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Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.

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Chalconas , Chalconas/farmacología , Chalconas/química , Humanos , Ensayos Clínicos como Asunto , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéutico

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The field of 3-dimensional (3D) bioprinting has significantly expanded capabilities in producing precision-engineered hydrogel constructs, and recent years have seen the development of various stimuli-responsive bio- and photoinks. There is, however, a distinct lack of digital light processing (DLP)-compatible photoinks with thermoresponsivity. To remedy this, this work focuses on formulating and optimizing a versatile ink for DLP printing of thermoresponsive hydrogels, with numerous potential applications in tissue engineering, drug delivery, and adjacent biomedical fields. Photoink optimization was carried out using a multifactorial study design. The optimized photoink yielded crosslinked hydrogels with strong variations in hydrophobicity (contact angles of 44.4° LCST), indicating marked thermoresponsivity. Mechanical- and rheological characterization of the printed hydrogels showed significant changes above the LCST: storage- and loss moduli both increased and loss tangent and compressive modulus decreased above this temperature (P ≤ 0.01). The highly cytocompatible hydrogel microwell arrays yielded both single- and multilayer spheroids with human dermal fibroblasts (HDFs) and HeLa cells successfully. Evaluation of the release of encapsulated model macro- (bovine serum albumin, BSA) and small molecule (rhodamine B) drugs in a buffer solution showed an interestingly inverted thermoresponsive release profile with >80% release at room temperature and about 50-60% release above the gels' LCST. All told, the optimized ink holds great promise for multiple biomedical applications including precise and high-resolution fabrication of complex tissue structures, development of smart drug delivery systems and 3D cell culture.

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OBJECTIVE: Concerns exist about clinical and operative skill decay in surgery residents when they dedicate time away from clinical training to pursue research. However, it remains undetermined how to best prevent these negative impacts. Our study evaluated the perspectives of surgical research residents on interventions to improve their reentry into clinical training. DESIGN, SETTING, AND PARTICIPANTS: An anonymous web-based survey was distributed between 5/01/2023 and 6/01/2023 to 102 current and former (within the previous 3 years) general surgery research residents from 4 academic medical centers in Boston, MA. RESULTS: Survey response rate was 35.3% (36/102 residents). About 22 of 36 residents (61.1%) felt that their clinical aptitude decreased during the research years, whereas 33 of 36 (91.7%) reported reduced surgical skills. When reflecting on their re-entry to residency, former research residents reported feeling anxious and less confident (3.84/5 on a 1-5 Likert scale) as well as being below the expected level of clinical performance (3.42/5). Most of them (12 of 17; 70.6%) reported that it took up to 6 months, whereas 5 of them (29.4%) up to 12 months to feel at the expected level. When compared to nonmoonlighting residents, those who moonlighted often and operated during moonlighting, denied a decrease in clinical and surgical skills, and reported less anxiety, higher confidence, and a quicker return to the expected level of performance. Interventions proposed for improving their clinical re-entry included individualized development plans for 3 months before returning to clinical training, established curriculum for clinical work throughout the research years, clinical preceptorships throughout the research years, and simulation curriculum throughout the research years. CONCLUSIONS: General surgery residents feel that their clinical and surgical skills decreased during the research years, leading to anxiety and lack of confidence when returning to residency. Therefore, comprehensive interventions are needed to improve the reentry of the research residents into clinical training.

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Transgender/non-binary (TNB) adolescents are at increased risk for mental health concerns, and caregiver awareness is important to facilitate access to care. Yet, limited research has examined caregiver awareness of TNB mental health. Thus, we examined (1) the prevalence of internalizing symptoms (depression, generalized anxiety, separation anxiety, social anxiety) among TNB adolescents and (2) associations between adolescent and caregiver reports of adolescent mental health symptoms. TNB adolescents (N = 75) aged 12-18 and a caregiver were recruited from a multidisciplinary gender clinic in Ohio. Adolescents self-reported their mental health symptoms via the CDI and SCARED. Caregivers reported their perceptions of the adolescent's mental health symptoms via the CASI-5. Descriptive statistics assessed participant characteristics, adolescent self-reported mental health symptoms, and caregiver proxy reports of adolescent mental health symptoms. Pearson's correlations and scatterplots were used to compare adolescent and caregiver reports and McNemar tests assessed if the differences were statistically significant. Most TNB adolescents reported elevated symptoms of depression (59%), generalized anxiety (75%), separation anxiety (52%), and social anxiety (78%). Caregiver and adolescent reports were significantly correlated for depression (r = .36, p = .002), separation anxiety (r = .39, p < .001), and social anxiety (r = .47, p < .001). Caregiver and adolescent reports of generalized anxiety were not significantly correlated (r = .21, p = .08). McNemar tests were significant (all p < .001), such that adolescents' reports met clinical cutoffs far more than their caregivers' reports. CONCLUSIONS: Though adolescent and caregiver reports were low to moderately correlated, youth reports were consistently higher, suggesting the importance of interventions to increase caregiver understanding of TNB adolescent mental health. WHAT IS KNOWN: • Transgender/non-binary adolescents are at high risk for mental health concerns and caregivers are essential to coordinate care. WHAT IS NEW: • This study expands the diagnostic mental health sub-categories examined in transgender/non-binary adolescents, noting elevated symptoms of separation and social anxiety. • Transgender/non-binary adolescents reported more symptoms of depression, generalized anxiety, separation anxiety, and social anxiety than caregivers.

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Background: In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Methods: Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences -0.07 (95% CI -0.13, -0.02), -0.09 (-0.15, -0.02), -0.08 (95% CI -0.14, -0.02), and -0.08 (-0.13, -0.03) µg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

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Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition.

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Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.

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Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales , Inmunidad Innata , Lipoilación , Membranas Mitocondriales , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Membranas Mitocondriales/metabolismo , Aciltransferasas/metabolismo , Células HEK293 , Mitocondrias/metabolismo , Animales , Cisteína/metabolismo , Transducción de Señal/inmunología , Agregado de Proteínas

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BACKGROUND: In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes. METHODS: Design: We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam. PARTICIPANTS: Sexually active MSM (n=564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants (n=20) in each arm will be selected for longitudinal qualitative interviews; an additional subset (n=48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders (n=35). INTERVENTION: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use. OUTCOMES: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders. DISCUSSION: This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings. TRIAL REGISTRATION: NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

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Consumo de Bebidas Alcohólicas , Infecciones por VIH , Homosexualidad Masculina , Profilaxis Pre-Exposición , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Masculino , Vietnam , Homosexualidad Masculina/psicología , Infecciones por VIH/prevención & control , Consumo de Bebidas Alcohólicas/prevención & control , Consumo de Bebidas Alcohólicas/efectos adversos , Profilaxis Pre-Exposición/métodos , Resultado del Tratamiento , Adulto , Adulto Joven

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Water supply and sanitation are essential household services frequently shared in resource-poor settings. Shared sanitation can increase the risk of enteric pathogen transmission due to suboptimal cleanliness of facilities used by large numbers of individuals. It also can potentially increase the risk of respiratory disease transmission. As sanitation is an essential need, shared sanitation facilities may act as important respiratory pathogen transmission venues even with strict control measures such as stay-at-home recommendations in place. This analysis explores how behavioral and infrastructural conditions surrounding shared sanitation may individually and interactively influence respiratory pathogen transmission. We developed an individual-based community transmission model using COVID-19 as a motivating example parameterized from empirical literature to explore how transmission in shared latrines interacts with transmission at the community level. We explored mitigation strategies, including infrastructural and behavioral interventions. Our review of empirical literature confirms that shared sanitation venues in resource-poor settings are relatively small with poor ventilation and high use patterns. In these contexts, shared sanitation facilities may act as strong drivers of respiratory disease transmission, especially in areas reliant on shared facilities. Decreasing dependence on shared latrines was most effective at attenuating sanitation-associated transmission. Improvements to latrine ventilation and handwashing behavior were also able to decrease transmission. The type and order of interventions are important in successfully attenuating disease risk, with infrastructural and engineering controls being most effective when administered first, followed by behavioral controls after successful attenuation of sufficient alternate transmission routes. Beyond COVID-19, our modeling framework can be extended to address water, sanitation, and hygiene measures targeted at a range of environmentally mediated infectious diseases.

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Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies' sequencing platforms. A composite machine learning model was then used to classify transcriptional profiles into clinically actionable tumor types and subtypes. In total, 95.6% and 89.7% of pediatric solid tumors and lymphoma specimens were correctly classified, respectively. 71.5% of pediatric solid tumors had prediction probabilities > 0.8 and were classified with 100% accuracy. Similarly, for lymphomas, 72.4% of samples that had prediction probabilities > 0.6 were classified with 97.6% accuracy. Additionally, FOXO1 fusion status was predicted accurately for 97.4% of rhabdomyosarcomas and MYCN amplification was predicted with 88% accuracy in neuroblastoma. Whole transcriptome sequencing from FFPE-derived pediatric solid tumor and lymphoma samples has the potential to provide clinical classification of both tissue lineage and core genomic classification. Further expansion, refinement, and validation of this approach is necessary to explore whether this technology could be part of the solution of addressing the diagnostic limitations in LMIC.

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Perfilación de la Expresión Génica , Linfoma , Humanos , Niño , Linfoma/genética , Linfoma/diagnóstico , Linfoma/clasificación , Perfilación de la Expresión Génica/métodos , Transcriptoma , Aprendizaje Automático , Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/clasificación , Preescolar , Masculino , Femenino , Proteína Forkhead Box O1/genética , Rabdomiosarcoma/genética , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/clasificación , Biomarcadores de Tumor/genética , Adolescente , Lactante

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There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate cancer progression. Additionally, optimized machine learning classifier analysis reveals proteomic signatures capable of detecting the disease prior to biopsy, performing on par with an accepted clinical risk calculator benchmark.

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Biomarcadores de Tumor , Neoplasias de la Próstata , Proteómica , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/sangre , Biomarcadores de Tumor/sangre , Proteómica/métodos , Espectrometría de Movilidad Iónica/métodos , Antígeno Prostático Específico/sangre , Anciano , Aprendizaje Automático , Persona de Mediana Edad

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In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels-the key constituents of the vascular system-are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease.

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Células Endoteliales , Enfermedades Renales , Riñón , Humanos , Células Endoteliales/metabolismo , Animales , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología

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Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.

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Proteínas de la Matriz Extracelular , Matriz Extracelular , Degeneración Macular , Epitelio Pigmentado de la Retina , Animales , Ratones , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de los fármacos , Degeneración Macular/patología , Degeneración Macular/genética , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Humanos , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Piridinas/farmacología , Pirimidinas/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/genética , Modelos Animales de Enfermedad , Distrofias Retinianas/metabolismo , Distrofias Retinianas/patología , Distrofias Retinianas/genética , Drusas del Disco Óptico/congénito

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OBJECTIVE: This study, conducted in collaboration with the University of North Carolina (UNC)-Chapel Hill's Ackland Art Museum, assessed student experiences in a facilitated visual art experience designed to foster cultural intelligence among 143 first-year Doctor of Pharmacy students at the UNC Eshelman School of Pharmacy. METHODS: A post-event survey was used to collect data on student perceptions of this experience and its implications. Quantitative items were analyzed using descriptive statistics. Qualitative items were deductively coded using the 4 domains of the Cultural Intelligence Framework: cultural awareness, cultural knowledge, cultural practice, and cultural desire. A convergent parallel mixed-methods approach was used to gain a deeper understanding of the data. RESULTS: Of the 143 students who completed the survey (response rate = 99%), nearly all agreed (n = 60, 42%) or strongly agreed (n = 70, 49%) that the art experience was valuable. Students indicated that it increased their confidence in having open dialogue concerning equity, inclusivity, and race, expanded their perspectives about the implications of inequities, and provided knowledge they can apply in their careers as health science professionals. Findings revealed students' acknowledgment of their own backgrounds, enhanced understanding of bias and historical contexts, recognition of relevance to pharmacy practice, and expressed a desire for further cultural understanding. CONCLUSION: This research underscores the potential of visual art and museum partnerships in fostering positive perceptions and beliefs about cultural intelligence among aspiring pharmacists.

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Medical researchers are increasingly utilizing advanced LLMs like ChatGPT-4 and Gemini to enhance diagnostic processes in the medical field. This research focuses on their ability to comprehend and apply complex medical classification systems for breast conditions, which can significantly aid plastic surgeons in making informed decisions for diagnosis and treatment, ultimately leading to improved patient outcomes. Fifty clinical scenarios were created to evaluate the classification accuracy of each LLM across five established breast-related classification systems. Scores from 0 to 2 were assigned to LLM responses to denote incorrect, partially correct, or completely correct classifications. Descriptive statistics were employed to compare the performances of ChatGPT-4 and Gemini. Gemini exhibited superior overall performance, achieving 98% accuracy compared to ChatGPT-4's 71%. While both models performed well in the Baker classification for capsular contracture and UTSW classification for gynecomastia, Gemini consistently outperformed ChatGPT-4 in other systems, such as the Fischer Grade Classification for gender-affirming mastectomy, Kajava Classification for ectopic breast tissue, and Regnault Classification for breast ptosis. With further development, integrating LLMs into plastic surgery practice will likely enhance diagnostic support and decision making.

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Children infer personality traits from faces when they are asked explicitly which face appears nice or mean. Less is known about how children use face-trait information implicitly to make behavioral evaluations. We used the Ambiguous Situations Protocol to explore how children use face-trait information to form interpretations of ambiguous situations when the behavior or intention of the target child was unclear. On each trial, children (N = 144, age range = 4-11.95 years; 74 girls, 67 boys, 3 gender not specified; 70% White, 10% other or mixed race, 5% Asian, 4% Black, 1% Indigenous, 9% not specified) viewed a child's face (previously rated high or low in niceness) before seeing the child's face embedded within an ambiguous scene (Scene Task) or hearing a vignette about a misbehavior done by that child (Misbehavior Task). Children described what was happening in each scene and indicated whether each misbehavior was done on purpose or by accident. Children also rated the behavior of each child and indicated whether the child would be a good friend. Facial niceness influenced children's interpretations of ambiguous behavior (Scene Task) by 4 years of age, and ambiguous intentions (Misbehavior Task) by 6 years. Our results suggest that the use of face-trait cues to form interpretations of ambiguous behavior emerges early in childhood, a bias that may lead to differential treatment for peers perceived with a high-nice face versus a low-nice face.

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Grupo Paritario , Percepción Social , Humanos , Masculino , Femenino , Niño , Preescolar , Reconocimiento Facial , Conducta Infantil/psicología , Personalidad , Conducta Social

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BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive genetic condition that results in reduced enzymatic functioning within the phenylalanine hydroxylase (PAH) pathway, which is involved in the metabolism of phenylalanine (Phe) into tyrosine (Tyr). Without dietary intervention, individuals with PKU exhibit significantly elevated levels of Phe, which is presumed to cause severe neurological dysfunction and other associated health risks. Carriers of PKU are heterozygotes for a PAH gene mutation and are typically described in the literature as "unaffected." However, decades of existing research challenges this classical thinking and it is plausible that these individuals currently classified as carriers may present with an intermediate phenotype or may be "moderately affected." SUMMARY: The purpose of this scoping review was to explore this hypothesis further, by searching for and summarizing existing literature on metabolism and health outcomes among PKU carriers. Preliminary research has suggested that some PKU carriers exhibit reduced PAH enzyme function, and relatedly, elevated circulating Phe levels compared to noncarriers. In addition, Phe dosing trials have further demonstrated that carriers have increased Phe levels and decreased Tyr levels compared to noncarriers. Because of these metabolic perturbations, it is biologically plausible for carriers to experience an intermediate phenotype in terms of metabolic consequences and clinical outcomes. While these outcomes have yet to be thoroughly explored, early research has found associations between PKU carrier status and lower IQs as well as decreased executive functioning, memory, processing speed, and inhibitory control. The PAH pathway is also involved in melanogenesis, and research has demonstrated increased melanoma risk among PKU carriers. However, there are many limitations to this research, and thus whether or not carriers are clinically impacted cannot yet be conclusively determined. KEY MESSAGE: Overall, while preliminary research suggests a possible intermediate phenotype among PKU carriers, the current available research is limited and PKU carriers are still clinically considered "unaffected." This review outlines the current literature while discussing future research endeavors related to the metabolism and health of PKU carriers.

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Heterocigoto , Fenilalanina Hidroxilasa , Fenilalanina , Fenilcetonurias , Fenilcetonurias/genética , Humanos , Fenilalanina Hidroxilasa/genética , Fenilalanina Hidroxilasa/metabolismo , Fenilalanina/sangre , Fenilalanina/metabolismo , Fenotipo , Mutación , Tirosina

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The Gram-negative ESKAPE bacterium Pseudomonas aeruginosa has become a pathogen of serious concern due its extensive multi-drug resistance (MDR) profile, widespread incidences of hospital-acquired infections throughout the United States, and high occurrence in wound infections suffered by warfighters serving abroad. Bacteriophage (phage) therapy has received renewed attention as an alternative therapeutic option against recalcitrant bacterial infections, both as multi-phage cocktails and in combination with antibiotics as synergistic pairings. Environmental screening and phage enrichment has yielded three lytic viruses capable of infecting the MDR P. aeruginosa strain PAO1. Co-administration of each phage with the carbapenem antibiotics ertapenem, imipenem, and meropenem generated enhanced overall killing of bacteria beyond either phage or drug treatments alone. A combination cocktail of all three phages was completely inhibitory to growth, even without antibiotics. The same 3× phage cocktail also disrupted PAO1 biofilms, reducing biomass by over 75% compared to untreated biofilms. Further, the phage cocktail demonstrated broad efficacy as well, capable of infecting 33 out of 100 diverse clinical isolate strains of P. aeruginosa. Together, these results indicate a promising approach for designing layered medical countermeasures to potentiate antibiotic activity and possibly overcome resistance against recalcitrant, MDR bacteria such as P. aeruginosa. Combination therapy, either by synergistic phage-antibiotic pairings, or by phage cocktails, presents a means of controlling mutations that can allow for bacteria to gain a competitive edge.

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Antibacterianos , Carbapenémicos , Farmacorresistencia Bacteriana Múltiple , Terapia de Fagos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/virología , Pseudomonas aeruginosa/efectos de los fármacos , Carbapenémicos/farmacología , Antibacterianos/farmacología , Infecciones por Pseudomonas/terapia , Infecciones por Pseudomonas/microbiología , Biopelículas/efectos de los fármacos , Bacteriófagos/fisiología , Pruebas de Sensibilidad Microbiana , Humanos , Fagos Pseudomonas/fisiología , Imipenem/farmacología

RESUMEN

Background: Large population-based registries, such as the Surveillance, Epidemiology and End Results (SEER) Registry, help in the study of rare tumors, including medullary thyroid cancer (MTC), but lack data to understand the natural history of the disease. The Medullary Thyroid Cancer Collaborative Registry (MTCCoRe) is an exhaustive multi-institutional collection of demographic, clinical, and pathological data. To determine the extent to which MTCCoRe represents the real-world MTC population, we compared the characteristics of patients enrolled in MTCCoRe with patients enrolled in population-based cancer registries. Methods: Comparison of demographic and clinical characteristics of MTC patients who were enrolled in MTCCoRe, Texas Cancer Registry (TCR), California Cancer Registry (CCR), and SEER between 1995 and 2018. Results: A total of 1416 patients were identified in MTCCoRe, 329 in TCR, 2105 in CCR, and 3820 in SEER. Percentages of patients 20-54 years in MTCCoRe were 58.0%, 50.2% in TCR, 47.2% in CCR, and 44.8% in SEER (p < 0.0001). About half of the patients were female (55.9% in MTCCoRe, 61.4% in TCR, 59% in CCR, and 57.5% in SEER (p = 0.3). Percentages of Hispanic and Black patients differed among cohorts (10.1% and 3.8% for MTCCoRe, 23.7% and 8.2% for TCR, 24.8% and 4.9% in CCR, and 15.9% and 8.2% for SEER, respectively; p < 0.001). MTCCoRe patients presented with more advanced T and N classifications than patients in the other registries (MTCCoRe, 28.6% T3-4 and 49.4% N1; TCR, 12.7% and 32.2%; CCR, 18.6% and 32.4%; and SEER, 24% and 37.8%; p < 0.0001). Prevalence of M1 disease was 10% in MTCCoRe, 11.9% in TCR, 14.1% in CCR, and 9.5% in SEER (p < 0.0001). In the MTCCoRe, 11.4% underwent systemic therapy (compared with 0.3% in TCR and 5.6% in CCR). Conclusions: The clinicodemographic profile of patients with MTC enrolled in a multi-institutional registry differs from those enrolled in population-based databases, with lower proportions of Hispanic and Black patients but additive data on treatment modalities. Moving forward, MTCCoRe and other registry and clinical trial enrollment efforts should intentionally include underrepresented groups via community engagement techniques, patient stakeholder involvement, and inclusion of languages other than English in study materials to yield more generalizable results and conclusions.

Asunto(s)

Carcinoma Neuroendocrino , Sistema de Registros , Programa de VERF , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Femenino , Masculino , Persona de Mediana Edad , Adulto , Carcinoma Neuroendocrino/epidemiología , Carcinoma Neuroendocrino/patología , Adulto Joven , Anciano , Adolescente , California/epidemiología , Niño , Texas/epidemiología , Anciano de 80 o más Años

RESUMEN

BACKGROUND: Breast cancer is one of the most common types of cancer, with around 2.3 million cases diagnosed in 2020. One in five cancer patients develops chronic lymphedema caused by multifactorial triggers and treatment-related factors. This can lead to swelling, skin infections, and limb dysfunction, negatively affecting the patient's quality of life. This retrospective cohort study aimed to determine the associations between demographic and breast cancer characteristics and postoperative cellulitis in breast cancer survivors who underwent lymphovenous bypass surgery (LVB) at Mayo Clinic, Florida. METHODS: We performed a retrospective chart review. Data were collected retrospectively from 2016 to 2022. Sixty adult breast cancer survivors who underwent LVB were included in the final analysis based on specific inclusion and exclusion criteria. Patients were excluded if they did not meet the inclusion criteria or had incomplete follow-up data. Demographic and surgical data were extracted, including body mass index (BMI), type of anastomosis, number of anastomoses, and preoperative cellulitis status. Lymphedema measurements were performed using tape measurements. Fisher's exact test was used to determine statistically significant associations between variables and postoperative cellulitis. RESULTS: Postoperative cellulitis was more common in patients aged 60 to 69 years (43.2%), whites (75.0%), overweight or obese (90.9%), with one to four anastomoses (81.8%), and nonsmokers (79.5%). The mean International Society of Lymphology (ISL) criteria for both postoperative cellulitis and no postoperative cellulitis was 1.93. Statistically significant associations with postoperative cellulitis were found for the number of anastomoses (p = 0.021), smoking status (p = 0.049), preoperative cellulitis (p = 0.04), and the length of years with lymphedema diagnosis variable (p = 0.004). CONCLUSION: Our results suggest that a greater number of anastomoses, smoking, preoperative cellulitis, and years with lymphedema are significantly associated with an increased risk of postoperative cellulitis. Awareness of these risk factors is crucial for monitoring and early treatment of infections following surgery.