Faculty Bibliography

G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR₂) in colitis. To localize PAR₂ and assess redistribution during disease, we generated knockin mice expressing PAR₂ fused to monomeric ultrastable green fluorescent protein (muGFP). PAR₂-muGFP signaled and trafficked normally. PAR₂ messenger RNA was detected at similar levels in Par₂-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR₂) and Gfp probes revealed that PAR₂-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR₂-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR₂-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR₂ PAR₂ agonists stimulated endocytosis of PAR₂ and recruitment of Gα_q, Gα_i, and β-arrestin to early endosomes of T84 colon carcinoma cells. PAR₂ agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR₂ endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR₂ endocytosis sustains protease-evoked inflammation and nociception and PAR₂ in endosomes is a potential therapeutic target for colitis.

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.

SUMMARY/CONCLUSIONS:As the field of plastic surgery continues to advance, so too do the number and complexity of ethical challenges faced by plastic surgeons. There is a paucity of literature, however, focusing on ethics in plastic surgery. Therefore, the authors offer a timely special topic series discussing ethical issues relevant to the field of plastic surgery. The goals of this series are four-fold: (1) to increase awareness of both frequently and less commonly encountered ethical issues in plastic surgery, (2) to foster discussion and debate of relevant and significant ethical issues, (3) to facilitate clinical ethics education and scholarship in plastic surgery, and (4) to apply an understanding and analysis of ethical issues in a way that optimizes clinical decision-making and delivery of patient care. In this introductory article, the authors discuss the current state of medical ethics scholarship in plastic surgery and introduce the first of several topics that will be detailed in the series. Ultimately, the hope is that increased awareness of the ethical challenges faced by surgeons and patients will improve the practice of plastic surgery.

BACKGROUND:Patients with head and neck cancer (HNC) treated with radiation therapy (RT) are at risk for jaw osteoradionecrosis (ORN), which is largely characterized by the presence of exposed necrotic bone. This report describes the incidence and clinical course of and risk factors for exposed intraoral bone in the multicenter Observational Study of Dental Outcomes in Head and Neck Cancer Patients (OraRad) cohort. METHODS:Participants were evaluated before RT and at 6, 12, 18, and 24 months after RT. Exposed bone was characterized by location, sequestrum formation, and other associated features. The radiation dose to the affected area was determined, and the history of treatment for exposed bone was recorded. RESULTS:The study enrolled 572 participants; 35 (6.1%) were diagnosed with incident exposed bone at 6 (47% of reports), 12 (24%), 18 (20%), and 24 months (8%), with 60% being sequestrum and with 7 cases (20%) persisting for >6 months. The average maximum RT dose to the affected area of exposed bone was 5456 cGy (SD, 1768 cGy); the most frequent associated primary RT sites were the oropharynx (42.9%) and oral cavity (31.4%), and 76% of episodes occurred in the mandible. The diagnosis of ORN was confirmed in 18 participants for an incidence rate of 3.1% (18 of 572). Risk factors included pre-RT extractions (P = .008), a higher RT dose (P = .039), and tobacco use (P = .048). CONCLUSIONS:The 2-year incidence of exposed bone in the OraRad cohort was 6.1%; the incidence of confirmed ORN was 3.1%. Exposed bone after RT for HNC is relatively uncommon and, in most cases, is a short-term complication, not a recurring or persistent one.

BACKGROUND:In 1968, Ralph Millard published his "Millard II" method for repair of wide, complete unilateral cleft lip and nose deformity. In 1979, Murawski published a major modification of the Millard II procedure in Polish. This motif was taken up 8 years later by Mohler and 22 years later by Cutting. The Murawski variation on the Millard II procedure has become a dominant motif in unilateral cleft lip repair worldwide. This brief report intends to introduce the method to the English language literature and present long-term results. METHODS:The Murawski method alters the Millard II procedure by changing the upper medial curve into a point in the columellar base. This creates a broad C flap used to fill the entire defect produced by downward rotation of the medial lip. Millard's lateral advancement flap becomes unnecessary. A lateral approach to primary nasal reconstruction allows the lateral C flap to be used to construct the nasal floor and sill. The method is described using a physics-based surgical simulator. RESULTS:Long-term results of the method are demonstrated with four patients with 15 to 25-year follow-up. None of these patients had any revisions to the lip or nose. CONCLUSIONS:The Murawski repair was the first to modify the Millard II repair by sharpening the medial columellar incision, eliminating the need for a lateral advancement flap. This motif was put forth in the years to follow by Mohler and Cutting. Long-term results of the method are presented.

STATEMENT OF PROBLEM/BACKGROUND:Head and neck care has been transformed by the introduction of advanced digital technologies that will continue to be important change drivers for maxillofacial prosthodontics. Insight into these changes is important in answering the question of whether maxillofacial prosthodontics is appropriately prepared to contribute effectively to future multidisciplinary care of the head and neck. PURPOSE/OBJECTIVE:The purpose of this survey was to gain insight into the perception of changes experienced by maxillofacial prosthodontists in relation to clinical practice. The findings of this survey may assist the future development of the subspecialty. MATERIAL AND METHODS/METHODS:An exploratory cross-sectional survey was conducted by using a convenience sample of members of the American Academy of Maxillofacial Prosthetics. The survey considered 10 domains and 31 questions. Fully completed surveys (164) provided a 59% response. Descriptive statistics used percentage responses to reduce and characterize perceptions across respondents. RESULTS:Eighty-four percent of the respondents were from the United States. Results should be interpreted based on this cohort. Respondents reported a change in care delivered over the past 10 years (72%), with the most important causes of change attributed to surgery (60%) and advanced digital technologies (56%). Respondents perceived advanced digital technologies as being central to the future of maxillofacial prosthodontics (89%) and important in attracting younger colleagues (88%). Sixty-three percent believed training programs were not providing adequate education and training in the use of advanced digital technology. CONCLUSIONS:The perception of maxillofacial prosthodontists regarding changes taking place in care delivery was that the most important changes in the past 10 years were attributed to surgery and advanced digital technologies, that persisting pressures related to few institutional positions, that the subspecialty was poorly visible, that remuneration for care was inadequate and referring disciplines did not understand the subspecialty, that advanced digital technologies were considered central to the future of maxillofacial prosthodontics and important to attract younger colleagues to the subspecialty, that barriers to advanced digital technology use included funding for equipment acquisition, institutional funding support, and remuneration for their use in care delivery, and that maxillofacial prosthodontic programs were not providing adequate education and training in advanced digital technologies.

The method of skin closure and post-operative wound management has always been important in orthopedic surgery and plays an even larger role now that surgical site infection (SSI) is a national healthcare metric for both surgeons and hospitals. Wound related issues remain some of the most feared complications following orthopedic trauma procedures and are associated with significant morbidity. In order to minimize the risk of surgical site complications, surgeons must be familiar with the physiology of wound healing as well as the patient and surgical factors affecting healing potential. The goal of all skin closure techniques is to promote rapid healing with acceptable cosmesis, all while minimizing risk of infection and dehiscence. Knowledge of the types of closure material, techniques of wound closure, surgical dressings, negative pressure wound therapy, and other local modalities is important to optimize wound healing. There is no consensus in the literature as to which closure method is superior but the available data can be used to make informed choices. Although often left to less experienced members of the surgical team, the process of wound closure and dressing the wound should not be an afterthought, and instead must be part of the surgical plan. Wounds that are in direct communication with bony fractures are particularly at risk due to local tissue trauma, resultant swelling, hematoma formation, and injured vasculature.

Background/UNASSIGNED:Transmasculine individuals may not have undergone gender-affirming mastectomy and retain natal breast tissue. Our center offers simultaneous oncologic mastectomy with gender-affirming reconstruction to patients who are diagnosed with breast cancer. This study is the first reported series of concurrent gender-affirming and oncologic mastectomies. Methods/UNASSIGNED:A retrospective chart review of all patients undergoing gender-affirming mastectomy at a single institution from February 2017 to October 2021 was performed. Patients were included who had breast cancer diagnoses or pathologic lesions preoperatively. Demographic factors, comorbidities, surgical details, and oncologic history were collected. Both plastic surgery and breast surgery were present for the gender-affirming oncologic mastectomies. Results/UNASSIGNED:Five patients were identified who presented for gender-affirming mastectomy in the context of breast pathologies. Average patient age was 50.2 ± 14.8 years, and no patients used testosterone at any time. Two (40%) patients had a prior breast surgery that included a breast reduction in one patient and breast conserving lumpectomies in another. Sentinel lymph node biopsies were performed in all patients. Only one patient had a positive sentinel lymph node and was subsequently referred for postoperative radiation and chemotherapy. No oncologic recurrence has been detected with 20.6 and 10.0 months of mean and median follow-up. Conclusions/UNASSIGNED:When performed in a multidisciplinary and collaborative setting with breast surgeons and plastic surgeons, oncologic mastectomy can be performed safely while concurrently offering patients an aesthetic gender-affirming reconstructive outcome.

Pre- and postoperative imaging is increasingly used in plastic and reconstructive surgery for the evaluation of bony and soft tissue anatomy. Imaging plays an important role in preoperative planning. In the postoperative setting, imaging is used for the assessment of surgical positioning, bone healing and fusion, and for the assessment of early or delayed surgical complications. This article will focus on imaging performed for surgical reconstruction of the face, including orthognathic surgery, facial feminization procedures for gender dysphoria, and face transplantation.