bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Studies of the Effect of Different Types of Iron Tonics on Umbilical and Middle Cerebral Blood Flow in Cases of Moderate Iron Deficiency Anemia in Late Second Trimester of Pregnant Women
Authors: Elbehiry Basma M. , El-Dakhakhni Raghda A. , Dawood Mohamed F. , Esmail Mohamed M.
Published: March 2021

Background: Maternal anemia is frequently associated with premature delivery, reduced neonatal weight, infant iron deficiency, neonatal death, and low Apgar scores at 1 min. It is also suspected to reduce the oxygen supply to the growing fetus, leading to the redistribution of fetal blood flow. This study aims to evaluate the effect of the different types of iron medications given to anemic patients on fetal Doppler indices namely umbilical artery and middle cerebral artery in the late second trimester of pregnancy.

Materials and Methods: This cohort prospective study. This study conducted at department of obstetrics and gynecology at Tanta university hospital. Participants consisted of 90 pregnant women during their gestational age (20-28 weeks) they were attended or admitted to obstetric unit.divided into 3 groups. Lactoferrin group included 30 cases received 250 mg lactoferrin capsules once daily for 4 weeks. Iron amino acid chelated group included 30 cases received ferrous bis – glycine chelate (FeBC) 15 mg/day for 4 weeks. Ferrous fumarate group included 30 cases received 350 mg dried ferrous fumarate capsules once daily for 4 weeks. Pre-and post-treatment Doppler measurement of umbilical artery and middle cerebral artery parameter compared 4 weeks after the start of treatment for patients whose anemia successfully treated.

Results: Post hoc analysis of maternal serum hemoglobin of the studied groups show insignificant different between the groups. Pre- and Post-treatment follow-up of resistance index (RI) of the studied groups, Pre- and Post-treatment follow-up of pulsatility index (PI) of the studied groups, Post hoc analysis of pulsatility index (PI) of the studied groups and Post hoc analysis of resistance index (RI) of the studied groups show insignificant different between groups.

Conclusion: Based on our results, it can be concluded that cerebral vasodilatation due to severe maternal anemia is a reversible condition that can be corrected through the prompt treatment of anemia. Additionally, the three therapeutics tested in the current study showed a comparable effect in treating maternal anemia, with subsequent improvement of doppler indices.
The Effect of Different Exercise Intensities on Plasma Endostatin in Healthy Volunteers
Authors: Shah Inayat , Arif Tasleem , Baxendale Ron H. , Iftikhar Muhammad , Khan Alamgir
Published: March 2021

Background: Physical activity decreases the risk and development of many angiogenesis related health problems including atherosclerosis. Physiological influence of different physical activities on plasma endostatin concentration is contradictory. This study aimed to determine the effects of mild, moderate and vigorous exercise on the concentration of endostatin.

Methodology: 22 participants, 16 males (age = 30.6 ± 7.8 years) and 6 females (age = 26.5 ± 5 years) were recruited. Weekly session of different intensities exercise based on predicted maximum heart (60% (low), 70% (moderate) and 80% (vigorous)] were carried out. One pre and two post exercise samples were taken at 10 and 60 minutes.

Results: Low intensity exercise insignificantly decreased the endostatin concentration at 10 and 60 minutes (P = 0.5 and 0.8). However, moderate (P values = 0.022. 0.004) and vigorous intensities (P= < 0.001, 0.02) increased the endostatin concentrations significantly at both intervals respectively. The effects were not significantly influenced by gender, exercise mode (walking vs running), components of exercise (HR, Speed, Gradients, distance, duration) or metabolism during exercise (VO2 max, VCO2, RER, Energy expenditure).

Conclusion: Low intensity exercises did not influence endostatin concentration. However, moderate to high intensity exercises significantly increase endostatin concentration and may have potential benefits.
Willingness to Test for COVID-19: A Cross-Sectional Study on the Population in the Ha’il Region, KSA
Authors: Khalifa Amany M. , Alshammari Areeb F. , Alrimali Asma M. , Alshammari Rozan A.
Published: March 2021

Aims: To measure the degree to which the Ha’il community is willing to test for COVID-19 and assess the possible factors that may influence their decision.

Study Design: Descriptive and analytical cross-sectional study.

Place and Duration of Study: The study was conducted in Ḥaʼil Community. And the data was collected from October to November of 2020.

Methodology: Participants comprised of both Saudi and non-Saudi males and females who were 18 years or older and living within the Ha’il region. Participants were recruited via convenience sampling by distributing the electronic questionnaire throughout various social media platforms.

Results: Of the 664 participants, 80.9% reported their willingness to test for COVID-19 if they had olfactory dysfunction with, 80.3% reporting their willingness to test if they had difficulty breathing. However, only 61.7% of participants said that they would be willing to be tested if they had been in contact with someone who had tested positive, whilst they themselves were asymptomatic. More than half of the participants reported that they were confident in the results (81%). Bio-demographic factors that influence the degree of public trust were as follows; females (83.8%); living with others (81.8%); history of not gathering with more than 10 people outside their household (87.9%).

Conclusion: Our finding revealed that the vast majority of the Ha’il community are willing to test for COVID-19, with a high proportion of females, participants who are living with others and participants who do not usually mix with more than 10 people at the same time showing a greater degree of trust in the results of the COVID-19 test. Furthermore, when participants had experienced olfactory dysfunction or\and breathing difficulties themselves, they tended to exhibit greater trust in the COVID-19 test results.
Control Delivery of Multiple Growth Factors to Actively Steer Differentiation and Extracellular Matrix Protein Production
Authors: Damanik Febriyani F. R. , Verkoelen Niels , van Blitterswijk Clemens , Rotmans Joris , Moroni Lorenzo
Published: March 2021

In tissue engineering, biomaterials have been used to steer the host response. This determines the outcome of tissue regeneration, which is modulated by multiple growth factors (GFs). Hence, a sustainable delivery system for GFs is necessary to control tissue regeneration actively. A delivery technique of single and multiple GF combinations, using a layer‐by‐layer (LBL) procedure to improve tissue remodeling, is developed. TGF‐β1, PDGF‐ββ, and IGF‐1 are incorporated on tailor‐made polymeric rods, which could be used as a tool for potential tissue engineering applications, such as templates to induce the formation of in situ tissue engineered blood vessels (TEBVs). Cell response is analyzed in vitro using rat and human dermal fibroblasts for cellular proliferation, fibroblast differentiation, and extracellular matrix (ECM) protein synthesis. Results revealed a higher loading efficiency and control release of GFs incorporated on chloroform and oxygen plasma‐activated (COX) rods. Single PDGF‐ββ and IGF‐1 release, and dual release with TGF‐β1 from COX rods, showed higher cell proliferation when compared to COX rods alone. A substantial increase in α‐smooth muscle actin (α‐SMA) is also observed in GF releasing COX rods, with TGF‐β1 COX rods providing the most pronounced differentiation. A significant increase in collagen and elastin synthesis is observed on all GF releasing COX rods compared to control, with COX rods releasing TGF‐β1 and IGF‐1 providing the highest secretion. TGF‐β1 and IGF‐1 releasing COX rods induced higher Glycosaminoglycan (GAG)/DNA amounts than the other GF releasing COX rods. As PDGF‐ββ and TGF‐β1/PDGF‐ββ COX rods displayed the highest fibroblast attachment, these rods provided the highest total collagen and elastin production. The attractive results from efficiently incorporating single and multiple GFs on COX rods and their sustainable release to steer cellular behavior suggest a promising route to enrich the formation of in situ engineered tissues.
Mechanical Characteristics of Superimposed 316L Lattice Structures under Static and Dynamic Loading
Authors: Chang Chao , Wu Wei , Zhang Hui , Chen Jianjun , Xu Yongze , Lin Jinbao , Ding Lifen
Published: March 2021

Additive Manufacturing (AM) discrete patterns made of stainless steel 316 L offer potential energy absorption for engineering applications, including blast and impact protection systems and aircraft structure. Herein, three different superimposed stainless steel 316 L lattice structures varying rod diameter are manufactured by selective laser melting (SLM). Compression experiments and split Hopkinson pressure bar (SHPB) tests are conducted to determine the quasi‐static and impact behavior of different lattice structures for the strain rate from 10−3 to 1000 s−1. The compressive response, strain rate dependency, and energy absorption capacity of the lattice structures are mechanically characterized. In addition, numerical simulations are conducted to complement the experimental work in which the deformation modes of the lattice under mechanical responses have been studied. The results indicate that vertical truss in structure plays a bearing role in the whole process of compression, which is better than inclined truss structures. Due to the combined effect of two deformation modes in the superimposed structure, it has shown superior energy absorption capacity compared with other structures. The superiority of the superimposed structure provides a new idea for the design of lattice structure.
Antibody Engineered Platelets Attracted by Bacteria‐Induced Tumor‐Specific Blood Coagulation for Checkpoint Inhibitor Immunotherapy
Authors: Fan Jin‐Xuan , Liu Xin‐Hua , Wang Xia‐Nan , Niu Mei‐Ting , Chen Qi‐Wen , Zheng Di‐Wei , Wei Jian‐Shuang , Yang Xiao‐Quan , Zeng Xuan , Zhang Xian‐Zheng
Published: March 2021

Bacteria can act as a promising anti‐tumor platform due to their specific targeting capacity to the tumor microenvironment. In this study, it is discovered that intravenous administration of Escherichia coli TOP10 induces rapid and intense blood coagulation in tumor tissues instead of normal tissues. It is demonstrated that E. coli TOP10 can act as an activator of a coagulation cascade to trigger abnormal hemorrhage, blood coagulation, and inflammation with abundant macrophages recruitment in tumors. In addition, the recruited macrophages are principally polarized by lipopolysaccharide in the bacterial wall to the anti‐tumor M1‐like phenotype. Based on the above finding, coagulation‐tropism blood platelets decorated with CD47 antibodies (Anti‐CD47), which possess tropism for bacteria‐treated tumors are further prepared. As a result, Anti‐CD47 blocks the “don't eat me” signal from tumor cells, consequently promoting the phagocytosis of polarized M1‐like phenotype macrophages for tumor cells. This manipulation of local blood coagulation in tumors may find great potential for accurately delivering immune checkpoint inhibitors and facilitating tumor immunotherapy.
Recent Advances in Electrocatalysts for Proton Exchange Membrane Fuel Cells and Alkaline Membrane Fuel Cells
Authors: Xiao Fei , Wang Yu‐Cheng , Wu Zhi‐Peng , Chen Guangyu , Yang Fei , Zhu Shangqian , Siddharth Kumar , Kong Zhijie , Lu Aolin , Li Jin‐Cheng , Zhong Chuan‐Jian , Zhou Zhi‐You , Shao Minhua
Published: March 2021

The rapid progress of proton exchange membrane fuel cells (PEMFCs) and alkaline exchange membrane fuel cells (AMFCs) has boosted the hydrogen economy concept via diverse energy applications in the past decades. For a holistic understanding of the development status of PEMFCs and AMFCs, recent advancements in electrocatalyst design and catalyst layer optimization, along with cell performance in terms of activity and durability in PEMFCs and AMFCs, are summarized here. The activity, stability, and fuel cell performance of different types of electrocatalysts for both oxygen reduction reaction and hydrogen oxidation reaction are discussed and compared. Research directions on the further development of active, stable, and low‐cost electrocatalysts to meet the ultimate commercialization of PEMFCs and AMFCs are also discussed.
Solution‐Processed Lead‐Free Perovskite Nanocrystal Scintillators for High‐Resolution X‐Ray CT Imaging
Authors: Zhou Jiaer , An Kang , He Peng , Yang Jie , Zhou Chang , Luo Yi , Kang Wei , Hu Wei , Feng Peng , Zhou Miao , Tang Xiaosheng
Published: March 2021

The physical properties of scintillators determine X‐ray detection performance directly, which plays a vital role in computed tomography (CT) imaging for medical radiography and security checks. Recently, lead halide perovskite materials have shown higher photoluminescence quantum yield (PLQY) than conventional X‐ray scintillators, but there are still some limitations, including instability and the use of heavy metal lead. In this study, a low‐temperature solution method is used to prepare 0D lead‐free Cs3Cu2I5 perovskite nanocrystals (NCs), and a corresponding optical fiber panel with Cs3Cu2I5 NCs is fabricated for high‐resolution X‐ray CT imaging. The Cs3Cu2I5 NCs exhibit a high PLQY of 59% and outstanding stability for more than three months. Importantly, the Cs3Cu2I5 NCs show a high radioluminescence (RL) light yield, that is four times higher than that of CsPbBr3 NCs (80 kV, 70 µA). In addition, an X‐ray detector based on a Cs3Cu2I5 NC scintillator is designed. Using this system, a clear projection image of a chip is obtained, and a 3D CT image of a snail is reconstructed. Therefore, the use of lead‐free perovskite nanocrystal scintillators is a promising technique for commercial X‐ray detection.
Bayesian hybrid analytics for uncertainty analysis and real‐time crop management
Authors: Meenken Esther D. , Triggs Christopher M. , Brown Hamish E. , Sinton Sarah , Bryant Jeremy R. , Noble Alasdair D.L. , Espig Martin , Sharifi Mostafa , Wheeler David M.
Published: March 2021

Dynamic, deterministic agricultural models, and current machine learning technologies based on sensor data, enable and support decision making for on‐farm management. However, their predictions are subject to various sources of uncertainty. Hybrid analytics that leverage both modelled and sensor data provide predictive information that makes the best of both approaches in a timely fashion to inform operational decision making and enable inclusive uncertainty quantification. We describe and evaluate a probabilistic Bayesian data assimilation tool that combines the state variables from the Sirius wheat (Triticum aestivum L.) development model with time‐series environmental and leaf count data. Additionally, the uncertainty associated with input parameters is quantified via expert opinion. The Bayesian approach obtained point estimates through time that were accompanied by inclusive, probabilistic, 95% credible intervals. At the end of simulation, a typical model predicted a final leaf number of 6.6 leaves, Sirius alone predicted seven leaves and the mean of the observed data was 6.7 leaves. The 95% credible interval was estimated as 5.1–8.4 leaves. Importantly, the tool was able to “redirect” simulated outputs if input parameters such as minimum leaf number or base phyllochron were incorrectly specified, with the implication that on‐farm decision makers would have advance warning of variation in expected harvest date. Relatively few plants with time‐intensive data were sufficient to fit the model, however, more plants would be desirable to reduce the rather wide range of credible intervals. Nevertheless, the tool shows potential and could be readily implemented with low resource requirements, providing more finely tuned harvest date information, with probabilistic uncertainty quantification built‐in, for on‐farm decisions.
Effects of work stress, sleep, and shift work on suicidal ideation among female workers in an electronics company
Authors: Son Junseok , Lee Sangyoon
Published: March 2021

Background

Suicide is the leading cause of death in young adults in Korea. Stress in the workplace affects the suicide rate; young female workers are particularly vulnerable to adverse work environments. We investigated the relationships of shift work, sleep, and work stress to suicidal ideation.

Methods

This study used data from 508 female workers aged 22–40 years in an electronics company. Data on baseline characteristics, work patterns, sleep quality (using the Pittsburgh Sleep Quality Index), and work stress levels using the Korean Occupational Stress Scale (KOSS) were obtained from questionnaires. We examined associations between suicidal ideation and shift work, sleep quality, and KOSS scores.

Results

Suicidal ideation was significantly higher among shift workers (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.31–4.32), those with poor sleep (OR, 2.84; 95% CI, 1.68–4.84), and those with high work stress (OR, 3.30; 95% CI, 1.82–6.00). Both 3 × 12 h shift workers (OR, 2.98; 95% CI, 1.35–6.57) and 4 × 8 h shift workers (OR, 2.14; 95% CI, 1.03–4.45) had increased suicidal ideation. High work stress (OR, 11.55; 95% CI, 2.93–45.48) had stronger associations with suicidal ideation than poor sleep (OR, 3.86; 95% CI, 1.21–12.33) in shift workers. The combined effect of poor sleep and high KOSS on suicidal ideation was stronger in shift workers (OR, 13.39; 95% CI, 3.22–55.62) than day workers (OR, 4.31; 95% CI, 1.03–18.01).

Conclusions

Shift workers are more vulnerable than day workers to the combination of work stress and poor sleep quality as well as to work stress alone.
Struktur eines an virusähnliche Partikel gekoppelten Antigens: Analyse einer Impfstoff‐Formulierung
Authors: Jaudzems Kristaps , Kirsteina Anna , Schubeis Tobias , Casano Gilles , Ouari Olivier , Bogans Janis , Kazaks Andris , Tars Kaspars , Lesage Anne , Pintacuda Guido
Published: March 2021

Die Strukturbestimmung Wirkverstärker‐gekoppelter Antigene ist für eine rationale Impfstoffentwicklung unerlässlich, wurde aber bisher durch den recht geringen Antigengehalt in Impfstoff‐Formulierungen und durch deren heterogene Zusammensetzung erschwert. Wir zeigen, dass die Festkörper‐NMR mit Magic Angle Spinning (MAS) zur Bestimmung der Struktur des Influenza‐Virus‐Hämagglutinin‐Stiel‐Antigens verwendet werden kann, und dies sowohl in seiner freien Form sowie nach chemischer Kopplung an die Oberfläche großer virusähnlicher Partikel (VLPs). Die Steigerung der Sensitivität durch dynamische nukleare Polarisation (DNP) und Protonen‐Detektion bei schnellen MAS‐Raten ermöglicht es, den mit der Antigenverdünnung verbundenen Nachteil auszugleichen. Der Vergleich der MAS‐NMR‐Fingerabdrücke zwischen freier und VLP‐gekoppelter Antigenform liefert strukturelle Beweise für die Erhaltung seiner nativen Faltung nach der Bio‐Konjugation. Die hochempfindliche MAS‐NMR ist reif, um eine wichtige Rolle bei Impfstoffdesign, Formulierungsstudien und der Entwicklung von Herstellungsprozessen zu spielen.
NHC‐Catalyzed Desymmetrization of N‐Aryl Maleimides Leading to the Atroposelective Synthesis of N‐Aryl Succinimides
Authors: Barik Soumen , Shee Sayan , Das Soumik , Gonnade Rajesh G. , Jindal Garima , Mukherjee Subrata , Biju Akkattu T.
Published: March 2021

Although the construction of axially chiral C−C bonds leading to the atroposelective synthesis of biaryls and allied compounds are well‐known, the related synthesis of compounds bearing axially chiral C−N bonds are relatively rare. Described herein is the N‐heterocyclic carbene‐catalyzed atroposelective synthesis of N‐aryl succinimides having an axially chiral C−N bond via the desymmetrization of N‐aryl maleimides. The NHC involved intermolecular Stetter‐aldol cascade of dialdehydes with prochiral N‐aryl maleimides followed by oxidation afforded N‐aryl succinimides in good yields and ee values. Preliminary studies on rotation barrier for the C−N bond, the temperature dependence, and detailed DFT studies on mechanism are also provided.
Beyond Classical Coordination Chemistry: The First Case of a Triply Bridging Phosphine Ligand
Authors: Baranov Andrey Y. , Pritchina Elena A. , Berezin Alexey S. , Samsonenko Denis G. , Fedin Vladimir P. , Belogorlova Nataliya A. , Gritsan Nina P. , Artem'ev Alexander V.
Published: March 2021

The first example of a triply bridging (μ3‐P) phosphine ligand has been discovered in the crown‐shaped [Cu3(μ2‐Hal)3L] (Hal=Cl, Br, or I) complexes supported by tris[2‐(2‐pyridyl)ethyl]phosphine (L). Theoretical analysis completely confirms the observed μ3‐P‐bridging pattern, revealing the interaction of the same lone pair of phosphorus with three valence 4s‐orbitals of Cu atoms. The presented complexes exhibit outstanding blue phosphorescence (λem=442–465 nm) with the quantum efficiency reaching 100 %. The complex [Cu3(μ2‐I)3L] also exhibits remarkable thermo‐ and mechanochromic luminescence resulting in a sharp change in the emission colour upon external stimuli. These findings essentially contribute to coordination chemistry of the pnictine ligands.
Chemo‐Enzymatic Modification of the 5′ Cap Maintains Translation and Increases Immunogenic Properties of mRNA
Authors: van Dülmen Melissa , Muthmann Nils , Rentmeister Andrea
Published: March 2021

Eukaryotic mRNAs are emerging modalities for protein replacement therapy and vaccination. Their 5′ cap is important for mRNA translation and immune response and can be naturally methylated at different positions by S‐adenosyl‐l‐methionine (AdoMet)‐dependent methyltransferases (MTases). We report on the cosubstrate scope of the MTase CAPAM responsible for methylation at the N6‐position of adenosine start nucleotides using synthetic AdoMet analogs. The chemo‐enzymatic propargylation enabled production of site‐specifically modified reporter‐mRNAs. These cap‐propargylated mRNAs were efficiently translated and showed ≈3‐fold increased immune response in human cells. The same effects were observed when the receptor binding domain (RBD) of SARS‐CoV‐2—a currently tested epitope for mRNA vaccination—was used. Site‐specific chemo‐enzymatic modification of eukaryotic mRNA may thus be a suitable strategy to modulate translation and immune response of mRNAs for future therapeutic applications.
Chemical Evolution of Antivirals Against Enterovirus D68 through Protein‐Templated Knoevenagel Reactions
Authors: Tauber Carolin , Wamser Rebekka , Arkona Christoph , Tügend Marisa , Abdul Aziz Umer Bin , Pach Szymon , Schulz Robert , Jochmans Dirk , Wolber Gerhard , Neyts Johan , Rademann Jörg
Published: March 2021

The generation of bioactive molecules from inactive precursors is a crucial step in the chemical evolution of life, however, mechanistic insights into this aspect of abiogenesis are scarce. Here, we investigate the protein‐catalyzed formation of antivirals by the 3C‐protease of enterovirus D68. The enzyme induces aldol condensations yielding inhibitors with antiviral activity in cells. Kinetic and thermodynamic analyses reveal that the bioactivity emerges from a dynamic reaction system including inhibitor formation, alkylation of the protein target by the inhibitors, and competitive addition of non‐protein nucleophiles to the inhibitors. The most active antivirals are slowly reversible inhibitors with elongated target residence times. The study reveals first examples for the chemical evolution of bio‐actives through protein‐catalyzed, non‐enzymatic C−C couplings. The discovered mechanism works under physiological conditions and might constitute a native process of drug development.
In situ polymerization of ethylene in the presence of graphene by α‐diimine Nickel (II)/MAO catalyst system: Thermal and rheological study
Authors: Abedini Ali , Shafiei Mohammad , Jamjah Roghayeh , Ghasemi Ismaeil
Published: March 2021

In situ polymerization of ethylene with pretreated graphene nano‐platelet (GNP) was carried out by (α‐diimine nickel)/MAO catalyst system. The molecular weight of the synthesized samples was determined using rheometric mechanical spectroscopy. The number of branches and melting temperature values was evaluated by regular differential scanning calorimetry (DSC) and successive self‐nucleation and annealing (SSA) technique. According to obtained results, the molecular weight of the samples was increased from 72,730 to 260,100 g/mol for neat PE and high‐filled GNP, respectively. The number of chain branches decreased by the addition of GNP from 61.51 per 1,000 carbon atoms to 37.10 for neat PE and the sample containing 22.36 wt% of GNP. Obtained results revealed that the samples containing low branches and high molecular weight were achieved in the presence of highly loaded GNP. Also, the electrical conductivity, storage modulus, loss modulus, and complex viscosity of the samples improved by increasing GNP weight fraction.
Synthesis of novel sulfonamides with anti‐Alzheimer and antioxidant capacities
Authors: Gök Nihal , Akıncıoğlu Akın , Erümit Binici Edanur , Akıncıoğlu Hülya , Kılınç Namık , Göksu Süleyman
Published: March 2021

A series of novel dopamine analogs incorporating urea and sulfonamide functional groups was synthesized from 3,4‐dimethoxyphenethylamine. The reaction of 3,4‐dimethoxyphenethylamine with N,N‐dimethylcarbamoyl chloride, followed by the sulfonyl chlorination of the urea derivative, gave benzene‐1‐sulfonyl chloride 9, which was reacted with NH3 (aq) or N‐alkyl amines to give related sulfonamides. The O‐demethylation reaction of the subsequent compounds with BBr3 afforded four novel phenolic dopamine analogs including sulfonamide and urea in the same structure. The anticholinergic and antioxidant effects of the synthesized compounds were examined. Compound 13 exhibited inhibition at the micromolar level for both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The IC50 value of 13 was calculated as 298 ± 43 µM for AChE and 321 ± 29 µM for BChE. The antioxidant and antiradical effects of the molecules were investigated by five different methods. Among the synthesized compounds 10–18, the best antioxidant and antiradical activities belong to the phenolic compounds 15–18. Compounds 16 and 18 have a higher reducing power than the standards used, that is, butylated hydroxytoluene, butylated hydroxyanisole, Trolox, and α‐tocopherol, for Fe3+–Fe2+ and Cu2+–Cu+ reducing activities. For the DPPH• radical scavenging method, compounds 16–18 have a much better scavenging power than the standard molecules. In addition, it has been determined by the induced‐fit docking method that compound 13 is well‐fitted in the active site of the enzymes. ADME studies reveal that the pharmacokinetic and physicochemical properties of all synthesized compounds are within an acceptable range.
Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: Khanna Puja P. , Khanna Dinesh , Cutter Gary , Foster Jeff , Melnick Joshua , Jaafar Sara , Biggers Stephanie , Rahman A. K. M. Fazlur , Kuo Hui‐Chien , Feese Michelle , Kivitz Alan , King Charles , Shergy William , Kent Jeff , Peloso Paul M. , Danila Maria I. , Saag Kenneth G.
Published: March 2021

Objective

Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase.

Methods

Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24‐week durability of serum urate level ≤6 mg/dl. Fisher’s exact test and Wilcoxon’s 2‐sample test were used for analyses, along with Kaplan‐Meier estimates and log rank tests.

Results

A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF‐treated patients versus 30% of placebo‐treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%).

Conclusion

Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.
Prenatal developmental toxicity of alkyl dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride in CD rats and New Zealand White rabbits
Authors: Hostetler Keith A. , Fisher Louan C. , Burruss Benjamin L.
Published: March 2021

The prenatal developmental toxicity potential of alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC) was evaluated in regulatory‐compliant studies. Pregnant female CD rats (25/group) and New Zealand White rabbits (16/group) were administered ADBAC (0, 10, 30, or 100 mg/kg/day and 0, 1, 3, or 9 mg/kg/day, respectively), or DDAC (0, 1, 10, or 20 mg/kg/day and 0, 1, 3, or 10 mg/kg/day, respectively), by oral gavage on gestation days (GD) 6–15 for rats and GD 6–18 for rabbits. At scheduled termination (GD 21 for rats; GD 29 for rabbits), maternal necropsies were conducted and live fetuses were weighed and examined for external, visceral, and skeletal malformations and variations. Clinical signs of maternal toxicity were observed in rats and rabbits dosed with ADBAC, resulting in no‐observed‐adverse‐effect levels (NOAELs) of 10 and 3 mg/kg/day, respectively. Despite the treatment‐related maternal toxicity of ADBAC, the NOAEL for prenatal developmental toxicity was 100 and 9 mg/kg/day for rats and rabbits, respectively, the highest doses evaluated. Repeated oral doses of DDAC resulted in maternal toxicity in both species at the top two doses, with 25% mortality noted in rabbits at 10 mg/kg/day. No teratogenic effects were observed at any dose for either species. However, increased incidence of dead fetuses per litter and decreased fetal body weights were observed in rabbits at the maternally lethal dose of 10 mg/kg/day. The NOAEL for maternal toxicity of DDAC was 1 mg/kg/day for both species and the NOAEL for prenatal developmental toxicity was 20 and 3 mg/kg/day, for rats and rabbits, respectively.
Enantioselective Synthesis of 3‐Substituted 3‐Amino‐2‐oxindoles by Amination with Anilines
Authors: Yang Wenkun , Dong Pei , Xu Jian , Yang Jian , Liu Xiaohua , Feng Xiaoming
Published: March 2021

A chiral N,N′‐dioxide‐nickel(II) complex‐catalyzed asymmetric amination of 3‐bromo‐3‐substituted oxindoles with anilines has been developed. A series of alkyl or aryl 3‐amino‐indolinones with quaternary stereocenters were obtained in high yields with excellent ee values in one step (up to 99 % yield, up to 96 % ee). The method provided a ready route to optically active intermediates of 3‐amino‐2‐oxindole‐based bioactive compounds. Moreover, a possible transition‐state model is proposed so as to elucidate the origin of the chirality based on the X‐ray crystal structure of the catalyst and the adduct.
Evaluation of Drug‐Drug Interaction Liability for Buprenorphine Extended‐Release Monthly Injection Administered by Subcutaneous Route
Authors: Kharidia Jahnavi , Howgate Eleanor M. , Laffont Celine M. , Liu Yongzhen , Young Malcolm A.
Published: March 2021

Buprenorphine extended‐release (BUP‐XR) formulation is a once‐monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Buprenorphine undergoes extensive cytochrome P450 (CYP) 3A4 metabolism, leading to potential drug‐drug interactions (DDIs) as reported for sublingual buprenorphine. Sublingual buprenorphine is subject to first‐pass extraction, as a significant proportion of the dose is swallowed. Because subcutaneous administration avoids first‐pass extraction, the DDI with CYP3A4 inhibitors is expected to be less than the 2‐fold increase reported for the sublingual route. The objective of this analysis was to predict the magnitude of DDI following coadministration of BUP‐XR with a strong CYP3A4 inhibitor or inducer using physiologically based pharmacokinetic (PBPK) modeling. Models were developed and verified by comparing predicted and observed data for buprenorphine following intravenous and sublingual dosing. Comparison of predicted and observed pharmacokinetic (PK) profiles and PK parameters demonstrated acceptable predictive performance of the models (within 1.5‐fold). Buprenorphine plasma concentrations following administration of a single dose of BUP‐XR (300 mg) were simulated using a series of intravenous infusions. Daily coadministration of strong CYP3A4 inhibitors with BUP‐XR predicted mild increases in buprenorphine exposures (AUC, 33%‐44%; Cmax, 17‐28%). Daily coadministration of a strong CYP3A4 inducer was also associated with mild decreases in buprenorphine AUC (28%) and Cmax (22%). In addition, the model predicted minimal increases in buprenorphine AUC (8%‐11%) under clinical conditions of 2 weeks’ treatment with CYP3A4 inhibitors administered after initiation of BUP‐XR. In conclusion, the PBPK predictions indicate that coadministration of BUP‐XR with strong CYP3A4 inhibitors or inducers would not result in clinically meaningful interactions.
Depression in childhood may increase vulnerability to opioid euphoria in young adulthood
Authors: Knopf Alison
Published: March 2021

Researchers have found that childhood depression as well as tobacco use were associated with later opioid use in general, weekly opioid use, and heroin use. The cohort study, based on the Great Smoky Mountains Study (GSMS), concluded that children with chronic depression may take opioids to alleviate the physical symptoms — including pain — that often accompany depression. While depression may not be an evident cause of such symptoms, these complaints may lead to unnecessary opioid prescriptions, and the child's first exposure to opioid‐associated euphoria. Childhood somatic complaints — and elevated inflammation and injury — were associated with progression from any to weekly non‐heroin opioid use.
Assessment of biological matrices for the detection of in utero cannabis exposure
Authors: Concheiro Marta , Gutierrez Frank Martin , Ocampo Alejandro , Lendoiro Elena , González‐Colmenero Eva , Concheiro‐Guisán Ana , Peñas‐Silva Patricia , Macías‐Cortiña Manuel , Cruz‐Landeira Angelines , López‐Rivadulla Manuel , de‐Castro‐Ríos Ana
Published: March 2021

Cannabis consumption has been increasing worldwide among pregnant women. Due to the negative effects of prenatal cannabis exposure, it is necessary to develop an objective, sensitive, and specific method to determine cannabinoids use during pregnancy. In this study, we compared four different biological samples, maternal hair, meconium, umbilical cord, and placenta, for the detection of in utero cannabis exposure. The biological samples were collected from 627 mother–newborn dyads. All hair and meconium samples were analyzed, and umbilical cord and placenta if hair and/or meconium were positive for cannabinoids. Meconium and hair showed to complement each other, with an agreement between hair and meconium results of 96.7% but only 34.3% if just positive results were considered. Umbilical cord and placenta results showed a better agreement with meconium (91.3% and 92.6%, respectively) than with hair (39.1% and 34.6%, respectively). The predominant metabolites in meconium were 11‐nor‐carboxy‐THC (THCCOOH) and 8,11‐dihydroxy‐THC (diOHTHC), and in umbilical cord and placenta was THCCOOH‐glucuronide. Cannabidiol (CBD) and cannabinol (CBN) were detected in meconium but not in any umbilical cord or placenta. For the first time, prenatal marijuana exposure was analyzed and compared in paired hair, meconium, umbilical cord, and placental samples. Hair and meconium positivity rate was similar, but a more sensitive and specific analytical method for the hair may resolve discrepancies between the matrices. Umbilical cord and placenta may be considered suitable alternative matrices to meconium through the determination of THCCOOH‐glucuronide as a biomarker of cannabis exposure.
Sensitivity of Amphibians to Copper
Authors: Azizishirazi Ali , Klemish Jaimie L. , Pyle Gregory G.
Published: March 2021

Amphibian populations are declining globally. Major drivers of these global declines are known. However, the contribution of these major drivers to population declines varies by the presence or absence and the interactive effect of drivers, thus creating local challenges for conservation of populations. Studies have determined that environmental contaminants contribute to amphibian population declines. However, there is a disagreement over the use of amphibians as sentinel species in ecotoxicological testing rather than the traditional taxa used, fish and invertebrates. Reviews of ecotoxicological studies have demonstrated that amphibians are generally less sensitive than fish and invertebrates to different groups of contaminants. Nonetheless, because of the distinct nature and mechanism of toxicity of various contaminants, it is necessary to study contaminants individually to be able to come to any conclusion on the relative sensitivity of amphibians. Copper is one of the most studied environmental contaminants. We conducted a literature review of Cu toxicity to amphibians and the relative sensitivity of amphibians to other aquatic animals. The available data suggest that although amphibians may be tolerant of acute Cu exposure, they are relatively sensitive to chronic exposure (i.e., 100-fold greater sensitivity to chronic compared to acute exposure). In addition, ecologically relevant endpoints specific to amphibians (e.g., duration of metamorphosis and behavior) are shown to provide a better understanding of their sensitivity compared to traditional endpoints (e.g., survival and growth). Our current knowledge on amphibian sensitivity is far from complete. Considering the current status of this globally threatened class of animals, it is necessary to fill the knowledge gaps regarding their sensitivity to individual contaminants, beginning with Cu. Environ Toxicol Chem 2021;40:1808–1819. © 2021 SETAC

Abstract

Although amphibians seem to be tolerant of acute copper exposure, they are relatively sensitive to chronic exposure.
Patients Left Behind: Ethical Challenges in Caring for Indirect Victims of the Covid‐19 Pandemic
Authors: Bruno Bethany , Rose Susannah
Published: March 2021

In response to the Covid‐19 pandemic, health care systems worldwide canceled or delayed elective surgeries, outpatient procedures, and clinic appointments. Although such measures may have been necessary to preserve medical resources and to prevent potential exposures early in the pandemic, moving forward, the indirect effects of such an extensive medical shutdown must not outweigh the direct harms of Covid‐19. In this essay, we argue for the reopening of evidence‐based health care with assurance provided to patients about the safety and necessity of high‐value vaccinations, screenings, therapeutics, and procedures. To ensure that virtually all non‐Covid‐related services do not come to a halt again, health care systems and physician practices must preemptively increase their capacity, secure adequate personal protective equipment to safeguard health care personnel, and develop a measured approach to reclosing such routine health care, should it become necessary in the future.
A Heart without Life: Artificial Organs and the Lived Body
Authors: Walker Mary Jean
Published: March 2021

The use of artificial organs is likely to increase in the future, given technological advances, increases in chronic diseases, and limited donor organs. This article examines how artificial organs could affect people's experience and conceptualization of bodies and our understanding of the relation of body to self. I focus on artificial heart devices and argue that these have two conflicting potential influences. First, they may influence people to regard the body as machinelike and separable from the self. Second, they may effect changes to subjective experience that can be understood as changes to the self, confirming the self's embodiment. My primary purpose is to increase our understanding of what might change if it becomes more usual to have a body that is partly nonorganic. But I also argue that the analysis points to potential ethical concerns related to strengthening biomedical conceptions of the body and to the devaluing of bodies and body parts.
Considerations for toxicity experiments and risk assessments with PFAS mixtures
Authors: McCarthy Christopher J. , Roark Shaun A. , Middleton Elizabeth T.
Published: March 2021

Per- and polyfluoroalkyl substances (PFAS) have been around for decades and have been the subject of laboratory and field research studies for nearly as long. Although attention to PFAS has grown in recent years, many unanswered questions remain. Accordingly, the number of research projects designed to improve our understanding of PFAS toxicity, bioaccumulation, and biomagnification, and to improve our ability to predict the interactions of PFAS mixtures, is also increasing. The growing number of ongoing and future research projects focusing on these chemicals will benefit from lessons learned in previous studies. This perspectives article discusses available approaches to mixture risk assessment with specific focus on application to PFAS mixtures. We discuss ongoing research as well as lessons learned from approaches to handling mixtures of other groups of chemicals. Many of these approaches require some detailed understanding of a manageable number of representative chemicals, yet only limited toxicological data are available for most PFAS. With the limited amount of published data currently available, the need for single-chemical and binary-mixture studies persists. Based on our previous work with single-chemical exposures for understudied PFAS, we explored some of the challenges of trying to design and interpret an aquatic concentration–response experiment for a binary mixture of two commonly detected PFAS: perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS). Based on our findings, we propose that addressing risk from PFAS mixtures will likely require combinations of approaches incorporating findings from traditional whole-organism toxicity studies and novel methods relying on in vitro assays, read-across, or quantitative structure activity relationships. Complicating a limited understanding of PFAS mixture toxicity is that relative concentrations of PFAS mixtures vary across sites and time, even at one site. Thus, reliance on empirical data, such as site-specific toxicity sampling or community structure studies, may be needed to fully understand potential impacts of mixtures. Integr Environ Assess Manag 2021;17:697–704. © 2021 SETAC

KEY POINTS

Due to their ubiquity, PFAS exist commonly in mixtures and it is important to consider PFAS mixture effects in risk assessments. Some studies with PFAS mixtures have been published or are ongoing, but more field and laboratory studies are still needed to adequately support the risk assessment of PFAS mixtures. Previous approaches for assessing the risk of adverse effects from mixtures of other chemicals provides an excellent starting point to unravelling the challenges associated with mixtures of PFAS. Understanding and managing PFAS mixtures is complex and will likely require multiple approaches.
Cost effective optimised synthetic surface modification strategies for enhanced control of neuronal cell differentiation and supporting neuronal and Schwann cell viability
Authors: Taylor Caroline S. , Chen Rui , D' Sa Raechelle , Hunt John A. , Curran Judith M. , Haycock John W.
Published: March 2021

Enriching a biomaterial surface with specific chemical groups has previously been considered for producing surfaces that influence cell response. Silane layer deposition has previously been shown to control mesenchymal stem cell adhesion and differentiation. However, it has not been used to investigate neuronal or Schwann cell responses in vitro to date. We report on the deposition of aminosilane groups for peripheral neurons and Schwann cells studying two chain lengths: (a) 3‐aminopropyl triethoxysilane (short chain‐SC) and (b) 11‐aminoundecyltriethoxysilane (long chain‐LC) by coating glass substrates. Surfaces were characterised by water contact angle, AFM and XPS. LC–NH2 was produced reproducibly as a homogenous surface with controlled nanotopography. Primary neuron and NG108‐15 neuronal cell differentiation and primary Schwann cell responses were investigated in vitro by S100β, p75, and GFAP antigen expression. Both amine silane surface supported neuronal and Schwann cell growth; however, neuronal differentiation was greater on LC aminosilanes versus SC. Thus, we report that silane surfaces with an optimal chain length may have potential in peripheral nerve repair for the modification and improvement of nerve guidance devices.
Machine Learning Solutions for Osteoporosis—A Review
Authors: Smets Julien , Shevroja Enisa , Hügle Thomas , Leslie William D , Hans Didier
Published: March 2021

Osteoporosis and its clinical consequence, bone fracture, is a multifactorial disease that has been the object of extensive research. Recent advances in machine learning (ML) have enabled the field of artificial intelligence (AI) to make impressive breakthroughs in complex data environments where human capacity to identify high-dimensional relationships is limited. The field of osteoporosis is one such domain, notwithstanding technical and clinical concerns regarding the application of ML methods. This qualitative review is intended to outline some of these concerns and to inform stakeholders interested in applying AI for improved management of osteoporosis. A systemic search in PubMed and Web of Science resulted in 89 studies for inclusion in the review. These covered one or more of four main areas in osteoporosis management: bone properties assessment (n = 13), osteoporosis classification (n = 34), fracture detection (n = 32), and risk prediction (n = 14). Reporting and methodological quality was determined by means of a 12-point checklist. In general, the studies were of moderate quality with a wide range (mode score 6, range 2 to 11). Major limitations were identified in a significant number of studies. Incomplete reporting, especially over model selection, inadequate splitting of data, and the low proportion of studies with external validation were among the most frequent problems. However, the use of images for opportunistic osteoporosis diagnosis or fracture detection emerged as a promising approach and one of the main contributions that ML could bring to the osteoporosis field. Efforts to develop ML-based models for identifying novel fracture risk factors and improving fracture prediction are additional promising lines of research. Some studies also offered insights into the potential for model-based decision-making. Finally, to avoid some of the common pitfalls, the use of standardized checklists in developing and sharing the results of ML models should be encouraged. © 2021 American Society for Bone and Mineral Research (ASBMR).