Acta Neurochirurgica

JEDI (jugular entrapment, dilated ventricles, intracranial hypertension) syndrome: a new clinical entity? A case report Abstract Patients with idiopathic intracranial hypertension are frequently obese women with normal/slit ventricles. Patients with high-pressure hydrocephalus, instead, present enlarged ventricles. We describe a 63-year-old woman with signs and symptoms of intracranial hypertension. Brain MRI revealed hydrocephalus. Venous Doppler ultrasound showed external compression of the omohyoid muscles on the internal jugular veins. During jugular vein decompression, intracranial pressure dropped from 18 to 6 mmHg. Patient is asymptomatic at 2-year follow-up, with decreased brain ventricles. These findings could represent a novel form of high-pressure hydrocephalus that can be successfully treated without a CSF shunt. We called this syndrome JEDI (jugular entrapment dilated ventricles intracranial hypertension).

Thromboembolic infarction caused by an unknown patent foramen ovale 30 years after VA shunt insertion: a case report and review of the literature Abstract Background Ventriculoatrial shunt (VA) insertion is one of the possible surgical procedures to treat hydrocephalus. However, it is also associated with several complications such as obstruction and shunt infection as well as life-threatening complications like intraatrial thrombus or thrombosis on the distal catheter. In this case report, we share a rare case of a patient with a VA shunt, who was admitted to our hospital with a stroke. Case description A 56-year-old female patient with suspected acute stroke was admitted to the stroke unit. CT and MRI scans showed multiple cerebral infarctions in both hemispheres. The transesophageal echocardiography (TEE) showed at the tip of the VA shunt catheter, which was implanted about 30 years ago due to aqueduct stenosis, also a thrombotic formation as the reason of stroke. Interestingly, the tip of the catheter was not in the right atrium as expected, but in the left atrium. Further evaluation showed a patent foramen ovale (PFO), through which the catheter migrated from the right to the left side. At first, conservative treatment with anticoagulation was started with the aim to dissolve the thrombotic formation; however, a control TEE showed an unchanged mass at the catheter tip. Therefore, a ventriculoperitoneal shunt was implanted and the proximal shunt catheter was removed with an additional closure of the PFO by our heart surgeons. Postoperatively, the patient was discharged 10 days later in good condition to a rehabilitation center. Conclusions Thromboembolic events due to a PFO are rare but possible life-threatening complication after VA shunt insertion. Therefore, preoperative cardiac diagnostic might be clinically relevant prior to a VA shunt implantation to avoid such complications.

Fraction of anisotropy and apparent diffusion coefficient as diagnostic tools in trigeminal neuralgia

Diabetes insipidus—an extremely rare complication from replacement of an external ventricular drain Abstract Insertion of an external ventricular drain (EVD) is one of the most common and most important lifesaving procedures encountered in the neurologic intensive care unit, but often done by the junior members of the team. A good number of complications may follow the insertion of EVD. In the available literature, only one case was reported with the placement of EVD in suprasellar cistern. There is no report of insertion or replacement of an EVD in the sella. Diabetes insipidus (DI) is also an unheard of complication of EVD. Here, we report a case where a patient with subarachnoid haemorrhage (SAH) with acute hydrocephalus needed CSF diversion and had an EVD, during replacement of which through the same tract, the new EVD went into the sellar floor and she developed diabetes insipidus (DI) eventually. The catheter was pulled out and the DI settled. DI may occur as a consequence of SAH. The rationale behind reporting this case is to differentiate the cause of DI; as following insertion of EVD in a patient of SAH, the development of DI should raise the suspicion of misplaced EVD, should not be left as a consequence of SAH and appropriate imaging should be obtained. To prevent this happening, preoperative verification of CT, image-guided insertion, measurement of the length of the tubing and careful anchorage of EVD to surrounding tissue are necessary.

Correction to: Ruptured PICA aneurysms: presentation and treatment outcomes compared to other posterior circulation aneurysms. A Swiss SOS study Incorrect authorgroup and authorname.

A rare case of cervical junction ligamentous cyst Abstract Ligamentous cyst is a cystic formation arising from degeneration of ligamentous structures all around the spinal cord. They can cause spinal cord compression, like synovial cyst. Unlike synovial cyst, there is no spinal instability in pathogenesis of ligamentous cyst. Differential diagnosis through pre-operative MRI is difficult and intraoperative findings plus histopathology are crucial to achieve a diagnosis. In this case report, we deal with a rare case of cervical junction ligamentous cyst. A 59-year-old Caucasian female was admitted in our ward with left-sided hemiparesis, cervical pain, and upper limb diffused paresthesias, due to an oval-shaped formation into ALL, of 13 mm in maximum diameter, with peripheral contrast enhancement. The patient underwent, under general anesthesia, a surgery through a posterolateral suboccipital approach which aimed to decompress the spinal cord and to drain the cyst with total removal of the compression by emptying the cyst and fulfilling it with muscle graft and glue. No posterior fixation was needed. After the surgery, symptoms improved and a post-operative MRI scan demonstrated the good result of the surgery.

Delirium in neurosurgery

Progress in Neurological Surgery (Vol. 30–32)Editors: Chernov MF, Muragahi Y, Kesari S, McCutcheon I.E. (2018), ISBN: 978-3-318-06074-4 Karger

How I do it: 3D exoscopic endoscope-assisted microvascular decompression Abstract Background Microvascular decompression (MVD) is an effective treatment for drug-resistant trigeminal neuralgia and hemifacial spasm. However, failure of symptomatic improvement can arise from difficulties in identifying and/or decompressing the offending vessel. Microscopic and endoscopic techniques have been used to improve visualisation and safety of the procedure but there are limitations to each technique. Method A 3D exoscopic endoscope-assisted MVD technique is described, including advice on potential pitfalls. Conclusion Compared with the standard microscope-assisted techniques, the 3D exoscopic endoscope-assisted MVD offers an improved visualisation without compromising the field of view within and outside the surgical field.

Decompressive craniectomy in cerebral venous sinus thrombosis during pregnancy: a case report Abstract Pregnancy and puerperium are risk factors for cerebral venous sinus thrombosis (CVST), a condition which nowadays is treated non-operatively. Decompressive craniectomy is reserved only for emergency settings. We present a 22-year-old pregnant lady, who was transferred at the emergency department with a reduced level of consciousness, headache, and nuchal rigidity. Her MRI study showed CVST, causing hemorrhagic infarct and midline shift. She underwent decompressive craniectomy with partial removal of the hemorrhagic parenchyma. Remarkably, she recovered without any neurological deficits regardless of the substantial temporal lobe damage, while the thrombus nearly resolved using anticoagulation. Decompressive craniectomy can be life-saving in selected CVST patients, followed by anticoagulantion to augment the recanalization process.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Applied Biochemistry and Biotechnology

Author Correction: Drier Climatic Conditions Increase Withanolide Content of Withania coagulans Enhancing its Inhibitory Potential against Human Prostate Cancer Cells The original version of this article unfortunately contained a mistake in the image of Figure 1 and in Table 4. The corrected version of the figure and table is shown here.

Application of Acid and Cold Stresses to Enhance the Production of Clavulanic Acid by Streptomyces clavuligerus Abstract Clavulanic acid (CA) is frequently prescribed for treatment of bacterial infections. Despite the large number of studies concerning CA production, there is still a need to search for more effective and productive processes because it is mainly produced by biochemical route and is chemically unstable. This paper evaluates the influence of acid and cold stresses on CA production by Streptomyces clavuligerus in bench scale stirred tank bioreactor. Four batch cultures were conducted at constant pH (6.8 or 6.3) and temperature (30, 25, or 20 °C) and five batch cultures were performed with application of acid stress (pH reduction from 6.8 to 6.3), cold stress (reduction from 30 to 20 °C), or both. The highest maximum CA concentration (684.4 mg L−1) was obtained in the culture conducted at constant temperature of 20 °C. However, the culture under acid stress, in which the pH was reduced from 6.8 to 6.3 at a rate of 0.1 pH unit every 6 h, provided the most promising result, exhibiting a global yield coefficient of CA relative to cell formation (YCA/X) of 851.1 mgCA gX−1. High YCA/X values indicate that a small number of cells are able to produce a large amount of antibiotic with formation of smaller amounts of side byproducts. This could be especially attractive for decreasing the complexity and cost of the downstream processing, enhancing CA production.

Synthesis and Evaluation of Novel Cholestanoheterocyclic Steroids as Anticancer Agents Abstract Modification of steroid molecules by introducing heterocyclic ring into the core structure of steroids has been utilized as an attractive approach for either cancer prognosis or diagnosis. Several new cholestanoheterocyclic steroids were synthesized, and analytical and spectral data proved the validity of the novel synthesized steroid derivatives. The cytotoxicity of synthesized compounds 3, 4, 5, 7, 9, 10, 13, 15b, and 16b was evaluated using human colorectal cancer HCT 116 and Caco-2, cervical cancer HeLa, hepatoma HepG2, and breast cancer MCF7 cell lines. Intriguingly, compound 13 has the highest cytotoxic effect when applied on the majority of cancer cells. In conclusion, compound 13 may be considered as a promising anticancer candidate against all cancer cell lines, because it recorded the lowest IC50 of the majority of the cancer cell lines used. Furthermore, a molecular docking study was employed to determine the binding modes against aromatase cytochrome P450 (CYP19), cyclin-dependent kinase 2 (CDK2), and B-cell lymphoma (BCL-2) proteins, which are major proteins involved in the pathogenesis of cancer. Molecular docking analyses revealed that compounds 13, 3, and 5 (free energy of binding = − 9.2, − 9.1, and − 9.0 kcal/mol, respectively) were the best docked ligand against aromatase CYP19; compounds 16b, 3, 9, and 10 (free energy of binding = − 9.6, − 9.3, and − 9.2 kcal/mol, respectively) were the best docked ligand against CDK2, while compounds 15b, 16b, and 13 (free energy of binding = − 9.1, − 9.0, and− 8.7 kcal/mol, respectively) were the best docked ligand against BCL2. In conclusion, compounds 3, 13, and 16b were the most promising compounds with the lowest IC50s against most of the tested cancer cell lines, and they displayed the lowest binding energies, critical hydrogen bonds, and hydrophobic interactions with the three molecular targets compared to other tested compounds.

Fabrication and Cytocompatibility Evaluation of Psyllium Husk (Isabgol)/Gelatin Composite Scaffolds Abstract Psyllium husk or isabgol contains xylan backbone linked with arabinose, rhamnose, and galacturonic acid units (arabinoxylans). In this study, we demonstrate the fabrication and characterization of a macroporous three-dimensional (3D) composite scaffold by mixing psyllium husk powder (PH) and gelatin (G) in different ratios, viz.100 PH, 75/25 PH/G, and 50/50 PH/G (w/w), using an EDC-NHS coupling reaction followed by freeze-drying method. The reaction was performed in aqueous as well as in alcoholic media to determine the most appropriate solvent system for this purpose. The mechanical strength of the scaffold system was improved from 151 to 438 kPa. The fabricated scaffolds exhibited enhanced structural stability, remarkable swelling capacity, and escalated cell growth and proliferation. ATR-FTIR analysis showed the presence of amide and ester bonds indicating covalent crosslinking. SEM micrographs revealed the porous nature of the scaffolds with pores ranging from 30 to 150 μm, and further pore size distribution curve indicated that 75/25 PH/G (w/w%) EDC-NHS-alcohol scaffold exhibited the best fit to the Gaussian distribution. Swelling capacity of the 100 PH EDC-NHS-alcohol scaffolds was found to be nearly 40% from its original weight in 48 h. MTT assay using fibroblast cells revealed ~ 80% cellular proliferation by 6th day within the fabricated scaffolds in comparison to control. Graphical Abstract ᅟ

Adsorption Study of Acid Soluble Lignin Removal from Sugarcane Bagasse Hydrolysate by a Self-Synthesized Resin for Lipid Production Abstract An adsorption resin CX-6 was synthesized and used for acid soluble lignin (ASL) removal from sugarcane bagasse hydrolysate (SCBH). The adsorption conditions of pH value, amount of adsorbent, initial ASL concentration, and temperature on ASL adsorption were discussed. The results showed the adsorption capacity of ASL was negatively affected by increasing temperature, solution pH, and adsorbent dose, and was positively affected by increasing initial concentration. The maximum adsorption capacity of ASL was 135.3 mg/g at initial ASL concentration 6.46 g/L, adsorption temperature 298 K, and pH 1. Thermodynamic study demonstrated that the adsorption process was spontaneous and exothermic. Equilibrium and kinetics experiments were proved to fit the Freundlich isotherm model and pseudo-second-order model well, respectively. Fermentation experiment showed that the SCBH after combined overliming with resin adsorption as fermentation substrate for microbial lipid production by Trichosporon cutaneum and Trichosporon coremiiforme was as better as that of SCBH by combined overliming with active charcoal adsorption, and more efficient than that of SCBH only by overliming. Moreover, the regeneration experiment indicated that the CX-6 resin is easy to regenerate and its recirculated performance is stable. In conclusion, our results provide a promising adsorbent to detoxify lignocellulose hydrolysate for further fermentation.

Hydrolysis of Corn Stover by Talaromyces cellulolyticus Enzymes: Evaluation of the Residual Enzymes Activities Through the Process Abstract The obtainment of sugars from lignocellulosic residues represents a sustainable and versatile platform for the production of a number of bio-based products. Cellulases are a family of enzymes which can effectively hydrolyze the biomass polysaccharides at mild conditions. Cellulolytic fungi belonging to the genera Trichoderma and Aspergillus are the most commonly source of commercial cellulases used so far. More recently, Talaromyces cellulolyticus was also scored as a promising cellulases producer. In comparison to the Trichoderma and Aspergillus systems, Talaromyces enzymes have been less investigated. The present research dealt with the conversion of steam-pretreated corn stover by commercial blend of T. cellulolyticus enzymes with respect to the common blends. The paper also investigated the stability of the enzyme preparation and tested the use of additives (namely Tween 80, Tween 20, and BSA) to improve the enzymes performances and the hydrolysis efficiency. The results indicated that, at the same process conditions, T. cellulolyticus cellulases were more effective and yielded 20% more sugars compared to control blends. Furthermore, the cellulase components displayed a synergistic interaction with hemicellulases. The results indicate that cellulases from T. cellulolyticusare less affected by the high dry matter consistency and the use of additives could increase the total activity by around 50% and β-glucosidase capacity by 10–15%.

Effect of High Pressure on Paracoccus denitrificans Growth and Polyhydroxyalkanoates Production from Glycerol Abstract The performance of fermentation under non-conventional conditions, such as high pressure (HP), is a strategy currently tested for different fermentation processes. In the present work, the purpose was to apply HP (10–50 MPa) to fermentation by Paracoccus denitrificans, a microorganism able to produce polyhydroxyalkanoates (PHA) from glycerol. In general, cell growth and glycerol consumption were both reduced by HP application, more extensively at higher pressure levels, such as 35 or 50 MPa. PHA production and composition was highly dependent on the pressure applied. HP was found to decrease polymer titers, but increase the PHA content in cell dry mass (%), indicating higher ability to accumulate these polymers in the cells. In addition, some levels of HP affected PHA monomeric composition, with the polymer produced at 10 and 35 MPa showing considerable differences relative to the ones obtained at atmospheric pressure. Therefore, it is possible to foresee that the changes in polymer composition may also affect its physical and mechanical properties. Overall, the results of this study demonstrated that HP technology (at specific levels) can be applied to P. denitrificans fermentations without compromising the ability to produce PHA, with potentially interesting effects on polymer composition.

The Profile of Plasma Free Amino Acids in Type 2 Diabetes Mellitus with Insulin Resistance: Association with Microalbuminuria and Macroalbuminuria Abstract Altered plasma levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) may predict the development of insulin resistance and other type 2 diabetes mellitus (T2DM) associated comorbidities. To elucidate the role of plasma free amino acids (PFAAs) profile as a biomarker for early detection of diabetic kidney disease, quantitative measurement of PFAAs profile was determined for 90 T2DM subjects, 30 were free of nephropathy, 30 with microalbuminuria, 30 with macroalbuminuria, and in addition to 30 healthy controls. The plasma levels of valine, leucine, isoleucine, phenylalanine, citrulline, and total BCAAs were significantly increased in diabetic normoalbuminuria group when compared to controls. However, the total BCAAs level was significantly decreased in diabetic patients with micro and macroalbuminuria. Other amino acid plasma levels as tyrosine, arginine, ornithine, glycine, and the total AAAs level were significantly decreased in all diabetic subgroups compared to controls. Significant positive correlations between total BCAAs, valine, leucine, isoleucine, serum insulin, glucose, and HOMA-IR values in the diabetic normoalbuminuria group were found. The use of altered PFAAs profile as a prognostic factor in T2DM patients at risk for microalbuminuria or macroalbuminuria might reduce or prevent the incidence of end-stage diabetic renal disease.

Expanding of Phospholipid:Diacylglycerol AcylTransferase (PDAT) from Saccharomyces cerevisiae as Multifunctional Biocatalyst with Broad Acyl Donor/Acceptor Selectivity Abstract Triacylglycerols are considered one of the most promising feedstocks for biofuels. Phospholipid:diacylglycerol acyltransferase (PDAT), responsible for the last step of triacylglycerol synthesis in the acyl-CoA-independent pathway, has attracted much attention by catalyzing membrane lipid transformation. However, due to lack of biochemical and enzymatic studies, PDAT has not carried forward in biocatalyst application. Here, the PDAT from Saccharomyces cerevisiae was expressed in Pichia pastoris. The purified enzymes were studied using different acyl donors and acceptors by thin layer chromatography and gas chromatography. In addition of the preferred acyl donor of PE and PC, the results identified that ScPDAT was capable of using broad acyl donors such as PA, PS, PG, MGDG, DGDG, and acyl-CoA, and ScPDAT was more likely to use unsaturated acyl donors comparing 18:0/18:1 to 18:0/18:0 phospholipids. With regard to acyl acceptors, ScPDAT preferred 1,2 to 1,3-diacylglycerol (DAG), while 12:0/12:0 DAG was identified as the optimal acyl acceptor, followed by 18:1/18:1 and 18:1/16:0 DAG. Additionally, ScPDAT reveals esterification activity that can utilize methanol as acyl acceptor to generate fatty acid methyl esters. The results fully expand the enzymatic selectivity of ScPDAT and provide fundamental knowledge for synthesis of triacylglycerol-derived biofuels.

Determination of Fucose Concentration in a Lectin-Based Displacement Microfluidic Assay Abstract We compare three different methods to quantify the monosaccharide fucose in solutions using the displacement of a large glycoprotein, lactoferrin. Two microfluidic analysis methods, namely fluorescence detection of (labeled) lactoferrin as it is displaced by unlabeled fucose and the displacement of (unlabeled) lactoferrin in SPR, provide fast responses and continuous data during the experiment, theoretically providing significant information regarding the interaction kinetics between the saccharide groups and binding sites. For comparison, we also performed a static displacement ELISA. The stationary binding site in all cases was immobilized S2-AAL, a monovalent polypeptide based on Aleuria aurantia lectin. Although all three assays showed a similar dynamic range, the microfluidic assays with fluorescent or SPR detection show an advantage in short analysis times. Furthermore, the microfluidic displacement assays provide a possibility to develop a one-step analytical platform.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Mind & Society

Brexit behaviourally: lessons learned from the 2016 referendum Abstract Nobel Prize winner Richard Thaler was among those who expected Remain to win the EU referendum. Yet on 23 June 2016, a majority in the UK voted to Leave by a margin of 52–48%. A study of over 450 Leave voters, based on the MINDSPACE framework, looks at whether behavioural factors affected the outcome and at what lessons could be learned for any future votes. It finds that voters had low levels of knowledge which may have undermined any 'status quo bias'; that messengers used by the Remain campaign didn't work for this audience; that the Remain campaign's loss-framed figure of £4300 per household per year was judged to be less than the Leave campaign's figure of £350 m a week (it is six times larger); and that behaviourally-based arguments on immigration might have had an impact. It notes how behavioural science was used successfully to increase turnout. The implication for communicators is that a 'Test, Learn, Adapt' strategy could be helpful in future campaigns.

The quantum-like approach to modeling classical rationality violations: an introduction Abstract Psychological empirical research has shown that human choice behavior often violates the assumptions of classical rational choice models. In the last few decades a new research field has emerged which aims to account for the observed choice behavior by resorting to the concepts and mathematical techniques developed in the realm of quantum physics, such as the "mental state vector" defined in a Hilbert space and the interference of quantum probability. This article is a short introduction to the quantum-like approach to the description of cognitive processes. I argue that the mathematical apparatus of quantum physics can account for the observed violations of classical logic and can help develop effective models of psychological and cognitive phenomena. This is illustrated through the so-called conjunction and disjunction fallacies by providing an alternative interpretation of the results of Linda test and Hawaii test. No-fallacy configurations are made possible in the quantum-like approach by sequential modeling of mental states transitions.

Are measures of life satisfaction linked to admiration for celebrities? Abstract A pattern of research findings indicates that excessive devotion to a favorite celebrity is linked to attitudes and behaviors that are psychologically unhealthy and may predict low life satisfaction. This study examines whether four common measures of life satisfaction (i.e., curiosity, meaning in life, gratitude, and flexibility) predict admiration for celebrities in two university samples and one community sample of young adults. Our results showed significant correlations between celebrity admiration and two measures of life satisfaction (curiosity and gratitude). We also found that the predictors of life satisfaction correlate with each other in ways that are consistent with previous research in positive psychology. Our research suggests an inverse relationship between celebrity admiration and life satisfaction. In addition, the results contribute to establishing the validity of four contemporary life satisfaction measures.

Rationality in a fatalistic world: explaining revolutionary apathy in pre-Soviet peasants Abstract This paper studies the attempts (and failure) of Russian revolutionaries to mobilize the peasantry in the decade leading to the Soviet revolution of 1917. Peasants, who had been emancipated from serfdom only four decades earlier, in 1861, were still largely propertyless and poor. This would, at first glance, make them a ripe target for revolutionary activity. But peasants were largely refractory. We explain this lack of revolutionary spirit through two models. First, despite their lack of education and political awareness, the peasants were rational in their refusal to participate in revolutionary activity; they engaged in a cost–benefit calculus which pushed them away from revolt and political organization. Second, based on the Wildavsky–Thompson cultural types, Russian peasants were largely fatalist: they believed they had no influence on the world, so it was not worth attempting to change it. This paper sheds light on some aspects of the Russian revolution, but also encourages further research in history and economic sociology on the interaction between culture and incentives.

The Role of the Brand on Choice Overload Abstract Current research on choice overload has been mainly conducted with choice options not associated with specific brands. This study investigates whether the presence of brand names in the choice set affects the occurrence of choice overload. Across four studies, we find that when choosing among an overabundance of alternatives, participants express more positive feelings (i.e., higher satisfaction/confidence, lower regret and difficulty) when all the options of the choice set are associated with familiar brands, rather than unfamiliar brands or no brand at all. We also find that choice overload only appears in the absence of brand names, but disappears when all options contain brand names—either familiar or unfamiliar. Theoretical and practical implications are discussed.

Is irrational thinking associated with lower earnings and happiness? Abstract This study investigates the individual outcomes of irrational thinking, including belief in the paranormal and non-scientific thinking. These modes of thinking are identified through factor analysis of eleven questions asked in a large-scale survey conducted in Japan in 2008. Income and happiness are used as measures of individual performance. We propose two hypotheses. Previous studies in finance lead us to consider Hypothesis 1 that both higher belief in the paranormal and non-scientific thinking are associated with lower income. Literature on the association between religion, the paranormal, and happiness suggest Hypothesis 2 that higher belief in the paranormal is associated with greater happiness, while higher non-scientific thinking is associated with greater unhappiness. To examine these hypotheses, we regress income and happiness on belief in the paranormal and non-scientific thinking with appropriate control variables. We employ the Mincer-type wage function as the income equation. Income, sex, and age are controlled in the happiness equation. Analysis supports both hypotheses, which highlights the complex features of irrationality. Although irrationality results in diminishing financial profitability, the component of belief in the paranormal improves the psychological state.

Meta-moral cognition: an introduction Abstract This paper examines the literature on meta-moral cognition and juxtaposes that with meta-cognition. At a basic level, the moral agent coordinates and assigns meaning to the various micro-concepts and moral concepts involved in a moral judgment. These concepts are combined to make moral assumptions. Meta-moral cognition is a higher level cognitive skill. The skill helps the moral agent to understand the cognitive process, control it, regulate the concepts and strategies used, and helps to reflect on the right and wrong of the formulated moral judgment. To develop such moral taxonomy, the moral agent needs to understand the process of reasoning.

Scientific discovery, causal explanation, and process model induction Abstract In this paper, I review two related lines of computational research: discovery of scientific knowledge and causal models of scientific phenomena. I also report research on quantitative process models that falls at the intersection of these two themes. This framework represents models as a set of interacting processes, each with associated differential equations that express influences among variables. Simulating such a quantitative process model produces trajectories for variables over time that one can compare to observations. Background knowledge about candidate processes enables search through the space of model structures and associated parameters to find explanations of time-series data. I discuss the representation of such process models, their use for prediction and explanation, and their discovery through heuristic search, along with their interpretation as causal accounts of dynamic behavior.

Inconsistency is not pathological: a pragmatic perspective Abstract Both behavioral and standard neoclassical economists place a heavy emphasis on the consistency of preferences. In particular, transitive preferences are considered a desideratum. This paper attempts to show that consistency at the level of individual choice may be pragmatically irrelevant. Consistently following an environmentally adapted rule can result in intransitive preferences without negative consequences for individual or social goals. I give three examples of this. Social scientists should look at intransitivity of choices as a challenge to offer better explanations rather than as a normative defect.

Assessing social care policy through a behavioural lens Abstract Over recent years, a number of behavioural economic-informed policy frameworks have been developed, ranging from soft and hard forms of paternalism, to regulation against negative externalities, the so-called nudge, shove and budge approaches. This article considers these different frameworks as applied to some of the challenges posed by the social care needs of contemporary societies. It is argued that all of the frameworks are worthy of serious consideration in this policy domain, in that they offer food for thought on how financial contributions to pay for social care might be increased, and how the quality of social care provision may be improved given available resources.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Molecular Medicine

Correction to: Critical role of interleukin-23 in development of asthma promoted by cigarette smoke The original publication of this paper contains a mistake.

Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress Abstract Response to stressors in our environment and daily lives is an adaptation conserved through evolution as it is beneficial in enhancing the survival and continuity of humans. Although stressors have evolved, the drastic physiological response they elicit still remains unchanged. The chronic secretion and circulation of catecholamines to produce physical responses when they are not required may result in pathological consequences which affect cardiac function drastically. This review seeks to point out the probable implication of chronic stress in inducing an inflammation disorder in the heart. We discussed the likely synergy of a G protein-independent stimuli signaling via β2-adrenergic receptors in both cardiomyocytes and immune cells during chronic catecholamine stress. To explain this synergy, we hypothesized the possibility of adenylyl cyclases having a regulatory effect on G protein-coupled receptor kinases. This was based on the negative correlations they exhibit during normal cardiac function and heart failures. As such, the downregulation of adenylyl cyclases in cardiomyocytes and immune cells during chronic catecholamine stress enhances the expressions of G protein-coupled receptor kinases. In addition, we explain the maladaptive roles played by G protein-coupled receptor kinase and extracellular signal-regulated kinase in the synergistic cascade that pathologically remodels the heart. Finally, we highlighted the therapeutic potentials of an adenylyl cyclases stimulator to attenuate pathological cardiac hypertrophy (PCH) and improve cardiac function in patients developing cardiac disorders due to chronic catecholamine stress.

Bone marrow chimeras—a vital tool in basic and translational research Abstract Bone marrow chimeras are used routinely in immunology research as well as in other fields of biology. Here, we provide a concise state-of-the-art review about the types of chimerisms that can be achieved and the type of information that each model generates. We include separate sections for caveats and future developments. We provide examples from the literature in which different types of chimerism were employed to answer specific questions. While simple bone marrow chimeras allow to dissect the role of genes in distinct cell populations such as the hematopoietic cells versus non-hematopoietic cells, mixed bone marrow chimeras can provide detailed information about hematopoietic cell types and the intrinsic and extrinsic roles of individual genes. The advantages and caveats of bone marrow chimerism for the study of microglia are addressed, as well as alternatives to irradiation that minimize blood-brain-barrier disruption. Elementary principles are introduced and their potential is exemplified through summarizing recent studies.

A rapid, safe, and quantitative in vitro assay for measurement of uracil-DNA glycosylase activity Abstract Base excision repair (BER) is a frontline repair mechanism that operates through the G1 phase of the cell cycle, which ensures the genome integrity by repairing thousands of DNA lesions due to endogenous and exogenous agents. Its correct functioning is fundamental for cell viability and the health of the organism. Uracil is one of the most prevalent lesions that appears in DNA arising by spontaneous or enzymatic deamination of cytosine or misincorporation of the deoxyuridine 5′-triphosphate nucleotide (dUTP) in place of deoxythymidine 5′-triphosphate (dTTP) during DNA replication. In the first pathway, the uracil will preferentially pair with adenine, leading to C:G → T:A transition. When uracil in DNA arises from misincorporation of dUTP instead of dTTP, this process will result in A:U pairs. Organisms counteract the mutagenic effects of uracil in DNA using the BER repair system, which is mediated by a member of the uracil-DNA glycosylase (UDG) superfamily. Several assays evaluating the in vitro BER enzyme activity have been described so far. Some of these measure the BER activity by an oligonucleotide incision assay using radiolabeled duplex oligo. Others use circular double-stranded DNA substrates containing a defined lesion. The novelty of our method resides in its rapidity and safety (radioactive free detection) as well as in the possibility of having a reliable quantitative determination of UDG activity in both cell and tissue extracts. We also demonstrated the effectiveness of our method in assessing UDG activity in cell lines with a reduced DNA repair capacity and in different kinds of tissues. Key messages • Base excision repair is a fundamental repair mechanism ensuring the genome integrity. • Uracil is one of the most prevalent lesions that appears in DNA. • The mutagenic effects of uracil in DNA are mitigated by the uracil-DNA glycosylase. • Several assays evaluating the in vitro BER activity have been described so far. • A safe and quantitative assay evaluating the in vitro UDG activity is required.

The protean world of non-coding RNAs in glioblastoma Abstract Non-coding ribonucleic acids (ncRNAs) are a diverse group of RNA molecules that are mostly not translated into proteins following transcription. We review the role of ncRNAs in the pathobiology of glioblastoma (GBM), and their potential applications for GBM therapy. Significant advances in our understanding of the protean manifestations of ncRNAs have been made, allowing us to better decipher the molecular complexity of GBM. A large number of regulatory ncRNAs appear to have a greater influence on the molecular pathology of GBM than thought previously. Importantly, also, a range of therapeutic approaches are emerging whereby ncRNA-based systems may be used to molecularly target GBM. The most successful of these is RNA interference, and some of these strategies are being evaluated in ongoing clinical trials. However, a number of limitations exist in the clinical translation of ncRNA-based therapeutic systems, such as delivery mechanisms and cytotoxicity; concerted research endeavors are currently underway in an attempt to overcome these. Ongoing and future studies will determine the potential practical role for ncRNA-based therapeutic systems in the clinical management of GBM. These applications may be especially promising, given that current treatment options are limited and prognosis remains poor for this challenging malignancy.

Mevalonate promotes differentiation of regulatory T cells Abstract Mevalonate is a precursor in a biosynthetic pathway that is important for the coordination of regulatory T cell (Treg) proliferation and upregulation of the suppressive function that establishes the functional competency of Tregs. The extensive role of mevalonate and its underlying effect on Treg differentiation are still unclear. We found that mevalonate increases in vitro differentiation of induced Tregs (iTregs) without broadly affecting Th1 and Th17 cell differentiation. Furthermore, an adoptive transfer study showed that mevalonate enhanced peripherally induced Treg cells (pTregs) in mesenteric lymphocytes in vivo. Mevalonate-treated iTregs exhibited greater suppressive activity against effector cells than untreated Tregs. Mechanistically, mevalonate enhanced transforming growth factor (TGF)-β signaling by increasing the phosphorylation of Smad3, but not Smad2, and by promoting Foxp3 expression. Furthermore, we demonstrated that mevalonate treatment ameliorated dextran sulfate sodium (DSS)-induced colitis and resulted in an increased percentage of Tregs in vivo. Our results suggest that mevalonate enhanced Treg differentiation and ameliorated DSS colitis, indicating its potential for treatment of inflammatory diseases.

RPSAP52 lncRNA is overexpressed in pituitary tumors and promotes cell proliferation by acting as miRNA sponge for HMGA proteins Abstract Long non-coding RNAs (lncRNAs) are emerging as fundamental players in cancer biology. Indeed, they are deregulated in several neoplasias and have been associated with cancer progression, tumor recurrence, and resistance to treatment, thus representing potential biomarkers for cancer diagnosis, prognosis, and therapy. In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis. We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for the HMGA2 gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in somatotroph adenomas. We also demonstrate that RPSAP52 enhances HMGA2 protein expression in a ceRNA-dependent way acting as sponge for miR-15a, miR-15b, and miR-16, which have been already described to be able to target HMGA2. Interestingly, RPSAP52 also positively modulates HMGA1, the other member of the High-Mobility Group A family. Moreover, functional studies indicate that RPSAP52 promotes cell growth by enhancing the G1-S transition of the cell cycle. The results reported here reveal a novel mechanism, based on the overexpression of the lncRNA RPSAP52, which contributes to pituitary tumorigenesis, and propose this lncRNA as a novel player in the development of these tumors. Key Messages RPSAP52 is overexpressed in pituitary adenomas. RPSAP52 increases HMGA protein levels. A ceRNA mechanism is proposed for the increased HMGA1/2 expression.

Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM Abstract Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by ventricular hypertrophy, myofibrillar disarray, and fibrosis, and is primarily caused by mutations in sarcomeric genes. With no definitive cure for HCM, there is an urgent need for the development of novel preventive and reparative therapies. This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at Ser15-RLC phosphorylation site (S15D-RLC) into the hearts of humanized HCM-D166V mice. Improvement of heart function was monitored by echocardiography, invasive hemodynamics (PV-loops) and muscle contractile mechanics. A significant increase in cardiac output and stroke work and a decrease in relaxation constant, Tau, shown to be prolonged in HCM mice, were observed in AAV- vs. PBS-injected HCM mice. Strain analysis showed enhanced myocardial longitudinal shortening in AAV-treated vs. control mice. In addition, increased maximal contractile force was observed in skinned papillary muscles from AAV-injected HCM hearts. Our data suggest that myosin RLC phosphorylation may have important translational implications for the treatment of RLC mutations-induced HCM and possibly play a role in other disease settings accompanied by depressed Ser15-RLC phosphorylation. Key messages HCM-D166V mice show decreased RLC phosphorylation and decompensated function. AAV9-S15D-RLC gene therapy in HCM-D166V mice, but not in WT-RLC, results in improved heart performance. Global longitudinal strain analysis shows enhanced contractility in AAV vs controls. Increased systolic and diastolic function is paralleled by higher contractile force. Phosphomimic S15D-RLC has a therapeutic potential for HCM.

Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis Abstract Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. Key messages • Entinostat potently inhibits ES both in vitro and in vivo. • EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. • Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. • HDAC3 is a transcriptional target of EWS-FLI1. • HDAC3 is essential for ES cell viability and genomic stability maintenance.

Critical role of interleukin-23 in development of asthma promoted by cigarette smoke Abstract It has been recently reported that cigarette smoke exposure during allergen sensitization facilitates the development of allergic asthma; however, the underlying mechanisms remain elusive. We evaluated the role of interleukin (IL-23) in a cigarette smoke extract (CSE)-induced Dermatophagoides pteronyssinus (Dp)-allergic asthma mouse model. BALB/c mice were exposed to CSE during allergen sensitization period. Anti-IL-23p19 or IL-23R antibody was administered during the sensitization period. And we evaluated several immunological responses. The expression of IL-23 and IL-23 receptor (IL-23R) was examined in lung tissue. IL-23 and IL-23R expression was increased in the airway epithelium of Dp/CSE co-administered mice. CSE administration during the sensitization promoted Dp-allergic sensitization and the development of asthma phenotypes. Additionally, the proportion of innate lymphoid type 2 cells (ILC2) was also increased by CSE and Dp co-instillation. Anti-IL-23 or IL-23R antibody treatment during allergen sensitization significantly diminished phenotypes of allergic asthma and the ILC2 population. The levels of IL-33 and thymic stromal lymphopoietin (TSLP) were also significantly reduced by anti-IL-23 or IL-23R antibody treatment. IL-23 may thus play a significant role in cigarette smoke-induced allergic sensitization and asthma development. Clinically, the increase in allergen sensitization due to cigarette exposure causes onset of asthma, and IL-23 may be important in this mechanism. Key messages IL-23 and IL-23R expression was increased in the lung epithelium of Dp and CSE co-exposed mice during sensitization period. The population of ILC2s was increased in Dp and CSE co-exposed mice during sensitization period. Anti-IL23 or IL-23R antibody treatment with co-administration of CSE and HDM during sensitization period significantly suppresses ILC2. In vitro, IL-23 blockade in Dp and CSE-stimulated epithelial cells suppressed IL-13 expression in ILC2.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Neuroradiology

Performance of a Deep-Learning Neural Network to Detect Intracranial Aneurysms from 3D TOF-MRA Compared to Human Readers Abstract Purpose To study the clinical potential of a deep learning neural network (convolutional neural networks [CNN]) as a supportive tool for detection of intracranial aneurysms from 3D time-of-flight magnetic resonance angiography (TOF-MRA) by comparing the diagnostic performance to that of human readers. Methods In this retrospective study a pipeline for detection of intracranial aneurysms from clinical TOF-MRA was established based on the framework DeepMedic. Datasets of 85 consecutive patients served as ground truth and were used to train and evaluate the model. The ground truth without annotation was presented to two blinded human readers with different levels of experience in diagnostic neuroradiology (reader 1: 2 years, reader 2: 12 years). Diagnostic performance of human readers and the CNN was studied and compared using the χ2-test and Fishers' exact test. Results Ground truth consisted of 115 aneurysms with a mean diameter of 7 mm (range: 2–37 mm). Aneurysms were categorized as small (S; <3 mm; N = 13), medium (M; 3–7 mm; N = 57), and large (L; >7 mm; N = 45) based on the diameter. No statistically significant differences in terms of overall sensitivity (OS) were observed between the CNN and both of the human readers (reader 1 vs. CNN, P = 0.141; reader 2 vs. CNN, P = 0.231). The OS of both human readers was improved by combination of each readers' individual detections with the detections of the CNN (reader 1: 98% vs. 95%, P = 0.280; reader 2: 97% vs. 94%, P = 0.333). Conclusion A CNN is able to detect intracranial aneurysms from clinical TOF-MRA data with a sensitivity comparable to that of expert radiologists and may have the potential to improve detection rates of incidental findings in a clinical setting.

Effect of MRI-based semiautomatic size-assessment in cerebral metastases on the RANO-BM classification Abstract Aim Evaluation of a semiautomatic software algorithm for magnetic resonance imaging (MRI)-based assessment of cerebral metastases in cancer patients. Material and Methods Brain metastases (n = 131) in 38 patients, assessed by contrast-enhanced MRI, were retrospectively evaluated at two timepoints (baseline, follow-up) by two experienced neuroradiologists in a blinded manner. The response assessment in neuro-oncology (RANO) criteria for brain metastases (RANO-BM) were applied by means of a software (autoRANO-BM) as well as manually (manRANO-BM) at an interval of 3 weeks. Results The average diameter of metastases was 12.03 mm (SD ± 6.66 mm) for manRANO-BM and 13.97 mm (SD ± 7.76 mm) for autoRANO-BM. Diameter figures were higher when using semiautomatic measurements (median = 11.8 mm) as compared to the manual ones (median = 10.2 mm; p = 0.000). Correlation coefficients for intra-observer variability were 0.993 (autoRANO-BM) and 0.979 (manRANO-BM). The interobserver variability (R1/R2) was 0.936/0.965 for manRANO-BM and 0.989/0.998 for autoRANO-BM. A total of 19 lesions (15%) were classified differently when using semiautomatic measurements. In 14 cases with suspected disease progression by manRANO-BM a stable course was found according to autoRANO-BM. Conclusion Computerized measuring techniques can aid in the assessment of cerebral metastases by reducing examiner-dependent effects and may consequently result in a different classification according to RANO-BM criteria.

Effectiveness of Revive SE in the RAPID registry Abstract Purpose The prospective, multicenter Revive Acute ischemic stroke Patients ImmeDiately (RAPID) trial was carried out to evaluate the real-world safety and efficacy of the Revive SE stent retriever. Methods From January 2017 the study planned to enroll 100 patients with acute ischemic stroke who were treated with the Revive SE as a first pass. The study primary outcomes were rates of favorable reperfusion using the modified thrombolysis in cerebral infarction score [mTICI] 2b/3 and rates of favorable outcome with the modified Rankin Scale (mRS) ≤2 at 3 months. The secondary outcomes were time interval from puncture to vascular reperfusion, number of passes by Revive SE stent-retriever, incidence of distal embolization and into new territories and rate of symptomatic intracranial hemorrhage (SICH) within 24 h post intervention. Results A total of 100 treated patients (mean age: 65.6 ± 11.3 years) were enrolled. The median National Institutes of Health Stroke Scale before the procedure was 16. Target vessel occlusions were as follows: middle cerebral artery (MCA) M1 in 48, M2 in 6, anterior cerebral artery (ACA) in 3, internal carotid artery (ICA) in 22, basilar artery (BA) in 17, and vertebral artery (VA) in 4. Reperfusion rate with Revive SE without rescue devices was 69%. Reperfusion rate with Revive SE only was 83.3% in MCA M2, followed by 82.4% in BA. Thromboembolic complications and SICH developed in 10% and 2% of patients, respectively. Overall, a satisfactory reperfusion was achieved in 92% and a favorable outcome at 90 days in 48%. Conclusion Use of the Revive SE for thrombectomy appeared to be effective and safe but these findings need be confirmed in larger clinical trials (RAPID ClinicalTrials.gov number, NCT03007082).

Microstructural White Matter Alterations in Mild Cognitive Impairment and Alzheimer's Disease Abstract Purpose To investigate microstructural alterations in white matter in mild cognitive impairment (MCI) and Alzheimer's disease (AD) using neurite orientation dispersion and density imaging (NODDI) and to assess the potential diagnostic performance of NODDI-derived parameters. Methods In this study 14 MCI patients, 14 AD patients, and 14 healthy controls (HC) were recruited. The diffusion tensor imaging(DTI)-derived fractional anisotropy (FA) and NODDI-derived neurite density index (NDI), orientation dispersion index (ODI), and volume fraction of isotropic water molecules (Viso) were calculated from the diffusion data. The tract-based spatial statistics (TBSS) method was used for statistical analysis with one-way ANOVA. The correlations between the parameter values and mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) scores were examined. A receiver operating characteristic (ROC) curve was conducted to assess the diagnostic performance of different parameters. Results Compared with the HC group, the NDI and ODI values decreased significantly and the Viso values were significantly increased in the MCI and AD groups (p < 0.01, threshold-free cluster enhancement (TFCE)-corrected); however, there were no significant differences in FA values in the MCI group. The NDI, ODI, and Viso values of multiple fibers were significantly correlated with MMSE and MoCA scores. For the diagnosis of AD, the area under the ROC curve (AUC) for the NDI value of the splenium of corpus callosum was larger than the FA value (AUC = 0.885, 0.714, p = 0.042). The AUC of the Viso value of the right cerebral peduncle was larger than FA value (AUC = 0.934, 0.531, p = 0.004). Conclusion The NDI is more sensitive to white matter microstructural changes than FA and NODDI could be superior to DTI in the diagnosis of AD.

Aggregometry Response to Half-dose Prasugrel in Flow-diverting Stent Implantation Abstract Purpose The aim of this study was to determine whether half-dose loading (30 mg) of prasugrel is sufficient to achieve adequate platelet inhibition, and whether such a loading dose of prasugrel together with aspirin followed by a 10 mg/day prasugrel maintenance, could serve as a first-line antiplatelet strategy for patients undergoing flow-diverting stent (FDS) implantation. Methods Data from a group of consecutive patients treated for intracranial aneurysm with FDS were retrospectively collected. Platelet P2Y12 receptor responsiveness was assessed by a rapid platelet function test just prior to the procedure. All ischemic and hemorrhagic complications as well as morbidity and mortality rates were documented. Results A total of 138 patients with 153 aneurysms (32 were symptomatic and 121 were incidental) underwent FDS treatment in a total of 147 loading sessions. Adequate platelet inhibition was obtained in 136/138 (98.5%) patients and 145/147 (98.6%) loading sessions. Overall, there was one case of (hemorrhagic) mortality (0.7%), one of (ischemic) morbidity (0.7%), one of symptomatic (hemorrhagic) clinical complications without permanent deficits (0.7%), and six transient ischemic attacks (4.1%). The 6‑month control angiography, available for all patients, revealed a 95.4% aneurysm occlusion rate. Conclusion Half-dose (30 mg) prasugrel loading results in effective platelet P2Y12 receptor inhibition in more than 98% of patients. Dual antiaggregant loading with half dose prasugrel followed by prasugrel maintenance as a first-line therapy appears to be feasible in patients treated with FDS implantation for intracranial aneurysm.

Correction to: Accuracy and Reliability of Multiphase CTA Perfusion for Identifying Ischemic Core Correction to: Clin Neuroradiol 2018 https://doi.org/10.1007/s00062-018-0717-x Unfortunately, the author list of the original version of this article contains a mistake. The middle name of the author "Rani Gupta Sah" was erroneously tagged as part of the surname in the article's metadata. This mistake

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions Abstract Purpose Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI). Methods All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions. Results Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and—among those randomized—had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011). Conclusion Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.

Correction to: Cranial MR-guided Focused Ultrasound for Essential Tremor Correction to: Clin Neuroradiol 2018 https://doi.org/10.1007/s00062-018-0709-x The original version of this article unfortunately contained a mistake. The tagging of the name J. Levi Chazen was incorrect. The correct information is given …

Future Neuroradiology

Lateral rectus atrophy in cavernous sinus thrombosis

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical Pharmacology

Balancing medication use in nursing home residents with life-limiting disease Abstract Purpose Balancing medications that are needed and beneficial and avoiding medications that may be harmful is important to prevent drug-related problems, and improve quality of life. The aim of this study is to describe medication use, the prevalence of deprescribing of medications suitable for deprescribing, and the prevalence of new initiation of potentially inappropriate medications (PIMs) in nursing home (NH) residents with life-limiting disease in Flanders. Methods NH residents aged ≥ 65, suffering from end stage organ failure, advanced cancer, and/or dementia (n = 296), were included in this cross-sectional study with retrospective analyses of medication use at the time of data collection (t2) and 3 to 6 months before (t1). The appraisal of appropriateness of medications was done using a list of medications documented as suitable for deprescribing, and STOPPFrail criteria. Results Residents' (mean age 86 years, 74% female) mean number of chronic medications increased from 7.4 (t1) to 7.9 (t2). In 31% of those using medications suitable for deprescribing, at least one medication was actually deprescribed. In 30% at least one PIM from the group of selected PIMs was newly initiated. In the subgroup (n = 76) for whom deprescribing was observed, deprescribing was associated with less new initiations of PIMs (r = − 0.234, p = 0.042). Conclusion Medication use remained high at the end of life for NH residents with life-limiting disease, and deprescribing was limited. However, in the subgroup of 76 residents for whom deprescribing was observed, less new PIMs were initiated.

Prevalence of medication and off-label medication use in acquired brain injury at a neurorehabilitation hospital Abstract Purpose Patients who suffer acquired brain injury (ABI) require a great variety of drugs. Furthermore, the lack of evidence on the medication effects in this type of patient increases off-label prescription. The aim of this study was to describe the pattern of medication use and the practice of prescribing off-label drugs in these patients. Methods A cross-sectional study was conducted in patients with ABI, of either traumatic or non-traumatic cause, admitted to a neurorehabilitation hospital for rehabilitation. Demographic and clinical data and prevalence of medication use and off-label prescription were collected. Results The majority of the studied patients (85.2%) were considered polymedicated since they were prescribed ≥ 6 drugs concomitantly. In traumatic brain injury (TBI) patients, antidepressants (81.5%) were the Anatomical Therapeutic Chemical (ATC) group's most prescribed versus antithrombotic agents (80.5%) in non-traumatic brain injury (N-TBI) patients. Up to 37.3% of all active substances prescribed in TBI patients were off-label compared with 24.9% in N-TBI patients. The most prescribed off-label active substances in both groups were those related to the Nervous System (N) ATC group to treat neurobehavioural problems. Conclusion A multidisciplinary pharmacotherapeutic follow-up of these patients would be essential to address the high prescription rate of medications and the off-label prescription practice. In this way, medication problems related to polypharmacy could be minimised and the benefit-risk ratio of prescribed off-label drugs could be ensured according to the available medical evidence.

Verification of pharmacogenomics-based algorithms to predict warfarin maintenance dose using registered data of Japanese patients Abstract Purpose Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9(CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences. Methods Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097–1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC). Results For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy. Conclusion The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.

Relationship between hemoglobin levels and vancomycin clearance in patients with sepsis Abstract Purpose It is important to accurately estimate accurate vancomycin (VCM) clearance (CLvcm) for appropriate VCM dosing in the treatment of patients with sepsis. However, the pathophysiology of sepsis can make CLvcm prediction less accurate. Clearance of hydrophilic antibiotics is disturbed by organ dysfunction, and hemoglobin levels are negatively correlated with sequential organ function assessment scores. We investigated whether hemoglobin levels are associated with CLvcm in sepsis patients. Methods We performed a retrospective cohort study of patients treated with VCM in the Emergency and Critical Care Center of Nihon University Itabashi Hospital between 2005 and 2015. We enrolled 72 patients after exclusion of patients who received renal replacement therapy or surgery, had a change in hemoglobin levels more than 2 g/dL or received an erythrocyte infusion during the interval between initial VCM administration and measurement of initial trough levels, had a serum baseline creatinine level of ≥ 2 mg/dL, or were under 18 years old. Results Enrolled patients consisted of 13 non-sepsis patients and 59 sepsis patients. In sepsis patients, although CLvcm was correlated with CrCl in HGB ≥ 9 group as well as in non-sepsis patients, its correlation was not observed in HGB < 9 group. Hemoglobin levels were correlated with CLvcm in sepsis patients but not in non-sepsis patient. Multiple linear regression analysis also indicated that lower CLvcm was associated with lower hemoglobin and CrCl. Conclusion Lower hemoglobin levels influence a relationship between CLvcm and CrCl in sepsis patients. We propose that VCM dosing should be adjusted for hemoglobin levels in sepsis patients.

Antipsychotic utilization patterns among patients with schizophrenic disorder: a cross-national analysis in four countries Abstract Purpose The aim of the present study was to describe antipsychotic utilization patterns among patients with schizophrenic disorder in Italy, Spain, the UK, and the USA. Methods A retrospective cohort study was conducted. Patients aged 15 and over with schizophrenic disorder were identified in the Caserta claims database (Italy), the Valencia electronic medical record (EMR) database (Spain), in The Health Improvement Network EMR database (UK), and in databases of publicly and privately insured populations in the United States (US). Results The frequency of first-generation or second-generation antipsychotic use and of long-acting or other formulations was described. Persistence to antipsychotics was estimated. Overall, 1,403,240 patients with schizophrenic disorder having a total of 765,573 new antipsychotic treatment episodes were identified. The median follow-up time ranged from 0.8 (IQR 0.2–1.9) years in the US commercially-insured population to 1.2 (IQR 0.1–1.7) years in the Spanish population. Second-generation antipsychotics were more frequently used than first-generation antipsychotics in all countries (on average, from 64.4% in the UK to 87% in US): the use of this class increased over time in Italy, Spain, and US (Medicaid). The use of long-acting formulations was heterogeneous across countries, but generally much lower than other formulations. Persistence to antipsychotic treatment at 1 year was low in all countries, ranging from 40 in Spain to 30% in Italy. Conclusions Antipsychotic utilization was heterogeneous among persons with schizophrenic disorder. Nevertheless, low persistence was an issue in all the countries, as less than half of the patients continued their treatment beyond 1 year.

Use of statins in the elderly according to age and indication—a cross-sectional population-based register study Abstract Purpose To investigate statin use in the elderly by age (≥ 80 vs. 65–79 years) in relation to established indications. Methods A population-based cohort, including data from four registers, encompassing inhabitants in Region Västra Götaland, Sweden, was used. Statin users were defined as those filling statin prescriptions ≥ 75% of the year 2010. Primary care and hospital diagnoses in 2005–2010 regarding ischemic heart disease, stroke, transient ischemic attacks, and diabetes were considered established indications. Results A total of 278,205 individuals were analyzed. In individuals aged ≥ 80 and 65–79 years (n = 81,885 and n = 196,320, respectively), 17% (95% confidence interval 17%; 18%) and 23% (23%; 23%) respectively, were statin users. Among the statin users, 74% (73%; 74%) of those aged ≥ 80 and 60% (59%; 60%) of those aged 65–79 years had ≥ 1 established indication. Conversely, of those with ≥ 1 established indication, 30% (30%; 31%) and 53% (52%; 53%) were on statins in the respective age groups. Logistic regression revealed that age, nursing home residence, and multi-dose drug dispensing were the most prominent negative predictors for statin use; adjusted odds ratios (95% confidence interval): 0.45 (0.44; 0.46), 0.39 (0.36; 0.42), and 0.47 (0.44; 0.49), respectively. Conclusions In the oldest old (≥ 80 years), statin users were fewer and had more often an established indication, suggesting that physicians extrapolate scientific evidence for beneficial effects in younger age groups to the oldest, but require a more solid ground for treatment. As the oldest old, nursing home residents, and those with multi-dose drug-dispensing were statin users to a lesser extent, physicians may often refrain from treatment in those with lower life expectancy, either due to age or to severely reduced health status. In both age groups, our results however also indicate some over- as well as undertreatment.

Evaluation of the effects of ontogenetic or maturation functions and chronic heart failure on the model analysis for the dose-response relationship of warfarin in Japanese children Abstract Purpose We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects. Methods Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects. Results Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%. Conclusion The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects.

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults Abstract Aim There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. Methods Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. Results A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2–46.2%), whereas it did not impact the volume of distribution (p = 0.704). Conclusions This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation Abstract Purpose High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. Methods All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. Results A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3–5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71–4.62, p = 0.218 and HR 1.08, 95% CI 0.39–2.99, p = 0.780) in univariate and multivariate analyses, respectively. Conclusions Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

Discontinuation of therapy among COPD patients who experience an improvement in exacerbation status Abstract Purpose A subset of patients with chronic obstructive pulmonary disease (COPD) experience a decrease in exacerbation frequency, leading to a diminished need for treatment with inhaled corticosteroids (ICS). We investigated prescribing and discontinuation patterns of long-acting bronchodilators and ICS in COPD patients according to exacerbation frequency. Methods Using the nationwide Danish health registries, we conducted a drug utilization study among patients who had at least two exacerbations or one hospitalization due to an exacerbation during 2011–2012. This study population was stratified according to consistency of exacerbation occurrence after 12, 24, 36, and 48 months of follow-up and the groups were described according to use of ICS, long-acting β2-agonists (LABA), and long-acting anticholinergics (LAMA), and combinations thereof. Results We identified 29,010 COPD exacerbators during 2011–2012. Upon inclusion, 70% received ICS-containing regimens, in combination with LABA (23%) or both LABA and LAMA (41%). The proportion of prevalent users of ICS-containing regimens decreased to 56% during follow-up among exacerbation-free individuals, while it increased to 86% in individuals who experienced at least one exacerbation annually. Persistence to ICS-containing regimens was 58% after 4 years in individuals without exacerbations compared to 74% among those with annual exacerbations. Similar patterns were observed for triple therapy which was the most extensively used drug combination regardless of consistency of exacerbation occurrence. Conclusions The extensive use of ICS and the relatively high persistence to ICS-containing regimens in individuals who had a decrease in exacerbation occurrence highlight a need for the development and implementation of de-escalation strategies in clinical practice.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com