John M. Simpson’s research while affiliated with Guy's and St Thomas' NHS Foundation Trust and other places

INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP). This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores. 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13–28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference − 6%, 95% CI − 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance. In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.

BACKGROUND Covered stent correction (CSC) of a superior sinus venosus atrial septal defect is an alternative to surgery in selected patients, but anatomic variation means that assessment for CSC requires a 3-dimensional anatomic understanding. Heart VR is a virtual reality (VR) system that rapidly displays and renders multimodality imaging without prior image segmentation. The aim of this study was to evaluate the performance of the Heart VR system to assess patient suitability for CSC. METHODS In a blinded fashion, 2 interventionalists reviewed preprocedural computed tomography scans using Heart VR to assess the feasibility of CSC, including the potential need for pulmonary vein protection. The total review time using VR was recorded. RESULTS Using conventional imaging, 15 patients were deemed suitable for CSC, but at catheterization, 3 cases were unsuitable. Using VR, when both interventionalists agreed that a case was suitable for CSC (n=12), all proved technically feasible. In the 3 cases that were unsuitable for CSC, the interventionalists using VR were either uncertain (n=1) or did not agree on suitability (n=2). The strategy for pulmonary vein protection was correctly identified by interventionalist 1 and 2 in 9/12 and 8/12 cases, respectively. In cases where pulmonary vein protection was required intraprocedurally (n=5), this was correctly identified using Heart VR. Using VR, in 3 cases it was determined that pulmonary vein protection would be required, but this was not the case on balloon interrogation. VR data loading and review times were 82 seconds and 7 minutes, respectively. Verbal feedback indicated that Heart VR assisted in the assessment of case suitability. CONCLUSIONS Heart VR is a rapid and effective tool for predicting suitability for CSC in patients with a superior sinus venosus atrial septal defect and could be a feasible alternative to segmented virtual or physical 3-dimensional models.

Accurate prenatal diagnosis of coarctation of the aorta (CoA) is challenging due to high false positive rate burden and poorly understood aetiology. Despite associations with abnormal blood flow dynamics, fetal arch anatomy changes and alterations in tissue properties, its underlying mechanisms remain a longstanding subject of debate hindering diagnosis in utero. This study leverages computational fluid dynamics (CFD) simulations and statistical shape modelling to investigate the interplay between fetal arch anatomy and blood flow alterations in CoA. Using cardiac magnetic resonance imaging data from 188 fetuses, including normal controls and suspected CoA cases, a statistical shape model of the fetal arch anatomy was built. From this analysis, digital twin models of false and true positive CoA cases were generated. These models were then used to perform CFD simulations of the three-dimensional fetal arch haemodynamics, considering physiological variations in arch shape and blood flow conditions across the disease spectrum. This analysis revealed that independent changes in the shape of. the arch and the balance of left-to-right ventricular output led to qualitatively similar haemodynamic alterations. Transitioning from a false to a true positive phenotype increased retrograde flow through the aortic isthmus. This resulted in the appearance of an area of low wall shear stress surrounded by high wall shear stress values at the flow split apex on the aortic posterior wall opposite the ductal insertion point. Our results suggest a distinctive haemodynamic signature in CoA characterised by the appearance of retrograde flow through the aortic isthmus and altered wall shear stress at its posterior side. The consistent link between alterations in shape and blood flow in CoA suggests the need for comprehensive anatomical and functional diagnostic approaches in CoA. This study presents an application of the digital twin approach to support the understanding of CoA mechanisms in utero and its potential for improved diagnosis before birth.

Corresponding Author

Background In double aortic arch (DAA), one of the arches can demonstrate atretic portions postnatally, leading to diagnostic uncertainty due to overlap with isolated right aortic arch (RAA) variants. The main objective of this study is to demonstrate the morphological evolution of different DAA phenotypes from prenatal to postnatal life using three-dimensional (3D) fetal cardiac magnetic resonance (CMR) imaging and postnatal computed tomography (CT)/CMR imaging. Methods Three-dimensional fetal CMR was undertaken in fetuses with suspected DAA over a 6-year period (January 2016–January 2022). All cases with surgical confirmation of DAA were retrospectively studied and morphology on fetal CMR was compared to postnatal CT/CMR and surgical findings. Results Thirty-four fetuses with surgically confirmed DAA underwent fetal CMR. The RAA was dominant in 32/34 (94%). Postnatal CT/CMR was undertaken at a median age of 3.3 months (interquartile range 2.0–3.9) demonstrating DAA with patency of both arches in 10/34 (29%), with 7 showing signs of coarctation of the left aortic arch (LAA). The LAA isthmus was not present on CT/CMR in 22/34 (65%), and the transverse arch between left carotid and left subclavian artery was not present in 2 cases. Conclusion Fetal CMR provides novel insights into perinatal evolution of DAA. The smaller LAA can develop coarctation or atresia related to postnatal constriction of the arterial duct, making diagnosis of DAA challenging with contrast-enhanced CT/CMR. This highlights the potentially important role for prenatal 3D vascular imaging and might improve the interpretation of postnatal imaging.

Background Artificial intelligence (AI) has shown potential in improving the performance of screening fetal anomaly ultrasound scans. We aimed to assess the effect of AI on fetal ultrasound scanning, in terms of diagnostic performance, biometry, scan duration, and sonographer cognitive load. Methods This was a randomised, single centre, open label trial in a large teaching hospital. Pregnant participants with fetal congenital heart disease (CHD) and with healthy fetuses were recruited and scanned with both methods. Screening sonographers were recruited from regional hospitals and were randomised to scan with the AI tool or in the standard fashion, blinded to the fetal CHD status. For the AI-assisted scans, the AI models identified and saved 13 standard image planes, and measured four biometrics. Findings 78 pregnant participants (26 with fetal CHD) and 58 sonographers were recruited. The sensitivity and specificity of the AI-assisted scan in detecting fetal malformation was 88.9% and 98.0% respectively, with the standard scan achieving 81.5% and 92.2% (not significant). AI-assisted scans were significantly shorter than standard scans (median 11.4 min vs 19.7 min, p <0.001). Sonographer cognitive load was significantly lower in the AI-assisted group (median NASA TLX score 35.2 vs 46.5, p <0.001). For all biometrics, the AI repeatability and reproducibility was superior to manual measurements. Interpretation AI assistance in the routine fetal anomaly ultrasound scan results in a significant time saving, along with a reduction in sonographer cognitive load, without a reduction in diagnostic performance. Funding The study was funded by an NIHR doctoral fellowship (NIHR301448) and was supported by grants from the Wellcome Trust (IEH Award, 102431), by core funding from the Wellcome Trust/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z), and the London AI Centre for Value Based Healthcare via funding from the Office for Life Sciences.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood ¹ . Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

To report the prevalence of coarctation of the aorta (CoA) in fetuses with single left superior vena cava (SL-SVC) and to evaluate changes in echocardiographic measurements. Additionally, to report the prevalence of associated malformations. Retrospective observational study of fetuses diagnosed with SL-SVC between 2012 and 2021 at a tertiary fetal cardiology unit. In fetuses without intracardiac abnormalities, Z-scores of the ventricles, great arteries, and Doppler flow patterns are reported. We identified 47 fetuses with SL-SVC of which 8/47 (17%) had abnormal intracardiac anatomy. One fetus was lost to follow-up. Of those with normal intracardiac anatomy and postnatal follow-up (38), karyotype abnormalities were confirmed in 2/38 (5%) and ECA in 8/38 (21%). 33/38 were live-born. None developed CoA postnatally. Paired analysis of Z-scores between early and late scans of 24 fetuses showed that diameters of the right heart structures and Doppler flows of tricuspid valve increased significantly during pregnancy, while the left heart structures and flow patterns did not change. The median risk of CoA did not change between the early and the late scan. We did not observe CoA in this cohort. A degree of ventricular asymmetry was present, but this was due to right heart dominance rather than hypoplasia of left heart structures. This likely reflects redistribution of blood and does not appear to confer increased risk of CoA. Predictive models of the postnatal development of CoA which set the dimensions of right and left heart structures in relation might not be applicable in this situation.