International consensus recommendations on face transplantation: A 2-step Delphi study.

Face transplantation is a viable reconstructive approach for severe craniofacial defects. Despite the evolution witnessed in the field, ethical aspects, clinical and psychosocial implications, public perception, and economic sustainability remain the subject of debate and unanswered questions. Furthermore, poor data reporting and sharing, the absence of standardized metrics for outcome evaluation, and the lack of consensus definitions of success and failure have hampered the development of a "transplantation culture" on a global scale. We completed a 2-round online modified Delphi process with 35 international face transplant stakeholders, including surgeons, clinicians, psychologists, psychiatrists, ethicists, policymakers, and researchers, with a representation of 10 of the 19 face transplant teams that had already performed the procedure and 73% of face transplants. Themes addressed included patient assessment and selection, indications, social support networks, clinical framework, surgical considerations, data on patient progress and outcomes, definitions of success and failure, public image and perception, and financial sustainability. The presented recommendations are the product of a shared commitment of face transplant teams to foster the development of face transplantation and are aimed at providing a gold standard of practice and policy.

Analyzing the reduction quality of the distal radioulnar joint after closed K-wire transfixation in a cadaver model: is supination or neutral position superior?

INTRODUCTION: Distal radioulnar joint (DRUJ) instabilities are challenging and their optimal treatment is controversial. In special cases or when reconstruction of the stabilizing triangular fibrocartilage complex (TFCC) fails, K-wire transfixation can be performed. However, no consensus has been reached regarding the rotational position of the forearm in which this should be done. Therefore, it was investigated whether anatomical reduction would best be achieved by transfixation in neutral position or supination of the forearm. MATERIALS AND METHODS: Twelve cadaveric upper limbs were examined before dissection of the DRUJ stabilizing ligaments and after closed transfixation in both positions by C-arm cone-beam CT. Whether this was first done in neutral position or in supination was randomized. The change in the radioulnar ratio (RR) in percentage points (%points) was analyzed using Student's t-test. RR was used since it is a common and sensitive method to evaluate DRUJ reduction, expressing the ulnar head's position in the sigmoid notch as a length ratio. RESULTS: The analysis showed an increased change in RR in neutral position with 5.4 ± 9.7%points compared to fixation in supination with 0.2 ± 16.1%points, yet this was not statistically significant (p = 0.404). CONCLUSIONS: Neither position leads to a superior reduction in general. However, the result was slightly closer to the anatomical position in supination. Thus, transfixation of the DRUJ should be performed in the position in which reduction could best be achieved and based on these data, that tends to be in supination. Further studies are necessary to validate these findings and to identify influential factors.

Plain Anabaptists and Healthcare Ethics.

Plain Anabaptists are a small but rapidly growing ethnoreligious society with significant concentrations of population in a number of regions in North America. Among the most widely known of the various groups of Plain Anabaptists are the Amish and the Old Order Mennonites. It is the purpose of this article to provide insight into the culture and values of the Plain Anabaptists so that those who may be called upon to address ethical conflict involving Plain Anabaptists can do so with appropriate knowledge and sensitivity. The discussion of the culture and values of the Plain Anabaptists will be organized as follows: first we will explore the implications of Plain Anabaptist culture and values for applying the ethical principles of respect for autonomy and beneficence/nonmaleficence. Second, a brief description of several elements of Plain Anabaptist culture will be discussed with attention to the potential they create for ethical conflict in the healthcare setting.

The Angry Amish Grandfather: Cultural Competence and Empathy: A Case Commentary.

Crosscultural encounters are common in the delivery of healthcare, and cultural differences may contribute to misunderstandings and ethical conflict. Encounters between members of the Amish ethno-religious group and modern, science-based healthcare providers hold a high potential for misunderstanding and conflict because the Amish stridently maintain a countercultural outlook and they approach such encounters with suspicion and anxiety. This commentary on the case presented by Amy E. Caruso Brown, MD,1 involving a grandfather's resistance to treating a child with leukemia commends this physician for successfully managing the case and deriving important insights from reflection upon it. It argues, however, that the level of conflict most likely would have been reduced if the care team had made more of an effort to listen to the grandfather and acknowledge the emotional trauma he had suffered.

Make It Plain: Strengthening the Ethical Foundation of First-Person Authorization for Organ Donation.

One response to the chronic shortage of organs for transplant in the United States has been the passage of laws establishing first-person authorization for donation of organs, providing legal grounds for the retrieval of organs and tissues from registered donors, even over the objections of their next of kin. The ethical justification for first-person authorization is that it is a matter of respecting the donor's wishes. The objection of some next of kin may be that the donor would not have wished for his or her loved ones to have their preferences overridden, had they considered that possibility. This article examines the basis of the conflict and suggests a remedy grounded in the provision of donor-intent options that have the ability to clarify the donor's wishes.

An exploration of trunk reposition error in subjects with acute stroke: An observational design.

BACKGROUND & OBJECTIVE: Trunk reposition error (TRE) is a component of trunk control, yet has not been reported in acute stroke. The purpose of this study was to quantify TRE in acute stroke and report this with related rehabilitation outcomes. METHODS: Sixty subjects, 30 with acute stroke and 30 healthy controls, completed this study. Subjects with acute stroke were measured before and after an in-patient acute rehabilitation stay. MEASURES: TRE using an electromagnetic tracking device, Berg Balance Scale, Postural Assessment Scale for Stroke, and Functional Independence Measures. Pre-post measures were analyzed with paired t-tests. Between-group measures were analyzed with independent w-tests. RESULTS: There were significant between group differences (acute stroke vs. controls) for all functional outcome measures (P < 0.001) and for three-dimensional TRE (P = 0.001). There were significant improvements in all functional outcome measures following an in-patient rehabilitation stay (P < 0.001). All measures of TRE reduced but did not achieve significance. CONCLUSION: TRE was not as severely impaired as anticipated and was variable based on plane of measure. Time in a rehabilitation setting produced significant improvements in functional outcomes but TRE improvements were not as robust. These results indicate a need for further investigation of the strength of the interrelationship between TRE and function.

What we still don't know about vascularized composite allotransplantation (VCA) outcomes and quality of life measurements.

Vascularized composite allotransplants (VCA) are the only organ transplants purported to be conducted principally to improve quality of life (QOL), rather than to extend or save life - hence they are described as "life-enhancing" (or "life-rescuing"). This is in contrast to "life-extending" solid organ transplantation (SOT). Yet despite more than 20 years of VCA practice (1997-present), little is known about the actual "life-enhancing" impact(s) of VCA on the patient or their families. This article presents an overview of the state of the VCA field and what we still don't know about VCA outcomes, specifically focussing on face and hand transplants as both visible, emotional, and communicative organs. The current measurement of QOL in VCA is insufficient, both conceptually and analytically. It is also, critically, conducted without reference to patient-reported outcomes, or the experiences of family and carers. Drawing on published research in VCA and SOT, as well as preliminary, anecdotal VCA patient interview research, this paper highlights how and why the QOL practices in the field of VCA are not fit for purpose and proposes new ways of analysing QOL. In conclusion, it outlines what needs to happen for the VCA field to move forward positively, and with patients and their families more central to VCA practice and research.

Human papillomavirus infection and tumor microenvironment are associated with the microbiota in patients with oropharyngeal cancers-pilot study.

BACKGROUND: Previous microbiome studies of oropharyngeal cancer have shown that there are differences in the oral microbiota between human papillomavirus (HPV)-positive and HPV-negative patients. METHODS: We collected saliva, normal tissue, and tumor biopsies from 13 patients with oropharyngeal cancer (eight HPV-positive, five HPV-negative). We obtained basic clinical data from each patient. Extracted DNA was 16S rRNA gene sequenced. Analysis was based on HPV status and sample site using univariate, multivariate, and mixed effect regression methods. RESULTS: Multivariate analysis methods separated samples based on HPV status (Adonis, p < 0.001). Comparison of patients showed that there were significant changes in microbial richness across all sites based on HPV status (linear mixed effects regression, p = 0.0002). CONCLUSIONS: We found significant differences in overall microbial community and bacterial richness between oropharyngeal patients based on HPV status. Our results suggest that there are significant differences in the microbiome in patients with oropharyngeal cancer based on HPV status.

The importance of smoking status at diagnosis in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Smoking status at point of diagnosis is not used in defining risk groups for human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) despite its prognostic value in head and neck cancer. METHODS: Retrospective analysis of consecutive patients treated with chemoradiotherapy between January 2005 and July 2017 was performed with multivariable analysis to explore the impact of smoking status at diagnosis (current/former/never) on overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). RESULTS: Median follow-up was 61 months. Four hundred and four patients were included. Current smokers had inferior OS versus never and former smokers [adjusted HR 2.37 (95% CI 1.26-4.45, p < 0.01) and 2.58 (95% CI 1.40-4.73, p < 0.01), respectively] and inferior PFS versus never smokers [adjusted HR 1.83 (95% CI 1.00-3.35, p = 0.04)]. Smoking status did not predict for CSS. CONCLUSION: Detailed smoking behavior should be considered in refining risk groups in HPV-associated OPC treated with radiotherapy and in future trial design eligibility and stratification.

Evaluation of ABM/P-15 versus autogenous bone in an ovine lumbar interbody fusion model.

A prospective, randomized study was performed in an ovine model to compare the efficacy of an anorganic bovine-derived hydroxyapatite matrix combined with a synthetic 15 amino acid residue (ABM/P-15) in facilitating lumbar interbody fusion when compared with autogenous bone harvested from the iliac crest. P-15 is a biomimetic to the cell-binding site of Type-I collagen for bone-forming cells. When combined with ABM, it creates the necessary scaffold to initiate cell invasion, binding, and subsequent osteogenesis. In this study, six adult ewes underwent anterior-lateral interbody fusion at L3/L4 and L4/L5 using PEEK interbody rings filled with autogenous bone at one level and ABM/P-15 at the other level and no additional instrumentation. Clinical CT scans were obtained at 3 and 6 months; micro-CT scans and histomorphometry analyses were performed after euthanization at 6 months. Clinical CT scan analysis showed that all autograft and ABM/P-15 treated levels had radiographically fused outside of the rings at the 3-month study time point. Although the clinical CT scans of the autograft treatment group showed significantly better fusion within the PEEK rings than ABM/P-15 at 3 months, micro-CT scans, clinical CT scans, and histomorphometric analyses showed there were no statistical differences between the two treatment groups at 6 months. Thus, ABM/P-15 was as successful as autogenous bone graft in producing lumbar spinal fusion in an ovine model, and it should be further evaluated in clinical studies.

The declining role of post-treatment neck dissection in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND AND PURPOSE: Human papillomavirus-associated oropharyngeal cancer (HPV+ OPC) with regional lymph node metastases has a good prognosis following (chemo)radiation therapy (C/RT) but lymph nodes may remain detectable for several months. Delayed [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) can identify patients who may avoid post-treatment neck dissection (PTND). We investigated the rate of PTND in HPV+ OPC treated with C/RT and delayed PET-directed management of the neck. MATERIALS AND METHODS: This is a retrospective cohort study from a prospectively updated institutional database. Eligible patients were treated between January 2005 and July 2017 with a minimum of 18 months follow up, had node-positive, non-distant metastatic HPV+ OPC and were treated with RT (70 Gy/35#/5 per week) with concurrent Cisplatin or Cetuximab, or accelerated RT alone (68 Gy/34#/6 per week). The primary endpoint was rate of PTND. Secondary endpoints were locoregional failure free survival (LRFFS), regional failure free survival (RFFS), distant metastatic failure free survival (DMFFS), overall survival (OS) and oropharyngeal cancer-specific survival (CSS). RESULTS: 418 patients were eligible. Nineteen patients (4.5%) received a PTND. None of the tested variables were associated with an increased risk of PTND. Five-year probabilities for LRFFS, RFFS, DMFS, OS and CSS were, 91.2% (95% CI 88.3-94.2), 93.4% (95% CI 90.8-96.0), 91.2% (95% CI 88.3-94.2), 86.4% (95% CI 83.0-90.1) and 90.2% (95% CI 87.1-93.4), respectively. CONCLUSION: In a large cohort with good median follow up and protocolized C/RT, delayed PET-directed management of the neck affords a lower rate of PTND than reported in historical series without compromising disease control and survival.

Upper extremity and craniofacial vascularized composite allotransplantation: ethics and immunosuppression.

Vascularized composite allotransplantation (VCA) is the name most often used to refer to the transplantation of anatomical units composed of multiple tissue types (skin, bone, muscle, tendon, nerves, vessels, etc.) when such transplants do not have the primary purpose of extending life, as is the case in the more familiar field of solid organ transplantation (SOT). A serious interest in VCA developed in the late twentieth century following advances in immunosuppression which had led to significant improvements in short and medium-term survival among SOT recipients. Several ethical concerns have been raised about VCA, with many being connected in one way or another to the limitations, burdens, and risks associated with immunosuppression. This article will focus on upper extremity and craniofacial VCA, beginning with a brief review of the history of VCA including reported outcomes, followed by a discussion of the range of ethical concerns, before exploring in greater detail how immunological issues inform and shape several of the ethical concerns.

How to Help Patients Considering VCA.

Patients who might benefit from some form of vascularized composite allotransplantation (VCA) can be expected to have prior long-standing relationships with one or more primary care professionals or specialists who are well-positioned to help patients make well-informed decisions about whether and when to pursue VCA. Helping patients decide requires becoming familiar with VCA, its various forms, eligibility criteria, prior and possible outcomes, and potential risks and benefits. This article shares key points for helping patients.

Existing and Evolving Bioethical Dilemmas, Challenges, and Controversies in Vascularized Composite Allotransplantation: An International Perspective From the Brocher Bioethics Working Group.

Early results of hand and face transplants and other grafts such as those of uterus, penis, trachea, larynx, or abdominal wall have confirmed the potential for vascularized composite allotransplantation (VCA) to restore appearance, anatomy, function, independence, and social integration in patients suffering from devastating tissue deficits untreatable by conventional treatment options. Despite such promise, these novel and complex procedures face challenges and controversies that remain open to discussion and debate. Indeed, many barriers to clinical advancement and negative stakeholder perceptions still exist. The bioethical challenges surrounding VCA include but are not limited to justice and vulnerability of subjects, and their experiences with risks, benefits and outcomes, provider economy of fame, public awareness and attitudes toward transplantation, and policy and regulatory issues shaping progress of the field. The First International Workshop on Bioethical Challenges in Reconstructive Transplantation was organized by the Brocher Foundation in Hermance, Switzerland. VCA professionals representing teams from across the world examined bioethical issues in VCA related to standards for safety, efficacy, feasibility, privacy, confidentiality, and equitability. Key discussion topics from the workshop were included in a survey questionnaire implemented across VCA professionals attending the 13th Congress of International Society of VCA held in Salzburg, Austria. The insights from the Brocher workshop and International Society of VCA survey as presented here could help inform the future development of clinical practice and policy strategies in VCA to ensure value, accessibility, and acceptance of these procedures by potential donors, potential or actual recipients and their families, and providers and payers.

A Call to Accountability: Reporting Outcomes in Vascularized Composite Allotransplantation.

Because nearly all the vascularized composite allotransplants performed in the United States have been proposed and carried out as research, the ethical duty to report outcomes pertains. This duty is set forth in several international statements, including the World Health Organization's Statement on Public Disclosure of Clinical Trial Results, the 2013 Helsinki Declaration, and the Singapore Statement on Research Integrity. These international statements call for the reporting of negative and inconclusive outcomes as well as positive outcomes, and for the reporting of results from previously unreported past research. In 2014, the Organ Procurement and Transplant Network vascularized composite allotransplant committee proposed mandatory data collection and submission requirements for transplants, but only for those which took place in September 2015 or later. Reporting of data for the allotransplants which took place before September 2015 was regarded as optional, even though the pre-September 2015 transplants represent the majority of vascularized composite allotransplants in the United States and all the long-term outcome data. We encourage the American Society of Reconstructive Transplantation and the Organ Procurement and Transplant Network committee to embrace the international ethical standards and to hold all vascularized composite allotransplant programs in the United States accountable for reporting data on outcomes of pre-September 2015 transplants.

Aqueous and methanol extracts of Paullinia pinnata L. (Sapindaceae) improve inflammation, pain and histological features in CFA-induced mono-arthritis: Evidence from in vivo and in vitro studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Paullinia pinnata L. (Sapindaceae) is an African woody vine, traditionally used for the treatment of itch and pain-related conditions such as rheumatoid arthritis. AIM: This work evaluates, in vitro and in vivo, the anti-inflammatory and analgesic effects of aqueous (AEPP) and methanol (MEPP) extracts from Paullinia pinnata leaves. METHODS: AEPP and MEPP (100, 200 and 300 mg/kg/day) were administered orally in monoarthritic rats induced by a unilateral injection of 50 µl of Complete Freund's Adjuvant (CFA) in the ankle joint. During the 14 days of treatment, pain and inflammation were evaluated alternatively in both ankle and paw of the CFA-injected leg. Malondialdehyde (MDA) and glutathione (GSH) levels were assessed in serum and spinal cord. Histology of soft tissue of the ankle was also analyzed. For in vitro studies, AEPP and MEPP (10, 30 and 100 µg/ml) were evaluated against nitric oxide (NO) production by macrophages that were either non-stimulated or stimulated with LPS, 8-Br-AMPc and the mixture of both substances after 8 h exposure. These extracts were also evaluated on TNF-α and IL-1ß production in cells stimulated with LPS for 8 h. Finally, the ability of the extracts to bind to neuroactive receptors was evaluated in vitro using competitive binding assays with >45 molecular targets. RESULTS: AEPP and MEPP significantly reduced by 20-98% (p < 0.001) the inflammation and pain sensation in both the ankle and paw. AEPP significantly increased glutathione levels (p < 0.05) in serum. Both extracts reduced MDA production in serum and spinal cord (p < 0.001), and significantly improved tissue reorganization in treated arthritic rats. P. pinnata extracts did not affect NO production in non-stimulated macrophages but significantly reduced it by 47-88% in stimulated macrophages. AEPP and MEPP also significantly inhibited TNF-α (35-68%) and IL-1ß (31-36%) production in LPS stimulated macrophages. No cytotoxic effect of plant extracts was observed. MEPP showed concentration-dependent affinity for Sigma 2 receptors with an IC50 of 50 µg/ml. CONCLUSION: These results demonstrate the analgesic and anti-inflammatory effects of P. pinnata extracts on monoarthritis and further support its traditional use for pain and inflammation. These activities are at least partly due to the ability of these extracts to inhibit the production of NO, TNF-α, IL-1ß and to likely modulate Sigma 2 receptors.

Utility of a repeat PET/CT scan in HPV-associated Oropharyngeal Cancer following incomplete nodal response from (chemo)radiotherapy.

OBJECTIVES: To assess the utility of a repeat positron emission tomography/computed tomography (PET/CT) instead of immediate neck dissection (ND) for incomplete nodal response (IR) in Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC) following chemoradiotherapy/radiotherapy [(chemo)RT]. MATERIALS AND METHODS: Patients with non-distant metastatic, node positive (N+) disease treated between Jan/2005 to Jan/2016, achieved complete response at the primary with no distant relapse on a 12-week re-staging PET/CT were evaluated. Patients underwent surveillance after complete nodal response (CR). Patients with IR underwent repeat PET/CT at 16 weeks to direct neck management. Primary endpoints were CR conversion rate and subsequent regional failure following a 16-week PET/CT directed ND. Secondary endpoints were predictive values (PV) of the 12- and 16-week PET/CT for residual nodal disease, predictors for requiring the 16-week PET/CT, 5 year regional, locoregional failure free survival (FFS) and overall survival (OS). RESULTS: 235 patients were evaluated. Median follow up was 56 (range 19-60) months. 41 patients underwent 16-week re-staging PET/CT, 29 (71%) converted to CR. No subsequent regional failures occurred following a 16-week PET/CT directed ND. Positive and negative PV of the 12- and 16-week PET/CT for residual nodal disease was 12% & 98%, and 33% & 97%, respectively. N-category (AJCC/UICC 7th edition) predicted for requiring a 16-week PET/CT on univariate analysis (P-value 0.02). 5 year regional, locoregional FFS and OS was 95.8%, 93.4% and 90.8%, respectively. CONCLUSION: For N+ HPV-associated OPC achieving IR on the 12-week re-staging PET/CT following (chemo)RT, a repeat 16-week PET/CT can spare patients from unnecessary surgery.

Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Repair of sheep long bone cortical defects filled with COLLOSS, COLLOSS E, OSSAPLAST, and fresh iliac crest autograft.

COLLOSS and COLLOSS E are osteoinductive bone void fillers consisting of bone collagen and noncollagenous proteins from bovine and equine bone, respectively. The aim of this study was to compare COLLOSS, COLLOSS E, iliac bone autograft, sintered beta tricalcium phosphate (beta-TCP; OSSAPLAST), and COLLOSS E plus OSSAPLAST. Materials were placed for 4, 8, or 24 weeks in 5-mm cortical bone defects in sheep long bones. Histological sections in a plane perpendicular to the long axis of the bone were used to measure the total repair area (original defect plus callus) and the area of bone within the total repair area. The incidence of defect union was also evaluated. At 4 and 8 weeks, defects treated with COLLOSS and COLLOSS E with or without OSSAPLAST had total repair and bone areas equivalent to autograft, and larger than OSSAPLAST-treated defects. At 8 weeks, the incidence of defect union was higher in defects treated with autograft or COLLOSS E plus OSSAPLAST than in untreated defects. At 24 weeks, the incidence of union was 100% in all treatment groups and 0% in untreated defects. The incidence of union was related to the degree of remodeling between 8 and 24 weeks. This was greater in all treated than nontreated defects. In conclusion, COLLOSS and COLLOSS E were equivalent to each other and to autograft, and superior to beta-TCP, in this study model.