Development of Gender Non-Contentedness During Adolescence and Early Adulthood.

Adolescence is an important period for the development of gender identity. We studied the development of gender non-contentedness, i.e., unhappiness with being the gender aligned with one's sex, from early adolescence to young adulthood, and its association with self-concept, behavioral and emotional problems, and adult sexual orientation. Participants were 2772 adolescents (53% male) from the Tracking Adolescents' Individual Lives Survey population and clinical cohort. Data from six waves were included (ages 11-26). Gender non-contentedness was assessed with the item "I wish to be of the opposite sex" from the Youth and Adult Self-Report at all six waves. Behavioral and emotional problems were measured by total scores of these scales at all six waves. Self-concept was assessed at age 11 using the Global Self-Worth and Physical Appearance subscales of the Self-Perception Profile for Children. Sexual orientation was assessed at age 22 by self-report. In early adolescence, 11% of participants reported gender non-contentedness. The prevalence decreased with age and was 4% at the last follow-up (around age 26). Three developmental trajectories of gender non-contentedness were identified: no gender non-contentedness (78%), decreasing gender non-contentedness (19%), and increasing gender non-contentedness (2%). Individuals with an increasing gender non-contentedness more often were female and both an increasing and decreasing trajectory were associated with a lower global self-worth, more behavioral and emotional problems, and a non-heterosexual sexual orientation. Gender non-contentedness, while being relatively common during early adolescence, in general decreases with age and appears to be associated with a poorer self-concept and mental health throughout development.

Understanding priorities and needs for child and adolescent mental health in Greece from multiple informants: an open resource dataset.

The Child and Adolescent Mental Health Initiative (CAMHI) aims to enhance mental health care capacity for children and adolescents across Greece. Considering the need for evidence-based policy, the program developed an open-resource dataset for researching the field within the country. A comprehensive, mixed-method, community-based research was conducted in 2022/2023 assessing the current state, needs, barriers, and opportunities according to multiple viewpoints. We surveyed geographically distributed samples of 1,756 caregivers, 1,201 children/adolescents, 404 schoolteachers, and 475 health professionals using validated instruments to assess mental health symptoms, mental health needs, literacy and stigma, service use and access, professional practices, training background, and training needs and preferences. Fourteen focus groups were conducted with informants from diverse populations (including underrepresented minorities) to reach an in-depth understanding of those topics. A dataset with quantitative and qualitative findings is now available for researchers, policymakers, and society [ https://osf.io/crz6h/ and https://rpubs.com/camhi/sdashboard ]. This resource offers valuable data for assessing the needs and priorities for child and adolescent mental health care in Greece. It is now freely available to consult, and is expected to inform upcoming research and evidence-based professional training. This initiative may inspire similar ones in other countries, informing methodological strategies for researching mental health needs.

Six case reports of NTHL1-associated tumor syndrome further support it as a multi-tumor predisposition syndrome.

NTHL1-associated tumor syndrome (NATS) is an autosomal recessive condition characterized by an increased risk for colorectal polyposis and colorectal cancer (CRC). Only 46 case reports have been previously published. In a retrospective review, we analyzed the clinical histories of six patients found to have NATS after genetic counseling and testing. NATS appears to be associated with an increased risk for colorectal polyposis, CRC, female breast cancer, meningiomas, and endometrial cancer. Although research is limited, prior publications have reported a multi-tumor predisposition for individuals with biallelic pathogenic or likely pathogenic variants in NTHL1. Additional data are necessary to further define the cancer risks so affected individuals can be appropriately managed.

Alterations in the inferior fronto-occipital fasciculus - a specific neural correlate of gender incongruence?

BACKGROUND: Increasing numbers of adolescents seek help for gender-identity questions. Consequently, requests for medical treatments, such as puberty suppression, are growing. However, studies investigating the neurobiological substrate of gender incongruence (when birth-assigned sex and gender identity do not align) are scarce, and knowledge about the effects of puberty suppression on the developing brain of transgender youth is limited. METHODS: Here we cross-sectionally investigated sex and gender differences in regional fractional anisotropy (FA) as measured by diffusion MR imaging, and the impact of puberty on alterations in the white-matter organization of 35 treatment-naive prepubertal children and 41 adolescents with gender incongruence, receiving puberty suppression. The transgender groups were compared with 79 age-matched, treatment-naive cisgender (when sex and gender align) peers. RESULTS: We found that transgender adolescents had lower FA in the bilateral inferior fronto-occipital fasciculus (IFOF), forceps major and corpus callosum than cisgender peers. In addition, average FA values of the right IFOF correlated negatively with adolescents' cumulative dosage of puberty suppressants received. Of note, prepubertal children also showed significant FA group differences in, again, the right IFOF and left cortico-spinal tract, but with the reverse pattern (transgender > cisgender) than was seen in adolescents. CONCLUSIONS: Importantly, our results of lower FA (indexing less longitudinal organization, fiber coherence, and myelination) in the IFOF of gender-incongruent adolescents replicate prior findings in transgender adults, suggesting a salient neural correlate of gender incongruence. Findings highlight the complexity with which (pubertal) sex hormones impact white-matter development and add important insight into the neurobiological substrate associated with gender incongruence.

Development and Validation of a Quantitative LC-MS/MS Method for CDK4/6 Inhibitors Palbociclib, Ribociclib, Abemaciclib, and Abemaciclib-M2 in Human Plasma.

BACKGROUND: The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, palbociclib, ribociclib, and abemaciclib, are standard-of-care agents for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative metastatic breast cancer. In support of therapeutic drug monitoring and clinical pharmacokinetic studies, a liquid chromatography coupled with tandem mass spectrometry assay for the simultaneous quantitation of CDK4/6 inhibitors and the major active metabolite M2 of abemaciclib in human plasma has been developed. METHODS: Analytes were extracted from 50 µL of human plasma by precipitating proteins with methanol and then collecting the supernatant. Reversed-phase high-performance liquid chromatography was performed for analyte separation using a biphasic gradient at a flow rate of 0.25-0.5 mL/min. The total run time was 9.5 minutes. The analytes were detected using MS/MS with electrospray ionization operating in positive ion mode. RESULTS: Validation according to the US Food and Drug Administration's guidance showed that the new assay produced accurate (94.7%-107%) and precise (within-run: 1.2%-8.2%; between-run: 0.6%-7.5%) measurements of all analytes over a concentration range of 5-2000 ng/mL. Overall, analyte recoveries were consistent (mean values: 110%-129%). The analytes were also stable in human plasma and the final extract under various storage conditions. Finally, the clinical applicability of the assay was confirmed by quantitation of all analytes in plasma samples obtained from patients treated with CDK4/6 inhibitors. Reproducibility of the measured analyte concentrations in study samples was confirmed successfully by incurred sample reanalysis. CONCLUSIONS: A sensitive liquid chromatography coupled with tandem mass spectrometry method to measure CDK4/6 inhibitors was developed and validated according to the Food and Drug Administration criteria. Quantitation of all analytes in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring and clinical pharmacokinetic studies of CDK4/6 inhibitors.

How to Ensure Inclusivity in Large-Scale General Population Cohort Studies? Lessons Learned with Regard to Including and Assessing Sex, Gender, and Sexual Orientation.

Despite recent advances in the measurement of sex, gender, and sexual orientation in large-scale cohort studies, the three concepts are still gaining relatively little attention, may be mistakenly equated, or non-informatively operationalized. The resulting imprecise or lacking information hereon in studies is problematic, as sex, gender, and sexual orientation are important health-related factors. Omission of these concepts from general population cohort studies might dismiss participants' identity and experiences and pushes research on sexual or gender minority populations toward purposive sampling, potentially introducing selection bias. It also reinforces the unintentional notion of irrelevance of these concepts to health research, ultimately disadvantaging sexual and gender minority populations. Similarly, a lack of uniform measures on sex, gender, and sexual orientation hampers multi-cohort studies in which data from multiple studies are combined, facilitating increased statistical power. This paper discusses the encountered pitfalls and lessons learned on including and assessing sex, gender, and sexual orientation in large-scale general population cohort studies, exemplified by the Dutch Lifelines Cohort Study. Additionally, we propose hands-on strategies on how to operationalize these concepts in an inclusive manner that is useful for large-scale general population cohort studies.

The science of child and adolescent mental health in Greece: a nationwide systematic review.

Evidence-based information is essential for effective mental health care, yet the extent and accessibility of the scientific literature are critical barriers for professionals and policymakers. To map the necessities and make validated resources accessible, we undertook a systematic review of scientific evidence on child and adolescent mental health in Greece encompassing three research topics: prevalence estimates, assessment instruments, and interventions. We searched Pubmed, Web of Science, PsycINFO, Google Scholar, and IATPOTEK from inception to December 16th, 2021. We included studies assessing the prevalence of conditions, reporting data on assessment tools, and experimental interventions. For each area, manuals informed data extraction and the methodological quality were ascertained using validated tools. This review was registered in protocols.io [68583]. We included 104 studies reporting 533 prevalence estimates, 223 studies informing data on 261 assessment instruments, and 34 intervention studies. We report the prevalence of conditions according to regions within the country. A repository of locally validated instruments and their psychometrics was compiled. An overview of interventions provided data on their effectiveness. The outcomes are made available in an interactive resource online [ https://rpubs.com/camhi/sysrev_table ]. Scientific evidence on child and adolescent mental health in Greece has now been cataloged and appraised. This timely and accessible compendium of up-to-date evidence offers valuable resources for clinical practice and policymaking in Greece and may encourage similar assessments in other countries.

Discordance between Adolescents and Parents in Functional Somatic Symptom Reports: Sex Differences and Future Symptom Prevalence.

Functional somatic symptoms, i.e., physical complaints that cannot be sufficiently explained by an objectifiable biomedical abnormality, become increasingly more prevalent in girls than in boys during adolescence. Both parents and adolescents report more functional somatic symptoms in girls, but their reports correspond only limitedly. It remains unknown whether parent-adolescent discordance contributes to the higher symptom prevalence in girls. This study investigated parent-adolescent discordance in reported functional somatic symptoms throughout adolescence, examined the longitudinal association of parent-adolescent discordance with symptom prevalence in early adulthood and focused on sex differences in these processes. Participants included 2229 adolescents (50.7% female) from four assessments (age 11 to 22 years) of the TRAILS population cohort. Parents and adolescents reported significantly more symptoms in girls than in boys during adolescence. Variance analyses showed that throughout adolescence, parents reported fewer symptoms than girls self-reported and more than boys self-reported. Regression analyses using standardized difference scores showed that lower parent-report than self-report was positively associated with symptom prevalence in early adulthood. Polynomial regression analyses revealed no significant interaction between parent-reported and adolescent self-reported symptoms. Associations did not differ between boys and girls. The findings show that lower parent-reported than self-reported symptoms predict future symptom prevalence in both sexes, but this discordance was more observed in girls. The higher functional somatic symptom prevalence in girls might be partly explained by parental underestimation of symptoms.

Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. METHODS: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. RESULTS: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. CONCLUSIONS: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.

Polymer Dots with Enhanced Photostability, Quantum Yield, and Two-Photon Cross-Section using Structurally Constrained Deep-Blue Fluorophores.

Semiconducting polymer dots (Pdots) have emerged as versatile probes for bioanalysis and imaging at the single-particle level. Despite their utility in multiplexed analysis, deep blue Pdots remain rare due to their need for high-energy excitation and sensitivity to photobleaching. Here, we describe the design of deep blue fluorophores using structural constraints to improve resistance to photobleaching, two-photon absorption cross sections, and fluorescence quantum yields using the hexamethylazatriangulene motif. Scanning tunneling microscopy was used to characterize the electronic structure of these chromophores on the atomic scale as well as their intrinsic stability. The most promising fluorophore was functionalized with a polymerizable acrylate handle and used to give deep-blue fluorescent acrylic polymers with Mn > 18 kDa and D < 1.2. Nanoprecipitation with amphiphilic polystyrene-graft-(carboxylate-terminated poly(ethylene glycol)) gave water-soluble Pdots with blue fluorescence, quantum yields of 0.81, and molar absorption coefficients of (4 ± 2) × 108 M-1 cm-1. This high brightness facilitated single-particle visualization with dramatically improved signal-to-noise ratio and photobleaching resistance versus an unencapsulated dye. The Pdots were then conjugated with antibodies for immunolabeling of SK-BR3 human breast cancer cells, which were imaged using deep blue fluorescence in both one- and two-photon excitation modes.