Although early-life stress and trauma may influence cortical development and increase vulnerability to gender dysphoria (GD), the relationship between brain function and childhood traumatic experiences in GD remains unexplored. This study aims to investigate the neurobiological mechanisms underlying GD by examining functional brain alterations and their associations with childhood trauma, neurotransmitter systems, and gene expression patterns. This study recruited 44 transgender women (TW) with GD, 40 cisgender men, and 42 cisgender women controls. Participants were assessed using the Childhood Trauma Questionnaire (CTQ) and Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA), while resting-state fMRI data were analyzed for amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) measures. The transcriptional data were sourced from the Allen Human Brain Atlas. The JuSpace toolbox was used to investigate the atlas-based nuclear imaging-derived neurotransmitter maps. Compared to cisgender controls, TW with GD showed decreased ALFF in the posterior cingulate cortex (PCC) but increased ALFF in the cerebellar lobule IX. TW with GD exhibited decreased fALFF in the right PCC compared to cisgender women. TW with GD also reported higher CTQ total and subscale scores. GIDYQ-AA scores were negatively correlated with ALFF in the PCC. Notably, CTQ total and its subscale scores [emotional abuse and emotional neglect (EN)] were negatively correlated with decreased ALFF in the PCC. Multivariate regression analysis further revealed that interactions between fALFF value of the right PCC × CTQ total and fALFF value of the right PCC × EN independently predicted GIDYQ-AA scores in TW with GD. The altered brain activity in TW with GD was linked to genes enriched in mRNA catabolism and synaptic function, and was correlated with dopaminergic and serotonergic neurotransmission. TW with GD shows PCC hypofunction and cerebellar hyperactivation, which are associated with childhood trauma, especially emotional neglect. These neural alterations are correlated with gene expression and neurotransmitter pathways, suggesting a multilevel neurophysiological framework in TW with GD.
Women are disproportionately affected by depressive disorders relative to men, and mid-life differences like menopause can exacerbate symptoms. Hormone therapy (HT) is a common treatment to ease menopause transitions, including vasomotor and depressive symptoms, that may occur due to menopause-related hormonal changes, but its effects on later-life depressive symptoms remain unclear. Our objective was to examine the association between self-reported post-menopausal HT use and longitudinal changes in depressive symptoms in cognitively unimpaired age-matched older men and women from the Harvard Aging Brain Study and affiliated studies, along with sub-analyses examining interactions with Alzheimer’s Disease (AD) risk factors and neuroimaging markers. Linear mixed-effect models examined the relationship between HT use and changes in the Geriatric Depression Scale (GDS). Secondary analyses tested the moderating effects of apolipoprotein ε4 (APOEε4) status, white matter hyperintensities (WMH), amyloid-β (Aβ) status, medial temporal lobe tau, and hippocampal volume on the association between HT and GDS scores over time. In a sample of 585 individuals (58.3
Gut microbiota induce intestinal Th17 cells in both physiological and disease states, yet whether there are shared mechanisms remains unclear. We previously identified the Fbxw7-Trim21 axis as critical for Alcaligenes faecalis-driven physiological Th17 differentiation. Here, we reveal its dual role in inflammatory bowel disease (IBD)-associated Th17 cell induction. The IBD model was adopted by DSS-induced acute colitis, TNBS-induced acute colitis, Il10−/− chronic mice and Rag1−/− mice transferred with CD4+ T cell chronic colitis. Fbxw7fl/fl, dLck-Cre, Rag1−/−, Il10−/−, Il17aGFP and Trim21−/− mice were used in this paper. Mechanistic studies used molecular and multiomics approaches. mEVs/αCD4/TΔR were constructed by coincubation at 37 °C for 3 h. Dubosiella newyorkensis (D. newyorkensis) were colonized to prevent IBD. Key findings were validated in DSS-induced colitis by orally mEVs/αCD4/TΔR treatment or D. newyorkensis colonized. Indole from IBD-gut microbiota reinforces the interaction between protein kinase PKA and transcription factor SP1, promoting SP1 phosphorylation and activation. Then, SP1 induces more E3 ubiquitin ligase Fbxw7 degradation by promoting E3 ubiquitin ligase Trim21 transcription, causing Th17 cell overproduction. Tryptophan-rich feeding enhances Indole production, aggravating IBD, while D. newyorkensis colonization alleviates IBD by shifting tryptophan catabolism toward Kynurenine. Furthermore, blocking Trim21 function through CD4+ T cell-targeting extracellular vesicles carrying RING domain-deficient Trim21 suppresses Th17 cell generation, mitigating IBD. Our data indicate that Indole-induced Trim21 upregulation is crucial for Th17 cell generation in IBD and propose microbial interventions and Trim21 inhibition as potential therapeutic strategies.
Prescribing cascades, defined as initiation of medications to treat adverse drug reactions caused by other medications, may contribute to polypharmacy in people with type 2 diabetes. We aimed to determine whether commonly used diabetes and cardiovascular medications were associated with subsequent initiation of treatments for their known adverse drug reactions, indicating potential prescribing cascades. We conducted two parallel cohort studies using prescription sequence symmetry analysis to assess asymmetry in the initiation sequence of index medications and corresponding marker medications. Twelve index-marker medication dyads were selected a priori from published literature. Data were obtained from the Scottish Diabetes Research Network national diabetes registry and the Welsh Secure Anonymised Information Linkage Databank between January 2015 and December 2023. Adults aged 40 years or older with type 2 diabetes were eligible if they had incident use of both an index and marker medication within a 365-day period. Adjusted sequence ratios comparing initiation of marker medications after versus before index medications were calculated after adjustment for secular prescribing trends. Ratios greater than 1.0 indicated potential prescribing cascades. Sensitivity analyses examined age, sex, socioeconomic position, comorbidity, and shorter observation windows (90 and 180 days). Estimates from both datasets were pooled using random-effects meta-analysis. A total of 387,338 individuals from the Scottish Diabetes Research Network and 296,582 from the Welsh Secure Anonymised Information Linkage Databank were eligible. Seven of 12 medication dyads showed evidence of prescribing cascades: sodium-glucose cotransporter-2 inhibitors followed by urinary tract infection antibiotics (pooled adjusted sequence ratio 1.14, 95
Rotator cuff tear (RCT) is a leading cause of shoulder pain, disability, and healthcare utilization worldwide, imposing notable individual and societal burden. Despite its high prevalence and impact on quality of life and healthcare costs, the contribution of inherited susceptibility to clinically manifest RCT remains unclear. We conducted a nationwide, population-based twin study by linking the Danish Twin Registry with the Danish National Patient Registry, including all monozygotic (MZ) and dizygotic (DZ) twin pairs born 1940–1980 and alive on January 1st, 1980. RCT cases between 1994 and 2014 were identified using relevant ICD-8 and ICD-10 codes. Cumulative incidence of receiving an RCT diagnosis was estimated, and familial aggregation was assessed using casewise concordance. Genetic and environmental contributions to liability were quantified using biometric twin models. By age 70, the population-based cumulative incidence of RCT was higher in men (6.5
