T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival.

Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened TH1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.

Reconstruction of an Octogenarian Major Pretibial Degloving Injury Utilizing Negative Pressure Wound Therapy and Subsequently Combining Fenestrated-Type Artificial Dermis Without Skin Grafting.

Major pretibial degloving injuries are complex wounds, which can be challenging to treat. Despite recent advances in reconstructive options, most of these injuries still require a prolonged healing period and may result in amputation. Few reports have been published on the management of these complex traumatic injuries. In this article, we present a case of an octogenarian, frail patient with a major pretibial degloving injury. Treatment included serial surgical debridements in combination with negative pressure wound therapy aimed at salvaging the avulsed tissue. Subsequently, a fenestrated-type artificial dermis and negative pressure wound therapy were used as combined therapy so as to obtain adequate soft tissue coverage. The patient made an unremarkable recovery and was discharged on day 22 after injury. The wound healed by secondary intention without need for skin grafting.

Combination of Autologous Fat Grafting and Negative-Pressure Wound Therapy for the Treatment of Scalp Linear Scleroderma.

ABSTRACT: Scalp linear scleroderma (LSc) is a subtype of localized scleroderma which typically affects young patients and which can be severely disfiguring. Traditional treatment options include bone grafting or tissue expansion. in this report, we present the case of a patient with scalp LSc successfully treated with scar release, autologous fat grafting, and negative-pressure wound therapy (NPWT). A 55-year-old female, with a history of craniectomy for a benign sellar tumor 10 years previously, developed LSc over the frontal scalp with exposure of titanium plates and screws. She was treated with removal of metalwork, scar release, autologous fat grafting from the abdominal wall and immediate application of NPWT. At 3-month postoperative follow-up, the appearance of the depressed lesion and of its margins had significantly improved. Our experience suggests that the combination of autologous fat grafting and NPWT is an effective treatment modality for scalp LSc.

A Stepwise Approach to the "Frozen Neck" for Secondary Microsurgical Reconstruction.

Supplemental Digital Content is available in the text.

Negative-Pressure Wound Therapy in the Prevention and Management of Complications From Prosthetic Breast Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Complications from prosthetic breast reconstruction are distressing for patients, and their management is challenging. For decades, negative-pressure wound therapy (NPWT) has been successfully used for the closure of complex wounds. This study analyzes the outcomes of NPWT use in the prevention and management of complications from prosthetic breast reconstruction. METHOD: A systematic search of studies published until August 2020 was conducted using the PubMed/MEDLINE, EMBASE, and Ebscohost/CINAHL databases and using the following key words: "negative-pressure wound therapy," "breast reconstruction," and "prosthesis" (including breast implants and tissue expanders). Analyzed endpoints were outcomes of NPWT use in prosthetic breast reconstruction compared with conventional dressings. The methodological quality of included studies was assessed independently. Comparative studies were further meta-analyzed to obtain pooled odds ratios (ORs) describing the effectiveness of NPWT in prosthetic breast reconstruction. RESULTS/DISCUSSION: Ten studies were included with a total of 787 patients (1230 breasts) undergoing prosthetic breast reconstruction with breast implants or tissue expanders. Three case-control studies focused on preventing breast wound complications. The meta-analysis of the 3 studies included 502 breasts receiving NPWT and 698 breasts receiving conventional wound care. The meta-analysis favored NPWT for less mastectomy flap necrosis (5.6% vs 14.3%; OR, 0.46; 95% confidence interval, 0.27 -0.77; P = 0.004; I2 = 0%) and less overall wound complications (10.6% vs 21.1%; OR, 0.49; 95% confidence interval, 0.35-0.70; P < 0.00001; I2 = 0%). In the management of nipple-areolar complex venous congestion, 1 case report demonstrated 85% rescue of nipple-areolar complex after using NPWT (-75 mm Hg) for a total of 12 days. In the management of periprosthetic infections, 2 case series used NPWT with instillation. It accelerated the treatment of infection and maintained the breast cavity for future reconstruction. Conventional NPWT also showed good salvage outcome in four studies. CONCLUSIONS: Current evidence suggests that prophylactic use of NPWT in prosthetic breast reconstruction reduces the rate of overall wound complications and mastectomy flap necrosis. In the management of complications from prosthetic breast reconstructions, NPWT may be a promising option showing beneficial results. Additional high-quality trials are warranted to corroborate the findings of this systematic review.

Mortality Within 30 Days After Head and Neck Free Flap Reconstruction: A Systematic Review.

OBJECTIVE: The aim of this systematic review is to analyze the 30-day postoperative mortality in patients undergoing free flap reconstruction for head and neck cancer published in literature and to identify associated factors. METHODS: The authors performed a literature search between January 1950 and February 2020 in PubMed, EMBASE, and Scopus, using a combination of Medical Subject Headings headings and text keywords related to head and neck cancer; microsurgery or free flap reconstruction; and 30-day mortality. Inclusion criteria were: original studies in English reporting on 30-day mortality after head and neck free flap reconstruction in adult population. RESULTS: Thirty-one publications reported on a total of 13,447 patients who underwent head and neck free flap reconstruction. The published 30-day postoperative mortality ranged from 0% to 6.3%, with an average of 1.21%. A number of studies examined the association between mortality and body mass index, American Society of Anesthesiologists, and comorbidity score and age. One study found that underweight patients had significantly higher mortality. Two studies found no association between the American Society of Anesthesiologists score and 30-day postoperative mortality; however, 1 study reported significantly higher mortality with increased comorbidity score. Regarding association with age, 3 studies found significant higher mortality in older patients, while 5 studies found no difference. CONCLUSIONS: The average 30-day postoperative mortality in patients undergoing head and neck free flap reconstruction is 1.21% and is; therefore, not negligible. Careful patient selection and preoperative optimization are essential in order to reduce mortality in head neck free flap reconstruction.

Reconstruction of Craniofacial Skin Cancer Resection Defect in Octogenarian Patients Using Fenestrated-type Artificial Dermis Without Skin Grafting.

ABSTRACT: Reconstructive surgery following skin cancer resection in octogenarian patients can be challenging. Despite current advancements in reconstructive options, most of these wide excision defects require local or even free flap coverage, causing physical and emotional impairment. Few reports have been published on the management of these complex craniofacial defects. We present our experience in 2 octogenarian patients with craniofacial skin cancer treated with wide excision under wide-wake local anesthesia and subsequently reconstructed with fenestrated-type artificial dermis. Both patients had uneventful recovery. The wounds healed by secondary intention without skin grafting.

Systematic Review and Meta-Analysis of Complications Following Mastectomy and Prosthetic Reconstruction in Patients With and Without Prior Breast Augmentation.

BACKGROUND: There is limited evidence available in the literature with regard to the complication profile of mastectomy and immediate prosthetic reconstruction in augmented patients. OBJECTIVES: The aim of this systematic review and meta-analysis was to compare postoperative complications between women with vs without prior augmentation undergoing skin- or nipple-sparing mastectomy and immediate prosthetic reconstruction. METHODS: A systematic search was conducted in February 2020 for studies comparing women with vs without prior augmentation undergoing skin- or nipple-sparing mastectomy and immediate prosthetic reconstruction with documentation of postoperative complications. Outcomes analyzed included early, late, and overall complications. Pooled odds ratios (ORs) with 95% CIs were obtained through meta-analysis. RESULTS: Our meta-analysis, which included 6 studies comparing 241 breasts with prior augmentation and 1441 without, demonstrated no significant difference between the 2 groups in rates of early (36.7% vs 24.8%: OR, 1.57; 95% CI, 0.94-2.64; P = 0.09), late (10.1% vs 19.9%: OR, 0.53; 95% CI, 0.06-4.89; P = 0.57), and overall complications (36.5% vs 31.2%: OR, 1.23; 95% CI, 0.76-2.00; P = 0.40). Subgroup analysis showed a significantly higher rate of hematoma formation in the augmented group (3.39% vs 2.15%: OR, 2.68; 95% CI, 1.00-7.16; P = 0.05), but no difference in rates of seroma, infection, mastectomy skin flap necrosis, and prosthesis loss. CONCLUSIONS: Our meta-analysis suggests that prior augmentation does not significantly increase overall postoperative complications in women undergoing skin- or nipple-sparing mastectomy and immediate prosthetic reconstruction. However, the significantly higher rate of hematoma formation in augmented patients warrants further investigation and preoperative discussion.

War trauma in Homer's Iliad: a trauma registry perspective.

PURPOSE: Homer's Iliad reports detailed descriptions of war traumas, with precise anatomical references, so that the Iliad can be considered the first trauma registry. We aimed to analyse the Iliad from the perspective of a modern trauma registry: that is, to find historical and local prognostic factors through the epidemiological study of the reported traumas. METHODS: Two different editions of Homer's Iliad-one in English and one in Italian-were thoroughly studied and epidemiological data were statistically analysed. RESULTS: 148 reports of human traumas were analysed. The majority of traumas (73.6%) involved Trojan warriors, with spears being the most frequent wounding agent (71%). Overall mortality was 84.5% and was higher in the Trojan field (90.8% vs 61.5%). Despite the high mortality, median New Injury Severity Score (NISS) was low, probably due to high prevalence of penetrating mono-systemic trauma. Median NISS was higher in the Trojan group. Compared to the Achaeans, the Trojans had more torso injuries, whereas Achaeans had more injuries to limbs and superficial tissues. However, in both fields, head and neck were more frequently injured. CONCLUSIONS: Homer's Iliad gives us an interesting insight into war traumas during the siege of Troy. The reported higher mortality within the Trojan army can be explained not only by poetic reasons but also by different military skills.

Diagnosing pelvic osteomyelitis in patients with pressure ulcers: a systematic review comparing bone histology with alternative diagnostic modalities.

Accurate diagnosis of osteomyelitis underlying pressure ulcers is essential, as overdiagnosis exposes patients to unnecessary and prolonged antibiotic therapy, while failure to diagnose prevents successful treatment. Histopathological examination of bone biopsy specimens is the diagnostic gold standard. Bone biopsy can be an invasive procedure, and, for this reason, other diagnostic modalities are commonly used. However, their accuracy is questioned in literature. This systematic review aims to assess accuracy of various modalities (clinical, microbiological and radiological) for the diagnosis of pelvic osteomyelitis in patients with pressure ulcers as compared to the gold standard. A systematic literature search was conducted in July 2019 using the MEDLINE (Medical Literature Analysis and Retrieval System - MEDLARS - Online) and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases. The search terms were "decubitus ulcer", "pressure ulcer", "pressure sore", "bedsore" and "osteomyelitis". The inclusion criteria were original full-text articles in English comparing the results of bone histology with those of other diagnostic modalities in adult patients with pelvic pressure ulcers. Six articles were included in the systematic review. Clinical diagnosis was found to be neither specific nor sensitive. Microbiological examination, and in particular cultures of bone biopsy specimens, displayed high sensitivity but low specificity, likely reflecting contamination. Radiological imaging in the form of X-ray and CT (computed tomography) scans displayed high specificity but low sensitivity. MRI (magnetic resonance imaging), bone scanning and indium-labelled scintigraphy displayed high sensitivity but low specificity. Our systematic review did not find any diagnostic method (clinical, microbiological or radiological) to be reliable in the diagnosis of pelvic osteomyelitis associated with pressure ulcers as compared to bone histology.

Rifampicin for Treatment of Cholestatic Pruritus Caused by Drug-Induced Acute Liver Injury as Assessed by the RUCAM Classification.

A male bodybuilder of 39 years of age developed severe pruritus, nausea, and jaundice after injecting anabolic steroids purchased on the black market. The patient had no history of liver disease and no risk factors for viral hepatitis. Extensive laboratory testing, radiographic imaging, and liver biopsy excluded a majority of potential pathologies. The patient was diagnosed with drug-induced acute liver injury and secondary acute renal failure most likely caused by testosterone purchased on the black market. The pruritus caused insomnia and significant psychological distress. Treatment was initiated with cholestyramine and naltrexone for one week with no effect on the pruritus. Subsequently, all medications were stopped, and rifampicin was started. Pruritus resolved after starting rifampicin, and liver and kidney function improved rapidly and normalized within 5 months.

A novel rat microsurgical model to study the immunological characteristics of male genital tissue in the context of penile transplantation.

Penis transplantation represents an exciting new avenue for restoration of male genitalia and function after devastating tissue loss. This animal model is designed to fill a critical void to study immunologic aspects related to reconstructive transplantation of male genitalia. A rat penile graft dissection was designed based on the internal pudendal arteries and dorsal penile vein and includes the skin of the prepuce. A nonsuture cuff technique was used to anastomose the graft vessels to the recipient superficial epigastric and femoral vessels. Seventy-seven penile transplantations were performed. Graft design yields suitable caliber and length of vessels at the radix of the penis. Anastomosis of the dorsal penile vein and the internal pudendal arteries insures optimal graft perfusion. The nonsuture cuff technique allows for successful microvascular anastomosis by a single surgeon with an average overall operative time of 2.5 h. Long-term graft survival (>30 days) was observed in syngeneic transplants. We have established a robust murine model with ideal vascular perfusion of penile tissue to study the unique immunobiology of male genitourinary allotransplantation. Heterotopic inset further allows for visual monitoring of graft viability, while the native penis serves as an optimal control.

A systematic review and meta-analysis of antibiotic prophylaxis in skin graft surgery: A protocol.

INTRODUCTION: There is little evidence-based guidance on the use of prophylactic antibiotics in skin surgery; whilst antibiotics may protect against surgical site infections (SSI), they have associated side effects, increase the risk of adverse events, and can propagate antibiotic resistance. We present a protocol for a systematic review to establish whether the benefit of prophylactic antibiotics overrides the risk, for patients undergoing autograft surgery. METHODS: The systematic review will be registered a priori on researchregistry.com and will be conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A search strategy will be devised to investigate 'skin graft surgery and use of antibiotics'. The following electronic databases will be searched, 1979-2018: PubMed, MEDLINE®, EMBASE, SCOPUS, CINAHL, PsychINFO, SciELO, The Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effect (DARE), the Cochrane Methodology Register, Health Technology Assessment Database, the NHS Economic Evaluation Databases and Cochrane Groups, ClinicalTrials.gov, Current Controlled Trials Database, the World Health Organisation (WHO) International Clinical Trials Registry Platform, UpToDate.com, NHS Evidence and the York Centre for Reviews and Dissemination. Grey literature will be searched. All comparative study designs reporting on the use of antibiotics in skin graft surgery will be considered for inclusion, namely randomized controlled trials (RCTs). Two trained independent teams will screen all titles and abstracts, followed by relevant full texts, for eligibility. Data will be extracted under standardized extraction fields into a preformatted database. Note will be made of the indication for skin graft surgery (traumatic, congenital, malignant, benign), the graft site (head & neck, trunk, upper extremities, lower extremities), type of skin graft (split thickness, full-thickness). The primary outcome will be occurrence of SSI at the donor and/or recipient sites. Secondary outcomes, if reported, will include: length of hospital stay, revision surgery required, cost of medical care, time to wound healing and cosmetic outcome. ETHICS AND DISSEMINATION: The systematic review will be published in a peer-reviewed journal and presented at national and international meetings within fields of plastic, reconstructive, and aesthetic surgery. The work will be disseminated electronically and in print. Brief reports of the review and findings will be disseminated to interested parties through email and direct communication. The review aims to guide healthcare practice and policy.

Characterization of Clinical and Histological Rejection of Male Genital Tissues Using a Novel Microsurgical Rat Penile Transplantation Model.

BACKGROUND: Penis transplantation represents an exciting new avenue for restoration of male urogenitalia. However, little is known about the specific immunological features of penile transplants, limiting their application in complex urogenital reconstruction. To properly study this emerging form of transplantation, adequate preclinical models are a necessity. The purpose of this study is to establish a clinical and histological rejection classification of urogenital tissue transplants using a new rat heterotopic penile transplant model that includes preputial skin. METHODS: Syngeneic and allogeneic heterotopic penile transplantations were performed on Lewis and Brown Norway rats using a new model designed by our group. Grafts were clinically and histologically monitored at postoperative days (POD) 3-30. RESULTS: Six syngeneic and 25 allogeneic transplants were performed. All syngeneic and tacrolimus-treated grafts survived until endpoint. Allogeneic graft rejection is shown to follow a 4-stage clinical progression with all untreated allografts developing epidermal sloughing at POD7 and full rejecting between POD14 and POD16. Histological samples were used to develop a specific 4-grade rejection classification analogous to the 2007 Banff Criteria for skin-containing allografts. CONCLUSIONS: Graft skin and urethral lining tissue are first rejection targets followed by tunica albuginea and corpora cavernosa in a distal to proximal pattern. We established a robust and reproducible murine model to study the immunobiology of male genital tissue in the context of transplantation and developed a novel 4-grade clinical and histological rejection scale based on graft skin and urethral lining as the main targets of rejection.

Stem cells in burn wound healing: A systematic review of the literature.

INTRODUCTION: Severe burns are often associated with high morbidity and unsatisfactory functional and esthetic outcomes. Over the last two decades, stem cells have generated great hopes for the treatment of numerous conditions including burns. The aim of this systematic review is to evaluate the role of stem cell therapy as a means to promote burn wound healing. METHODS: Comprehensive searches in major databases were carried out in March 2017 for articles on stem cell therapy in burn wound healing. In total 2103 articles were identified and screened on the basis of pre-determined inclusion and exclusion criteria. RESULTS: Fifteen experimental and two clinical studies were included in the review. The majority of studies reported significant improvement in macroscopic burn wound appearance as well as a trend toward improved microscopic appearance, after stem cell therapy. Other parameters evaluated, such as re-vascularization, collagen formation, level of pro- and anti-inflammatory mediators, apoptosis and cellular infiltrates, yielded heterogeneous results across studies. CONCLUSION: Stem cell therapy appears to exert a positive effect in burn wound healing. There is, therefore, justification for continued efforts to evaluate the use of stem cells as an adjunct to first-line therapies in burns.

Assessing the Compliance of Randomized Controlled Trials Published in Craniofacial Surgery Journals With the CONSORT Statement.

BACKGROUND: Randomized controlled trials (RCTs) are gold standard assessments for healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) statement was published to maximize RCT reporting transparency. The authors conducted a systematic review to assess current compliance of RCTs published within craniofacial surgery with the CONSORT statement. METHODS: The Thomson Reuters Impact Factor Report 2016 was consulted to identify craniofacial surgery journals. PubMed was used to search for recent RCTs published within the 5 journals identified. Two independent researchers assessed each study for inclusion and performed data extraction. The primary outcome was compliance of each RCT with the CONSORT statement. Secondary outcomes were the pathology and interventions examined, impact factor, multi-versus-single center, number of authors, and publication date. RESULTS: Eighty-six studies met the inclusion criteria, across which a median of 56% (range 33%-94%) applicable CONSORT items were reported. The 5 least reported items were: trial design (3a); registration number and name of trial registry (23); who generated random allocation sequences, enrolled participants, and assigned participants to interventions (10); sample size determination (7a); mentioning "randomized trial" in the title (1a). CONCLUSION: The compliance of craniofacial surgery RCTs with the CONSORT statement requires improvement. Areas in need are identified, and methods to improve reporting transparency, are discussed.

Stem Cell Mobilization Is Lifesaving in a Large Animal Preclinical Model of Acute Liver Failure.

INTRODUCTION: Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial. METHODS: Male Yorkshire pigs (14-18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 µg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline. RESULTS: All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004). CONCLUSIONS: Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.

Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice.

Destruction of insulin-producing ß-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type-I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in nonobese diabetic mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.