TIST-Net: style transfer in dynamic contrast enhanced MRI using spatial and temporal information.

Training deep learning models for image registration or segmentation of dynamic contrast enhanced (DCE)-MRI data is challenging. This is mainly due to the wide variations in contrast enhancement within and between patients. To train a model effectively, a large dataset is needed, but acquiring it is expensive and time consuming. Instead, style transfer can be used to generate new images from existing images. In this study, our objective is to develop a style transfer method that incorporates spatio-temporal information to either add or remove contrast enhancement from an existing image. We propose a Temporal Image-to-Image Style Transfer Network (TIST-Net), consisting of an auto-encoder combined with convolutional long short-term memory (LSTM) networks. This enables disentanglement of the content and style latent spaces of the time series data, using spatio-temporal information to learn and predict key structures . To generate new images , we use deformable and adaptive convolutions which allow fine grained control over the combination of the content and style latent spaces. We evaluate our method, using popular metrics and a previously proposed contrast weighted structural similarity index measure (CW-SSIM). We also perform a clinical evaluation, where experts are asked to rank images generated by multiple methods. Our model achieves state-of-the-art performance on three datasets (kidney, prostate and uterus) achieving an SSIM of 0.91±0.03, 0.73±0.04, 0.88±0.04 respectively when performing style transfer between a non-enhanced image and a contrast-enhanced image. Similarly, SSIM results for style transfer from a contrast-enhanced image to a non-enhanced image were 0.89±0.03, 0.82±0.03, 0.87±0.03. In the clinical evaluation, our method was ranked consistently higher than other approaches. TIST-Net can be used to generate new DCE-MRI data from existing images. In future, this may improve models for tasks such as image registration or segmentation by allowing small training datasets to be expanded.

Thoracic aortic microcalcification activity in combined positron emission tomography and magnetic resonance imaging.

INTRODUCTION: Non-invasive detection of pathological changes in thoracic aortic disease remains an unmet clinical need particularly for patients with congenital heart disease. Positron emission tomography combined with magnetic resonance imaging (PET-MRI) could provide a valuable low-radiation method of aortic surveillance in high-risk groups. Quantification of aortic microcalcification activity using sodium [18F]fluoride holds promise in the assessment of thoracic aortopathies. We sought to evaluate aortic sodium [18F]fluoride uptake in PET-MRI using three methods of attenuation correction compared to positron emission tomography computed tomography (PET-CT) in patients with bicuspid aortic valve, METHODS: Thirty asymptomatic patients under surveillance for bicuspid aortic valve disease underwent sodium [18F]fluoride PET-CT and PET-MRI of the ascending thoracic aorta during a single visit. PET-MRI data were reconstructed using three iterations of attenuation correction (Dixon, radial gradient recalled echo with two [RadialVIBE-2] or four [RadialVIBE-4] tissue segmentation). Images were qualitatively and quantitatively analysed for aortic sodium [18F]fluoride uptake on PET-CT and PET-MRI. RESULTS: Aortic sodium [18F]fluoride uptake on PET-MRI was visually comparable with PET-CT using each reconstruction and total aortic standardised uptake values on PET-CT strongly correlated with each PET-MRI attenuation correction method (Dixon R = 0.70; RadialVIBE-2 R = 0.63; RadialVIBE-4 R = 0.64; p < 0.001 for all). Breathing related artefact between soft tissue and lung were detected using Dixon and RadialVIBE-4 but not RadialVIBE-2 reconstructions, with the presence of this artefact adjacent to the atria leading to variations in blood pool activity estimates. Consequently, quantitative agreements between radiotracer activity on PET-CT and PET-MRI were most consistent with RadialVIBE-2. CONCLUSION: Ascending aortic microcalcification analysis in PET-MRI is feasible with comparable findings to PET-CT. RadialVIBE-2 tissue attenuation correction correlates best with the reference standard of PET-CT and is less susceptible to artefact. There remain challenges in segmenting tissue types in PET-MRI reconstructions, and improved attenuation correction methods are required.

A novel deep learning method for large-scale analysis of bone marrow adiposity using UK Biobank Dixon MRI data.

Background: Bone marrow adipose tissue (BMAT) represents > 10% fat mass in healthy humans and can be measured by magnetic resonance imaging (MRI) as the bone marrow fat fraction (BMFF). Human MRI studies have identified several diseases associated with BMFF but have been relatively small scale. Population-scale studies therefore have huge potential to reveal BMAT's true clinical relevance. The UK Biobank (UKBB) is undertaking MRI of 100,000 participants, providing the ideal opportunity for such advances. Objective: To establish deep learning for high-throughput multi-site BMFF analysis from UKBB MRI data. Materials and methods: We studied males and females aged 60-69. Bone marrow (BM) segmentation was automated using a new lightweight attention-based 3D U-Net convolutional neural network that improved segmentation of small structures from large volumetric data. Using manual segmentations from 61-64 subjects, the models were trained to segment four BM regions of interest: the spine (thoracic and lumbar vertebrae), femoral head, total hip and femoral diaphysis. Models were tested using a further 10-12 datasets per region and validated using datasets from 729 UKBB participants. BMFF was then quantified and pathophysiological characteristics assessed, including site- and sex-dependent differences and the relationships with age, BMI, bone mineral density, peripheral adiposity, and osteoporosis. Results: Model accuracy matched or exceeded that for conventional U-Nets, yielding Dice scores of 91.2% (spine), 94.5% (femoral head), 91.2% (total hip) and 86.6% (femoral diaphysis). One case of severe scoliosis prevented segmentation of the spine, while one case of Non-Hodgkin Lymphoma prevented segmentation of the spine, femoral head and total hip because of T2 signal depletion; however, successful segmentation was not disrupted by any other pathophysiological variables. The resulting BMFF measurements confirmed expected relationships between BMFF and age, sex and bone density, and identified new site- and sex-specific characteristics. Conclusions: We have established a new deep learning method for accurate segmentation of small structures from large volumetric data, allowing high-throughput multi-site BMFF measurement in the UKBB. Our findings reveal new pathophysiological insights, highlighting the potential of BMFF as a novel clinical biomarker. Applying our method across the full UKBB cohort will help to reveal the impact of BMAT on human health and disease.

Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia.

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (ß = -0.25, 95 % CI = -0.49, -0.02, competitive p = 0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (ß = 0.05, 95 % CI = -0.18, 0.27, competitive p = 0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. CONCLUSIONS: Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Manganese-Enhanced Magnetic Resonance Imaging of the Heart.

Manganese-based contrast media were the first in vivo paramagnetic agents to be used in magnetic resonance imaging (MRI). The uniqueness of manganese lies in its biological function as a calcium channel analog, thus behaving as an intracellular contrast agent. Manganese ions are taken up by voltage-gated calcium channels in viable tissues, such as the liver, pancreas, kidneys, and heart, in response to active calcium-dependent cellular processes. Manganese-enhanced magnetic resonance imaging (MEMRI) has therefore been used as a surrogate marker for cellular calcium handling and interest in its potential clinical applications has recently re-emerged, especially in relation to assessing cellular viability and myocardial function. Calcium homeostasis is central to myocardial contraction and dysfunction of myocardial calcium handling is present in various cardiac pathologies. Recent studies have demonstrated that MEMRI can detect the presence of abnormal myocardial calcium handling in patients with myocardial infarction, providing clear demarcation between the infarcted and viable myocardium. Furthermore, it can provide more subtle assessments of abnormal myocardial calcium handling in patients with cardiomyopathies and being excluded from areas of nonviable cardiomyocytes and severe fibrosis. As such, MEMRI offers exciting potential to improve cardiac diagnoses and provide a noninvasive measure of myocardial function and contractility. This could be an invaluable tool for the assessment of both ischemic and nonischemic cardiomyopathies as well as providing a measure of functional myocardial recovery, an accurate prediction of disease progression and a method of monitoring treatment response. EVIDENCE LEVEL: 5: TECHNICAL EFFICACY: STAGE 5.

Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome is an acute cardiac emergency characterized by transient left ventricular systolic dysfunction typically following a stressful event. Despite its rapidly rising incidence, its pathophysiology remains poorly understood. Takotsubo syndrome may pass unrecognized, especially if timely diagnostic imaging is not performed. Defective myocardial calcium homeostasis is a central cause of contractile dysfunction and has not been explored in takotsubo syndrome. We aimed to investigate myocardial calcium handling using manganese-enhanced magnetic resonance imaging during the acute and recovery phases of takotsubo syndrome. METHODS: Twenty patients with takotsubo syndrome (63±12 years of age; 90% female) and 20 volunteers matched on age, sex, and cardiovascular risk factors (59±11 years of age; 70% female) were recruited from the Edinburgh Heart Centre between March 2020 and October 2021. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging during index hospitalization with repeat manganese-enhanced magnetic resonance imaging performed after at least 3 months. RESULTS: Compared with matched control volunteers, patients had a reduced left ventricular ejection fraction (51±11 versus 67±8%; P<0.001), increased left ventricular mass (86±11 versus 57±14 g/m2; P<0.001), and, in affected myocardial segments, elevated native T1 (1358±49 versus 1211±28 ms; P<0.001) and T2 (60±7 versus 38±3 ms; P<0.0001) values at their index presentation. During manganese-enhanced imaging, kinetic modeling demonstrated a substantial reduction in myocardial manganese uptake (5.1±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min], respectively; P<0.0001), consistent with markedly abnormal myocardial calcium handling. After recovery, left ejection fraction, left ventricular mass, and T2 values were comparable with those of matched control volunteers. Despite this, native and postmanganese T1 and myocardial manganese uptake remained abnormal compared with matched control volunteers (6.6±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min]; P<0.0001). CONCLUSIONS: In patients with takotsubo syndrome, there is a profound perturbation of myocardial manganese uptake, which is most marked in the acute phase but persists for at least 3 months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema, suggesting abnormal myocardial calcium handling may be implicated in the pathophysiology of takotsubo syndrome. Manganese-enhanced magnetic resonance imaging has major potential to assist in the diagnosis, characterization, and risk stratification of patients with takotsubo syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04623788.

Non-invasive in vivo assessment of 11ß-hydroxysteroid dehydrogenase type 1 activity by 19F-Magnetic Resonance Spectroscopy.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11ß-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 µmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11ß-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.

Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, ß = 3.73, 95% CI = 1.26-6.20, P = 0.004; Glx, ß = 3.38, 95% CI = 0.84-5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (ß = 3.12, 95% CI = 0.01-6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Quantifying sodium [18F]fluoride uptake in abdominal aortic aneurysms.

BACKGROUND: Aortic microcalcification activity is a recently described method of measuring aortic sodium [18F]fluoride uptake in the thoracic aorta on positron emission tomography. In this study, we aimed to compare and to modify this method for use within the infrarenal aorta of patients with abdominal aortic aneurysms. METHODS: Twenty-five patients with abdominal aortic aneurysms underwent an sodium [18F]fluoride positron emission tomography and computed tomography scan. Maximum and mean tissue-to-background ratios (TBR) and abdominal aortic microcalcification activity were determined following application of a thresholding and variable radius method to correct for vertebral sodium [18F]fluoride signal spill-over and the nonlinear changes in aortic diameter, respectively. Agreement between the methods, and repeatability of these approaches were assessed. RESULTS: The aortic microcalcification activity method was much quicker to perform than the TBR method (14 versus 40 min, p < 0.001). There was moderate-to-good agreement between TBR and aortic microcalcification activity measurements for maximum (interclass correlation co-efficient, 0.67) and mean (interclass correlation co-efficient, 0.88) values. These correlations sequentially improved with the application of thresholding (intraclass correlation coefficient 0.93, 95% confidence interval 0.89-0.95) and variable diameter (intraclass correlation coefficient 0.97, 95% confidence interval 0.94-0.99) techniques. The optimised method had good intra-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.36 and limits of agreement - 0.43 to 0.43) and inter-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.47 and limits of agreement - 0.53 to 0.53) repeatability. CONCLUSIONS: Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of sodium [18F]fluoride uptake that are comparable to established methods.

Vascular biomechanics and molecular disease activity in the thoracic aorta: a novel imaging method.

AIMS: The influence haemodynamics have on vessel wall pathobiology in aortic disease is incomplete. This aim of this study was to develop a repeatable method for assessing the relationship between aortic wall shear stress (WSS) and disease activity by fusing 4D flow cardiovascular magnetic resonance (CMR) with hybrid positron emission tomography (PET). METHODS AND RESULTS: As part of an ongoing clinical trial, patients with bicuspid aortic valve (BAV) were prospectively imaged with both 18F-sodium fluoride (18F-NaF) PET, a marker of calcification activity, and 4D flow CMR. We developed novel software allowing accurate 3D co-registration and high-resolution comparison of aortic peak systolic WSS and 18F-NaF PET uptake (maximum tissue-to-background ratio). Intra-observer repeatability of both measurements was determined using Bland-Altman plots and intra-class correlation coefficients (ICCs). The relationship between localized WSS and 18F-NaF uptake was analysed using linear mixed-effect models. Twenty-three patients with BAV (median age 50 [44-55] years, 22% female) were included. Intra-observer repeatability for WSS (ICC = 0.92) and 18F-NaF (ICC = 0.91) measurements obtained within 1.4 ± 0.6 cm2 regions of interest was excellent. On multivariable analysis, 18F-NaF PET uptake was independently and negatively associated with WSS as well as diastolic blood pressure (both P < 0.05), adjusted for age. CONCLUSION: Fused assessment of WSS and 18F-NaF PET uptake is feasible and repeatable, demonstrating a clear association between these two factors. This high spatial resolution approach has major potential to advance our understanding of the relationship between vascular haemodynamics and disease activity.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel. Results A total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12-1.82] vs 1.26 [IQR, 0.99-1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel. Conclusion Fluorine 18-labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome. Clinical trial registration no. NCT03215550 and NCT03215563 © RSNA, 2022 Online supplemental material is available for this article.

DNA methylation in relation to gestational age and brain dysmaturation in preterm infants.

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10-8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (ß = 0.349, P = 8.37 × 10-10) and peak width skeletonized neurite density index (ß = 0.364, P = 4.15 × 10-5), but not with peak width skeletonized fraction anisotropy (ß = -0.035, P = 0.510); these relationships mirrored the imaging metrics' associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.

MRI and CT coronary angiography in survivors of COVID-19.

OBJECTIVES: To determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19. METHODS: In a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis. RESULTS: In 52 patients (median age: 54 (IQR 51-57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; p<0.0003) but reduced myocardial manganese uptake (6.9±0.9 (95% CI 6.5 to 7.3) vs 7.9±1.2 (95% CI 7.4 to 8.5) mL/100 g/min; p=0.01). Compared with comorbidity-matched volunteers (n=26), patients had preserved left ventricular function but reduced right ventricular systolic function (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 59.3±4.9 (95% CI 51.0 to 66.5)%; p=0.0005) with comparable native T1 values (1225±46 (95% CI 1205 to 1240) vs 1227±51 (95% CI 1208 to 1246) ms; p=0.99), ECV (31±4 (95% CI 29.6 to 32.1) vs 29±5 (95% CI 27.0 to 31.2)%; p=0.35), presence of late gadolinium enhancement and manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of myocardial injury or ongoing symptoms. CONCLUSIONS: Patients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities. TRIAL REGISTRATION NUMBER: NCT04625075.

Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

INTRODUCTION: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource. Hepatic macrophages can promote both liver fibrogenesis and fibrosis regression. The safety and feasibility of peripheral infusion of ex vivo matured autologous monocyte-derived macrophages in patients with compensated cirrhosis has been demonstrated. METHODS AND ANALYSIS: The efficacy of autologous macrophage therapy, compared with standard medical care, will be investigated in a cohort of adult patients with compensated cirrhosis in a multicentre, open-label, parallel-group, phase 2, randomised controlled trial. The primary outcome is the change in Model for End-Stage Liver Disease score at 90 days. The trial will provide the first high-quality examination of the efficacy of autologous macrophage therapy in improving liver function, non-invasive fibrosis markers and other clinical outcomes in patients with compensated cirrhosis. ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by Scotland A Research Ethics Committee (reference 15/SS/0121), National Health Service Lothian Research and Development department and the Medicine and Health Care Regulatory Agency-UK. Final results will be presented in peer-reviewed journals and at relevant conferences. TRIAL REGISTRATION NUMBERS: ISRCTN10368050 and EudraCT; reference 2015-000963-15.

Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.

Assessment of stunned and viable myocardium using manganese-enhanced MRI.

OBJECTIVE: In a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling. METHODS: Healthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Differential manganese uptake was described using a two-compartment model. RESULTS: After manganese administration, healthy control and remote non-infarcted myocardium showed a sustained 25% reduction in T1 values (mean reductions, 288±34 and 281±12 ms). Infarcted myocardium demonstrated less T1 shortening than healthy control or remote myocardium (1157±74 vs 859±36 and 835±28 ms; both p<0.0001) with intermediate T1 values (1007±31 ms) in peri-infarct regions. Compared with LGE, MEMRI was more sensitive in detecting dysfunctional myocardium (dysfunctional fraction 40.5±11.9 vs 34.9%±13.9%; p=0.02) and tracked more closely with abnormal wall motion (r2=0.72 vs 0.55; p<0.0001). Kinetic modelling showed reduced myocardial manganese influx between remote, peri-infarct and infarct regions, enabling absolute discrimination of infarcted myocardium. After 3 months, manganese uptake increased in peri-infarct regions (16.5±3.5 vs 22.8±3.5 mL/100 g/min, p<0.0001), but not the remote (23.3±2.8 vs 23.0±3.2 mL/100 g/min, p=0.8) or infarcted (11.5±3.7 vs 14.0±1.2 mL/100 g/min, p>0.1) myocardium. CONCLUSIONS: Through visualisation of intracellular calcium handling, MEMRI accurately differentiates infarcted, stunned and viable myocardium, and correlates with myocardial dysfunction better than LGE. MEMRI holds major promise in directly assessing myocardial viability, function and calcium handling across a range of cardiac diseases. TRIAL REGISTRATION NUMBERS: NCT03607669; EudraCT number 2016-003782-25.