bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive treatment allocation for comparative clinical studies with recurrent events data
Authors: Gao Jingya , Su Pei‐Fang , Hu Feifang , Cheung Siu Hung 
Published: July 2019

AbstractIn long‐term clinical studies, recurrent event data are sometimes collected and used to contrast the efficacies of two different treatments. The event reoccurrence rates can be compared using the popular negative binomial model, which incorporates information related to patient heterogeneity into a data analysis. For treatment allocation, a balanced approach in which equal sample sizes are obtained for both treatments is predominately adopted. However, if one treatment is superior, then it may be desirable to allocate fewer subjects to the less‐effective treatment. To accommodate this objective, a sequential response‐adaptive treatment allocation procedure is derived based on the doubly adaptive biased coin design. Our proposed treatment allocation schemes have been shown to be capable of reducing the number of subjects receiving the inferior treatment while simultaneously retaining a test power level that is comparable to that of a balanced design. The redesign of a clinical study illustrates the advantages of using our procedure.
Fast Approximation of Laplace‐Beltrami Eigenproblems
Authors: Nasikun Ahmad , Brandt Christopher , Hildebrandt Klaus 
Published: July 2019

AbstractThe spectrum and eigenfunctions of the Laplace‐Beltrami operator are at the heart of effective schemes for a variety of problems in geometry processing. A burden attached to these spectral methods is that they need to numerically solve a large‐scale eigenvalue problem, which results in costly precomputation. In this paper, we address this problem by proposing a fast approximation algorithm for the lowest part of the spectrum of the Laplace‐Beltrami operator. Our experiments indicate that the resulting spectra well‐approximate reference spectra, which are computed with state‐of‐the‐art eigensolvers. Moreover, we demonstrate that for different applications that comparable results are produced with the approximate and the reference spectra and eigenfunctions. The benefits of the proposed algorithm are that the cost for computing the approximate spectra is just a fraction of the cost required for numerically solving the eigenvalue problems, the storage requirements are reduced and evaluation times are lower. Our approach can help to substantially reduce the computational burden attached to spectral methods for geometry processing.
Experiences of patient‐centred care in alcohol and other drug treatment settings: A qualitative study to inform design of a patient‐reported experience measure
Authors: Hinsley Kathryn , Kelly Peter J. , Davis Esther 
Published: July 2019

AbstractIntroduction and AimsA growing body of literature supports the use of patient‐reported experience measures (PREMs) to monitor the provision of patient‐centred care to people accessing health services. However, there is an absence of research into PREMs in the alcohol and other drugs (AOD) field. The aim of this study was to explore patient experiences of AOD care and to develop a PREM for AOD treatment settings.Design and MethodsFive focus groups were conducted with people accessing AOD treatment services in New South Wales, Australia (N = 39). Data were analysed using iterative categorisation. A draft PREM was developed based on focus group findings and was modified following a subsequent review by consumers and service providers.ResultsParticipants emphasised the importance of timely access to integrated care delivered in a structured program by staff members who genuinely care. Furthermore, participants described positive experiences when services addressed the problems that maintain addiction, held them responsible for themselves and facilitated self‐reflection. The PREM for Addiction Treatment (PREMAT) is a 33‐item measure that captures what participants said regarding their experience of patient‐centred care in AOD treatment.Discussion and ConclusionsThe experiences of people accessing AOD treatment provided useful feedback that can be translated into service improvements and that informed the design of a PREM for AOD treatment settings. Future research is necessary to further investigate the validity of the PREMAT.
Long‐term efficacy and safety of combined insulin and glucagon‐like peptide‐1 therapy: Evidence from the LEADER trial
Authors: Tack Cees J. , Jacob Stephan , Desouza Cyrus , Bain Stephen C. , Buse John B. , Nauck Michael A. , Petrie John R. , Poulter Neil R. , Pratley Richard E. , Stegmann Helen Vanya B. K. , Bosch‐Traberg Heidrun , Startseva Elena , Zinman Bernard ,   the LEADER Publication Committee on behalf of the LEADER Trial Investigators
Published: July 2019

AbstractAimGlucagon‐like peptide‐1 receptor agonist (GLP‐1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long‐term data are lacking. The aim was to assess the long‐term efficacy of the GLP‐1RA liraglutide in subgroups by insulin use in the LEADER trial.Materials and MethodsLEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal‐only insulin, other insulin or no insulin). Insulin was a non‐random treatment allocation as part of standard of care therapy.ResultsAt baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal‐only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no‐insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal‐only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal‐only and no‐insulin subgroups.ConclusionsIn patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.
Dieback and decline of wild almond (Amygdalus scopariaSpach) in the Harat protected forest of Yazd Province, Iran
Authors: Mirabdollahi Shamsi Morteza , Akbarinia Moslem , Mirabolfathy Mansoureh , Manzari Shahab , Ahmadikhah Asadollah 
Published: July 2019

AbstractWild almond (Amygdalus scoparia) is a dominant shrub species in mountain forests of the Irano‐Turanian region. Dieback and decline symptoms of wild almond shrubs were first observed in Harat protected forest (Yazd, Iran) in the autumn of 2014. Since then, the incidence and severity of the disease have increased. To study the aetiology and estimate losses from the disease, field studies were conducted in 2016 and 2017. For this purpose, eight stands were selected, in which 24%–99% of the trees were wild almond in their species composition. In total, 50 cankers and 50 infected twigs of wild almond shrubs were collected. Fungal isolates were identified based on morphological and cultural characteristics, as well as sequence data of ITS1 + 5.8S + ITS2 rDNA. Pathogenicity of fungi was checked on detached shoots and evaluated after 40 days by measuring the discoloured lesion length at the inoculation site. Among 681 wild almond shrubs checked, 84.44% showed decline symptoms with different severities; only 15.56% did not show observable disease symptoms. The most frequent colonizers of infected tissues taken from cankers wereWilsonomyces carpophilus(56%),Thyrostroma cornicola(40%) andCollophorina paarla(30%). Infected twigs were extensively colonized byW. carpophilus(36%),Th. cornicola(24%) andUlocladium consortiale(24%). Other species, such asEndoconidioma populi, Microsphaeropsis olivacea,Trichoderma asperellum, Paecilomyces formosus, Saccothecium rubi, Preussiasp.andChaetomium globosum,had lower isolation frequencies.W. carpophilus, Th. cornicola,C. paarlaandU. consortialewere found as pathogens on detached wild almond shoots. Based on the frequency of the isolates and the pathogenicity tests, four fungi, such asW. carpophilus,Th. cornicola,C. paarlaandU. consortiale, are considered serious contributing agents playing a significant role in the dieback and decline of wild almond. All isolated species are reported for the first time on the wild almond shrubs of the world.
Seizure specificities in patients with antibody‐mediated autoimmune encephalitis
Authors: Vogrig Alberto , Joubert Bastien , André‐Obadia Nathalie , Gigli Gian Luigi , Rheims Sylvain , Honnorat Jérome 
Published: July 2019

AbstractAccumulating data on patients with autoimmune encephalitis have shed light on specificities concerning clinical presentation and outcomes, which are dependent on the antigen targeted by the autoantibodies found in the patients’ cerebrospinal fluid or sera. Such specificities include seizure‐related clinical manifestations as well as the responsiveness to antiepileptic drugs. Although increased enthusiasm accompanies the discovery of novel antibodies and their associated clinical syndromes, several issues remain unsettled. First, it appears that therapy needs to be personalized in the view of the severity of each antibody‐mediated syndrome, patient‐related characteristics, and timing of treatment. Second, the lack of randomized controlled trials is a major drawback in the formulation of an appropriate immunotherapeutic strategy. In this review, we discuss the novel developments and challenges for the diagnosis and treatment of epilepsy in patients with well‐characterized autoimmune encephalitis, and delineate the principles for a rational approach toward precision medicine in this emerging field.
Melatonin as a potential modulator of Nrf2
Authors: Ahmadi Zahra , Ashrafizadeh Milad 
Published: July 2019

AbstractNuclear factor erythroid 2‐related factor 2 (Nrf2) is considered as the sensor of oxidative stress, and the main aim of this signaling pathway is to maintain physiological condition by induction of redox balance. Also, this pathway exerts anti‐inflammatory effects via antioxidant response element. Oxidative stress is a key factor in a variety of pathological conditions and high level of oxidative stress is associated with damages in lipids, proteins, genetic material, and cell membrane. Multiple drugs have been developed in order to diminish oxidative stress. However, synthetic drugs suffer from various drawbacks such as high cost and side effects. On the other hand, naturally occurring compounds are of interest due to their minimal side effects and valuable biological activities. Melatonin is a hormone of pineal gland which is found in different plants. This compound has a variety of favorable biological and therapeutic activities such as antioxidant, anti‐inflammatory, anti‐tumor, anti‐diabetic, and cardioprotection. At the present review, we demonstrate that Nrf2 signaling pathway explains some of the therapeutic and biological effects of melatonin.
Heterozygous loss of epilepsy geneKCNQ2alters social, repetitive and exploratory behaviors
Authors: Kim Eung Chang , Patel Jaimin , Zhang Jiaren , Soh Heun , Rhodes Justin S. , Tzingounis Anastasios V. , Chung Hee Jung 
Published: July 2019

AbstractKCNQ/Kv7 channels conduct voltage‐dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits Kv7.2/KCNQ2 and Kv7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous Kv7.2 mutations are associated with early‐onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of Kv7.2‐containing Kv7 channels in behaviors especially autism‐associated behaviors has not been described. Because pathogenic Kv7.2 mutations in patients are typically heterozygous loss‐of‐function mutations, we investigated the contributions of Kv7.2 to exploratory, social, repetitive and compulsive‐like behaviors by behavioral phenotyping of both male and femaleKCNQ2+/−mice that were heterozygous null for theKCNQ2gene. Compared with their wild‐type littermates, male and femaleKCNQ2+/−mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase,KCNQ2+/−group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While maleKCNQ2+/−mice displayed enhanced compulsive‐like behavior and social dominance, femaleKCNQ2+/−mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of Kv7.2 induces behavioral abnormalities including autism‐associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss‐of‐function Kv7.2 mutations and the behavioral comorbidities of Kv7.2‐associated epilepsy.
Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia
Authors: Peyvandi Flora , Garagiola Isabella 
Published: July 2019

AbstractGene therapy is rapidly becoming a new therapeutic strategy for haemophilia A and B treatment. In the 1990s, studies in animal models showed that adeno‐associated vectors (AAV) exhibited an efficient expression of factor IX (FIX). In the first clinical trial in patients with haemophilia B, therapeutic levels of FIX were documented but the expression remained only for few weeks. Subsequently, improvements in vector design, such as the use of different AAV serotypes, the development of the self‐complementary vector, the engineering of the transgene with codon optimization and liver‐specific expression cassette resulted in circulating FIX level between 2% and 5% for long‐lasting period. Recently, a natural gain of function FIX variant (Padua) inserted in the F9 cDNA improved the expression of FIX achieving a level of more than 30% resulting in cessation of infusions and in a greatly reduction of bleeding events. Encouraging clinical progresses have been also obtained from trials of gene therapy for haemophilia A. Transgene expression persisted for three years with circulating FVIII activity levels of 52.3% in patients treated with AAV vector containing a codon‐optimized F8 cDNA. A complication, reported in both clinical trials for haemophilia A and B, was the elevation of liver enzymes, which resolved with steroid treatment in a large group of patients. However, to date, the pathophysiological mechanism for the liver toxicity remains still unclear. Clinical trials with adeno‐associated vectors have documented a significant success for haemophilia gene therapy demonstrating potential to transform haemophilia treatment offering hope for a long‐term expression.
Investigation of nutraceutical potential of the microalgae Chlorella vulgaris and Arthrospira platensis
Authors: Matos Joana , Cardoso Carlos L. , Falé Pedro , Afonso Cláudia M. , Bandarra Narcisa M. 
Published: July 2019

SummaryThe microalgae Chlorella vulgaris and Arthrospira platensis were evaluated as nutraceuticals. It was observed that Arthrospira platensis is richer in saturated fatty acids (FA) and Chlorella vulgaris richer in monounsaturated FA. Within polyunsaturated FA (PUFA), n3 PUFA content was below 1% in Arthrospira sp and over 10% in Chlorella vulgaris. This microalga had the lowest polyphenolic content. The highest value was found in the aqueous extract of Arthrospira platensis, 334 ± 32 mg GAE per 100 g dw. Regarding DPPH, only aqueous extracts of Chlorella vulgaris yielded antioxidant activity with an inhibitory activity of 80 ± 1%. ABTS results showed stronger inhibition through the aqueous extracts than through the ethanolic extracts, 89%–93% vs. 24%–32%. Concerning cytotoxicity, ethanolic extracts of Chlorella vulgaris induced a cell viability decrease of approximately 80%. The biochemical characterisation and bioactivity assessment of Chlorella vulgaris and Arthrospira platensis showed that these microalgae have potential for nutraceutical applications.
Long‐term outcome of hypertensive patients with heart failure with mid‐range ejection fraction: The significance of blood pressure control
Authors: Marketou Maria E. , Maragkoudakis Spyros , Fragiadakis Kostantinos , Konstantinou John , Patrianakos Alexandros , Kassotakis Spyridon , Anastasiou Ioannis , Alevizaki Afroditi , Kostaki Artemis , Chlouverakis Gregory , Vardas Panos E. , Parthenakis Fragiskos I. 
Published: July 2019

AbstractHeart failure (HF) with mid‐range ejection fraction (HFmrEF) is a newly suggested entity in HF. Since it has been inadequately addressed, there is an urgent need to determine the profile of HFmrEF patients and the optimal approach to their management. The present study aimed to assess the long‐term clinical outcomes of hypertensive patients with HFmrEF and the impact of blood pressure (BP) on their mortality and cardiovascular outcome. We performed a retrospective observational study that included 121 hypertensive patients with HFmrEF and 149 hypertensives with heart failure and preserved ejection fraction (HFpEF). The median follow‐up was 84 months (22‐122). Our analysis did not reveal any statistically significant difference between the two groups in total mortality (P = 0.34) or cardiovascular mortality (P = 0.54). The total mean survival time was 102.9 months (100.5‐110.1), while the mean survival time was 105.3 months (80.4‐90.2) in HFpEF and 97.6 months (92.7‐102.6) in HFmrEF. An office systolic BP > 139 mm Hg and diastolic BP > 89 mm Hg were significantly associated with both all‐cause mortality (P = 0.02 and P = 0.013, respectively) and cardiovascular mortality (P = 0.02 for both). In HFpEF patients, no significant association was found between outcome and office BP. HFpEF and HFmrEF have similar long‐term outcomes. Suboptimal BP levels are a significant risk factor for an adverse outcome in HFmrEF. Our results emphasize the importance of good BP control in order to achieve better outcomes in hypertensives with impaired EF and HF symptomatology.
HBx combined with AFB1 triggers hepatic steatosis via COX‐2‐mediated necrosome formation and mitochondrial dynamics disorder
Authors: Chen Yuan‐Yuan , Lin Yi , Han Pei‐Yu , Jiang Shan , Che Lin , He Cheng‐Yong , Lin Yu‐Chun , Lin Zhong‐Ning 
Published: July 2019

AbstractHepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure have been recognized as independent risk factors for the occurrence and exacerbation of hepatic steatosis but their combined impacts and the potential mechanisms remain to be further elucidated. Here, we showed that exposure to AFB1 impaired mitochondrial dynamics and increased intracellular lipid droplets (LDs) in the liver of HBV‐transgenic mice in vivo and the hepatitis B virus X protein (HBx)‐expressing human hepatocytes both ex vivo and in vitro. HBx combined with AFB1 exposure also up‐regulated receptor interaction protein 1 (RIP1), receptor interaction protein 3 (RIP3) and activated mixed lineage kinase domain like protein (MLKL), providing evidence of necrosome formation in the hepatocytes. The shift of the mitochondrial dynamics towards imbalance of fission and fusion was rescued when MLKL was inhibited in the HBx and AFB1 co‐treated hepatocytes. Most importantly, based on siRNA or CRISPR/Cas9 system, we found that the combination of HBx and AFB1 exposure increased cyclooxygenase‐2 (COX‐2) to mediate up‐regulation of RIP3 and dynamin‐related protein 1 (Drp1), which in turn promoted location of RIP3‐MLKL necrosome on mitochondria, subsequently exacerbated steatosis in hepatocytes. Taken together, these findings advance the understanding of mechanism associated with HBx and AFB1‐induced hepatic necrosome formation, mitochondrial dysfunction and steatosis and make COX‐2 a good candidate for treatment.
Linoleic acid‐derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron‐glia co‐cultures in a sex‐dependent manner
Authors: Hennebelle Marie , Morgan Rhianna K. , Sethi Sunjay , Zhang Zhichao , Chen Hao , Grodzki Ana Cristina , Lein Pamela J. , Taha Ameer Y. 
Published: July 2019

AbstractIn adult rats, omega‐6 linoleic acid (LA, 18:2n‐6) serves as a precursor to oxidized LA metabolites (OXLAMs) known to regulate multiple signaling processes in the brain. However, little is known regarding the levels or role(s) of LA and its metabolites during brain development. To address this gap, fatty acids within various brain lipid pools, and their oxidized metabolites (oxylipins) were quantified in brains from 1‐day‐old male and female pups using gas chromatography and liquid chromatography coupled to tandem mass spectrometry, respectively. Primary neuron‐glia co‐cultures derived from postnatal day 0–1 male and female rat neocortex were exposed to vehicle (0.1% ethanol), LA, the OXLAM 13‐hydroxyoctadecadienoic acid (13‐HODE), or prostaglandin E2 at 10–1000 nM for 48 h to test their effects on neuronal morphology. In both male and female pups, LA accounted for 1–3% of fatty acids detected in brain phospholipids and cholesteryl esters. It was not detected in triacylglycerols, and free fatty acids. Unesterified OXLAMs constituted 47–53% of measured unesterified oxylipins in males and females (vs. ~5–7% reported in adult rat brain). Of these, 13‐HODE was the most abundant, accounting for 30–33% of measured OXLAMs. Brain fatty acid and OXLAM concentrations did not differ between sexes. LA and 13‐HODE significantly increased axonal outgrowth. Separate analyses of cultures derived from male versus female pups revealed that LA at 1, 50, and 1000 nM, significantly increased axonal outgrowth in female but not male cortical neurons, whereas 13‐HODE at 100 nM significantly increased axonal outgrowth in male but not female cortical neurons. prostaglandin E2 did not alter neuronal outgrowth in either sex. This study demonstrates that OXLAMs constitute the majority of unesterified oxylipins in the developing rat brain despite low relative abundance of their LA precursor, and highlights a novel role of LA and 13‐HODE in differentially influencing neuronal morphogenesis in the developing male and female brain.
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