Secondary Facial Gender Surgery: Causes of Poor Outcomes and Strategies for Avoidance and Correction.

SUMMARY: Facial feminization surgery covers a broad spectrum of procedures across both hard and soft tissues. Despite the fact that this is a decidedly predictable surgery, because of the high demand for the procedures, a growing number of patients are requiring revision surgery, whether to correct unexpected results or to treat mid-term to long-term functional and aesthetic complications. This Special Topic article categorizes unsatisfactory outcomes encountered after forehead surgery, lower jaw surgery, and thyroid chondroplasty; key steps to avoid these pitfalls; and strategies for structured analysis and operative planning in revision cases.

Shaping the Lower Jaw Border with Customized Cutting Guides: Development, Validation, and Application in Facial Gender-Affirming Surgery.

Importance: Three-dimensional planning software is not standardized in facial gender-affirming surgery. Objective: To develop and validate surgical planning software to create cutting guides to contour the lower jaw border. Design, Setting, and Participants: A 3-year prospective case series study done in three phases: software development, validation, and surgical guide application. Ethics committee approval was obtained to enroll the patients (Clinical Research Ethics Committee, Hospital Costa del Sol, Marbella, Spain). Main Outcomes and Measures: Validation phase: degree of agreement between the planned and obtained results, modification of cephalometric parameters, and surgical times. Application phase: surgical technique description, complications, and patient-reported outcome measures. Results: The degree of agreement between the planned and obtained results was inframillimetric (0.31 ± 0.70 mm). The guides reduced the mandible to within feminine parameters (p < 0.05). Surgical times decreased by 10.96% with chin ostectomies (p < 0.05) and 23.06% with lower jaw border (angle-to-angle) surgeries (p < 0.001). In the application phase, revision surgery was required for 11 patients out of 260 (4.23%). Conclusions and Relevance: The use of cutting guides on the lower jaw border is effective, helps reach standard feminine parameters, and decreases surgical times.

Facial Gender Confirmation Surgery: The Lower Jaw. Description of Surgical Techniques and Presentation of Results.

BACKGROUND: Of the primary procedures associated with facial gender confirmation surgery, those involving the mentomandibular complex have received the least attention in the literature. METHODS: The authors present their experience with 837 trans feminine patients operated on for facial gender confirmation surgery who underwent mandibular bone contouring procedures, including bone contouring, chin and mandibular body and angle ostectomies, and osteotomies to reposition the chin. The authors describe the surgical techniques and materials used, and present a customized lower border-supported cutting guide designed by their team and used with 205 patients. A femininity perception score was calculated preoperatively and 12 months postoperatively, and satisfaction with the results was measured 12 months postoperatively. RESULTS: The postoperative follow-up ranged from 12 to 110 months. The mean femininity perception score increased from 47.86 preoperatively to 76.41 at 12 months postoperatively (p < 0.001). No emergency surgical operations were required. In no case was there any permanent damage to the mental or inferior dental nerve. The reoperation percentage because of problems detected during the postoperative period was 2.63 percent (22 patients). CONCLUSIONS: With facial gender confirmation surgery of the jawline and chin, it is possible to modify the transverse and vertical components of the jaw; soften the gonial angles; change the format, bone volume, and position of the chin; and harmonize the entire mandibular line. The facial feminization achieved high satisfaction scores regarding the results and feminine gender appearance 12 months after surgery. The future of mandibular bone contouring techniques includes planning with virtual software and surgical support with patient-specific cutting guides.

Facial Gender Surgery: Systematic Review and Evidence-Based Consensus Guidelines from the International Facial Gender Symposium.

BACKGROUND: Increasing societal acceptance of transgender people has led to broader availability of gender surgery and rapid growth in transition-related operations. Facial gender surgery aims to modify patients' facial features to be more congruent with their physical expression of gender, reducing gender dysphoria and improving quality of life. Growth in research and technique evolution has not kept pace with growth in clinical volume. Therefore, the first International Facial Gender Symposium was held at Johns Hopkins University in 2019, convening surgeons who perform facial gender surgery to share ideas and assess the state of clinical evidence. METHODS: To review the literature on facial gender surgery, the authors developed a search strategy for seven electronic databases (PubMed, PsycINFO, Embase, CINAHL, Web of Science, Cochrane, and Gender Studies) through May of 2019, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review guidelines. RESULTS: Based on the English language literature and clinical experience, the authors suggest guidelines for screening, management, and appropriate surgical technique for patients undergoing facial gender surgery. They highlight facial gender surgery as a medically necessary intervention and identify shortcomings in current guidelines. CONCLUSIONS: Facial gender surgery represents a complex array of craniofacial and soft-tissue procedures that require application of advanced skills and decision-making. Facial gender operations are not cosmetic, are medically necessary, and require development of new CPT codes specific to facial gender surgery. It is imperative to create educational programs and methods to define sufficient training for facial gender surgery surgeons. Research priorities include better procedural outcomes data, more quality-of-life studies, and insight into variation in both patient and procedural subgroups.

Social Perception of Facial Feminization Surgery Outcomes: Does Gender Identity Alter Gaze?

BACKGROUND: The evaluation of gender-affirming facial feminization surgery (FFS) outcomes can be highly subjective, which has resulted in a limited understanding of the social perception of favorable gender and aesthetic facial appearance following FFS. Eye-tracking technology has introduced an objective measure of viewer subconscious gaze. OBJECTIVES: The aim of this study was to use eye-tracking technology to measure attention and perception of surgery-naive cisgender female and feminized transgender faces, based on viewer gender identity. METHODS: Thirty-two participants (18 cisgender and 14 transgender) were enrolled and shown 5 photographs each of surgery-naive cisgender female and feminized transgender faces. Gaze was captured with a Tobii Pro X2-60 eye-tracking device (Tobii, Stockholm, Sweden) and participants rated the gender and aesthetic appearance of each face on Likert-type scales. RESULTS: Total image gaze fixation time did not differ by participant gender identity (6.00 vs 6.04 seconds, P = 0.889); however, transgender participants spent more time evaluating the forehead/brow, buccal/mandibular regions, and chin (P < 0.001). Multivariate regression analysis showed significant associations between viewer gender identity, age, race, and education, and the time spent evaluating gender salient facial features. Feminized faces were rated as more masculine with poorer aesthetic appearance than surgery-naive cisgender female faces; however, there was no significant difference in the distribution of gender appearance ratings assigned to each photograph by cisgender and transgender participants. CONCLUSIONS: These results demonstrate that gender identity influences subconscious attention and gaze on female faces. Nevertheless, differences in gaze distribution did not correspond to subjective rated gender appearance for either surgery-naive cisgender female or feminized transgender faces, further illustrating the complexity of evaluating social perception of favorable FFS outcomes.

Prospective Quality-of-Life Outcomes after Facial Feminization Surgery: An International Multicenter Study.

BACKGROUND: No data exist on the prospective outcomes of facial feminization surgery. This study set out to determine the effects of facial feminization surgery on quality-of-life outcomes for gender-diverse patients. METHODS: A prospective, international, multicenter, cohort study with adult gender-diverse patients with gender dysphoria was undertaken. Facial feminization outcome score was calculated preoperatively and postoperatively (1-week to 1-month and >6 months). Photogrammetric cephalometries were measured at the same time points. Self-perceived preoperative masculinity and femininity were recorded. Externally rated gender appearance (scale of 1 to 5, with 1 being most feminine) and general aesthetics (scale of 1 to 10, with 10 being very good) for 10 facial feminization surgery patients were compared with those of five cisgender controls. Univariate linear regression analyses were used to predict outcomes from facial feminization surgery. RESULTS: Sixty-six consecutive patients were enrolled. Patients noted that their brows, jaws, and chins were the most masculine aspects of their faces (54.5 percent, 33.3 percent, and 30.3 percent, respectively). Median facial feminization outcome score increased from 47.2 preoperatively to 80.6 at 6 months or more postoperatively (p < 0.0001). Mean satisfaction was excellent (3.0 at both 1-month and ≥6-month follow-up; p = 0.46). Cephalometric values were significantly more feminine after surgery. Gender appearance was feminine to very feminine (1.83 ± 0.96) and general aesthetics were good (6.09 ± 2.01) but different from those of cisgender women controls (1.25 ± 0.49 and 7.63 ± 1.82, respectively; p < 0.001 for each). CONCLUSION: Facial feminization achieved improved quality of life, feminized cephalometries, feminine gender appearance, good overall aesthetics, and high satisfaction that were present at 1 month and stable at more than 6 months. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Facial Gender Confirmation Surgery: A Protocol for Diagnosis, Surgical Planning, and Postoperative Management.

During the past 10 years, academic publications that address facial feminization surgery have largely examined the technical aspects of the different surgical procedures involved and clinical evaluations of postoperative results. This Special Topic article focuses on aspects that are underdeveloped to date but useful with regard to taking the correct therapeutic approach to transgender patients who are candidates for facial gender confirmation surgery. The authors propose a protocolized sequence, from the clinical evaluation to the postoperative period, based on a sample size of more than 1300 trans feminine patients, offering facial gender confirmation surgery specialists standardized guidelines to handle their patients' needs in a way that is both objective and reproducible.

The Upper Third in Facial Gender Confirmation Surgery: Forehead and Hairline.

The upper third of the face contains 2 features that are particularly important for facial gender recognition: the frontonasoorbital region and the hairline. The supraorbital ridge, which determines the position and exposure of the eyebrows, is almost invariably more developed in the male than in the female. Surgical modification of the frontonasoorbital complex, considered a standard procedure in facial feminization, is reliable and predictable, and also delivers satisfactory results that are stable over time.A prototypical male hairline has an M-shaped pattern compared to the more rounded shape often seen in female hairlines. Feminization of the hairline requires minimizing the temples as well as rounding out the overall shape, optimizing hair density, and occasionally changing the height of the hairline.This article provides an update on our forehead reconstruction technique and our experience in the treatment of hairline redefinition.

Facial Feminization Surgery: Simultaneous Hair Transplant during Forehead Reconstruction.

BACKGROUND: Reconstruction of the frontonaso-orbital complex is one of the best-described and most commonly used procedures in the field of facial feminization surgery. To a large extent, this complex determines the facial expression and plays a key role in the visual identification of facial gender. After the forehead, the hairline pattern is the second most important feature of gender identification within the upper third of the face. The combined evaluation of these two features should be a basic premise of facial feminization surgery. METHODS: The authors present a new surgical sequence developed by their group in which reconstruction of the frontonaso-orbital complex and redefinition of the hairline by means of an autologous hair transplant are carried out during the same operation: forehead reconstruction and simultaneous hair transplantation. RESULTS: Sixty-five male-to-female transgender patients treated with forehead reconstruction and simultaneous hair transplantation are presented along with the surgical technique, sequence used, and the results obtained. A classification method for hairlines in male-to-female transgender patients is proposed based on the observation of 492 patients. A modified temporoparietooccipital coronal (posterior coronal) approach is also described. CONCLUSION: The forehead reconstruction and simultaneous hair transplant technique makes it possible to address the entire upper third of the face in a single facial feminization operation.

Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis.

BACKGROUND AND AIMS: Intestinal microbiota is required to maintain immune homeostasis and intestinal barrier function. At the same time, intraluminal bacteria are considered to be involved in inflammatory bowel disease and are required for colitis induction in animal models, with the possible exception of dextran sulphate sodium [DSS] colitis. This study was carried out to ascertain the mechanism underlying the induction of colitis by DSS in the absence of bacteria. METHODS: Conventional and germ-free [GF] Naval Medical Research Institute [NMRI] mice were used, plus conventional mice treated with an antibiotic cocktail to deplete the intestinal microbiota ['pseudo-GF' or PGF mice]. The differential response to DSS was assessed. RESULTS: Conventional mice developed DSS-induced colitis normally, whereas GF mice showed only minimal inflammation [no colonic thickening, lower myeloperoxidase activity, IL-6, IL-17, TNF-α, and IFN-γ secretion by splenocytes and mesenteric cell cultures, etc.]. However, these mice suffered enhanced haemorrhage, epithelial injury and mortality as a consequence of a weakened intestinal barrier, as shown by lower occludin, claudin 4, TFF3, MUC3, and IL-22. In contrast, PGF mice had a relatively normal, albeit attenuated, inflammatory response, but were less prone to haemorrhage and epithelial injury than GF mice. This was correlated with an increased expression of IL-10 and Foxp3 and preservation barrier-related markers. CONCLUSIONS: We conclude that enteric bacteria are essential for the development of normal DSS-induced colitis. The absence of microbiota reduces DSS colonic inflammation dramatically but it also impairs barrier function, whereas subtotal microbiota depletion has intermediate effects at both levels.

Fructooligosaccharides exert intestinal anti-inflammatory activity in the CD4+ CD62L+ T cell transfer model of colitis in C57BL/6J mice.

PURPOSE: Fructooligosaccharides (FOS) are used as functional foods due to their prebiotic effects. Intestinal anti-inflammatory activity has been established in most, but not all, studies in animal models of colitis, using mainly chemically induced inflammation. Our goal was to test the effect of FOS (degree of polymerization 2-8) in the chronic, lymphocyte-driven CD4+ CD62L+ T cell transfer model of colitis. METHODS: Colitis was induced by transfer of CD4+ CD62L+ T cells to C57BL/6J Rag1(-/-) mice. FOS (75 mg day(-1)) was administered by gavage as a post-treatment. Three groups were established: non-colitic (NC), colitic control (C, CD4+ CD62L+ transferred mice treated with vehicle) and colitic+FOS (C+FOS, similar but treated with FOS). Mice were killed after 13 days. RESULTS: Treatment of mice with FOS ameliorated colitis, as evidenced by an increase in body weight, a lesser myeloperoxidase and alkaline phosphatase activities, a lower secretion of proinflammatory cytokines by mesenteric lymph node cells ex vivo (IFN-γ, IL-17, and TNF-α), and a higher colonic expression of occludin (C+FOS vs. C, p < 0.05). Increased relative abundance of lactic acid bacteria was observed in FOS-treated mice (p < 0.05). CONCLUSIONS: FOS exert intestinal anti-inflammatory activity in T lymphocyte-dependent colitis, suggesting it may be useful in the management of inflammatory bowel disease in appropriate conditions.

Prebiotic oligosaccharides directly modulate proinflammatory cytokine production in monocytes via activation of TLR4.

SCOPE: Prebiotic oligosaccharides are currently used in a variety of clinical settings for their effects on intestinal microbiota. Here, we have examined the direct, microbiota independent, effects of prebiotics on monocytes and T lymphocytes in vitro. METHODS AND RESULTS: Prebiotics generally evoked cytokine secretion (TNF-α, IL-6, and IL-10) by mouse splenocytes but inhibited LPS -induced IFN-γ and IL-17 release. Inulin was found to enhance LPS-induced IL-10 secretion. Splenocytes from TLR4(-/-) (where TLR is Toll-like receptor) mice showed a markedly depressed response. Conversely, in both basal and LPS-stimulated conditions, prebiotic inhibition of IFN-γ levels was preserved. These results suggested a predominant effect on monocytes via TLR4 ligation and possible inhibition of T cells. Hence, we studied the modulation of primary rat monocytes and T lymphocytes, focusing on fructooligosaccharides (FOS) and inulin. In monocytes, FOS and inulin induced TNF-α, growth-regulated oncogene α, and IL-10, but not IL-1ß release. The NF-κB inhibitor Bay 11-7082 fully prevented these effects. Pharmacological evidence also indicated a significant involvement of mitogen-activated protein kinase and phosphatidylinositol-3-kinase. There was little effect on T cells. FOS and inulin also generally increased TNF-α, IL-1ß, and IL-10, but not IL-8, in human peripheral blood monocytes. CONCLUSION: We conclude that prebiotics may act as TLR4 ligands or as indirect TLR4 modulators to upregulate cytokine secretion in monocytes.

Discovery of a new binding site on human choline kinase α1: design, synthesis, crystallographic studies, and biological evaluation of asymmetrical bispyridinium derivatives.

Human choline kinase α (CKα) is a validated drug target for the treatment of cancer. In recent years, a large number of CK inhibitors have been synthesized, and one of them is currently being evaluated in Phase I clinical trials as a treatment for solid tumors. Here we have evaluated a new series of asymmetrical biscationic CK inhibitors by means of enzymatic, crystallographic, and antitumor studies. We demonstrate that one of these structures adopts a completely new binding mode not observed before inducing the aperture of an adjacent binding site. This compound shows antiproliferative and apoptotic effects on cancer cells through activation of caspase-3. Therefore, this study not only provides fruitful insights into the design of more efficient compounds that may target different regions in CKα1 but also explains how these compounds induce apoptosis in cancer cells.

Validation of bovine glycomacropeptide as an intestinal anti-inflammatory nutraceutical in the lymphocyte-transfer model of colitis.

Milk κ-casein-derived bovine glycomacropeptide (GMP) exerts immunomodulatory effects. It exhibits intestinal anti-inflammatory activity in chemically induced models of colitis. However, to validate its clinical usefulness as a nutraceutical, it is important to assess its effects in a model with a closer pathophysiological connection with human inflammatory bowel disease. Therefore, in the present study, we used the lymphocyte-transfer model of colitis in mice and compared the effects of GMP in this model with those obtained in the dextran sulphate sodium (DSS) model. GMP (15 mg/d) resulted in higher body-weight gain and a reduction of the colonic damage score and myeloperoxidase (MPO) activity in Rag1(-/-) mice with colitis induced by the transfer of naïve T cells. The colonic and ileal weight:length ratio was decreased by approximately 25%, albeit non-significantly. GMP treatment reduced the percentage of CD4⁺ interferon (IFN)-γ⁺ cells in mesenteric lymph nodes (MLN). The basal production of IL-6 by MLN obtained from the GMP-treated mice ex vivo was augmented. However, concanavalin A-evoked production was similar. The colonic expression of regenerating islet-derived protein 3γ, S100A8, chemokine (C-X-C motif) ligand 1 and IL-1ß was unaffected by GMP, while that of TNF-α and especially IFN-γ was paradoxically increased. In the DSS model, GMP also reduced the activity of colonic MPO, but it failed to alter weight gain or intestinal weight:length ratio. GMP augmented the production of IL-10 by MLN cells and was neutral towards other cytokines, except exhibiting a trend towards increasing the production of IL-6. The lower effect was attributed to the lack of the effect of GMP on epithelial cells. In conclusion, GMP exerts intestinal anti-inflammatory effects in lymphocyte-driven colitis.

Host-microbe interactions: the difficult yet peaceful coexistence of the microbiota and the intestinal mucosa.

The immune system has evolved to live in a collaborative relationship with the microbiota, while still serving its seminal function to fight off invasive pathogenic bacteria. The mechanisms that rule the interactions between the intestinal microbiota and the intestinal immune system are the focus of intense research. Here, we describe how the innate immunity is, to a great extent, in charge of the control of the microbiota in the intestine and relies on non-specific receptors called pathogen-recognition receptors. While the microbiota has a well-defined effect on the host immune homoeostasis, it has become clear that the opposite is also true, i.e., the mucosal immune system has the capacity to shape the microbial population. The mechanisms that rule the reciprocal regulation between host immunity and commensal bacteria (including specific bacteria) are currently being elucidated and will be described here. A better knowledge of how the host and bacteria interact and how the intestinal microbiota and the immune system are co-regulated will provide the basis for a better understanding of intestinal and systemic immunopathologies and for the development of new therapeutic approaches.