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he research groups of Dr Zamin Iqbal and Professor Derrick Crook, working in collaboration with teams at the OUCRU and the Foundation for Medical Research, Mumbai, aim to develop a rapid handheld TB test using the Oxford Nanopore MinION device.
Evaluation of the Wondfo G6PD/Hb Test for glucose-6-phosphate dehydrogenase deficiency: preliminary performance, matrix equivalence, and usability.
BackgroundCurrent treatment guidelines for radical cure of Plasmodium vivax malaria recommend the use of 8-aminoquinolines, which can result in life-threatening complications in people with glucose-6-phsophate dehydrogenase (G6PD) deficiency. Testing for this condition is recommended prior to administering such drugs. The Wondfo G6PD/Hb Test (Guangzhou Wondfo Biotech Co., Ltd., China) is a novel, quantitative point-of-care (POC) G6PD test that may help decentralize testing, expanding access to safe treatment options.MethodsTwo studies were conducted: a retrospective diagnostic accuracy study on frozen venous whole blood specimens and a prospective matrix equivalency study. First, 300 frozen specimens from Mae Sot, Thailand were tested from July-August 2022 using the Wondfo test in laboratory and simulated field conditions. Reference testing for G6PD and Hb (spectrophotometer [Pointe Scientific, USA] and HemoCue [HemoCue AB, Sweden], respectively) was completed in the laboratory. Usability was evaluated among 10 intended users. Next, 225 participants were enrolled into a prospective matrix equivalency study from March-May 2023 in Memphis, Tennessee, USA. The Wondfo test was conducted at the POC with fingerstick capillary blood, and Wondfo and HemoCue tests were completed on fresh venous (K2EDTA) blood within 12 h. Remaining specimens were shipped to PATH for repeat Wondfo and reference testing.ResultsThe Wondfo G6PD measurement showed strong correlation under both laboratory and field conditions (R2>0.9). The area under the curve was 1.00 for deficient (95% CI: 1.00-1.00) and 0.99 for intermediate individuals (95% CI: 0.99-1.00). Sensitivity was high (1.00) across all conditions and groups (lower bound of the 95% CI ≥0.85). Good correlation was observed in both capillary and fresh venous blood against the reference and each other (R2>0.75). McNemar's test showed no significant differences in classification between venous and capillary specimens. The Wondfo test achieved 98.2% (95%CI: 95.5-99.5%) overall agreement. All usability participants successfully completed quality control and test procedures, rating the test system highly for ease of use.ConclusionsThe Wondfo G6PD/Hb Test demonstrates good diagnostic performance using current manufacturer thresholds across various conditions and both venous and capillary specimens. Comparable performance in both specimen types supports matrix equivalence. Usability is acceptable for end users, though refinements were recommended.
Safety and tolerability of metformin in overweight and obese patients with dengue: An open-label clinical trial (MeDO)
Background Despite dengue being a major public health problem, there are no antiviral or adjunctive treatments for the disease. Novel therapeutics are needed, particularly for patients at high risk of severe disease, including those living with obesity. Metformin reduces dengue viral replication in vitro through AMPK activation and may also have beneficial immunomodulatory effects. Methods We conducted an open label trial at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, enrolling 120 patients with dengue and obesity (60 treatment arm, 60 control arm receiving standard of care only). Within the treatment arm, the first 10 patients were prescribed low dose metformin, and the remaining 50 patients received weight-based dosing of 1-1.5g/day. The primary outcome was the number of adverse events (AEs), and secondary outcomes were clinical and laboratory parameters, including fever clearance time, platelet nadir, percentage of haematocrit change from baseline, maximum creatinine and highest AST/ALT, and the kinetics of plasma viraemia and NS1 antigenaemia. Results The majority of patients in both groups had dengue with warning signs. Six patients in the metformin group and 5 controls developed dengue shock syndrome, and no patients died. There were more AEs recorded in the metformin treated group than in the control group (mean±SD: 15 ± 4 vs. 11 ± 6), particularly the high-dose metformin group (15 ± 5). Twenty-five patients (42%) had to stop the study drug due to AEs, including severe diarrhea (n = 12), dengue shock (n = 5), increased lactate of >3mmol/L (n = 4), hypoglycemia (n = 3), and persistent vomiting (n = 1). There were no clear differences in secondary outcomes between the two groups. Conclusions Metformin was poorly tolerated in patients with dengue, mainly due to gastrointestinal side effects. Metformin did not beneficially affect clinical evolution or virological parameters compared to supportive care alone. Our data does not support progression to larger phase 3 trials of metformin in patients with dengue. Trial registration ClinicalTrials.gov: NCT04377451 (May 6th, 2020).
Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin
Abstract Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4–6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell–cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.
Optimizing dog population control strategies in Thailand using mathematical and economic modeling.
A mathematical model was constructed to investigate dog population dynamics and explore the impact of population management and rabies prevention. We aimed to evaluate cost-effective sterilization and vaccination strategies for dog population control and rabies prevention in Thailand. The developed compartmental model was calibrated with dog population data from Lopburi province (between 2019 and 2022) and simulated five sterilization scenarios. These measures included a combined 80% coverage of the rabies vaccine and 20% coverage of a sterilization program among non-specific dog types. Our findings indicated that sterilization programs targeting female indoor, outdoor, and stray dogs may prove to be the most effective in reducing the total dog population above 50% over a five-year period, surpassing the efficacy of the current intervention. Furthermore, the cost-effectiveness analysis showed that the two female dog sterilization strategies were cost-saving compared to the current practice, as the total costs of sterilization and vaccination decreased over time due to the reduction in the dog population. In conclusion, targeting female dog sterilization could reduce the population and was cost-saving compared to current strategies. Further data to inform dog population demographic and available resources including manpower, rabies vaccine, sterilization toolkits, and related materials will be required to fully explore intervention accessibility and feasibility within the context of rabies prevention and control in Thailand.
Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K ( Actc1 E99K ) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1–knockout ( Rag-1 KO ) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1 E99K mice. Detailed characterization of cardiac regulatory T cells (T reg cells) demonstrated a time-dependent increase in Actc1 E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic T reg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1 E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti–IL-2 complex (IL-2/c), which specifically induced T reg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1 E99K mice. These data contribute to our understanding of HCM and support the use of T reg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1 + macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β–responsive stromal subsets that up-regulate expression of disease risk–associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
The Risk-Benefit Balance of Oral Corticosteroid Treatment for Asthma Attacks: A Discrete Choice Experiment of Patients and Healthcare Professionals in the UK and New Zealand.
Background and objectiveOral corticosteroids (OCS) are the guideline recommended treatment for all asthma attacks, but benefits must be considered alongside the potential for cumulative side-effects. There is interest in trialling biomarker-directed management of attacks to rationalise OCS treatment in those with least benefit. Understanding stakeholder perspectives on the risks and benefits associated with OCS treatment can inform trial design and shared decision-making discussions in clinical practice. The aim was to examine patients' and healthcare professionals' preferences for the risks and benefits associated with OCS treatment for asthma attacks.MethodsDiscrete choice experiment (DCE) by patients with asthma and HCPs in the UK and New Zealand. Preferences were analysed using logit models.ResultsEight hundred and twenty-four patients and 171 HCPs completed the DCE. Avoiding the risks of permanent side effects had the greatest impact on treatment preference by patients and HCPs. Avoidance of side effects was weighted higher by patients than HCPs. Patients with uncontrolled asthma were more prepared to trade risk for benefit. Symptom recovery was the most valued clinical benefit to patients and HCPs. Patients preferred 'improving lung function' over 'avoiding additional GP treatment or hospitalisation', whereas HCPs preferred avoidance of further healthcare utilisation. Based on their responses we estimated the minimum clinically important difference for the treatment failure outcome at 20%.ConclusionPatients and HCPs will trade-off treatment benefits to avoid the side-effects associated with OCS. The risk-benefit balance of OCS should feature in shared decision-making discussions with patients experiencing outpatient asthma attacks. The findings support developing trials to personalise acute asthma treatment.
Small for Gestational Age sub-groups have differential morbidity, growth and neurodevelopment at age 2: the INTERBIO-21<sup>st</sup> Newborn Study.
BackgroundSmall for Gestational Age (SGA) is a complex perinatal syndrome associated with increased neonatal morbidity, mortality, and impaired childhood growth and neurodevelopment. Current classifications rely primarily on birth weight, which does not capture the heterogeneity of the condition nor predict long-term health outcomes. Here we aim to identify and characterise distinct SGA sub-groups and assess their neonatal and early childhood health trajectories.ObjectivesTo refine the classification of SGA by identifying sub-groups based on maternal, fetal, and environmental factors and evaluating their associations with neonatal morbidity, growth, and neurodevelopment at age 2.Study designProspective Cohort Study. In six countries worldwide, between 2012 and 2018, the INTERBIO-21st Study enrolled SGA and non-SGA newborns defined by the <10th centile of international standards with moderate (≥3rd to <10th centile) and severe (<3rd centile) SGA sub-groups; we assessed their growth, health, nutrition, motor development, and neurodevelopment up to age 2. We used 2-step cluster analysis to identify SGA sub-groups, and a probabilistic approach to choose the optimal sub-group model based on a statistical measure of fit. We performed logistic regression analysis (OR; 95% CI) to assess health and development outcomes among sub-groups using the non-SGA as reference group, adjusting for key confounders.ResultsWe enrolled 5153 non-SGA and 1549 SGA newborns: moderate (≥3rd to <10th centile) SGA=947 and severe (<3rd centile) SGA=602). We identified nine SGA sub-groups: 'no main condition detected' (29.0%); 'previous low birth weight (LBW)/preterm birth (PTB)' (14.6%); 'severe maternal disease' (12.0%); 'maternal short stature (11.6%); 'hypertensive disorders' (9.6%); 'extrauterine infection' (6.8%); 'previous miscarriage(s)' (6.5%); 'smoking' (5.2%), and 'maternal under-nutrition' (4.7%). Severe SGA newborns in the 'severe maternal disease' (OR: 3.2; 95% CI, 1.8-6.0), 'previous LBW/PTB' (OR: 2.8; 95% CI, 1.6-4.8), and 'smoking' (OR: 5.4; 95% CI, 1.3-21.8) sub-groups had increased risk of neonatal and long-term morbidity, and low anthropometric measures at age 2 as compared to the non-SGA group. Moderate SGA newborns in the "hypertensive disorders" sub-group had increased risk of neonatal morbidity (OR: 2.6; 95% CI, 1.5-4.6), and higher odds of scoring <10th centile of normative values in language (OR: 3.5; 95%CI, 1.0-12.0) and positive behavior (OR: 2.2; 95%CI, 1.1-4.5). The 'severe maternal disease' sub-group had also higher risk of deficit (<10th centile of normative values) in language (OR: 5.7; 95%CI, 1.3-24.8), positive behavior (OR: 3.4; 95%CI, 1.5-7.6).ConclusionsSGA comprises heterogeneous sub-groups with distinct patterns of neonatal morbidity, postnatal growth, and neurodevelopmental outcomes up to age 2.
Risk factors of metabolic dysfunction-associated steatotic liver disease in a cohort of patients with chronic hepatitis B.
Background and aimsChronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) commonly co-exist, with conflicting data in prevalence and disease severity. We aimed to investigate these discrepancies.MethodsThis multicentre study included consecutive CHB patients from 19 European centres. A survey on standard of care for MASLD screening in CHB was circulated.Results1709 CHB patients were included; median age: 53 (42-64), males 60.7%, BMI 25.6 (14-63), 57.3% White. MASLD prevalence (1510 consecutive patients) was 42.3%. BMI (OR=1.27, 95% CI:1.19-1.36), ferritin (OR=1.00, 95% CI:1.00-1.00) and type-2-diabetes (T2DM) (OR=2.60, 95% CI:1.12-6.02) were independently associated with MASLD. The prevalence of advanced fibrosis was 18% (255/1420) in the whole cohort, 25.4% (162/639) among CHB with MASLD, and 13.7% in those without MASLD. Independent predictors of advanced fibrosis were MASLD (OR:2.76, 95%CI:1.50-5.05), BMI (OR:1.08, 95%CI:1.02-1.15), ALT (OR:1.01, 95%CI:1.00-1.03), lower PLTs (OR:0.99, 95%CI:0.98-0.99), insulin-treatment (OR:13.88, 95%CI:2.95-65.28) and long-term antivirals (OR:4.86, 95%CI:2.40-9.85). During follow-up (48 months), only patients without MASLD showed significant LSM improvement over time (p<0.001). Among patients with MASLD, FIB-4 and LSM performed moderately at predicting advanced fibrosis (AUROC 0.71 vs 0.70, p=0.38), against histology. As standard of care, 68.4% centres screened all CHB patients for MASLD. 52.6% followed the same treatment indication in those with CHB and MASLD vs CHB only.ConclusionIn this large European cohort, MASLD and fibrosis were highly prevalent among CHB, while MASLD aggravated liver fibrosis. Though screening strategies remain inconsistent, ferritin levels, increased BMI and T2DM may inform on the presence of MASLD. Biomarkers showed modest performance in predicting fibrosis.
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma.
BackgroundTargeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.ObjectiveAssess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics.MethodsProteomic analysis (Olink®, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n= 43) & at first exacerbation (n=26).ResultsClustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1β, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters.ConclusionIn a cohort of T2-high severe asthma patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2-biologics which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer
AbstractThe CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain‐of‐function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1‐mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in‐house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH‐mutant CRCs were CIMP‐positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH‐mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging‐related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH‐mutant CRCs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Intersectin and endophilin condensates prime synaptic vesicles for release site replenishment.
Following synaptic vesicle fusion, vacated release sites are replenished immediately by new vesicles for subsequent neurotransmission. These replacement vesicles are assumed to be located near release sites and used by chance. Here we find in mouse hippocampal excitatory synapses that replacement vesicles are clustered near the active zone where release sites reside by intersectin-1. Specifically, intersectin-1 forms dynamic molecular condensates with endophilin A1 and sequesters vesicles around this region. In the absence of intersectin-1, fewer vesicles cluster within 20 nm of the plasma membrane, and consequently vacated sites cannot be replenished rapidly, leading to synaptic depression. Mutations in intersectin-1 that disrupt endophilin A1 binding result in similar phenotypes. In the absence of endophilin A1, intersectin-1 is mislocalized, and this replacement pool of vesicles cannot be accessed, suggesting that endophilin A1 is needed to mobilize these vesicles. Thus, our work describes the replacement zone within a synapse, where replacement vesicles are stored for replenishment of the release site.