Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform.

Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS, BRAF, and ALK mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.

Protamines and the sperm nuclear basic proteins Pandora's Box of insects.

Insects are the largest group of animals when it comes to the number and diversity of species. Yet, with the exception of Drosophila, no information is currently available on the primary structure of their sperm nuclear basic proteins (SNBPs). This paper represents the first attempt in this regard and provides information about six species of Neoptera: Poecillimon thessalicus, Graptosaltria nigrofuscata, Apis mellifera, Nasonia vitripennis, Parachauliodes continentalis, and Tribolium castaneum. The SNBPs of these species were characterized by acetic acid urea gel electrophoresis (AU-PAGE) and high-performance liquid chromatography fractionated. Protein sequencing was obtained using a combination of mass spectrometry sequencing, Edman N-terminal degradation sequencing and genome mining. While the SNBPs of several of these species exhibit a canonical arginine-rich protamine nature, a few of them exhibit a protamine-like composition. They appear to be the products of extensive cleavage processing from a precursor protein which are sometimes further processed by other post-translational modifications that are likely involved in the chromatin transitions observed during spermiogenesis in these organisms.

The "Cycle" of HIV: Limits of Personal Responsibility in HIV Vulnerability Among Transgender Adolescents and Young Women in Lima, Peru.

Globally, transgender women (TW) face a high burden of the HIV epidemic. In Peru, HIV prevalence among TW rises at age 25, indicating a need to understand HIV vulnerability as adolescents reach adulthood. The life course of TW is often marked by abuse, discrimination and poverty fueled by transphobic stigma. Approaches to the HIV epidemic among TW and adolescents emphasize problem behaviors such as unprotected sex and substance. However, there has been a call for HIV research and interventions to understand and leverage community strengths. This qualitative study utilized a transgender-oriented, strength-based, intersectional and feminist approach to understand the strengths and protective health behaviors among 17 transgender adolescents and young women (TAYW) age 16-24 in Lima, Peru. Most participants re-located to Lima from the Amazon due to familial rejection, and engaged in obligatory sex work. TAYW demonstrated self-knowledge, motivation for education, efforts to secure employment, strong community networks, legal advocacy, avoiding problem substance use, HIV knowledge and condom use. However, strengths were impeded by multi-level barriers such as familial physical abuse, educational discrimination, and sexual assault which led to increased HIV vulnerability. We created a conceptual model of the "cycle" of HIV to describe the limits of personal responsibility within a vulnerable community denied access to family, education, employment and human rights. We recommend researchers, clinicians and public health workers follow the lead of TAYW at the frontlines of the HIV epidemic, and support beloved communities and enabling environments which may permit protective behaviors to mitigate HIV vulnerability.

RESUMEN: A nivel mundial, las mujeres transgénero (MT) enfrentan una alta carga de la epidemia del VIH. En Perú, la prevalencia del VIH entre las MT aumenta a los 25 años, lo que indica la necesidad de comprender la vulnerabilidad al VIH a medida que las adolescentes llegan a la edad adulta. El curso de vida de las MT suele estar marcado por el abuso, la discriminación y la pobreza por culpa del estigma transfóbico. Los enfoques sobre la epidemia del VIH entre las MT y los adolescentes enfatizan conductas problemáticas como el sexo sin protección o el uso de sustancias. Sin embargo, existe un llamado a realizar investigaciones e intervenciones sobre el VIH para comprender y aprovechar las fortalezas de la comunidad. Este estudio cualitativo utilizó un enfoque feminista, interseccional, basado en fortalezas y orientado a las personas transgénero para comprender las fortalezas y los comportamientos protectores de la salud entre 17 adolescentes y mujeres jóvenes transgénero de 16 a 24 años en Lima, Perú. La mayoría de las participantes migraron a Lima desde la Amazonía debido al rechazo familiar y se dedicaron al trabajo sexual obligatorio. Las adolescentes y mujeres jóvenes transgénero demostraron autoconocimiento, motivación para la educación, esfuerzos para conseguir empleo, redes comunitarias sólidas, defensa legal, evitar el uso problemático de sustancias, conocimiento sobre el VIH y uso de condones. Sin embargo, las fortalezas se vieron obstaculizadas por barreras de múltiples niveles, como el abuso físico familiar, la discriminación educativa y la agresión sexual, que llevaron a una mayor vulnerabilidad al VIH. Desarrollamos un modelo conceptual del "ciclo" del VIH para describir los límites de la responsabilidad personal dentro de una comunidad vulnerable a la que se le niega el acceso a la familia, la educación, el empleo y los derechos humanos. Recomendamos que los investigadores, médicos y trabajadores de la salud pública sigan el ejemplo de adolescentes y mujeres jóvenes transgénero en la primera línea de la epidemia del VIH y apoyen a comunidades queridas y entornos propicios que puedan permitir conductas protectoras para mitigar la vulnerabilidad al VIH.

Rapid interrogation of cancer cell of origin through CRISPR editing.

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

Integrative Analysis of Transcriptomic Profiles and Physiological Responses Provide New Insights into Drought Stress Tolerance in Oil Palm (Elaeis guineensis Jacq.).

Oil palm (Elaeis guineensis Jacq.) is a highly productive crop economically significant for food, cosmetics, and biofuels. Abiotic stresses such as low water availability, salt accumulation, and high temperatures severely impact oil palm growth, physiology, and yield by restricting water flux among soil, plants, and the environment. While drought stress's physiological and biochemical effects on oil palm have been extensively studied, the molecular mechanisms underlying drought stress tolerance remain unclear. Under water deficit conditions, this study investigates two commercial E. guineensis cultivars, IRHO 7001 and IRHO 2501. Water deficit adversely affected the physiology of both cultivars, with IRHO 2501 being more severely impacted. After several days of water deficit, there was a 40% reduction in photosynthetic rate (A) for IRHO 7001 and a 58% decrease in IRHO 2501. Further into the drought conditions, there was a 75% reduction in A for IRHO 7001 and a 91% drop in IRHO 2501. Both cultivars reacted to the drought stress conditions by closing stomata and reducing the transpiration rate. Despite these differences, no significant variations were observed between the cultivars in stomatal conductance, transpiration, or instantaneous leaf-level water use efficiency. This indicates that IRHO 7001 is more tolerant to drought stress than IRHO 2501. A differential gene expression and network analysis was conducted to elucidate the differential responses of the cultivars. The DESeq2 algorithm identified 502 differentially expressed genes (DEGs). The gene coexpression network for IRHO 7001 comprised 274 DEGs and 46 predicted HUB genes, whereas IRHO 2501's network included 249 DEGs and 3 HUB genes. RT-qPCR validation of 15 DEGs confirmed the RNA-Seq data. The transcriptomic profiles and gene coexpression network analysis revealed a set of DEGs and HUB genes associated with regulatory and transcriptional functions. Notably, the zinc finger protein ZAT11 and linoleate 13S-lipoxygenase 2-1 (LOX2.1) were overexpressed in IRHO 2501 but under-expressed in IRHO 7001. Additionally, phytohormone crosstalk was identified as a central component in the response and adaptation of oil palm to drought stress.

Intersectional stigma and the arc of intranational migration: experiences of transgender adolescents and women who migrate within Peru.

BACKGROUND: Migration is recognized as a key determinant of health. Yet, limited research addresses the arc of intranational migration and, even less, the experiences of transgender (trans) adolescents and women migrants and the associated health vulnerabilities. Using intersectional stigma as a theoretical frame, this study seeks to better understand the sexual health vulnerabilities and needs of trans women migrants in Peru. METHODS: Between October and November 2016, in-depth interviews (n = 14) and two focus groups (n = 20) were conducted in Spanish with trans women in three Peruvian cities. To explore pre- and during migration experiences, focus groups were conducted in Pucallpa and Iquitos, key cities in the Amazon where trajectories often originate. To assess during migration and post-migration experiences, we conducted interviews in Pucallpa, Iquitos, and Lima to better understand processes of relocation. Audio files were transcribed verbatim and analysed via an immersion crystallization approach, an inductive and iterative process, using Dedoose (v.6.1.18). RESULTS: Participants described migration as an arc and, thus, results are presented in three phases: pre-migration; during migration; and post-migration. Intersectional stigma was identified as a transversal theme throughout the three stages of migration. The pre-migration stage was characterized by poverty, transphobia, and violence frequently motivating the decision to migrate to a larger city. Exploitation was also described as pervasive during migration and in relocation. Many participants spoke of their introduction to sex work during migration, as key to economic earning and associated violence (police, clients). CONCLUSION: Findings advance understandings of intranational migration and forced displacement as key determinants of trans women's health. Dimensions of violence at the intersection of classism and cisgenderism render trans women highly vulnerable at every step of their migratory journeys. Experiences of intranational mobility and relocation were described as uniquely tied to age, intersectional transphobic stigma, engagement in sex work, and multiple forms of violence, which impact and can magnify sexual health vulnerabilities for transgender women in Peru who migrated intranationally.

Mental health and substance use risks and resiliencies in a U.S. sample of transgender and gender diverse adults.

PURPOSE: Victimization contributes to mental and behavioral health inequities among transgender and gender diverse (TGD) people, but few studies have simultaneously examined health-promoting resiliencies. We sought to identify classes of risk and resilience among TGD adults, assess characteristics associated with these classes, and examine their relationship with mental health and substance use outcomes. METHODS: Cross-sectional data were from the 2015 US Transgender Survey, a non-probability study including 26,957 TGD adults. Using latent class analysis, we classified patterns of vulnerability and resilience based on risk (past-year denial of equal treatment, verbal harassment, physical attack, bathroom-related discrimination; lifetime sexual assault, intimate partner violence) and protective (activism; family, work, classmate support) factors. Regression models were fit to (1) determine the association between sociodemographic and gender affirmation characteristics and latent classes; (2) model associations between latent classes and mental health (current serious psychological distress, past-year and lifetime suicidal thoughts and attempts, and lifetime gender identity/transition-related counseling) and substance use (current binge alcohol use, smoking, illicit drug use; past-year drug/alcohol treatment) outcomes. RESULTS: Three latent classes were identified: high risks, with activism involvement ("risk-activism," 35%); low risks, with not being out about one's TGD identity ("not-out," 25%); and low risks, with high family support ("family-support," 40%). Gender affirmation and sociodemographic characteristics, such as race/ethnicity and sexual orientation, were associated with latent classes. Risk-activism class membership was associated with higher odds of negative mental health and substance use outcomes, while the family-support class had lower odds of these outcomes. CONCLUSIONS: Interventions leveraging family support, and policy protections from discrimination and victimization, may promote TGD mental and behavioral health.

Covid-19 en la población LGBTIQ+ en Ecuador: Perspectivas de una junta asesora comunitaria.

No disponible.

Sexual Behaviors and HIV/STI Prevention Strategies Among Sexual Minority Men in Ecuador Who Use Geosocial Networking Apps.

Around the world, geosocial networking apps have become widely popular among sexual minority men (SMM). This research analyzed the sexual behaviors and HIV and STI prevention strategies (HIV/STI testing, HIV/STI inquiry, and HIV/STI disclosure) of an online-recruited sample of 284 SMM living in Ecuador. Sexting and oral sex were the most common sexual behaviors among SMM in the sample. Most participants had low perceptions of HIV and STI risk; 85% reported being tested for HIV and 70% for STIs. Being older predicted higher odds of being tested for either HIV or STIs at least once. Being single also predicted HIV testing. Future interventions in the country should explore apps' utility as intervention tools to spread information about sexual health and HIV prevention strategies, such as condom use and event-driven PrEP. Apps can also facilitate connections to sexual health services, including programs for PrEP initiation and linkage to HIV treatment. They should also focus on promoting sexual harm reduction conversations among potential app-met sexual partners.

Perceptions of power and sexual pleasure associated with sexual behaviour profiles among Latino sexual minority men.

In a body of research typically focused on risk reduction and disease prevention, other factors motivating the sexual behaviours of Latino sexual minority men, such as resource-based power and sexual pleasure, are less well understood. To this end, Latino immigrant sexual minority men living in New York City were surveyed about their sexual behaviours, perceived power differentials, and pleasure from insertive and receptive anal intercourse. Power and pleasure were examined as associations with behavioural profiles identified through latent class analysis, adjusting for age and partner type. Four latent classes of Latino sexual minority men were identified based on behaviours reported during the most recent sexual event: behaviourally insertive (14.2%), behaviourally versatile (25.9%), behaviourally receptive (29.2%), and limited penetrative behaviour (30.7%). Participants who derived pleasure from insertive and receptive anal intercourse had higher odds of belonging in the behaviourally insertive and behaviourally receptive class, respectively. Perceptions of resource-based power were not associated with class membership. Findings highlight the importance of sexual pleasure as a driver of sexual behaviour, irrespective of power dynamics. Sexual health curricula and interventions for sexual minority men should consider sexual pleasure and sex-affirmative frameworks when providing sexuality education and promoting sexual wellbeing.

[Dermatological manifestations of monoclonal gammopathies]. / Patologías cutáneas asociadas a gammapatías monoclonales: ¿qué sabemos hasta ahora?

Monoclonal gammopathies of uncertain significance (MGUS) correspond to pre-malignant hematological disorders characterized by the production of a monoclonal protein and infiltration of less than 10% of the bone marrow by plasma cells. Its importance lies in the risk of progression to malignant disorders and in the association with different renal, neurological and skin manifestations. There are pathophysiological mechanisms that support a causal relationship between monoclonal gammopathies (MGs) and different skin diseases, such as type I cryoglobulinemia (CG), primary systemic amyloidosis (PSA) or necrobiotic xanthogranuloma (NXG). However, there is a group of skin diseases associated with MGs whose pathogenesis has not been elucidated. In this context, the role of the dermatologist is crucial in the suspicion of different haematological disorders based on skin manifestations and in the multidisciplinary treatment of these patients. In this article, we carry out an exhaustive review of the literature published in this area and propose a screening algorithm for MGs in patients with specific skin diseases.

Rapid modelling of cooperating genetic events in cancer through somatic genome editing.

Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras(G12D)-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras(G12D) combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.

Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancer-selective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.

Evolution of high mobility group nucleosome-binding proteins and its implications for vertebrate chromatin specialization.

High mobility group (HMG)-N proteins are a family of small nonhistone proteins that bind to nucleosomes (N). Despite the amount of information available on their structure and function, there is an almost complete lack of information on the molecular evolutionary mechanisms leading to their exclusive differentiation. In the present work, we provide evidence suggesting that HMGN lineages constitute independent monophyletic groups derived from a common ancestor prior to the diversification of vertebrates. Based on observations of the functional diversification across vertebrate HMGN proteins and on the extensive silent nucleotide divergence, our results suggest that the long-term evolution of HMGNs occurs under strong purifying selection, resulting from the lineage-specific functional constraints of their different protein domains. Selection analyses on independent lineages suggest that their functional specialization was mediated by bursts of adaptive selection at specific evolutionary times, in a small subset of codons with functional relevance-most notably in HMGN1, and in the rapidly evolving HMGN5. This work provides useful information to our understanding of the specialization imparted on chromatin metabolism by HMGNs, especially on the evolutionary mechanisms underlying their functional differentiation in vertebrates.

Characterization of mussel H2A.Z.2: a new H2A.Z variant preferentially expressed in germinal tissues from Mytilus.

Histones are the fundamental constituents of the eukaryotic chromatin, facilitating the physical organization of DNA in chromosomes and participating in the regulation of its metabolism. The H2A family displays the largest number of variants among core histones, including the renowned H2A.X, macroH2A, H2A.B (Bbd), and H2A.Z. This latter variant is especially interesting because of its regulatory role and its differentiation into 2 functionally divergent variants (H2A.Z.1 and H2A.Z.2), further specializing the structure and function of vertebrate chromatin. In the present work we describe, for the first time, the presence of a second H2A.Z variant (H2A.Z.2) in the genome of a non-vertebrate animal, the mussel Mytilus. The molecular and evolutionary characterization of mussel H2A.Z.1 and H2A.Z.2 histones is consistent with their functional specialization, supported on sequence divergence at promoter and coding regions as well as on varying gene expression patterns. More precisely, the expression of H2A.Z.2 transcripts in gonadal tissue and its potential upregulation in response to genotoxic stress might be mirroring the specialization of this variant in DNA repair. Overall, the findings presented in this work complement recent reports describing the widespread presence of other histone variants across eukaryotes, supporting an ancestral origin and conserved role for histone variants in chromatin.

Bordetella pertussis filamentous hemagglutinin itself does not trigger anti-inflammatory interleukin-10 production by human dendritic cells.

Filamentous hemagglutinin (FHA) is an important adhesin of the whooping cough agent Bordetella pertussis and is contained in most acellular pertussis vaccines. Recently, FHA was proposed to exert an immunomodulatory activity through induction of tolerogenic IL-10 secretion from dendritic cells. We have re-evaluated the cytokine-inducing activity of FHA, placing specific emphasis on the role of the residual endotoxin contamination of FHA preparations. We show that endotoxin depletion did not affect the capacity of FHA to bind primary human monocyte-derived dendritic cells, while it abrogated the capacity of FHA to elicit TNF-α and IL-10 secretion and strongly reduced its capacity to trigger IL-6 production. The levels of cytokines induced by the different FHA preparations correlated with their residual contents of B. pertussis endotoxin. Moreover, FHA failed to trigger cytokine secretion in the presence of antibodies that block TLR2 and/or TLR4 signaling. The TLR2 signaling capacity appeared to be linked to the presence of endotoxin-associated components in FHA preparations and not to the FHA protein itself. These results show that the endotoxin-depleted FHA protein does not induce cytokine release from human dendritic cells.

Comparative structure of vertebrate sperm chromatin.

A consistent feature of sperm nuclei is its exceptionally compact state in comparison with somatic nuclei. Here, we have examined the structural organization of sperm chromatin from representatives of three vertebrate lineages, bony fish (Danio rerio), birds (Gallus gallus domesticus) and mammals (Mus musculus) using light and transmission electron microscopy (TEM). Although the three sperm nuclei are all highly compact, they differ in morphology and in the complement of compaction-inducing proteins. Whereas zebrafish sperm retain somatic histones and a nucleosomal organization, in the rooster and mouse, histones are largely replaced by small, arginine-rich protamines. In contrast to the mouse, the rooster protamine contains no cysteine residues and lacks the potential stabilizing effects of S-S bonds. Protamine driven chromatin compaction results in a stable, highly condensed chromatin, markedly different from the somatic nucleosome-based beads-on-a-string architecture, but its structure remains poorly understood. When prepared gently for whole mount TEM, the rooster and mouse sperm chromatin reveal striking rod-like units 40-50 nm in width. Also present in the mouse, which has very flattened sperm nuclei, but not rooster, where nuclei take the form of elongated cylinders, are toroidal shaped structures, with an external diameter of about 90 nm. In contrast, similarly prepared zebrafish sperm exhibit nucleosomal chromatin. We also examined the early stages in the binding of salmine (the salmon protamine) to defined sequence DNA. These images suggest an initial side-by-side binding of linear DNA-protamine complexes leading to the nucleation of thin, flexible rods with the potential to bend, allowing the ends to come into contact and fuse to form toroidal structures. We discuss the relationship between these in vitro observations and the rods and toroids seen in nuclei, and suggest an explanation for the apparent absence of these structures in TEM images of fully condensed sperm nuclei.

HIV vulnerabilities and psychosocial health among young transgender women in Lima, Peru: results from a bio-behavioural survey.

INTRODUCTION: Peruvian young transgender women (YTW) ages 16-24 years are a critical but understudied group for primary HIV prevention efforts, due to sharp increases in HIV prevalence among TW ages 25 years and older. METHODS: Between February and July 2022, a cross-sectional quantitative study with YTW ages 16-24 years in Peru (N = 211) was conducted consisting of a bio-behavioural survey accompanied by laboratory-based testing for HIV and sexually transmitted infections (STIs). Bivariate and multivariable Poisson regression models were used to estimate prevalence ratios between socio-demographic and behavioural characteristics and HIV status. RESULTS: HIV prevalence was 41.5% (95% CI: 33.9-49.4%), recent syphilis acquisition 19.4% (95% CI: 12.7-28.4), chlamydia 6.3% (95% CI: 3.1-11.1) and gonorrhoea 12.3% (95% CI: 7.9-18.7). Almost half (47.9%) reported condomless anal sex in the past 6 months, 50.7% reported sex work in the past 30 days and 13.7% reported accepting more money for condomless sex. There were no significant differences in reported sexual behaviours by HIV status. Only 60.8% of participants reported ever having been tested for HIV, and 25.6% reported a past 6-month STI test. More than two-thirds (67.8%) had not heard of antiretroviral pre-exposure prophylaxis (PrEP) and only 4.7% had taken PrEP in the past month. Current moderate-to-severe psychological distress was endorsed by 20.3%, 10.0% reported attempting suicide in the past 6 months and 85.4% reported alcohol misuse. CONCLUSIONS: Findings show that the HIV epidemic for YTW in Lima, Peru is situated in the context of widespread social exclusion, including economic vulnerabilities, violence victimization and the mental health sequelae of transphobic stigma that starts early in life. Future research should aim to further understand the intersection of these vulnerabilities. Moreover, there is an urgent necessity to design and evaluate HIV prevention programmes that address the root systems driving HIV vulnerabilities in YTW and that focus on developmentally specific clusters of stigma-related conditions.