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Journal articleJebreel WMA, Abdel Hamid MM, Mustafa SA, et al., 2026, , BMC Infectious Diseases, Vol: 26, ISSN: 1471-2334
BackgroundMalaria 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 articleWan Y, Wong JLC, Sanchez-Garrido J, et al., 2026, , BMC Genomic Data, Vol: 27, ISSN: 2730-6844
Background 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 articleCelsa C, Pressiani T, Nishida N, et al., 2026, , JHEP Reports, Vol: 8, ISSN: 2589-5559
Background & 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 articleCorbaux P, You B, McNeish I, et al., 2026, , International Journal of Gynecological Cancer, Vol: 36, ISSN: 1048-891X
Objective: Growing evidence suggests potential ethnic and geographical variations in chemotherapy efficacy. The CA125 ELIMination rate constant K score is a pragmatic and reproducible indicator of tumor chemosensitivity in newly diagnosed ovarian cancer. We compared ELIMination rate constant K distributions and prognostic performances between patients enrolled in Japanese and Western trials who had stage III/IV serous ovarian cancer from the Gynecologic Cancer InterGroup individual-patient-data Meta-Analysis in OVarian cancer. Methods: The ELIMination rate constant K values were previously estimated for 5884 women receiving first-line chemotherapy for ovarian cancer. Data from 246 women enrolled in the Japanese JGOG-3016 trial were compared to 2561 patients from Western trials. ELIMination rate constant K was analyzed as a binary variable (favorable ≥1.0 vs unfavorable <1.0). Prognostic value for progression-free survival and overall survival was assessed using univariable and multi-variable models. A standardization cut-off specific to patients enrolled in the Japanese trial was explored using maximally selected rank statistics. Results: KELIM was significantly higher in patients enrolled in the Japanese trial (median 0.071 day<sup>-1</sup> vs 0.056 day<sup>-1</sup>; p <.0001). Using the standard cut-off, favorable ELIMination rate constant K was independently associated with improved progression-free survival (hazard ratio 0.59, 95% confidence interval 0.43 to 0.83) and overall survival (hazard ratio 0.53, 95% confidence interval 0.36 to 0.79) in patients from the Japanese trial. Applying the exploratory cut-off of 0.07 day<sup>-1</sup> strengthened prognostic discrimination (progression-free survival: hazard ratio 0.35, 95% confidence interval 0.25 to 0.49, p <.0001; overall survival: hazard ratio 0.40, 95% confidence interval 0.26 to 0.61, p <.0001). Conclusions: Potential higher ELIMination rate constant K-asse
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Journal articlePawa R, Derecichei I, Klein K, et al., 2026, , iScience, Vol: 29
RNA viruses are responsible for many zoonotic disease transmission events, and remain a global health challenge. To evade immune detection, RNA viruses suppress the numbers of immunostimulatory oligonucleotide motifs (INMs) present in their genomes. Although this is thought to occur in human immunodeficiency virus-1 (HIV-1), our bioinformatic analysis on well characterized clinical datasets, along with in vitro studies, demonstrate that HIV-1 is enriched for INMs within its transmitted/founder (T/F) population relative to non-transmitting variants. Importantly, our data suggests that within the host, there is an evolutionary genetic replacement of T/F viruses that otherwise exhibit high transmission fitness and low replicative fitness, with variants having low transmission fitness but high replicative fitness. These findings provide insights into HIV-1 transmission by studying within-host and between-host evolutionary dynamics, enabling us to identify a framework for HIV infection biology, with viral RNA playing a role in transmission and replication processes.
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Journal articleAltmann DM, Boyton RJ, 2026, , Nature Immunology, ISSN: 1529-2908
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Journal articleDurmisevic A, Openy J, Majid A, et al., 2026, , Nucleic Acids Research (NAR), Vol: 54, ISSN: 0305-1048
Gaining control over DNA G-quadruplex topology bears potential to modulate and study their interaction with other biomacromolecules such as proteins. To achieve this, we introduced bipyridine ligands into short oligonucleotide strands derived from telomeric regions of humans and Tetrahymena as well as into an oncogenic promoter region capable of forming such G-quadruplexes. This modification makes it possible to dynamically access different G-quadruplex topologies through the formation of chelate complexes within the quadruplex loop regions using metals such as Cu2+, Ni2+, Zn2+, Co2+ and Cd2+. The metal coordinated systems show enhanced stability towards thermal denaturation as well as a solvation-related response in the presence of molecular crowding reagents. Furthermore, herein introduced G-quadruplexes modified with bipyridine-metal complexes stay folded in cellulo and therefore show potential for creating new oligonucleotide-based diagnostic agents and therapeutics. Metal-stabilized G-quadruplexes will be suited as robust probes for finding new protein binders, inducers for cellular pathways or decoys to sequester transcription factors.
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Journal articleGoodship A, Preston R, Hicks J, et al., 2026,
Effect of ovarian hormones on long COVID and myalgic encephalomyelitis: an analysis of prospectively collected digital health app data
, The Lancet: Digital Health, ISSN: 2589-7500BackgroundLong COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) disproportionately affect females, suggesting modulation by sex hormones. We aimed to determine whether symptom severity is affected by changes in sex hormones over the menstrual cycle or by hormonal contraception. MethodsWe analysed data prospectively collected via the Visible app from individuals with long COVID, ME/CFS, or both (7th September 2022-6th March 2024). We examined associations between symptom severity, menstrual cycle phase and contraception type using mixed-effects models. Users of the Hertility menstrual cycle tracking app (7th September 2022-28th September 2025) formed a population comparison cohort. Findings948 users were included in the disease cohort, and 501 users in the population cohort, all of which were female. 92.6% (878/948) of the disease cohort and 99.6% (499/501) of the population cohort identified as women. Crashes (sudden and severe worsening of symptoms following exertion) were significantly more frequent during menstruation than other phases (odds ratio (OR) compared with the late luteal phase = 0·888, 95% confidence interval (CI): 0·838-0·941). Users of combined hormonal contraception (n=70) had reduced crash incidence (OR = 0·548, 95% CI: 0·350–0·856) and overall symptom score (incidence rate ratio = 0·827, 95% CI: 0·690–0·992) compared to those not using contraception (n=786). Fatigue, brain fog, and headache showed phase-specific variation in both disease and population cohorts, albeit that these are less frequently reported in the population cohort.InterpretationOur findings suggest a role for ovarian hormones in modulating symptoms. We adjusted for individual, disease type, age and gravidity, however, residual confounding accounting for differences in disease severity associated with contraceptive use cannot be excluded. Nevertheless, these findings could empower menst
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Journal articleBoloko L, Schutz C, Ward A, et al., 2026, , J Infect
BACKGROUND: Sepsis pathobiology is shaped by both pathogen load and host characteristics, yet pathogen load is rarely measurable in clinical cohorts. Severe HIV-associated tuberculosis (TB), a leading cause of critical illness in Africa, provides a unique model in which Mycobacterium tuberculosis bacilli load can be quantified. We investigated how pathogen load and age influence sepsis pathophysiology and mortality in this high-risk population. METHODS: We conducted a prospective cohort study of adults admitted with severe HIV-associated TB. Systemic bacillary load was estimated from multiple routinely collected TB diagnostics. Blood-based sepsis markers were summarised using principal components analysis, and pathophysiological processes were evaluated using directed acyclic graphs and regression modelling. FINDINGS: Among 519 patients with microbiologically confirmed TB, 75 (14.5%) died by day 28. Two major axes of host response were identified: PC1, capturing IL-6, CRP, and procalcitonin; and PC2, reflecting venous lactate, aspartate aminotransferase, and cytopenias. Both strongly correlated with bacilli load (PC1 r=0.46; PC2 r=0.43; both p<0.001) but not with age. Mortality independently associated with infection severity - whether defined by bacilli load (aOR 2.1, 95%CI 1.6-2.9) or by inflammatory axes (PC1 aOR 2.3, 95%CI 1.7-3.1; PC2 aOR 1.9, 95%CI 1.5-2.5) - and with age (aOR 1.84, 95%CI 1.4-2.4). Absolute mortality risk therefore reflected an interaction between pathogen load and age. Hyperlactataemia, metabolic acidosis, kidney dysfunction, and temperature were all correlated with bacilli load, inflammation and mortality (all p<0.001). Older patients showed less respiratory compensation for metabolic acidosis, higher blood glucose at a given lactate level, and attenuated fever response at a given bacilli load. INTERPRETATION: Pathogen load and associated inflammatory responses define infection severity in HIV-associated TB and interact with age to pre
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Journal articleFrankel G, 2026, , Nature Communications, ISSN: 2041-1723
Enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium (CR) are extracellular enteric attaching and effacing (A/E) pathogens of humans and mice, respectively. Their virulence relies on intimate bacterial attachment and a network of type III secretion system effectors. Here, through systematic reduction and redesign of the effector network in CR, we develop an attenuated strain, CRV (CR Vaccine), encoding a subset of ten effectors. CRV colonises C57BL/6 mice ~100-fold lower than wild type CR (CRWT) without causing overt pathogenesis. Moreover, C3H/HeN mice, which succumb to CRWT infection, survive CRV challenge. Vaccination with CRV confers protection against subsequent CRWT infection in both mouse strains. Serological analysis reveals a repertoire of dominant CR antigens, including the O-antigen, the virulence factors intimin, EspA and Tir and the outer membrane proteins Lpp, OmpA, MetQ and CARC (an AIDA-like autotransporter). We show that CRWT and CRV immunisation elicits comparable B cell and antibody responses, which is contingent on intimate bacterial attachment. A corresponding EPEC strain (E. coli Vaccine, ECV) effectively colonises epithelial cells in a gut-on-chip model. These findings establish effector network minimisation as a generalisable strategy for rational bacterial attenuation and live-attenuated vaccine design.
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