bluuebunny/crossref_metadata_2025 huggingface dataset:
A MOF@COF Composite with Enhanced Uptake through Interfacial Pore Generation
Authors: Garzón‐Tovar Luis , Pérez‐Carvajal Javier , Yazdi Amirali , Hernández‐Muñoz Jose , Tarazona Pedro , Imaz Inhar , Zamora Félix , Maspoch Daniel
Published: May 2019

Herein, we describe a new class of porous composites comprising metal–organic framework (MOF) crystals confined in single spherical matrices made of packed covalent‐organic framework (COF) nanocrystals. These MOF@COF composites are synthesized through a two‐step method of spray‐drying and subsequent amorphous (imine‐based polymer)‐to‐crystalline (imine‐based COF) transformation. This transformation around the MOF crystals generates micro‐ and mesopores at the MOF/COF interface that provide far superior porosity compared to that of the constituent MOF and COF components added together. We report that water sorption in these new pores occurs within the same pressure window as in the COF pores. Our new MOF@COF composites, with their additional pores at the MOF/COF interface, should have implications for the development of new composites.
Preparation of five‐membered bis(cyclic carbonate)s at atmospheric pressure for polyhydroxyurethane coatings
Authors: Dai Jingtao , Wu Zhijun , Tang Liuyang , Qu Jinqing
Published: May 2019

Cyclic carbonates reacted with diamines or polyamines have been proposed as a greener and safer method to prepare free isocyanate polyurethane coatings. Here, five kinds of bis(cyclic carbonate)s (TDC: toluene bis(cyclic carbonate), MDC: 4,4′‐diphenylmethane bis(cyclic carbonate), IPDC: isophorone bis(cyclic carbonate), HMDC: 4,4′‐methylenebis(cyclohexyl cyclic carbonate), HDC: hexamethylene bis(cyclic carbonate)) were prepared by reacting glycerol carbonate with diisocyanate under atmospheric pressure. Their structures were verified by 1H‐NMR and 13C‐NMR. These difunctional cyclic carbonates were then reacted with several amines to prepare new polyhydroxyurethane (PHU) coatings, and the film properties were tested. It was found that PHUs based on aromatic and alicyclic structures including TDC, MDC, IPDC, and HMDC displayed high hardness but had poor flexibility and impact resistance, whereas PHUs based on aliphatic structures such as HDC exhibited good flexibility and impact resistance and low hardness. When the length of the alkyl groups in the amine curing agents increased, the impact resistance and flexibility of the PHUs increased, but their pencil hardness decreased. PHUs from TDC, MDC, and IPDC had excellent chemical resistance, but the PHUs from HMDC and HDC had less chemical resistance. Some films displayed excellent properties including 4H pencil hardness, 100 cm kg impact resistance, and excellent flexibility. Some PHUs exhibited good thermal stability, with T5% values all above 242°C. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47957.
The Pathosome: A Dynamic Three‐Dimensional View of Disease–Environment Interaction
Authors: Lenart Peter , Scheringer Martin , Bienertova‐Vasku Julie
Published: May 2019

Most contemporary models of disease development consider the interaction between genotype and environment as static. The authors argue that because time is a key factor in genotype–environment interaction, this approach oversimplifies the pathology analysis and may lead to wrong conclusions. In reviewing the field, the authors suggest that the history of genotype–environment interactions plays an important role in the development of diseases and that this history may be analyzed using the phenotype as a proxy. Furthermore, a theoretical and experimental framework is proposed based on the assumption that phenotypes do not change from one to another randomly but are interconnected and follow certain phenotype trajectories. It then follows that analysis of such phenotype trajectories might be useful to predict the future phenotypes including the onset of disease. In addition, an analysis of phenotype trajectories can be subsequently used to choose better control subjects in comparative studies reducing noise and bias in studies investigating disease mechanisms.
Correlation between the inframammary fold and sixth rib: Application to breast reconstruction
Authors: Oh Sangho , Kim Dongseok , Kim Junhyung , Choi Jaehoon , Jeong Woonhyeok , Han Kihwan , Son Daegu
Published: May 2019

The inframammary fold (IMF) is an essential aesthetic element that influences the outcome of breast surgery. In this study, we introduced a new method for finding the IMF based on retrospective analysis of chest computed tomography (CT) scans of women's breasts. Sagittal sections of 80 female chest CTs were analyzed. Sagittal sections of 80 female chest CTs were analyzed by a single plastic surgeon. The distances between the fifth, sixth, and seventh ribs and the IMF were measured using Photoshop, and the location of the IMF was statistically analyzed according to age and height using paired t tests and Pearson's correlation test. As determined by our new method, the average distance between the IMF and the sixth rib was 5.33 mm, which was less than that between the IMF and any other rib. The IMF was closest to the sixth rib in all age groups (P < 0.001), and all IMFs were located between 39.5 mm superior and 24 mm inferior to the sixth rib. The sixth rib, one of the most visible reference structures in women's surface anatomy, is the “sentinel rib” for the IMF and the most predictive indicator of the location of the IMF. Knowing the original anatomic location of the IMF will enable better outcomes during breast surgery. Clin. Anat. 33:165–172, 2020. © 2019 Wiley Periodicals, Inc.
Stabilization of All‐in‐Water Emulsions To Form Capsules as Artificial Cells
Authors: Douliez Jean‐Paul , Perro Adeline , Béven Laure
Published: May 2019

Building artificial cells through a bottom‐up approach is a remarkable challenge that would be of interest for our understanding of the origin of life, research into the minimal conditions required for life, the formation of bioreactors, and for industrial applications. To date, capsules such as liposomes, including polymersomes, are widely used, but the low membrane permeability and method to encapsulate biological materials within these structures hamper their use. By contrast, all‐in‐water emulsion droplets, including coacervate droplets, are promising compartments, mainly because they can spontaneously sequester chemicals. However, they lack a membrane necessary to control exchange between the inner and outer media. Moreover, droplets tend to coalesce with time, yielding macroscopic phase separation that is deleterious for any use as artificial cells. Recent advances, which are reviewed herein, have shown that such droplets can be stabilized by using lipid membranes, liposomes, polymers, proteins, and particles, and thus, preventing coalescence. Finally, different strategies that could allow the future development of artificial cells from these stabilized all‐in‐water emulsion droplets are discussed.
Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules
Authors: Dohno Chikara , Nakatani Kazuhiko
Published: May 2019

We introduce the concept of molecular glues for RNA, in which specific RNA‐binding small molecules induce designed structural changes in target functional RNAs, resulting in modulation of the functions. (Z)‐NCTS is an RNA‐mismatch‐binding small molecule that recognizes 5′‐r(XGG)‐3′/5′‐r(XGG)‐3′ sequences (X=U or A) and acts as a molecular glue for RNA. The binding of (Z)‐NCTS brings two distinct 5′‐r(XGG)‐3′ domains into contact with each other, and this can result in higher‐order structural changes of target RNAs. We applied (Z)‐NCTS to induce the formation of a proposed tertiary structure of a ribozyme together with activation of RNA‐cleaving ability. The concept of a molecular glue could inspire new small‐molecule‐based strategies for regulating biological functions: a synthetic small molecule targeting functional RNAs could regulate the RNA structure and function.
Some Recent Advances in the Design and Use of Molecular Balances for the Experimental Quantification of Intramolecular Noncovalent Interactions of π Systems
Authors: Aliev Abil E. , Motherwell William B.
Published: May 2019

Herein, various molecular balances used for comparing the strengths of intramolecular noncovalent interactions are reviewed. Our overview indicates that considerable quantitative insight into the strength of noncovalent interactions can be gained through the careful design of molecular balances. Many exciting opportunities certainly exist for the design of further new balances to quantify and dissect the relative strengths of noncovalent interactions as a function of solvation and the importance of the many factors that contribute to overall molecular recognition. However, even simple model molecules can show a multiplicity of intramolecular noncovalent interactions acting in a combined fashion. It is therefore essential to undertake a detailed computational analysis to identify all possible noncovalent interactions present in a selected molecular balance prior to a quantitative experimental assessment of the strength of a particular noncovalent interaction. It is also argued that the words “torsion” and “molecular balance” seem to have become inextricably linked and, in consequence, even top pan and seesaw balances have been mistakenly referred to in these terms.
A Self‐Assembled Cage with Endohedral Acid Groups both Catalyzes Substitution Reactions and Controls Their Molecularity
Authors: Bogie Paul M. , Holloway Lauren R. , Ngai Courtney , Miller Tabitha F. , Grewal Divine K. , Hooley Richard J.
Published: May 2019

A self‐assembled Fe4L6 cage complex internally decorated with acid functions is capable of accelerating the thioetherification of activated alcohols, ethers and amines by up to 1000‐fold. No product inhibition is seen, and effective supramolecular catalysis can occur with as little as 5 % cage. The substrates are bound in the host with up to micromolar affinities, whereas the products show binding that is an order of magnitude weaker. Most importantly, the cage host alters the molecularity of the reaction: whereas the reaction catalyzed by simple acids is a unimolecular, SN1‐type substitution process, the rate of the host‐mediated process is dependent on the concentration of nucleophile. The molecularity of the cage‐catalyzed reaction is substrate‐dependent, and can be up to bimolecular. In addition, the catalysis can be prevented by a large excess of nucleophile, where substrate inhibition dominates, and the use of tritylated anilines as substrates causes a negative feedback loop, whereby the liberated product destroys the catalyst and stops the reaction.
Organic Mesopore Generating Agents (OMeGAs) for Hierarchical Zeolites: Combining Functions on Multiple Scales
Authors: Hong Mei , Dong Lei , Yang Shihe
Published: May 2019

In the synthesis of porous zeolites, small organic molecules usually function as organic structure‐directing agents (OSDAs) or zeolite growth modifiers (ZGMs), while mesoporous zeolites are typically synthesized by employing the physical space‐filling strategy with mesoscale templates including carbons, surfactants, and polymers. Recently, we discovered that a class of small organic molecules including the common amino acids could mediate the formation of zeolite mesopores based on a chemical bond‐breaking mechanism. This class of organic mesopore generating agents (OMeGAs) are distinguished by their ability to form organic anions in situ. In this minireview, we briefly introduce the widely recognized role of OSDA and ZGM, and then focus on the interesting function of OMeGA for the intracrystalline void generation. Comparison of OMeGA with the mesoscale templates especially surfactants are made in terms of their mesopore‐forming mechanisms, and the potential implications on a possible dissociative‐associative crystallization pathway are discussed. We end this review with the prospects of future research on the small molecule OMeGA, such as function integration and structure optimization.
Dalbavancin Population Pharmacokinetic Modeling and Target Attainment Analysis
Authors: Carrothers Timothy J. , Chittenden Jason T. , Critchley Ian
Published: May 2019

Dalbavancin is indicated for the treatment of acute bacterial skin and skin structure infections caused by susceptible gram‐positive microorganisms. This analysis represents the update of the population pharmacokinetics (popPK) modeling and target attainment simulations performed with data from the single‐dose safety and efficacy study and an unrelated but substantial revision of the preclinical pharmacokinetic/pharmacodynamic target (fAUC/MIC, free area under concentration‐time curve/minimum inhibitory concentration ratio). A 3‐compartment distribution model with first‐order elimination provided an appropriate fit, with typical dalbavancin clearance of 0.05 L/h and total volume of distribution of ∼15 L. Impact of intrinsic factors was modest, although statistically significant (P < .05) relationships with total clearance were found for the following covariates: creatinine clearance, weight, and albumin — dose adjustment was only indicated for severe renal impairment. Under the new nonclinical target, simulations of the popPK model projected that >99% of subjects would achieve the nonclinical target at MIC values up to and including 2 mg/L.
Potential‐Energy Surface and Dynamics Simulation of THBDBA: An Annulated Tetraphenylethene Derivative Combining Aggregation‐Induced Emission and Switch Behavior
Authors: Ding Wei‐Lu , Peng Xing‐Liang , Cui Gang‐Long , Li Ze‐Sheng , Blancafort Lluís , Li Quan‐Song
Published: May 2019

Electronic structure calculations and nonadiabatic dynamics simulations were carried out on the excited state decay mechanism of a typical aggregation‐induced emission (AIE)‐active molecule, 10,10′,11,11′‐tetrahydro‐5,5′‐bidibenzo[a,d][7]annulenylidene (THBDBA), which was experimentally found to be almost non‐emissive in THF solution but highly luminescent as an aggregate. At the MS‐CASPT2//CASSCF level, the decay path from S1 leads to a conical intersection (CI) seam with the ground state (S0) via a cyclization process of two neighboring phenyl groups. Nonadiabatic dynamics simulations of 367 surface hopping trajectories show that all the structures of hopping points resemble those of the S1/S0 CI seam with cyclized geometry. The final structures of trajectories hopping to S0 belong to either Franck‐Condon (FC) like structures (66.8 %) or cyclized conformers (33.2 %), which agrees well with the experimental result of 23 % cyclization product (Y. Cai et al. Chem. Sci., 2011, 2, 2029–2034). Our results also indicate that long‐time irradiation leads to a photostationary state where the open and cyclized forms interconvert photochemically. The preference for photocyclization over double bond isomerization is due to the rigidity of the dihydrofulvene rings. From the point of view of AIE, the calculations suggest that THBDBA follows our restricted access to a CI (RACI) model because the photocyclization requires large displacements of the phenyl rings. These displacements must be blocked in the aggregate phase, inhibiting the decay and leading to luminescence. Our study contributes to understand the AIE and switch behavior of THBDBA and will be useful to support the design of new molecules with these features.
A per‐protocol initiation of sacubitril/valsartan in an advanced heart failure disease management programme in the Middle East Gulf Region
Authors: Atallah Bassam , Sadik Ziad G. , Hisham Mohamed , Kalagieh Oussama , Hamour Iman , Gabra Guirgis , El Banna Mosaad , Soliman Medhat , Cherfan Antoine , Bader Feras
Published: May 2019

Aims

The aim of this study is to evaluate the utilization and success in therapy intensification after initiation of sacubitril/valsartan using a specified protocol within an advanced heart failure and transplant programme in the Middle East Gulf Region.

Methods and results

We studied a single‐centre, retrospective cohort in a 364‐bedded multi‐speciality hospital located in the United Arab Emirates (February 2016 to July 2017). The advanced heart failure and transplant programme formulated an institutional protocol for initiation of sacubitril/valsartan with defined criteria for switching from angiotensin‐converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Prescribing this drug is intended for patients with heart failure with reduced ejection fraction with left ventricular ejection fraction ≤40%. We excluded patients (i) with age below 18 years or (ii) initiated on sacubitril/valsartan from an outside hospital with or without follow‐up in our outpatient clinic. We included 102 patients with an average initial dose of 78.9 ± 44.2 mg twice daily. Only 17 patients were on target doses of ACEI or ARB prior to switching to sacubitril/valsartan. Up‐titration was successful in 55 patients during the follow‐up period. In addition, 6.9% patients were hospitalized with heart failure exacerbation. In patients with elevated baseline serum potassium prior to initiating this medication, the serum potassium levels decreased post‐initiation by 0.5 ± 0.3 mmol/L (P = 0.0008).

Conclusions

Initiating sacubitril/valsartan through a defined protocol selects for appropriate candidates and guides starting dose and titration. Overall, significant success can be achieved in replacing ACEI or ARB by sacubitril/valsartan in symptomatic heart failure with reduced ejection fraction patients.
A Photoswitchable Triple Chemosensor for Cyanide Anion Based on Dicyanovinyl‐Functionalized Dithienylethene
Authors: Li Ziyong , Dai Yijie , Lu Zhiqiang , Pei Yingying , Song Yufei , Zhang Lilei , Guo Hui
Published: May 2019

The development of new sensors for the accurate detection of cyanide anion has attracted more and more attention due to their potential applications in environmental and biological systems. Here, two novel near‐infrared (NIR) photochromic compounds 1a and 1b, which were modified by the dicyanovinyl fragment with cyanide recognition function, have been developed. Surprisingly, 1a presented an unprecedented triple sensing performance for cyanide anion (colorimetric‐fluorescent‐colorimetric), which can be utilized as a potential precision sensor for CN– in environmental and biological systems. Although 1b did not show triple detection behavior for CN–, it could recognize CN– and F– synchronously and selectively by naked eyes. Moreover, their NIR photochromic behaviors could be modulated by the cyanide anion. Their sensing mechanism for CN– or F– was confirmed by absorption spectral studies, NMR titration, and DFT calculations.
Catalytic Friedel‐Crafts Reactions on Saturated Heterocycles and Small Rings for sp3‐sp2 Coupling of Medicinally Relevant Fragments
Authors: Croft Rosemary A. , Dubois Maryne A. J. , Boddy Alexander J. , Denis Camille , Lazaridou Anna , Voisin‐Chiret Anne Sophie , Bureau Ronan , Choi Chulho , Mousseau James J. , Bull James A.
Published: May 2019

gem‐Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4‐ to 6‐membered O‐ and N‐heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3‐Diaryltetrahydrofurans, 4,4‐diaryltetrahydropyrans, 3,3‐diarylpyrrolidines, 4,4‐diaryl‐piperidines, as well as diarylcyclobutanes are examined, with results for 3,3‐diaryloxetanes and 3,3‐diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5‐ and 6‐membered substrates by elimination of water are obtained under the same reaction conditions.
Rare variant association testing for multicategory phenotype
Authors: Bocher Ozvan , Marenne Gaëlle , Saint Pierre Aude , Ludwig Thomas E. , Guey Stéphanie , Tournier‐Lasserve Elisabeth , Perdry Hervé , Génin Emmanuelle
Published: May 2019

Genetic association studies have provided new insights into the genetic variability of human complex traits with a focus mainly on continuous or binary traits. Methods have been proposed to take into account disease heterogeneity between subgroups of patients when studying common variants but none was specifically designed for rare variants. Because rare variants are expected to have stronger effects and to be more heterogeneously distributed among cases than common ones, subgroup analyses might be particularly attractive in this context. To address this issue, we propose an extension of burden tests by using a multinomial regression model, which enables association tests between rare variants and multicategory phenotypes. We evaluated the type I error and the power of two burden tests, CAST and WSS, by simulating data under different scenarios. In the case of genetic heterogeneity between case subgroups, we showed an advantage of multinomial regression over logistic regression, which considers all the cases against the controls. We replicated these results on real data from Moyamoya disease where the burden tests performed better when cases were stratified according to age‐of‐onset. We implemented the functions for association tests in the R package “Ravages” available on Github.
Memory improvement in African Americans with amnestic mild cognitive impairment
Authors: Rovner Barry W. , Casten Robin J. , Leiby Benjamin
Published: May 2019

Objective

Amnestic mild cognitive impairment (aMCI) has an uncertain course. Valid methods to evaluate memory change will best identify predictors of course. This issue is especially relevant to older persons in minority groups, who may have encountered life course factors that adversely affect cognition.

Methods/Design

Growth curve mixture models were used to identify trajectories of memory test scores obtained every 6 months over 2 years in 221 African Americans with aMCI.

Results

Participants sorted into two classes, with clinically and statistically significant differences in memory scores over time. Class 1 (n = 28 [14.7%]) had sustained improved scores. Class 2 (n = 162 [85.3%]) scores remained low, fluctuated, or declined. Class 1 had better baseline cognition and daily function than class 2.

Conclusions

The observed rate of improved memory is lower than reported reversion rates from aMCI to normal cognition. Evaluating trajectories of memory test scores rather than changes in categorical diagnoses of aMCI, which may depend on recalling (or not recalling) one or two words, may yield a more valid indicator of cognitive change.

These approaches require further study in minority groups.
Intricate role of yes‐associated protein1 in human liver cirrhosis: TGF‐β1 still is a giant player
Authors: Mohagheghi Sina , Geramizadeh Bita , Nikeghbalian Saman , Khodadadi Iraj , Karimi Jamshid , Khajehahmadi Zohreh , Gharekhanloo Farideh , Tavilani Heidar
Published: May 2019

Numerous investigations have been performed on the role of the transforming growth factor‐β1 (TGF‐β1) pathway in the development of chronic liver diseases (CLDs); however, they failed to explain the underlying mechanism of its pathogenesis, suggesting that other alternative pathways might have been overlooked. The involvement of yes‐associated protein1 (YAP1) has been attributed to liver fibrosis; yet, the precise function of this protein has not been fully understood. Therefore, this study aimed to investigate the activity of the YAP1 pathway in human liver cirrhosis (regardless of its causality) and its correlation with the TGF‐β1 and sonic hedgehog (SHH) pathways. In this case–control study, the immunohistochemical and quantitative real‐time polymerase chain reaction analyses were carried out to determine the activation of the YAP1 pathway in patients with liver cirrhosis (n = 38) and control 1 individuals (n = 10). The western blot analysis and ELISA method were also performed to assess the SHH and TGF‐β1 pathways. Although significantly increased expression of cytoplasmic YAP1 was found in patients with liver cirrhosis (P < 0.045), the rate of the nuclear YAP1 expression was similar to that of the control 1 subjects. Moreover, the hepatic expression of amphiregulin (AREG), known as the YAP1 target, along with proteins involved in the TGF‐β1 pathway was significantly elevated in all cirrhotic patients, compared with the control subjects. Our results showed that the increased activity of the TGF‐β1 pathway is strongly associated with the expression of AREG, denoting a direct and positive relationship between the TGF‐β1 and YAP1 pathways. It seems that, unlike the TGF‐β1 and SHH pathways, the YAP1 pathway does not play a significant role in the development of liver cirrhosis.
Visible light‐induced photocatalytic and antibacterial activity of N‐doped TiO2
Authors: Iwatsu Misato , Kanetaka Hiroyasu , Mokudai Takayuki , Ogawa Toru , Kawashita Masakazu , Sasaki Keiichi
Published: May 2019

Previous reports of some studies have described that nitrogen (N)‐doped titanium dioxide (TiO2) exhibits photocatalytic antibacterial activity under visible light irradiation and that reactive oxygen species (ROS) is involved in its activity. For prevention and treatment of peri‐implantitis, an inflammatory lesion caused by the bacterial infection of plaque adhering to the circumference of an implant, we considered that applying N‐doped TiO2 to dental implant surfaces can be effective. For this study, we aimed at evaluating visible light‐induced antibacterial activity of titanium (Ti) treated with NaOH and hot water, and subsequently heated in an ammonia (NH3) gas atmosphere at 500°C for 3 hr to quantify the generated amount of ROS available for antibacterial activity. N‐doped anatase‐type titania (TiO2‐xNx) is formed on the Ti substrate surface. Under visible light, markedly more hydroxyl radicals were generated with a nitrogen‐doped titanium dioxide plate than with a pure titanium plate. Hydrogen peroxide exhibited the same tendency. Furthermore, it showed visible light‐induced antibacterial effects over Escherichia coli. Results demonstrate that N‐doped TiO2 can be useful as a dental implant surface with low risk of postoperative infection when using visible light irradiation.
Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended‐Release Case Study
Authors: Kim Sarah , Sharma Vishnu D. , Lingineni Karthik , Farhan Nashid , Fang Lanyan , Zhao Liang , Brown Joshua D. , Cristofoletti Rodrigo , Vozmediano Valvanera , Ait‐Oudhia Sihem , Lesko Lawrence J. , Trame Mirjam N. , Schmidt Stephan
Published: May 2019

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended‐release (ER) tablets on dissolution, pharmacokinetic, and exercise‐induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach. Using a previously developed physiologically based absorption pharmacokinetic model in DDDPlus and GastroPlus, we simulated the changes in drug release and exposure as the result of quantitative changes in the release‐controlling excipient, hydroxylpropylmethylcellulose, for 50 and 200 mg. The similarity of dissolution profiles was assessed using thef2test, and bioequivalence was tested on the simulated pharmacokinetic profiles. We used the simulated concentration‐time profiles following formulation changes as pharmacokinetic input into a population pharmacokinetic/pharmacodynamic model newly developed in NONMEM to determine if changes in pharmacokinetics lead to clinically significant changes in pharmacodynamics. Pharmacodynamic assessment was based on the percentage reduction in the EIHR from baseline. Therapeutic effect was considered similar when the model‐predicted EIHR was within 50% to 85% of the average maximum EIHR of healthy 30‐year‐old subjects. A 40% or more increase in the release rate constant resulted in dissimilarity in dissolution profiles and bioINequivalence in pharmacokinetics for both 50 and 200 mg. Formulation‐related differences in drug release of metoprolol ER tablets can lead to differences in pharmacokinetics. However, the evaluated pharmacokinetic differences do not lead to clinically meaningful differences in EIHR, suggesting that EIHR may not be sensitive enough to detect changes in pharmacokinetics of metoprolol ER products.
Optic nerve sonography and ophthalmic artery Doppler velocimetry in healthy pregnant women: an Australian cohort study
Authors: Kane Stefan C. , Dennis Alicia T. , Da Silva Costa Fabrício , Kornman Louise H. , Cade Thomas J. , Brennecke Shaun P.
Published: May 2019

Purpose

Maternal ocular sonography offers a window into cerebrovascular and intracranial pressure changes in pregnancy. This study aimed to determine the Doppler velocimetric variables of the ophthalmic artery, and the mean diameter of the optic nerve sheath (ONSD), in an Australian cohort of healthy pregnant women.

Methods

A prospective observational cohort study of healthy women with uncomplicated singleton pregnancies in the third trimester was undertaken in a tertiary maternity service. A single prenatal ultrasonographic examination was performed on all participants, with a postnatal examination performed on a subgroup with uncomplicated deliveries.

Results

Fifty women were examined at a mean gestation of 35 weeks. The mean ± SD Doppler variables in the ophthalmic artery were peak systolic velocity (PSV) 41.89 ± 13.13 cm/s, second peak velocity 20.63 ± 8.97 cm/s, end diastolic velocity 9.29 ± 5.13 cm/s, pulsatility index 1.97 ± 0.53, resistive index 0.78 ± 0.07, peak ratio (second peak velocity/PSV) 0.49 ± 0.12, while the mean ONSD was 4.34 ± 0.4 mm. None of these variables had a demonstrable relationship with gestation or mean arterial pressure (MAP), nor did the sheath diameter have a relationship with any of the Doppler variables.

Conclusions

The ocular sonographic variables observed in this population are similar to those reported in other cohorts. No clear relationship could be identified in this cohort between ophthalmic artery Doppler variables and the ONSD, and between each of these variables and gestation or MAP.
Scanning electron microscopy and histomorphology of the epiglottis in dromedaries: A study revealing unusual structure with the probable functional role
Authors: Eshrah Eman A. , Kassab Ahmed A.
Published: May 2019

While epiglottis is essentially a mammalian structure, studying its microstructure in any placental model will add an important information to the field of comparative anatomy and the related branches of biology. The aim of this study was to describe the structure of the epiglottis in dromedary camels using light and scanning electron microscopy (SEM), with reference to the possible functions. A total of 11 epiglottis cartilages from 11 larynges were used. The study revealed unusual, deeply situated glands just beneath the cartilage plate. They have unusually, wide surface‐openings, while their ducts were partly located within the cartilage. This is presumed to be an adaptation to the need for rapid and efficient mucosal surface hydration in the arid conditions. The possible secretion transport mechanisms in these glands were also discussed. Furthermore, the SEM revealed for the first time, the presence of taste buds in camel epiglottis. However, in histological sections, visibility of taste buds was dependent upon the staining techniques. The taste buds were not seen with standard H& E stain, as they blended imperceptibly with the surrounding epithelium. Conversely, Mallory's trichrome showed contrasting colors, and taste buds were visible. In conclusion, camel epiglottis has an unusual structure, which may be correlated to environmental adaptation and important for the general health of upper respiratory tract in this species.
Quantitative vs. semiquantitative assessment of intratumoral susceptibility signals in patients with different grades of glioma
Authors: Bhattacharjee Rupsa , Gupta Rakesh Kumar , Patir Rana , Vaishya Sandeep , Ahlawat Suneeta , Singh Anup
Published: May 2019

Background

Susceptibility weighted imaging (SWI) provides vascular information and plays an important role in improving the diagnostic accuracy of preoperative glioma grading. Intratumoral susceptibility signal intensities (ITSS) obtained from SWI has been used in glioma grading. However, the current method for estimation of ITSS is semiquantitative, manual count‐dependent, and includes hemorrhage as well as vasculature.

Purpose

To develop a quantitative approach that calculates the vasculature volume within tumors by filtering out the hemorrhage from ITSS using R2* values and connected component analysis‐based segmentation algorithm; to evaluate the accuracy of the proposed ITSS vasculature volume (IVV) for differentiating various grades of glioma; and compare it with reported semiquantitative ITSS approach.

Study Type

Retrospective.

Subjects

Histopathologically confirmed 41 grade IV, 19 grade III, and 15 grade II glioma patients.Field Strength/Sequence: SWI (four echoes: 5.6, 11.8, 18, 24.2 msec) along with conventional MRI sequences (T2‐weighted, T1‐weighted, 3D‐fluid‐attenuated inversion recovery [FLAIR], and diffusion‐weighted imaging [DWI]) at 3.0T.

Assessment

R2* relaxation maps were calculated from multiecho SWI. The R2* cutoff value for hemorrhage ITSS was determined. A segmentation algorithm was designed, based on this R2* hemorrhage combined with connected component shape analysis, to quantify the IVV from all slices containing tumor by filtering out hemorrhages. Semiquantitative ITSS scoring as well as total ITSS volume (TIV) including hemorrhages were also calculated.

Statistical Tests

One‐way analysis of variance (ANOVA) and Tukey–Kramer post‐hoc tests were performed to see the difference among the three grades of the tumor (II, III, and IV) in terms of semiquantitative ITSS scoring, TIV, and IVV. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the three methods individually in discriminating between grades of glioma.

Results

One‐way ANOVA showed that only the proposed IVV significantly differentiated different grades of gliomas having visible ITSS. ROC analysis showed that IVV provided the highest AUC for the discrimination of grade II vs. III (0.93), grade III vs. IV (0.98), and grade II vs. IV glioma (0.94). IVV also provided the highest sensitivity and specificity for differentiating grade II vs. III (87.44, 98.41), grade III vs. IV (97.15, 94.12), and grade II vs. IV (98.72, 92.31).

Data Conclusion

The proposed quantitative method segregates hemorrhage from tumor vasculature. It scores above the existing semiquantitative method in terms of ITSS estimation and grading accuracy.

Level of Evidence: 4

Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:225–233.
Acute and one year outcome of premature ventricular contraction ablation guided by contact force and automated pacemapping software
Authors: Capulzini Lucio , Vergara Pasquale , Mugnai Giacomo , Salghetti Francesca , Abugattas Juan Pablo , El Bouchaibi Said , Iacopino Saverio , Sieira Juan , Enriquez Coutiño Hugo , Ströker Erwin , Brugada Pedro , Chierchia Gianbattista , de Asmundis Carlo
Published: May 2019

Background

Radiofrequency (RF) ablation is a well‐established approach to treat premature ventricular contractions (PVC) and is associated with good outcomes.

Aim

The present study sought to analyze the acute efficacy and 1‐year outcomes of PVC ablation using RF technology with an approach based on automated pace‐mapping and contact force (CF) information.

Methods

Sixty‐one consecutive patients (52.4% males, age 45.9 ± 12.5) underwent catheter ablation for symptomatic monomorphic PVC. All procedures were guided by a 3‐dimensional mapping system; site of ablation was selected based on PASO™ aided pace‐mapping; RF was started on the selected location when stable catheter position with >10 g of CF were obtained.

The procedure was defined as acutely effective if the PVC was eliminated and it did not recur during within 30 minutes. Long‐term efficacy was defined as a decrease by more than 95% at 1 year of the initial PVC burden at ECG Holter monitoring.

Results

The PVC ablation was performed in the right ventricular outflow tract in 37 patients (60.7%), left ventricle in 15 patients (24.6%), coronary cusps in 6 patients (9.8%), right ventricle in 3 patients (4.9%); PVC ablation was acutely successful in 59 of patients (96.7%). At 1‐year efficacy was obtained in 57 patients (93.4%). No major complications occurred. Mean procedural and fluoroscopy time were 94.5 ± 20.9 and 4.3 ± 2.5 minutes respectively.

Conclusion

Premature ventricular contraction RF ablation mainly guided by PASO™ and CF showed high success rate in both acute and 1‐year follow‐up (96.7% and 93.4% respectively). The best efficacy cut‐off for RF ablation of PVCs has been identified in presence of both PASO™ ≥95% and CF >10 g.
Changes in daily temperature extremes relative to the mean in Coupled Model Intercomparison Project Phase 5 models and observations
Authors: Gross Mia H. , Donat Markus G. , Alexander Lisa V.
Published: May 2019

Changes in characteristics of the distribution of temperature, in addition to shifts towards warmer temperatures, can have substantial implications for society and the environment. A change in shape, for example, can be caused by differences in the rates of warming of cold and warm extremes relative to average temperatures. These rates of warming vary both spatially and temporally, with strong geographic and seasonal differences in how local extremes are changing relative to local average temperatures. In this paper, we investigate how seasonal warm and cold tails of both daily maximum and minimum temperatures are changing relative to corresponding seasonal mean temperatures. Analysing gridded observations over land areas and climate models from the CMIP5 archive, we show that in recent decades, the greatest differences between warming rates of extremes and the mean occur in the cold tails of the distribution for many regions in the Northern Hemisphere extratropics during all seasons except boreal summer. Globally, June through August show the smallest differences between extremes and mean warming rates. While the climate models show relatively low spatial correlations in their change patterns with each other as well as the observations for past decades, future simulated changes are shown to be systematic and robust, with a clear signal in the warming of extremes relative to the mean. The strongest differences between warming rates of extremes and the mean are projected for Northern Hemisphere mid‐ to high‐latitude regions, where the cold tails warm more than the average for all seasons except boreal summer. This is especially widespread in autumn and spring, where the models predict cold extremes to warm at least 3°C more than mean temperatures for much of the Northern Hemisphere extratropics. The results presented here highlight the importance of considering all aspects of the distribution when analysing changes in temperature.
The Furan Fatty Acid 9M5 Acts as a Partial Ligand to Peroxisome Proliferator‐Activated Receptor gamma and Enhances Adipogenesis in 3T3‐L1 Preadipocytes
Authors: Lauvai Judith , Becker Anna‐Karina , Lehnert Katja , Schumacher Monika , Hieronimus Bettina , Vetter Walter , Graeve Lutz
Published: May 2019

A food that has been praised for its beneficial effects on overall health is fish, particularly its polyunsaturated n‐3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). However, it has recently been suggested that minor fatty acids such as furan fatty acids are needed in combination with DHA and EPA to exert these positive effects of fish and fish oils. Only recently have furan fatty acids become available in quantities that allow the investigation of their biofunctional properties. In this study, the uptake and effect of the furan fatty acid 9‐(3‐methyl‐5‐pentylfuran‐2‐yl)‐nonanoic acid (9M5) as a sole component and in combination with DHA and EPA on adipogenesis were analyzed using the 3T3‐L1 cell model. 9M5 is taken up and metabolized into 7M5, 5M5, and 3M5 in 3T3‐L1 adipocytes during a 24‐h period as shown with gas chromatography with mass spectrometry (GC/MS). Furthermore, 9M5 significantly increased lipid accumulation during the differentiation process of 3T3‐L1 preadipocytes into adipocytes. In addition, the combinations of DHA + 9M5 and EPA + DHA + 9M5 also exerted a significant increase compared to control adipocytes. 3T3‐L1 cells incubated with 9M5 resulted in an increased protein expression of PPARγ, C/EBPα, FABP4, and adiponectin, although not to the extent that DHA as a sole component or DHA + 9M5 did. Earlier studies have shown that DHA is a natural ligand for PPARγ, thus being a potential alternative to the antidiabetic thiazolidinediones. We show that 9M5 activates a PPARγ‐responsive reporter gene and could therefore be a natural ligand for PPARγ.
Controlled Synthesis of Block Copolymers by Mechanistic Transformation from Atom Transfer Radical Polymerization to Iniferter Process
Authors: Aydogan Cansu , Ciftci Mustafa , Yagci Yusuf
Published: May 2019

A straightforward transformation protocol combining two distinct living polymerization methods for the controlled synthesis of block copolymers is described. In the first step, bromo‐terminated poly(methyl methacrylate) is prepared by atom transfer radical polymerization (ATRP). Then, a bromide end group is substituted with a triphenylmethyl (trityl) functionality under visible light irradiation using dimanganese decacarbonyl (Mn2(CO)10) photochemistry. The resulting polymers with trityl end groups are used as macroiniferter for the polymerization of styrene and tert‐butyl acrylate (tBA) to yield desired block copolymers with narrow molecular weight distribution. Moreover, the amphiphilic copolymers with acrylic acid functionalities are obtained by the hydrolyzation of poly(tert‐butyl acrylate) containing block copolymers with trifluoroacetic acid.
Vascular pedicle division during free flap re‐inset in pharyngoesophageal reconstruction
Authors: Yegin Mehmet Emre , Chen Shih‐Heng , Chen Hung‐Chi
Published: May 2019

Background

Free intestinal flaps for pharyngolaryngoesophagus reconstruction may require revision operations, including free flap re‐inset for functional improvement. This report aimed to present our experience on vascular pedicle division at the secondary procedure of free flap re‐inset for functional improvement in pharyngoesophageal reconstruction.

Patients and Methods

Eight male and seven female patients, with a mean age of 52 years old (range: 28–78 years), underwent pharyngoesophageal stricture (n = 7) and hypopharynx carcinoma reconstruction (n = 8) with three free jejunal and 12 free ileocolonic flaps. During revision procedure to shorten the flap for functional improvement, which was performed at 3 months after the initial operation, there were 11 venous and 4 arterial pedicle division cases. The intestinal flap circulation signs, such as presence of normoperistalsis, pink color, moderate secretion, and bleeding at puncture site, were observed for 1 hr.

Results

No venous pedicle divisions required reanastomosis. However, all arterial pedicle division cases required immediate restoration with a vein graft because of immediate intestinal changes. No postoperative complications were seen, excluding a patient with anterior wall reconstruction who had arterial division and reanastomosis. Patients were followed up for a median duration of 28 months.

Conclusion

For revision operations involving free intestinal flaps, the arterial pedicle must be protected or repaired if transected, whereas the venous pedicle does not necessitate such a maneuver.
Accurate colorectal tumor segmentation for CT scans based on the label assignment generative adversarial network
Authors: Liu Xiaoming , Guo Shuxu , Zhang Huimao , He Kan , Mu Shengnan , Guo Yu , Li Xueyan
Published: May 2019

Purpose

Colorectal tumor segmentation is an important step in the analysis and diagnosis of colorectal cancer. This task is a time consuming one since it is often performed manually by radiologists. This paper presents an automatic postprocessing module to refine the segmentation of deep networks. The label assignment generative adversarial network (LAGAN) is improved from the generative adversarial network (GAN) and assigns labels to the outputs of deep networks. We apply the LAGAN to segment colorectal tumors in computed tomography (CT) scans and explore the performances of different combinations of deep networks.

Material and methods

A total of 223 patients with colorectal cancer (CRC) are enrolled in the study. The CT scans of the colorectal tumors are first segmented by FCN32 and Unet separately, which output probabilistic maps. Then, the probabilistic maps are labeled by the LAGAN and finally, the binary segmentation results are obtained. The LAGAN consists of a generating model and a discriminating model. The generating model utilizes the probabilistic maps from deep networks to imitate the distribution of the ground truths, and the discriminating model attempts to distinguish generations and ground truths. Through competitive training, the generating model of the LAGAN can realize label assignments for the probabilistic maps.

Results

The LAGAN increases the DSC of FCN32 from 81.83% ± 0.35% to 90.82% ± 0.36%. In the Unet‐based segmentation, the LAGAN increases the DSC from 86.67% ± 0.70% to 91.54% ± 0.53%. It takes approximately 10 ms to refine a single CT slice.

Conclusions

The results demonstrate that the LAGAN is a robust and flexible module, which can be used to refine the segmentation of diverse deep networks. Compared with other networks, the LAGAN can achieve desirable segmented accuracy for colorectal tumors.