Precision measurement of cardiac structure and function in cardiovascular magnetic resonance using machine learning.

BACKGROUND: Measurement of cardiac structure and function from images (e.g. volumes, mass and derived parameters such as left ventricular (LV) ejection fraction [LVEF]) guides care for millions. This is best assessed using cardiovascular magnetic resonance (CMR), but image analysis is currently performed by individual clinicians, which introduces error. We sought to develop a machine learning algorithm for volumetric analysis of CMR images with demonstrably better precision than human analysis. METHODS: A fully automated machine learning algorithm was trained on 1923 scans (10 scanner models, 13 institutions, 9 clinical conditions, 60,000 contours) and used to segment the LV blood volume and myocardium. Performance was quantified by measuring precision on an independent multi-site validation dataset with multiple pathologies with n = 109 patients, scanned twice. This dataset was augmented with a further 1277 patients scanned as part of routine clinical care to allow qualitative assessment of generalization ability by identifying mis-segmentations. Machine learning algorithm ('machine') performance was compared to three clinicians ('human') and a commercial tool (cvi42, Circle Cardiovascular Imaging). FINDINGS: Machine analysis was quicker (20 s per patient) than human (13 min). Overall machine mis-segmentation rate was 1 in 479 images for the combined dataset, occurring mostly in rare pathologies not encountered in training. Without correcting these mis-segmentations, machine analysis had superior precision to three clinicians (e.g. scan-rescan coefficients of variation of human vs machine: LVEF 6.0% vs 4.2%, LV mass 4.8% vs. 3.6%; both P < 0.05), translating to a 46% reduction in required trial sample size using an LVEF endpoint. CONCLUSION: We present a fully automated algorithm for measuring LV structure and global systolic function that betters human performance for speed and precision.

Saturation-pulse prepared heart-rate independent inversion-recovery (SAPPHIRE) biventricular T1 mapping: inter-field strength, head-to-head comparison of diastolic, systolic and dark-blood measurements.

BACKGROUND: To assess the feasibility of biventricular SAPPHIRE T1 mapping in vivo across field strengths using diastolic, systolic and dark-blood (DB) approaches. METHODS: 10 healthy volunteers underwent same-day non-contrast cardiovascular magnetic resonance at 1.5 Tesla (T) and 3 T. Left and right ventricular (LV, RV) T1 mapping was performed in the basal, mid and apical short axis using 4-variants of SAPPHIRE: diastolic, systolic, 0th and 2nd order motion-sensitized DB and conventional modified Look-Locker inversion recovery (MOLLI). RESULTS: LV global myocardial T1 times (1.5 T then 3 T results) were significantly longer by diastolic SAPPHIRE (1283 ± 11|1600 ± 17 ms) than any of the other SAPPHIRE variants: systolic (1239 ± 9|1595 ± 13 ms), 0th order DB (1241 ± 10|1596 ± 12) and 2nd order DB (1251 ± 11|1560 ± 20 ms, all p < 0.05). In the mid septum MOLLI and diastolic SAPPHIRE exhibited significant T1 signal contamination (longer T1) at the blood-myocardial interface not seen with the other 3 SAPPHIRE variants (all p < 0.025). Additionally, systolic, 0th order and 2nd order DB SAPPHIRE showed narrower dispersion of myocardial T1 times across the mid septum when compared to diastolic SAPPHIRE (interquartile ranges respectively: 25 ms, 71 ms, 73 ms vs 143 ms, all p < 0.05). RV T1 mapping was achievable using systolic, 0th and 2nd order DB SAPPHIRE but not with MOLLI or diastolic SAPPHIRE. All 4 SAPPHIRE variants showed excellent re-read reproducibility (intraclass correlation coefficients 0.953 to 0.996). CONCLUSION: These small-scale preliminary healthy volunteer data suggest that DB SAPPHIRE has the potential to reduce partial volume effects at the blood-myocardial interface, and that systolic SAPPHIRE could be a feasible solution for right ventricular T1 mapping. Further work is needed to understand the robustness of these sequences and their potential clinical utility.

The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence-Based Approach Using Perfusion Mapping.

BACKGROUND: Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF). METHODS: A 2-center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for comorbidities and cardiovascular magnetic resonance parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization, and death. RESULTS: A total of 1049 patients were included with a median follow-up of 605 (interquartile range, 464-814) days. There were 42 (4.0%) deaths and 188 MACE in 174 (16.6%) patients. Stress MBF and MPR were independently associated with both death and MACE. For each 1 mL·g-1·min-1 decrease in stress MBF, the adjusted hazard ratios for death and MACE were 1.93 (95% CI, 1.08-3.48, P=0.028) and 2.14 (95% CI, 1.58-2.90, P<0.0001), respectively, even after adjusting for age and comorbidity. For each 1 U decrease in MPR, the adjusted hazard ratios for death and MACE were 2.45 (95% CI, 1.42-4.24, P=0.001) and 1.74 (95% CI, 1.36-2.22, P<0.0001), respectively. In patients without regional perfusion defects on clinical read and no known macrovascular coronary artery disease (n=783), MPR remained independently associated with death and MACE, with stress MBF remaining associated with MACE only. CONCLUSIONS: In patients with known or suspected coronary artery disease, reduced MBF and MPR measured automatically inline using artificial intelligence quantification of cardiovascular magnetic resonance perfusion mapping provides a strong, independent predictor of adverse cardiovascular outcomes.

Use of quantitative cardiovascular magnetic resonance myocardial perfusion mapping for characterization of ischemia in patients with left internal mammary coronary artery bypass grafts.

BACKGROUND: Quantitative myocardial perfusion mapping using cardiovascular magnetic resonance (CMR) is validated for myocardial blood flow (MBF) estimation in native vessel coronary artery disease (CAD). Following coronary artery bypass graft (CABG) surgery, perfusion defects are often detected in territories supplied by the left internal mammary artery (LIMA) graft, but their interpretation and subsequent clinical management is variable. METHODS: We assessed myocardial perfusion using quantitative CMR perfusion mapping in 38 patients with prior CABG surgery, all with angiographically-proven patent LIMA grafts to the left anterior descending coronary artery (LAD) and no prior infarction in the LAD territory. Factors potentially determining MBF in the LIMA-LAD myocardial territory, including the impact of delayed contrast arrival through the LIMA graft were evaluated. RESULTS: Perfusion defects were reported on blinded visual analysis in the LIMA-LAD territory in 27 (71%) cases, despite LIMA graft patency and no LAD infarction. Native LAD chronic total occlusion (CTO) was a strong independent predictor of stress MBF (B = - 0.41, p = 0.014) and myocardial perfusion reserve (MPR) (B = - 0.56, p = 0.005), and was associated with reduced stress MBF in the basal (1.47 vs 2.07 ml/g/min; p = 0.002) but not the apical myocardial segments (1.52 vs 1.87 ml/g/min; p = 0.057). Extending the maximum arterial time delay incorporated in the quantitative perfusion algorithm, resulted only in a small increase (3.4%) of estimated stress MBF. CONCLUSIONS: Perfusion defects are frequently detected in LIMA-LAD subtended territories post CABG despite LIMA patency. Although delayed contrast arrival through LIMA grafts causes a small underestimation of MBF, perfusion defects are likely to reflect true reductions in myocardial blood flow, largely due to proximal native LAD disease.

Human-modified landscapes narrow the isotopic niche of neotropical birds.

Deforestation and habitat loss resulting from land use changes are some of the utmost anthropogenic impacts that threaten tropical birds in human-modified landscapes (HMLs). The degree of these impacts on birds' diet, habitat use, and ecological niche can be measured by isotopic analysis. We investigated whether the isotopic niche width, food resources, and habitat use of bird trophic guilds differed between HMLs and natural landscapes (NLs) using stable carbon (δ13C) and nitrogen isotopes (δ15N). We analyzed feathers of 851 bird individuals from 28 landscapes in the Brazilian Atlantic Forest. We classified landscapes into two groups according to the percentage of forest cover (HMLs ≤ 30%; NLs ≥ 47%), and compared the isotopic niche width and mean values of δ13C and δ15N for each guild between landscape types. The niches of frugivores, insectivores, nectarivores, and omnivores were narrower in HMLs, whereas granivores showed the opposite pattern. In HMLs, nectarivores showed a reduction of 44% in niche width, while granivores presented an expansion of 26%. Individuals in HMLs consumed more resources from agricultural areas (C4 plants), but almost all guilds showed a preference for forest resources (C3 plants) in both landscape types, except granivores. Degraded and fragmented landscapes typically present a lower availability of habitat and food resources for many species, which was reflected by the reduction in niche width of birds in HMLs. Therefore, to protect the diversity of guilds in HMLs, landscape management strategies that offer birds more diverse habitats must be implemented in tropical regions.

Quantitative cardiac MRI.

Cardiac MRI has become an indispensable imaging modality in the investigation of patients with suspected heart disease. It has emerged as the gold standard test for cardiac function, volumes, and mass and allows noninvasive tissue characterization and the assessment of myocardial perfusion. Quantitative MRI already has a key role in the development and incorporation of machine learning in clinical imaging, potentially offering major improvements in both workflow efficiency and diagnostic accuracy. As the clinical applications of a wide range of quantitative cardiac MRI techniques are being explored and validated, we are expanding our capabilities for earlier detection, monitoring, and risk stratification of disease, potentially guiding personalized management decisions in various cardiac disease models. In this article we review established and emerging quantitative techniques, their clinical applications, highlight novel advances, and appraise their clinical diagnostic potential. Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:693-711.

Improvement of vegetation structure enhances bird functional traits and habitat resilience in an area of ongoing restoration in the Atlantic Forest.

Ecological restoration is a traditional option for recovering biodiversity and ecosystem functions. Birds perform pollination, seed dispersal, and pest-control services, which catalyze increases in habitat structure. Habitat complexity changes bird composition, but there is little evidence of its effects on bird functional diversity in Neotropical restorations. We tested whether bird functional diversity and composition respond to increased habitat complexity. Point-counts were performed (January-December 2015) in an area undergoing restoration (536 ha) in the Atlantic Forest of southeastern Brazil, in restorations with less and more structured vegetation and pastures and forest-fragments. The functional bird traits considered were diet, habitat, biomass, environmental sensitivity, and foraging strata. Increased habitat complexity was evaluated using plant characteristics (exotic grass, canopy, herbaceous cover, and diameter at breast height). A total of 172 bird species (5% endemic; 12% migratory) were recorded. Increased vegetation structure in both restored sites and forest-fragments drove a reorganization and addition of functional bird traits, which positively influenced functional richness, dispersion, and evenness. Shifts in plant-characteristics rearranged bird functional traits (diet-forest-dependence and diet-strata-foraging). The rapid development of vegetation structure is a key factor for restoration because it provides additional habitat for semi-dependent forest birds and enhances resilience and sustainability in new man-made forests.

Quantitative myocardial perfusion in coronary artery disease: A perfusion mapping study.

BACKGROUND: Cardiac MR stress perfusion remains a qualitative technique in clinical practice due to technical and postprocessing challenges. However, automated inline perfusion mapping now permits myocardial blood flow (MBF, ml/g/min) quantification on-the-fly without user input. PURPOSE: To investigate the diagnostic performance of this novel technique in detecting occlusive coronary artery disease (CAD) in patients scheduled to undergo coronary angiography. STUDY TYPE: Prospective, observational. SUBJECTS: Fifty patients with suspected CAD and 24 healthy volunteers. FIELD STRENGTH: 1.5T. SEQUENCE: "Dual" sequence multislice 2D saturation recovery. ASSESSMENT: All patients underwent cardiac MR with perfusion mapping and invasive coronary angiography; the healthy volunteers had MR with perfusion mapping alone. STATISTICAL TESTS: Comparison between numerical variables was performed using an independent t-test. Receiver operator characteristic (ROC) curves were generated for transmyocardial, endocardial stress MBF, and myocardial perfusion reserve (MPR, the stress:rest MBF ratio) to diagnose severe (>70%) stenoses as measured by 3D quantitative coronary angiography (QCA). ROC curves were compared by the method of DeLong et al. RESULTS: Compared with volunteers, patients had lower stress MBF and MPR even in vessels with <50% stenosis (2.00 vs. 3.08 ml/g/min, respectively). As stenosis severity increased (<50%, 50-70%, >70%), MBF and MPR decreased. To diagnose occlusive (>70%) CAD, endocardial and transmyocardial stress MBF were superior to MPR (area under the curve 0.92 [95% CI 0.86-0.97] vs. 0.90 [95% CI 0.84-0.95] and 0.80 [95% CI 0.72-0.87], respectively). An endocardial threshold of 1.31 ml/g/min provided a per-coronary artery sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 90%, 82%, 50%, and 98%, with a per-patient diagnostic performance of 100%, 66%, 57%, and 100%, respectively. DATA CONCLUSION: Perfusion mapping can diagnose occlusive CAD with high accuracy and, in particular, high sensitivity and NPV make it a potential "rule-out" test. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:756-762.

Comparative Reliability of Screening Parameters for Anthracnose Resistance in Water Yam (Dioscorea alata).

Anthracnose, caused by Colletotrichum gloeosporioides, is one of the major constraints limiting water yam (Dioscorea alata) production in the tropics. In this region, yam anthracnose control is mostly achieved by the deployment of moderately resistant yam genotypes. Therefore, screening for new sources of anthracnose resistance is an important aspect of yam research in the tropics. The reliability and applicability of different yam anthracnose rating parameters has not been fully examined. Disease severity on detached leaves in the laboratory and leaf severity, lesion size, and spore production on whole plants in the greenhouse were used to screen an F1 yam population and correlate screening results with field evaluations. Anthracnose lesion size had the smallest predicted residual means but whole-plant severity and detached-leaf severity had the best variance homogeneity and relatively small predicted residual means. The concordance correlation coefficient (rc) and κ statistic were used to determine the agreement between anthracnose rating parameters and field evaluations. Detached-leaf (rc = 0.95, κ = 0.81) and whole-plant (rc = 0.96, κ = 0.86) evaluations had high positive agreement with field evaluation but spore production (κ = 0.69) and lesion size (κ = 0.57) had moderate positive agreement. These results suggest that all the evaluated rating parameters can be used to successfully screen yam germplasm for anthracnose resistance but lesion size and spore production data may need to be transformed.

Disturbance of energy and redox homeostasis and reduction of Na+,K+-ATPase activity provoked by in vivo intracerebral administration of ethylmalonic acid to young rats.

Ethylmalonic acid (EMA) accumulation occurs in various metabolic diseases with neurological manifestation, including short acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy (EE). Since pathophysiological mechanisms responsible for brain damage in these disorders are still poorly understood, we investigated the ex vivo effects of acute intrastriatal administration of EMA on important parameters of energy and redox homeostasis in striatum from young rats. We evaluated CO(2) production from glucose, glucose utilization and lactate production, as well as the activities of the citric acid cycle (CAC) enzymes, the electron transfer chain (ETC) complexes II-IV (oxidative phosphorylation, OXPHOS) and synaptic Na(+),K(+)-ATPase. We also tested the effect of EMA on malondialdehyde (MDA) levels (marker of lipid oxidation) and reduced glutathione (GSH) levels. EMA significantly reduced CO(2) production, increased glucose utilization and lactate production, and reduced the activities of citrate synthase and of complexes II and II-III of the ETC, suggesting an impairment of CAC and OXPHOS. EMA injection also reduced Na(+),K(+)-ATPase activity and GSH concentrations, whereas MDA levels were increased. Furthermore, EMA-induced diminution of Na(+),K(+)-ATPase activity and reduction of GSH levels were prevented, respectively, by the antioxidants melatonin and N-acetylcysteine, indicating that reactive species were involved in these effects. Considering the importance of CAC and ETC for energy production and Na(+),K(+)-ATPase for the maintenance of the cell membrane potential, the present data indicate that EMA compromises mitochondrial homeostasis and neurotransmission in striatum. We presume that these pathomechanisms may be involved to a certain extent in the neurological damage found in patients affected by SCADD and EE.

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms.

3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various organic acidemias whose patients present neurodegeneration events in children coursing with metabolic acidurias. Limited evidence describes the toxic mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions of adult rat brains to provide novel information on early mechanisms evoked by this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, but decreased mitochondrial function only at 5 mM concentration. Despite less intense effects were obtained at 1 mM concentration, its co-administration with the kynurenine pathway (KP) metabolite and N-methyl-D-aspartate receptor (NMDAr) agonist, quinolinic acid (QUIN, 50 and 100 µM), produced toxic synergism on markers of oxidative stress and mitochondrial function. The toxicity of 3MGA per se (5 mM) was prevented by the cannabinoid receptor agonist WIN55,212-2 and the NMDAr antagonist kynurenic acid (KYNA), suggesting cannabinoid and glutamatergic components in the 3MGA pattern of toxicity. The synergic model (3MGA + QUIN) was also sensitive to KYNA and the antioxidant S-allylcysteine, but not to the nitric oxide synthase inhibitor L-nitroarginine methyl ester. These findings suggest various underlying mechanisms involved in the neurotoxicity of 3MGA that may possibly contribute to the neurodegeneration observed in acidemias.

Pristanic acid provokes lipid, protein, and DNA oxidative damage and reduces the antioxidant defenses in cerebellum of young rats.

Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats. The effect of Prist on DNA damage was also evaluated in blood of these animals. Some parameters were also evaluated in cerebellum from neonatal rats and in cerebellum neuronal cultures. Prist significantly increased malondialdehyde (MDA) levels and carbonyl formation and reduced sulfhydryl content and glutathione (GSH) concentrations in cerebellum of young rats. It also caused DNA strand damage in cerebellum and induced a high micronuclei frequency in blood. On the other hand, this fatty acid significantly reduced α-ketoglutarate dehydrogenase and aconitase activities in rat cerebellum. We also verified that Prist-induced increase of MDA levels was totally prevented by melatonin and attenuated by α-tocopherol but not by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, indicating the involvement of reactive oxygen species in this effect. Cerebellum from neonate rats also showed marked alterations of redox homeostasis, including an increase of MDA levels and a decrease of sulfhydryl content and GSH concentrations elicited by Prist. Finally, Prist provoked an increase of dichlorofluorescein (DCFH) oxidation in cerebellum-cultivated neurons. Our present data indicate that Prist compromises redox homeostasis in rat cerebellum and blood and inhibits critical enzymes of the citric acid cycle that are susceptible to free radical attack. The present findings may contribute to clarify the pathogenesis of the cerebellar alterations observed in patients affected by ZS and some peroxisomal disorders in which Prist is accumulated.

Fibroelastoma, an Incidentaloma Disease? - Image Cases of Fibroelastomas as Incidental Findings in Four Patients, Four Different Valves. / Fibroelastoma, uma Doença Incidentaloma? ­ Imagem de Casos de Fibroelastomas como Achados Incidentais em Quatro Pacientes, Quatro Valvas Diferentes.

Fibroelastomas are the second most common benign cardiac tumor1. They are small avascular structures with a mean size of 9mm, ranging up to 70mm, usually attached to the heart valves' surface (aortic and mitral are the most affected, followed by tricuspid and pulmonary valves). Their etiology is unclear, but the hypothesis of coalescence of microthrombus at the coaptation margins of valves is the most widely accepted theory. On echocardiography, they are pedicled, mobile, with a filamentous surface, and usually have a speckled appearance with echolucencies and a stippled pattern near the edges. Clinically, they may be associated with embolic phenomena; however, in most cases, the diagnosis is incidental. We present a series of four clinical cases with an incidental diagnosis of fibroelastomas across the four cardiac valves as assessed by transthoracic echocardiography (Video 1; Figure 1). Video 1 From left to right and top to bottom: fibroelastomas of the anterior leaflet of the tricuspid valve, anterior leaflet of the mitral valve, left cusp of the pulmonary valve and left cuspid of the aortic valve, each corresponding to a different patient. Link: http://abccardiol.org/supplementary-material/2024/12102/2023-0222_IM_video01.mp4 Figure 1 From left to right and top to bottom: fibroelastomas of the anterior leaflet of the tricuspid valve, anterior leaflet of the mitral valve, left cusp of the pulmonary valve and left cuspid of the aortic valve, each corresponding to a different patient.

Os fibroelastomas são o segundo tumor cardíaco benigno mais comum. São estruturas pequenas, avasculares, com uma dimensão média de 9mm, podendo atingir até 70mm, habitualmente aderentes à superfície das válvulas cardíacas (válvulas aórtica e mitral são as mais comumente afetadas, seguidas das válvulas tricúspide e pulmonar). A etiologia não é clara, sendo a hipótese de formação de microtrombos nas margens de coaptação das válvulas a mais aceite. Na ecocardiografia apresentam aspeto pediculado, móvel, com superfície filamentosa, tipicamente com uma aparência pontilhada nas margens e ecolucente. Do ponto de vista clínico, podem estar associados a fenómenos embólicos, no entanto, na maioria dos casos o diagnóstico é incidental. Apresentamos de seguida quatro casos de diagnóstico incidental de fibroelastomas nas quatro válvulas cardíacas, diagnosticados por ecocardiograma transtorácico (ETT) (Vídeo 1; Figura 1). Vídeo 1Da esquerda para a direita, de cima para baixo: fibroelastomas no folheto anterior da válvula tricúspide, folheto anterior da válvula mitral, cúspide esquerda da válvula pulmonar e cúspide esquerda da válvula aórtica, cada um correspondendo a um doente diferente. Em: http://abccardiol.org/supplementary-material/2024/12102/2023-0222_IM_video01.mp4 Figura 1Da esquerda para a direita, de cima para baixo: fibroelastomas no folheto anterior da válvula tricúspide, folheto anterior da válvula mitral, cúspide esquerda da válvula pulmonar e cúspide esquerda da válvula aórtica, cada um correspondendo a um doente diferente.

PrOgnosis in Pulmonary Embolism (PoPE): 30-Day mortality risk score based on five admission parameters.

INTRODUCTION AND OBJECTIVE: Several scoring systems have been developed for risk stratification in patients with acute pulmonary embolism (PE). The Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) are among the most used, however the high number of variables hinder its application. Our aim was to derive an easy-to-perform score based on simple parameters obtained at admission to predict 30-day mortality in acute PE patients. METHODS: Retrospective study in 1115 patients with acute PE from two institutions (derivation cohort n=835, validation cohort n=280). The primary endpoint was all-cause mortality at 30 days. Statistically and clinically relevant variables were selected for multivariable Cox regression analysis. We derived and validated a multivariable risk score model and compared to other established scores. RESULTS: The primary endpoint occurred in 207 patients (18.6%). Our model included five variables weighted as follows: modified shock index ≥1.1 (hazard ratio [HR] 2.57, 1.68-3.92, p<0.001), active cancer (HR 2.27, 1.45-3.56, p<0.001), altered mental state (HR 3.82, 2.50-5.83, p<0.001), serum lactate concentration ≥2.50 mmol/L (HR 5.01, 3.25-7.72, p<0.001), and age ≥80 years (HR 1.95, 1.26-3.03, p=0.003). The prognostic ability was superior to other scores (area under curve [AUC] 0.83 [0.79-0.87] vs 0.72 [0.67-0.79] in PESI and 0.70 [0.62-0.75] in sPESI, p<0.001) and its performance in the validation cohort was deemed good (73 events in 280 patients, 26.1%, AUC=0.76, 0.71-0.82, p<0.0001) and superior to other scores (p<0.05). CONCLUSIONS: The PoPE score (https://tinyurl.com/ybsnka8s) is an easy tool with superior performance to predict early mortality in patients admitted for PE with non-high-risk PE.

Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia.

Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl-d-aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH.

Marked inhibition of Na+, K(+)- ATPase activity and the respiratory chain by phytanic acid in cerebellum from young rats: possible underlying mechanisms of cerebellar ataxia in Refsum disease.

Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.

Neurochemical evidence that the metabolites accumulating in 3-methylcrotonyl-CoA carboxylase deficiency induce oxidative damage in cerebral cortex of young rats.

Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats. 3MCG and 3MCA significantly increased TBA-RS and carbonyl formation, indicating that these compounds provoke lipid and protein oxidation, respectively. In contrast, nitric oxide production was not affected by 3MCG and 3MCA. Furthermore, 3MCG- and 3MCA-induced elevation of TBA-RS values was fully prevented by melatonin, trolox and reduced glutathione, but not by the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester or the combination of catalase plus superoxide dismutase, indicating that reactive oxygen species were involved in the oxidative damage caused by these compounds. We also found that the activity of the antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase and glutathione reductase were not altered in vitro by 3MCG and 3MCA. It is therefore presumed that alterations of the cellular redox homeostasis caused by the major metabolites accumulating in 3MCCD may potentially be involved in the pathophysiology of the neurological dysfunction and structural brain alterations found in patients affected by this disorder.

Effect of direct oral anticoagulants versus vitamin K antagonists or warfarin in patients with left ventricular thrombus outcomes: A systematic review and meta-analysis.

INTRODUCTION: Left ventricular thrombus commonly occurs as a complication of acute anterior myocardial infarction and nonischemic cardiomyopathies with severe left ventricular systolic dysfunction. Its frequency is still high despite medical advances. Current guidelines recommend the use of vitamin k antagonists as first-line therapy, however, the off-label use of direct oral anticoagulants is becoming more frequent and attractive, given the better pharmacological and clinical profile, with the improvement of the patient's quality of life. AIM: To provide an update on the currently existing evidence regarding the outcomes of efficacy and safety of direct oral anticoagulants (DOACs) as first-line therapy in left ventricular thrombus, in comparison to vitamin K antagonists (VKAs). METHODS: A systematic review and meta-analysis of studies on the effects of direct oral anticoagulants versus vitamin K antagonists on left ventricular thrombi and on the results was performed. RESULTS: Fourteen studies were included in the meta-analysis, with a total of 2498 patients (n=631 direct oral anticoagulants and n=1867 for VKAs). No significant differences were found in efficacy and safety outcomes (odds ratio (OR) 0.86; 95% confidence interval (CI), 0.55-1.33; p=0.50; I2=32%) and (OR 1.0; 95% CI, 0.78-1.30; p=0.93; I2=2%) respectively. No difference was noted in all-cause mortality (OR 0.92; 95% CI, 0.58-1.45; p=0.74; I2=0%). Thrombus resolution was observed in 288/416 in direct oral anticoagulants vs. 732/1085 patients treated with VKAs (OR 1.14; 95% CI, 0.77-1.66; p=0.50; I2=33%). CONCLUSIONS: The findings of this meta-analysis suggest the potential utility of DOACs as a first-line strategy in patients with left ventricular thrombus.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. METHODS: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. RESULTS: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (ß-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). CONCLUSIONS: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.