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Journal articleTikhomirov R, Boichenko V, Reilly-O'Donnell B, et al., 2026,
Interleukin 11-Induced MicroRNAs as Functional Mediators and Circulating Biomarkers of Cardiac Fibrosis.
, Circ Res, Vol: 138BACKGROUND: Cardiac fibrosis can be triggered by several pathologies, including ischemic heart disease and aortic stenosis. Cardiac fibrosis is brought about by uncontrolled ECM (extracellular matrix) deposition by myofibroblasts. IL (interleukin)-11 (Il11) has been demonstrated as a trigger of multiorgan fibrosis. However, the molecular mechanisms underpinning IL-11-induced fibrosis require further characterization. Recent studies indicate that microRNA dysregulation contributes to the pathogenesis of cardiac fibrosis and can be targeted therapeutically. This study explored the hypothesis that microRNAs act as downstream effectors of IL-11-induced cardiac fibrosis. Moreover, we investigated the translational potential of IL-11-regulated microRNAs as circulating biomarkers of cardiac fibrosis in patients with aortic stenosis. METHODS: A bioinformatic microRNA target prediction analysis was used to identify candidate microRNAs regulated by IL-11. Experimental validation was performed in cardiac fibroblasts from postinfarction failing and healthy rat hearts, after IL-11 stimulation. Functional studies assessed the effects of microRNA modulation on fibrotic gene expression in cardiac fibroblasts using microRNA inhibitor-based and mimic-based transfection. Bioinformatic analysis and luciferase assay identified candidate microRNA targets downstream of IL-11. Findings were further evaluated in transverse aortic constriction and cardiomyocyte-specific Il11-overexpression (Tg-Il11 [transgenic mouse model with cardiomyocyte-specific Il11 overexpression]) mouse models and in left ventricular tissue, peripheral plasma, and plasma extracellular vesicles from patients with aortic stenosis. RESULTS: MicroRNA-27b-5p and microRNA-497-5p were identified as novel downstream effectors of IL-11 signaling. IL-11 increased the expression of both microRNAs in cardiac fibroblasts; transfection with either microRNA inhibitor reduced, whereas microRNA mimics increased, profibrotic mRNA level
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Journal articleMukhopadhyay S, Cheng L, Jones RE, et al., 2026,
Prevalence and Clinical Importance of Right Ventricular Involvement in Mild Dilated Cardiomyopathy.
, J Am Heart Assoc, Vol: 15 -
Journal articleAustin R, Zuhair M, Kaza N, et al., 2026,
When infective endocarditis masquerades as gastrointestinal disease: a case report
, British Journal of Hospital Medicine, Vol: 87, ISSN: 1750-8460Aims/Background:Infective endocarditis (IE) is a serious and potentially life-threatening condition characterised by inflammation and infection of the endocardium. While cardiac manifestations are well-recognised, extracardiac manifestations of IE, particularly in the gastrointestinal tract, are less commonly reported. We report the first known case of IE presenting with colitis-like symptoms in the absence of identifiable colonic pathology.Case Presentation:A 34-year-old male patient presented to primary care with gastrointestinal symptoms, including fever, weight loss, and bloody diarrhoea. There was an absence of detectable intestinal pathology on colonoscopy, and subsequent findings revealed a link between the gastrointestinal symptoms and IE-related complications. The patient later developed right-sided flank pain, a pansystolic murmur, and splinter haemorrhages in two fingernails. Imaging studies indicated renal infarcts suspicious for septic emboli, and echocardiography revealed severe mitral regurgitation with an anterior leaflet vegetation. Blood cultures were negative, likely due to prior antibiotic administration.Results:The patient was therefore treated with empirical intravenous antibiotics (amoxicillin, flucloxacillin and gentamicin), resulting in the resolution of gastrointestinal symptoms.Conclusion:This case highlights the importance of considering IE in patients with unexplained gastrointestinal symptoms and systemic features, even in the absence of visible colonic lesions. Early recognition and appropriate management may improve outcomes.
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Journal articleTonko JB, 2026,
Epicardial Pulsed Field Ablation for Bachmann Bundle-Mediated Atrial Tachycardia: Expanding Indications and Identifying Limitations.
, JACC Case Rep, Vol: 31 -
Journal articleVissing CR, Axelsson Raja A, Helms AS, et al., 2026,
Differences in Disease Trajectory, Comorbidities, and Mortality in Sarcomeric and Nonsarcomeric Hypertrophic Cardiomyopathy.
, Circulation, Vol: 153, Pages: 1104-1116BACKGROUND: Sarcomere gene variants are a key cause of hypertrophic cardiomyopathy (HCM), and have been associated with worse prognosis. However, it is unclear how comorbidities influence clinical trajectories, the timing of events, and causes of death in sarcomeric and nonsarcomeric HCM. METHODS: We conducted a multicenter longitudinal cohort study of genotyped patients with HCM in the Sarcomeric Human Cardiomyopathy registry (SHaRe). Patients were classified as sarcomeric HCM (pathogenic/likely pathogenic sarcomere variant) or nonsarcomeric HCM (genetically elusive). The influence of genetic classification and comorbidities on the sequence of cardiovascular events were assessed in time-varying Cox proportional hazards models. RESULTS: Among 6120 patients (40% women; 87% probands; 50% sarcomeric HCM), followed for a median of 5.3 years, sarcomeric HCM (n=3082) was associated with a younger age at diagnosis (median 38.1 versus 54.3 years; P<0.001), a higher proportion of women and less obesity, hypertension, and left ventricular (LV) obstruction. After age standardization, sarcomeric HCM was associated with a higher burden of atrial fibrillation (age-standardized incidence [ASI] ratio, 1.28 [CI, 1.16-1.40]), LV systolic dysfunction (ASI ratio, 1.31 [CI, 1.15-1.48]), and ventricular arrhythmias (ASI ratio, 1.37 [CI, 1.17-1.52]) than nonsarcomeric HCM. All-cause mortality was similar (10.4% versus 9.4%; P=0.20); however, patients with sarcomeric HCM died younger (mean 7.8 years; P<0.001), with model-based survival-analysis estimating 3.5 life-years lost between ages 44 and 85. Sarcomeric HCM was also associated with higher HCM-related mortality (hazard ratio [HR], 1.61 [CI, 1.18-2.20]). Temporal analysis identified atrial fibrillation as the strongest disease-modifier, increasing the risk of LV systolic dysfunction (HR, 2.54 [CI 2.07-3.11]), ventricular arrhythmias (HR, 3.13 [CI, 2.36-4.20]), and mortality (HR, 1.94 [CI, 1.64-2.31]) in both groups. Genotype-inte
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Journal articleBola H, Melamed T, Allaf M, et al., 2026,
Ethanol infusion of the vein of marshall-based strategies for persistent atrial fibrillation: a systematic review and meta-analysis of randomized trials.
, Europace, Vol: 28AIMS: Pulmonary vein isolation (PVI) alone achieves modest arrhythmia freedom in persistent atrial fibrillation (PeAF). Ethanol infusion of the vein of Marshall (EIVOM) overcomes heat-sink effects, facilitating mitral isthmus (MI) block, and may represent an effective adjunctive ablation strategy. We aimed to quantify the efficacy and safety of EIVOM through a meta-analysis of randomized controlled trials (RCTs). METHODS AND RESULTS: Systematic review of MEDLINE, Web of Science, and PubMed identified 5 RCTs enrolling 1179 patients (602 EIVOM, 577 control). The primary endpoint was 12-month freedom from any atrial arrhythmia. Random-effects models generated risk ratios (RRs) with 95% confidence intervals (CI). Time-to-event data were pooled using a generic inverse-variance approach to derive hazard ratios (HR). EIVOM-based strategies improved freedom from any arrhythmia (RR 1.16, 95% CI 1.04-1.29; P < 0.001; number needed to treat (NNT) = 10) and from atrial fibrillation (RR 1.11, 95% CI 1.05-1.18; P < 0.001; NNT = 13). Time-to-event analysis demonstrated a sustained reduction in recurrence hazard (HR 0.72, 95% CI 0.64-0.81; P = 0.003; I2 = 0%). Repeat ablation was reduced (RR 0.61; P = 0.009). Fluoroscopy time increased (+9.08 min; P = 0.007), while major complications were comparable (2.5% vs. 2.8%; P = 0.47). Trial sequential analysis confirmed that the cumulative Z-curve crossed the monitoring boundary for benefit for the primary endpoint, indicating that the available evidence is sufficient. CONCLUSION: In PeAF, EIVOM-based ablation strategies significantly improve 12-month arrhythmia-free survival and reduce repeat procedures without increasing major adverse events. However, the observed benefit reflects composite ablation sets rather than ethanol infusion in isolation, and the predominance of high-volume expert centres may limit generalizability.
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Journal articleChristou N, Fitikides N, Yan X, et al., 2026,
Cobalt(III) complexes as promoters of amyloid-β fibril destabilization
, ChemMedChem, ISSN: 1860-7179Alzheimer’s disease is linked to the formation of pathological aggregates of the amyloid-β peptide in the brain. The N-terminus of amyloid-β plays an important role in modulating aggregation through metal- ion binding. It also remains solvent-accessible in both the monomers and the amyloid fibrils. This observation inspired us to synthesize cobalt(III) metal complexes featuring functionalized aromatic ligands, aimed at targeting amyloid-β N-terminus to influence aggregation. Through chemical kinetic analysis, we found that our cobalt(III) complexes modulate both primary and secondary nucleation pathways. Furthermore, total internal reflection fluorescence microscopy demonstrated that the compounds could disrupt preformed amyloid fibrils. Under physiologically relevant oxidative conditions, inhibition of fibril formation was reduced, whereas fibril disassembly remained largely preserved. This indicates that oxidation selectively impairs the aggregation-inhibiting mechanism without substantially affecting fibril disassembly. These findings suggest that inhibition of aggregation depends on interactions with protein species, e.g., monomers and oligomers, whose conformations are likely altered in an oxidative environment, thereby diminishing compound efficacy. In contrast, the structural features of mature fibrils formed under oxidative conditions remain susceptible to compound-induced destabilization. The preserved disaggregation activity of the cobalt(III) complexes under oxidative conditions resembling those associated with late-stage Alzheimer’s disease supports further investigation of their therapeutic potential.
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Journal articleda Rocha GL, Feiner J, Lazarte J, et al., 2026,
Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype.
, J Am Coll Cardiol, Vol: 87, Pages: 1279-1299BACKGROUND: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled. OBJECTIVES: We sought to explore the impact of disease-causing cardiomyopathy variants on the risk of AF after adjustment for incident ventricular cardiomyopathy and clinical heart failure in 2 cohort studies (UK Biobank [UKB] and All of Us [AoU]) and evaluate the utility of polygenic risk scores (PRS) to further discern the risk of atrial and ventricular phenotypes in carriers. METHODS: Cox regression was used to evaluate for associations between disease-causing variants within genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy) and AF. Disease-specific PRSs for AF, DCM, and HCM stratified study participants into quintiles. A HR random-effects meta-analysis was performed using the DerSimonian-Laird method. The Kaplan-Meier method was used to ascertain cumulative incidence from birth to 75 years of age. RESULTS: Among 655,796 individuals from UKB and AoU, presence of a disease-causing variant was associated with an increased AF hazard (HR: 1.73; 95% CI: 1.59-1.89; P < 0.001), including after adjustment for incident ventricular cardiomyopathy or clinical heart failure (adjusted to HR: 1.55; 95% CI: 1.46-1.64, P < 0.001). The cumulative AF risk for study participants with a putative disease-causing rare variant and a PRSAF within the top-risk quintile ranged from 32.5% (UKB) to 32.4% (AoU) relative to 9.8% (UKB) and 11.0% (AoU) for individuals without a putative disease-causing variant and a PRSAF within the lowest-risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a putative disease-causing variant and a disease-specific PRS within the top-risk quintile ranged from 5.9% (UKB) to 15.2% (AoU) for DCM and from 11.7% (UKB) to 19.1% (AoU) for HCM. CONCLUSIONS: Genetic variants that cause cardiomyopathy also
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Journal articleInciardi RM, Halliday B, Lombardi CM, et al., 2026,
Ethnicity and Disparities in Heart Failure: Hunt for an Equity Paradigm.
, J Am Coll Cardiol, Vol: 87, Pages: 1257-1260 -
Journal articleClark GT, Zhao Y, Reeve RE, et al., 2026,
Circadian Dysregulation in Aging Alters Senescence and Inflammatory Pathways in a Sex- and Time-of-Day-Dependent Manner.
, bioRxivThe circadian rhythm orchestrates gene expression and critical physiological processes but becomes disrupted with aging, contributing to disease. How this disruption interacts with cellular senescence-a key driver of aging pathology-remains poorly defined. We studied renal gene expression at four timepoints over 24hrs in 6- and 24-month-old genetically diverse UM-HET3 mice of both sexes and performed complementary analyses in synchronized fibroblasts sampled at seven timepoints. Aging dysregulated core clock relationships, including loss of the canonical anti-phase expression between Bmal1 and Per2. Senescence-associated genes were not static but exhibited pronounced oscillations, with senescence phenotypes varying by sex and time of day. Differential expression analysis revealed immune activation, metabolic rewiring, and epigenetic changes that were sex- and time-dependent. Variance analysis uncovered increased transcriptional noise in aging, particularly in circadian-regulated pathways such as RNA splicing, ribosome biogenesis, and TOR signaling. Single-nucleus RNA-Seq identified two cell populations lacking the normal Bmal1-Cdkn1a expression relationship: one senescent-like and another profibrotic, revealing distinct cell states linked to circadian dysregulation. Fibroblasts recapitulated key age-related circadian changes seen in the kidneys, including phase shifts in mTOR and oxidative phosphorylation. Together, this work demonstrates that senescence phenotypes are dynamic, sex-specific, and time-of-day dependent, and introduces a new framework for detecting senescent cells based on circadian gene relationships. These findings underscore the need to integrate temporal context into aging research and therapeutic strategies.
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Journal articleZeidaabadi B, Patlatzoglou K, Barker J, et al., 2026,
Image based artificial intelligence-enhanced ECG prediction of incident atrial fibrillation
, Heart Rhythm, Vol: 23, Pages: 515-524, ISSN: 1547-5271BackgroundEarly prediction of atrial fibrillation (AF) is crucial for reducing adverse outcomes. While artificial intelligence-enhanced ECG (AI-ECG) analysis shows promise in predicting AF, most approaches require digital ECG signals, limiting their application in settings where ECGs are stored as images.ObjectiveWe aimed to develop and validate an image-based AI-ECG approach for predicting incident AF across multiple datasets.MethodsWe used 1,163,401 ECGs from 189,539 patients in the Beth Israel Deaconess Medical Center (BIDMC) dataset and 70,655 ECGs from 65,610 participants in the UK Biobank. The AI-ECG model was trained on ECG images processed to 310x868 pixels.ResultsThe model achieved C-statistics of 0.754 (95% CI: 0.747-0.761) in the BIDMC dataset and 0.723 (95% CI: 0.704-0.741) in the UK Biobank for predicting incident AF. Performance was maintained across key subgroups including outpatients, females, and non-White individuals. Compared to the CHARGE-AF risk score, the AI-ECG model showed superior performance (c-statistic 0.696 vs 0.667, p<0.05) and provided significant additive value when combined (c-statistic 0.711, p<0.0001). The model also performed well on smartphone-photographed ECGs (c-statistic 0.736). Saliency mapping indicated the model primarily focused on P-wave morphology and PR interval regions.ConclusionThis image-based approach enables AI-ECG prediction of AF in settings without digital ECG infrastructure and provides additive value to known clinical risk scores
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Journal articleKelshiker MA, Chhatwal K, Bachtiger P, et al., 2026,
Safety and effectiveness of remote monitoring and prioritization of patients awaiting transcatheter aortic valve implantation: a propensity-matched prospective observational cohort study.
, Eur Heart J Digit Health, Vol: 7AIMS: Health systems face increasing waiting times for transcatheter aortic valve implantation (TAVI), incurring excess deaths and morbidity. To determine whether remote patient monitoring (RPM) using connected technologies can mitigate these risks by prioritizing patients awaiting TAVI, we aimed to measure the clinical safety and effectiveness of an RPM-based prioritization programme. METHODS AND RESULTS: Prospective observational cohort study of all patients awaiting TAVI at Imperial College Healthcare NHS Trust, London, UK, between 24th April 2023 and 15th November 2023. An RPM pathway was implemented for all patients accepted for TAVI. These patients responded to a weekly symptom questionnaire via web, smartphone RPM platform or telephone monitoring; with rule-based clinical escalation. The primary endpoint was the rate of adverse events (defined as emergency department presentation, unplanned hospitalization, or death), compared with a propensity score-matched (PSM) historical control group. Secondary endpoints included pathway performance characteristics for detection of deterioration. 200 patients met inclusion criteria. Despite growth of the waiting list, responsible for longer waiting times experienced by the RPM group [median 104 days (IQR 61.00-176.00) vs. 75 days (IQR 38.75-118.00)], there was no difference in rates of adverse events between RPM-patients and historical controls (Log rank P = 0.9). The RPM pathway had high sensitivity for prediction of waiting list death (100%). Patients deemed at high-risk of deterioration experienced shorter waiting times to treatment. CONCLUSION: RPM for patients awaiting TAVI is feasible and may mitigate the adverse effects of longer waiting times through accurate detection of deterioration and by informing prioritization decisions.
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Journal articleHatipoglu S, Voges I, Pushparajah K, et al., 2026,
Stress imaging in paediatric and congenital heart disease patients.
, Eur Heart J Cardiovasc Imaging, Vol: 27, Pages: 567-581Stress imaging in paediatric cardiology and congenital heart disease patients has an increasing role for functional assessment. Indications include coronary artery anomalies and disease in association with anomalous aortic origin of coronary arteries, Kawasaki disease or surgical manipulation of the coronary ostia, as well as assessment of elevated filling pressures, dynamic left ventricular outflow obstruction or significance of valvular heart disease. This review provides practical guidance focused on commonly used stress echocardiography and stress cardiovascular magnetic resonance in context of their clinical indications for this age group.
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Journal articleKoch C, Sakthimani S, Noakes VM, et al., 2026,
Machine learning-driven nanopore sensing for quantitative, label-free miRNA detection
, Small Methods, Vol: 10, ISSN: 2366-9608Nanopore sensors offer exceptional sensitivity for detecting single molecules, making them ideal for early disease diagnostics. In this study, we present a multiplexed nanopore-based assay that combines DNA-barcoded probes with advanced computational analysis to detect microRNAs (miRNAs) with high specificity and quantitative accuracy. Each probe selectively binds its target biomarker and induces a characteristic delay in the ionic current signal upon translocation through the nanopore, enabling label-free detection. We evaluated three analytical strategies for classifying delayed versus non-delayed events: (1) moving standard deviation (MSD), (2) spectral entropy (SE), and (3) a convolutional neural network (CNN). While MSD and SE rely on manually defined thresholds and exhibit limited sensitivity, the CNN model, trained on image representations of raw current traces, achieved near-perfect classification performance across all metrics (accuracy = 0.99, precision = 0.99, recall = 0.99). Grad-CAM visualisation confirmed that the CNN focused on biophysically relevant signal regions, enhancing interpretability and generalisability. All methods produced sigmoidal concentration-response curves consistent with expected binding kinetics, and nanopore-derived delay metrics closely matched RT-qPCR validation data. All three methods were capable of distinguishing between signal classes; however, the CNN model demonstrated superior sensitivity and robustness. This work highlights the importance of data interpretation in nanopore sensing and presents a comparative framework for binary event classification. The findings pave the way for the development of machine learning-driven nanopore diagnostics capable of detecting diverse biomarker types at the single-molecule level.
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Journal articleKirupananthavel A, Woldman S, Jones DA, et al., 2026,
Feasibility, safety and outcomes of a virtual ward with remote monitoring for patients awaiting urgent coronary artery bypass graft surgery.
, Open Heart, Vol: 13, ISSN: 2053-3624BACKGROUND: Delays in performing urgent coronary artery bypass graft (CABG) surgery are increasing across the UK, with national wait times now exceeding guideline targets. Prolonged preoperative admissions contribute to hospital bed pressures, increased costs and negative psychosocial effects for patients. Virtual wards using remote patient monitoring (RPM) may enable safe early discharge for clinically stable patients awaiting surgery. OBJECTIVES: To evaluate the feasibility, safety and outcomes of a virtual ward pathway using RPM for patients awaiting urgent CABG surgery. METHODS: A prospective, multicentre, single-arm study was conducted across three UK cardiac centres (December 2022-May 2025). Eligible patients were discharged home with daily symptom reporting via a digital platform and structured clinician review. The primary outcome was preoperative major adverse cardiovascular events (MACE). Secondary outcomes included 30-day mortality, resternotomy, time to surgery, postoperative stay, readmissions and patient experience. RESULTS: 128 patients were enrolled (mean age 61 years; 87% male). No preoperative MACE occurred (0%; 95% CI 0.0% to 2.3%). 30-day mortality was 0% (95% CI 0.0% to 2.9%), and resternotomy occurred in 2.3%, comparable to national rates. Median time from discharge to surgery was 10 days, saving an estimated 1152 inpatient bed-days. Postoperative length of stay was 7.0 days compared with a national average of 8.0 (p=0.084). Patient experience was favourable: 95% felt safe at home, and 89% found the platform easy to use. CONCLUSIONS: A virtual ward pathway with remote monitoring for selected patients awaiting urgent CABG was safe, feasible and associated with high patient acceptability and major reductions in inpatient utilisation. These findings support this model as a scalable approach to managing urgent surgical pathways while preserving safety and surgical timelines.
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Journal articleSau A, Liang Y, Ng FS, 2026,
AI-ECG for predicting regurgitant valve disease-addressing implementation challenges.
, Eur Heart J -
Journal articleStroeks SLVM, Oko-Osi S, Arasu A, et al., 2026,
Sex differences in dilated cardiomyopathy: evidence gaps and future directions
, JACC, Vol: 87, Pages: 723-735, ISSN: 0735-1097Dilated cardiomyopathy (DCM), which affects 1 in 250 people, is a leading global cause of heart failure and the most common indication for heart transplantation. Evidence suggests that DCM is more prevalent in men, but whether this reflects biological differences or underdiagnosis in women remains uncertain. This review explores the impact of sex on DCM, examining differences in epidemiology, etiology, clinical presentation, treatment response, and outcomes. Women often present with less severe cardiac phenotypes, including lower levels of fibrosis and better left ventricular function, yet the long-term prognosis of DCM in women is less clear. Through a systematic review and meta-analysis, we found that male DCM patients with variants in PLN, DSP, and LMNA had higher arrhythmic event rates compared with TTNtv and BAG3 carriers. In female patients with DCM, those with RBM20, DSP, and PLN variants faced the highest arrhythmic risk, and TTNtv carriers the lowest. PLN and LMNA variants had the highest heart failure risk in both sexes, whereas BAG3, RBM20, and TTN variants had lower heart failure rates in female compared with male carriers. These findings highlight the influence of sex and genotype on clinical outcomes. Current risk-stratification tools, such as those used for implantable cardioverter-defibrillators, may undertreat women owing to reliance on sex-neutral thresholds. We highlight the role of genetic, environmental, and reproductive factors in shaping these disparities, including the influence of pregnancy, pregnancy complications, and menopause. This review identifies key gaps in knowledge and calls for expanded representation of women in DCM studies and the development of sex-specific risk models. Addressing these gaps is essential to improving outcomes and advancing equitable personalized care for all DCM patients.
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Journal articleKelshiker MA, Bächtiger P, Petri CF, et al., 2026,
Triple cardiovascular disease detection with an artificial intelligence-enabled stethoscope (TRICORDER) in the UK: a cluster-randomised controlled implementation trial
, The Lancet, Vol: 407, Pages: 704-715, ISSN: 0140-6736BackgroundEarly detection of cardiovascular disease is a global public health priority. Artificial intelligence (AI)-enabled stethoscopes offer robust performance characteristics in point-of-care detection of heart failure, atrial fibrillation, and valvular heart disease (VHD). We conducted a pragmatic, cluster-randomised controlled implementation trial to determine the real-world effect and implementation challenges of AI-stethoscopes.MethodsUK primary care practices were cluster randomised 1:1 to intervention (training and implementation in use of AI-stethoscopes in routine care) or control (routine care). Given the nature of the intervention, masking of participants (practices, clinicians, and patients) was not feasible. During cardiac examinations, the AI stethoscope recorded 15 s of single-lead electrocardiogram and phonocardiogram signals for input to three AI algorithms that returned binary predictions for the presence or absence of reduced left ventricular ejection fraction (≤40%), atrial fibrillation, and VHD (all with regulatory approval). The primary endpoint was incidence of any newly coded diagnosis of heart failure (all subtypes), expressed per 1000 patient-years (incidence rate ratio [IRR]), derived from a UK National Health Service Secure Data Environment. A coprimary endpoint stratified detection of heart failure by place of diagnosis (community-based vs via hospital admission). Secondary endpoints included atrial fibrillation and VHD detection rates, performance characteristics of the AI-stethoscope, use rates, and clinician-reported implementation barriers and enablers.FindingsBetween Oct 30, 2023, and May 22, 2024, 205 practices were randomly assigned (96 to the intervention arm [701 933 registered patients] and 109 to the control arm [851 242 registered patients]). Intervention practices recorded 12 725 patient examinations with the AI-stethoscope, across 972 clinical users. Intention-to-treat analysis found heart failure
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Journal articleAnderson A, Perucca P, Vianca E, et al., 2026,
Transcription Factor Binding and Individual Genetic Risk of Valproate Teratogenicity.
, Neurology, Vol: 106BACKGROUND AND OBJECTIVES: Valproate (VPA) use during pregnancy is associated with a wide range of structural birth defects, but not all exposed children are affected and there is evidence for a genetic predisposition. The development of a pharmacogenomic biomarker test that can be used for preconception counseling, allowing access to women unnecessarily denied VPA treatment because of concern about teratogenic risks if they were to become pregnant, is challenged by a poor understanding of how variation in maternal DNA could modify the risk. We hypothesized that genomic variants that affect the binding affinity of transcription factors (TFs), key regulators of gene expression, are integral to VPA-associated teratogenicity and a plausible explanation for both variance in interindividual risk and the wide range of birth defect types. METHODS: We interrogated genomic variants within maternal exomes from women recruited through international epilepsy pregnancy registries and genomics consortia. We applied a network-based approach that contextualized the variant spectra to genes associated with diverse birth defect types, gene burden tests, and evidence from multiple modalities to identify variant-sensitive TFs. RESULTS: Sixty-six pregnancies were exposed to VPA as monotherapy or polytherapy, leading to 28 cases with birth defects, and 184 were exposed to other antiseizure medications (ASMs), leading to 20 cases with birth defects. The variant burden within genes associated with 32 different birth defect types was higher for those exposed to VPA compared with those exposed to other ASMs (OR 1.73 [95% CI 1.39 to 2.13], p < 0.0001). Variants in a network comprising significant genes from VPA-exposed mothers were predicted to modify the binding affinity of 359 TFs. These variant-sensitive TFs formed a highly connected protein-protein interaction network, among which the acetyltransferase EP300 connected to 41% (147/359) of all proteins. Profiling of coexpression between
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Journal articleHay CD, Mahutanattan SM, Pilkington CP, et al., 2026,
Affordable, cleanroom-free millifluidic production of targeted lipid nanocarriers via additive manufacturing.
, Lab Chip, Vol: 26, Pages: 635-649Lipid nanocarriers utilise the self-assembly of amphiphilic molecules to generate particle formulations capable of drug encapsulation and dynamic interactions with user-defined cell types, enabling applications within targeted therapeutic delivery. This offers increased bioavailability, stability, and reduced off-target effects, with the promise of application to numerous cell types and consequently, diseases. Here, we have developed a highly accessible, cleanroom-free method for the fabrication of poly(methyl methacrylate) millifluidic vertical flow focusing (VFF) devices via laser cutting, multilayered solvent and heat-assisted bonding. We demonstrate that these can be used for one-step production of targeted lipid nanocarriers via the production of cardiomyocyte-targeting vesicle nanoparticles loaded with the hydrophobic drug menadione. We characterise vesicle size using dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM), whilst also probing the membrane viscosity of vesicles produced via flow-focusing for the first time using molecular rotors. Finally, we apply cardiomyocyte-targeting, menadione-loaded vesicles to H9C2 tissue culture demonstrating significant inhibition of cell viability via targeted delivery, showcasing the potential of our device to produce formulations for therapeutic delivery. As a flow-based method, VFF can facilitate rapid formulation investigation and produce large sample volumes for cell-based validation studies, whilst avoiding inter-batch sample variation. Furthermore, the accessible nature of this VFF approach will help to democratise millifluidics, facilitating the wider adoption of flow-based production methods to develop nanomedical formulations.
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