Faculty Bibliography

BACKGROUND:The authors present outcomes analysis of the nasoalveolar molding treatment protocol in patients with a cleft followed from birth to facial maturity. METHODS:A single-institution retrospective review was conducted of cleft patients who underwent nasoalveolar molding between 1990 and 2000. Collected data included surgical and orthodontic outcomes and incidence of gingivoperiosteoplasty, alveolar bone grafting, surgery for velopharyngeal insufficiency, palatal fistula repair, orthognathic surgery, nose and/or lip revision, and facial growth. RESULTS:One hundred seven patients met inclusion criteria (69 with unilateral and 38 with bilateral cleft lip and palate). Eighty-five percent (91 of 107) underwent gingivoperiosteoplasty (unilateral: 78 percent, 54 of 69; bilateral: 97 percent, 37 of 38). Of those patients, 57 percent (52 of 91) did not require alveolar bone grafting (unilateral: 59 percent, 32 of 54; bilateral: 54 percent, 20 of 37). Twelve percent (13 of 107) of all study patients underwent revision surgery to the lip and/or nose before facial maturity (unilateral: 9 percent, six of 69; bilateral: 18 percent, seven of 38). Nineteen percent (20 of 107) did not require a revision surgery, alveolar bone grafting, or orthognathic surgery (unilateral: 20 percent, 14 of 69; bilateral: 16 percent, six of 38). Cephalometric analysis was performed on all patients with unilateral cleft lip and palate. No significant statistical difference was found in maxillary position or facial proportion. Average age at last follow-up was 20 years (range, 15 years 4 months to 26 years 10 months). CONCLUSIONS:Nasoalveolar molding demonstrates a low rate of soft-tissue revision and alveolar bone grafting, and a low number of total operations per patient from birth to facial maturity. Facial growth analysis at facial maturity in patients who underwent gingivoperiosteoplasty and nasoalveolar molding suggests that this proposal may not hinder midface growth. CLINICAL QUESTION/LEVEL OF EVIDENCE/METHODS:Therapeutic, IV.

ABSTRACT/UNASSIGNED:Velopharyngeal insufficiency (VPI) after cleft palate repair remains an intriguing problem for the cleft surgeon. While other options for the treatment of VPI, in many ways the sphincter pharyngoplasty has become a reliable and satisfying operation. When the applied to the properly selected patient, it rearranges the palatopharyngeus muscles to provide dynamic closure of the newly created central velopharngeal port. The dynamic action is particularly satisfying to the surgeon. The surgery evolved in part because of the dedication and creativity of Dr. Ian Jackson who's description is closest to the design used today. In his memory we felt it fitting to review Dr. Jackson's involvement with the surgery over the decades as well as include our own thoughts on the advantages of the procedure.

BACKGROUND:Robotic-assisted peritoneal flap gender-affirming vaginoplasty (RPGAV) with the da Vinci Xi system has been reported to be a safe alternative to traditional penile inversion vaginoplasty. Utilizing the Single Port (SP) robot system, our surgical approach has evolved. OBJECTIVE:To describe a step-by-step technique for RPGAV using the SP robot and to compare outcomes between Xi and SP systems. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A total of 145 transgender women underwent RPGAV between September 2017 and December 2019. We retrospectively reviewed data for patients with a minimum 6 mo of follow-up. SURGICAL PROCEDURE/METHODS:Peritoneal flaps are harvested from the posterior bladder and pararectal fossa. The vaginal space is dissected transabdominally. Inverted penile flap with or without scrotal graft is sutured to the peritoneal flaps, which form the neovaginal apex. MEASUREMENTS/METHODS:Demographics, perioperative data, and clinical outcomes were evaluated. RESULTS AND LIMITATIONS/CONCLUSIONS:A total of 100 (Xi = 47; SP = 53) patients had a minimum 6 mo of follow-up. The mean age was 36.2 (range 16.1-71.4) yr. Average procedure times were 4.2 and 3.7 h in Xi and SP cohorts, respectively (p <0.001). At the mean follow-up of 11.9 (range 6.0-25.4) mo, vaginal depth and width were 13.6 (range 9.7-14.5) and 3.7 (range 2.9-3.8) cm in the Xi group, and 14.1 (range 9.7-14.5) and 3.7 (range 3.5-3.8) cm in the SP group (p =0.07 and 0.04, respectively). Complications included transfusion (6%), rectovaginal fistula (1%), bowel obstruction (2%), pelvic abscess (1%), and vaginal stenosis (7%). CONCLUSIONS:RPGAV using the SP robot reduces operative time by facilitating a dual-surgeon abdominal-perineal approach. There is no difference in complication rates between the two approaches. PATIENT SUMMARY/UNASSIGNED:We studied the outcomes of robotic peritoneal flap vaginoplasty with two robot systems. With both systems, patients had good vaginal depth and width at an average follow-up of 1 yr. Surgery time was shorter with the Single Port (SP) robot.

Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease lacking effective therapeutic options due to little understanding of the complex immune response within the lesional skin. Using single-cell transcriptomic analyses, we examined the signature changes in each immune cell types during HS progression, as well as in silico ligand-receptor predictions between different immune cell types to construct the interaction network that contribute to HS pathogenesis. Our results revealed a predominant Th17 response, as well as a distinct regulatory T cells existing in the lesional skin. We found that M1-polarized macrophages likely facilitate chemotaxis and IL1B responses in perilesional skin, while regulate lymphocyte activation and tissue remodeling in the lesional skin. In addition, we identified a significant increase of CCR7 expressing dendritic cells, as well as activated stromal fibroblasts expressing CCR7-ligand CCL19, which together support the organization of tertiary lymphoid organ (TLO)-like aggregates that contribute to persistent local inflammation. Importantly, we demonstrated a dense infiltration of plasma cells near sinus tracts, and that clonal expansion of the plasma cells frequently exists in HS patients. Together, our work provides a comprehensive understanding of immune responses and cytokine networks defining disease chronicity in HS, as well as significant implications for future therapeutics.
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Over the past 15 years, landmark achievements have established facial transplantation (FT) as a feasible reconstructive option for otherwise irreparable craniofacial defects. However, as the field matures and long-term outcomes begin to emerge, FT teams around the world are now facing new challenges. Data for this review were identified by searches of the PubMed/MEDLINE database from inception through August 2020. All English-language articles pertaining to FT were included. Significant advances in candidate selection, technology, operative technique, posttransplant care, and immunosuppressive management have contributed to the tremendous expansion of the field, culminating in the execution in the past 3 years of 2 facial re-transplantations, and most recently the world's first successful combined face and double hand transplant in August 2020. Despite these achievements, the allograft donor pool remains limited, with long wait times, requiring surgical experimentation with cross-sex FT. Immunosuppressive management has improved, but significant adverse events continue to be reported. Most recently, the COVID-19 pandemic has placed an unprecedented strain on the healthcare system, with various implications for the practice of reconstructive transplantation. In this article, we provide the most comprehensive and up-to-date FT review, highlighting fundamental lessons learned and recent advancements, while looking toward the challenges ahead. Over the past 15 years, extensive multidisciplinary efforts have been instrumental to the establishment of FT as a feasible reconstructive option. As novel challenges are beginning to emerge, continued collaborative and multispecialty research efforts are needed to further this field.

Hidradenitis suppurativa (HS) is a prevalent inflammatory skin disease. HS causes deep, painful, recurrent abscesses. African Americans and females are at an increased risk. A lack of effective therapies and limited knowledge about HS pathogenesis contribute to unmet needs. Unlike other common inflammatory skin diseases, there has never been a genome-wide association study (GWAS) conducted for HS. Here, we performed a first GWAS for HS using data from the eMERGE network of electronic health record linked biorepositories (project NT227). We used HS diagnosis codes to identify cases and controls. We estimated ancestry with principal component analysis using a set of 40,156 SNPs. Our final cohort consisted of 600 HS cases and 82,611 controls with comparable multi-ethnic ancestry (lambda=1.005). Our cohort recapitulated HS race and gender predilections with genetically African female participants accounting for 35% of cases, but only 10% of controls. Genotype data for 6 million variants was tested for association, adjusting for five principal components. No locus exceeded our threshold for statistical significance. Importantly, there was no evidence for HLA association supporting classification of HS as inflammatory rather than autoimmune. Several loci approached the significance threshold, suggesting that an expansion in cohort size is needed to provide adequate power to detect associations. Interestingly, the lead SNP at one of the most significant loci (rs11075745; p=8x10^-7) is an eQTL for NFAT5, a mediator of NOTCH signaling whose expression is downregulated in HS lesional skin relative to patient-matched nonlesional skin. The risk allele influences expression in tissue specific manner. Our group is constructing multi-ethnic replication cohorts that will allow us to expand this study in the near future.
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Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease affecting human apocrine sweat gland-bearing skin regions. The overall prevalence of HS ranges from 0.05-4.1% with higher occurrence among females and African Americans, and strong associations with smoking and obesity. One unique feature of HS is the development of highly immunogenic keratinized sinus tracts that grow deeply in the dermis which further complicate HS pathogenesis and treatment. Using single cell transcriptomic analyses, we finely dissected different epidermal cell types in the HS lesional skin and revealed significant dysregulation of skin barrier function in the sinus tracts. We demonstrated that sinus tract keratinocytes exhibit dual cell fates of surface epidermis and skin appendages, and derived from progenitors in infundibulum of the apocrine-pilosebaceous unit. By analyzing ligand-receptor expressions between different skin appendages and immune cells, we highlighted Th17 and TNF responses at early and late stages during HS progression, respectively. Our work provides unprecedented understanding of pathological epidermal remodeling in human inflammatory diseases and important implications for therapeutics.
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