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“Reconstruction of segmental defect of flexor tendons of the wrist and hand using extensor digitorum longus”
No full textPlastic and hand surgeons rely on traditional tendon grafts, but severe bilateral multi-level trauma may render these unusable. We report a 30-year-old man with extensive forearm loss reconstructed using the entire extensor digitorum longus tendon, nerve and vein grafts, and an ALT flap, demonstrating EDL’s versatility and minimal donor morbidity
A prospective cohort study to describe the morphology of buboes in patients with bubonic plague using ultrasound imaging
No full textBackground: Bubonic plague, caused by Yersinia pestis, is characterised by painful, enlarged lymph nodes (“buboes”). Despite centuries of clinical recognition, bubo morphology has been described only through observation and palpation. This study aimed to characterise the sonographic features of buboes over time in confirmed bubonic plague and evaluate the validity of digital calliper measurements compared to ultrasound. Methods/principle findings: We conducted a prospective cohort study at three rural health centres in Madagascar between January and March 2024. Participants with suspected bubonic plague underwent ultrasound imaging and digital calliper measurements of enlarged lymph nodes at inclusion (D1), and follow-up on D4 and D11. Bubo size and morphology were assessed by clinicians – who received targeted ultrasound training for the study – using portable ultrasound devices, with expert radiologist oversight. Neither clinicians or radiologists were blind to clinical information or outcomes. Final diagnoses were retrospectively assigned using WHO criteria and national laboratory results. Of 16 enrolled participants, 12 were confirmed plague cases. Most buboes exhibited normal morphology on D1, with limited change over time despite clinical improvement. No association was found between bubo size or morphology and clinical status. Digital calliper measurements differed substantially from ultrasound. Study sonographers achieved good agreement with radiologists on bubo size, but lower agreement on structural features. Conclusions/significance: Bubo morphology and size do not appear to correlate with clinical status, challenging their use as indicators of treatment response. Digital callipers introduce significant measurement error. Newly trained clinicians can perform size measurements reliably, but further training is needed for accurate sonographic characterisation
Human immune challenge to assess proof-of-mechanism in drug development
No full textBackground: High attrition rates in immunomodulatory drug development, particularly in Phase II clinical trials, are largely driven by failure to demonstrate efficacy at this key development stage. First-principles and observational evidence indicate that establishing proof of mechanism (PoM) early is essential to support robust go/no-go decisions. Human immune challenge (HIC) models provide an experimental platform to elicit mechanism-relevant pharmacodynamic (PD) biomarkers in healthy volunteers, thereby bridging the translational gap between preclinical evidence and Phase I proof of concept (PoC). However, existing HIC models—including those employing the widely used challenge antigen keyhole limpet haemocyanin (KLH)—are characterised by substantial methodological heterogeneity, limited standardisation, and narrowly restricted outcome measures. In parallel, despite rapid growth in the number of druggable immunological targets and clinical-stage investigational medicinal products (IMPs), there remains a lack of validated HIC paradigms capable of eliciting many target pathways in healthy volunteers, precluding mechanism-relevant PD interrogation for a large proportion of immunomodulatory IMPs in Phase I. Collectively, these limitations constrain the feasibility and decision-making value of HIC-enabled PoM studies in contemporary drug development.This thesis tests the hypothesis that systematic optimisation of challenge agent, dose, adjuvant, tissue, and assessment timing enables HIC models to generate robust, mechanism-specific PD readouts in healthy volunteers. It further hypothesises that formal integration of these readouts within a Bayesian decision-theoretic framework yields more informative and economically optimal go/no-go decisions than conventional Phase I development strategies that either lack mechanism-relevant PD assessment or incorporate such evidence informally.Methods: To address these aims, a multi-modal experimental and analytical research programme was conducted:1. An observational study of modified vaccinia Ankara (MVA) vaccination to characterise immunogenicity and assess its potential as a viral HIC model relevant to PD evaluation of immunomodulatory agents targeting innate viral signalling, T-helper 1 (Th1), and CD8+ T-cell pathways.2. A systematic review of 46 studies employing KLH challenge in drug development to identify design limitations and opportunities for model optimisation.3. Two randomised, single-blind HIC studies (KLH1 and KLH2) designed to optimise the KLH model, including evaluation of adjuvants (Alhydrogel vs. Montanide), Bayesian modelling of the intradermal KLH rechallenge dose–response relationship using Emax models, and characterisation of the temporal evolution of cutaneous immune responses via multiparameter flow cytometry.4. A pilot study evaluating contrast-enhanced ultrasound (CEUS) to improve identification of primary draining lymph nodes—a site of increasing interest for invasive sampling to enable tissue-based readouts of HIC and PD activity.5. A Bayesian decision-theoretic simulation examining how HIC-derived PD data can be formally integrated with economic utility to optimise go/no-go decision thresholds.Results: The MVA-BN study demonstrated the feasibility of MVA-BN as a viral HIC agent, subject to further optimisation. MVA-BN elicited robust Th1-biased and CD8+ T-cell responses; however, substantial inter-individual variability was observed in serological and cellular responses measured in blood. These findings indicate a need for further characterisation of statistical operating characteristics, dose–response relationships, and endpoint selection, particularly with respect to immune responses at the site of intradermal administration. In the KLH optimisation studies, Montanide elicited significantly greater systemic T-cell responses (IFNγ and IL-4) than Alhydrogel, despite comparable serological effects, with both adjuvants demonstrating greater immunogenicity than unadjuvanted subunit KLH. Bayesian modelling identified 10 μg as the optimal intradermal rechallenge dose, balancing response consistency with expected modulation-sensitivity. Temporal analyses revealed a shift in the cutaneous immune infiltrate from a mixed myeloid (classical monocyte)–lymphoid phenotype at 48 hours to a Th1-polarised response with enrichment of intermediate and non-classical monocytes at later timepoints (Days 5 and 14). The CEUS study was terminated early for futility due to failure to reliably identify target lymph node enhancement, demonstrating the utility of adaptive experimental designs in efficiently evaluating feasibility in experimental medicine studies. Finally, the decision-theoretic simulation showed that conventional frequentist significance thresholds are likely suboptimal from an economic perspective, supporting the use of utility-calibrated probabilistic decision rules to guide go/no-go decisions.Conclusions: This thesis delivers a standardised and optimised protocol for the KLH HIC model and provides PoC evidence for MVA-BN as a promising viral HIC agent capable of eliciting innate and adaptive antiviral immune pathways. It demonstrates that assessment timepoints must be tailored to the biomarker and mechanism of interest, with early timepoints (e.g., 48 hours) optimally capturing innate and myeloid responses and later timepoints (Days 5–14) required to interrogate adaptive T-cell modulation and local tissue adaptation in KLH HIC. By integrating optimised experimental platforms with rigorous Bayesian decision-theoretic analysis, this work advances the feasibility and decision-making value of HIC-enabled Phase I PoM assessment in immunomodulatory drug development
Restoring function to a variant of p53 in solid tumors
No full textThe author describes the scientific foundations of a study of rezatapopt, which targets a variant form of p53, to treat patients with solid tumors
Sustaining community-based malaria services through stakeholder engagement: lessons from co-creation in northeastern Thailand
No full textIntroduction: In remote communities in the Greater Mekong Subregion, maintaining community-based malaria care is vital to achieving the goal of malaria elimination. This project aimed to collaborate with the community members and implementers of malaria and health programmes, our key stakeholders, to co-create engagement activities that promote the integration of community-based malaria activities that best fit the local context. This article describes the design, implementation and results of this co-creation process, and highlights key learnings and insights, enabling factors and challenges. Method: In Buntharik district, Ubon Ratchathani province bordering Laos in northeastern Thailand, we adopted a co-creation framework to design and develop iterative and responsive engagement activities, and used a theory of change framework to outline the necessary steps and conditions to achieve the desired co-creation outcomes. Data were recorded in engagement logs, meeting minutes, observation notes, and participant evaluation to measure the results of engagement and extract key learnings from implementation. Findings: Between April 2023 and June 2024, 36 in-person engagement activities were conducted with approximately 550 participants, to co-create and evaluate locally-owned health education materials—the 2024 Buntharik health calendar—that integrates malaria information with priority local health issues. The co-created calendar offered one potential entry point to maintain malaria awareness in low transmission areas, but future initiatives ideally should secure additional funding sources to maintain the capacity of local health workers. We found that responding to local health concerns and expectations of the communities and stakeholders is the key enabler to co-creation. However, in the context of changing policy, careful thought about the range of scenarios in which co-creation is applied is crucial to plan for sustainability of the integration. Learning from the context of this engagement, new champions could emerge from involving additional stakeholders beyond those involved in malaria service implementation. Conclusion: Drawing from this stakeholder engagement work, the co-creation process showed strong potential for ensuring the sustainability of community-based health care in the context of declining awareness and advocacy, such as in the case of malaria elimination. The process and its learning can be adopted to any ongoing local collaborative partnership and future participatory action research and community-informed policy considerations
Mother-blame by design: patriarchy, epistemic practices, and parental alienation in family courts
No full textThis article develops and applies a four-part patriarchal framework to explain how family courts translate normative ideals into outcomes in domestic-abuse cases. It links: (1) the juridical construction of intensive, facilitative motherhood alongside a thin yet symbolically central fatherhood; (2) an institutional field oriented to settlement and the preservation of contact; (3) epistemic practices that generate testimonial deficits and hermeneutic gaps; and (4) parental alienation (PA) as an epistemic technology that reinterprets children’s fear and mothers’ protective conduct as manipulation. Conceptually, the article reconceives PA as a circulating repertoire of inferences and tools that stabilise mother-blame in family-court decision-making, even where the label is avoided or formally condemned.
Empirically, the framework is applied to multi-site qualitative data from England & Wales, France, Italy, Spain, and Bosnia & Herzegovina, drawing on interviews and focus groups with survivors, judges, lawyers, and court-appointed experts, and situated against each jurisdiction’s legal and policy context. Common patterns emerge: PA persists ‘in all but name’; abuse is historicised or reframed as conflict; contact-first managerialism dominates risk assessment; expert evidence is highly influential despite uneven regulation; and children’s participation is delayed, discounted, or instrumentalised. These dynamics converge to produce secondary victimisation and institutional betrayal, with predictable consequences for the safety of women and children.
By connecting maternal ideology, institutional logics, epistemic injustice, and PA within a single explanatory framework, the article demonstrates how patriarchal norms shape incentives, credibility judgments, and outcomes in family courts, and why reforms that target labels without addressing underlying logics have limited effect
Improving the High-Temperature Mechanical Properties of L-PBF CM247LC Through HIPing and Aging Treatments
Full text linkCM247LC was fabricated using L-PBF with optimized build parameters to minimize cracking. This paper explores the potential for using HIPing, followed directly by aging heat treatments, to optimize tensile and creep properties while reducing the number of heat treatments and the cost of processing. Samples were HIPed at 1250 °C and 100 MPa followed by aging treatments chosen to replicate those given to the DS alloy after solutioning. Heat treatments at 1250 °C, both the furnace only and HIP, have similar effects on grain structure, but change γ′ morphology. The slow cool following HIPing results in large (~2 µm) octo-dendritic primary γ′, and the subsequent anneals have radically different effects on the microstructure. The best tensile performance at 900 °C is produced by minimizing the volume fraction of primary γ′ during the anneal at 1080 °C and peak-aging the secondary γ′, formed during the cool from 1080 °C, and aging at 870 °C. Creep tests at 982 °C and 179 MPa show that the HIP treatment is essential to prevent early failure. It is remarkable that the optimum tensile microstructure performs well in creep despite large primary γ′. Omitting a separate solution treatment gives a radically different microstructure but tensile properties that match those from the cast alloy, without compromising the creep performance at low strain
African Decolonial Theory: A Conversation
Full text linkAntipode has become a key platform for engaging with decolonial and anticolonial scholarship, as well as adjacent fields such as Black geographies, Indigenous studies, Latin American feminism, and work on settler‐colonialism. African reference points in this literature, however, have been far less common, both in the journal and more broadly in radical geography. Recognizing that there are several loci of enunciation for decolonial and anticolonial work, we committed to curating a series of conversations with and interventions by leading scholars from Africa and its diaspora associated with these epistemic and political projects. This long‐read article, a first for the journal, brings these conversations and interventions together, highlighting the power of each as well as the common threads that connect them
Crystal structure of Schistosoma mansoni cathepsin D1 in complex with a nanobody reveals the conformation of the propeptide‐bound state
Full text linkSchistosoma mansoni cathepsin D1 (SmCD1) has been shown to be an essential enzyme for helminth metabolism due to its role in haemoglobin degradation: a key amino‐acid source for the developing parasite. Therefore, the enzyme is a potential target for the development of antischistosomal inhibitors. SmCD1 has significant sequence identity to cathepsin D‐like proteases found in other schistosome species and homology to mammalian aspartic proteases. Here, we report the first crystal structures of a helminth cathepsin D, SmCD1, and have identified a single‐domain antibody (nanobody) that specifically binds to SmCD1 with nanomolar affinity but does not recognize human cathepsin D. We have mapped the epitope of the nanobody by determining the crystal structure of the enzyme–nanobody complex, revealing the conformation of SmCD1 in the propeptide‐bound state