Optimising the diagnostic accuracy of First post-contrAst SubtracTed breast MRI (FAST MRI) through interpretation-training: a multicentre e-learning study, mapping the learning curve of NHS Breast Screening Programme (NHSBSP) mammogram readers using an enriched dataset.

BACKGROUND: Abbreviated breast MRI (FAST MRI) is being introduced into clinical practice to screen women with mammographically dense breasts or with a personal history of breast cancer. This study aimed to optimise diagnostic accuracy through the adaptation of interpretation-training. METHODS: A FAST MRI interpretation-training programme (short presentations and guided hands-on workstation teaching) was adapted to provide additional training during the assessment task (interpretation of an enriched dataset of 125 FAST MRI scans) by giving readers feedback about the true outcome of each scan immediately after each scan was interpreted (formative assessment). Reader interaction with the FAST MRI scans used developed software (RiViewer) that recorded reader opinions and reading times for each scan. The training programme was additionally adapted for remote e-learning delivery. STUDY DESIGN: Prospective, blinded interpretation of an enriched dataset by multiple readers. RESULTS: 43 mammogram readers completed the training, 22 who interpreted breast MRI in their clinical role (Group 1) and 21 who did not (Group 2). Overall sensitivity was 83% (95%CI 81-84%; 1994/2408), specificity 94% (95%CI 93-94%; 7806/8338), readers' agreement with the true outcome kappa = 0.75 (95%CI 0.74-0.77) and diagnostic odds ratio = 70.67 (95%CI 61.59-81.09). Group 1 readers showed similar sensitivity (84%) to Group 2 (82% p = 0.14), but slightly higher specificity (94% v. 93%, p = 0.001). Concordance with the ground truth increased significantly with the number of FAST MRI scans read through the formative assessment task (p = 0.002) but by differing amounts depending on whether or not a reader had previously attended FAST MRI training (interaction p = 0.02). Concordance with the ground truth was significantly associated with reading batch size (p = 0.02), tending to worsen when more than 50 scans were read per batch. Group 1 took a median of 56 seconds (range 8-47,466) to interpret each FAST MRI scan compared with 78 (14-22,830, p < 0.0001) for Group 2. CONCLUSIONS: Provision of immediate feedback to mammogram readers during the assessment test set reading task increased specificity for FAST MRI interpretation and achieved high diagnostic accuracy. Optimal reading-batch size for FAST MRI was 50 reads per batch. Trial registration (25/09/2019): ISRCTN16624917.

Toward the quantification of α-synuclein aggregates with digital seed amplification assays.

The quantification and characterization of aggregated α-synuclein in clinical samples offer immense potential toward diagnosing, treating, and better understanding neurodegenerative synucleinopathies. Here, we developed digital seed amplification assays to detect single α-synuclein aggregates by partitioning the reaction into microcompartments. Using pre-formed α-synuclein fibrils as reaction seeds, we measured aggregate concentrations as low as 4 pg/mL. To improve our sensitivity, we captured aggregates on antibody-coated magnetic beads before running the amplification reaction. By first characterizing the pre-formed fibrils with transmission electron microscopy and size exclusion chromatography, we determined the specific aggregates targeted by each assay platform. Using brain tissue and cerebrospinal fluid samples collected from patients with Parkinson's Disease and multiple system atrophy, we demonstrated that the assay can detect endogenous pathological α-synuclein aggregates. Furthermore, as another application for these assays, we studied the inhibition of α-synuclein aggregation in the presence of small-molecule inhibitors and used a custom image analysis pipeline to quantify changes in aggregate growth and filament morphology.

Children's visual acuity tests without professional supervision: a prospective repeated measures study.

BACKGROUND: Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy. METHODS: Children attending outpatient clinics had visual acuity measured 3 times at the same appointment: Once by a registered orthoptist per clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Test Pro, Kay Pictures), and once by an unsupervised parent/carer using the tablet-based test. RESULTS: In total, 42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median and interquartile ranges (IQR) for clinical standard, orthoptic-led and parent/carer-led iSight Test Pro visual acuity measurements were 0.155 (0.18 IQR), 0.180 (0.26 IQR), and 0.300 (0.33 IQR) logMAR respectively. The iSight Test Pro in the hands of parents/carers was significantly different from the standard of care measurements (P = 0.008). In the hands of orthoptists. There was no significant difference between orthoptists using the iSight Test Pro and standard of care (P = 0.289), nor between orthoptist iSight Test Pro and parents/carer iSight Test Pro measurements (P = 0.108). CONCLUSION: This technique of unsupervised visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making. Future work should focus on improving the accuracy of the test through better training, equipment/software or supervision/support.

Quantitative background parenchymal enhancement and fibro-glandular density at breast MRI: Association with BRCA status.

OBJECTIVES: To investigate whether MRI-based measurements of fibro-glandular tissue volume, breast density (MRBD), and background parenchymal enhancement (BPE) could be used to stratify two cohorts of healthy women: BRCA carriers and women at population risk of breast cancer. METHODS: Pre-menopausal women aged 40-50 years old were scanned at 3 T, employing a standard breast protocol including a DCE-MRI (35 and 30 participants in high- and low-risk groups, respectively). The dynamic range of the DCE protocol was characterised and both breasts were masked and segmented with minimal user input to produce measurements of fibro-glandular tissue volume, MRBD, and voxelwise BPE. Statistical tests were performed to determine inter- and intra-user repeatability, evaluate the symmetry between metrics derived from left and right breasts, and investigate MRBD and BPE differences between the high- and low-risk cohorts. RESULTS: Intra- and inter-user reproducibility in estimates of fibro-glandular tissue volume, MRBD, and median BPE estimations were good, with coefficients of variation < 15%. Coefficients of variation between left and right breasts were also low (< 25%). There were no significant correlations between fibro-glandular tissue volume, MRBD, and BPE for either risk group. However, the high-risk group had higher BPE kurtosis, although linear regression analysis did not reveal significant associations between BPE kurtosis and breast cancer risk. CONCLUSIONS: This study found no significant differences or correlations in fibro-glandular tissue volume, MRBD, or BPE metrics between the two groups of women with different levels of breast cancer risk. However, the results support further investigation into the heterogeneity of parenchymal enhancement. KEY POINTS: • A semi-automated method enabled quantitative measurements of fibro-glandular tissue volume, breast density, and background parenchymal enhancement with minimal user intervention. • Background parenchymal enhancement was quantified over the entire parenchyma, segmented in pre-contrast images, thus avoiding region selection. • No significant differences and correlations in fibro-glandular tissue volume, breast density, and breast background parenchymal enhancement were found between two cohorts of women at high and low levels of breast cancer risk.

Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2-/- Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.

Harnessing the Plasma Proteome to Mirror Current and Predict Future Cardiac Remodeling After Myocardial Infarction.

To identify plasma proteins that mirror current and predict future remodeling after myocardial infarction (MI), we retrospectively interrogated plasma proteomes of day (D)0 control (n = 16) and D3 MI (n = 15) from C57BL/6 J mice (20 ± 1 months). A total of 165 unique proteins were correlated with cardiac physiology variables. We prospectively tested the hypothesis that candidates identified retrospectively would predict cardiac physiology at an extended timepoint (D7 MI) in a second cohort of mice (n = 4 ± 1 months). We also examined human plasma from healthy controls (n = 18) and patients 48 h after presentation for MI (n = 41). Retrospectively, we identified 5 strong reflectors of remodeling (all r ≥ 0.60 and p < 0.05). Prospectively, ApoA1, IgA, IL-17E, and TIMP-1 mirrored current and predicted future remodeling. In humans, cytokine-cytokine receptor signaling was the top enriched KEGG pathway for all candidates. In summary, we identified plasma proteins that serve as useful prognostic indicators of adverse remodeling and progression to heart failure.

Aryl-diazonium salts offer a rapid and cost-efficient method to functionalize plastic microfluidic devices for increased immunoaffinity capture.

Microfluidic devices have been used for decades to isolate cells, viruses, and proteins using on-chip immunoaffinity capture using biotinylated antibodies, proteins, or aptamers. To accomplish this, the inner surface is modified to present binding moieties for the desired analyte. While this approach has been successful in research settings, it is challenging to scale many surface modification strategies. Traditional polydimethylsiloxane (PDMS) devices can be effectively functionalized using silane-based methods; however, it requires high labor hours, cleanroom equipment, and hazardous chemicals. Manufacture of microfluidic devices using plastics, including cyclic olefin copolymer (COC), allows chips to be mass produced, but most functionalization methods used with PDMS are not compatible with plastic. Here we demonstrate how to deposit biotin onto the surface of a plastic microfluidic chips using aryl-diazonium. This method chemically bonds biotin to the surface, allowing for the addition of streptavidin nanoparticles to the surface. Nanoparticles increase the surface area of the chip and allow for proper capture moiety orientation. Our process is faster, can be performed outside of a fume hood, is very cost-effective using readily available laboratory equipment, and demonstrates higher rates of capture. Additionally, our method allows for more rapid and scalable production of devices, including for diagnostic testing.

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia-Reperfusion: Roles of Sympathetic Innervation and Sex Differences.

Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 µg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post-I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (-4.2±7.9 versus -68.2±3.8 Δ%) compared with vehicle-treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad-lib fed or pair-fed saline-treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD+/NADH content (≈10-fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.

Phenotypic continuum between POLE-related recessive disorders: A case report and literature review.

POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading-associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss-of-function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE-related recessive disorders.

Evaluating the effectiveness of abbreviated breast MRI (abMRI) interpretation training for mammogram readers: a multi-centre study assessing diagnostic performance, using an enriched dataset.

BACKGROUND: Abbreviated breast MRI (abMRI) is being introduced in breast screening trials and clinical practice, particularly for women with dense breasts. Upscaling abMRI provision requires the workforce of mammogram readers to learn to effectively interpret abMRI. The purpose of this study was to examine the diagnostic accuracy of mammogram readers to interpret abMRI after a single day of standardised small-group training and to compare diagnostic performance of mammogram readers experienced in full-protocol breast MRI (fpMRI) interpretation (Group 1) with that of those without fpMRI interpretation experience (Group 2). METHODS: Mammogram readers were recruited from six NHS Breast Screening Programme sites. Small-group hands-on workstation training was provided, with subsequent prospective, independent, blinded interpretation of an enriched dataset with known outcome. A simplified form of abMRI (first post-contrast subtracted images (FAST MRI), displayed as maximum-intensity projection (MIP) and subtracted slice stack) was used. Per-breast and per-lesion diagnostic accuracy analysis was undertaken, with comparison across groups, and double-reading simulation of a consecutive screening subset. RESULTS: 37 readers (Group 1: 17, Group 2: 20) completed the reading task of 125 scans (250 breasts) (total = 9250 reads). Overall sensitivity was 86% (95% confidence interval (CI) 84-87%; 1776/2072) and specificity 86% (95%CI 85-86%; 6140/7178). Group 1 showed significantly higher sensitivity (843/952; 89%; 95%CI 86-91%) and higher specificity (2957/3298; 90%; 95%CI 89-91%) than Group 2 (sensitivity = 83%; 95%CI 81-85% (933/1120) p < 0.0001; specificity = 82%; 95%CI 81-83% (3183/3880) p < 0.0001). Inter-reader agreement was higher for Group 1 (kappa = 0.73; 95%CI 0.68-0.79) than for Group 2 (kappa = 0.51; 95%CI 0.45-0.56). Specificity improved for Group 2, from the first 55 cases (81%) to the remaining 70 (83%) (p = 0.02) but not for Group 1 (90-89% p = 0.44), whereas sensitivity remained consistent for both Group 1 (88-89%) and Group 2 (83-84%). CONCLUSIONS: Single-day abMRI interpretation training for mammogram readers achieved an overall diagnostic performance within benchmarks published for fpMRI but was insufficient for diagnostic accuracy of mammogram readers new to breast MRI to match that of experienced fpMRI readers. Novice MRI reader performance improved during the reading task, suggesting that additional training could further narrow this performance gap.

Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure.

Clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs developed for treating diabetes mellitus, improve prognosis of patients with heart failure (HF). However, the mechanisms for cardioprotection by SGLT2 inhibitors are still unclear. Mitochondrial dysfunction and oxidative stress play important roles in progression of HF. This study tested the hypothesis that empagliflozin (EMPA), a highly selective SGLT2 inhibitor, improves mitochondrial function and reduces reactive oxygen species (ROS) while enhancing cardiac performance through direct effects on the heart in a non-diabetic mouse model of HF induced by transverse aortic constriction (TAC). EMPA or vehicle was administered orally for 4 weeks starting 2 weeks post-TAC. EMPA treatment did not alter blood glucose or body weight but significantly attenuated TAC-induced cardiac dysfunction and ventricular remodeling. Impaired mitochondrial oxidative phosphorylation (OXPHOS) in failing hearts was significantly improved by EMPA. EMPA treatment also enhanced mitochondrial biogenesis and restored normal mitochondria morphology. Although TAC increased mitochondrial ROS and decreased endogenous antioxidants, EMPA markedly inhibited cardiac ROS production and upregulated expression of endogenous antioxidants. In addition, EMPA enhanced autophagy and decreased cardiac apoptosis in TAC-induced HF. Importantly, mitochondrial respiration significantly increased in ex vivo cardiac fibers after direct treatment with EMPA. Our results indicate that EMPA has direct effects on the heart, independently of reductions in blood glucose, to enhance mitochondrial function by upregulating mitochondrial biogenesis, enhancing OXPHOS, reducing ROS production, attenuating apoptosis, and increasing autophagy to improve overall cardiac function in a non-diabetic model of pressure overload-induced HF.

Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma.

ENPP1 encodes ENPP1, an ectonucleotidase catalyzing hydrolysis of ATP to AMP and inorganic pyrophosphate (PPi), and an endogenous plasma protein physiologically preventing ectopic calcification of connective tissues. Mutations in ENPP1 have been reported in association with a range of human genetic diseases. In this mutation update, we provide a comprehensive review of all the pathogenic variants, likely pathogenic variants, and variants of unknown significance in ENPP1 associated with three autosomal recessive disorders-generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and pseudoxanthoma elasticum (PXE), as well as with a predominantly autosomal dominant disorder-Cole disease. The classification of all variants is determined using the latest ACMG guidelines. A total of 140 ENPP1 variants were curated consisting of 133 previously reported variants and seven novel variants, with missense variants being the most prevalent (70.0%, 98/140). While the pathogenic variants are widely distributed in the ENPP1 gene of patientsgen without apparent genotype-phenotype correlation, eight out of nine variants associated with Cole disease are confined to the somatomedin-B-like (SMB) domains critical for homo-dimerization of the ENPP1 protein.

Macrophages secrete murinoglobulin-1 and galectin-3 to regulate neutrophil degranulation after myocardial infarction.

Inflammation presides early after myocardial infarction (MI) as a key event in cardiac wound healing. Ischemic cardiomyocytes secrete inflammatory cues to stimulate infiltration of leukocytes, predominantly macrophages and neutrophils. Infiltrating neutrophils degranulate to release a series of proteases including matrix metalloproteinase (MMP)-9 to break down extracellular matrix and remove necrotic myocytes to create space for the infarct scar to form. While neutrophil to macrophage communication has been explored, the reverse has been understudied. We used a proteomics approach to catalogue the macrophage secretome at MI day 1. Murinoglobulin-1 (MUG1) was the highest-ranked secreted protein (4.1-fold upregulated at MI day 1 vs. day 0 pre-MI cardiac macrophages, p = 0.004). By transcriptomics evaluation, galectin-3 (Lgals3) was 2.2-fold upregulated (p = 0.008) in MI day 1 macrophages. We explored the direct roles of MUG1 and Lgals3 on neutrophil degranulation. MUG1 blunted while Lgals3 amplified neutrophil degranulation in response to phorbol 12-myristate 13-acetate or interleukin-1ß, as measured by MMP-9 secretion. Lgals3 itself also stimulated MMP-9 secretion. To determine if MUG1 regulated Lgals3, we co-stimulated neutrophils with MUG1 and Lgals3. MUG1 limited degranulation stimulated by Lgals3 by 64% (p < 0.001). In vivo, MUG1 was elevated in the infarct region at MI days 1 and 3, while Lgals3 increased at MI day 7. The ratio of MUG1 to Lgals3 positively correlated with infarct wall thickness, revealing that MUG1 attenuated infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and Lgals3 to accentuate neutrophil degranulation to regulate infarct wall thinning.

Faster skin wound healing predicts survival after myocardial infarction.

Both skin wound healing and the cardiac response to myocardial infarction (MI) progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3-mm skin wound using a disposable biopsy punch and the skin wound was imaged daily until closure. The same set of animals was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology was measured by echocardiography at baseline and MI days 3 and 7. Animals that survived until day 7 were grouped as survivors, and animals that died from MI were grouped as nonsurvivors. Survivors had faster skin wound healing than nonsurvivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). N-glycoproteome profiling of MI day 3 plasma revealed α2-macroglobulin and ELL-associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. To investigate the clinical relevance of α2-macroglobulin, we mapped the plasma glycoproteome in patients with MI 48 h after admission and in healthy controls. In patients, α2-macroglobulin was increased 48 h after MI. Apolipoprotein D, another plasma glycoprotein, detrimentally regulated both skin and cardiac wound healing in male but not female mice by promoting inflammation. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.NEW & NOTEWORTHY Faster skin wound healers had more efficient cardiac healing after myocardial infarction (MI). Two plasma proteins at D3 MI, EAF1 and A2M, predicted MI death in 66% of cases. ApoD regulated both skin and cardiac wound healing in male mice by promoting inflammation. The skin was a mirror to the heart and common pathways linked wound healing across organs.

Predicting Risk of Reoffending in Persons with Child Sexual Exploitation Material Offense Histories: The Use of Child Pornography Offender Risk Tool in a Scottish Population.

In the past decade, there has been an increase in child sexual exploitation material (CSEM) offenses and convictions. Although research shows that individuals with CSEM offence histories generally are at low risk of reoffending, certain factors do increase in CSEM convictions, in order to assist with case prioritization, management and supervision, risk assessment is helpful across agencies. The Child Pornography Offender Risk Tool (CPORT) was created specifically for this population and shows significant predictive validity for various outcomes. This study aimed to validate the use of the CPORT in a Scottish sample of 141 adult males who were convicted of CSEM offenses. Receiver Operating Characteristic (ROC) and logistic regression analyses indicated that the CPORT significantly predicted any recidivism (Area Under the Curve = .81), any sexual recidivism (AUC = .78) and CSEM recidivism (AUC = .74), suggesting that it is a valid risk assessment tool for Scottish populations. Recommendations for further research and clinical implications are discussed.

Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism.

Myocardial infarction (MI) is one of the leading causes of mortality and cardiovascular disease worldwide. MI is characterized by a substantial inflammatory response in the infarcted left ventricle (LV), followed by transition of quiescent fibroblasts to active myofibroblasts, which deposit collagen to form the reparative scar. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is an important mechanism by which these cell types transition towards reparative phenotypes. Thus, we hypothesized that dimethyl fumarate (DMF), a clinically approved anti-inflammatory agent with metabolic actions, would improve post-MI remodeling via modulation of macrophage and fibroblast metabolism. Adult male C57BL/6J mice were treated with DMF (10 mg/kg) for 3-7 days after MI. DMF attenuated LV infarct and non-infarct wall thinning at 3 and 7 days post-MI, and decreased LV dilation and pulmonary congestion at day 7. DMF improved LV infarct collagen deposition, myofibroblast activation, and angiogenesis at day 7. DMF also decreased pro-inflammatory cytokine expression (Tnf) 3 days after MI, and decreased inflammatory markers in macrophages isolated from the infarcted heart (Hif1a, Il1b). In fibroblasts extracted from the infarcted heart at day 3, RNA-Seq analysis demonstrated that DMF promoted an anti-inflammatory/pro-reparative phenotype. By Seahorse analysis, DMF did not affect glycolysis in either macrophages or fibroblasts at day 3, but enhanced macrophage OXPHOS while impairing fibroblast OXPHOS. Our results indicate that DMF differentially affects macrophage and fibroblast metabolism, and promotes anti-inflammatory/pro-reparative actions. In conclusion, targeting cellular metabolism in the infarcted heart may be a promising therapeutic strategy.

"Real-world" radiomics from multi-vendor MRI: an original retrospective study on the prediction of nodal status and disease survival in breast cancer, as an exemplar to promote discussion of the wider issues.

BACKGROUND: Most MRI radiomics studies to date, even multi-centre ones, have used "pure" datasets deliberately accrued from single-vendor, single-field-strength scanners. This does not reflect aspirations for the ultimate generalisability of AI models. We therefore investigated the development of a radiomics signature from heterogeneous data originating on six different imaging platforms, for a breast cancer exemplar, in order to provide input into future discussions of the viability of radiomics in "real-world" scenarios where image data are not controlled by specific trial protocols but reflective of routine clinical practice. METHODS: One hundred fifty-six patients with pathologically proven breast cancer underwent multi-contrast MRI prior to neoadjuvant chemotherapy and/or surgery. From these, 92 patients were identified for whom T2-weighted, diffusion-weighted and contrast-enhanced T1-weighted sequences were available, as well as key clinicopathological variables. Regions-of-interest were drawn on the above image types and, from these, semantic and calculated radiomics features were derived. Classification models using a variety of methods, both with and without recursive feature elimination, were developed to predict pathological nodal status. Separately, we applied the same methods to analyse the information carried by the radiomic features regarding the originating scanner type and field strength. Repeated, ten-fold cross-validation was employed to verify the results. In parallel work, survival modelling was performed using random survival forests. RESULTS: Prediction of nodal status yielded mean cross-validated AUC values of 0.735 ± 0.15 (SD) for clinical variables alone, 0.673 ± 0.16 (SD) for radiomic features only, and 0.764 ± 0.16 (SD) for radiomics and clinical features together. Prediction of scanner platform from the radiomics features yielded extremely high values of AUC between 0.91 and 1 for the different classes examined indicating the presence of confounding features for the nodal status classification task. Survival analysis, gave out-of-bag prediction errors of 19.3% (clinical features only), 36.9-51.8% (radiomic features from different combinations of image contrasts), and 26.7-35.6% (clinical plus radiomics features). CONCLUSIONS: Radiomic classification models whose predictive ability was consistent with previous single-vendor, single-field strength studies have been obtained from multi-vendor, multi-field-strength data, despite clear confounding information being present. However, our sample size was too small to obtain useful survival modelling results.

Interaction of Obesity and Hypertension on Cardiac Metabolic Remodeling and Survival Following Myocardial Infarction.

Background Obesity and hypertension are risk factors for myocardial infarction (MI); however, their potential interactions on post-MI outcomes are unclear. We examined interactions of obesity and hypertensionon post-MI function, remodeling, metabolic changes, and recovery. Methods and Results Male and female C57BL/6J mice were provided standard chow or high-fat/fructose diet for 8 weeks and then infused with angiotensin II for 2 weeks to induce hypertension. MI was then induced by surgical ligation of the left coronary artery for 7 days. Obesity alone did not cause cardiac injury or exacerbate hypertension-induced cardiac dysfunction. After MI, however, obese-normotensive mice had lower survival rates compared with chow-fed mice (56% versus 89% males; 54% versus 75% females), which were further decreased by hypertension (29% males; and 35% females). Surviving obese-normotensive males displayed less left ventricular dilation and pulmonary congestion compared with chow-fed males after MI; hypertension reversed left ventricular dilation because of high-fat/fructose diet and promoted significant pulmonary congestion compared with chow-fed controls. Obese-normotensive males displayed higher left ventricular α-MHC (alpha-myosin heavy chain) protein, phosphorylated Akt (protein kinase B) and AMPK (adenosine-monophosphate activated kinase), PPAR-γ (peroxisome proliferator activated receptor gamma), and plasma adiponectin levels after MI, indicating favorable contractile and metabolic changes. However, these favorable contractile and metabolic changes were attenuated by hypertension. Obese-hypertensive males also had lower levels of collagen in the infarcted region, indicating decreased ability to promote an adaptive wound healing response to MI. Conclusions Obesity reduces post-MI survival but is associated with improved post-MI cardiac function and metabolism in surviving normotensive mice. When hypertension accompanies obesity, favorable metabolic pathways associated with obesity are attenuated and post-MI cardiac function and remodeling are adversely impacted.

Prevalence and correlates of individuals with sexual interest in children: A systematic review.

BACKGROUND: Despite debates on what should constitute sexual interest in children in terms of definition and diagnostic criteria and its strong association with individuals who commit sexual offences against children, research in this area has shown that sexual interest in children is also commonly seen in the general population. Studies in this field have investigated its prevalence and its correlates. However, most research on this topic has focused on men and most particularly sex offender populations. When investigating the general population, again the vast majority of studies used male samples and students. OBJECTIVE: This systematic review aimed to critically evaluate previous research on the prevalence of sexual interest in children across populations and to examine its correlates. METHODS: A search of relevant databases was conducted as well as a hand search of selected journals to identify eligible papers. Studies meeting the inclusion criteria had their data extracted and were assessed for risk of bias, with a second rater to establish inter-rater reliability. RESULTS: A total of 30 studies were reviewed and results indicated a mean prevalence rate of sexual interest in children between 2 %-24 %. Findings also indicated correlates such as the presence of mental health problems and adverse childhood experiences. Most studies showed poor external validity, with the majority of them scoring high on risk of bias. CONCLUSION: Overall, the findings indicate inconsistencies in terms of methodology and definition/diagnostic criteria of sexual interest in children. Further research in this area using recommended methodology to avoid biases is recommended.