The role of artificial intelligence in coronary CT angiography.

Coronary CT angiography (CCTA) offers an efficient and reliable tool for the non-invasive assessment of suspected coronary artery disease through the analysis of coronary artery plaque and stenosis. However, the detailed manual analysis of CCTA is a burdensome task requiring highly skilled experts. Recent advances in artificial intelligence (AI) have made significant progress toward a more comprehensive automated analysis of CCTA images, offering potential improvements in terms of speed, performance and scalability. This work offers an overview of the recent developments of AI in CCTA. We cover methodological advances for coronary artery tree and whole heart analysis, and provide an overview of AI techniques that have shown to be valuable for the analysis of cardiac anatomy and pathology in CCTA. Finally, we provide a general discussion regarding current challenges and limitations, and discuss prospects for future research.

Platform Reagents Enable Synthesis of Ligand-Directed Covalent Probes: Study of Cannabinoid Receptor 2 in Live Cells.

Pharmacological modulation of cannabinoid receptor type 2 (CB2R) holds promise for the treatment of neuroinflammatory disorders, such as Alzheimer's disease. Despite the importance of CB2R, its expression and downstream signaling are insufficiently understood in disease- and tissue-specific contexts. Herein, we report the first ligand-directed covalent (LDC) labeling of CB2R enabled by a novel synthetic strategy and application of platform reagents. The LDC modification allows visualization and study of CB2R while maintaining its ability to bind other ligands at the orthosteric site. We employed in silico docking and molecular dynamics simulations to guide probe design and assess the feasibility of LDC labeling of CB2R. We demonstrate selective, covalent labeling of a peripheral lysine residue of CB2R by exploiting fluorogenic O-nitrobenzoxadiazole (O-NBD)-functionalized probes in a TR-FRET assay. The rapid proof-of-concept validation with O-NBD probes inspired incorporation of advanced electrophiles suitable for experiments in live cells. To this end, novel synthetic strategies toward N-sulfonyl pyridone (N-SP) and N-acyl-N-alkyl sulfonamide (NASA) LDC probes were developed, which allowed covalent delivery of fluorophores suitable for cellular studies. The LDC probes were characterized by a radioligand binding assay and TR-FRET experiments. Additionally, the probes were applied to specifically visualize CB2R in conventional and imaging flow cytometry as well as in confocal fluorescence microscopy using overexpressing and endogenously expressing microglial live cells.

The influence of dispersal on a predator-prey system with two habitats.

Dispersal between different habitats influences the dynamics and stability of populations considerably. Furthermore, these effects depend on the local interactions of a population with other species. Here, we perform a general and comprehensive study of the simplest possible system that includes dispersal and local interactions, namely a 2-patch 2-species system. We evaluate the impact of dispersal on stability and on the occurrence of bifurcations, including pattern forming bifurcations that lead to spatial heterogeneity, in 19 different classes of models with the help of the generalized modelling approach. We find that dispersal often destabilizes equilibria, but it can stabilize them if it increases population losses. If dispersal is nonrandom, i.e. if emigration or immigration rates depend on population densities, the correlation of stability with dispersal rates is positive in part of the models. We also find that many systems show all four types of bifurcations and that antisynchronous oscillations occur mostly with nonrandom dispersal.

Automatic Coronary Artery Plaque Quantification and CAD-RADS Prediction Using Mesh Priors.

Coronary artery disease (CAD) remains the leading cause of death worldwide. Patients with suspected CAD undergo coronary CT angiography (CCTA) to evaluate the risk of cardiovascular events and determine the treatment. Clinical analysis of coronary arteries in CCTA comprises the identification of atherosclerotic plaque, as well as the grading of any coronary artery stenosis typically obtained through the CAD-Reporting and Data System (CAD-RADS). This requires analysis of the coronary lumen and plaque. While voxel-wise segmentation is a commonly used approach in various segmentation tasks, it does not guarantee topologically plausible shapes. To address this, in this work, we propose to directly infer surface meshes for coronary artery lumen and plaque based on a centerline prior and use it in the downstream task of CAD-RADS scoring. The method is developed and evaluated using a total of 2407 CCTA scans. Our method achieved lesion-wise volume intraclass correlation coefficients of 0.98, 0.79, and 0.85 for calcified, non-calcified, and total plaque volume respectively. Patient-level CAD-RADS categorization was evaluated on a representative hold-out test set of 300 scans, for which the achieved linearly weighted kappa ( κ ) was 0.75. CAD-RADS categorization on the set of 658 scans from another hospital and scanner led to a κ of 0.71. The results demonstrate that direct inference of coronary artery meshes for lumen and plaque is feasible, and allows for the automated prediction of routinely performed CAD-RADS categorization.

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists.

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structure-based design of cannabinoid receptor type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity for CB2R with Kd = 39.1 nM and serves as a platform for the synthesis of a wide variety of probes. Notably, for the first time these fluorescent probes retain their inverse agonist functionality, high affinity, and selectivity for CB2R independent of linker and fluorophore substitution. Ligands (S)-1, (R)-1, and their derivatives act as inverse agonists in CB2R-mediated cAMP as well as G protein recruitment assays and do not trigger ß-arrestin-receptor association. Furthermore, no receptor activation was detected in live cell ERK1/2 phosphorylation and Ca2+-release assays. Confocal fluorescence imaging experiments with (R)-7 (Alexa488) and (R)-9 (Alexa647) probes employing BV-2 microglial cells visualized CB2R expressed at endogenous levels. Finally, molecular dynamics simulations corroborate the initial docking data in which inverse agonists restrict movement of toggle switch Trp2586.48 and thereby stabilize CB2R in its inactive state.

Spatio-temporal physics-informed learning: A novel approach to CT perfusion analysis in acute ischemic stroke.

CT perfusion imaging is important in the imaging workup of acute ischemic stroke for evaluating affected cerebral tissue. CT perfusion analysis software produces cerebral perfusion maps from commonly noisy spatio-temporal CT perfusion data. High levels of noise can influence the results of CT perfusion analysis, necessitating software tuning. This work proposes a novel approach for CT perfusion analysis that uses physics-informed learning, an optimization framework that is robust to noise. In particular, we propose SPPINN: Spatio-temporal Perfusion Physics-Informed Neural Network and research spatio-temporal physics-informed learning. SPPINN learns implicit neural representations of contrast attenuation in CT perfusion scans using the spatio-temporal coordinates of the data and employs these representations to estimate a continuous representation of the cerebral perfusion parameters. We validate the approach on simulated data to quantify perfusion parameter estimation performance. Furthermore, we apply the method to in-house patient data and the public Ischemic Stroke Lesion Segmentation 2018 benchmark data to assess the correspondence between the perfusion maps and reference standard infarct core segmentations. Our method achieves accurate perfusion parameter estimates even with high noise levels and differentiates healthy tissue from infarcted tissue. Moreover, SPPINN perfusion maps accurately correspond with reference standard infarct core segmentations. Hence, we show that using spatio-temporal physics-informed learning for cerebral perfusion estimation is accurate, even in noisy CT perfusion data. The code for this work is available at https://github.com/lucasdevries/SPPINN.

Physics-informed neural networks for myocardial perfusion MRI quantification.

Tracer-kinetic models allow for the quantification of kinetic parameters such as blood flow from dynamic contrast-enhanced magnetic resonance (MR) images. Fitting the observed data with multi-compartment exchange models is desirable, as they are physiologically plausible and resolve directly for blood flow and microvascular function. However, the reliability of model fitting is limited by the low signal-to-noise ratio, temporal resolution, and acquisition length. This may result in inaccurate parameter estimates. This study introduces physics-informed neural networks (PINNs) as a means to perform myocardial perfusion MR quantification, which provides a versatile scheme for the inference of kinetic parameters. These neural networks can be trained to fit the observed perfusion MR data while respecting the underlying physical conservation laws described by a multi-compartment exchange model. Here, we provide a framework for the implementation of PINNs in myocardial perfusion MR. The approach is validated both in silico and in vivo. In the in silico study, an overall decrease in mean-squared error with the ground-truth parameters was observed compared to a standard non-linear least squares fitting approach. The in vivo study demonstrates that the method produces parameter values comparable to those previously found in literature, as well as providing parameter maps which match the clinical diagnosis of patients.

Endocrine correlates of acute nausea and vomiting.

This paper gives an overview of studies investigating endocrine changes in acute nausea and vomiting. The aetiology of nausea and vomiting is not fully understood, but it has been shown that different stress hormones are released into circulation during motion sickness. Studies with animals and humans have shown that acute nausea activates the hypothalamo-pituitary-adrenal axis and the neurohypophyseal system. So-called stress hormones, like adrenocorticotropic hormone, cortisol, and antidiuretic hormone, are released concomitant with nausea and vomiting in motion sickness, but do not seem to be involved in the aetiology of motion sickness. Nevertheless, plasma levels of stress hormones more or less correlate to the intensity of nausea related symptoms. Although gastroenteropancreatic hormones are involved in gastrointestinal motility, there are only few data describing their changes in response to acute nausea or vomiting.

Kidney transplantation across positive B and T cell crossmatches.

Cadaveric renal transplants were performed despite a positive conventional crossmatch (usually intermediate positive) resulting from donor-specific B cell lymphocytotoxins (both IgG and IgM) or IgM cold-reactive T cell lymphocytotoxins. Graft survival at 2 months was 72% in the 14 patients with B cell-specific antibodies and 71% in the 7 recipients with T cell antibodies. No correlation was observed between graft rejection and warm (mainly IgG) or cold (IgM) B cell-specific antibodies. These results indicate that not all positive crossmatches are a contraindication to transplantation. Attempts should be made to study the nature of the lymphocytotoxins before withholding the allograft from the recipient.

Wound infections in renal transplant recipients--a complication of urinary tract infections during allograft malfunction.

Both wound and urinary tract infections are common in renal transplant recipients. Certain recipients, however, develop detrimental complications following such infections, and our aim was to analyze factors that predisposed recipients to such complications. Analysis of 174 consecutive transplants performed over a 7-year period ending December 1980 demonstrated that a urinary infection developing during acute tubular malfunction (ATM) led to serious septic complications. The complication rate was 70% in the 30 recipients in whom urinary tract infection occurred during ATM but only 10% in the 20 recipients with infection in the absence of ATM (P less than 0.001). Similarly, analysis of 14 deep wound infections showed that the source of the organisms was the urinary tract (12 cases), especially when the urinary tract infection occurred in the setting of ATM. Deep injections led to high rates of morbidity and mortality. Conversely, superficial wound infections (10 cases) contained staphylococci and healed without complications. We suggest that urinary tract organisms, which are difficult to eradicate with antibiotics because of low urinary concentration of antibiotics during ATM, lead to infection of the perirenal tissues.

Abdominal pain. An analysis of 1,000 consecutive cases in a University Hospital emergency room.

In the majority of patients in this series of 1,000, acute abdominal pain was due to conditions that required neither surgical intervention nor hospitalization. Eleven of the 1,000 patients had an early missed diagnosis in the emergency clinic for which a subsequent operation was needed, and twenty underwent an operation which subsequent diagnosis showed was not required. All false-negative evaluations occurred in patients with early appendicitis or small bowel obstruction. Most false-positive results were due to acute infections of the female genitourinary tract in patients operated on to exclude appendicitis or a tubo-ovarian abscess. The following factors help identify the high risk patient with an acute surgical abdomen: (1) pain for less than 48 hours; (2) pain followed by vomiting; (3) guarding and rebound tenderness on physical examination; (4) advanced age; (5) a prior surgical procedure. The presence of these features demands careful evaluation and a liberal policy of admission and observation. White blood cell counts, body temperature, and abnormal abdominal roentgenograms may add confirmatory evidence but are not particularly helpful as screening devices.

New anti-MRSA and anti-VRE carbapenems; synthesis and structure-activity relationships of 1beta-methyl-2-(thiazol-2-ylthio)carbapenems.

Discovery of novel antimicrobial agents effective against infections caused by drug-resistant pathogens is an important objective. In order to find a new parenteral carbapenem antibiotic, which has potent antibacterial activity especially against methicillin-resistant staphylococci, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, a series of 1beta-methylcarbapenems with thiazol-2-ylthio groups at the C-2 position have been synthesized. Structure-activity relationships were investigated which led to SM-197436 (27), SM-232721 (44) and SM-232724 (41), being selected for further evaluation.

Therapeutic embolization for delayed rectal hemorrhage following episiotomy: a case report.

A case of severe, delayed rectal bleeding following an episiotomy was treated with selective pelvic arteriography and embolization after surgery failed to control the hemorrhage.

Nymphal diapause and its photoperiodic control in the tick Ixodes scapularis (Acari: Ixodidae).

It is shown experimentally that the option between developmental diapause and non-diapause development in nymphs of Ixodes scapularis Say, 1821 (Middle Atlantic population) is determined by photoperiodic conditions according to a two-step photoperiodic reaction of short-day long-day type. Diapause arrest of development is induced by an impact of either long day upon unfed nymphs, or short day upon engorged nymphs, while non-diapause development completed in 2-2.5 months at 20 degrees C needs the change from short-day to long-day conditions. Some ecophysiological aspects of mechanisms controlling seasonal development of ticks belonging to Ixodes ricinus complex are discussed.

Influence of microgravity on plasma levels of gastroenteropancreatic peptides: a case study.

BACKGROUND: No data are available about the short- or long-term influences of microgravity in space on the release of gastroenteropancreatic peptides, although these peptides are involved in the regulation of gastrointestinal functions. METHODS: Fasting plasma samples were gained during the EUROMIR-94 mission from a European Space Agency (ESA) astronaut who experienced no signs of space motion sickness in orbit. Plasma concentrations of nine gastroenteropancreatic peptides were measured with sensitive and specific radioimmunoassays. RESULTS: Fasting plasma levels of motilin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), and secretin were increased and plasma level of cholecystokinin (CCK) was decreased by acute exposure of the astronaut to microgravity. Chronic (4 wk) exposure caused an enhancement of plasma CCK, motilin, neurotensin, VIP, and insulin whereas plasma concentrations of PP, secretin, gastrin, and somatostatin showed no changes. During the 25-d stay on MIR station plasma levels of CCK, motilin, and neurotensin increased. Short-time body rotations caused an elevation of plasma levels of PP but decreased plasma motilin. CONCLUSIONS: As the influence of microgravity on the peptide levels was not uniform, an effect due to other factors (e.g., change in fluid balance or body weight) is unlikely. Moreover, adaptive changes of some peptides occurred during the stay in orbit. The release of PP and motilin seems to be very sensitive to rotation forces. These results have to be confirmed in more subjects in space to be able to link changes of gastroenteropancreatic peptide release to alterations of gastrointestinal functions.

Cholecystokinin revisited: CCK and the hunger trap in anorexia nervosa.

OBJECTIVE: Despite a number of studies in the past decades, the role of Cholecystokinin (CCK) in anorexia nervosa (AN) has remained uncertain. In this study a highly specific assay for the biologically active part of CCK was used in patients with bulimic as well as with the restricting type of AN who were followed over the course of weight gain. METHODS: Ten patients with restricting and 13 with bulimic AN were investigated upon admission (T0), after a weight gain of at least 2 kg on two consecutive weighting dates (T1), and during the last week before discharge (T2) from inpatient treatment in a specialized clinic. Blood samples were drawn under fasting conditions and 20 and 60 minutes following a standard meal (250 kcal). Data were compared to those of eight controls matched for sex and age. Gastrointestinal complaints of patients were measured by a questionnaire at each of the follow-up time points. RESULTS: At admission, AN patients exhibited CCK-levels similar to controls both prior to and after a test meal. Pre and post-meal CCK levels increased significantly after an initial weight gain but decreased again with further weight improvement. CCK release was somewhat lower in bulimic than in restricting type AN but both subgroups showed a similar profile. There was no significant association of CCK release to either initial weight or BMI, or their changes, but CCK levels at admission predicted gastrointestinal symptom improvement during therapy. CONCLUSIONS: Normal CCK profiles in AN at admission indicates hormonal responses adapted to low food intake while change of eating habits and weight gain results in initially increased CCK release (counteracting the attempts to alter eating behavior) that returns towards normal levels with continuous therapy.

Influence of acute exposure to high altitude on basal and postprandial plasma levels of gastroenteropancreatic peptides.

Acute mountain sickness (AMS) is characterized by headache often accompanied by gastrointestinal complaints that vary from anorexia through nausea to vomiting. The aim of this study was to investigate the influence of high altitude on plasma levels of gastroenteropancreatic (GEP) peptides and their association to AMS symptoms. Plasma levels of 6 GEP peptides were measured by radioimmunoassay in 11 subjects at 490 m (Munich, Germany) and, after rapid passive ascent to 3454 m (Jungfraujoch, Switzerland), over the course of three days. In a second study (n = 5), the same peptides and ghrelin were measured in subjects who consumed standardized liquid meals at these two elevations. AMS symptoms and oxygen saturation were monitored. In the first study, both fasting (morning 8 a.m.) and stimulated (evening 8 p.m.) plasma levels of pancreatic polypeptide (PP) and cholecystokinin (CCK) were significantly lower at high altitude as compared to baseline, whereas gastrin and motilin concentrations were significantly increased. Fasting plasma neurotensin was significantly enhanced whereas stimulated levels were reduced. Both fasting and stimulated plasma motilin levels correlated with gastrointestinal symptom severity (r = 0.294, p = 0.05, and r = 0.41, p = 0.006, respectively). Mean O(2)-saturation dropped from 96% to 88% at high altitude. In the second study, meal-stimulated integrated (= area under curve) plasma CCK, PP, and neurotensin values were significantly suppressed at high altitude, whereas integrated levels of gastrin were increased and integrated VIP and ghrelin levels were unchanged. In summary, our data show that acute exposure to a hypobaric hypoxic environment causes significant changes in fasting and stimulated plasma levels of GEP peptides over consecutive days and after a standardized meal. The changes of peptide levels were not uniform. Based on the inhibition of PP and neurotensin release a reduction of the cholinergic tone can be postulated.

Anti-infective strategies of the future: is there room for species-specific antibacterial agents?

Broad-spectrum antibiotics, directed against conserved bacterial targets, are the mainstay of antibacterial therapy. Increasing resistance, however, demands new strategies. Over time a number of therapeutic concepts have evolved, starting out with the use of polyclonal antisera, which were rapidly replaced by the easier to use antibiotics. Other concepts, such as immunotherapy, radioimmunotherapy, anti-virulence agents, phage therapy and others are under evaluation and often limited in application. In the discovery process of new antibiotics in the pharmaceutical industry quite a number of new agents have emerged, which exhibit a surprisingly high degree of species-specificity. None of them has been considered for development so far. Some examples from the literature which show selectivity for Helicobacter pylori, Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, anaerobes, and others, will be discussed here. It is postulated that there is a room for such agents in future antibacterial therapy, e.g. in difficult to treat infections caused by nonfermenters such as multiresistant P. aerugoinosa, Acinetobacter, Enterobacteriaceae, and S.aureus, including MRSA. Their application would include monotherapy as well as combination therapy with other antibiotics, anti-virulence agents or immunotherapy and these possibilities would greatly expand the current anti-infective armamentarium.

Cultivation and quantitative proteomic analyses of acidophilic microbial communities.

Acid mine drainage (AMD), an extreme environment characterized by low pH and high metal concentrations, can support dense acidophilic microbial biofilm communities that rely on chemoautotrophic production based on iron oxidation. Field determined production rates indicate that, despite the extreme conditions, these communities are sufficiently well adapted to their habitats to achieve primary production rates comparable to those of microbial communities occurring in some non-extreme environments. To enable laboratory studies of growth, production and ecology of AMD microbial communities, a culturing system was designed to reproduce natural biofilms, including organisms recalcitrant to cultivation. A comprehensive metabolic labeling-based quantitative proteomic analysis was used to verify that natural and laboratory communities were comparable at the functional level. Results confirmed that the composition and core metabolic activities of laboratory-grown communities were similar to a natural community, including the presence of active, low abundance bacteria and archaea that have not yet been isolated. However, laboratory growth rates were slow compared with natural communities, and this correlated with increased abundance of stress response proteins for the dominant bacteria in laboratory communities. Modification of cultivation conditions reduced the abundance of stress response proteins and increased laboratory community growth rates. The research presented here represents the first description of the application of a metabolic labeling-based quantitative proteomic analysis at the community level and resulted in a model microbial community system ideal for testing physiological and ecological hypotheses.