Direct neurotization of free nipple grafts with cadaveric nerve grafts following mastectomy for gender affirming surgery.

BACKGROUND: Free nipple grafting makes sensory recovery challenging. Permanent decreased sensation to touch and temperature in skin-grafted skin is common. Direct neurotization of the nipple-areolar complex (NAC) graft has been described. However, quantitative data regarding degree of nipple reinnervation possible is unknown. This study aims to quantify and qualify sensation recovery following nerve coaptation to reinnervate the NAC. METHODS: Patients undergoing mastectomy for gender dysphoria from 2020 to 2022 were offered nerve allograft to restore nipple sensation. A lateral intercostal nerve was selected and coapted to allograft which was embedded beneath the nipple graft. Semmes Weinstein testing was used to assess nipple sensation. Assessments were made at visits <1 year and >1 year from surgery. Filaments used represented normal sensation, minor diminished sensation, diminished sensation, loss of protective sensation, and deep pressure sensation only. RESULTS: A total of 115 patients elected for direct neurotization. Semmes Weinstein testing was limited to 46 patients representing 46 encounters and 92 nipples in the <1 year group and 24 encounters and 48 nipples in the >1 year group. Of the 92 nipples in the <1 year group, 17 (18.5%) noted return of normal sensation and 37 (40.2%) noted minor diminished or diminished sensation, indicating nerve reinnervation. There were 38 (41%) nipples with loss of protective sensation or deep sensation only. There were 48 nipples included in the >1 year group. Of the 48 nipples, 4 (8.3%) noted normal sensation and 30 (62.5%) noted minor diminished or diminished sensation, indicating nerve reinnervation. For the remaining 14 nipples, 14 (29%) noted loss of protective sensation or deep sensation only. CONCLUSION: Sensory outcomes in NAC grafts used for reconstruction in patients undergoing double incision mastectomy remain poor. Sensation restoration beyond that expected from full thickness skin grafts can be achieved in the majority of patients with nerve allograft via direct neurotization.

Detection and identification of cis-regulatory elements using change-point and classification algorithms.

BACKGROUND: Transcriptional regulation is primarily mediated by the binding of factors to non-coding regions in DNA. Identification of these binding regions enhances understanding of tissue formation and potentially facilitates the development of gene therapies. However, successful identification of binding regions is made difficult by the lack of a universal biological code for their characterisation. RESULTS: We extend an alignment-based method, changept, and identify clusters of biological significance, through ontology and de novo motif analysis. Further, we apply a Bayesian method to estimate and combine binary classifiers on the clusters we identify to produce a better performing composite. CONCLUSIONS: The analysis we describe provides a computational method for identification of conserved binding sites in the human genome and facilitates an alternative interrogation of combinations of existing data sets with alignment data.

Identification of community structure-based brain states and transitions using functional MRI.

Brain function relies on a precisely coordinated and dynamic balance between the functional integration and segregation of distinct networks. Characterizing the way in which brain regions reconfigure their interactions to give rise to distinct but hidden brain states remains an open challenge. In this paper, we propose a Bayesian method for characterizing community structure-based latent brain states and showcase a novel strategy based on posterior predictive discrepancy using the latent block model to detect transitions between community structures in blood oxygen level-dependent (BOLD) time series. The set of estimated parameters in the model includes a latent label vector that assigns network nodes to communities, and also block model parameters that reflect the weighted connectivity within and between communities. Besides extensive in-silico model evaluation, we also provide empirical validation (and replication) using the Human Connectome Project (HCP) dataset of 100 healthy adults. Our results obtained through an analysis of task-fMRI data during working memory performance show appropriate lags between external task demands and change-points between brain states, with distinctive community patterns distinguishing fixation, low-demand and high-demand task conditions.

Superficial temporal artery perforator flaps for reconstruction of intraoral defects.

BACKGROUND: Intraoral defects after tumor resection are often reconstructed with free tissue transfer. However, in patients who are not good candidates for free tissue transfer, regional flaps based on the superficial temporal artery can be utilized. The authors present our technique to reconstruct intraoral defects with the superficial temporal artery perforator (STAP) flap and early outcomes. METHODS: Five patients underwent STAP flaps for defects including the hard palate, buccal sulcus, floor of mouth, and retromolar trigone between 2017 and 2019. The mean defect size was 5.6 × 3.4 cm2 (3 × 3 cm2 - 7 × 4 cm2 ). The mean age was 74 (57-88) and all patients had recurrent cancer. External Doppler, indocyanine green laser angiography, and FLIR thermal imaging were used intra-operatively to identify the best perforators and plan for flap design. RESULTS: The mean flap size was 7.6 × 3.5 cm2 (6 × 3 cm2 - 10 × 5 cm2 ). Four flaps were based off of the posterior branch of the STA, while the fifth was based off of the anterior branch. Two donor sites were closed primarily, and three required skin grafts. One patient experienced partial flap necrosis. There were no complete flap losses and no donor site complications. Average follow up was 14.6 months (9-20 months). All patients maintained preoperative level of speech, mastication, and oral continence. CONCLUSIONS: The STAP flap can be based on the anterior or posterior branch of the superficial temporal artery and is a useful regional flap for intraoral defects after tumor resection.

Barriers To Finding A Gender Affirming Surgeon.

BACKGROUND: Gender affirmation surgery is increasingly prevalent; however, finding a surgeon continues to be difficult. Additionally, the majority of transgender patients utilize the internet for information before elective surgery. Therefore, it is imperative to explore potential online barriers in finding a gender affirming surgeon. AIMS: The authors sought to use the Internet to search for gender affirming surgeons practicing in the USA, and therefore, reflect the process that patients potentially undergo. We highlight the barriers to information and care that we encountered. METHODS: We conducted a comprehensive review of public online transgender surgery directories for currently practicing surgeons that provide facial feminization, facial masculinization, breast augmentation, chest masculinization, vaginoplasty, metoidioplasty, and/or phalloplasty in the USA. Each surgeon's name, surgical specialty, the current practice's name, state, and zip code, and procedures provided were recorded. Chi-square analysis was used for comparisons of categorical variables. RESULTS: There are currently 660 gender affirmation surgeons in the USA, with most specializing in plastic surgery, followed by otolaryngology and urology. In total, 30.5% of surgeons practice in the West, 25.6% in the Northeast, 25.3% in the South, and 18.6% in the Midwest. The most common surgery provided was chest masculinization (70.2%), followed by facial feminization (42.7%) and chest feminization (42.6%). CONCLUSION: Plastic surgeons are most likely to perform gender affirmation surgery compared to other specialties. Geographic distribution of surgeons, does not, however, match the distribution of patients. Additionally, we encountered significant hardship in confirming that a surgeon performs the procedure listed in their profile on popular online gender affirmation surgeon directories. LEVEL OF EVIDENCE: V.

A Three-Step Technique for Optimal Nipple Position in Transgender Chest Masculinization.

BACKGROUND: The ideal position of the nipple-areola complex (NAC) in the transgender population can be a challenge to determine. OBJECTIVES: The authors sought to determine the best location and aesthetics of the female to male NAC. METHODS: Patients who underwent female to male mastectomy with free nipple grafting were included. NAC position is confirmed utilizing a vertical coordinate at the level of the 4th rib near the border of the pectoralis muscle and a horizontal coordinate determined by dividing each unilateral chest into vertical thirds from midline to anterior axillary line laterally. The NAC position is confirmed at the junction of the middle and lateral third. Symmetry is ensured bilaterally by creating a triangle and transposing it side to side; the base lies from sternal notch to inframammary fold in the midline and the apex is adjusted to the NAC. A 24-question survey utilizing a 5-point Likert scale was distributed postoperatively to assess the patient's thoughts about their chest, nipples, scar, and overall experience with the gender affirmation process. RESULTS: Thirty-one patients were included in this study. Eighteen patients responded to the postmastectomy survey, all of whom were highly satisfied with the aesthetic result postoperatively. All patients felt comfortable with their exposed chest. Nipple location was particularly highly received with 100% satisfaction rate (mean Likert score, 4.72). Nipple size and shape received a mean Likert score of 4.17 and 3.89, respectively. CONCLUSIONS: The triple confirmation technique is an easy, reproducible method to guide the surgeon in relocation of the NAC.

Female-to-Male Transgender Chest Contouring: A Systematic Review of Outcomes and Knowledge Gaps.

PURPOSE: The number of gender affirmation surgeries performed in the United States is increasing. Frequently, chest contouring is the first surgery for female-to-male transgender patients; it fosters assimilation into the new gender role with a desired sense of masculinity. Creating an aesthetic male chest requires adjustment of breast tissue volume, proper nipple-areolar complex placement, and abolishment of the inframammary fold. Although much has been published on various techniques and outcomes, there is no consensus on how to approach transmale top surgery. We have reviewed the most up-to-date literature and in so doing have uncovered significant knowledge gaps. METHODS: An electronic literature review was performed. PubMed search keywords included combinations of "female-to-male," "transgender surgery," "chest contour," and "nipple-areolar complex." Articles were included if the patients were transgender female to male. RESULTS: Our literature search yielded 67 unique articles, 22 of which met our inclusion criteria. A total of 2447 unique patients were analyzed. The articles discussed aspects of chest surgery in female-to-male transsexuals including mastectomy and nipple aesthetics. Relevant data trends were extracted and subsequently investigated. DISCUSSION: Female-to-male transgender patients often undergo chest contouring as their initial gender affirmation surgery. As the surgical treatment of gender dysphoria continues to grow, it is imperative for plastic surgeons to understand the surgical options and associated outcomes for transmasculine top surgery. Future research is needed to improve patient selection, surgical decision making, and patient-reported outcomes for different chest contouring techniques. In addition, there is a significant knowledge gap for the ideal nipple-areolar complex shape, size, and location.

Outcomes in Chest Wall Reconstruction Using Methyl Methacrylate Prostheses: A Review of the Literature and Case Series Utilizing a Novel Approach with Biologic Mesh.

BACKGROUND: Composite defects after chest wall resection may leave patients at risk with lack of protection of vital structures and potentially respiratory compromise secondary to flail segments. Reconstruction of the chest wall with various alloplastic materials is possible and well described. Here, the authors present a novel technique in chest wall reconstruction utilizing a methyl methacrylate (MMA) "sandwich" with biologic mesh. The authors also sought to determine outcomes in chest wall reconstruction with MMA to optimize surgical decision making and minimize patient morbidity. METHODS: A literature review was conducted using MEDLINE and the Cochrane Collaboration Library for primary research articles on chest wall reconstruction using MMA. Data related to surgical techniques and patient outcomes were extracted and analyzed. The authors also present their case series and outcomes utilizing a novel technique with biologic mesh. RESULTS: Seventy-four articles met inclusion criteria, which included a total of 562 patients. Reconstruction methods included three main variations of the MMA prosthesis and six institution-specific variations. Complications were reported in 13.7% of patients; the most common complications included infection (5.6%), respiratory failure (3.3%), and atelectasis (1.7%). Less commonly reported complications included prosthesis dislocation (1.2%), pneumonia (1.0%), and lung collapse (0.4%). Overall mortality due to respiratory causes was observed in nine patients (1.6%). In our case series, complications included respiratory failure and seroma was reported in one patient, with no complications at long-term follow-up. CONCLUSION: There are a variety of options available for rigid and nonrigid prosthetic repair of the chest wall. We present the first successful reported case series of reconstruction using biologic mesh as a component of the MMA sandwich prosthesis. MMA appears to be a safe and effective choice for rigid reconstruction when used alone or in conjunction with synthetic or biologic mesh.

Agent-based models of malaria transmission: a systematic review.

BACKGROUND: Much of the extensive research regarding transmission of malaria is underpinned by mathematical modelling. Compartmental models, which focus on interactions and transitions between population strata, have been a mainstay of such modelling for more than a century. However, modellers are increasingly adopting agent-based approaches, which model hosts, vectors and/or their interactions on an individual level. One reason for the increasing popularity of such models is their potential to provide enhanced realism by allowing system-level behaviours to emerge as a consequence of accumulated individual-level interactions, as occurs in real populations. METHODS: A systematic review of 90 articles published between 1998 and May 2018 was performed, characterizing agent-based models (ABMs) relevant to malaria transmission. The review provides an overview of approaches used to date, determines the advantages of these approaches, and proposes ideas for progressing the field. RESULTS: The rationale for ABM use over other modelling approaches centres around three points: the need to accurately represent increased stochasticity in low-transmission settings; the benefits of high-resolution spatial simulations; and heterogeneities in drug and vaccine efficacies due to individual patient characteristics. The success of these approaches provides avenues for further exploration of agent-based techniques for modelling malaria transmission. Potential extensions include varying elimination strategies across spatial landscapes, extending the size of spatial models, incorporating human movement dynamics, and developing increasingly comprehensive parameter estimation and optimization techniques. CONCLUSION: Collectively, the literature covers an extensive array of topics, including the full spectrum of transmission and intervention regimes. Bringing these elements together under a common framework may enhance knowledge of, and guide policies towards, malaria elimination. However, because of the diversity of available models, endorsing a standardized approach to ABM implementation may not be possible. Instead it is recommended that model frameworks be contextually appropriate and sufficiently described. One key recommendation is to develop enhanced parameter estimation and optimization techniques. Extensions of current techniques will provide the robust results required to enhance current elimination efforts.

Use of FLIR ONE Smartphone Thermography in Burn Wound Assessment.

OBJECTIVE: Forward-looking infrared (FLIR) thermography technology uses a handheld camera that measures skin infrared emissivity, captures photographs, and can be analyzed through specialized software. Forward-looking infrared images can be used to analyze and correlate burn wound temperature with burn depth, burn progression, and the number of days needed for healing. FLIR ONE is a miniature, smartphone-compatible thermal imaging camera that has been used to assess inflammation in diabetic foot ulcers, as well as locating perforators in flap surgery. However, FLIR ONE's reliability in burn wound assessment has not been evaluated. This case series investigates the accuracy of FLIR ONE in comparison with the widely used indocyanine green (ICG) angiography in assessing burn wounds. METHODS: Five acute third-degree burn wounds were assessed using ICG angiography and FLIR ONE imaging (infrared thermography) to determine burn extent before surgical intervention. Patients were taken to the operating room within 48 hours of presentation; FLIR ONE images were captured approximately 35 to 45 cm above the wound surface. Margins of unsalvageable tissue as determined by ICG and FLIR ONE were marked and compared. RESULTS: The area of unsalvageable tissue as determined by FLIR ONE closely corresponded to the area determined by ICG. FLIR ONE overestimated unsalvageable tissue margins by approximately 1 to 2 cm. The area estimated by ICG consistently overlapped with more than 90% of the area estimated by FLIR ONE. CONCLUSIONS: There is a strong correlation between FLIR ONE and ICG when assessing salvageable tissue in third-degree burn wounds. FLIR ONE maximizes the convenience and cost-effectiveness of infrared thermography technology but may overestimate unsalvageable tissue area. FLIR ONE is promising as an adjunct to current imaging modalities such as ICG but requires further study for comparison.

Peripheral Pruning: A Safe Approach to Thinning Extra-Large Anterolateral Thigh Flaps.

BACKGROUND: Thinning of anterolateral thigh (ALT) flaps has been described to achieve optimal contouring. Previous studies caution against thinning large flaps owing to the risk of vascular compromise leading to partial or total flap necrosis. This study aims to demonstrate a reliably safe method for thinning extra-large (>240 cm) flaps. METHODS: A retrospective review of 53 consecutive ALT flaps performed at a single institution was completed. Of these flaps, 18 (34%) were thinned primarily by sharp excision of sub-Scarpa's fat along the periphery of the flap using loupe magnification. A central cuff of fat is left to surround and protect the perforator. RESULTS: There were 53 total flaps in our series. Eighteen of the flaps were thinned by peripheral pruning. Eleven (61%) of the flaps reconstructed defects of the lower extremity, whereas 4 (22%) reconstructed upper extremity defects and 3 (17%) reconstructed scalp defects (Table 1). The mean size of the thinned flap group was 35% larger than the nonthinned group (n = 18, 261 cm ± 109 cm vs n = 35, 192 cm ± 146 cm). Ten thinned flaps (55%) were extra large, with flap areas over 240 cm. The average amount of excised fat weighed 41 g ± 18 g. The average body mass index in the thinned flap group was 28.8 kg/m, which is classified as overweight. The average body mass index in the nonthinned flap group was 24.6 kg/m, which is classified as normal weight (Table 2). There were no cases of partial flap necrosis in the thinned flap group. A single case of total flap loss occurred in the thinned flap group secondary to hematoma formation during administration of therapeutic heparin for a mechanical heart valve. There were no other complications in the thinned flap group. CONCLUSIONS: This is the first study to demonstrate a reliable technique for primary thinning of extra-large ALT flaps in the Western population. No complications related to thinning were observed. Peripheral pruning of sub-Scarpa's fat is a safe and reliable method of thinning extra-large ALT flaps without increasing the risk of flap necrosis.

Genome-wide identification of conserved intronic non-coding sequences using a Bayesian segmentation approach.

BACKGROUND: Computational identification of non-coding RNAs (ncRNAs) is a challenging problem. We describe a genome-wide analysis using Bayesian segmentation to identify intronic elements highly conserved between three evolutionarily distant vertebrate species: human, mouse and zebrafish. We investigate the extent to which these elements include ncRNAs (or conserved domains of ncRNAs) and regulatory sequences. RESULTS: We identified 655 deeply conserved intronic sequences in a genome-wide analysis. We also performed a pathway-focussed analysis on genes involved in muscle development, detecting 27 intronic elements, of which 22 were not detected in the genome-wide analysis. At least 87% of the genome-wide and 70% of the pathway-focussed elements have existing annotations indicative of conserved RNA secondary structure. The expression of 26 of the pathway-focused elements was examined using RT-PCR, providing confirmation that they include expressed ncRNAs. Consistent with previous studies, these elements are significantly over-represented in the introns of transcription factors. CONCLUSIONS: This study demonstrates a novel, highly effective, Bayesian approach to identifying conserved non-coding sequences. Our results complement previous findings that these sequences are enriched in transcription factors. However, in contrast to previous studies which suggest the majority of conserved sequences are regulatory factor binding sites, the majority of conserved sequences identified using our approach contain evidence of conserved RNA secondary structures, and our laboratory results suggest most are expressed. Functional roles at DNA and RNA levels are not mutually exclusive, and many of our elements possess evidence of both. Moreover, ncRNAs play roles in transcriptional and post-transcriptional regulation, and this may contribute to the over-representation of these elements in introns of transcription factors. We attribute the higher sensitivity of the pathway-focussed analysis compared to the genome-wide analysis to improved alignment quality, suggesting that enhanced genomic alignments may reveal many more conserved intronic sequences.

Agent-based Bayesian approach to monitoring the progress of invasive species eradication programs.

Eradication of an invasive species can provide significant environmental, economic, and social benefits, but eradication programs often fail. Constant and careful monitoring improves the chance of success, but an invasion may seem to be in decline even when it is expanding in abundance or spatial extent. Determining whether an invasion is in decline is a challenging inference problem for two reasons. First, it is typically infeasible to regularly survey the entire infested region owing to high cost. Second, surveillance methods are imperfect and fail to detect some individuals. These two factors also make it difficult to determine why an eradication program is failing. Agent-based methods enable inferences to be made about the locations of undiscovered individuals over time to identify trends in invader abundance and spatial extent. We develop an agent-based Bayesian method and apply it to Australia's largest eradication program: the campaign to eradicate the red imported fire ant (Solenopsis invicta) from Brisbane. The invasion was deemed to be almost eradicated in 2004 but our analyses indicate that its geographic range continued to expand despite a sharp decline in number of nests. We also show that eradication would probably have been achieved with a relatively small increase in the area searched and treated. Our results demonstrate the importance of inferring temporal and spatial trends in ongoing invasions. The method can handle incomplete observations and takes into account the effects of human intervention. It has the potential to transform eradication practices.

Sampling phylogenetic tree space with the generalized Gibbs sampler.

A recent article published in Cladistics is critical of a number of heuristic methods for phylogenetic inference based on parsimony scores. One of my papers is among those criticized, and I would appreciate the opportunity to make a public response. The specific criticism is that I have re-invented an algorithm for economizing parsimony calculations on trees that differ by a subtree pruning and regrafting (SPR) rearrangement. This criticism is justified, and I apologize for incorrectly claiming originality for my presentation of this algorithm. However, I would like to clarify the intent of my paper, if I can do so without detracting from the sincerity of my apology. My paper is not about that algorithm, nor even primarily about parsimony. Rather, it is about a novel strategy for Markov chain Monte Carlo (MCMC) sampling in a state space consisting of trees. The sampler involves drawing from conditional distributions over sets of trees: a Gibbs-like strategy that had not previously been used to sample tree-space. I would like to see this technique incorporated into MCMC samplers for phylogenetics, as it may have advantages over commonly used Metropolis-like strategies. I have recently used it to sample phylogenies of a biological invasion, and I am finding many applications for it in agent-based Bayesian ecological modelling. It is thus my contention that my 2005 paper retains substantial value.

Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression.

OBJECTIVE: To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure. BACKGROUND: Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol ("Pittsburgh protocol"). METHODS: Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring. RESULTS: All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates. CONCLUSIONS: Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.

A Bayesian method for comparing and combining binary classifiers in the absence of a gold standard.

BACKGROUND: Many problems in bioinformatics involve classification based on features such as sequence, structure or morphology. Given multiple classifiers, two crucial questions arise: how does their performance compare, and how can they best be combined to produce a better classifier? A classifier can be evaluated in terms of sensitivity and specificity using benchmark, or gold standard, data, that is, data for which the true classification is known. However, a gold standard is not always available. Here we demonstrate that a Bayesian model for comparing medical diagnostics without a gold standard can be successfully applied in the bioinformatics domain, to genomic scale data sets. We present a new implementation, which unlike previous implementations is applicable to any number of classifiers. We apply this model, for the first time, to the problem of finding the globally optimal logical combination of classifiers. RESULTS: We compared three classifiers of protein subcellular localisation, and evaluated our estimates of sensitivity and specificity against estimates obtained using a gold standard. The method overestimated sensitivity and specificity with only a small discrepancy, and correctly ranked the classifiers. Diagnostic tests for swine flu were then compared on a small data set. Lastly, classifiers for a genome-wide association study of macular degeneration with 541094 SNPs were analysed. In all cases, run times were feasible, and results precise. The optimal logical combination of classifiers was also determined for all three data sets. Code and data are available from http://bioinformatics.monash.edu.au/downloads/. CONCLUSIONS: The examples demonstrate the methods are suitable for both small and large data sets, applicable to the wide range of bioinformatics classification problems, and robust to dependence between classifiers. In all three test cases, the globally optimal logical combination of the classifiers was found to be their union, according to three out of four ranking criteria. We propose as a general rule of thumb that the union of classifiers will be close to optimal.

Model selection in Bayesian segmentation of multiple DNA alignments.

MOTIVATION: The analysis of multiple sequence alignments is allowing researchers to glean valuable insights into evolution, as well as identify genomic regions that may be functional, or discover novel classes of functional elements. Understanding the distribution of conservation levels that constitutes the evolutionary landscape is crucial to distinguishing functional regions from non-functional. Recent evidence suggests that a binary classification of evolutionary rates is inappropriate for this purpose and finds only highly conserved functional elements. Given that the distribution of evolutionary rates is multi-modal, determining the number of modes is of paramount concern. Through simulation, we evaluate the performance of a number of information criterion approaches derived from MCMC simulations in determining the dimension of a model. RESULTS: We utilize a deviance information criterion (DIC) approximation that is more robust than the approximations from other information criteria, and show our information criteria approximations do not produce superfluous modes when estimating conservation distributions under a variety of circumstances. We analyse the distribution of conservation for a multiple alignment comprising four primate species and mouse, and repeat this on two additional multiple alignments of similar species. We find evidence of six distinct classes of evolutionary rates that appear to be robust to the species used. AVAILABILITY: Source code and data are available at http://dl.dropbox.com/u/477240/changept.zip.

Multiple evolutionary rate classes in animal genome evolution.

The proportion of functional sequence in the human genome is currently a subject of debate. The most widely accepted figure is that approximately 5% is under purifying selection. In Drosophila, estimates are an order of magnitude higher, though this corresponds to a similar quantity of sequence. These estimates depend on the difference between the distribution of genomewide evolutionary rates and that observed in a subset of sequences presumed to be neutrally evolving. Motivated by the widening gap between these estimates and experimental evidence of genome function, especially in mammals, we developed a sensitive technique for evaluating such distributions and found that they are much more complex than previously apparent. We found strong evidence for at least nine well-resolved evolutionary rate classes in an alignment of four Drosophila species and at least seven classes in an alignment of four mammals, including human. We also identified at least three rate classes in human ancestral repeats. By positing that the largest of these ancestral repeat classes is neutrally evolving, we estimate that the proportion of nonneutrally evolving sequence is 30% of human ancestral repeats and 45% of the aligned portion of the genome. However, we also question whether any of the classes represent neutrally evolving sequences and argue that a plausible alternative is that they reflect variable structure-function constraints operating throughout the genomes of complex organisms.

Pathological Evaluation of Breast Specimens in Transgender Chest Masculinization: Incidental Findings and Effect of Prior Chest Binding and Androgen Therapy in 74 Consecutive Patients.

Background: The rate of masculinizing chest surgery for gender affirmation continues to increase. With a paucity of literature on pathological evaluation of breast specimens in this patient population, there is a need for these data and for protocols on the handling of these specimens. Methods: A retrospective chart review was performed between 2015 and 2020 on all patients who underwent chest masculinization surgery for gender dysphoria by the senior author (J.D.K.). Inclusion criteria were any patient with sex assigned female at birth who underwent removal of breast and/or nipple areolar complex tissue for gender affirmation. Patient demographics were recorded. Bilateral breast tissue was sent for routine pathology in all cases and findings were recorded. A p-value of <0.05 was considered significant. Results: Seventy-four consecutive patients and 148 breast specimen reports were identified from a database and included in the study. The mean age was 26 years (15-49). Thirty-nine patients had a known history of chest wall binding and 60 patients had undergone preoperative androgen therapy. There was no invasive or in situ carcinoma found in any breast tissue specimens. Thirty-four patients had a benign lesion in one or both breast specimens. Atypical lobular hyperplasia was found in one patient's specimen. A history of chest wall binding was not correlated with any benign lesions (p=0.79) or stromal fibrosis (p=0.94). A history of testosterone use was not correlated with any benign lesions (p=0.35) or stromal fibrosis (p=0.20). Conclusions: The prevalence (1.4%) of significant breast pathology and of benign findings (46%) in our study closely correlates with the rates in the literature. We found no correlation between significant breast pathology or benign lesions and a history of chest wall binding or preoperative androgen therapy. We recommend all breast specimens removed during chest masculinization surgery be sent for pathological evaluation.