bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fostemsavir: The first oral attachment inhibitor for treatment of HIV-1 infection
Authors: Chahine Elias B 
Published: February 2021

Abstract

Purpose
The pharmacology, pharmacokinetics, and role in therapy of fostemsavir in management of HIV-1 infection are reviewed, with an emphasis on clinical efficacy and safety data from phase 2 and phase 3 clinical trials.

Summary
Fostemsavir (Rukobia, ViiV Healthcare), is a prodrug of temsavir, a novel pyridine compound with potent activity against HIV-1. Fostemsavir, the first oral attachment inhibitor, was approved and granted the breakthrough therapy designation by the Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in heavily treatment-experienced adults. As absorption of temsavir is not altered with increased gastric pH, patients may take acid suppressive agents such as famotidine during fostemsavir therapy.Temsavir is primarily metabolized through hydrolysis but also via cytochrome P-450 (CYP) oxidation; therefore, coadministration of fostemsavir with strong CYP3A inducers such as rifampin, carbamazepine, phenytoin, mitotane, enzalutamide, or St John’s wort is contraindicated because it may result in significantly lower temsavir exposure, which can ultimately impair virologic response. The most common adverse reactions associated with fostemsavir use include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbance.

Conclusion
Fostemsavir may be an effective option for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Fostemsavir is a particularly attractive treatment option for patients who are no longer able to achieve viral suppression with use of currently available antiretroviral therapies and who are able to adhere to a twice-daily oral regimen.
Evidence and manipulation of O-GlcNAcylation in granulosa cells of bovine antral follicles†
Authors: Maucieri Abigail M , Townson David H 
Published: February 2021

Abstract
Glucose is a preferred energy substrate for metabolism by bovine granulosa cells (GCs). O-linked N-acetylglucosaminylation (O-GlcNAcylation), is a product of glucose metabolism that occurs as the hexosamine biosynthesis pathway (HBP) shunts O-GlcNAc sugars to serine and threonine residues of proteins. O-GlcNAcylation through the HBP is considered a nutrient sensing mechanism that regulates many cellular processes. Yet little is known of its importance in GCs. Here, O-GlcNAcylation in GCs and its effects on GC proliferation were determined. Bovine ovaries from a slaughterhouse, staged to the mid-to-late estrous period were used. Follicular fluid and GCs were aspirated from small (3–5 mm) and large (&gt;10 mm) antral follicles. Freshly isolated GCs of small follicles exhibited greater expression of O-GlcNAcylation and O-GlcNAc transferase (OGT) than large follicles. Less glucose and more lactate was detectable in the follicular fluid of small versus large follicles. Culture of GCs revealed that inhibition of the HBP via the glutamine fructose-6-phosphate aminotransferase inhibitor, DON (50 μM), impaired O-GlcNAcylation and GC proliferation, regardless of follicle size. Direct inhibition of O-GlcNAcylation via the OGT inhibitor, OSMI-1 (50 μM), also prevented proliferation, but only in GCs of small follicles. Augmentation of O-GlcNAcylation via the O-GlcNAcase inhibitor, Thiamet-G (2.5 μM), had no effect on GC proliferation, regardless of follicle size. The results indicate GCs of bovine antral follicles undergo O-GlcNAcylation, and O-GlcNAcylation is associated with alterations of glucose and lactate in follicular fluid. Disruption of O-GlcNAcylation impairs GC proliferation. Thus, the HBP via O-GlcNAcylation constitutes a plausible nutrient-sensing pathway influencing bovine GC function and follicular growth.
Current progress, challenges, and future prospects of testis organoids†
Authors: Cham Tat-Chuan , Chen Xiongbiao , Honaramooz Ali 
Published: February 2021

AbstractSpermatogenic failure is believed to be a major cause of male infertility. The establishment of a testis organoid model would facilitate the study of such pathological mechanisms and open the possibility of male fertility preservation. Because of the complex structures and cellular events occurring within the testis, the establishment of a compartmentalized testis organoid with a complete spermatogenic cycle remains a challenge in all species. Since the late 20th century, a great variety of scaffold-based and scaffold-free testis cell culture systems have been established to recapitulate de novo testis organogenesis and in vitro spermatogenesis. The utilization of the hydrogel scaffolds provides a 3D microenvironment for testis cell growth and development, facilitating the reconstruction of de novo testis tissue-like structures and spermatogenic differentiation. Using a combination of different strategies, including the use of various scaffolding biomaterials, the incorporation of the living cells with high self-assembling capacity, and the integration of the advanced fabrication techniques, a scaffold-based testis organoid with a compartmentalized structure that supports in vitro spermatogenesis may be achieved. This article briefly reviews the current progress in the development of scaffold-based testis organoids while focusing on the scaffolding biomaterials (hydrogels), cell sources, and scaffolding approaches. Key challenges in current organoid studies are also discussed along with recommendations for future research.
Law, Value and Norm: The Constitution of a Culture-Bound Ethical Dilemma in Social Work in the Ultra-Orthodox Community
Authors: Gemara Netanel , Nadan Yochay 
Published: February 2021

Abstract
Multi-cultural encounters pose challenges and ethical dilemmas for social workers. A common form of dilemma in these settings stems from the clash between the ethical requirement of cultural sensitivity and contradictory ethical principles. This article presents qualitative findings from an exploratory study of social workers (n = 30) working with Jewish Ultra-Orthodox families and children who are at risk in Israel. Our exploration was guided by the following research question: What are the constructions, perceptions, beliefs and meanings associated with the dilemmas social workers face while working with the Ultra-Orthodox community in Israel around issues of child well-being, risk and protection? A thematic analysis of 30 in-depth interviews yielded three themes of dilemma: the collectivist nature of the Ultra-Orthodox community, religion and spirituality and gender and sexuality. Further analysis of the findings revealed a typology of three elements that constitute a culture-bound dilemma: laws, values and norms. This article, which also addresses limitations and recommendations for future research, suggests how the understanding of what components make up a specific dilemma can aid social workers in managing the dilemma and may require a different course of action.
Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia
Authors: Shaw Siobhán R , El-Omar Hashim , Roquet Daniel , Hodges John R , Piguet Olivier , Ahmed Rebekah M , Whitton Alexis E , Irish Muireann 
Published: February 2021

Abstract
Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer’s disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer’s disease, and 51 healthy older control participants. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer’s disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular cortices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.
Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder
Authors: Zhou Liche , Li Guanglu , Zhang Yuyao , Zhang Miao , Chen Zhichun , Zhang Lina , Wang Xiaojin , Zhang Ming , Ye Guanyu , Li Yuanyuan , Chen Shengdi , Li Biao , Wei Hongjiang , Liu Jun 
Published: February 2021

Abstract
Imaging markers sensitive to neurodegeneration in the substantia nigra are critically needed for future disease-modifying trials. Previous studies have demonstrated the utility of posterior substantia nigra free water as a marker of progression in Parkinson’s disease. In this study, we tested the hypothesis that free water is elevated in the posterior substantia nigra of idiopathic REM sleep behaviour disorder, which is considered a prodromal stage of synucleinopathy. We applied free-water imaging to 32 healthy control subjects, 34 patients with idiopathic REM sleep behaviour disorder and 38 patients with Parkinson’s disease. Eighteen healthy control subjects and 22 patients with idiopathic REM sleep behaviour disorder were followed up and completed longitudinal free-water imaging. Free-water values in the substantia nigra were calculated for each individual and compared among groups. We tested the associations between posterior substantia nigra free water and uptake of striatal dopamine transporter in idiopathic REM sleep behaviour disorder. Free-water values in the posterior substantia nigra were significantly higher in the patients with idiopathic REM sleep behaviour disorder patients than in the healthy control subjects, but were significantly lower in patients with idiopathic REM sleep behaviour disorder than in patients with Parkinson’s disease. In addition, we observed significantly negative associations between posterior substantia nigra free-water values and dopamine transporter striatal binding ratios in the idiopathic REM sleep behaviour disorder patients. Longitudinal free-water imaging analyses were conducted with a linear mixed-effects model, and showed a significant Group × Time interaction in posterior substantia nigra, identifying increased mean free-water values in posterior substantia nigra of idiopathic REM sleep behaviour disorder over time. These results demonstrate that free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials.
Synthesis and Chiral Separation of Some 4-thioflavones
Authors: Zaid Mohammed El Amin , Belboukhari Nasser , Sekkoum Khaled , Ibtissam Bousmaha , Enein Hassan Y Aboul 
Published: February 2021

Abstract
A thionation reaction was performed on some chiral flavanones using Lawesson’s reagent (LR) and leads to the formation of new chiral thiocarbonyl flavanes. LR in this thionation reaction with Hesperetin and Naringenin gives new flavan-4-thiones with yields ranged between 41 and 52%. Based on the Wittig reaction principle, LR is currently the most widely used reagent for this type of reaction. Enantiomeric separation by high-performance liquid chromatography methods was then set-up using three different polysaccharide-based chiral stationary phases (CSPs). Chiral separations were successfully accomplished with high resolution (1.22 ≤ Rs ≤ 5.23). The chiral discrimination mechanism(s) between the analytes under study, mobile phase, and the CSPs were discussed.
Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa
Authors: Verrest Luka , Kip Anke E , Musa Ahmed M , Schoone Gerard J , Schallig Henk D F H , Mbui Jane , Khalil Eltahir A G , Younis Brima M , Olobo Joseph , Were Lilian , Kimutai Robert , Monnerat Séverine , Cruz Isra , Wasunna Monique , Alves Fabiana , Dorlo Thomas P C 
Published: February 2021

Abstract

Background
To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes.

Methods
Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at 6 months.

Results
The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within 6 months of follow-up at a cutoff of 20 parasites/mL (area under the curve 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ = 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a &gt; 80% power to detect a difference in cure rate between treatment regimens if this difference was high (&gt; 50%) and when minimally 30 patients were included per regimen.

Conclusions
Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.
Some Combinatorial Problems in Power-Law Graphs
Authors: Jiang Che , Xu Wanyue , Zhou Xiaotian , Zhang Zhongzhi , Kan Haibin 
Published: February 2021

Abstract
The power-law behavior is ubiquitous in a majority of real-world networks, and it was shown to have a strong effect on various combinatorial, structural and dynamical properties of graphs. For example, it has been shown that in real-life power-law networks, both the matching number and the domination number are relatively smaller, compared with homogeneous graphs. In this paper, we study analytically several combinatorial problems for two power-law graphs with the same number of vertices, edges and the same power exponent. For both graphs, we determine exactly or recursively their matching number, independence number, domination number, the number of maximum matchings, the number of maximum independent sets and the number of minimum dominating sets. We show that power-law behavior itself cannot characterize the combinatorial properties of a heterogenous graph. Since the combinatorial properties studied here have found wide applications in different fields, such as structural controllability of complex networks, our work offers insight in the applications of these combinatorial problems in power-law graphs.
Ebstein anomaly, left ventricular hypertrabeculation and ventricular septal defect associated with a myh7 mutation
Authors: Korkmaz B , Aydogdu U , Inan D , Keles N , Yildirimturk O 
Published: February 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.
Ebstein anomaly is an extremely rare anomaly of &lt;1% among all congenital heart diseases. Pathologically, the septal and / or posterior leaflet of the tricuspid valve has abnormal locations towards the right ventricular apex. Ebstein anomaly is especially accompanied by atrial septal defect, patent ductus arteriosus, wolf parkinson white syndrome and pulmonary atresia.
Defects located in the interventricular septum are called the ventricular septal defect (VSD). They can be single or multiple and congenital or acquired. Isolated VSDs are the most common congenital anomaly in childhood and constitute 20-30% of all congenital heart diseases. VSD can be a part of major congenital malformations ,such as, fallot tetralogy, transposition of the major arteries, double ventricular right ventricle.
Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease .
A combination of Ebstein anomaly, hypertrabeculation and ventricular septal defect is a rare condition.

Case Report
A 49-year-old male patient presented to the emergency room with shortness of breath and swelling of the legs. The patient had diagnosed an Ebstein anomaly while the military examination in 1988. Already it ‘s known that he has gout disease and uses colchicine but no family history of any disease. On examination of the patient, bilateral ral in respiratory sounds and +++ / +++ pretibial edema in the lower extremity were detected. On his electrocardiogram, the sinus rhythm with first-degree atrioventricular block was observed. The findings on his echocardiographic examination are ejection fraction 30-35% with global left ventricular hypokinesia, Ebstein anomaly (Figure ), perimembranous type VSD, atrial septal aneurysm type 2 and left ventricular hypertrabeculation. His blood table was normal. Medical treatment of heart failure was started for the patient who was interneed to the service. After getting clinical relief, the patient was discharged under medical treatment. Genetic tests were studied while following up at the heart failure outpatient clinic. In the MYH7 gene, splice-acceptor-2 (PVS1) variation heterozygous was detected. This variant has not been seen in national data banks of genetics.

Conclusion
The MYH7 gene, localized on chromosome 14p12, is composed of 41 exons and encodes the b-myosin heavy chain, expressed in cardiac muscle. Mutations in the MYH7 gene have been identified in association with left ventricular hypertrabeculation and Ebstein anomaly. In conclusion, this is the first known report of Ebstein anomaly associated with the splice-acceptor-2 variation heterozygous of the MYH7 gene.
Abstract Figure
Use of speckle-tracking echocardiography to stratify risk of atrial fibrillation-related stroke: comparison of left atrial and atrial appendage mechanics
Authors: Mao Y , Yang Y , Yu C , Ma MM , Wang YH , Jiang RH , Jiang CY 
Published: February 2021

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): the National Natural Science Foundation of China

onbehalf
Sir Run Run Shaw Hospital,Zhejiang University,School of Medicine

Background
Left atrial (LA) and appendage (LAA) dysfunction were associated with increased risk of stroke in atrial fibrillation. However, usefulness of LA and LAA mechanics has not been fully compared. Methods:201 AF patients were prospectively enrolled. 42(20.8%) had previous stroke/TIA. Speckle tracking was used to measure LA and LAA peak postive strain. LA and LAA MD was defined as the SD of time to peak positive strain corrected by the R-R interval. Results:LA MD and LAA MD were independently associated with stroke/TIA. The model based on CHA2DS2-VASc score for discrimination of stroke was significantly improved by adding LA MD or LAA MD (P &lt; 0.01). Diagnostic value of LA MD was better than LAA MD in patients with normal LA volumes, while LAA MD was more useful in patients with LA enlargement.Conclusion:Both LA and LAA mechanics had incremental value over CHA2DS2VASc score. However, priorities of strain assessment depend on patients’ LA volume.
Variables Univariate analysis Multivariate analysis Model 1 Model 2 Model 3 OR (95% CI) P value OR (95% CI) P value OR (95% CI) p value OR (95% CI) P value Clinical parameters Age 1.09(1.04-1.14) &lt;0.001 1.11(1.04-1.17) 0.001 1.11(1.05-1.17) 0.001 1.11(1.04-1.17) 0.001 BMI 0.988(0.89-1.10) 0.84 1.07(0.92-1.25) 0.40 1.07(0.91-1.25) 0.40 CHA2DS2-VASc score 1.52(1.15-2.00) 0.003 1.08(0.67-1.74) 0.76 1.08(0.65-1.80) 0.77 1.10(0.69-1.76) 0.69 Persistent AF 1.88(0.94-3.74) 0.07 0.75(0.23-2.40) 0.63 0.87(0.27-2.81) 0.82 Therapeutic anticoagulation 0.56(0.28-1.11) 0.10 0.22(0.09-0.57) 0.002 0.23(0.09-0.59) 0.002 0.22(0.09-0.57) 0.002 LA parameters LAEF 0.96(0.94-0.99) 0.002 0.982(0.953-1.01) 0.26 iLAVmin 1.03(1.01-1.05) 0.006 0.98(0.94-1.02) 0.27 LA MD 1.22(1.10-1.36) &lt;0.001 1.16(1.02-1.32) 0.02 1.18(1.03-1.34) 0.02 1.16(1.02-1.32) 0.02 LA GLS 0.935(0.893-0.98) 0.005 1.0(0.953-1.14) 0.36 1.02(0.94-1.12) 0.59 1.02(0.94-1.10) 0.72 LAA parameters LAAEV 0.12(0.02-0.74) 0.02 3.34(0.31-36.06) 0.32 LAA EF 0.98(0.96-1.00) 0.06 1.01(0.98-1.04) 0.65 LAA GLS 0.85(0.77-0.94) 0.001 0.96(0.86-1.07) 0.46 0.97(0.87-1.08) 0.59 0.96(0.87-1.06) 0.44 LAA dense SEC/thrombus 3.12(1.39-6.99) 0.006 2.02(0.75-5.45) 0.167 LAA MD 1.19(1.09-1.29) &lt;0.001 1.19(1.08-1.31) 0.001 1.19(1.08-1.31) 0.001 1.19(1.08-1.31) 0.001 Univariable and multivariable logistic regression analyses of associations between clinical and echocardiographic covariates with stroke Abstract Figure.