Beyond struggle: A strengths-based qualitative study of cannabis use among queer and trans youth in Québec.

BACKGROUND: Queer and trans (QT) youth report higher rates of cannabis use than their cisgender and heterosexual peers. Explanations for this have overwhelmingly focused on the difficulties QT youth face, while little research has examined how cannabis use can relate to QT youth's strengths. We sought to explore how cannabis use could be involved in the experiences of QT youth from a strengths-based perspective. METHODS: We conducted a QT youth-led, community-based study composed of 27 semi-structured interviews with QT young adults aged 21-25 years and living in Québec who use(d) cannabis regularly. Through reflexive thematic analysis (Braun & Clarke, 2019), we used a strengths-based lens informed by the Minority Strengths Model (Perrin et al., 2020) to explore how cannabis use featured in participants' efforts to survive and thrive. RESULTS: We generated three themes representing how cannabis featured in participants' efforts to survive and thrive. First, cannabis was used to facilitate the production of an authentic QT self, a process that involved self-discovery, introspection, exploration, awareness, and expression. Cannabis supported, accompanied, and/or complicated this process. Second, cannabis use (and non-use) was involved in building QT community and connection, which constituted a crux of participants' wellbeing. Third, cannabis was used to face adversity, such as marginalization, QT oppression, mental health challenges, and structural under-resourcing. This adversity contrasted experiences of QT identities themselves, which were described as a source of joy and pride. CONCLUSION: Our analysis illustrates many ways in which cannabis use (and non-use) features in QT youth's efforts to survive and thrive. As a result, we encourage loved ones, clinicians, researchers and policy makers to adopt a view of QT cannabis use that is expansive and inclusive of QT youth's strengths.

Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer's disease spectrum.

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer's disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aß plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated Aß compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct Aß signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of Aßx-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more Aßx-40 and less Aßx-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the Aß peptide content in coarse grain plaques resembled that of vascular Aß deposits (CAA) though with relatively higher levels of Aß1-42 and pyroglutamated Aßx-40 and Aßx-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aß43 and atypical clinical manifestations.

INTRODUCTION: Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely. METHODS: To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). RESULTS: An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aß43). PSEN1 peptide maturation was unimpaired. DISCUSSION: We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation. HIGHLIGHTS: PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aß43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.

Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

FixNCut: single-cell genomics through reversible tissue fixation and dissociation.

The use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.

Effect of a selective personality-targeted prevention program on 7-year illicit substance related outcomes: A secondary analysis of a cluster randomized controlled trial.

BACKGROUND: This study evaluated the efficacy of the selective personality-targeted PreVenture program in reducing cannabis and stimulant use over a 7-year period spanning adolescence and early adulthood. METHODS: A cluster randomized controlled trial was conducted in 14 Australian schools. Schools were randomized to PreVenture, a brief personality-targeted selective intervention, comprising two 90-minute facilitator-led sessions delivered one week apart, or a control group (health education as usual). Only students who scored highly on one of four personality traits (anxiety sensitivity, negative thinking, impulsivity, sensation seeking) were included. Students completed online self-report questionnaires between 2012 and 2019: at baseline; post-intervention; 1-, 2-, 3-, 5.5- and 7-years post-baseline. Outcomes were past 6-months cannabis use, stimulant use (MDMA, methamphetamine or amphetamine) and cannabis-related harms. RESULTS: The sample comprised 438 adolescents (Mage=13.4 years; SD=0.47) at baseline. Retention ranged from 51% to 79% over the 7-years. Compared to controls, the PreVenture group had significantly reduced odds of annual cannabis-related harms (OR=0.78, 95% CI=0.65-0.92). However, there were no significant group differences in the growth of cannabis use (OR=0.84, 95% CI=0.69-1.02) or stimulant use (OR=1.07, 95% CI=0.91-1.25) over the 7-year period. CONCLUSIONS: PreVenture was effective in slowing the growth of cannabis-related harms over time, however owing to missing data over the 7-year trial, replication trials may be warranted to better understand the impact of the PreVenture intervention on cannabis and stimulant use among young Australians. Alternative implementation strategies, such as delivering the intervention in later adolescence and/or providing booster sessions, may be beneficial.

The Role of Executive Function at 6 Years in the Association between Behavioral Inhibition at 5 Years and Anxiety at 7 Years.

EF skills play a central role in the etiology and maintenance of anxiety, but it is unclear whether they act as moderators or mediators in the relation between early behavioral inhibition (BI) and later anxiety. The current study tested two models by examining whether two executive functions (EF) skills (cognitive flexibility and working memory) assessed at age 6 acted as moderators or mediators in the relation between BI at 5 years and anxiety symptoms at 7 years. The sample consisted of 422 children from the Quebec Longitudinal Study of Child Development. We tested the moderation model, main and interaction effects using hierarchical multiple regression analyses and the mediation model with the product of coefficients test. Results showed that higher BI at 5 years predicted high anxiety at 7 years only at low levels of cognitive flexibility or working memory at 6 years. This suggests that high levels of cognitive flexibility or working memory at 6 years may act as protective factors. In contrast, neither cognitive flexibility nor working memory at age 6 acted as mediators in the association between BI at 5 years and anxiety at 7 years. Results support the hypothesis that goal-driven cognitive control processes act as moderators and promote adaptive functioning by dampening the effect of early BI on later anxiety.

Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone.

Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aß) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aß as the root cause of AD. We previously reported human transmission of Aß pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt-Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aß seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aß can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aß assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.

Peroxisomal ß-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer.

BACKGROUND: Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal ß-oxidation (perFAO) to PCa viability and therapy response. METHODS: Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa. RESULTS: DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation. CONCLUSION: Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.

Longitudinal Study of Early Adversity and Disturbing Dream Frequency: Moderating Role of Early Negative Emotionality.

Although disturbing dreams are prevalent in youth and are associated with psychopathology, little is known about their developmental course and risk factors. We aimed to examine the association between early social environment and subsequent disturbing dream frequency across adolescence as moderated by early negative emotionality. Measures of children's early social environment and negative emotionality were collected from the mothers of 410 children (5-42 months old) and measures of disturbing dream frequency directly from the children (13-18 years old). Preliminary steps identified subgroups of families with distinct profiles of social environment using latent variable mixture modeling, and captured changes in disturbing dream frequency using latent growth modeling. Regression and moderation analyses were conducted to test the study objectives. Results showed that the diverse family patterns were best captured by two profiles reflecting adverse and positive social environments and that overall disturbing dream frequency decreased during adolescence. Moderation analyses showed that when early negative emotionality was higher, DD frequency was not only more elevated in an adverse environment, but lower in a positive environment. These results indicate that the development of disturbing dreams is most strongly associated with a combination of individual and environment factors. Our study adds to the literature by refining our conception of individual traits and disturbing dream development and has implications for the prevention of bad dreams, nightmares, and associated psychopathologies.

Emotion Dysregulation Is Associated With Increased Problem Cannabis Use Among Emerging Adults During COVID-19.

OBJECTIVE: Emerging adulthood (18-25 years) is associated with peak prevalence of cannabis use. Although population-based longitudinal studies have found little change in cannabis use among emerging adults during COVID-19, research examining changes among vulnerable subgroups is lacking. The present study examined the association between emotion dysregulation at 23 years and change in cannabis use frequency and problem cannabis use among a large sample of emerging adults, from before to during the COVID-19 pandemic. METHOD: Longitudinal data were analyzed from 1,226 emerging adults (59% female; n = 738 reported cannabis use) who completed online surveys before the pandemic (2019; age 21) and 1 year into COVID-19 (2021; age 23) as part of the Québec Longitudinal Study of Child Development. RESULTS: There was no significant overall within-person change in cannabis use outcomes during COVID-19 among the emerging adult sample. However, emotional clarity (a dimension of emotion dysregulation) at 23 years significantly moderated change in problem cannabis use during COVID-19. Namely, low emotional clarity at 23 years was associated with increased problem cannabis use (B = 0.79, 95% CI [0.23, 1.34]), whereas high emotional clarity at 23 years was associated with decreased problem cannabis use (B = -0.68, 95% CI [-1.27, -0.09]) during COVID-19, among men only. CONCLUSIONS: Findings highlight the need to consider changes in cannabis use during COVID-19 among emerging adults with elevated emotion dysregulation (and particularly, low emotional clarity among men) and reiterate the need for supports and targeted interventions to reduce cannabis use and decrease associated harms as society emerges from COVID-19.

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer.

BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.

Clinical considerations in early-onset cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-ß CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognized and may result from genetic or iatrogenic causes that warrant specific and focused investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-ß CAA (APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2) and non-amyloid-ß CAA (associated with ITM2B, CST3, GSN, PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognized iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease.

A thorough investigation of the bifactor model of psychopathology in a representative birth cohort: Testing internal and predictive validity to inform models of comorbidity.

This study used symptom dimensions reflecting DSM-V internalizing, externalizing, eating disorders, and substance use (SU) and related problems to thoroughly investigate the structure of psychopathology in mid-adolescence (15 and 17 years, N = 1,515, 52% female). Compared to other hierarchical configurations (unidimensional, correlated factors, or higher-order model), a bifactor model of psychopathology wherein all first-order symptom dimensions loaded onto a second-order general psychopathology factor (P factor) and one of three, second-order specific internalizing, externalizing, or SU factors, best captured the structure of the psychopathology in mid-adolescence. This bifactor model was then used to predict several distinct mental health disorders and alcohol use disorder (AUD) at 20 years, via a structural equation model (SEM). The P factor (bifactor model) was associated with all but one outcome (suicidal ideation without an attempt), at 20 years. Controlling for the P factor, there were no additional, positive, temporal cross-associations (i.e., between mental health (mid-adolescence) and AUD at 20 years, or between SU (mid-adolescence) and mental health problems at 20 years). These results are bolstered by findings from a well-fitting correlated factors model. Namely, when mid-adolescent psychopathology was modeled using an adjusted correlated factors model, associations with outcomes at 20 years were largely masked, with no significant partial, temporal cross-associations. Thus, collectively, findings indicate that comorbidity between SU and mental health in youth may be largely attributable to an underlying liability to experience both problems (i.e., P factor). Ultimately, results support targeting the common liability to psychopathology in the prevention of later mental health problems and AUD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The PSEN1 E280G mutation leads to increased amyloid-ß43 production in induced pluripotent stem cell neurons and deposition in brain tissue.

Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer's disease alter the processing of amyloid precursor protein, leading to the generation of various amyloid-ß peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-ß peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-ß peptide profiles and presenilin 1 protein maturity. We also compared amyloid-ß peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-ß ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-ß ratios. Amyloid-ß42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-ß42:40 was not increased in the R278I line compared with controls. The amyloid-ß43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-ß peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer's disease may inform our understanding of clinical heterogeneity.

Transactional associations between vocabulary and disruptive behaviors during the transition to formal schooling.

This study investigated the transactional relations between vocabulary and disruptive behaviors (DB; physical aggression and opposition/rule breaking/theft and vandalism), during the transition to formal schooling, using a community sample of 572 children. Cross-lagged panel model analyses were used to examine bidirectional relationships, comparing physical aggression to non-aggressive DB. Transactional associations between vocabulary and DB were observed, coinciding with school entry. Lower vocabulary in preschool (60mo.) was predictive of higher physical aggression scores in kindergarten. In turn, higher physical aggression in kindergarten was predictive of lower vocabulary in 1st grade. For non-aggressive DB, recurrent associations were found. Lower verbal skills in preschool (42mo.) and kindergarten predicted higher non-aggressive DB scores later in preschool and in 1st grade respectively. In turn, higher non-aggressive DB in kindergarten predicted lower vocabulary scores in 1st grade. In contrast to transactional paths from vocabulary to DB, transactional paths from DB to vocabulary observed after the transition to elementary school remained significant after controlling for comorbid hyperactivity, impulsivity and inattention behaviors, suggesting these links were specific to aggressive and non-aggressive DB. Practical implications for prevention are discussed.