Triclosan administration to humanized UDP-glucuronosyltransferase 1 neonatal mice induces UGT1A1 through a dependence on PPARα and ATF4.

Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the impact of lactational TCS on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) neonatal mice. In hUGT1 mice, expression of the hepatic UGT1A1 gene is developmentally delayed resulting in elevated total serum bilirubin (TSB) levels. We found that newborn hUGT1 mice breastfed or orally treated with TCS presented lower TSB levels along with induction of hepatic UGT1A1. Lactational and oral treatment by gavage with TCS leads to the activation of hepatic nuclear receptors CAR, PPARα, and stress sensor, ATF4. When CAR-deficient hUGT1 mice (hUGT1/Car-/-) were treated with TCS, TSB levels were reduced with a robust induction of hepatic UGT1A1, leaving us to conclude that CAR is not tied to UGT1A1 induction. Alternatively, when PPARα-deficient hUGT1 mice (hUGT1/Pparα-/-) were treated with TCS, hepatic UGT1A1 was not induced. Additionally, we had previously demonstrated that TCS is a potent inducer of ATF4, a transcriptional factor linked to the integrated stress response. When ATF4 was deleted in liver of hUGT1 mice (hUGT1/Atf4ΔHep), and these mice treated with TCS, we observed superinduction of hepatic UGT1A1. Oxidative stress genes in livers of hUGT1/Atf4ΔHep treated with TCS were increased, suggesting that ATF4 protects liver from excessive oxidative stress. The increase oxidative stress may be associated with superinduction of UGT1A1. The expression of ATF4 in neonatal hUGT1 hepatic tissue may play a role in the developmental repression of UGT1A1.

Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

The Effect of COVID-19 on Oncology Care for Adolescents and Young Adults in Latin America.

Children with cancer in low- and middle-income countries were disproportionately impacted by the COVID-19 pandemic, but little is known about how adolescents and young adults (AYAs) with cancer were affected. Sixty-seven physicians and nonphysician providers were interviewed about their experiences caring for AYAs with cancer in Latin America. Quotes related to the COVID-19 pandemic were identified and grouped into themes. Barriers from the COVID-19 pandemic included limited space, restrictions on travel, reduced funding, limited staff, limited services, and changes to treatment. However, improvements to care that arose from the COVID-19 pandemic included better access to distance learning and telemedicine.

Improving glycemic control in diabetes through virtual interdisciplinary rounds.

OBJECTIVE: A team-based disease management approach that considers comorbid conditions, social drivers of health, and clinical guidelines improves diabetes care but can be costly and complex. Developing innovative models of care is crucial to improving diabetes outcomes. The objective of this analysis was to evaluate the efficacy of virtual interdisciplinary diabetes rounds in improving glycemic control. STUDY DESIGN: Retrospective cohort study using observational data from July 2018 to December 2021. METHODS: This study employed difference-in-differences analysis to compare change in hemoglobin A1c (HbA1c) in a group of patients whose providers received advice as part of virtual interdisciplinary rounds and a group of patients whose providers did not receive rounds advice. Patients with diabetes were identified for rounding (1) based on attribution to an accountable care organization along with an upcoming primary care appointment and an HbA1c between 8% and 9% or (2) via provider referral. RESULTS: The rounded group consisted of 481 patients and the comparison group included 1806 patients. There was a 0.3-point reduction in HbA1c (95% CI, 0.1-0.4) associated with rounds overall. In a subanalysis comparing provider adoption of recommendations among those rounded, provider adoption was associated with an HbA1c reduction of 0.5 points (95% CI, 0.1-0.9) at 6 months post rounds, although there was no significant difference in the full year post rounds. CONCLUSIONS: Interdisciplinary rounds can be an effective approach to proactively provide diabetes-focused recommendations. This modality allows for efficient, low-cost, and timely access to an endocrinologist and team to support primary care providers in diabetes management.

Receipt of Guideline-Concordant Care Is Associated With Improved Survival in Patients With Osteosarcoma in California: A Population-Based Analysis.

PURPOSE: To examine the relationship between guideline-concordant care (GCC) on the basis of national clinical practice guidelines and survival in children (0-14 years), adolescents and young adults (AYAs, 15-39 years), and adults (40 years and older) with osteosarcoma, and to identify sociodemographic and clinical factors associated with receipt of GCC and survival. METHODS: We used data from the California Cancer Registry (CCR) on patients diagnosed with osteosarcoma during 2004-2019, with detailed treatment information extracted from the CCR text fields, including chemotherapy regimens. Multivariable logistic and Cox proportional hazard regression were used for statistical analyses. RESULTS: Of 1,716 patients, only 47% received GCC, with variation by age at diagnosis: 67% of children, 43% of AYAs, and 30% of adults. In multivariable models, patients who received part or all care (v none) at specialized cancer centers were more likely to receive GCC. AYAs and adults were less likely to receive GCC than children (odds ratio [OR], 0.38 [95% CI, 0.30 to 0.50] and OR, 0.40 [95% CI, 0.28 to 0.56], respectively). In a model excluding adults, patients treated by pediatric (v medical) oncologists were more likely to receive GCC (OR, 3.44 [95% CI, 2.40 to 4.94]). Patients with metastatic osteosarcoma at diagnosis who did not receive GCC had a greater hazard of death (hazard ratio [HR], 2.02 [95% CI, 1.55 to 2.63]) but no statistical differences were found in those diagnosed at earlier stages (HR, 1.15 [95% CI, 0.92 to 1.43]). CONCLUSION: GCC was associated with improved survival in patients with metastatic osteosarcoma in California. However, we found disparities in the delivery of GCC, highlighting the need for target interventions to improve delivery of GCC in this patient population.

Comparison of S100A8 and PRAME as biomarkers for distinguishing melanoma from melanocytic naevus: a case-control analysis.

BACKGROUND: S100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME. OBJECTIVES: To compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case-control study. METHODS: A previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0-4%; 2 = 5-25%; 3 = 26-50%; 4 = 51-75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1-50%; 3 = > 50%). A positive test was defined as > 50% staining. RESULTS: The area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6-52.8%] and 98.2% (95% CI 93.6-99.8%) for S100A8, and 79.8% (95% CI 70.5-87.2%) and 87.3% (95% CI 79.6-92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7-49.7%) and specificity of 99.1% (95% CI 95.0-100.0%). CONCLUSIONS: S100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma.

Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial.

INTRODUCTION: Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs). METHODS: Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint. CONCLUSION: PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

Large Ascending Aortic Pseudoaneurysm with Focal Dissection after Coronary Artery Bypass Surgery.

Background There are many known complications that occur after surgical revascularization for patients with significant left main coronary artery disease. Case Description This case report highlights the preoperative workup, surgical approach, and postoperative management of a patient who presents with an aortic pseudoaneurysm and dissection 2 years after the index CABG. Conclusion The development of an aortic pseudoaneurysm in combination with an ascending aortic dissection after prior coronary artery bypass grafting (CABG) is a rare compilation of complications that has scarcely been reported in the literature.

Effects of Early Life Oral Arsenic Exposure on Intestinal Tract Development and Lipid Homeostasis in Neonatal Mice: Implications for NAFLD Development.

BACKGROUND: Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults. OBJECTIVES: The present study examined how oral iAs administration to neonatal mice impacts the intestinal tract, which acts as an early mediator for NAFLD. METHODS: Neonatal mice were treated with a single dose of iAs via oral gavage. Effects on the small intestine were determined by histological examination, RNA sequencing, and biochemical analysis. Serum lipid profiling was analyzed by fast protein liquid chromatography (FPLC), and hepatosteatosis was characterized histologically and biochemically. Liver X receptor-alpha (LXRα) knockout (Lxrα-/-) mice and liver-specific activating transcription factor 4 (ATF4)-deficient (Atf4ΔHep) mice were used to define their roles in iAs-induced effects during the neonatal stage. RESULTS: Neonatal mice exposed to iAs via oral gavage exhibited accumulation of dietary fat in enterocytes, with higher levels of enterocyte triglycerides and free fatty acids. These mice also showed accelerated enterocyte maturation and a longer small intestine. This was accompanied by higher levels of liver-derived very low-density lipoprotein and low-density lipoprotein triglycerides, and a lower level of high-density lipoprotein cholesterol in the serum. Mice exposed during the neonatal period to oral iAs also developed hepatosteatosis. Compared with the control group, iAs-induced fat accumulation in enterocytes became more significant in neonatal Lxrα-/- mice, accompanied by accelerated intestinal growth, hypertriglyceridemia, and hepatosteatosis. In contrast, regardless of enterocyte fat accumulation, hepatosteatosis was largely reduced in iAs-treated neonatal Atf4ΔHep mice. CONCLUSION: Exposure to iAs in neonatal mice resulted in excessive accumulation of fat in enterocytes, disrupting lipid homeostasis in the serum and liver, revealing the importance of the gut-liver axis and endoplasmic reticulum stress in mediating iAs-induced NAFLD at an early age. https://doi.org/10.1289/EHP12381.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Main outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Veterinary telerehabilitation was as satisfactory as in-person consultations.

Objective: To evaluate client satisfaction with telerehabilitation consultations compared to in-person consultations for veterinary rehabilitation referrals. Animals: We surveyed the owners of 32 client-owned dogs. Procedure: Dog owners were scheduled for telemedicine (telerehabilitation group) or in-person (control group) based on a combination of owner requests and medical recommendations. Medical records were obtained before evaluation. Owners were sent an electronic questionnaire following in-person or telerehabilitation consultations. A total of 32 surveys were received (16 for each group). The response rate was 55% (32/58 surveys sent). Mann-Whitney U tests were used to compare ordinal characteristics between satisfied and unsatisfied clients. Descriptive statistics for the client population, including ranges and medians, were calculated for owner travel distance and patient signalment. Results: Satisfaction regarding scheduling appointments was higher in the telerehabilitation group compared to the group receiving in-person consultations (P < 0.001). For all other aspects of client satisfaction, there were no significant differences between groups. Conclusion: This study demonstrated high client satisfaction with using telemedicine for canine rehabilitation consultations that was comparable to that for in-person consultations. Clinical relevance: Telerehabilitation is a viable option that can be easily implemented by rehabilitation practitioners for assessment, progression, and monitoring of canine patients. Further studies are indicated to evaluate the efficacy of telerehabilitation.

La téléréadaptation vétérinaire a été aussi satisfaisante que les consultations en personne. Objectif: Évaluer la satisfaction des clients à l'égard des consultations de téléréadaptation par rapport aux consultations en personne pour les patients aiguillés en réadaptation vétérinaire. Animaux: Enquêtes auprès des propriétaires de 32 chiens appartenant à des clients. Procédure: Les propriétaires étaient programmés en télémédecine (groupe de téléréadaptation) ou en personne (groupe témoin) en fonction d'une combinaison de demandes de propriétaires ou de recommandations médicales. Les dossiers médicaux ont été obtenus avant l'évaluation. Les propriétaires ont reçu un questionnaire électronique à la suite de consultations en personne ou par téléréadaptation. Au total, 32 sondages ont été reçus (16 pour chaque groupe). Le taux de réponse a été de 55 % (32 sondages sur 58). Les tests Mann-Whitney U ont été utilisés pour comparer les caractéristiques ordinales entre les patients satisfaits et ceux qui ne l'étaient pas. Des statistiques descriptives pour la population de clients, y compris la portée et les médianes, ont été calculées pour la distance de déplacement du propriétaire et la signalisation du patient. Résultats: La satisfaction à l'égard des rendez-vous était plus élevée dans le groupe de la téléréadaptation comparativement aux consultations en personne (P < 0,001). Pour tous les autres aspects de la satisfaction des clients, il n'y avait pas de différences significatives entre les groupes. Conclusion: Cette étude a démontré une satisfaction élevée des clients qui utilisent la télémédecine pour des consultations de réadaptation canine, comparable aux consultations en personne. Pertinence clinique: La téléréadaptation est une option viable qui peut être facilement mise en œuvre par les praticiens de la réadaptation pour l'évaluation, la progression et le suivi des patients canins. D'autres études sont indiquées pour évaluer l'efficacité de la téléréadaptation.(Traduit par les auteurs).

RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.

Somatic and germline gain-of-function point mutations in RAF, one of the first oncogenes to be discovered in humans, delineate a group of tumor-prone syndromes known as the RASopathies. In this study, we document the first human phenotype resulting from the germline loss-of-function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met variant segregating with a neonatal lethal syndrome with cutaneous, craniofacial, cardiac, and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: (i) ensure RAF1's stability and phosphorylation, (ii) maintain its kinase activity toward substrates of the MAPK pathway, and (iii) protect from stress-induced apoptosis mediated by ASK1. In Xenopus embryos, mutant RAF1T543M failed to phenocopy the effects of normal and overactive FGF/MAPK signaling, confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel lethal syndrome with progeroid features, highlighting the importance of RTK signaling for human development and homeostasis.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Oral arsenic administration to humanizedUDP-glucuronosyltransferase1 neonatal mice induces UGT1A1 through a dependence on Nrf2 and PXR.

Inorganic arsenic (iAs) is an environmental toxicant that can lead to severe health consequences, which can be exacerbated if exposure occurs early in development. Here, we evaluated the impact of oral iAs treatment on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) mice. We found that oral administration of iAs to neonatal hUGT1 mice that display severe neonatal hyperbilirubinemia leads to induction of intestinal UGT1A1 and a reduction in total serum bilirubin values. Oral iAs administration accelerates neonatal intestinal maturation, an event that is directly associated with UGT1A1 induction. As a reactive oxygen species producer, oral iAs treatment activated the Keap-Nrf2 pathway in the intestinal tract and liver. When Nrf2-deficient hUGT1 mice (hUGT1/Nrf2-/-) were treated with iAs, it was shown that activated Nrf2 contributed significantly toward intestinal maturation and UGT1A1 induction. However, hepatic UGT1A1 was not induced upon iAs exposure. We previously demonstrated that the nuclear receptor PXR represses liver UGT1A1 in neonatal hUGT1 mice. When PXR was deleted in hUGT1 mice (hUGT1/Pxr-/-), derepression of UGT1A1 was evident in both liver and intestinal tissue in neonates. Furthermore, when neonatal hUGT1/Pxr-/- mice were treated with iAs, UGT1A1 was superinduced in both tissues, confirming PXR release derepressed key regulatory elements on the gene that could be activated by iAs exposure. With iAs capable of generating reactive oxygen species in both liver and intestinal tissue, we conclude that PXR deficiency in neonatal hUGT1/Pxr-/- mice allows greater access of activated transcriptional modifiers such as Nrf2 leading to superinduction of UGT1A1.

Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.

Choosing Castration: A Thematic Analysis of the Perceived Pros and Cons of Genital Injuries and Ablation by Men Who Voluntarily Sought Castration.

Some men elect castration voluntarily without any clear medical reason. Here we aim to document their perception of genital ablation and injuries to better understand their motivations for castration. Participants completed an online survey with open-ended questions related to their perspectives on castration, genital ablation, and genital injuries. Thematic analyses were performed on the responses to these questions. Responses were obtained from 208 male castrated individuals (51.9 ± 16.0 years old). Among these, 154 were physically castrated, 36 chemically castrated, and 18 nullified (had testicles and penis removed). The majority learned about castration from media (55.8%) or animal castration (23.4%). The circumstances when they first wanted to be castrated varied greatly. Most (46.3%) wished to achieve an idealized self motivated by gender dysphoria, body integrity dysphoria, or wanting to be conspicuously non-sexual. The top themes we identified related to the respondents' perceptions of the pros of genital ablation were physical appearance, psychological benefit (i.e., a "eunuch calm"), and being non-sexual. Conversely, themes related to the cons they saw in having no genitals ranged from no disadvantages to loss of sexual/reproductive capability. Some perceived performing genital injury as a step toward ultimate castration or nullification. The respondents similarly varied in whether they saw any loss in having non-functional testicles. Perceptions in this regard appeared to differ depending on whether the respondents were taking supplemental androgens post-castration. Motivations for castration vary greatly between individuals. Clinicians need to understand men's diverse perceptions on castration in order to provide appropriate care for individuals with strong castration desire.

Use of convolutional neural networks in skin lesion analysis using real world image and non-image data.

Background: Understanding performance of convolutional neural networks (CNNs) for binary (benign vs. malignant) lesion classification based on real world images is important for developing a meaningful clinical decision support (CDS) tool. Methods: We developed a CNN based on real world smartphone images with histopathological ground truth and tested the utility of structured electronic health record (EHR) data on model performance. Model accuracy was compared against three board-certified dermatologists for clinical validity. Results: At a classification threshold of 0.5, the sensitivity was 79 vs. 77 vs. 72%, and specificity was 64 vs. 65 vs. 57% for image-alone vs. combined image and clinical data vs. clinical data-alone models, respectively. The PPV was 68 vs. 69 vs. 62%, AUC was 0.79 vs. 0.79 vs. 0.69, and AP was 0.78 vs. 0.79 vs. 0.64 for image-alone vs. combined data vs. clinical data-alone models. Older age, male sex, and number of prior dermatology visits were important positive predictors for malignancy in the clinical data-alone model. Conclusion: Additional clinical data did not significantly improve CNN image model performance. Model accuracy for predicting malignant lesions was comparable to dermatologists (model: 71.31% vs. 3 dermatologists: 77.87, 69.88, and 71.93%), validating clinical utility. Prospective validation of the model in primary care setting will enhance understanding of the model's clinical utility.

Paraphilic Sexual Attraction to Males Without Genitals Is Associated with Traumatic Childhood Experience, Body Image, and Thoughts/Behaviors Related to Genital Ablation.

In rare cases, some male individuals are sexually attracted to men who have their genitals removed. We investigate here if paraphilic attraction to men without genitals was associated with childhood experience, body image, and thoughts/behaviors related to body modification. An online survey, consisting of both validated questionnaires and questions developed by our team, was launched on the Eunuch Archive and MTurk websites. Out of 875 participants, 48.5 and 32.2% reported being attracted to males without testicles or without a penis, respectively; 49.7 and 31.0% felt they would themselves be attractive without testicles and without a penis, respectively. In terms of body modification, many reported having tattoos (19.0%) and piercings (26.1%). About half (48.3%) had played as children with male action figures without genitals, i.e., GI Joe, and Ken dolls. Additionally, some participants reported having: (1) witnessed animal castration (23.7%); (2) having been threatened with castration during their childhood (11.9%); (3) receiving genital injuries inflicted by others (11.0%); (4) pretending to be castrated (60.2%); (5) thinking of self-castration (54.2%); or (6) injuring their own penis (23.4%). Having received genital injuries inflicted by others was associated with attraction to males without testicles (OR = 1.997, p < .05), but not for attraction to males without a penis. Paraphilic attraction to males without genitals (i.e., castrated or penectomized) was associated with feeling attractive without genitals, having pretended to be castrated, considering self-castration, and having injured one's own penis. In conclusion, paraphilic attraction to males without genitals may be associated with traumatic early life events, body image, and desire for one's own genital ablation.

Lesion identification and malignancy prediction from clinical dermatological images.

We consider machine-learning-based lesion identification and malignancy prediction from clinical dermatological images, which can be indistinctly acquired via smartphone or dermoscopy capture. Additionally, we do not assume that images contain single lesions, thus the framework supports both focal or wide-field images. Specifically, we propose a two-stage approach in which we first identify all lesions present in the image regardless of sub-type or likelihood of malignancy, then it estimates their likelihood of malignancy, and through aggregation, it also generates an image-level likelihood of malignancy that can be used for high-level screening processes. Further, we consider augmenting the proposed approach with clinical covariates (from electronic health records) and publicly available data (the ISIC dataset). Comprehensive experiments validated on an independent test dataset demonstrate that (1) the proposed approach outperforms alternative model architectures; (2) the model based on images outperforms a pure clinical model by a large margin, and the combination of images and clinical data does not significantly improves over the image-only model; and (3) the proposed framework offers comparable performance in terms of malignancy classification relative to three board certified dermatologists with different levels of experience.