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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 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 articleLiang J, Papadaki A, Vincent TL, et al., 2026,
Systemic biomarkers of treatment response to methotrexate in people with painful knee osteoarthritis: a biological substudy of the PROMOTE randomised controlled clinical trial
, Osteoarthritis and Cartilage, Vol: 34, Pages: 1539-1549, ISSN: 1063-4584ObjectiveStratification of therapeutic responses may help identify efficacious therapies for osteoarthritis (OA). In the PROMOTE randomised trial, participants with elevated baseline high-sensitivity C-reactive protein (hs-CRP) showed greater pain reduction after methotrexate treatment. We set out to interrogate a broader panel of serum/plasma inflammatory response markers relevant to methotrexate actions as potential biomarkers of therapeutic effect. Our objectives were to: (i) characterize changes in these systemic markers during methotrexate treatment; determine whether (ii) baseline levels or (iii) changes in any marker during treatment were associated with treatment response; and (iv) compare these findings with the more established clinical inflammatory marker, hs-CRP.DesignPlasma/serum samples from participants in PROMOTE’s biological substudy were analysed for 35 inflammatory markers at baseline (pre-treatment) and at 6-months (post-treatment), by MesoScale V-plex multiplex assay. Those with paired biological and clinical data at both baseline and 6-months were included in the substudy analysis set. Relationships between markers and overall data structure were assessed by Pearson correlation and Principal Component analysis. Associations between markers (baseline levels or change over time) and change in average knee pain severity in past week (numerical rating scale, NRS) were evaluated by univariable linear regression, adjusting for baseline age, sex, and body mass index. Least Absolute Shrinkage and Selection Operator (LASSO) regression with bootstrap resampling enabled marker selection. Benjamini-Hochberg correction adjusted for multiple testing (Padj).Results87 participants with paired blood marker and clinical data were eligible for substudy analysis. 18/35 markers were quantifiable and analysed. Systemic IL-8 and TNF-α levels decreased (Padj=0.015, 0.048 respectively) while IL-15 increased (Padj=0.033) with methotrexate treatment over 6-mo
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Journal articleWade J, Thomas DC, Pickering MC, et al., 2026,
Complement and kidney diseases: unlocking the opportunity of targeted treatments for glomerular diseases, including IgA nephropathy.
, Pediatr Nephrol, Vol: 41, Pages: 3231-3246The imminent availability of multiple therapeutic complement inhibitors, which target different complement pathway components, could revolutionise treatment for a broad range of kidney diseases. However, the complexity of complement activity within and between kidney diseases, for which IgA nephropathy is an illustrative example, and the possible adverse effects of complement inhibition mean robust patient selection and stratification to appropriately targeted inhibitors will be needed to maximise this therapeutic opportunity. Despite promising candidates, novel biomarkers that stratify patients to targeted complement inhibition have not yet been validated for clinical practice.
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Journal articleDabas R, Kabir L, Navaratnam N, et al., 2026,
PGC1α expression using targeted redox-responsive nanogels protects against prostate cancer in vivo.
, J Control Release, Vol: 397Prostate cancer is among the most frequently diagnosed cancers in men in the UK and US. Increasing evidence implicates metabolic dysregulation as a critical driver of disease progression. Central to this process is peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) that promotes oxidative metabolism and mitochondrial biogenesis while inhibiting metastatic programs. This work investigated the therapeutic potential of PGC1α overexpression via mRNA delivery. Here, we report a prostate-specific, targeted disulphide-crosslinked nanogel system for intracellular delivery of mRNA encoding the N-terminal isoform of PGC1α (NT-PGC1α). Functionalization of the NGs with a peptide targeting prostate-specific membrane antigen (PSMA) enabled selective delivery of NT-PGC1α mRNA in PCa cells and 3D spheroid models. We confirmed sustained PGC1α expression, and increased mitochondrial protein content, indicative of enhanced mitochondrial biogenesis. These nanogels, which were prepared in situ using a nanopolymerization technique, exhibited high mRNA loading capacity, low cytotoxicity, and redox-responsive cargo release, enabling controlled cytosolic delivery following intracellular glutathione-mediated degradation. In vivo, systemic administration of the PSMA-targeted NT-PGC1α mRNA-loaded nanogels resulted in tumor-preferential accumulation and significant suppression of xenograft growth (by 73.4% relative to untreated control), with minimal systemic toxicity. This study presents the first example of a prostate-targeted, disulfide-crosslinked nanogel system for mRNA-mediated metabolic reprogramming in prostate cancer, and highlights its promise as a platform for future RNA-based targeted and precision stimuli-responsive cancer therapies.
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Journal articleGeorgiou C, Liu Q, Bruno F, et al., 2026,
Rare Hematopoietic Stem Cells resilient to infection-induced stress sense yet withstand inflammation.
, BloodHematopoietic stem cells (HSCs) sustain lifelong hematopoiesis as their progeny differentiate into all blood cell lineages. Homeostatic HSCs are mostly quiescent and only rarely divide, however their proliferation and differentiation rates can be modulated by external factors. Acute and chronic infections from a wide range of pathogens are known to challenge HSCs at the population level, being forced to respond to inflammation-mediated organismal demand to replenish the myeloid cell pool. However, less is known about the degree of heterogeneity in the HSCs' response to inflammation at the single cell level. Here, using a natural murine malaria model and an NHS-ester biotin dilution assay we identify two subsets of HSCs, BiotinLo and BiotinHi, with distinct proliferation kinetics. Using combined functional, single-cell transcriptomics and phenotypic analyses, we uncover that BiotinHi HSCs remain highly functional despite expressing strong interferon response signatures. These resilient HSCs are more poised to enter cell cycle than control HSCs, but do not divide. They maintain less active mitochondria and express higher levels of CD74 and MHC-II. Additionally, they express higher levels of integrin β2/CD18, which suggest they may have specific interactions with the bone marrow microenvironment. Similar patterns of NHS-ester biotin dilution were elicited by LPS and poly (I:C) challenges. These findings highlight previously unmeasured heterogeneity in the response of HSCs to acute infection-induced inflammation and demonstrate that a likely reserve pool of HSCs remains highly functional during Plasmodium infection not because cells are shielded, but because they maintain a stemness associated metabolic profile despite effectively sensing inflammation.
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Journal articleJiang T, Chan L-C, Wang W, et al., 2026,
Deep-learning-based radiomics score for knee replacement risk prediction compared with Kellgren-Lawrence grading: a multicentre cohort study
, The Lancet Medical Imaging & Theranostics, ISSN: 3117-4523
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