospitalization, all patients were contacted. Four agreed to partake in the study. Patients were tested with the Vancouver Scar Scale (VSS), QuickDASH questionnaire and Burn Specific Health Scale (BSHS). Incisional biopsies of BCSGs were compared with patients' autografts. RESULTS: From nine patients, mean age was 40 years and mean TBSA was 70.3%. For the four patients included, score averaged was 2.25 on the VSS, 29.5 on QuickDASH, 36/36 for psychosocial items and 63/84 for functional abilities on the BSHS. Compared with autografts, BCSGs demonstrated better pliability VSS and functionality. Biopsies showed no evidence of malignancy or atypical changes, but areas of hyperpigmentation. CONCLUSION: This is the first report investigating the long-term outcome of a newly developed BCSG. BCSGs demonstrated comparable results with patients' autografts, functional outcomes on self-reported questionnaires and excellent psychological states. Precaution given the extensive unexpected hyperpigmentation must be taken and a randomized controlled study is underway.