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Itacitinib in advanced hepatocellular cancer following first line therapy
Get PDFHepatocellular carcinoma (HCC) develops on background chronic liver disease where uncontrolled inflammation drives hepatocarcinogenesis. First-line therapies have limited response. There are no agents that specifically target the underlying liver inflammation. We investigated the safety and efficacy of itacitinib, a highly selective JAK1 inhibitor, as a potential second- or third-line therapy. Biomarkers of response were investigated. Participants with advanced stage HCC, Child Pugh ≤B7 who had progressed through at least one previous line of therapy received 400 mg of itacitinib QID every 28 days. Treatment-related adverse events (trAEs) were assessed weekly during cycle 1 then every 28 days (CTC-AE version 4.03). Response was assessed 8-weekly using RECIST 1.1. Progression-free (PFS) and overall survival (OS) were reported as secondary endpoints. Tumour samples were analysed for targeted transcriptomics. Sequential serum samples were assessed for metabonomic determinants of toxicity and response. 19 patients were enrolled. The most common trAEs were thrombocytopenia (31%), fatigue (26%) and palmar-plantar erythrodysesthesia syndrome (26%); four episodes of dose-limiting thrombocytopaenia were observed. Over a median follow-up of 3.5 months, the best overall response was stable disease (47%). Median PFS and OS were 3.5 (95% CI: 2.6 - 4.5 months) and 7.4 months (95% CI: 4.3-10.5 months), respectively. Subgroup analysis illustrated a significantly increased risk of progression for patients that had received combination immunotherapy prior to itacitinib (HR 4.7, 95%CI 1.3-16.6, p = 0.016). Untargeted tumour and serum transcriptomics identified a signature predictive of response. Itacitinib either as second- or third-line therapy showed promising activity. We identified a transcriptomic signature predictive of response.</p
Lifestyle behaviours can mediate socio-economic and sex inequalities in children's oral health:findings from Children's Dental Health Survey 2013, England, Wales, and Northern Ireland
Get PDFBACKGROUND: Oral health inequalities in adults are well documented but understudied in children.AIM: To investigate oral health inequality amongst children within the United Kingdom (UK) by sex and socio-economic status (SES), and whether such inequality may be mediated by healthy lifestyle.DESIGN: Secondary analysis of the Children's Dental Health Survey 2013 data for England, Wales, and Northern Ireland, including questionnaire responses on demographics, lifestyle, and clinically examined oral health measures in children aged 5, 8, 12, and 15 years in the UK. Descriptive statistics on the oral health inequalities and mediation analyses were performed, assessing lifestyle factors (regular dental attendance, sugary drink intake, and toothbrushing frequency) that potentially mediate sex and SES inequalities in oral health.RESULTS: A total of 9,866 children were included in this study. Oral health inequalities were observed by sex and SES amongst all aspects of oral health (dental caries, oral health-related quality of life, self-reported oral health, gingival status, and basic periodontal examination). Compared with males (35.8%), fewer females (24.1%, p < 0.001) had self-reported good dental health. Children from lower SES groups had more dental caries experience, i.e., decayed, missing, and filled teeth (DMFT), than those from middle and higher SES groups (1.0 ± 2.0 in lower vs. 0.8 ± 1.9 in middle vs. 0.4 ± 1.3 in higher, p = 0.027). Furthermore, there was evidence of lifestyle factors mediating the associations between sex, SES, and adolescents' oral health at 12 and 15 years.CONCLUSION: Inequality was observed for children's oral health by sex and SES; however, regular dental attendance, having less sugary drink intake and optimal toothbrushing mediated these associations in adolescents.</p
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
6-Nitrodopamine potentiates catecholamine-induced Ca<sup>2+</sup><sub>i</sub> release in human aortic smooth muscle and modulates vascular smooth muscle contractility
Get PDFBackground: In vascular smooth muscle, rises in intracellular calcium [Ca2+]i drive contraction downstream of α1-adrenoceptor activation via IP3. Endothelium-derived 6-nitrodopamine (6-ND) augments cardiac catecholamine actions, however its effect on [Ca2+]i is unknown. We hypothesized that 6-ND will increase intracellular [Ca2+]i and potentiate catecholamine-induced [Ca2+]i signalling in vascular smooth muscle cells, with resultant functional effects on vascular tone when measured in vitro. Methods: Human aortic smooth muscle cells (HASMCs) were loaded with fura-2AM (1μM) and [Ca2+]i measured using a CLARIOstar plate reader after addition of Hank’s balanced salt solution. Rat thoracic aorta rings, the endothelium removed, mounted in Krebs–Henseleit baths, and isometric force recorded via PowerLab. Results: 6-ND and classical catecholamines evoked concentration-dependent increases in HASMC Ca2+ flux, with 6-ND displaying the greatest potency. 6-ND potentiated the increases in HASMC Ca2+ flux induced by the classical catecholamines. Tetrodotoxin (TTX) caused concentration-dependent inhibition of responses to 6-ND and dopamine but did not alter noradrenaline- or adrenaline-induced [Ca2+]i rise. In endothelium-denuded aortic rings, 6-ND potentiated contractions elicited by catecholamines, and this potentiation was abolished by TTX. Conclusions: 6-ND is a potent modulator of [Ca2+]i in HASMCs and enhances catecholamine-driven vasoconstriction. Both effects are blocked by TTX, indicating that 6-ND modulates voltage-gated sodium channels upstream of Ca2+ entry/release in vascular smooth muscle cells. <br/
Inside Deception:How to Exploit a Target
Get PDFThis work is part of a program to formalise enablers of deception so that attempts at manipulation can be detected by an AI system. In this extended abstract, we report results from a formalisation workshop which focused on two factors commonly exploited in the deception of humans: repeated delivery of a falsehood via multiple channels; and the application of emotional accelerators such as trust, ego, urgency and social proof which can be used to pressure individuals into acting more in a deceiver's interests than their own
High dimensional threshold factor models with common stochastic trends
Get PDFWe study inference for threshold regression in the context of a large factor model with common stochastic trends. We develop a Least Squares estimator for the threshold level, deriving almost sure rates of convergence and proposing a novel way of constructing confidence intervals based on a randomised test. Our confidence intervals are constructed using the rates of convergence of the estimated threshold level, and no limiting distribution is required. We also develop a procedure to estimate the number of common trends in each regime, and investigate the properties of the Principal Component estimator for the loadings and common factors in both regimes. Our theoretical findings are corroborated through a comprehensive set of Monte Carlo experiments, and an application to equity prices and bond yields
Supramolecular Protecting Groups can impart Prosthetic Stereoselectivity to catalytic systems employing unmodified achiral heterogenous catalysts
Get PDFUse of homogeneous catalysis -typically based on scarce precious metals -remains a dominant approach to afford good yields of enantiopure compounds. Combining typical strengths of heterogenous catalysts (low cost, sustainable, recyclable) with those of precious metal-mediated homogenous catalysis (amenability to design for selectivity) is desirable: several approaches have been demonstrated (chiral material surfaces, modification of surfaces with chiral auxiliaries, immobilisation of chiral catalysts), but it remains a challenge. Here we present a systems catalysis approach, with a heterogeneous material providing catalytic activity, and a separate host species controlling access to the catalyst to impart 'prosthetic' chiral selectivity. Since this non-covalent analogue to conventional covalent protecting group strategies is modular, the same substrate/host combination may be applied to a range of catalytic surfaces. The potential of this approach to achieve effective kinetic resolution is demonstrated in stereoselective synthesis of the drug (R)-cinacalcet
The Development and Acceptability of a Psychology-Based Intervention for Debilitating Symptom Complexes Attributed to Ticks
No full textDebilitating Symptom Complexes Attributed to Ticks (DSCATT) is a chronic, debilitating illness associated with tick bites in Australia. DSCATT is of unknown aetiology, can impact emotional wellbeing, and has no recognised treatments
Borders and Businesses:Intersectional Resilience, Entrepreneurship and Health Promotion among Immigrant Women in the Post-Pandemic Global South
Get PDFThis theoretical paper examines immigrant women’s entrepreneurship in the post-pandemic Global South. We challenge conventional models that fail to capture economic engagement driven by necessity and survival. Using an intersectional lens, the analysis illuminates how structural vulnerabilities such as—gender, class, income, migratory status, and social hostility—hinder formal market integration. COVID-19 related restrictions exacerbated this precarity, disproportionately affecting informal businesses. We contend that entrepreneurship serves as a pivotal strategy for socio-economic resilience and our findings advocate for holistic public policies that transcend microcredit by integrating psychosocial support, language acquisition, and anti-discrimination measures. Furthermore, we underscore the role of collective strategies and community networks in ensuring business sustainability and shifting the focus toward systemic inclusion. By evidencing how entrepreneurship, when embedded in supportive policies and collective networks, contributes to mental health protection, stress reduction, and psychosocial well-being, this paper highlights immigrant women’s entrepreneurship as a relevant strategy for health promotion and social resilience in the Global South
Inside Deception:How to Exploit a Target
Get PDFThis work is part of a program to formalise enablers of deception so that attempts at manipulation can be detected by an AI system. In this extended abstract, we report results from a formalisation workshop which focused on two factors commonly exploited in the deception of humans: repeated delivery of a falsehood via multiple channels; and the application of emotional accelerators such as trust, ego, urgency and social proof which can be used to pressure individuals into acting more in a deceiver's interests than their own