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Pragmatic pluralism and problem framing: Why pragmatism demands pluralism
No full textIn this paper I focus on the benefits of scientific pluralism in practice. My main motivation is to investigate how do these benefits play out in practice, and how do different systems of knowledge come together to address particular questions? One might accept the epistemic benefits of plurality, yet still deem it undesirable for pragmatic reasons. My argument responds to this objection, which assumes that pragmatic demands can supersede the epistemic benefits of pluralism based on the problems at hand.
I argue that this objection fails because it assumes problems are independent of inquirers. Building on classical pragmatism, I argue that problems are framed by inquirers and cannot be seen as separate from practices. Rather than facing predefined problems, inquirers confront indeterminate situations, requiring judgements on how to formulate the situation. Different framings are possible based on who is involved in making these judgments. A lack of plurality among inquirers leads to frameworks that overlook certain aspects and complexity. Therefore, pluralism is pragmatically beneficial when framing a problem, enabling inquirers to explore various dimensions of complex situations and enrich problem framing.
I illustrate my argument by analysing the early responses to the UK COVID-19 outbreak, showing how the problem was initially framed as biomedical, neglecting social, logistical, and psychological aspects. The lack of plurality in the inquirer community led to shortcomings in the official response. Building on this case, I show that pragmatism demands pluralism when dealing with complex situations, demonstrating that plurality must be promoted in practice, going beyond recognized epistemic benefits
Using network analysis to identify processes of change in low-intensity CBT interventions for depression and anxiety disorders
No full textThis study explores processes of change for individuals who responded to low-intensity Cognitive Behavioural Therapy (CBT) for depression, Generalised Anxiety Disorder (GAD), or panic disorder.
Routinely collected data from NHS Talking Therapies for Anxiety and Depression (TTad) services (N = 11, 396, 69.2% female) were analysed using network analyses. Nine Gaussian graphical models (GGMs) were conducted: for each disorder, across three time phases (assessment to start-of-treatment; start to mid-point of treatment; mid-point to end-of-treatment). Each GGM included 19 nodes, based on PHQ-9, GAD-7,and NHS TTad phobia scores, using residuals as indices of change for each node.
Networks of symptom change were largely similar. Estimated network matrix similarity ranged between r = .74 and r = .91 across disorders, with depression and GAD networks more similar to each other than to panic disorder. Networks varied over time within the same disorder, more so for panic disorder (r = .61–.63) than GAD (r = .86–.90) or depression (r = .87–.93). There were close links between changes in worry-related items and feeling nervous or anxious, and between depressed mood and anhedonia across all networks, as well as links between sleep disturbance, appetite, trouble relaxing and irritability.
Findings suggest shared patterns of co-change across anxiety and depression. There is a potential indication that therapy may work by leveraging existing natural change mechanisms rather than by creating entirely new patterns of symptom interaction. Networks also show associations between symptom changes specific to certain disorders at certain points in therapy
From Parametric Determinism to Emergent Fusion: Data-Curated Style Control in Connectionist Architecture
No full textThis paper interrogates stylistic control in connectionist architectural design through a falsifiable, data-curated design experiment. The ‘cocktail hypothesis,’ which claims that style fusion can be deterministically steered by changing training-data proportions, was tested by training eleven Pix2Pix models on incremental mixes of cultural-facility and recycling-facility façade datasets. Outputs were evaluated through visual review and an independent classifier. At typological extremes, the models reproduced the expected styles consistently; in the mid-range, however, outputs collapsed into a blurred and unpredictable field, falsifying the assumption of linear control. The analysis treats this ‘indeterminate middle’ not as an error but as a signature of generative process—an emergent style fusion aesthetic arising from subsymbolic features rather than additive collage. Ultimately, these findings shift architectural authorship from deterministic control to the curation of emergence, a practice defined by the deliberate selection, proportioning, and weighting of data
Stakeholder perspectives on Relationships and Sex Education outcomes for students with intellectual disability to inform the development of a Core Outcome Set: a qualitative study
No full textLittle is known about how to deliver Relationships and Sex Education to students with intellectual disability and what outcomes to measure. UNESCO defines Relationships and Sex Education as a part of the curriculum that aims to provide students with comprehensive knowledge, skills and attitudes about their sexuality. Evaluations of Relationships and Sex Education for people with intellectual disability indicate inconsistent outcome measurement and a lack of stakeholder involvement in outcome selection. Development of a Core Outcome Set could address this limitation as it involves identifying a stakeholder consensus-based minimum set of outcomes to be used in research evaluations. This qualitative study explored student and adult stakeholders’ views on important Relationships and Sex Education outcomes for students with intellectual disability to inform a development of a Core Outcome Set. A total of 53 adult stakeholders (students’ parents, teachers, researchers and policy makers) took part in online interviews and workshops. Nineteen students with intellectual disability took part in visual data collection sessions. A list of 31 outcome domains was identified as important by stakeholders. These were grouped into eight themes: the human body and development through the life course; emotions and feelings; healthy relationships and associated social skills; sex and sexuality; keeping safe; consent and communication skills; self-esteem; and the human rights. Stakeholders’ rationale for outcome importance involved unique needs and difficulties experienced by this population. The list of outcomes will be used to establish consensus across stakeholders on the most important outcomes to be included in the Core Outcome Set. The findings provide stakeholder identified strategies for enabling students to achieve the outcomes. This study highlights the importance of including key stakeholders in the initial stages of a Core Outcome Set development and provides methodological insights on how to engage a diverse group of stakeholders
Trial design and enrolment characteristics of LATA (long-acting treatment in adolescents): A randomised, open-label, non-inferiority, 96-week trial evaluating the virological efficacy, safety, acceptability and quality-of-life of the dual long-acting injectable regimen cabotegravir/ rilpivirine compared to daily oral therapy in virologically suppressed adolescents with HIV-1 infection, aged 12 to <20 years, in Sub-Saharan Africa
No full textBACKGROUND: Alternatives to daily oral antiretroviral therapy (ART) are important for adolescents with HIV (AHIV) to improve adherence and outcomes. Long-Acting-injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) has demonstrated excellent efficacy and safety and strong patient preference in adults. METHODS: LATA is an ongoing randomised, open-label, 96-week, non-inferiority trial evaluating the efficacy, safety and acceptability of LAI CAB/RPV vs. daily oral therapy with tenofovir (disoproxil fumarate or alafenamide)/lamivudine/dolutegravir (TLD). Participants are virologically suppressed AHIV aged 12- < 20 years in Kenya/South Africa/Uganda/Zimbabwe. Randomisation was 1:1 to LAI CAB/RPV given once every 8 weeks (after optional oral lead-in) or daily oral TLD. The primary outcome is viral rebound (two consecutive viral loads ≥50 copies/mL by 96-weeks). Viral loads are measured every 24 weeks. The trial employs the Smooth Away From the Expected (SAFE) non-inferiority frontier, where the non-inferiority margin depends on the observed event rate in the control arm. Secondary outcomes include confirmed viral load ≥200 copies/mL by 96-weeks, HIV resistance, safety, patient-reported outcomes and cost-effectiveness. LAI participants return to oral ART at confirmed viral load ≥200 copies/mL; LAI participants who become pregnant are given the choice to continue on LAI or to switch back to daily oral ART, with optional pharmacokinetic sampling during pregnancy and post-partum in both groups. Enrolment of 476 AHIV completed in April 2024. Results will be reported in 2026. CONCLUSION: LATA is the first trial comparing the efficacy, safety and acceptability of LAI CAB/RPV to oral ART in AHIV, enrolled in Sub-Saharan Africa, using a programmatic approach to viral load testing. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov (NCT05154747)
ASPIRES 3. Young People's STEM Trajectories, Age 10-22: PHYSICS
No full textIn this report, we share evidence from the ASPIRES research project,
a fourteen-year, mixed methods investigation of the factors shaping
young people’s trajectories into and away from STEM education
(science, technology, engineering and mathematics), with a particular
focus on participation in physics. The study collected survey data from
over 47,000 young people and conducted over 760 qualitative
interviews with a longitudinal sample, which tracked 50 young people
(and their parents/ carers) between the ages of 10 and 22.
The project also conducted secondary analyses of UK National
Statistics and Higher Education Statistics Agency (HESA) data sets
on England domiciled students, aged 18 to 24. This report focuses
on analyses of survey data collected at age 21/22 and longitudinal
interviews conducted from age 10 to 22, to shed light on the factors
shaping physics trajectories, particularly at degree level
Diverse histopathological patterns in Fleischner-defined interstitial lung abnormalities: Radiologic-Pathologic correlation and reclassification using 2025 American Thoracic Society statement
No full textBackground: Interstitial lung abnormalities (ILA) are CT-detected interstitial abnormalities that may represent early-stage interstitial lung disease (ILD). However, histopathologic correlations remain limited, with previous studies reporting conflicting results. In 2025, the American Thoracic Society (ATS) established criteria defining the boundary between ILA and ILD. This study aimed to investigate the histopathological spectrum of Fleischner-defined ILA, correlate findings with CT features and outcomes, and reclassify cases according to 2025 ATS criteria. Methods: This retrospective study analyzed 30 consecutive patients who underwent surgical lung biopsy between January 2010 and December 2021. All cases had ILA per Fleischner Society criteria and were reclassified using 2025 ATS criteria. Three pulmonary pathologists evaluated dominant and co-existing histopathological patterns. Two chest radiologists independently assessed CT findings. Overall survival was compared between usual interstitial pneumonia (UIP)-related and non-UIP-related groups using Kaplan-Meier analysis. Results: Twenty patients (66.7 %) were men; mean age was 63.6 ± 6.5 years; 27 (90 %) had fibrotic ILA. The most common dominant pattern was UIP (43.3 %), followed by nonspecific interstitial pneumonia (NSIP) and bronchiolocentric interstitial pneumonia (BIP) (20 % each). Overall, 96.7 % of cases met 2025 ATS criteria for ILD (subclinical ILD). On CT, all UIP and NSIP cases showed reticular opacity and traction bronchiectasis, while BIP typically exhibited branching linear opacities. During median follow-up of 92.1 months, overall survival did not differ significantly between UIP-related and non-UIP-related groups (p = 0.595). Conclusions: This study of Fleischner-defined ILA, predominantly reclassified as subclinical ILD by 2025 ATS criteria, demonstrates diverse histopathological patterns beyond UIP, including BIP, highlighting pathological heterogeneity
Developing the Spatial Transcriptomics Method coppaFISH 3D to Study Selective Vulnerability in Tauopathies
No full textThe brain is composed of millions of diverse cells that can be divided into biologically relevant types. Tauopathies are neurodegenerative diseases that involve the intracellular accumulation of the hyperphosphorylated and aggregated tau protein. Frontotemporal dementia (FTD) is a primary tauopathy, while Alzheimer’s disease (AD) is a secondary tauopathy, it is accompanied by the aggregation of beta-amyloid in plaques. Tau accumulates in specific spatial patterns, but the most vulnerable cell types are still unknown.
Spatially resolved transcriptomics can detect mRNA and use it to determine each cells type, while maintaining its spatial position and local environment. However, most methods are only compatible with 2D sections, which only capture a small fraction of the tissue and can drastically warp it by stretching or shrinking different structures by different amounts. In this thesis I describe the process of developing coppaFISH 3D, a method that uses 50μm, PFA-fixed tissue sections, and the software packages needed to analyse 3D data. I optimised the method to improve reliability, accuracy and throughput. coppaFISH 3D can also be combined with in vivo calcium imaging to link transcriptomic cell types to neuronal activity.
I used coppaFISH 3D to compare the cell types most vulnerable to tau pathology in the hippocampus of control, FTD and AD model mice. I show that tau phosphorylated at different sites accumulates in different cell types, AT8 in oligodendrocytes and T231 primarily in excitatory neurons. I identify global and region-specific changes in gene expression in all major cell types. Oligodendrocytes show responses to tau pathology and upregulation of myelin genes specifically in AD model mice. I see heterogeneity in plaque-associated genes between individual plaques and identify a transcriptomic axis based on the expression of activated glial genes. This study establishes coppaFISH 3D as a cutting-edge method for studying selective vulnerability in neurodegenerative diseases and answering many other important biological questions
Generation of γδ T Cells Using iPSC Technology and Evaluation of Zoledronic Acid-Augmented γδ T Cell Therapy for Solid Tumours in a Multi-Organoid Immune-on-a-Chip
No full textGamma delta (γδ) T cells represent a promising candidate for off-the-shelf allogeneic solid tumour immunotherapy due to their immune surveillance in an MHC-independent manner. However, their low numbers in peripheral blood remain a significant barrier to clinical application.
In the first part of this project, we explored the generation of γδ T cells from γδ T cell-derived induced pluripotent stem cells (γδ T-iPSCs). We demonstrated their potential as an alternative renewable source through sequential differentiation from γδ T-iPSCs into haematopoietic stem and progenitor cells (HSPCs) and subsequently into γδ T cells.
The second part of this project assessed the anti-tumour activity of γδ T cells, particularly when combined with zoledronic acid (ZOL), an FDA-approved drug for bone disease. ZOL increases the susceptibility of tumour cells to γδ T cell killing by inhibiting the mevalonate pathway in tumour cells. This inhibition causes the accumulation of phosphoantigens, such as isopentenyl pyrophosphate (IPP) which γδ T cells recognise more effectively leading to stronger tumour cell targeting.
To investigate ZOL-augmented γδ T cell therapy, we used three distinct 3D solid tumour models. First, co-culture assays with 3D tumour spheroids in suspension were assessed for inherent killing activity of the γδ T cells. Second, gel-embedded spheroids allowed assessment of γδ T cell’s tracking and killing abilities. Third, a Multi-organoid Immune-on-a-chip platform was developed to assess potential off-target effects by incorporating iPSC-derived cerebral, liver and heart organoids alongside tumour spheroids.
This combined approach offers a physiologically relevant alternative to conventional 2D cancer models and animal experiments, improving predictive value and addressing ethical concerns. By integrating iPSC-derived γδ T cell generation with advanced 3D tumour models, this work demonstrates the potential of iPSC-derived γδ T cells as an alternative resource and establishes a framework for preclinical evaluation of ZOL-augmented γδ T cell therapy