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Transdiagnostic mental health symptom dimensions predict use of flexible model-based inference in complex environments
Get PDFSymptoms of common mental health problems often pertain to complex inference and decision problems (for example around future social interactions). Such patterns may reflect the breakdown of the fundamental computational processes that ordinarily underpin these behaviours, with the use of flexible goal-directed decision-making being a prime candidate. Here, we used a validated, naturalistic threat inference task to assess the use of goal-directed decision-making in complex interactive decision problems. Participants (n = 1025) completed this task alongside a battery of self-report measures of mental health symptoms and neurodevelopmental characteristics. Participants higher in inattentive/neurodevelopmental symptoms were better able to predict the predator’s behaviour, while those higher in externalising symptoms made more incorrect inferences. Variability in behaviour was better explained by these specific symptom dimensions than by more general factors. Using computational modelling, we show that these associations are mediated by the degree to which individuals use goal-directed decision-making to make inferences about the predator’s behaviour. Our results suggest that symptoms and traits that manifest in real-world environments may result from alterations in the use of complex computational mechanisms
Time on hold:Justice, governance, and the politics of transitions in critical mineral frontiers
Get PDFThis paper examines the concept of temporal justice in the governance of critical minerals, focusing on the period between mineral discovery and the onset of mining. Drawing on qualitative data from fieldwork in the lithium-rich communities of Ewoyaa, Krampa Krom, and Krofu in Ghana’s Mfantsiman municipality, the study examines how time becomes a contested dimension of just transitions. The analysis reveals that the interim period, often marked by legal ambiguities, delayed compensation, and exclusion from decision-making, produces a state of temporal suspension for affected communities. Livelihoods are disrupted, social life is put on hold, and the future becomes uncertain, yet these temporal losses are rarely acknowledged or compensated. The paper argues that this 'freezing of time' constitutes a form of distributive, procedural, and recognition injustice, with long-term implications for community well-being and trust in governance. By foregrounding temporality as a critical lens, the study contributes to our understanding of transition governance and the intersections of the spatial and temporal. It also contributes to emerging debates on just transitions and critical minerals governance, emphasising the need to account for time not only as a resource but as a right. The findings call for governance frameworks that recognise and remediate temporal harms, particularly in the Global South, where communities are often rendered passive in the face of extractive timelines driven by global demand
Integrating Clinical Pharmacists in Cancer Care:The PharmaCAP Model for Improving Pain Management in Low-Resource Settings
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Decoding cytokine networks in ulcerative colitis to identify pathogenic mechanisms and therapeutic targets
Get PDFUlcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract that is characterized by dysregulated cytokine signaling. Treatment outcomes for patients with UC remain suboptimal despite the advent of cytokine-targeting therapies, necessitating a better understanding of the interconnected cytokine signaling networks that are perturbed in patients with UC. To address this, we undertook systems immunology modeling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed patients with UC to build complex cytokine signaling networks underpinned by putative cytokine-cytokine interactions. The generated cytokine networks effectively captured known, physiologically relevant cytokine-cytokine interactions, which we validated in vitro in colonic epithelial organoids derived from patients with UC and with organoids cocultured with innate lymphoid cells. These networks revealed several previously unrecognized aspects of UC pathogenesis. These included the identification of a cytokine subnetwork that is unique to treatment-naive patients with UC, of cytokines with altered interaction patterns across UC disease states (including IL-22, TL1A, IL-23A, and OSM), and of cytokine-cytokine interactions that were mediated by specific members of the Janus-associated kinase (JAK) family. In particular, our network analysis positioned TL1A as an important upstream regulator of TNF and IL-23A (both of which are targeted by approved UC drugs) and suggested it as a potential therapeutic target. Together, these findings open several avenues for guiding future cytokine-targeting therapeutic approaches in UC, and the presented methodology can be readily applied to gain similar insights into other immune-mediated inflammatory diseases.</p
A comprehensive framework for the interpretation of TTN missense variants
No full textBACKGROUND: Missense variants in TTN pose a major challenge in genetic diagnostics due to their high frequency in the general population, the large size of the gene, and the complex multidomain architecture of the titin protein. While the contribution of truncating variants (TTNtv) to titinopathies is well established, the role of rare TTN missense variants remains poorly defined. Advances in computational prediction and functional testing offer new tools to assess their potential pathogenicity, which however are currently not fully utilized for clinical application.METHODS: We analyzed an international cohort of unsolved myopathy cases selected based on the presence of a rare missense variant in trans with a TTNtv. Clinical data were collected from neuromuscular centers worldwide. In silico predictions were generated using AlphaMissense and complemented by minor allele frequency (MAF) and exon usage information. Additional inclusion criteria were based on a MAF < 0.010 and an AlphaMissense score ≥ 0.792 for the missense variants, in accordance with the latest ClinGen guidelines. Selected missense variants were characterized in vitro through protein expression and cell imaging assays to assess their effects on domain solubility and aggregation.RESULTS: Thirty patients with TTNtv/missense combinations were identified, presenting with heterogeneous myopathic phenotypes, ranging from congenital to adult onset. An in-depth analysis on AlphaMissense predictions highlighted those changes most frequently predicted as possibly pathogenic. Functional assays showed that three selected variants with changes to proline, located in β-sheets of Ig domains, led to impaired folding, cytoplasmic aggregation and co-localisation with proteostasis markers. In our cohort, all non-proline mutations occurred at buried sites, while some proline substitutions affected exposed residues. Notably, the variant p.(Gln7023Pro) was identified in 5 unrelated families sharing a conserved haplotype, indicating a common ancestor. This variant and the previously reported p.(Arg25480Pro) now meet ACMG criteria for classification as likely pathogenic.CONCLUSIONS: By integrating clinical, computational, and functional evidence, we propose a framework for interpreting TTN missense variants. Combining multiple lines of evidence is essential for variants' classification and interpretation, especially given TTN complexity. Advancing diagnostic accuracy will require tailored interpretation guidelines and a global effort in data sharing and functional validation.</p
Religious Freedom and Principled Pragmatism:An Augustinian Reading of Finland’s Church-State Settlement
Get PDFThis article offers a theological commentary on religious freedom in Finland through an Augustinian reading of two developments in its contemporary church–state settlement: the Act on the Freedom of Religion (453/2003) and Prosecutor General v. Räsänen (KKO: R2024/57), the so-called Bible-Tweet Case. Together these developments illuminate how a constitutional order understands religion both as a historically embedded institutional reality and as a contested object of civil authority. Responding to the relative absence of sustained theology of law in Finnish church–state scholarship, the article articulates a form of Augustinian pragmatism distilled from Augustine’s mature reflections, especially The City of God and his anti-Donatist letters. This approach foregrounds ordered loves, earthly peace, constrained civil authority, and historical realism as principles for constitutional judgment. Read in this light, the Freedom of Religion Act appears as a constructive instance of such pragmatism, preserving the historically formative role of the Evangelical Lutheran and Orthodox Churches while widening legal recognition and safeguarding freedom of conscience under plural conditions. By contrast, the Bible-Tweet prosecution reveals the strain placed on religious freedom when criminal law is drawn toward adjudicating theological speech. An Augustinian account of limited civil jurisdiction cautions against extending penal authority into the governance of belief while affirming the state’s responsibility to secure civic peace and protect vulnerable groups. The result is not a fixed constitutional template but a disciplined mode of theological reasoning for pluralistic societies
Illness perceptions in Functional Neurological Disorder:A ‘think-aloud’ study of the Revised Illness Perception Questionnaire using content and thematic analysis
Get PDFObjective: To examine the responses of people with Functional Neurological Disorder (FND) regarding issues arising in the interpretation or application of the revised Illness Perception Questionnaire (IPQ-R). Secondly, to elicit themes relevant to understanding how people with FND conceptualise their illness.Methods and Measures: Nine participants with various FND symptoms took part in ‘think-aloud’ interviews whilst completing the IPQ-R. Participants’ responses were examined with content and thematic analysis. Results: 221 issues emerged during IPQ-R completion, with the most frequent being participants' uncertainty and insufficient knowledge about FND or treatments, leading to ‘I don’t know’ verbal comments and ‘neither agree nor disagree’ responses. Themes revealed 1) lack of personalised formulation, 2) significant impact of FND and comorbidities on quality of life and functioning, 3) isolation and difficulties in accessing support, and 4) nuanced ideas about the role of trauma and neurodiversity and maintaining hope. Conclusion: Illness perceptions in FND reflect a dynamic relationship between the complexity and uncertainty of the condition, comorbidities, stigma and treatment access difficulties. Co-produced qualitative work should explore different FND subtypes at serial timepoints in treatment to adapt the IPQ-R as a meaningful and sensitive measure for FND, which considers neurodivergent people and trauma survivors
A Rapid Appraisal of How Alcohol Is Screened and Treated Amongst Minoritised Ethnic Service Users Within Community Mental Health Settings
Get PDFIntroduction: Close to half of those engaged with community mental health teams (CMHT) report an alcohol or drug problem. UK public health guidance recommends that these services screen for harmful alcohol use, but reporting may be less likely amongst minoritised ethnic groups. This study aimed to explore: (i) the prevalence of screening and referrals to alcohol services within CMHTs and differences across ethnic groups; (ii) how alcohol use is assessed and treated in CMHTs, and tailored for minoritised ethnic service users; and (iii) staff and minoritised ethnic service users' experiences of assessing and reporting alcohol use. Methods: A rapid appraisal was conducted which triangulated data across patient healthcare records (aim 1), online survey (aim 2), interviews and focus groups (aim 3) with three CMHT services within an NHS Mental Health Foundation Trust in North-West England. Data was analysed using framework analysis. Results: Both patient notes and survey data showed that alcohol was seldom assessed using formal tools. Three themes were developed reflecting differences in the barriers of reporting and assessing alcohol use for minoritised ethnic service users and staff. With barriers for the former including information sharing and barriers for the latter including protecting the therapeutic relationship. Discussion and Conclusions: Triangulating data from across different sources highlights the complex challenges that services face in meeting the recommendations around alcohol screening in CMH services. Our findings have implications on the need for staff in mental health services to better understand and accommodate the needs of minoritised ethnic service users who may have co-occurring alcohol and mental health problems.</p
The association between violence exposure and general and cause-specific mortality in people using mental health services:cohort study
Get PDFBackground Many studies have observed a link between mortality and mental illness, although the contribution of violence exposure to mortality in people with mental illness remains under-researched. Aims To examine the association of violence exposure, such as being physically assaulted, with general and cause-specific mortality in a population using mental health services. Method We assembled a cohort study using electronic health records from a mental health and substance use treatment provider in south-east London. Records were linked to acute medical admission and emergency department presentation data, as well as to a national mortality register with death certificates for deaths registered in England and Wales. Cox regressions estimated the associations of binary and cumulative violence exposure, as indicated by assault admission and presentation to emergency departments for violence-related reasons. Mortality was adjusted for sociodemographic and clinical potential confounders. Results The hazard ratio for assault admission with all-cause mortality was 2.14 (95% CI: 1.93–2.36) following covariate adjustment. Adjusted associations were also found with mortality from the following causes: internal (natural) (hazard ratio 1.72, 95% CI: 1.50–1.98), external (hazard ratio 1.94, 95% CI: 1.51–2.48), suicide (hazard ratio 2.20, 95% CI: 1.38–3.52), respiratory (hazard ratio 2.01, 95% CI: 1.41–2.85), circulatory (hazard ratio 1.71, 95% CI: 1.27–2.28), diabetes-related (hazard ratio 2.86, 95% CI: 1.20–6.86) and alcohol-related (hazard ratio 1.56, 95% CI: 1.10–2.22). Results for cumulative assault were consistent with these in both direction and magnitude. There was evidence for an association of weapon-related assault admission with all-cause mortality (hazard ratio 1.58, 95% CI: 1.14–2.18). Conclusions People with mental illness, who are exposed to assault, experience greater mortality than those who are not exposed. Excess mortality attributable to violence exposure in people with mental illness was related to deaths from natural and external causes.</p