SUMMARY Vpu proteins of pandemic HIV-1 M strains degrade the viral receptor CD4 and antagonize human tetherin to promote viral release and replication. We find that Vpus from SIVgsn, SIVmus and SIVmon infecting Cercopithecus primate species also degrade CD4 and antagonize tetherin. In contrast, SIVcpz, the immediate precursor of HIV-1, whose Vpu shares a common ancestry with SIVgsn/mus/mon Vpu, uses Nef rather than Vpu to counteract chimpanzee tetherin. Human tetherin, however, is resistant to Nef and thus poses a significant barrier to zoonotic transmission of SIVcpz to humans. Remarkably, Vpu from non-pandemic HIV-1 O strains are poor tetherin antagonists while those from the rare group N viruses do not degrade CD4. Thus, only HIV-1 M evolved a fully functional Vpu following the three independent cross-species transmissions that resulted in HIV-1 groups M, N, and O. This may explain why group M viruses are almost entirely responsible for the gobal HIV/AIDS pandemic.

The tetherin/BST2/CD317 protein blocks the release of HIV-1 and other enveloped viruses by inducing tethering of nascent particles to infected cell surfaces. The HIV-1 Vpu protein antagonizes the antiviral activity of human but not monkey tetherins and many simian immunodeficiency viruses (SIVs) do not encode Vpu. Here, we show that the apparently ‘missing’ anti-tetherin activity in SIVs has been acquired by several SIV Nef proteins. Specifically, SIVMAC/SIVSMM, SIVAGM and SIVBLU Nef proteins can suppress tetherin activity. Notably, tetherin antagonism by SIV Nef proteins is species-specific, is genetically separable from other Nef activities and is most evident with simian rather than human tetherin proteins. Accordingly, a critical determinant of sensitivity to SIVMAC Nef in the tetherin cytoplasmic tail is variable in nonhuman primate tetherins and deleted in human tetherin, likely due to selective pressures imposed by viral antagonists, perhaps including Nef proteins.

Lentiviral Nef proteins have multiple functions and are important for viral pathogenesis. Recently, Nef proteins from many simian immunodefiency viruses were shown to antagonize a cellular antiviral protein, named Tetherin, that blocks release of viral particles from the cell surface. However, the mechanism by which Nef antagonizes Tetherin is unknown. Here, using related Nef proteins that differ in their ability to antagonize Tetherin, we identify three amino-acids in the C-terminal domain of Nef that are critical specifically for its ability to antagonize Tetherin. Additionally, divergent Nef proteins bind to the AP-2 clathrin adaptor complex, and we show that residues important for this interaction are required for Tetherin antagonism, downregulation of Tetherin from the cell surface and removal of Tetherin from sites of particle assembly. Accordingly, depletion of AP-2 using RNA interference impairs the ability of Nef to antagonize Tetherin, demonstrating that AP-2 recruitment is required for Nef proteins to counteract this antiviral protein.

Objective: To perform the first systematic review of all available genderaffirming surgery (GAS) publications across all procedures to assess both outcomes reported in the literature and the methods used for outcome assessment. Summary of Background Data: Rapidly increasing clinical volumes of gender-affirming surgeries have stimulated a growing need for high-quality clinical research. Although some procedures have been performed for decades, each individual procedure has limited data, necessitating synthesis of the entire literature to understand current knowledge and guide future research. Methods: A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify all outcomes measures in GAS cohorts, including PCOs, complications, and functional outcomes. Outcome data were pooled to assess currently reported complication, satisfaction, and other outcome rates. Results: Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications. Of non-genitoplasty titles, 35 were mastectomy, 6 mammoplasty, 21 facial feminization, and 31 voice/cartilage. Although 59.1% of non-genitoplasty papers addressed PCOs in some form, only 4.3% used instruments partially-validated in transgender patients. Overall, data were reported heterogeneously and were biased towards high-volume centers. Conclusions: This study represents the most comprehensive review of GAS literature. By aggregating all previously utilized measurement instruments, this study offers a foundation for discussions about current methodologic limitations and what dimensions must be included in assessing surgical success. We have assembled a comprehensive list of outcome instruments; this offers an ideal starting basis for emerging discussions between patients and providers about deficiencies which new, better instruments and metrics must address. The lack of consistent use of the same outcome measures and validated GAS-specific instruments represent the 2 primary barriers to highquality research where improvement efforts should be focused.

This report is an update and expansion of the 2006 Key Specialty Data: A Chart Book. An important addition to the report is a set of tables containing the data that are presented visually in the figures. This report is a companion to the 2007 State Physician Workforce Data Book, which presents data at the state level. Physician Specialty Data will be updated and published biennially.Effective decision making, whether at the national, regional, local or individual level, requires accurate information. This report is intended to provide the medical education community, specialty associations, health researchers, policy makers, and the public with data to better understand physician workforce trends and dynamics to inform their decision making.

Objective: To perform the first systematic review of all available GAS publications across all procedures to assess outcomes reported in the literature and the methods used for outcome assessment. Summary of Background Data: Assessment of GAS results is complex and multidimensional, involving not only complication rates but also anatomic (eg, vaginal depth), functional (eg, urinary), and psychosocial outcomes. A fully comprehensive aggregation of all prior research would offer an essential cornerstone for continued progress. Methods: A systematic review was performed after PRISMA guidelines to identify all outcomes measures in GAS cohorts, including patient-centered outcomes, complications, and functional outcomes. Data were aggregated to assess pooled rates of complications, satisfaction, and other outcomes. Results: Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications, including 171 vaginoplasty, 82 phalloplasty, 16 metoidioplasty, 23 oophorectomy/vaginectomy, and 21 with multiple procedures. Although 68.7% of genitoplasty papers addressed patient-centered outcomes, only 1.0% used metrics validated in the transgender population. Forty-three different outcome instruments were used. No instrument was used in more than 15% of published series and 38 were used in only 1 or 2 publications. Conclusions: Our review found high patient satisfaction for genital procedures but little concordance between study methods, with almost 90% of patient-focused outcome metrics appearing only once or twice. Standardization of outcome instruments and measurement methods through patientinclusive, multidisciplinary consensus efforts is the essential next step for quality improvement. As GAS continues to mature, building on current foundations with the goal of improving both surgical and patient-reported outcomes is essential.

Background: A growing number of transgender women present to plastic surgeons seeking breast augmentation. Despite some advocating their technical similarity, the authors have found substantially different planning and techniques are needed to obtain aesthetic results in transgender patients versus cosmetic breast augmentation. The authors sought to develop an approach for operative planning and technique to elucidate these differences and obtain consistent results. Methods: All patients who underwent breast augmentation at the Johns Hopkins Center for Transgender Health were included in this study. Anthropometric assessments were obtained and comparative statistics between operative and nonoperative cohorts were calculated. Outcomes were analyzed and a patient-reported survey was performed to evaluate patient satisfaction. Results: Fifty-nine consecutive transfemale patients presented for evaluation. Anthropometric measurements included base width (median, 15.0 ± 2.1 cm), notch–to-nipple distance (median, 22.0 cm), nipple-to-midline distance (median, 12.0 cm), areolar diameter (median, 3.5 ± 1.5 cm), and upper pole pinch (mean, 1.8 ± 1.1 cm). Thirty-six patients underwent augmentation mammaplasty. Postoperative complications (8.3 percent) included a minor hematoma and grade III capsular contracture in two patients. Patients were asked to complete a brief outcomes survey and reported an improvement in psychosocial well-being and high satisfaction rate (100 percent) with the overall cosmetic result. Conclusions: Transgender female patients represent a unique patient population requiring special consideration of anatomical differences in key planning decisions. The authors delineate the first systematic algorithm that addresses these differences, emphasizing maneuvers such as routine inframammary fold lowering. This can allow experienced augmentation surgeons to obtain excellent aesthetic and patient-reported outcomes in this population. As with cosmetic breast augmentation, patient satisfaction rates are high. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Reconstruction for total penile defects presents unique challenges due to its anatomical and functional complexity. Standard methods suffer from high complication rates and poor functional outcomes. In this work we have developed the first protocol for decellularizing whole-organ human penile specimens for total penile tissue engineering. The use of a hybrid decellularization scheme combining micro-arterial perfusion, urethral catheter perfusion and external diffusion enabled the creation of a full-size scaffold with removal of immunogenic components. Decellularization was complete as assessed by H&E and immunohistochemistry, while quantification of residual DNA showed acceptably low levels (<50 ng/mg). An intact ECM was maintained with histologic architecture preservation on H&E and SEM as well as preservation of key proteins such as collagen-1, laminin and fibronectin and retention of growth factors VEGF (45%), EGF (57%) and TGF-beta1 (42%) on ELISA. Post-decellularization patency of the cavernosal arteries for future use in reseeding was demonstrated. Scaffold biocompatibility was evaluated using human adipose-derived stromal vascular cells. Live/Dead stains showed the scaffold successfully supported cell survival and expansion. Influence on cellular behavior was seen with significantly higher expression of VWF, COL1, SM22 and Desmin as compared to cell monolayer. Preliminary evidence for regional tropism was also seen, with formation of microtubules and increased endothelial marker expression in the cavernosa. This report of successful decellularization of the complete human phallus is an initial step towards developing a tissue engineered human penile scaffold with potential for more successfully restoring cosmetic, urinary and sexual function after complete penile loss.