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Background and Objectives: Children with congenital heart diseases (CHDs) have an increased risk of developing neurologic deficits, even in the absence of apparent brain pathology. The aim of this work was to compare quantitative macro- and microstructural properties of subcortical gray matter structures of pediatric CHD patients with normal appearing brain magnetic resonance imaging to healthy controls. Methods: We retrospectively reviewed children with coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS) admitted to our hospital. We identified 24 pediatric CHD patients (17 COA, 7 HLHS) with normal-appearing brain MRI. Using an atlas-based approach, the volume and apparent diffusion coefficient (ADC) were determined for the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, cerebral white matter, cerebral cortex, and brainstem. Multivariate statistics were used to compare the extracted values to reference values from 100 typically developing children without any known cardiac or neurological diseases. Results: Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and sex as co-variates revealed a significant difference between pediatric CHD patients and healthy controls (p < 0.001). Post-hoc comparisons demonstrated significantly reduced brain volumes in most subcortical brain regions investigated and elevated ADC values in the thalamus for children with CHD. No significant differences were found comparing children with COA and HLHS. Conclusions: Despite normal appearing brain MRI, children with CHD exhibit wide-spread macro-structural and regional micro-structural differences of subcortical brain structures compared to healthy controls, which could negatively impact neurodevelopment, leading to neurological deficits in childhood and beyond. [ABSTRACT FROM AUTHOR]

The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF. [ABSTRACT FROM AUTHOR]

Results of experimental studies have shown that β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule, is an endogenous negative regulator of fat mass in mice, but it remains unclear whether that is the case in humans, though an enhanced BAIBA concentration in patients receiving sodium–glucose cotransporter 2 inhibitors was found in our recent study. The objective of this study was to analyze the determinants of circulating BAIBA concentration in humans, with focus on the possible link between circulating BAIBA and body composition including fat mass. Data for 188 consecutive patients with heart failure (HF, 64 ± 13 years; 70% male) who received a dual energy X ray absorptiometry (DEXA) scan for assessment of body composition including fat mass index (FMI) and appendicular skeletal muscle mass index (ASMI) were used in this study. Plasma BAIBA concentration in a fasting state after stabilization of HF was determined using ultraperformance liquid chromatography. Plasma BAIBA was detected in 66% of the patients. In simple linear regression analyses of data from patients in whom plasma BAIBA was detected, plasma BAIBA concentration was positively correlated with uric acid and was negatively correlated with body mass index (BMI), estimated glomerular filtration rate (eGFR), FMI, and % body fat. There were no correlations between plasma BAIBA concentration and indexes of muscle mass and bone mass. The results of multiple linear regression analyses showed that FMI and % body fat in addition to BMI, but not ASMI, were independent explanatory factors for plasma BAIBA concentration. In conclusion, plasma BAIBA concentration is inversely correlated with indexes of fat mass, indicating that BAIBA may be a therapeutic target for excessive fat accumulation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the influence of quantitative reports (QReports) on the radiological assessment of hippocampal sclerosis (HS) from MRI of patients with epilepsy in a setting mimicking clinical reality. Methods: The study included 40 patients with epilepsy, among them 20 with structural abnormalities in the mesial temporal lobe (13 with HS). Six raters blinded to the diagnosis assessed the 3T MRI in two rounds, first using MRI only and later with both MRI and the QReport. Results were evaluated using inter-rater agreement (Fleiss' kappa k ) and comparison with a consensus of two radiological experts derived from clinical and imaging data, including 7T MRI. Results: For the primary outcome, diagnosis of HS, the mean accuracy of the raters improved from 77.5% with MRI only to 86.3% with the additional QReport (effect size d = 1.43 ). Inter-rater agreement increased from k = 0.56 to k = 0.72 . Five of the six raters reached higher accuracies, and all reported higher confidence when using the QReports. Conclusion: In this pre-use clinical evaluation study, we demonstrated clinical feasibility and usefulness as well as the potential impact of a previously suggested imaging biomarker for radiological assessment of HS. [ABSTRACT FROM AUTHOR]

While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients. [ABSTRACT FROM AUTHOR]

Indistinct soft tissue sarcomas are a form of tumor that can be difficult to diagnose in a tremendous population. For earlier prediction of distant metastasis, some traditional classifications are suffered by technological issues, lack of enhancement methods, reliability, and so on. To provide a better classification, this paper introduces a new deep learning-based soft tissue sarcoma classification framework. Initially, spatial features and LVP features are extracted.The main aim of this phase is to generate LVP using each pixel vector and provides the benefits of inherent structures in edge patches. The subsequent classification phase is utilized an optimized Convolutional Neural Network (CNN). Moreover, the weight and filter size of CNN will be optimally tuned by the new Self Adaptive Bat Algorithm (SA-BA). Finally, SA-BA method is compared over some existing classifiers in terms of various measures. [ABSTRACT FROM AUTHOR]

Almost half of all heart failure (HF) disease burden is due to HF with preserved ejection fraction (HFpEF). The primary symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance and is associated with their reduced quality of life. Recently, studies showed that HFpEF patients have multiple skeletal muscle (SM) abnormalities, and these are associated with decreased exercise intolerance. The SM abnormalities are likely intrinsic to the HFpEF syndrome, not a secondary consequence of an epiphenomenon. These abnormalities are decreased muscle mass, reduced type I (oxidative) muscle fibers, and reduced type I-to-type II fiber ratio as well as a reduced capillary-to-fiber ratio, abnormal fat infiltration into the thigh SM, increased levels of atrophy genes and proteins, reduction in mitochondrial content, and rapid depletion of high-energy phosphate during exercise with markedly delayed repletion of high-energy phosphate during recovery in mitochondria. In addition, patients with HFpEF have impaired nitric oxide bioavailability, particularly in the microvasculature. These SM abnormalities may be responsible for impaired diffusive oxygen transport and/or impaired SM oxygen extraction. To date, exercise training (ET) and caloric restriction are some of the interventions shown to improve outcomes in HFpEF patients. Improvements in exercise tolerance following aerobic ET are largely mediated through peripheral SM adaptations with minimal change in central hemodynamics and highlight the importance of targeting SM to improve exercise intolerance in HFpEF. Focusing on the abnormalities mentioned above may improve the clinical condition of patients with HFpEF. [ABSTRACT FROM AUTHOR]

Purpose of Review: Aging leads to decline in bone mass and quality starting at age 30 in humans. All mammals undergo a basal age-dependent decline in bone mass. Osteoporosis is characterized by low bone mass and changes in bone microarchitecture that increases the risk of fracture. About a third of men over the age of 50 years are osteoporotic because they have higher than basal bone loss. In women, there is an additional acute decrement in bone mass, atop the basal rate, associated with loss of ovarian function (menopause) causing osteoporosis in about half of the women. Both genetics and environmental factors such as smoking, chronic infections, diet, microbiome, and metabolic disease can modulate basal age-dependent bone loss and eventual osteoporosis. Here, we review recent studies on the etiology of age-dependent decline in bone mass and propose a mechanism that integrates both genetic and environmental factors. Recent Findings: Recent findings support that aging and menopause dysregulate the immune system leading to sterile low-grade inflammation. Both animal models and human studies demonstrate that certain kinds of inflammation, in both men and women, mediate bone loss. Senolytics, meant to block a wide array of age-induced effects by preventing cellular senescence, have been shown to improve bone mass in aged mice. Based on a synthesis of the recent data, we propose that aging activates long-lived tissue resident memory T-cells to become senescent and proinflammatory, leading to bone loss. Targeting this population may represent a promising osteoporosis therapy. Summary: Emerging data indicates that there are several mechanisms that lead to sterile low-grade chronic inflammation, inflammaging, that cause age- and estrogen-loss dependent osteoporosis in men and women. [ABSTRACT FROM AUTHOR]

Objectives: To inform updates to the Pregnancy Risk Assessment Monitoring System (PRAMS) design and processes, African American/Black and Hispanic/Latina women in Florida provided feedback on their awareness and perceptions of the PRAMS survey, and preferences for survey distribution, completion, design and content. Methods: Focus groups were conducted in English and Spanish with 29 women in two large metropolitan counties. Participants completed a brief survey, reviewed the PRAMS questionnaire and recruitment materials, engaged in discussion, and gave feedback directly onto cover design posters. Results: Participants reported limited awareness of PRAMS. Preferences for survey distribution and completion varied by participant lifestyle. Interest in topics covered by PRAMS was as a motivator for completion, while distrust and confidentiality concerns were deterrents. Participants were least comfortable answering questions about income, illegal drug use, and pregnancy loss/infant death. Changes to the length of the survey, distribution methods, and incentives/rewards for completion were recommended. Conclusions for Practice: Results highlight the need to increase PRAMS awareness, build trust, and consider the design, length and modality for questionnaire completion as possible avenues to improve PRAMS response rates. [ABSTRACT FROM AUTHOR]

The clinical encounter begins with presentation of an illness experience; but throughout that encounter, something else is constructed from it – a symptom. The symptom is a particular interpretation of that experience, useful for certain purposes in particular contexts. The hermeneutics of medicine – the study of the interpretation of human experience in medical terms – has largely taken the process of symptom-construction to be transparent, focussing instead on how constellations of symptoms are interpreted as representative of particular conditions. This paper examines the hermeneutical activity of symptom-construction more closely. I propose a fourfold account of the clinical function of symptoms: as theoretical entities; as tools for communication; as guides to palliative intervention; and as candidates for medical explanation or intervention. I also highlight roles they might play in illness experience. I use this framework to discuss four potential failures of symptom-interpretation: failure of symptom-type and symptom-token recognition; loss of the complete picture of illness experience through overwhelming emphasis on its symptomatic interpretation; and intersubjective feedback effects of symptom description altering the ill person's own perceptions of their phenomenal experience. I conclude with some suggestions of potential remedies for failures in the process of symptom-construction. [ABSTRACT FROM AUTHOR]

Drug-resistant epilepsy is associated with poor health outcomes and increased economic burden. In the last three decades, various new antiseizure medications have been developed, but the proportion of people with drug-resistant epilepsy remains relatively unchanged. Developing strategies to address drug-resistant epilepsy is essential. Here, we define drug-resistant epilepsy and emphasize its relationship to the conceptualization of epilepsy as a symptom complex, delineate clinical risk factors, and characterize mechanisms based on current knowledge. We address the importance of ruling out pseudoresistance and consider the impact of nonadherence on determining whether an individual has drug-resistant epilepsy. We then review the principles of epilepsy drug therapy and briefly touch upon newly approved and experimental antiseizure medications. [ABSTRACT FROM AUTHOR]

Abstract—Damage to the nervous system is a common complication of obesity. In this regard, analysis of the content of neurotrophins in patients with obesity seems relevant. However, the risk of complications is determined by the metabolic type of the obesity, so our aim was to study the effect of the metabolic type of obesity on the content of neurotrophins in the blood serum. We found that the content of brain-derived neurotrophic factor (BDNF) does not change in obesity, but the serum concentration of nerve growth factor (NGF) significantly decreases, regardless of the metabolic type of obesity. Taking into account the literature data that obesity is accompanied by an increase in the plasma concentration of NGF, it may be assumed that obesity is associated with a disruption of NGF deposition in platelets and, as a result, acceleration of its elimination. At the same time, in patients with metabolically unhealthy obesity (MUO), the content of NGF was higher than in patients with metabolically healthy obesity (MHO). We also showed that muscle and adipose tissues make a significant contribution to the formation of the serum NGF pool in MHO. However, in MUO patients, the influence of adipose tissue on NGF content prevailed. In addition, in patients with MUO, we noted an effect of the secretory activity of muscle tissue on the content of BDNF, while in patients with MHO this effect was not observed. [ABSTRACT FROM AUTHOR]

Aim: Left ventricular diastolic dysfunction (DD), a common finding in the general population, is considered to be associated with heart failure with preserved ejection faction (HFpEF). Here we evaluate the prevalence and correlates of DD in subjects with and without HFpEF in a middle-aged sample of the general population. Methods and results: From the first 10,000 participants of the population-based Hamburg City Health Study (HCHS), 5913 subjects (mean age 64.4 ± 8.3 years, 51.3% females), qualified for the current analysis. Diastolic dysfunction (DD) was identified in 753 (12.7%) participants. Of those, 11.2% showed DD without HFpEF (ALVDD) while 1.3% suffered from DD with HFpEF (DDwHFpEF). In multivariable regression analysis adjusted for major cardiovascular risk factors, ALVDD was associated with arterial hypertension (OR 2.0, p < 0.001) and HbA1c (OR 1.2, p = 0.007). Associations of both ALVDD and DDwHFpEF were: age (OR 1.7, p < 0.001; OR 2.7, p < 0.001), BMI (OR 1.2, p < 0.001; OR 1.6, p = 0.001), and left ventricular mass index (LVMI). In contrast, female sex (OR 2.5, p = 0.006), atrial fibrillation (OR 2.6, p = 0.024), CAD (OR 7.2, p < 0.001) COPD (OR 3.9, p < 0.001), and QRS duration (OR 1.4, p = 0.005) were strongly associated with DDwHFpEF but not with ALVDD. Conclusion: The prevalence of DD in a sample from the first 10,000 participants of the population-based HCHS was 12.7% of whom 1.3% suffered from HFpEF. DD with and without HFpEF showed significant associations with different major cardiovascular risk factors and comorbidities warranting further research for their possible role in the formation of both ALVDD and DDwHFpEF. [ABSTRACT FROM AUTHOR]

Purpose: P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods: Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results: At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion: [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT. [ABSTRACT FROM AUTHOR]

Objective: 5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([18F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood–brain barrier (BBB) of [18F]MC225 in healthy subjects. Methods: [18F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [18F]MC225 injection. Dynamic [18F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [18F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). VT was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time–activity curves [TACs] and negative slope of calculated TACs) were compared with the VT values. Results: No serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was < 2%ID. Absorbed dose was the highest in the pancreas (mean ± SD, 203 ± 45 μGy/MBq) followed by the liver (83 ± 11 μGy/MBq). Mean effective dose with and without urination was 17 ± 1 μSv/MBq. [18F]MC225 readily entered the brain, distributing homogeneously in grey matter regions. 2-TCM provided lower Akaike information criterion scores than did 1-TCM. VT estimated by Logan plot was well correlated with that of 2-TCM (r2 > 0.9). AUCs of TACs were positively correlated with VT (2-TCM) values (r2: AUC0-60 min = 0.61, AUC0-30 min = 0.62, AUC30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with VT (2-TCM) values (r2 = 0.53, p < 0.0001). Conclusions: This initial evaluation indicated that [18F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB. [ABSTRACT FROM AUTHOR]

Found in the Upper Jurassic outcrops of Lourinhã, Portugal, and first published in 1997, the Paimogo dinosaur egg clutch is one of Portugal’s most remarkable fossils, with over one hundred eggs preserved in association with embryonic bones, of the allosauroid theropod Lourinhanosaurus. However, many questions about it have remained unanswered, even until the present day. After its discovery, this extraordinary fossil became the keystone of a small local museum, greatly kick-starting regional tourism, while also holding the fossils in trust for future generations to study. More than 20 years later, continually sustained paleontological interest from the public has even given rise to both a highly successful dinosaur theme park in the region and an aspiring UNESCO Geopark. Recently, a multidisciplinary team of preparators, paleontologists, sedimentologists, mineralogists, and geochemists revisited an unopened jacket from the original excavation using an array of techniques to address various questions. Studies are ongoing, but the corpus of information obtained and the methodologies utilized to gather data have offered an opportunity to design an exhibit around the history of the Paimogo clutch, highlighting the scientific methods involved, and asserting the importance of preserving geological heritage for the future, when new tools will doubtlessly become available to provide yet another new look at old fossils. Here, we describe our analytical procedures and present an innovative exhibit designed to introduce to the public the latest advances on the research behind an iconic piece of Portuguese geoheritage, increasing its value both as a research item and as an educational resource. [ABSTRACT FROM AUTHOR]

There is an established link between cardiometabolic abnormality, central arterial stiffness, and preserved ejection fraction heart failure (HFpEF). Adipocyte free fatty acid binding protein (a-FABP) has been shown to signal endothelial dysfunction through fatty acid toxicity, though its role in mediating ventricular-arterial dysfunction remains unclear. We prospectively examined the associations of a-FABP with central arterial pressure using non-invasive applanation tonometry (SphygmoCor) and cardiac structure/function (i.e., tissue Doppler imaging [TDI] and global longitudinal myocardial strain [GLS]) in patients with cardiometabolic (CM) risk (n = 150) and HFpEF (n = 50), with healthy volunteers (n = 49) serving as a control. We observed a graded increase of a-FABP across the healthy controls, CM individuals, and HFpEF groups (all paired p < 0.05). Higher a-FABP was independently associated with higher central systolic and diastolic blood pressures (CSP/CPP), increased arterial augmentation index (Aix), lower early myocardial relaxation velocity (TDI-e′), higher left ventricle (LV) filling (E/TDI-e′) and worsened GLS (all p < 0.05). During a median of 3.85 years (interquartile range: 3.68–4.62 years) follow-up, higher a-FABP (cutoff: 24 ng/mL, adjusted hazard ratio: 1.01, 95% confidence interval: 1.001–1.02, p = 0.04) but not brain natriuretic peptide, and higher central hemodynamic indices were related to the incidence of heart failure (HF) in fully adjusted Cox models. Furthermore, a-FABP improved the HF risk classification over central hemodynamic information. We found a mechanistic pathophysiological link between a-FABP, central arterial stiffness, and myocardial dysfunction. In a population with a high metabolic risk, higher a-FABP accompanied by worsened ventricular-arterial coupling may confer more unfavorable outcomes in HFpEF. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this meta-analysis was to estimate the clinical use value of 11C-FMZ and 18F-FDG in PET for the localization of epileptogenic zone and to provide evidence for practitioners' clinical decision-making. Methods: We searched PubMed and Embase in a time frame from inception to May 31, 2020. Studies utilizing FMZ or FDG-PET or FDG-PET/MRI used in patients with epilepsy, with EEG or surgical outcomes as the gold standard and corresponding outcomes such as concordance rates of PET or PET/MRI scan compared with reference standard, absolute numbers of participants with true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) results in FDG or FMZ PET. Pooled concordance rates, overall sensitivity, and specificity of 11C-FMZ-PET and 18F-FDG-PET were calculated. Results: In total, 44 studies met the inclusion criteria. The pooled concordance rates of FDG-PET, FMZ-PET, and FDG-PET/MRI coregistration compared with reference standard were 0.67 (95% CI: 0.60–0.73), 0.75 (95% CI: 0.57–0.93), and 0.93 (95% CI: 0.89–0.97), respectively. The concordance rate of 18F-FDG-PET in patients with temporal lobe epilepsy (TLE) was 0.79 (0.63; 0.92). The overall sensitivity and specificity of 18F-FDG-PET were 0.66 (95% CI: 0.58–0.73) and 0.71 (95% CI: 0.63–0.78), respectively. 11C-FMZ-PET displayed an overall sensitivity of 0.62 (95% CI: 0.49–0.73) and specificity of 0.73 (95% CI: 0.59–0.84). Conclusions: Both 11C-FMZ PET and 18F-FDG PET are the choice of modalities for the localization of epileptogenic zone, especially when coregistered with MRI. Key Points: •11C-FMZ-PET may be more helpful than18F-FDG-PET in the localization of epilepsy foci. • Coregistration of FDG-PET and MRI is recommended in the localization of epileptogenic zone. [ABSTRACT FROM AUTHOR]

Background: [18F]MC225 is a radiotracer for imaging P-glycoprotein (P-gp) function at the blood-brain barrier. The P-gp function can be altered due to different factors, for instance, decreased P-gp function has been described in patients with Alzheimer's or Parkinson's Disease. The current applied radiosynthesis of [18F]MC225 involves 2 steps, including the distillation of the [18F] fluoroethylbromide intermediate. To develop a more robust synthetic procedure, it is of interest to produce the radiotracer via a 1-step synthesis. The present study describes a new synthetic approach to produce [18F]MC225 via direct 18F-fluorination. Moreover, we also provide the appropriate conditions for the automation of the synthesis. A mesylate precursor was synthesized via a multi-step synthetic route and used for the radiolabeling. The nucleophilic substitution of the mesylate group by [18F] Fluoride was automated in two different synthesis modules: IBA Synthera and Eckert and Ziegler PharmTracer (E&Z). Results: The mesylate precursor was synthesized in 7 steps starting with 5-hydroxy-1-tetralone (commercially available) in practical yields. The stability of the precursor was improved via mesylate salt formation method. The radiolabeling was done by adding the mesylate precursor dissolved in DMF to the dried [18F]KF/K2.2.2 complex and heating at 140 °C for 30 min. Quality control by UPLC confirmed the production of [18F]MC225 with a molar activity (Am) higher than 100 GBq/micromole. The synthesis time in Synthera was 106 min and the product was obtained with a radiochemical purity higher than 95% and RCY of 6.5%, while the production in E&Z lasted 120 min and the product had a lower radiochemical purity (91%) and RCY (3.8%). Conclusions: [18F]MC225 was successfully produced via a 1-step reaction. The procedure is suitable for automation using commercially available synthesis modules. The automation of the radiosynthesis in the Synthera module allows the production of the [18F]MC225 by a reliable and simple method. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome with a complex aetiology often associated with several comorbidities, such as left ventricle pressure overload, diabetes mellitus, obesity, and kidney disease. Its pathophysiology remains obscure mainly due to the complex phenotype induced by all these associated comorbidities and to the scarcity of animal models that adequately mimic HFpEF. Increased oxidative stress, inflammation, and endothelial dysfunction are currently accepted as key players in HFpEF pathophysiology. However, we have just started to unveil HFpEF complexity and the role of calcium handling, energetic metabolism, and mitochondrial function remain to clarify. Indeed, the enlightenment of such cellular and molecular mechanisms represents an opportunity to develop novel therapeutic approaches and thus to improve HFpEF treatment options. In the last decades, the number of research groups dedicated to studying HFpEF has increased, denoting the importance and the magnitude achieved by this syndrome. In the current technological and web world, the amount of information is overwhelming, driving us not only to compile the most relevant information about the theme but also to explore beyond the tip of the iceberg. Thus, this review aims to encompass the most recent knowledge related to HFpEF or HFpEF-associated comorbidities, focusing mainly on myocardial metabolism, oxidative stress, and energetic pathways. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) does not exist as a singular clinical or pathological entity but as a syndrome encompassing a wide range of clinical and biological phenotypes. There is an urgent need to progress from the unsuccessful 'one-size-fits-all' approach to more precise disease classification, in order to develop targeted therapies, personalise risk stratification and guide future research. In this regard, this review discusses the current and emerging roles of cardiovascular imaging for the diagnosis of HFpEF, for distilling HFpEF into distinct disease entities according to underlying pathobiology and for risk stratification. [ABSTRACT FROM AUTHOR]

Purpose of review: Patients often present with a mixed phenotype of pulmonary vascular disease and heart failure with preserved ejection fraction (HFpEF). Identifying the exact hemodynamic culprits in such cases has important therapeutic implications. This review discusses the hemodynamic characterization and treatment options in patients with pulmonary vascular disease, HFpEF, and their combination. Recent findings: The threshold for pulmonary hypertension (PH) has been lowered toward a mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest. Exercise-induced PH is defined as mPAP > 30 mmHg during exercise with a mPAP/cardiac output slope > 3 mmHg/L/min. A blunted pulmonary vasodilatory reserve is observed early on in HFpEF, before an elevated pulmonary vascular resistance or right ventricular remodeling is evident. Long-term exposure to elevated left heart filling pressures in HFpEF induces hemangiomatosis-like endothelial cell proliferation and smooth muscular hypertrophy, predominantly at the venous side of the pulmonary circulation. Enhanced ventricular interdependence because of pericardial constraint may play an important role in the pathophysiology of HFpEF, especially when pulmonary vascular disease is present. Summary: Established and emerging treatment strategies for pulmonary vascular disease and HFpEF should target drivers of the underlying disease process and subsequent organ damage. Careful hemodynamic characterization is vital to guide treatment decisions. [ABSTRACT FROM AUTHOR]

The heart failure (HF) epidemic is growing and approximately half of the HF patients have heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome, characterized by a preserved left ventricular ejection fraction (LVEF ≥ 50%) with diastolic dysfunction, and is associated with high morbidity and mortality. Underlying comorbidities of HFpEF, i.e., hypertension, type 2 diabetes mellitus, obesity, and renal failure, lead to a systemic pro-inflammatory state, thereby affecting normal cardiac function. Increased inflammatory biomarkers predict incident HFpEF and are higher in patients with HFpEF as compared with heart failure with reduced ejection fraction (HFrEF). Randomized trials in HFpEF patients using traditional HF medication failed to demonstrate a clear benefit on hard endpoints (mortality and/or HF hospitalization). Therefore, therapies targeting underlying comorbidities and systemic inflammation in early HFpEF may provide better opportunities. Here, we provide an overview of the current state and future perspectives of immunomodulatory therapies for HFpEF. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Obesity increases the risk of new onset heart failure (HF), and particularly HF with preserved ejection fraction (HFpEF). Despite the observations of favorable clinical outcomes in HF patients with obesity in general, sometimes referred to as the "obesity paradox," it is important to recognize that severe obesity is associated with worse clinical outcomes. This review summarizes the effects of obesity treatment on cardiovascular health and HF clinical outcomes.Recent Findings: Treatment for obesity utilizes a variety of modalities to achieve purposeful weight loss including lifestyle intervention, medications, and bariatric surgery. There are a cluster of benefits of obesity treatment in terms of clinical outcomes in HF. The mechanisms of these benefits include both weight loss-dependent and weight loss-independent mechanisms. Obesity treatment is safe and associated with favorable clinical outcomes across the spectrum of the HF population. The potential benefits are facilitated through multiple mechanisms. [ABSTRACT FROM AUTHOR]

The extent to which the six basic human facial expressions perceptually differ from one another remains controversial. For instance, despite the importance of rapidly decoding fearful faces, this expression often is confused with other expressions, such as Surprise in explicit behavioral categorization tasks. We quantified implicit visual discrimination among rapidly presented facial expressions with an oddball periodic visual stimulation approach combined with electroencephalography (EEG), testing for the relationship with behavioral explicit measures of facial emotion discrimination. We report robust facial expression discrimination responses bilaterally over the occipito-temporal cortex for each pairwise expression change. While fearful faces presented as repeated stimuli led to the smallest deviant responses from all other basic expressions, deviant fearful faces were well discriminated overall and to a larger extent than expressions of Sadness and Anger. Expressions of Happiness did not differ quantitatively as much in EEG as for behavioral subjective judgments, suggesting that the clear dissociation between happy and other expressions, typically observed in behavioral studies, reflects higher-order processes. However, this expression differed from all others in terms of scalp topography, pointing to a qualitative rather than quantitative difference. Despite this difference, overall, we report for the first time a tight relationship of the similarity matrices across facial expressions obtained for implicit EEG responses and behavioral explicit measures collected under the same temporal constraints, paving the way for new approaches of understanding facial expression discrimination in developmental, intercultural, and clinical populations. [ABSTRACT FROM AUTHOR]

Introduction: With shifting demographics and declining response rates, state and national health surveys are considering mixed mode approaches. Most states field the Pregnancy Risk Assessment Monitoring System (PRAMS) surveillance project, but few have studied the effect of encouraging online responses. Methods: Like PRAMS, the 2016 Ohio Pregnancy Assessment Survey interviewed new mothers 2–4 months after delivery (n = 3382). Fielding included a traditional mailed paper questionnaire with telephone follow-up protocol and two experiments: a rotating web invitation added a web survey link at different points during the mail protocol, and a push-to-web protocol asked women to complete the survey online before mailing a questionnaire. This analysis examined the responses rates and tested for unweighted demographic differences using Pearson's chi-square. Results: The unweighted response rate was highest with the traditional contact protocol (30.0%) and slightly lower among the rotating web invite (27.4%) and the push-to-web (25.5%) groups. Nearly two-thirds (64%) of push-to-web protocol respondents completed the survey online, with 70% of those web surveys submitted before the first paper questionnaire was mailed. Women who responded to the web versus mail surveys were similar on most characteristics, although in both experimental groups, women who completed the web version were more likely to be college educated. Among the push-to-web group, 60% of web and 36% of mail respondents had a 4-year college degree (p <.001). Discussion: Given the potential for push-to-web to shift respondents to an online survey without greatly impacting response rates, researchers should continue to examine the utility of incorporating a web mode in surveys of new mothers. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes the evidence for the established vascular/hypoperfusion model and explores the new hypothesis that configures the heart/brain axis as an organ system where similar pathogenic mechanisms exploit physiological and pathological changes. Recent Findings: Although associated by common risk factors, similar epidemiological stratification and common triggers (including inflammation, oxidative stress, and hypoxia), heart failure and Alzheimer's disease have been, for long time, viewed as pathogenically separate illnesses. The silos began to be broken down with the awareness that vascular dysfunction, and loss of cardiac perfusion pump power, trigger biochemical changes, contributing to the typical hallmark of Alzheimer's disease (AD)—the accumulation of Aβ plaques and hyperphosphorylated Tau tangles. Compromised blood flow to the brain becomes the paradigm for the "heart-to-head" connection. Compelling evidence of common genetic variants, biochemical characteristics, and the accumulation of Aβ outside the brain suggests a common pathogenesis for heart failure (HF) and AD. These new findings represent just the beginning of the understanding the complex connection between AD and HF requiring further studies and interdisciplinary approaches. Summary: Altogether, the current evidence briefly summarized in this review, highlight a closer and complex relationship between heart failure and Alzheimer's that goes beyond the vascular/perfusion hypothesis. Genetic and biochemical evidence begin to suggest common pathogenic mechanisms between the two diseases involving a systemic defect in the folding of protein or a seeding at distance of the misfolded proteins from one organ to the other. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is a lack of effective treatments. In this meta-analysis, we assessed the efficacy and safety of inorganic nitrate in patients with HFpEF. Methods and Results: We systematically searched PubMed, Embase, and the Cochrane Library from the inception of the database through March 2020. We included randomized controlled trials that compared the efficacy and safety of inorganic nitrate with a placebo in the treatment of patients with HFpEF. The primary outcome of the meta-analysis was exercise capacity (measured as a change in peak oxygen uptake). We also assessed the effect of inorganic nitrate on diastolic function (measured as changes in E/A and E/e', assessed by echocardiography), quality of life (estimated using the Kansas City Cardiomyopathy Questionnaire), and rest and exercise hemodynamics (measured by invasive cardiac catheterization). In the pooled data analysis, there were no significant differences in peak oxygen uptake (mL/kg/min) [mean difference (MD), 0.25; 95% CI, − 0.07 to 0.57], diastolic function [E/A–standardized mean difference (SMD), 0.51; 95% CI, − 0.17 to 1.20; or E/e'–SMD, 0.02; 95% CI, − 0.23 to 0.27], or quality of life. However, a significant change was observed in the rest and exercise hemodynamics between the inorganic nitrate and placebo treatment in HFpEF patients. No study has reported the effect of inorganic nitrate on hospitalization and mortality of patients with HFpEF. Conclusions: In patients with HFpEF, the use of inorganic nitrate is not associated with improvements in exercise capacity, diastolic function, and quality of life but is associated with significant changes in rest and exercise hemodynamics. [ABSTRACT FROM AUTHOR]

Introduction: [18F]MC225 is a selective substrate for P-glycoprotein (P-gp) that has good metabolic stability and shows higher baseline uptake compared with other P-gp substrates such as (R)-[11C]Verapamil. Prior to clinical translation, it is necessary to perform process validation of the radiosynthesis, assessment of preclinical toxicity, and radiation dosimetry. Methods: The production of [18F]MC225 was automated on a CFN-MPS200 multipurpose synthesizer. The acute toxicity of MC225 was evaluated at a dose of 2.5 mg/kg bodyweight, which is more than 10,000-fold the postulated maximum clinical dose of [18F]MC225. The acute toxicity of [18F]MC225 injection at a 200-fold dose, to administer a postulated dose of 185 MBq of [18F]MC225, was also evaluated after the decay-out of 18F. The mutagenicity of MC225 was studied by a reverse mutation test using Salmonella typhimurium and Escherichia coli (Ames test). In vivo biodistribution and dosimetry studies of [18F]MC225 were carried out in normal mice. Human dosimetry was estimated using OLINDA software. Results: The mean decay-corrected yields of [18F]MC225 at end of synthesis were 13%, with > 99% radiochemical purity, > 1000 GBq/μmol molar activity, and ≤ 1.5 μg/185 MBq of total chemical contents. All process validation batches complied with the product specifications and the process was confirmed to be appropriate for the production of [18F]MC225. No acute toxicity of MC225 or [18F]MC225 injection was found. No mutagenic activity was observed for MC225. The biodistribution study demonstrated both hepatobiliary and renal excretion of radioactivity. The most critical organ was the pancreas, with (63.8 μGy/MBq) or without urination (63.9 μGy/MBq) at 360 min after injection. The estimated effective dose (μSv/MBq) with and without urination at 360 min after injection was calculated as 15.7 and 16.9, respectively. Conclusion: [18F]MC225 shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [18F]MC225 PET imaging is well within acceptable dose limits. [ABSTRACT FROM AUTHOR]

Background: Pediatric nuclear medicine is evolving, and its practice patterns are uncertain. Knowledge of the current trends in pediatric nuclear medicine might be helpful to direct local decisions, including expectations for patient care, needs for capital acquisitions, and staffing recruitment strategies.Objective: To provide data regarding the current practice of pediatric nuclear medicine via a Society for Pediatric Radiology (SPR) membership survey.Materials and Methods: The SPR emailed our 25-question survey to all 1,847 SPR members in August 2018 and we accepted responses until April 2019. Questions focused on nuclear medicine staffing, positron emission tomography (PET) utilization, and radiotherapy availability. Respondents could indicate their affiliated hospital, which we used for data cataloguing only. Analysis of survey responses was blinded to reported institution. We analyzed response data using contingency tables. Independence testing between categorical variables based on proportions of physicians with additional nuclear medicine board certification was performed on a subset of questions regarding PET and therapy practices.Results: Sixty-seven people from at least 29 hospitals responded to the survey, including all 10 of the 2018-2019 U.S. News & World Report best children's hospitals. The majority (48/67, 71.6%) of respondents indicated that pediatric nuclear medicine examinations were interpreted in the pediatric radiology department by pediatric radiologists and that most physicians interpreting the exams (43/67, 64.2%) did not have subspecialty certification in nuclear medicine or nuclear radiology. Most facilities offered PET/CT (57/67, 85.1%); few offered PET/MRI (12/67, 17.9%). Most facilities offered radiotherapies (57/67, 85.1%) but at most of these facilities (30/57, 52.6%), fewer than half the physicians who cover nuclear medicine were approved to administer therapies. In the subset analyses based on proportion of physicians with additional nuclear medicine board certification, there were statistically significant differences between the groups in availability of PET/MRI, lutetium-177 dotatate therapy programs, and percentages of physicians approved to administer therapies.Conclusion: Pediatric nuclear medicine is largely practiced by pediatric radiologists without subspecialty certification. Staffing, PET practices and therapies vary among practices, in part associated with the number of radiologists with nuclear medicine board certification. [ABSTRACT FROM AUTHOR]

Background: Hybrid PET/MRI can non-invasively improve localization and delineation of the epileptic focus (EF) prior to surgical resection in medically refractory epilepsy (MRE), especially when MRI is negative or equivocal. In this study, we developed a PET-guided diffusion tractography (PET/DTI) approach combining 18F-fluorodeoxyglucose PET (FDG-PET) and diffusion MRI to investigate white matter (WM) integrity in MRI-negative MRE patients and its potential impact on epilepsy surgical planning. Methods: FDG-PET and diffusion MRI of 14 MRI-negative or equivocal MRE patients were used to retrospectively pilot the PET/DTI approach. We used asymmetry index (AI) mapping of FDG-PET to detect the EF as brain areas showing the largest decrease in FDG uptake between hemispheres. Seed-based WM fiber tracking was performed on DTI images with a seed location in WM 3 mm from the EF. Fiber tractography was repeated in the contralateral brain region (opposite to EF), which served as a control for this study. WM fibers were quantified by calculating the fiber count, mean fractional anisotropy (FA), mean fiber length, and mean cross-section of each fiber bundle. WM integrity was assessed through fiber visualization and by normalizing ipsilateral fiber measurements to contralateral fiber measurements. The added value of PET/DTI in clinical decision-making was evaluated by a senior neurologist. Results: In over 60% of the patient cohort, AI mapping findings were concordant with clinical reports on seizure-onset localization and lateralization. Mean FA, fiber count, and mean fiber length were decreased in 14/14 (100%), 13/14 (93%), and 12/14 (86%) patients, respectively. PET/DTI improved diagnostic confidence in 10/14 (71%) patients and indicated that surgical candidacy be reassessed in 3/6 (50%) patients who had not undergone surgery. Conclusions: We demonstrate here the utility of AI mapping in detecting the EF based on brain regions showing decreased FDG-PET activity and, when coupled with DTI, could be a powerful tool for detecting EF and assessing WM integrity in MRI-negative epilepsy. PET/DTI could be used to further enhance clinical decision-making in epilepsy surgery. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Epileptologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We respond to a recent call to action for the Pregnancy Risk Assessment Monitoring System (PRAMS) to include a "core" question or validated measure on discrimination to allow for systematic assessment of the impact of racial discrimination on adverse birth outcomes among a large population-based sample in the United States. We outline activities of the CDC PRAMS project that relate to this call to action. [ABSTRACT FROM AUTHOR]

Background: The Paris Climate Agreement requires a rapid and efficient shift to renewable energies and a decarbonization of the energy system. Combined heat and power provision from biomass is one way to efficiently provide renewable heat. Despite this, many bioenergy plants in Germany are mainly used to generate electricity and the provision of externally usable heat still has untapped potential. In this study, we investigated gross quantities as well as the economically viable potential of Germany's current bioenergy plant stock in supplying renewable heat. Methods: We used a top-down GIS modeling approach to spatially and explicitly assess the heat demand of three different categories of heat sinks at sub-municipal level. These included residential, commercial, and industrial areas, as well as large individual heat consumers. We then calculated the plant-specific heat sales potential for two different district heating network options. In addition, we developed a method for assessing the economic efficiency of the previously identified technical heat sales volume for a set of 20 different clusters of bioenergy plants. Results: The results show that about 50% of the bioenergy plants have potential heat consumers in their immediate proximity. The overall technical heat sales potential for all three categories totals around 150 TWhth/a. However, this potential is not evenly distributed throughout Germany. Certain regions appear to be more favorable for investing in district heating networks powered by heat from biomass. The economically viable heat sales potential related to electrical energy generation ranges from − 0.128 to 0.160 €/kWhth. Conclusion: We concluded that, under certain conditions such as location or supply and demand structure, German bioenergy plants have the potential to provide a significant share to renewable energies in the heating sector. In addition, the heat sales potential is highly relevant for plant operators as the importance of heat as a business segment is set to increase. Furthermore, bioenergy plants could contribute 2.1% (16.3 TWhth/a) to the total demand for space heating in Germany (765 TWhth/a) when considering certain technical and economic constraints. [ABSTRACT FROM AUTHOR]

Aims: To examine the strength of evidence available for multiple facet joint injections (FJIs) and medial branch blocks (MBBs), and to report on the variations in the NHS England framework using the getting it right first time (GIRFT) data.Methods: Systematic review using patient, intervention, comparison, outcome and study strategy. The literature search using Cochrane, MEDLINE and EMBASE databases using MeSH terms: lumbar spine, spinal injection and facet joint ("Appendix A").Results: Three studies were identified that investigated the efficacy of multiple FJIs or MBBs. None of these studies reported sustained positive outcomes at long-term follow-up.Conclusion: There is a paucity of levels I and II evidence available for the efficacy of multiple FJIs and MBBs in treating low back pain. GIRFT data show a high degree of variation in the use of multiple FJIs, which would not be supported by the literature. These slides can be retrieved under Electronic Supplementary Material. [ABSTRACT FROM AUTHOR]

Copyright of Gruppe. Interaktion. Organisation: Zeitschrift für Angewandte Organisationspsychologie (GIO) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Production of the anticancer drug Taxol and its precursors in heterologous hosts is more sustainable than extraction from tissues of yew trees or chemical synthesis. Although attempts to engineer the Taxol pathway in microbes have made significant progress, challenges such as functional expression of plant P450 enzymes remain to be addressed. Here, we introduce taxadiene synthase, taxadiene-5α-hydroxylase, and cytochrome P450 reductase in a high biomass plant Nicotiana benthamiana. Using a chloroplastic compartmentalized metabolic engineering strategy, combined with enhancement of isoprenoid precursors, we show that the engineered plants can produce taxadiene and taxadiene-5α-ol, the committed taxol intermediates, at 56.6 μg g−1 FW and 1.3 μg g−1 FW, respectively. In addition to the tools and strategies reported here, this study highlights the potential of Nicotiana spp. as an alternative platform for Taxol production. Engineering Taxol pathway in microbes needs to overcome the difficulty of expressing plant P450 enzymes. Here, the authors use a compartmentalized metabolic engineering strategy to construct the taxanes production pathway in chloroplasts of Nicotiana benthamiana and realize the production of taxadience-5α-ol. [ABSTRACT FROM AUTHOR]

In recent years, more than half of the household PV systems in Germany were installed with battery storage systems to self-consume a higher share of the electricity produced. This development will have a large impact on the share of energy purchased from the electricity grid and this, in turn, will affect the distribution of the cost components of the household electricity price. This contribution therefore analyzes the impacts of increasing self-generation and self-consumption on the electricity price components. To obtain the nation-wide self-consumption potential, the results of a techno-economic optimization model on household system level are scaled up to all (semi-) detached houses in Germany. The additional PV feed-in remuneration and lacking contributions to the different taxes and levies are reallocated to the (remaining) electricity consumption from the grid. Changes in the regulatory framework, such as the abolishment of feed-in tariffs, a self-consumption charge, and different allocation schemes for the grid charges, are examined. The results indicate that under the current regulatory framework conditions, less than one third of the potential electricity price increase stems from self-consumption, while remuneration through feed-in tariffs has a much higher impact. Furthermore, the effects of self-consumption on the electricity price seem to be higher with capacity-based grid charges, because the contributions of PV storage owners to the grid charges are reduced through peak shaving with battery storage systems. Our findings also show that policy makers can strongly influence PV feed-in and self-consumption levels, as well as the resulting electricity price. [ABSTRACT FROM AUTHOR]

Purpose: FDG PET is an established tool in presurgical epilepsy evaluation, but it is most often used selectively in patients with discordant MRI and EEG results. Interpretation is complicated by the presence of remote or multiple areas of hypometabolism, which leads to doubt as to the true location of the seizure onset zone (SOZ) and might have implications for predicting the surgical outcome. In the current study, we determined the sensitivity and specificity of PET localization prospectively in a consecutive unselected cohort of patients with focal epilepsy undergoing in-depth presurgical evaluation. Methods: A total of 130 patients who underwent PET imaging between 2006 and 2015 matched our inclusion criteria, and of these, 86 were operated on (72% with a favourable surgical outcome, Engel class I). Areas of focal hypometabolism were identified using statistical parametric mapping and concordance with MRI, EEG and intracranial EEG was evaluated. In the surgically treated patients, postsurgical outcome was used as the gold standard for correctness of localization (minimum follow-up 12 months). Results: PET sensitivity and specificity were both 95% in 86 patients with temporal lobe epilepsy (TLE) and 80% and 95%, respectively, in 44 patients with extratemporal epilepsy (ETLE). Significant extratemporal hypometabolism was observed in 17 TLE patients (20%). Temporal hypometabolism was observed in eight ETLE patients (18%). Among the 86 surgically treated patients, 26 (30%) had hypometabolism extending beyond the SOZ. The presence of unilobar hypometabolism, included in the resection, was predictive of complete seizure control (p = 0.007), with an odds ratio of 5.4. Conclusion: Additional hypometabolic areas were found in one of five of this group of nonselected patients with focal epilepsy, including patients with "simple" lesional epilepsy, and this finding should prompt further in-depth evaluation of the correlation between EEG findings, semiology and PET. Hypometabolism confined to the epileptogenic zone as defined by EEG and MRI is associated with a favourable postoperative outcome in both TLE and ETLE patients. [ABSTRACT FROM AUTHOR]

Despite numerous studies reporting endophytic fungal production of metabolites chemically similar to the secondary metabolites produced by their host plants, how and why the fungi produce these metabolites remain largely unknown. Here, we review the literature on endophytic fungal production of taxol and camptothecin, two extensively studied plant secondary metabolites, and highlight critical gaps in our knowledge that need to be addressed to adequately answer the above questions. We show that detailed studies are required for conclusive demonstration of i) the production of these metabolites by the fungi, ii) the tolerance of the fungi to the produced cytotoxic metabolites, and iii) the adaptive significance of the metabolite production to the fungi. Although our focus is on two widely studied plant secondary metabolites produced by fungi, the questions addressed here are equally applicable to the production of a large number of other fungal metabolites that are similar to those produced by their host plants. [ABSTRACT FROM AUTHOR]

Main conclusions: Eukaryotic microalgae hold incredible metabolic potential for the sustainable production of heterologous isoprenoid products. Recent advances in algal engineering have enabled the demonstration of prominent examples of heterologous isoprenoid production.Isoprenoids, also known as terpenes or terpenoids, are the largest class of natural chemicals, with a vast diversity of structures and biological roles. Some have high-value in human-use applications, although may be found in their native contexts in low abundance or be difficult to extract and purify. Heterologous production of isoprenoid compounds in heterotrophic microbial hosts such as bacteria or yeasts has been an active area of research for some time and is now a mature technology. Eukaryotic microalgae represent sustainable alternatives to these hosts for biotechnological production processes as their cultivation can be driven by light and freely available CO2 as a carbon source. Their photosynthetic lifestyles require metabolic architectures structured towards the generation of associated isoprenoids (carotenoids, phytol) which participate in photon capture, energy dissipation, and electron transfer. Eukaryotic microalgae should, therefore, contain inherently high capacities for the generation of heterologous isoprenoid products. Although engineering strategies in eukaryotic microalgae have lagged behind the more genetically tractable bacteria and yeasts, recent advances in algal engineering concepts have demonstrated prominent examples of light-driven heterologous isoprenoid production from these photosynthetic hosts. This work seeks to provide practical insights into the choice of eukaryotic microalgae as biotechnological chassis. Recent reports of advances in algal engineering for heterologous isoprenoid production are highlighted as encouraging examples that promote their expanded use as sustainable green-cell factories. Current state of the art, limitations, and future challenges are also discussed.Graphical abstract: [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease with variable etiology and clinical manifestation, affecting more than 50 million people worldwide. Although the ultimate precipitators of seizures are neurons, it is becoming evident that epileptic activity is associated with changes in the function of other cell types, including those consisting the blood-brain barrier (BBB) and regulating its permeability. The interrelationships between impaired BBB function and epilepsy are complex, as BBB dysfunction may both lead to seizures and be induced by epileptic activity. In this article, we review alterations in key BBB properties that have been found in patients with epilepsy and in animal models of the disease. We highlight emerging biomarkers for individualized treatment, implications for pharmacotherapy, and potential BBB-related targets for drug development. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin. Non-responders were treated for 4 weeks with vehicle only or with the mTOR pathway inhibitor rapamycin at doses of 1, 3, and 6 mg/kg. Western blotting and immunohistochemistry were used to detect the expression of phospho-S6 (P-S6) and P-gp at different time points (1 h, 8 h, 1 day, 3 days, 1 weeks, 2 weeks, and 4 weeks) after the onset of treatment. Overexpression of P-S6 and P-gp was detected in both refractory mTLE patients and non-responder rats. Rapamycin showed an inhibitory effect on P-S6 and P-gp expression 1 week after treatment in rats. In addition, the expression levels of P-S6 and P-gp in the 6 mg/kg group were significantly lower than those in the 1 mg/kg or the 3 mg/kg group at the same time points (all P < 0.05). Moreover, rapamycin decreased the duration and number of CL-induced seizures, as well as the stage of non-responders (all P < 0.05). The current study indicates that the mTOR signaling pathway plays a critical role in P-gp expression in drug-resistant epilepsy. Inhibition of the mTOR pathway by rapamycin may be a potential therapeutic approach for pharmacoresistant epilepsy. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a neuroimaging method that offers insights into the molecular functioning of a human brain. It has been widely used to study metabolic and neurotransmitter abnormalities in people with epilepsy. This article reviews the development of several PET radioligands and their application in studying the molecular mechanisms of epilepsy. Over the last decade, tracers binding to serotonin and γ-aminobutyric acid (GABA) receptors have been used to delineate the location of the epileptic focus. PET studies have examined the role of opioids, cannabinoids, acetylcholine, and dopamine in modulating neuronal hyperexcitability and seizure termination. In vivo analyses of drug transporters, e.g., P-glycoprotein, have increased our understanding of pharmacoresistance that could inform new therapeutic strategies. Finally, PET experiments targeting neuroinflammation and glutamate receptors might guide the development of novel biomarkers of epileptogenesis. [ABSTRACT FROM AUTHOR]

Several relevant animal models of epileptogenesis and biomarkers have emerged for evaluating the antiepileptogenic potential of an investigational drug. Although several promising candidate compounds and approaches have been identified in these preclinical models, no treatment has yet successfully navigated the path from preclinical efficacy to clinical validation. Until such an agent can move from preclinical proof of concept to clinical success, the need remains to continually develop and optimize preclinical models and clinical trial design in an effort to guide potential clinical investigations. This review describes several available models of disease modification and/or epileptogenesis, preclinical studies in these models and potential biomarkers useful for evaluating the efficacy of a potential therapeutic agent in the preclinical setting. The results that emerge from such efforts may then guide the clinical evaluation of a candidate compound. This review discusses some of the known limitations and hurdles to moving compounds found effective in these models to clinical practice, in the hope that knowledge of this information will facilitate the design and conduct of clinical studies and effectively facilitate the identification of a first-in-class disease-modifying or antiepileptogenic agent. [ABSTRACT FROM AUTHOR]