Efforts to improve quality of life (QOL) in dementia depend on its accurate conceptualization and assessment. We employed a data-driven network approach to examine the structure of relationships between individual QOL items. This approach allowed us to capture the complexity and multidimensional nature of QOL from the perspective of the person with dementia and their carer. Participants with dementia (n = 128) and carers completed the Quality of Life in Alzheimer's Disease questionnaire (QOL-AD), and measures of depressive symptoms, cognition, and functional abilities of the person with dementia, and carer burden. Gaussian graphical models with regularized partial correlations of QOL-AD items were estimated and compared, and item communities were detected. Central elements that emerged in both self and carer-reported networks included Ability to do Things for Fun, Energy, and Life as a Whole. Memory and Money were less central. Distinct differences were also evident between self- and carer-networks. Whilst Self as a Whole was relatively more central in the self-reported network, Ability to Do Chores and Family were more central in the carer-reported network. Moreover, different communities were detected in the networks, corresponding to domains including socioeconomic, daily, self-referential, and instrumental functioning, with differential correlations to key clinical outcome variables. QOL in dementia is inherently multidimensional and differs when assessed from the viewpoint of the person living with dementia versus their carer. Network approaches offer the granularity required to ensure that targeted interventions can be tailored toward these complementary perspectives.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Increasing evidence implicates systemic lipid perturbation in ALS pathogenesis. However, the extent and nature of apolipoprotein changes underlying lipid perturbations in ALS remain largely unknown. To address this, we performed a comprehensive analysis of major apolipoproteins involved in lipid metabolism and examined their association with lipoprotein membrane lipids in sporadic ALS (n = 32) and age-matched healthy controls (n = 32), using ELISA and liquid chromatography-mass spectrometry. Compared with controls, serum levels of apoB, apoCI, apoCII, apoCIII and apoE were significantly elevated in ALS, whereas apoAI and apoAII were unchanged. Distributional analyses demonstrated a relative decrease in apoAI and an increase in apoB in ALS, resulting in an elevated apoB/apoAI ratio, a marker of atherogenic risk, alongside a reduced apoAI/apoE ratio. Correlation analyses revealed strengthened interrelationships among apolipoproteins in ALS, suggesting altered regulatory coordination. At the lipid level, phosphatidylcholine (PC) was increased, whereas sphingomyelin (SM) was reduced in ALS serum. Notably, the strong associations of apoB to both PC and SM observed in controls were absent in ALS. Biomarker analyses identified apoE as the strongest discriminator between ALS and control groups. Collectively, these findings demonstrate a coordinated disruption of apolipoproteins and lipoprotein-associated lipids in ALS serum, with likely functional consequences for lipoprotein metabolism. This study provides new insights into lipid dysregulation in ALS pathobiology and supports the emerging view that ALS encompasses not only neurodegenerative processes but also systemic metabolic reprogramming.
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Background and Objectives: Palmoplantar pustulosis (PPPust) and palmoplantar psoriasis (PPso) are distinct palm/sole dermatoses that have historically shared the abbreviation "PPP". Though the two-since the advent of advanced biotechnology-are now deemed separate diagnoses, each still falls under the 'palmoplantar spectrum'. It is important to note that PPso and PPPust are each distinct from generalized pustular psoriasis (GPP), a condition that is outside the scope of our study. We quantified the relative efficacy of biologic and small-molecule monotherapies on the palmoplantar spectrum using Bayesian network meta-analyses (NMAs). Materials and Methods: On 6 November 2025, we searched PubMed, Scopus, ClinicalTrials.gov, and citations (i.e., citation mining) for randomized trials of monotherapy reporting PPP Area and Severity Index (PPPASI) outcomes at 12 or 16 weeks; we secondarily investigated fresh pustule-related outcomes at 4 weeks. We ran Bayesian NMAs with uniform priors; nodes were defined by dose and timepoint. Interventions' Surface Under the Cumulative Ranking Curve (SUCRA) values were computed; pairwise effects with 95% credible intervals were also estimated. Sensitivity analyses adjusted for diagnosis (pustulosis vs. psoriasis) via network meta-regression. Results: Twenty trials (n = 2030) with 23 active comparators provided data for 10 endpoints (fresh pustules at 4 weeks; PPPASI-50/75 and mean percentage and absolute PPPASI change at 12 and 16 weeks). Conclusions: The NMA indicates efficacy of ixekizumab and brodalumab (IL-17 inhibitors), guselkumab (IL-23 inhibitor), and spesolimab (IL-36 inhibitor) in managing palmoplantar pustulosis.
Recently, the literature has expanded with peer-reviewed studies on immunomodulatory agents' efficacy on scalp psoriasis-which, in turn, widened knowledge gaps regarding these agents' relative effectiveness. We determined the relative efficacy of immunomodulatory monotherapies for scalp psoriasis. We ran Bayesian network meta-analyses (NMAs) using outcomes related to Psoriasis Scalp Severity Index (PSSI) and scalp-specific Physician's Global Assessment of clear (0) or almost clear (1) (Sc-PGA 0/1). We estimated the relative efficacy of 22 interventions (including placebo), and analyzed 9 outcomes, namely: proportion of participants who attained Sc-PGA 0/1, proportion of participants who achieved 100% improvement in PSSI (PSSI-100), and proportion of participants who achieved 90% improvement in PSSI (PSSI-90) at 8, 12, and 16 weeks. We are the first to provide comparative evidence on the efficacy of newly investigated agents such as deucravacitinib, tildrakizumab, roflumilast and icotrokinra. In general, the IL-17 inhibitors (bimekizumab, ixekizumab, secukinumab, brodalumab) and IL-23 inhibitors (icotrokinra, guselkumab, tildrakizumab) were effective depending upon the outcome and time-point being considered. At 16 weeks, for PSSI-100, ixekizumab 150 mg at weeks 0, 2, 4, 8, and 12 ranked highest; at 16 weeks, for Sc-PGA 0/1 bimekizumab 320 mg every 4 weeks ranked highest; at 8 weeks, for PSSI-100 ixekizumab 80 mg every 2 weeks ranked highest; at 8 weeks, for Sc-PGA 0/1 secukinumab 300 mg at weeks 1, 2, 3 and then every 4 weeks ranked highest. Small-molecule therapies (apremilast, deucravacitinib, roflumilast) improved scalp psoriasis modestly. Our work would guide the design of future studies and clinical decision-making.
Engaging in conversational and story-telling discourse involves an interplay of language and cognitive skills, including working memory, attention, and inference-making. Primary progressive aphasia (PPA) provides a model for exploring discourse, as both language and cognitive abilities change over time with changes in cortical atrophy. Here, associations between morphosyntactic discourse skills and patterns of cortical atrophy are measured over time in nonfluent (nfv), logopenic (lv) and semantic (sv) variants of PPA. Participants were 27 individuals with nfvPPA (M = 66.6 years ± 8.3), 30 lvPPA (M = 66.7 ± 7.3), 33 svPPA (M = 64.8 ± 6.7), and 36 healthy controls (HC; M = 65.5 ± 6.8). Picture descriptions were analysed for word density and diversity, sentence complexity, well-formedness, and fluency annually for up to three timepoints. Associations between language measures and cortical thickness on structural MRI scans were analysed. At timepoint 1, nfvPPA performed below other groups on most measures; lvPPA were differentiated from svPPA on fluency measures only. Longitudinally, utterance length declined in all variants. For nfvPPA, this was linked with reduced sentence complexity and cortical atrophy in regions engaged by higher attentional demand. For lvPPA, it was linked with increasing grammatical errors and atrophy extending into perisylvian language network. No associations were identified for svPPA. Findings provide insight into how discourse production is underpinned by a network that extends beyond classic language regions, with morphosyntactic elements of discourse associated in part with regions involved in domain-general cognitive skills such as error-monitoring and elaborative encoding. Findings can also inform assessment, prognosis, and intervention for communication through the PPA disease course.
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Androgenetic alopecia (AGA) is the most common cause of progressive hair thinning in adults and has traditionally been viewed as an androgen-driven inherited condition. Genomic research now demonstrates that AGA is a complex polygenic disorder involving multiple biological pathways, including androgen signaling, hair follicle development, cell survival, and extracellular matrix remodeling. Genome-wide association studies have identified numerous susceptibility loci, revealing that follicle miniaturization arises from interacting molecular mechanisms rather than a single pathogenic process. Genetic risk and predictive value vary across populations, with many loci identified in European cohorts showing limited transferability to other ancestries, highlighting the need for more diverse genetic studies. In women, genetic studies remain underpowered, and emerging data suggest partially distinct risk architecture compared with male AGA. Pharmacogenetic findings indicate that genetic variation may influence response to commonly used therapies, although no markers are currently validated for routine clinical use. Advances in single-cell and multi-omic approaches are improving understanding of how genetic risk translates into follicular dysfunction, supporting the development of more personalized and mechanism-based treatment strategies.
Organic light-emitting diodes (OLEDs) featuring circularly polarized (CP) electroluminescence (EL) are gaining tremendous attention for their potential in advanced display and photonic applications. Chiral organic molecules and 4d and 5d metal complexes have been extensively studied for their role in the emissive layer of these devices. Here, pioneering work demonstrating EL emission from a chromium(III) complex is presented. Notably, by leveraging the highly polarized spin-flip transitions of enantiopure CrIII complexes, a proof-of-concept device showcasing near-infrared (NIR) CP EL with peaks at 726 and 747 nm and corresponding dissymmetry values up to 0.015 and -0.029 is developed. These findings highlight the potential of earth-abundant CrIII complexes for cutting-edge chiral optoelectronic applications in medicine, security, and quantum communications.
Anxiety is an aggravating comorbidity of many psychiatric disorders that is often underdiagnosed and undertreated, and little is known on the mechanisms underlying its regulation. Here, we find that serum LPA16:0 abundance increases with trait anxiety in both humans and mice; while high LPA16:0 levels are sufficient to reduce the in vitro proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreases hippocampal neurogenesis and stress resilience, whereas LPA1 antagonism or the reduction of platelets, the main source of circulating LPA16:0, increases adult neurogenesis and resilience to acute stress. Conditional knockdown of LPA₁ receptor in neural stem cells is sufficient to enhance cell proliferation in the dentate gyrus. Finally, the inhibition of adult neurogenesis abolishes the beneficial effect of LPA1 antagonism on resilience against both acute and chronic stress. Together, these findings identify circulating LPA16:0 as a biomarker of trait anxiety and LPA16:0-LPA1 signaling as a regulation mechanism of mood-related behavior through the decrease of adult neurogenesis.
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Hidradenitis suppurativa (HS) is a highly comorbid condition understudied in pediatric populations. Furthermore, the underrepresentation of Canadians in HS research limits our evaluation of care in real-world Canadian settings. To describe the demographics, clinical characteristics, psychosocial burden, and management of pediatric HS at a Canadian hospital. We developed the infrastructure for a Canada-wide HS registry and piloted it at a pediatric HS tertiary care centre. A retrospective review of patients seen was performed using data collection forms (DCFs) developed for the registry. The 39 patients included were 53.8% female and 100.0% nonsmokers. Asians were overrepresented compared to other North American studies. Most had Hurley stage II (60.5%) or III (28.9%) disease. Mean delay to diagnosis was 2.1 ± 2.0 years. Obesity (57.9%), acne (30.7%), folliculitis (23.1%), and trisomy 21 (23.1%) were the most common comorbidities. Patients with trisomy 21 had an age of HS onset 3 years younger (P = .0087), and 44.0% had concomitant disseminate and recurrent infundibulofolliculitis. Moderate-to-severe quality of life (QOL) impact was seen in 56.8% of patients, and 17.6% had reported bullying. Of patients prescribed biologics (59.0%), most used 1 (56.6%), while 39.1% switched to a second and 4.3% to a third biologic. Most adalimumab-initiated patients clinically improved (81.0%), but only 2 patients achieved complete remission. Follow-up patients (n = 14) had significant improvements in QOL (P = .038) and pain (P = .026) scores. Distinct demographics, severe disease, and low remission rates characterized our complex HS cohort. Prospective use of these DCFs will enhance our understanding of HS in Canada.
Superficial dermatophyte infections are a common cause of fungal diseases worldwide. These filamentous fungi specialize in degrading keratinized tissues (skin, hair, nails) and show an evolutionary trajectory from zoophilic species to anthropophilic species. In recent years, major human pathogens have emerged from the Trichophyton genus, such as T. indotineae, causing outbreaks of chronic, extensive, and difficult-to-treat dermatophytoses. Herein, we discuss recent findings on host-dermatophyte interactions with a focus on Trichophyton. Since the establishment of infection models that have helped to uncover virulence factors in adhesion, germination, and tissue invasion, new research highlights the role of the transcriptional factor StuA and the serine protease subtilisin 6 in dermatophyte pathogenesis. We also emphasize dermatophyte immunity, as clinicians increasingly encounter patients with chronic infections or, in rare instances, patients with deep and disseminated infections. Although keratinocytes mediate early host defense mechanisms, it is apparent that T-cells, specifically T-helper (Th) cells 1 and 17, are required for controlling dermatophytosis. This protective response is characterized by IFN-γ and IL-17, as well as a delayed-type skin hypersensitivity reaction. By contrast, a skewed Th2-type response - marked by IL-4, IgE, and dermatophyte-specific IgG - is often associated with a worsened clinical prognosis, including the development of chronicity and exacerbation of atopic conditions. Through genomic sequencing, CARD9 was identified as a key signaling molecule in dermatophyte immunity and is linked to the development of deep dermatophytosis, possibly leading to extracutaneous disseminations. Further research efforts are warranted to decipher these complex interactions and to develop new treatment strategies.
The absorption spectra of lanthanide trihalide complexes were calculated using the multiconfigurational SO-CIS(PT2) method, which accounts for spin-orbit coupling, dynamic electron correlation, and the dynamic coupling with the ligands. These complexes exhibit well-characterized hypersensitive transitions whose oscillator strengths depend sensitively on the nature of the ligands. The good agreement among the calculated transition energies, absorption intensities, and experimental spectra highlights the potential of this method for predicting absorption spectra of lanthanide complexes with larger ligands from first principles. Judd-Ofelt parameters were derived from the spin-free manifolds (i.e., without spin-orbit coupling) to avoid state mixing arising from intermediate coupling. Only transitions between manifolds with ΔL = -2 exhibit hypersensitivity. The Judd-Ofelt parameters display a decreasing trend across the lanthanide series and, as expected, an increasing trend along the halide series. In this work, the dynamic coupling model is not expressed in terms of polarizability but is formulated in an orbital framework, facilitating a microscopic rationalization of the observed results.
Overlaps in symptom presentation limits the capacity to predict functional impairment and future care needs in younger-onset dementia syndromes. A general additive model (GAM) was applied to cross-sectional retrospective data from 375 participants with younger-onset dementia; 152 behavioral-variant frontotemporal dementia (bvFTD), 118 Alzheimer's disease (AD), 66 semantic dementia, and 39 progressive nonfluent aphasia (PNFA). This GAM aimed to explore the dynamic interrelationships between established measures of global cognition, apathy, and functional impairment. Our GAM significantly predicted functional impairment in all syndromes with a high explained variance (59.5%). Cognition and apathy emerged as significant predictors of functional impairment in each syndrome (p-values < .015). These relationships were consistently linear in AD, non-linear in SD, and mixed in bvFTD and PNFA (i.e., cognition linear and apathy non-linear). Our study shows the potential prognostic utility of GAMs for identifying syndrome-specific transition periods across group-level staging's of functional impairment. First study to apply a general additive model to functional impairment in younger-onset dementia.Studied 375 individuals with younger-onset Alzheimer's disease or frontotemporal dementia.Apathy and cognition were significant predictors of functional impairment in all syndromes.This modeling has significant implications for syndrome-specific prognosis and management.
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The aetiology of many inflammatory cutaneous diseases is T cell-driven and involves dysregulation of the immune response. The complex nature of the immune system's involvement in these diseases has made the development of effective, safe, and durable treatments challenging, resulting in a continued demand for the development of novel therapeutics. OX40 and its ligand OX40L have been previously identified as a crucial axis in T cell differentiation and function, and are promising targets for the treatment of T cell-driven disease. Development of OX40/OX40L agonists and inhibitors has potential uses in atopic dermatitis, alopecia areata, psoriasis, and more. While trials of these drugs have mainly been conducted in atopic dermatitis, they show promise in treating other dermatological conditions. Studies of amlitelimab and rocatinlimab have shown some efficacy but have demonstrated increased durability of response. Current concerns with the class are the potential for broad immune suppression with antagonists and the potential for worsening disease with agonists. Additional studies will enable us to determine their benefit-risk ratio in the real-world setting.
There is a lack of direct comparative studies evaluating the long-term efficacy of the approved biologic therapies bimekizumab, secukinumab and adalimumab for moderate-to-severe hidradenitis suppurativa (HS) beyond Week 16. To address this evidence gap, this study uses matching-adjusted indirect comparisons (MAIC) to assess and compare their sustained efficacy. To assess the long-term relative efficacy of bimekizumab 320 mg every 2 weeks/every 4 weeks (Q2W/Q4W) in moderate-to-severe HS compared with biologic therapies (secukinumab 300 mg Q2W and Q4W and adalimumab 40 mg every week [QW]) at Week 48-52. Relevant trials were identified as part of a systematic literature review. Individual patient data for bimekizumab trials (BE HEARD I/II; Week 48) were combined and subsequently weighted to match aggregate baseline characteristics of trials for secukinumab (SUNRISE/SUNSHINE; Week 52) and adalimumab (PIONEER I/II; Week 48). Weights for patients receiving bimekizumab were determined using a propensity score model. Unanchored comparisons of reweighted bimekizumab and comparator data for key HS efficacy outcomes were analysed. Bimekizumab Q2W/Q4W demonstrated significantly higher odds of response for all HS Clinical Response (HiSCR) and HS Severity Score System (IHS4) outcomes compared with secukinumab Q4W, including HiSCR50 (odds ratio [OR]: 2.68; 95% confidence interval [CI]: 1.71, 4.19), HiSCR75 (OR: 2.20; 95% CI: 1.48, 3.26) and IHS4-55 (OR: 2.27; 95% CI: 1.48, 3.48); and for HiSCR50/75 compared with adalimumab QW (OR: 2.57; 95% CI: 1.48, 4.44/OR: 1.84; 95% CI: 1.08, 3.13, respectively). Compared with other approved biologics, bimekizumab showed favourable efficacy across the majority of outcomes assessed at Week 48-52, indicating its potential as a durable long-term therapeutic option for patients with moderate-to-severe HS.