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PURPOSE: Gender-affirming surgery is being increasingly performed for transgender and gender-diverse individuals diagnosed with gender dysphoria. However, there is a group of patients who may seek outcomes that are either a combination of or altogether different from those of binary procedures such as penile inversion vaginoplasty or phalloplasty. METHODS: We describe surgical techniques for less commonly performed gender-affirming genital procedures, in order to introduce these procedures to the medical and surgical community. RESULTS: Operative techniques for phallus-preserving vaginoplasty, vagina-preserving phalloplasty, and removal of genitalia with creation of perineal urethrostomy are described. Demographic characteristics and complications of these procedures in 16 patients are reported. CONCLUSION: Individually customized gender-affirming genital procedures, such as phallus-preserving vaginoplasty, vaginal-preserving phalloplasty, and removal of genitalia and creation of perineal urethrostomy, may better affirm the identities of some gender-diverse patients, and may also preserve desired sexual function of natal genitalia.
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Cirugía de Reasignación de Sexo , Humanos , Femenino , Masculino , Cirugía de Reasignación de Sexo/métodos , Adulto , Disforia de Género/cirugía , Vagina/cirugía , Pene/cirugía , Personas Transgénero , Transexualidad/cirugíaRESUMEN
Importance: With the increasing legislation restricting health care access for transgender and nonbinary (trans) populations in recent years, there has been limited research on how awareness of and concerns about legislative restrictions and protections influence mental health outcomes. Objective: To examine whether awareness of and concerns about the current policy environment regarding trans individuals are associated with depression and anxiety symptoms among trans adults. Design, Setting, and Participants: This study uses cross-sectional data collected between March and April 2023 from the Washington Priority Assessment in Trans Health (PATH) Project, an online study designed by, with, and for trans communities. All participants were trans adults, aged 18 years or older, living in Washington state. Exposure: Awareness and concerns about the antitrans policy environment. Main Outcomes and Measures: The primary outcomes were depression and anxiety symptoms, assessed via the Patient Health Questionnaire-4. A series of multivariable regression models was used to assess the association between awareness and concerns about the antitrans policy environment and depression and anxiety symptoms. Models were adjusted for covariates, including demographics, social marginalization, and health care experiences. Results: A total of 797 participants (653 women [81.93%]; 455 aged 18-29 years [57.09%]) were included. The majority screened positive for current depression (689 individuals [86.45%]) and anxiety (686 individuals [86.07%]) symptoms. Trans individuals who were concerned or worried about their rights being taken away (vs not) had significantly higher odds of current depression symptoms (adjusted odds ratio [aOR], 1.66; 95% CI, 1.08-2.54), as well as current anxiety symptoms (aOR, 2.67; 95% CI, 1.63-4.36). Those who knew (vs did not know) about state-level protective legislation had significantly lower odds of current depression symptoms (aOR, 0.44; 95% CI, 0.28-0.67), as well as current anxiety symptoms (aOR, 0.11; 95% CI, 0.04-0.25). When examining interaction effect estimates, trans individuals who correctly knew about the protective policies and were not worried about having their rights taken away reported the lowest odds of depression and anxiety. Conclusions and Relevance: The findings of this cross-sectional study are consistent with research elucidating the negative mental health consequences of policies limiting health care access and provide insights into informing policies and interventions that target trans populations' worsened mental health outcomes as a result of antitrans legislation.
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Ansiedad , Depresión , Personas Transgénero , Humanos , Femenino , Adulto , Masculino , Estudios Transversales , Personas Transgénero/psicología , Personas Transgénero/estadística & datos numéricos , Depresión/epidemiología , Depresión/psicología , Ansiedad/epidemiología , Ansiedad/psicología , Persona de Mediana Edad , Washingtón/epidemiología , Adolescente , Adulto Joven , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Política de Salud/legislación & jurisprudenciaRESUMEN
Objectives: Chronic pain is a risk factor for worse outcomes following hip arthroscopy for femoroacetabular impingement syndrome (FAIS). Pain sensitization involves the central nervous system perceiving previously innocuous stimuli as noxious. Temporal summation can provide a surrogate measure of sensitization, and may be a clinical tool to identify patients at a higher risk for poor post-hip arthroscopy outcomes. Therefore, we aimed to 1) identify the prevalence of temporal summation in patients undergoing hip arthroscopy for FAIS, 2) determine if there a difference in postoperative improvement between individuals with and without preoperative temporal summation, and 3) examine preoperative predictors of poor postoperative recovery. Methods: 51 participants undergoing hip arthroscopy for FAIS underwent preoperative temporal summation testing. Three months postoperatively, 38 participants completed the 12-item International Hip Outcome Tool (iHOT-12) and reported their overall symptomatic improvement (0% to 100%, with 100% being normal). Participants were categorized on the presence ( Numeric Pain Rating Scale; NPRS 2) or absence ( NPRS < 2) of temporal summation. A Mann-Whitney U test was used to determine the difference in improvement between groups (temporal summation: temporal summation (TS), no temporal summation (NTS), and a linear regression was used to explore predictors of improvement. Results: 23 (45.1%) of 51 participants displayed preoperative temporal summation. In participants with postoperative data, those with temporal summation reported less improvement than those without (TS: 62.8% 29.7%; NTS: 82.7% 13.9%; p = 0.01; Cohen's d = -0.86). Temporal summation (Beta = -0.48; 95% CI -36.6, -8.7) and mental health disorder (Beta = -0.30; 95% CI -28.0, -0.48) predicted 28.1% of the variance in postoperative improvement (p = 0.002). Conclusion: The presence of preoperative temporal summation is common and related to worse postoperative recovery after hip arthroscopy for FAIS.
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BACKGROUND: Transgender and gender diverse (TGD) individuals have elevated mental and physical health disparities and a greater mortality risk compared to their cisgender (non-TGD) counterparts. METHODS: We assessed differences in the association of depression with all-cause and cardiovascular disease (CVD) mortality among TGD and cisgender Veterans Administration patients. A sample of 8981 TGD patients, matched 1:3 with cisgender patients (n = 26,924) patients, was created from administrative and electronic health record data from October 1, 1999 to December 31, 2016. Cox proportional regression models stratified by gender modality (i.e., TGD and cisgender) were used to assess the hazard of all-cause and CVD mortality associated with a history of depression. RESULTS: Adjusted models demonstrated that depression was significantly associated with a greater hazard of all-cause mortality among both TGD (aHR:1.18, 95 % CI: 1.04-1.34) and cisgender (aHR:1.22, 95 % CI: 1.17-1.28) patients. Similar to all-cause mortality, depression was significantly associated with a greater hazard of CVD mortality among cisgender patients ≥65 years (aHR = 1.23, 95 % CI = 1.13-1.35). Findings for TGD patients showed a similar pattern, though results were not significant. LIMITATIONS: Hazards may be underestimated since depression may be underdiagnosed. Further, we were unable to adjust for other health-related risk factors tied to mortality (e.g., smoking). CONCLUSION: Overall, depression was associated with a greater hazard of all-cause mortality among both TGD and cisgender patients. Future work should assess the equity of reach, quality, and outcomes of treatment for depression for TGD populations given the lack of attention to addressing the needs of this important patient demographic.
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Enfermedades Cardiovasculares , Depresión , Personas Transgénero , Humanos , Enfermedades Cardiovasculares/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Personas Transgénero/estadística & datos numéricos , Personas Transgénero/psicología , Adulto , Depresión/epidemiología , Depresión/mortalidad , Anciano , Estados Unidos/epidemiología , Causas de Muerte , Factores de Riesgo , Modelos de Riesgos Proporcionales , Veteranos/estadística & datos numéricos , Veteranos/psicologíaAsunto(s)
Minorías Sexuales y de Género , Humanos , Estados Unidos , Historia del Siglo XX , Masculino , Femenino , Historia del Siglo XXIRESUMEN
OBJECTIVES: To understand how frailty and healthcare delays differentially mediate the association between sexual and gender minority older adults (OSGM) status and healthcare utilization. MATERIALS AND METHODS: Data from the All of Us Research Program participants ≥50 years old were analyzed using marginal structural modelling to assess if frailty or healthcare delays mediated OSGM status and healthcare utilization. OSGM status, healthcare delays, and frailty were assessed using survey data. Electronic health record (EHR) data was used to measure the number of medical visits or mental health (MH) visit days, following 12 months from the calculated All of Us Frailty Index. Analyses adjusted for age, race and ethnicity, income, HIV, marital status ± general MH (only MH analyses). RESULTS: Compared to non-OSGM, OSGM adults have higher rates of medical visits (adjusted rate ratio [aRR]: 1.14; 95% CI: 1.03, 1.24) and MH visits (aRR: 1.85; 95% CI: 1.07, 2.91). Frailty mediated the association between OSGM status medical visits (Controlled direct effect [Rcde] aRR: 1.03, 95% CI [0.87, 1.22]), but not MH visits (Rcde aRR: 0.37 [95% CI: 0.06, 1.47]). Delays mediated the association between OSGM status and MH visit days (Rcde aRR: 2.27, 95% CI [1.15, 3.76]), but not medical visits (Rcde aRR: 1.06 [95% CI: 0.97, 1.17]). DISCUSSION: Frailty represents a need for medical care among OSGM adults, highlighting the importance of addressing it to improve health and healthcare utilization disparities. In contrast, healthcare delays are a barrier to MH care, underscoring the necessity of targeted strategies to ensure timely MH care for OSGM adults.
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Enfermedades Cardiovasculares , Personas Transgénero , Humanos , Personas Transgénero/psicología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Femenino , Masculino , Disparidades en Atención de Salud , Disparidades en el Estado de Salud , Factores de Riesgo de Enfermedad Cardiaca , Prioridades en Salud , Medición de Riesgo , Conocimientos, Actitudes y Práctica en SaludRESUMEN
PURPOSE: In radiotherapy of the head and neck (H&N) it is common for the clinical target volume (CTV) to extend to the patient's skin. Adding a margin for set-up uncertainty and delivery creates a planning target volume (PTV) that extends beyond the patient surface. This can result in excessive fluence being delivered to the build-up region and therefore the skin. This study evaluates four different planning methods used when inverse-planning H&N radiotherapy treatments with CTV extending to the skin. The aim of the study was to determine which planning method gives superior plan quality. METHOD: Ten H&N cancer patients with a CTV contoured to the skin were inverse-planned using four planning methods. The planning methods compared were: cropping the optimization PTV back from the skin surface by 5.0, 3.0, and 0.0 mm and a virtual bolus method. For each planning method, the increased fluence at the skin surface was analyzed. The CTV coverage and skin doses were compared. Plan robustness was evaluated by applying an isocenter shift of ±3.0 mm in the major axes. RESULTS: The planning method cropping the PTV 0.0 mm from the skin surface results in an increased fluence in the build-up region. The average volume of CTV receiving 98% of the prescription dose was 89.6% ± 3.4%, 91.6% ± 2.4%, and 93.5% ± 1.7% when cropped 5.0, 3.0, and 0.0 mm, respectively, and 93.4% ± 2.1% for the virtual bolus method. Introducing plan uncertainty affects CTV coverage the most when cropping 5.0 mm. When plan uncertainties are considered the methods of cropping 5.0, 3.0 mm, and the virtual bolus method have the same average skin dose within ±0.3%. CONCLUSION: This study shows that a virtual bolus planning method results in no increased fluence at the patient's surface, improves CTV coverage, and is the most robust to changes in setup and patient anatomy.
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DNA libraries are critical components of many biological assays. These libraries are often kept in plasmids that are amplified in E. coli to generate sufficient material for an experiment. Library uniformity is critical for ensuring that every element in the library is tested similarly and is thought to be influenced by the culture approach used during library amplification. We tested five commonly used culturing methods for their ability to uniformly amplify plasmid libraries: liquid, semisolid agar, cell spreader-spread plates with high or low colony density, and bead-spread plates. Each approach was evaluated with two library types: a random 80-mer library, representing high complexity and low coverage of similar sequence lengths, and a human TF ORF library, representing low complexity and high coverage of diverse sequence lengths. We found that no method was better than liquid culture, which produced relatively uniform libraries regardless of library type. However, when libraries were transformed with high coverage, the culturing method had minimal impact on uniformity or amplification bias. Plating libraries was the worst approach by almost every measure for both library types and, counterintuitively, produced the strongest biases against long sequence representation. Semisolid agar amplified most elements of the library uniformly but also included outliers with orders of magnitude higher abundance. For amplifying DNA libraries, liquid culture, the simplest method, appears to be best.
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Amplificación de Genes , Plásmidos , Plásmidos/genética , Humanos , Factores de Transcripción/genética , Escherichia coli/genética , Técnicas de Cultivo/métodosRESUMEN
The invention of nanosized biomaterials has paved the way for novel therapeutics that can manipulate cells on a nanoscale. Nanosized immunofilaments (IFs) are synthetic filamentous polymers consisting out of polyisocyanopeptides, which have been recently established as a powerful platform to activate specific immune cells in vivo such that they raise an antitumor immune response. However, toxicological effects or immunogenicity toward the IFs have not yet been investigated. In this study, we evaluated potential toxic or immunogenic effects in C57BL/6 mice upon intravenous or subcutaneous injection of nonfunctionalized IFs or immunostimulatory IFs over 30 days. We here present a detailed analysis of the gross pathology, hematological parameters, blood biochemistry, histology, and antibody-response against the IF backbone. Our results demonstrate that IFs do not induce severe acute or chronic toxicity in mice. After 30 days, we only found elevated IgG-titers in intravenously injected but not subcutaneously injected mice. In summary, we demonstrate that IFs can be administered into a living organism without adverse side effects, thereby establishing the safety of IFs as a therapeutic intervention.
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Due to their exceptional solubility and stability, nanobodies have emerged as powerful building blocks for research tools and therapeutics. However, their generation in llamas is cumbersome and costly. Here, by inserting an engineered llama immunoglobulin heavy chain (IgH) locus into IgH-deficient mice, we generate a transgenic mouse line, which we refer to as 'LamaMouse'. We demonstrate that LamaMice solely express llama IgH molecules without association to Igκ or λ light chains. Immunization of LamaMice with AAV8, the receptor-binding domain of the SARS-CoV-2 spike protein, IgE, IgG2c, and CLEC9A enabled us to readily select respective target-specific nanobodies using classical hybridoma and phage display technologies, single B cell screening, and direct cloning of the nanobody-repertoire into a mammalian expression vector. Our work shows that the LamaMouse represents a flexible and broadly applicable platform for a facilitated selection of target-specific nanobodies.
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Camélidos del Nuevo Mundo , Cadenas Pesadas de Inmunoglobulina , Ratones Transgénicos , Anticuerpos de Dominio Único , Glicoproteína de la Espiga del Coronavirus , Animales , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/inmunología , Camélidos del Nuevo Mundo/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Ratones , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Lectinas Tipo C/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/genética , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Inmunoglobulina E/inmunología , Humanos , Dependovirus/genética , Dependovirus/inmunología , Inmunoglobulina G/inmunología , COVID-19/inmunología , Linfocitos B/inmunologíaRESUMEN
Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.
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Linfocitos T CD8-positivos , Interferón gamma , Macrófagos , Mycobacterium tuberculosis , Serina , Tuberculosis , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Mycobacterium tuberculosis/inmunología , Ratones , Serina/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Tuberculosis/inmunología , Tuberculosis/microbiología , Ratones Endogámicos C57BL , Transaminasas/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Hipoxia/inmunología , Hipoxia/metabolismo , Femenino , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
In this work, crystallographic texture evolution in 3D printed trimodal polyethylene (PE) blends and high-density PE (HDPE) benchmark material were investigated to quantify the resulting material anisotropy, and the results were compared to materials made from conventional injection molded (IM) samples. Trimodal PE reactor blends consisting of HDPE, ultrahigh molecular weight PE (UHMWPE), and HDPE_wax have been used for 3D printing and injection molding. Changes in the preferred orientation and distribution of crystallites, i.e., texture evolution, were quantified utilizing the wide angle X-ray diffraction through pole figures and orientation distribution functions (ODFs) for 3D printed and IM samples. Since the change in weight-average molecular weight (Mw) of the blend was expected to significantly affect the resulting crystallinity and orientation, the overall Mw of the trimodal PE blend was varied while keeping the UHMWPE component weight fraction to 10% in the blend. The resulting texture was analyzed by varying the overall Mw of the trimodal blend and the process parameters in 3D printing and compared to the texture of conventional IM samples. The printing speed and orientation (defined with respect to the axis along the length of the samples) were used as the variable process parameters for 3D printing. The degree of anisotropy increases with an increase in the nonuniform distribution of intensities in pole figures and ODFs. All the highest intensity major texture components in IM and 3D printed samples (0° printing orientation) of reactor blends are observed to have crystals oriented in [001] or [001Ì ]. Overall, for the same throughput, 3D printed samples in the 0° orientation showed greater texture evolution and higher anisotropy compared to IM samples. Most notably, an increase in 3D printing speed increased the crystalline distribution closer to the 0° direction, increasing the anisotropy, while deviation from this printing orientation reduced crystalline distribution closer to the 0° direction, thus increasing isotropy. This demonstrates that tailoring material properties in specific directions can be achieved more effectively with 3D printing than with the injection molding process. Change in the overall Mw of the trimodal PE blend changed the preferential orientation distribution of the crystal planes to some degree. However, the degree of anisotropy remained the same in almost all cases, indicating that the effect of molecular weight distribution is not as significant as the printing speed and printing orientation in tailoring the resulting properties. The 3D printing process parameters (speed and orientation) were shown to have more influence on the texture than the material parameters associated with the blend.
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Type I interferon (IFN) production is crucial in tuberculosis pathogenesis, yet the bacterial factors initiating this process are incompletely understood. CpsA, protein of Mycobacterium marinum and Mycobacterium tuberculosis, plays a key role in maintaining bacterial virulence and inhibiting host cell LC3-associated phagocytosis. By utilizing CpsA full deletion mutant studies, we re-verified its essential role in infection-induced pathology and revealed its new role in type I IFN expression. CpsA deficiency hindered IFN production in infected macrophages in vitro as well as zebrafish and mice in vivo. This effect was linked to the cGAS-TBK1-IRF3 pathway, as evidenced by decreased TBK1 and IRF3 phosphorylation in CpsA-deficient bacterial strain-infected macrophages. Moreover, we further show that CpsA deficiency cause decreased cytosolic DNA levels, correlating with impaired phagosomal membrane rupture. Our findings reveal a new function of mycobacterial CpsA in type I IFN production and offer insight into the molecular mechanisms underlying mycobacterial infection pathology.
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INTRODUCTION: Cancer risk factors are more common among sexual minority populations (e.g., lesbian, bisexual) than their heterosexual peers, yet little is known about cancer incidence across sexual orientation groups. METHODS: The 1989-2017 data from the Nurses' Health Study II, a longitudinal cohort of female nurses across the United States, were analyzed (N = 101,543). Sexual orientation-related cancer disparities were quantified by comparing any cancer incidence among four sexual minority groups based on self-disclosure-(1) heterosexual with past same-sex attractions/partners/identity; (2) mostly heterosexual; (3) bisexual; and (4) lesbian women-to completely heterosexual women using age-adjusted incidence rate ratios (aIRR) calculated by the Mantel-Haenszel method. Additionally, subanalyses at 21 cancer disease sites (e.g., breast, colon/rectum) were conducted. RESULTS: For all-cancer analyses, there were no statistically significant differences in cancer incidence at the 5% type I error cutoff among sexual minority groups when compared to completely heterosexual women; the aIRR was 1.17 (95% CI,0.99-1.38) among lesbian women and 0.80 (0.58-1.10) among bisexual women. For the site-specific analyses, incidences at multiple sites were significantly higher among lesbian women compared to completely heterosexual women: thyroid cancer (aIRR, 1.87 [1.03-3.41]), basal cell carcinoma (aIRR, 1.85 [1.09-3.14]), and non-Hodgkin lymphoma (aIRR, 2.13 [1.10-4.12]). CONCLUSION: Lesbian women may be disproportionately burdened by cancer relative to their heterosexual peers. Sexual minority populations must be explicitly included in cancer prevention efforts. Comprehensive and standardized sexual orientation data must be systematically collected so nuanced sexual orientation-related cancer disparities can be accurately assessed for both common and rare cancers.
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Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently, we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.