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Conference paperLi Z, Zhao W, Yu K, et al., 2027,
CPAgents: Agentic Composite Phenotype Generation for Cardiac Disease Association
, Pages: 143-152, ISSN: 0302-9743Identifying robust associations between cardiac imaging phenotypes and clinical diseases is fundamental to population-scale cardiovascular research and reliable risk stratification. However, current phenome-wide association studies rely on pre-defined, single-variable phenotypes or expert-crafted features, which limits their ability to capture clinically meaningful non-linear effects and cross-phenotype interactions. To address this, we propose CPAgents, an iterative phenotype-Composition framework for cardiovascular Phenome-wide association study (PheWAS) that automatically constructs and validates interpretable composite phenotypes (e.g., polynomial, ratio, and interaction forms) from base imaging features. Specifically, our system coordinates three agents: (i) an Analyst that identifies statistical pathologies and nominates candidate transformations; (ii) a Proposer that generates constrained, medically and statistically motivated expressions under numerical safety rules; and (iii) a Verifier that evaluates candidates using multi-stage criteria and produces transparent evidence trails for accepted phenotypes. Evaluated on a population-scale cardiac imaging cohort, the discovered composite phenotypes markedly improve disease discrimination: across 72 classifier–disease–metric combinations, our variants achieve the top rank in 56 cases versus 18 for baselines, with gains observed across all nine clinical disease categories. Our framework yields compact, clinically interpretable phenotype formulas with transparent evidence trails, enabling scalable discovery of stronger phenotype-disease associations beyond expert-driven feature selection.
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Journal articleBruno F, Langhorne J, Lo Celso C, 2026,
Protocol for repeated Plasmodium chabaudi infection in a murine malaria model
, STAR Protocols, Vol: 7, ISSN: 2666-1667In malaria-endemic regions, individuals experience repeated malaria infection throughout life. Here, we present a protocol to investigate the immunological mechanisms triggered by repeated exposure using a murine model of sequential infections with the rodent parasite Plasmodium chabaudi chabaudi. We provide a detailed and standardized series of steps covering primary infection, natural recovery without treatment, and subsequent secondary infection. This approach offers a robust framework to investigate the effects and long-term consequences of repeated malaria infections on the host.
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Journal articleWan Y, Wong JLC, Sanchez-Garrido J, et al., 2026,
Genomic and molecular characterisation of a KPC-producing Klebsiella pneumoniae clinical isolate resistant to meropenem-vaborbactam, imipenem-relebactam, and ceftazidime-avibactam
, BMC Genomic Data, Vol: 27, ISSN: 2730-6844Background Resistance to carbapenems and third-generation cephalosporins is increasing in Klebsiella pneumoniae globally, restricting therapeutic options. The β-lactam/β-lactamase inhibitor combinations are widely used to circumvent β-lactamase-mediated resistance. In 2021, an unusual K. pneumoniae clinical isolate, KpMVR1, was recovered from a hospitalised patient in England, exhibiting resistance to meropenem-vaborbactam, imipenem-relebactam, and ceftazidime-avibactam. To investigate this phenomenon, we characterised the genome and antimicrobial susceptibility of KpMVR1 alongside two clonally related isolates susceptible to all three β-lactam/β-lactamase inhibitor combinations: KpMVS1, collected from the same patient 42 days earlier, and KpMVS2, from another patient in the same hospital. Methods Illumina and MinION whole-genome sequencing were conducted for these three isolates, followed by hybrid genome assembly. Annotated genome assemblies were compared to identify genetic variation. Mutagenesis experiments were performed to verify predicted functional alterations. Results All isolates belonged to clone ST8134 and carried blaKPC-2 alleles (KpMVR1: blaKPC-157; KpMVS1 and KpMVS2: blaKPC-2) in plasmids predicted to be conjugative. Insertion sequence ISEc68 caused a frameshift mutation in KpMVR1’s ompK36 gene, reducing susceptibility to meropenem-vaborbactam and imipenem-relebactam. KPC-157 demonstrated decreased hydrolysis of imipenem and ceftazidime when compared with KPC-2. KpMVR1 also encoded a disrupted transcriptional repressor MarR and a destabilising mutation in AcrB, a component of the AcrAB-TolC multidrug efflux pump. An intact, iron-transporting fec operon was identified on a novel IncFII(pKP91)/IncFIB(K) plasmid unique to KpMVS2, possibly accounting for the cefiderocol resistance observed in this isolate. ConclusionsKpMVR1 carried multiple resistance-associated genetic alterations and likely developed its resistance profile
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Journal articleTruter C, Hamilton MS, Le Roux C, et al., 2026,
Understanding ischemia in children with tuberculous meningitis (iThemba): a protocol paper
, BMC Pediatrics, Vol: 26, ISSN: 1471-2431BackgroundOne million children develop tuberculosis (TB) each year and a quarter of these die. TB meningitis (TBM) is the most severe form of TB disease and even if diagnosed and treated, 20% die and over 50% of survivors are left with permanent neurological disability. Much of the morbidity and mortality associated with TBM is due to infarction yet, despite this, our understanding of the pathogenesis of infarction in TBM remains limited, especially in children. MethodsThe iThemba study (Understanding ischemia in children with tuberculous meningitis), aims to recruit 100 children with probable or confirmed TBM and obtain samples of blood and cerebrospinal fluid (CSF). All children will undergo MRI and FDG PET/CT at baseline and will have repeat MRI with further blood and CSF samples collected at 2 weeks’ follow-up. MRI will then be carried out at 24 weeks with neurodevelopmental assessment at 48 weeks. Neuroimaging will focus on methods to identify and characterize ischemic penumbra and evaluate how this correlates with clinical outcomes. RNA sequencing of blood and CSF will be used to identify differentially expressed genes and identify implicated biological pathways between children with and without infarction. Targeted proteomic profiling will be performed on plasma and CSF to determine differences in protein abundance, with a focus on proteins involved in coagulation and endothelial function. Finally, we will integrate transcriptomic, proteomic and radiomic data to generate a comprehensive understanding of the pathogenesis of infarction in children with TBM. We aim to group children into relevant biological/anatomical phenotypes, each of which may benefit from a different therapeutic approach. Using computer simulation, we will then explore the impact of potential therapeutic interventions on biological pathways for each distinct phenotype. This work may pave the way for the development of point-of-care tests at diagnosis that could allow for stratified no
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Journal articleJebreel WMA, Abdel Hamid MM, Mustafa SA, et al., 2026,
Characterisation of malaria and glucose-6-phosphate dehydrogenase deficiency in conflict-affected zones of southern and eastern Sudan
, BMC Infectious Diseases, Vol: 26, ISSN: 1471-2334BackgroundMalaria causes high morbidity and mortality in Sudan. Malaria control efforts have been disrupted by conflict and displacement, which affected the whole health system. This study aimed to characterize malaria and glucose-6-phosphate dehydrogenase deficiency in conflict-affected zones of southern and eastern Sudan.MethodsThis cross-sectional study was conducted between 2023 and 2024, enrolling 717 patients with clinical symptoms suggestive of malaria in Kosti (southern Sudan, n = 252) and Kassala (Eastern Sudan, n = 465). Malaria infection was confirmed by light microscopy as a standard test, and qPCR was used as a reference method. Haematological indices were analysed on automated analysers, and PCR-RFLP was used to determine G6PD genotypes.ResultsMalaria prevalence was 62.6% (291/465; 95% CI 58.2–67.0%) in Kassala and 52% (133/252; 95% CI 46.6–59.0%) in Kosti using PCR. In Kassala, 157 cases (54%; 95% CI: 48.2–59.7%) were Plasmodium vivax (P.v), 99 (34%; 95% CI: 28.6–39.8%) were Plasmodium falciparum (P. f), and 35 (12%; 95% CI: 8.6–16.2%) were P. f/P. v infections. In Kosti, P. f was detected in 130 (97.7%) subjects, and P. v was detected in 3 (2.7%; all were negative by microscopy). There were 37 (8.7%) subjects not detected by microscopy but positive by PCR (submicroscopic), 20 (15%) in Kosti and 17 (5.8%) in Kassala. The G6PD B variant predominated in Kassala (438/94.2%) and Kosti (200/79.4%). The African A− variant was detected in 9 (3.5%) individuals in Kosti (7 males, 2 females). In Kosti females, BA, BA−, AA, and AA− were observed in 11 (7%), 4 (2.5%), 4 (2.5%), and 9 (5.7%), respectively, compared to 10 (4.1%), 4 (1.6%), and 7 (3%) BA, BA−, and AA cases in Kassala females. No significant association was observed between G6PD genotype and parasite density. Malaria prevalence did not differ significantly between Internally Displaced Persons (IDPs) and residents.Conclu
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Journal articlePashley SL, Hair M, Ukegbu CV, et al., 2026,
Plasmodium protein kinase 2 is required for ookinete-to-oocyst transition and parasite transmission.
, Life Sci Alliance, Vol: 9Plasmodium parasites rely on diverse protein kinases to regulate critical processes, yet many remain uncharacterised. Protein kinase 2 (PK2) is required for asexual blood-stage proliferation and merozoite invasion, but its role in sexual stages and transmission is unknown. Here, using live-cell and super-resolution imaging, ultrastructural analysis, functional phenotyping, and quantitative phosphoproteomics, we define the role of PK2 in Plasmodium berghei transmission. PK2 was expressed in merozoites, ookinetes, and sporozoites: the three invasive forms of the parasite. Conditional depletion of PK2 impaired ookinete motility, disrupted apical microneme positioning, abolished oocyst formation, and prevented mosquito-to-host transmission. Direct haemocoel injection of mutant ookinetes failed to restore sporozoite production, demonstrating an additional requirement for PK2 downstream of midgut traversal. Although global protein abundance was largely preserved, phosphoproteomic profiling identified altered phosphorylation of proteins associated with cytoskeletal organisation, host-cell interaction, midgut invasion, and gene regulation. These findings highlight PK2's critical role across multiple invasive stages, advancing understanding of malaria parasite transmission and identifying putative PK2-regulated pathways as potential targets for transmission-blocking interventions.
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Journal articleCelsa C, Pressiani T, Nishida N, et al., 2026,
Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study
, JHEP Reports, Vol: 8, ISSN: 2589-5559Background & AimsDurvalumab plus tremelimumab (STRIDE) has emerged as a first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC). This international multicentre study aimed to evaluate the efficacy and tolerability of STRIDE or durvalumab monotherapy in routine clinical practice, comparing outcomes between patients within and outside key eligibility criteria for the HIMALAYA trial.MethodsFrom a database of 1,423 patients with advanced/unresectable HCC treated with immunotherapy across 35 centres, we analysed 233 patients receiving STRIDE or durvalumab monotherapy. Patients were categorized as HIMALAYA-IN or HIMALAYA-OUT based on key trial eligibility criteria (no prior systemic therapy, ECOG-PS 0–1, Child-Pugh class A, no Vp4 thrombosis). Baseline characteristics were assessed for overall survival (OS) and hepatic decompensation using a multivariable Cox model and competing-risk analysis, respectively. Objective response rates and treatment-related adverse events were recorded.ResultsOf the 233 patients, 123 (53%) were HIMALAYA-IN and 110 (47%) were HIMALAYA-OUT. STRIDE was given in 95% of HIMALAYA-IN patients. After median follow-up of 6.0 months, median OS was 20.4 months (95% CI 11.7-NR) in the overall population. HIMALAYA-IN patients achieved significantly longer OS than HIMALAYA-OUT patients (23.0 vs. 12.2 months; hazard ratio 0.61; 95% CI 0.39-0.96; p = 0.03). Macrovascular invasion and hepatic decompensation were independent negative prognostic factors in the whole cohort. Hepatic decompensation occurred in 10.5% of patients within 12 months from treatment start. Objective response rate was 23.7% and 17.8% of HIMALAYA-IN and -OUT patients, respectively. Patients achieving disease control (whole cohort: 59.4%) demonstrated 24-month OS of 58.2% in HIMALAYA-IN and 44.8% in HIMALAYA-OUT groups. Grade 3-4 treatment-related adverse events occurred in 16.3% of patients.ConclusionsSTRIDE shows reproducible effectiveness and an ac
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Journal articleLian C, Li M, Fenech-Salerno B, et al., 2026,
A flexible graphene-printed sensing platform for real-time multi-analyte detection of pH, sodium, and potassium.
, Biosens Bioelectron, Vol: 312Flexible point-of-care testing (PoCT) with simultaneous, real-time biomarker monitoring is essential for next-generation wearable health platforms. Here, we present a graphene-printed electrolyte-gated field-effect transistor (EG-GFET) sensing platform fabricated on a flexible polyimide PCB substrate for multiplexed detection of pH, sodium (Na+), and potassium (K+). Graphene ink synthesised via liquid-phase exfoliation was spray-coated to form the active transistor channel. Optimised EG-GFET sensors achieved a pH sensitivity of 25.77 ± 1.42 mV/pH (shift of Dirac point) and 61.59 ± 3.17 μA/pH (modulation of drain current). Ion-selective membranes enabled selective Na+ and K+ sensing with sensitivities of - 61.28 ± 2.95 mV/log10 [Na+] and - 56.09 ± 3.28 mV/log10 [K+], respectively, over linear concentration ranges of 50 μM - 350 mM for Na+ and 50 μM - 150 mM for K+. The flexible devices maintained stable operation under bending angles up to 120°. Real-time dual-analyte experiments further demonstrated simultaneous pH/Na+ and pH/K+ monitoring with minimal observable cross-interference. The platform was further evaluated in acidic and alkaline artificial sweat for pH, Na+, and K+ sensing. These results establish a flexible printed EG-GFET platform for pH and electrolyte sensing in buffer solutions and selected artificial-biofluid matrices.
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Journal articleNester C, Tarnoff J, Brisendine S, et al., 2026,
SEISMIC: a multistakeholder summit addressing access issues in diagnosis and treatment of C3G nephropathy and IC-MPGN.
, Kidney Int, Vol: 110, Pages: 1141-1150C3 glomerulopathy (C3G)-primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) is an ultrarare disease spectrum associated with a significant health burden and for which there is a huge unmet need for safe and effective treatment. The underlying pathophysiology is dysregulation and overactivation of the alternative complement pathway. Two new therapeutic agents, iptacoplan and pegcetacoplan, that target proximal steps in the cascade, have demonstrated to be effective and have been approved for use in patients with C3G alone and with C3G/IC-MPGN, respectively. A key challenge to the nephrology community is how to incorporate these disease-modifying drugs into clinical practice in a timely and equitable manner. This report summarizes the deliberations and recommendations that emerged from the Addressing Access Issues in Diagnosis and Treatment of C3G Nephropathy and IC-MPGN (SEISMIC) summit in July 2025. The meeting assembled a broad panel of experts and patients and addressed the following 3 aims: (i) define issues in proper and timely diagnosis of this complex disease spectrum, (ii) assess management strategies in light of the availability of this new class of therapeutic agents, and (iii) identify barriers to access to care and treatment with these new therapeutic agents and design strategies to surmount them.
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Journal articleCooney LA, Lim N, Harris KM, et al., 2026,
Autologous Hematopoietic Transplantation Reduces Brain Inflammatory and Axoglial Damage Biomarkers in Multiple Sclerosis.
, Neurol Neuroimmunol Neuroinflamm, Vol: 13BACKGROUND AND OBJECTIVES: Autologous hematopoietic stem cell transplantation (AHSCT) can induce long-lasting immune tolerance and disease quiescence in patients with severe multiple sclerosis (MS), but the underlying mechanisms are not well understood. We hypothesized that AHSCT would induce persistent decreases in inflammatory cytokines, chemokines, and axoglial damage biomarkers in serum and CSF. METHODS: Longitudinal serum and CSF samples were obtained from 24 participants with severe MS undergoing AHSCT in the HALT-MS trial (NCT00288626), with serum collected at 9 time points from pretreatment through month 60 and CSF collected at 3 time points, including pretreatment, month 24, and month 48. Approximately 50 soluble biomarkers were analyzed to determine treatment-induced changes and associations with disease activity, including clinical and MRI parameters. RESULTS: AHSCT resulted in decreased expression of many proinflammatory cytokines, chemokines, and neuroinflammatory markers for several years in both serum and CSF, including neurofilament light chain (NfL). CSF levels of glial fibrillary acid protein and IL-7, on the contrary, increased after treatment. Expansion of cytomegalovirus and/or Epstein-Barr virus early after AHSCT resulted in transient increases in inflammatory cytokines in serum, but these changes did not persist. Changes in serum were largely distinct from changes in CSF, and concentrations of cytokines and chemokines in serum rarely correlated with concentrations in CSF, except for NfL. DISCUSSION: These results confirm the hypothesis that AHSCT results in long-lasting reductions in inflammatory cytokines, chemokines, and axoglial damage markers, consistent with persistent disease quiescence. The lack of relationships between biomarkers in serum and CSF suggests that these samples largely reflect distinct immunologic processes and compartments, and that analysis of CSF may be warranted for deeper understanding of disease processes in the CNS
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