bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad‐Spectrum Flavivirus Inhibitors: a Medicinal Chemistry Point of View
Authors: Felicetti Tommaso , Manfroni Giuseppe , Cecchetti Violetta , Cannalire Rolando 
Published: September 2020

AbstractInfections by flaviviruses, such as Dengue, West Nile, Yellow Fever and Zika viruses, represent a growing risk for global health. There are vaccines only for few flaviviruses while no effective treatments are available. Flaviviruses share epidemiological, structural, and ecologic features and often different viruses can co‐infect the same host. Therefore, the identification of broad‐spectrum inhibitors is highly desirable either for known flaviviruses or for viruses that likely will emerge in the future.Strategies targeting both virus and host factors have been pursued to identify broad‐spectrum antiflaviviral agents. In this review, we describe the most promising and best characterized targets and their relative broad‐spectrum inhibitors, identified by drug repurposing/libraries screenings and by focused medicinal chemistry campaigns. Finally, we discuss about future strategies to identify new broad‐spectrum antiflavivirus agents.
Thorough QT/QTc Study Evaluating the Effect of Macimorelin on Cardiac Safety Parameters in Healthy Participants
Authors: Lissy Michael , Demmel Valentin , Sachse Richard , Ammer Nicola , Kelepouris Nicky , Ostrow Vlady 
Published: September 2020

AbstractMacimorelin is an orally active growth hormone secretagogue indicated for the diagnosis of adult growth hormone deficiency. The primary objective of this study was to evaluate the effect of macimorelin on the baseline and placebo‐corrected mean QT interval using Fridericia's formula (ΔΔQTcF). Secondary objectives were to determine QTcF for moxifloxacin; evaluate the effects of macimorelin on other cardiac intervals (PR, QRS, RR), heart rate, and electrocardiogram morphology parameters; characterize pharmacokinetics; and assess safety of macimorelin. The phase 1 thorough QT/QTc study, designed according to the International Council for Harmonisation E14 guideline, was a randomized, placebo‐controlled, double‐blind, 3‐way complete crossover study comparing the effect of macimorelin 2.0 mg/kg with placebo and moxifloxacin 400 mg (positive control). Data were collected over a 3‐month span from male (n=36) and female participants (n=24) aged 18 to 55 years with body mass index between 18.5 and 30.0 kg/m2. Fifty‐six participants received all 3 treatments. The ΔΔQTcF for macimorelin showed a prolongation with a maximum mean value of 9.61 milliseconds (2‐sided 90% confidence interval, 7.81 milliseconds and 11.41 milliseconds) at 4 hours after dosing. The 2‐sided 90% confidence interval of this value also exceeded the 10 millisecond threshold at 3 hours after dosing. Assay sensitivity was confirmed with moxifloxacin. Other electrocardiogram parameters evaluated were not influenced by macimorelin. Macimorelin did not raise other safety concerns and was well tolerated. In summary, a single supratherapeutic dose of macimorelin prolonged cardiac repolarization according to the regulatory guideline.
Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects
Authors: Bauer Martin , Bamminger Karsten , Pichler Verena , Weber Maria , Binder Simon , Maier‐Salamon Alexandra , Tahir Ammar , Jäger Walter , Haslacher Helmuth , Tournier Nicolas , Hacker Marcus , Zeitlinger Markus , Langer Oliver 
Published: September 2020

The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood‐brain barrier (BBB) efflux transporter P‐gp and displays central nervous system (CNS) side effects (i.e., extrapyramidal symptoms and tardive dyskinesia) caused by dopamine D2 receptor blockade in the basal ganglia. These side effects occur with a higher incidence in elderly people. We used positron emission tomography to assess the brain distribution of [11C]metoclopramide in young (n = 11, 26 ± 3 years) and elderly (n = 7, 68 ± 9 years) healthy men both after administration of a microdose (9 ± 7 µg) and a microdose co‐injected with a therapeutic dose of unlabeled metoclopramide (10 mg). For both doses, elderly subjects had a significantly higher total volume of distribution (VT) of [11C]metoclopramide in the basal ganglia than young subjects (microdose: +26%, therapeutic dose: +41%). Increases in VT (= K1/k2) were caused by significant decreases in the transfer rate constant of [11C]metoclopramide from brain into plasma (k2, microdose: −18%, therapeutic dose: −30%), whereas the distributional clearance from plasma into brain (K1) remained unaltered. This reduction in the clearance of [11C]metoclopramide (k2) from the brains of elderly subjects may be caused by an age‐related decrease in the activity of P‐gp at the BBB and may contribute to the higher incidence of CNS side effects of metoclopramide in the aged population. Our data suggest that an age‐associated decrease in the clearance properties of the BBB may modulate the CNS effects or side effects of clinically used P‐gp substrates.
Composite restorations placed in non‐carious cervical lesions—Which cavity preparation is clinically reliable?
Authors: Lührs Anne‐Katrin , Jacker‐Guhr Silke , Günay Hüsamettin , Herrmann Peggy 
Published: September 2020

AbstractThe purpose of this in‐vivo study was to evaluate the clinical performance of restorations placed in non‐carious cervical lesions (NCCLs), using different cavity preparation designs, after 7.7 years. A total of 85 NCCLs with coronal margins in enamel and cervical margins in dentin were randomly assigned to the following treatment protocols: dentin surface cleaning, dentin surface roughening with round bur plus flowable composite, dentin surface roughening/cervical groove preparation with round bur, dentin surface roughening/cervical groove preparation with round bur plus flowable composite. After enamel beveling and selective enamel etching, the defects were restored with composite. The restorations were assessed by two independent, calibrated and blinded investigators, using modified USPHS criteria. At 7 years (7.7 (± 0.35)), a total of 64 restorations (75.3%) were available for follow‐up examination. The total retention rate, irrespective of the test groups, was 82.8%. Restorations placed without any preparation showed the highest loss rate (27.8%). Esthetic appearance, marginal adaptation, anatomic form and marginal discoloration did not differ significantly between the groups. Composites are long‐term stable materials for restoring NCCLs. Restorations placed without any dentin preparation (cavity cleaning only) showed the highest loss rate.
Nearly unbiased estimator of contemporaryNe/Nbased on kinship relationships
Authors: Akita Tetsuya 
Published: September 2020

AbstractThis study develops a nearly unbiased estimator of the ratio of the contemporary effective mother size to the census size in a population, as a proxy of the ratio of contemporary effective size (or effective breeding size) to census size (Ne/NorNb/N). The proposed estimator is based on both known mother–offspring (MO) and maternal‐sibling (MS) relationships observed within the same cohort, in which sampled individuals in the cohort probably share MO relationships with sampled mothers. The rationale is that the frequency of MO and MS pairs contains information regarding the contemporary effective mother size and the (mature) census size, respectively. Therefore, the estimator can be obtained only from genetic data. We also evaluate the performance of the estimator by running an individual‐based model. The results of this study provide the following: (a) parameter range for satisfying the unbiasedness, and (b) guidance for sample sizes to ensure the required accuracy and precision, especially when the order of the ratio is available. Furthermore, the results demonstrate the usefulness of a sibship assignment method for genetic monitoring, providing insights for interpreting environmental and/or anthropological factors fluctuatingNe/N(orNb/N), especially in the context of conservation biology and wildlife management.
Lake productivity and waterbird functional diversity across geographic and environmental gradients in temperate China
Authors: Zhang Yamian , Tan Wenzhuo , Zeng Qing , Tian Haitao , Jia Yifei , Lei Guangchun , Wen Li 
Published: September 2020

AbstractGeographical gradients in species diversity have long fascinated biogeographers and ecologists. However, the extent and generality of the effects of the important factors governing functional diversity (FD) patterns are still debated, especially for the freshwater domain. We examined the relationship between lake productivity and functional diversity of waterbirds sampled from 35 lakes and reservoirs in northern China with a geographic coverage of over 5 million km2. We used structural equation modeling (SEM) to explore the causal relationships between geographic position, climate, lake productivity, and waterbird FD. We found unambiguous altitudinal and longitudinal gradients in lake productivity and waterbird FD, which were strongly mediated by local environmental factors. Specifically, we found (a) lake productivity increased northeast and decreased with altitude. The observed geographic and altitudinal gradients were driven by climatic conditions and nutrient availability, which collectively explained 93% of the variations in lake productivity; (b) waterbird FD showed similar geographic and altitudinal gradients; the environmental factors which had direct and/or indirect effects on these gradients included climate and lake area, which collectively explained more than 39% of the variation in waterbird FD; and 3) a significant (p = .029) causality between lake productivity and waterbird FD was confirmed. Nevertheless, the causality link was relatively weak in comparison with climate and lake area (the standardized path coefficient was 0.55, 0.23, and 0.03 for climate, lake area, and productivity, respectively). Our study demonstrates how the application of multivariate technique (e.g., SEM) enables the illustration of complex causal paths in ecosystems, enhancing mechanistic explanations that underlie the observed broadscale biodiversity gradients.
Lizard predation by spiders: A review from the Neotropical and Andean regions
Authors: Reyes‐Olivares Claudio , Guajardo‐Santibáñez Andrés , Segura Bernardo , Zañartu Nicolás , Penna Mario , Labra Antonieta 
Published: September 2020

AbstractVertebrate predation by invertebrates has been classically underexplored and thus underestimated, despite the fact that many arthropods consume vertebrates. To shed some light on the relevance that spider predation may have upon lizards in the Neotropical and Andean regions, we compiled the available information in the literature on this trophic interaction. We found 50 reports of spiders consuming lizards in these regions, and the 88% of these were from the Neotropical region. Spiders belong to eight families, but Ctenidae and Theraphosidae were the most frequently reported predators. Lizards belong to 12 families, and the most commonly consumed species corresponded to the families Dactyloidae (all Anolis lizards), Gymnophthalmidae, and Sphaerodactylidae. Data suggest trophic spider–lizard associations between Ctenidae and Dactyloidae, followed by Theraphosidae and Liolaemidae. The body sizes of the spiders and lizards showed a positive relationship, and spiders were smaller than their prey. We conclude that various spider taxa can be considered lizard predators and they may be ecologically important in the Neotropical and Andean regions. However, spiders of prime predation relevance seem to be those of the Ctenidae and Theraphosidae families.
Transient top‐down and bottom‐up effects of resources pulsed to multiple trophic levels
Authors: McCary Matthew A. , Phillips Joseph S. , Ramiadantsoa Tanjona , Nell Lucas A. , McCormick Amanda R. , Botsch Jamieson C. 
Published: September 2020

AbstractPulsed fluxes of organisms across ecosystem boundaries can exert top‐down and bottom‐up effects in recipient food webs, through both direct effects on the subsidized trophic levels and indirect effects on other components of the system. While previous theoretical and empirical studies demonstrate the influence of allochthonous subsidies on bottom‐up and top‐down processes, understanding how these forces act in conjunction is still limited, particularly when an allochthonous resource can simultaneously subsidize multiple trophic levels. Using the Lake Mývatn region in Iceland as an example system of allochthony and its potential effects on multiple trophic levels, we analyzed a mathematical model to evaluate how pulsed subsidies of aquatic insects affect the dynamics of a soil–plant–arthropod food web. We found that the relative balance of top‐down and bottom‐up effects on a given food web compartment was determined by trophic position, subsidy magnitude, and top predators’ ability to exploit the subsidy. For intermediate trophic levels (e.g., detritivores and herbivores), we found that the subsidy could either alleviate or intensify top‐down pressure from the predator. For some parameter combinations, alleviation and intensification occurred sequentially during and after the resource pulse. The total effect of the subsidy on detritivores and herbivores, including top‐down and bottom‐up processes, was determined by the rate at which predator consumption saturated with increasing size of the allochthonous subsidy, with greater saturation leading to increased bottom‐up effects. Our findings illustrate how resource pulses to multiple trophic levels can influence food web dynamics by changing the relative strength of bottom‐up and top‐down effects, with bottom‐up predominating top‐down effects in most scenarios in this subarctic system.
Clinical presentation and outcomes of peripartum cardiomyopathy in the Middle East: a cohort from seven Arab countries
Authors: Salam Amar M. , Ahmed Mohamed Badie , Sulaiman Kadhim , Singh Rajvir , Alhashemi Mohammed , Carr Alison S. , Alsheikh‐Ali Alawi A. , AlHabib Khalid F. , Al‐Zakwani Ibrahim , Panduranga Prashanth , Asaad Nidal , Shehab Abdulla , AlMahmeed Wael , Al Suwaidi Jassim 
Published: September 2020

AbstractAimsPublished data on the clinical presentation of peripartum cardiomyopathy (PPCM) are very limited particularly from the Middle East. The aim of this study was to examine the clinical presentation, management, and outcomes of patients with PPCM using data from a large multicentre heart failure (HF) registry from the Middle East.Methods and resultsFrom February to November 2012, a total of 5005 consecutive patients with HF were enrolled from 47 hospitals in 7 Middle East countries. From this cohort, patients with PPCM were identified and included in this study. Clinical features, in‐hospital, and 12 months outcomes were examined. During the study period, 64 patients with PPCM were enrolled with a mean age of 32.5 ± 5.8 years. Family history was identified in 11 patients (17.2%) and hypertension in 7 patients (10.9%). The predominant presenting symptom was dyspnoea New York Heart Association class IV in 51.6%, class III in 31.3%, and class II in 17.2%. Basal lung crepitations and peripheral oedema were the predominant signs on clinical examination (98.2% and 84.4%, respectively). Most patients received evidence‐based HF therapies. Inotropic support and mechanical ventilation were required in 16% and 5% of patients, respectively. There was one in‐hospital death (1.6%), and after 1 year of follow‐up, nine patients were rehospitalized with HF (15%), and one patient died (1.6%).ConclusionsA high index of suspicion of PPCM is required to make the diagnosis especially in the presence of family history of HF or cardiomyopathy. Further studies are warranted on the genetic basis of PPCM.
Association of left ventricular ejection fraction with worsening renal function in patients with acute heart failure: insights from the RELAX‐AHF‐2 study
Authors: Feng Siting , Janwanishstaporn Satit , Teerlink John R. , Metra Marco , Cotter Gad , Davison Beth , Felker G. Michael , Filippatos Gerasimos , Pang Peter , Ponikowski Piotr , Sama Iziah E. , Voors Adriaan A. , Greenberg Barry 
Published: September 2020

AimsWhether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in‐hospital WRF and post‐discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post‐discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX‐AHF‐2.Methods and resultsA total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1–1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post‐discharge events.ConclusionsWorsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post‐discharge events except in patients in the lowest LVEF quartile.
Boosting the cathode function toward the oxygen reduction reaction in microbial fuel cell using nanostructured surface modification
Authors: Mahmoud Rehab H. , Samhan Farag A. , Ibrahim Mohamed K. , Ali Gamila H. , Hassan Rabeay Y. A. 
Published: September 2020

AbstractProduction of bioelectricity via microbial fuel cells (MFCs) may become an important source of energy in the near future due to the possibility of extracting electric current from a wide range of organic wastes. In this study, several nanostructures, such as platinum (Pt)‐reduced graphene oxide nanocomposite, graphene nanosheets, MnO2, and MnO2/RGO, were synthesized, characterized, and investigated as cathode catalysts for oxygen reduction reaction. The prepared catalysts were tested in a single‐chamber microbial fuel cell with anaerobic bacterial mixed culture. Power density produced from MFC closed circuit operation using the nanoengineered catalysts were about 68 times more than those obtained using the classical graphite electrodes. Moreover, there was a slight reduction of 5.8% in power density (from 170 to 160 mW/m2) when Pt nanoparticles were loaded on the RGO nanosheets compared to Pt/C cathode. By replacing the precious Pt catalyst with other nanomaterials, a significant reduction in power density was observed. For RGO‐based cathode, the MFC performance decreased by 31.1% (from 170 to 117 mW/m2) and the percent of reduction reached 48.5% (from 170 to 88 mW/m2) for MnO2‐based cathode MFC. However, in RGO/MnO2 nanocomposite cathode MFC, the percent of reduction in power density was 26.4% (from 170 to 125 mW/m2). It can be concluded that RGO nanosheets loaded with Pt nanoparticles is a starting point for finding an alternative economic and effective cathode.
Dynamic functional network reconfiguration underlying the pathophysiology of schizophrenia and autism spectrum disorder
Authors: Fu Zening , Sui Jing , Turner Jessica A. , Du Yuhui , Assaf Michal , Pearlson Godfrey D. , Calhoun Vince D. 
Published: September 2020

AbstractThe dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step‐wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole‐brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ‐ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in SZ (r = −.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders.
Appropriate and Potentially Inappropriate Medication Use in Decompensated Cirrhosis
Authors: Thomson Mary J. , Lok Anna S. F. , Tapper Elliot B. 
Published: September 2020

Background and Aims
Patients with decompensated cirrhosis are prescribed numerous medications. Data are limited as to whether patients are receiving medications they need and avoiding those they do not. We examined a large national claims database (2010‐2015) to characterize the complete medication profile as well as the factors associated with appropriate and potentially inappropriate medication use in 12,621 patients with decompensated cirrhosis.

Approach and Results
Clinical guidelines and existing literature were used to determine appropriate and potentially inappropriate medications in decompensated cirrhosis. The total medication days’ supply was calculated from pharmacy data and divided by the follow‐up period for each decompensation. Ascites was the most common (86.5%), followed by hepatic encephalopathy (HE; 37.8%), variceal bleeding (VB; 17.5%), hepatorenal syndrome (6.3%), and spontaneous bacterial peritonitis (SBP; 6.1%). For patients with ascites, 55.8% filled a diuretic. For patients with HE, 32.4% and 63.3% filled rifaximin and lactulose, respectively. After VB, 60.3% of patients filled a nonselective beta blocker, and after an episode of SBP, 48.0% of patients filled an antibiotic for prophylaxis. The minority (4.5%‐17.3%) had enough medication to cover >50% follow‐up days. Potentially inappropriate medication use was common: 53.2% filled an opiate, 46.0% proton pump inhibitors, 14.2% benzodiazepines, and 10.1% nonsteroidal anti‐inflammatory drugs. Disease severity markers were associated with more appropriate mediation use but not consistently associated with less inappropriate medication use.

Conclusions
Patients with decompensated cirrhosis are not filling indicated medications as often or as long as is recommended and are also filling medications that are potentially harmful. Future steps include integrating pharmacy records with medical records to obtain a complete medication list and counseling on medication use with patients at each visit.