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.

Pregnancy renders anatomical changes in hypothalamic substructures of the human brain that relate to aspects of maternal behavior.

Animal studies have shown that pregnancy is associated with neural adaptations that promote maternal care. The hypothalamus represents a central structure of the mammalian maternal brain and hormonal priming of specific hypothalamic nuclei plays a key role in the induction and expression of maternal behavior. In humans, we have previously demonstrated that becoming a mother involves changes in grey matter anatomy, primarily in association areas of the cerebral cortex. In the current study, we investigated whether pregnancy renders anatomical changes in the hypothalamus. Using an advanced delineation technique, five hypothalamic substructures were defined in longitudinal MRI scans of 107 women extracted from two prospective pre-conception cohort studies, including 50 women who were scanned before and after pregnancy and 57 nulliparous control women scanned at a similar time interval. We showed that becoming a mother is associated with volume reductions in the anterior-superior, superior tuberal and posterior hypothalamus. In addition, these structural changes related to hormonal levels during pregnancy and specific aspects of self-reported maternal behavior in late pregnancy, including maternal-fetal attachment and nesting behavior. These findings show that pregnancy leads to changes in hypothalamic anatomy and suggest that these contribute to the development of maternal behavior in humans, supporting the conservation of key aspects of maternal brain circuitry and their role in maternal behavior across species.

Recommendations for a Better Understanding of Sex and Gender in the Neuroscience of Mental Health.

There are prominent sex/gender differences in the prevalence, expression, and life span course of mental health and neurodiverse conditions. However, the underlying sex- and gender-related mechanisms and their interactions are still not fully understood. This lack of knowledge has harmful consequences for those with mental health problems. Therefore, we set up a cocreation session in a 1-week workshop with a multidisciplinary team of 25 researchers, clinicians, and policy makers to identify the main barriers in sex and gender research in the neuroscience of mental health. Based on this work, here we provide recommendations for methodologies, translational research, and stakeholder involvement. These include guidelines for recording, reporting, analysis beyond binary groups, and open science. Improved understanding of sex- and gender-related mechanisms in neuroscience may benefit public health because this is an important step toward precision medicine and may function as an archetype for studying diversity.

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.

Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.

BACKGROUND: In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL. OBJECTIVE: This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients. PATIENTS AND METHODS: In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m2) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3-6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1-2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness-of-fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection. RESULTS: Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified. CONCLUSIONS: A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT01959698.

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.

Antemortem network analysis of spreading pathology in autopsy-confirmed frontotemporal degeneration.

Despite well-articulated hypotheses of spreading pathology in animal models of neurodegenerative disease, the basis for spreading neurodegenerative pathology in humans has been difficult to ascertain. In this study, we used graph theoretic analyses of structural networks in antemortem, multimodal MRI from autopsy-confirmed cases to examine spreading pathology in sporadic frontotemporal lobar degeneration. We defined phases of progressive cortical atrophy on T1-weighted MRI using a published algorithm in autopsied frontotemporal lobar degeneration with tau inclusions or with transactional DNA binding protein of ∼43 kDa inclusions. We studied global and local indices of structural networks in each of these phases, focusing on the integrity of grey matter hubs and white matter edges projecting between hubs. We found that global network measures are compromised to an equal degree in patients with frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions compared to healthy controls. While measures of local network integrity were compromised in both frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, we discovered several important characteristics that distinguished between these groups. Hubs identified in controls were degraded in both patient groups, but degraded hubs were associated with the earliest phase of cortical atrophy (i.e. epicentres) only in frontotemporal lobar degeneration with tau inclusions. Degraded edges were significantly more plentiful in frontotemporal lobar degeneration with tau inclusions than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, suggesting that the spread of tau pathology involves more significant white matter degeneration. Weakened edges were associated with degraded hubs in frontotemporal lobar degeneration with tau inclusions more than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, particularly in the earlier phases of the disease, and phase-to-phase transitions in frontotemporal lobar degeneration with tau inclusions were characterized by weakened edges in earlier phases projecting to diseased hubs in subsequent phases of the disease. When we examined the spread of pathology from a region diseased in an earlier phase to physically adjacent regions in subsequent phases, we found greater evidence of disease spreading to adjacent regions in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions than in frontotemporal lobar degeneration with tau inclusions. We associated evidence of degraded grey matter hubs and weakened white matter edges with quantitative measures of digitized pathology from direct observations of patients' brain samples. We conclude from these observations that the spread of pathology from diseased regions to distant regions via weakened long-range edges may contribute to spreading disease in frontotemporal dementia-tau, while spread of pathology to physically adjacent regions via local neuronal connectivity may play a more prominent role in spreading disease in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions.

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.

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.

Longitudinal relations between autistic-like features and functional somatic symptoms in adolescence.

Abstract: Autistic-like features and functional somatic symptoms (FSS) frequently co-occur. It remains unknown how autistic-like features and FSS affect each other and develop throughout adolescence. This study examined reciprocal relations between autistic-like features and FSS in adolescence. Participants were 2772 adolescents (52.5% male) from the Tracking Adolescents' Individual Lives Survey population and clinical cohort. Data from four waves were included, covering the ages between 11 and 19 years. Autistic-like features were measured using the Children's Social Behavior Questionnaire. FSS were assessed using the Youth Self Report and Adult Self Report, respectively. Using the random intercept cross-lagged panel model, a stable positive, moderately strong between-persons association was found between autistic-like features and FSS. No within-persons reciprocal effects from wave to wave were observed. Secondary analyses revealed a consistent relation with FSS for three different domains of autistic-like features (social and communication behaviors, repetitive behaviors, and self-regulatory behaviors), and highly similar interrelations in a subsample of adolescents with a clinical autism spectrum disorder diagnosis. In conclusion, the co-occurrence between autistic-like features and FSS is stable throughout adolescence. Clinicians working with adolescents with autistic-like features should be alert to the presence FSS, and vice versa.

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.

Event-based modeling of T1-weighted MRI is related to pathology in frontotemporal lobar degeneration due to tau and TDP.

BACKGROUND: In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learning model that determines the characteristic sequence of changes, or "events", occurring during disease progression. EBM also estimates an individual patient's disease "stage" by identifying which events have already occurred. In the present study, we use an EBM analysis to derive stages of regional anatomic atrophy in FTLD-tau and FTLD-TDP, and validated these stages against pathologic burden. METHODS: Sporadic autopsy-confirmed patients with FTLD-tau (N = 42) and FTLD-TDP (N = 21), and 167 healthy controls with available T1-weighted images were identified. A subset of patients had quantitative digital histopathology of cortex performed at autopsy (FTLD-tau = 30, FTLD-TDP = 17). MRI images were processed, producing regional measures of cortical volumes. K-means clustering was used to find cortical regions with similar amounts of GM volume changes (n = 5 clusters). EBM was used to determine the characteristic sequence of cortical atrophy of identified clusters in autopsy-confirmed FTLD-tau and FTLD-TDP, and estimate each patient's disease stage by cortical volume biomarkers. Linear regressions related pathologic burden to EBM-estimated disease stages. RESULTS: EBM for cortical volume biomarkers generated statistically robust characteristic sequences of cortical atrophy in each group of patients. Cortical volume-based EBM-estimated disease stage was associated with pathologic burden in FTLD-tau (R2 = 0.16, p = 0.017) and FTLD-TDP (R2 = 0.51, p = 0.0008). CONCLUSIONS: We provide evidence that EBM can identify sequences of pathologically-confirmed cortical atrophy in sporadic FTLD-tau and FTLD-TDP.

The effectiveness of cognitive behavioural therapy for patients with concurrent hand and psychological disorders.

We investigated the effectiveness of cognitive behavioural therapy (CBT) for patients with psychological disorders thought to be influencing recovery from elective and traumatic hand conditions. Demographic data and psychological assessment scores (Primary Health Questionnaire 9 (PHQ9), General Anxiety Disorder Assessment (GAD7), Impact of Event Scale (IES)) were prospectively collected before and after CBT treatment. One hundred and fourteen patients underwent CBT with 81 completing treatment. Full data was available for 78 (68%) patients. Mean age was 43 (range 13-84) and 63% were women. Sixty-one per cent had sustained a traumatic hand injury. PHQ9, GAD7 and IES scores decreased significantly following treatment. Many patients with hand conditions have associated psychological problems that may influence outcome. CBT in a hand unit setting appears to be an effective treatment. Further research with a control group should investigate whether CBT improves psychological health or if this may occur as patients recover from their physical hand disorder regardless of CBT.Level of evidence: IV.

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.

Protocol Compliance Guiding Angiotensin II Use in Post Cardiovascular Surgery Vasoplegia.

Catecholamines and vasopressin are commonly used in patients with post cardiovascular surgery vasoplegia (PCSV). Multimodal therapy, including methylene blue (MB), hydroxocobalamin, and angiotensin II (Ang II), may improve outcomes in patients who remain hypotensive despite catecholamine and vasopressin therapy. However, a standardized approach has not been established. We created a protocol at Emory Healthcare (Emory Protocol), which provides guidance on norepinephrine equivalent dose (NED) and the use of noncatecholamines in the setting of PCSV and sought to determine the clinical significance of adherence to the protocol. DESIGN: Retrospective study. SETTING: Multisite study at Emory University Hospital. PATIENTS: Patients receiving Ang II for PCSV in any cardiovascular ICU from 2018 to 2020. INTERVENTIONS: Patient encounters were scored on Emory Protocol compliance based on NED (1-5), use of vasopressin (1-2), use of MB (1-2), and documentation of high-output shock (1-4). A compliant score was less than 7, moderately compliant 7 to 8, and poorly compliant greater than 8. Demographics, clinical data, and outcomes were abstracted from the medical records. MEASUREMENTS AND MAIN RESULTS: Of the 78 consecutive patients receiving Ang II for PCSV, overall ICU mortality was 26.9%, with an average compliance score of 6.2. ICU mortality was 21.1% for compliant cases (n = 38), 29.7% for moderately compliant cases (n = 24), and 37.5% for poorly compliant cases (n = 16). In regression analysis, the cumulative compliance score to the Emory Protocol was predictive of ICU mortality (p = 0.027). CONCLUSIONS: Compliance with the Emory Protocol, emphasizing early initiation of the noncatecholamines vasopressin, MB, hydroxocobalamin, and Ang II at lower catecholamine doses in high-output shock, is associated with improved ICU mortality.

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.

Phases of volume loss in patients with known frontotemporal lobar degeneration spectrum pathology.

Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated these findings with postmortem measures of pathological burden. Our frequency-based staging model revealed distinct loci of maximal early cortical atrophy in each group, including dorsolateral and medial frontal regions in FTLD-Tau and ventral frontal and anterior temporal regions in FTLD-TDP. Sørenson-Dice calculations between proteinopathy groups showed little overlap of phases. Conversely, within-group subtypes showed good overlap between 3R- and 4R-tauopathies, and between TDP-43 Types A and C for early regions with subtle divergence between subtypes in subsequent phases of atrophy. Postmortem validation found an association of imaging phases with pathologic burden within FTLD-tau (F(4, 238) = 17.44, p < 0.001) and FTLD-TDP (F(4,245) = 42.32, p < 0.001). These results suggest that relatively early, distinct markers of atrophy may distinguish FTLD proteinopathies during life.

Growing in generosity? The effects of giving magnitude, target, and audience on the neural signature of giving in adolescence.

Giving is essential for forming and maintaining social relationships, which is an important developmental task for adolescents. This pre-registered fMRI study investigated behavioral and neural correlates of adolescents' (N = 128, ages 9 - 19 years) small versus large size giving in different social contexts related to target (i.e., giving to a friend or unfamiliar peer) and peer presence (i.e., anonymous versus audience giving). Participants gave more in the small size than large size condition, more to friends than to unfamiliar peers, and more in the audience compared to anonymous condition. Giving very small or large amounts was associated with increased activity in the medial prefrontal cortex (mPFC) and anterior insula (AI), and older adolescents showed increased lateral and anterior PFC activation for small size giving. We observed activity in the intraparietal cortex (IPL), dorsolateral prefrontal cortex, and AI for giving to friends, but no age-related differences in this activity. Behaviorally, in contrast, we observed that older adolescents differentiated more in giving between friends and unfamiliar peers. Finally, we observed interactions between peer presence and target in the AI, and between giving magnitude and target in the precuneus. Together, findings reveal higher context-dependency of giving and more lateral PFC activity for small versus large giving in older adolescents.

Chronic aryl hydrocarbon receptor activity phenocopies smoking-induced skeletal muscle impairment.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact. METHODS: We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer). RESULTS: Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. CONCLUSIONS: These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.