bluuebunny/crossref_metadata_2025_split huggingface dataset:
A larger low‐flow‐mediated constrictor response is associated with augmented flow‐mediated dilation in the popliteal artery
Authors: O'Brien Myles W. , Petterson Jennifer L. , Johns Jarrett A. , Mekary Said , Kimmerly Derek S. 
Published: August 2021

AbstractIn the brachial artery, conflicting evidence exists regarding the relationship between the low‐flow–mediated constriction (L‐FMC) and subsequent flow‐mediated dilation (FMD) responses, which may confound interpretation of the latter. The popliteal artery is a common site for atherosclerotic development, which is preceded by endothelial dysfunction. We aimed to determine whether the magnitude of popliteal L‐FMC impacted FMD responses, which is currently unknown. L‐FMC and FMD were assessed in the popliteal artery via high‐resolution duplex ultrasonography and quantified as the percent change in diameter (from baseline) during ischaemia and in response to hyperaemia, respectively. Using partial correlations and multiple regression analyses, we evaluated the association between popliteal L‐FMC on FMD in 110 healthy participants (60 females; 42 ± 22 [19–77] years). All variables univariately associated (p < 0.05) with popliteal relative FMD (relative L‐FMC, log‐SRAUC, age, systolic blood pressure, diastolic blood pressure, resting shear rate) were inputted into a model that explained 35% of the variance. The reactive hyperaemia stimulus (log‐SRAUC: β = 1.10) and relative L‐FMC (β = −0.39) were the only independent predictors of FMD (both, p < 0.01). Relative L‐FMC was negatively correlated to relative FMD, after controlling for the significant univariate predictor variables listed above (R = −0.30; p = 0.002). An augmented (ie healthier) L‐FMC response was linked with a larger FMD response as determined by the independent inverse association observed between these shear‐stress–mediated measures of vasoreactivity.
Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling
Authors: Huth Felix , Schiller Hilmar , Jin Yi , Poller Birk , Schuhler Carole , Weis Wendy , Woessner Ralph , Drollmann Anton , End Peter 
Published: August 2021

AbstractRemibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.
Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1)
Authors: Wu Benjamin , Sternheim Nitzan , Agarwal Priya , Suchomel Julia , Vadhavkar Shweta , Bruno Rene , Ballinger Marcus , Bernaards Coen A. , Chan Phyllis , Ruppel Jane , Jin Jin , Girish Sandhya , Joshi Amita , Quarmby Valerie 
Published: August 2021

AbstractBaseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti‐drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti–PD‐L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13–54%) developed treatment‐emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA‐positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure‐response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.
Effect of sex chromosome number variation on attention‐deficit/hyperactivity disorder symptoms, executive function, and processing speed
Authors: Green Tamar , Flash Shira , Shankar Geeta , Bade Shrestha Sharon , Jo Booil , Klabunde Megan , Hong David S , Reiss Allan L 
Published: August 2021

AimTo study sex differences in attention‐deficit/hyperactivity disorder (ADHD) symptoms, we explored whether X chromosome absence or excess is independently associated with deficits in attention and hyperactivity, executive function, and processing speed.MethodWe assessed 116 children (ages 3y 10mo–11y 11mo, mean 8y 5mo, SD 1y 11mo) with a variable number of sex chromosomes: 36 females with Turner syndrome (45, X0), 20 males with Klinefelter syndrome (47, XXY), 37 typically developing females (XX), and 23 typically developing males (XY).ResultsX chromosome absence was associated with increased attention problems, hyperactivity, and deficits in inhibitory control, compared with female children with XX (all p<0.003). Conversely, X chromosome excess was associated with weakness in working memory (p=0.018) and approached significance for attention problems (p=0.071) but not with hyperactivity, or weakness in inhibitory control relative to male children with XY. Using non‐parametric effect size to quantify the clinical effect revealed that X chromosome absence affected attention, hyperactivity, executive function, and processing speed (all r>0.4), while X excess affected in‐laboratory as well as parent‐reported working memory (all r>0.4).InterpretationOur observations provide compelling evidence that the absence or excess of an X chromosome distinctly affects cognition and behaviors associated with ADHD.
From insulin injections to islet transplantation: An overview of the journey
Authors: Paget Michelle B. , Murray Hilary E. , Bailey Clifford J. , Downing Richard 
Published: August 2021

AbstractWhen, in 1869, Paul Langerhans detected the “islands of tissue” in the pancreas, he took the first step on a journey towards islet transplantation as a treatment for type 1 diabetes. The route has embraced developments across biosciences, surgery, gene therapy and clinical research. This review highlights major milestones along that journey involving whole pancreas transplantation, islet transplantation, the creation of surrogate insulin‐secreting cells and novel islet‐like structures using genetic and bio‐engineering technologies. To obviate the paucity of human tissue, pluripotent stem cells and non‐β‐cells within the pancreas have been modified to create physiologically responsive insulin‐secreting cells. Before implantation, these can be co‐cultured with endothelial cells to promote vascularisation and with immune defence cells such as placental amnion cells to reduce immune rejection. Scaffolds to contain grafts and facilitate surgical placement provide further opportunities to achieve physiological insulin delivery. Alternatively, xenotransplants such as porcine islets might be reconsidered as opportunities exist to circumvent safety concerns and immune rejection. Thus, despite a long and arduous journey, the prospects for increased use of tissue transplantation to provide physiological insulin replacement are drawing ever closer.
Responses of a pair‐living, sexually monogamous primate to the simulated presence of solitary individuals: A field playback experiment
Authors: Garcia de la Chica Alba , Wood David Bechtel , Rotundo Marcelo , Fernandez‐Duque Eduardo 
Published: August 2021

AbstractLoud calls play an important function in regulating the use of space and structuring social groups and mating systems in a wide range of taxa. In pair‐living territorial animals, where encounters with neighbors and solitary conspecifics are common, these calls are mainly associated with resource defense or mate guarding behaviors. Owl monkeys (Aotus azarae) live in groups of one pair of reproducing adults and 1–4 younger, non‐reproducing individuals. Both sexes disperse when they are around 3 years of age; they become solitary floaters who compete to replace same‐sex adults from other groups. Here, we examined the behavioral responses of Azara's owl monkey pairs toward calls of unpaired and unfamiliar males and females to better understand if the competition between floaters and groups is in relationship to the defense of their territory, their mates, or both. We collected behavioral data from six groups, before, during, and after the playing back of unfamiliar male and female loud calls and of a control stimulus at the center and border of their home ranges. Overall, our results showed that the playback location did not elicit differential responses in the monkeys and that both sexes were more reactive to male than female unfamiliar calls, as evidenced by higher rates of sociosexual and vocal responses, movement toward the playback, and intergroup encounters during and after the experiments. Our study indicates that paired male and female owl monkeys mainly defend their partners toward intruders and emphasizes the need of including the role of sexual competition on both sexes in models about the evolution of pair‐living social organizations and sexual monogamy mating systems.
Takeover duration and negotiation process
Authors: Calcagno Riccardo , de Bodt Eric , Demidova Irina 
Published: August 2021

AbstractWe study the relations between takeover negotiations duration, competition and learning, focusing on the private phase of bidder‐initiated transactions. While the negotiation goes on, both parties learn about true deal synergies. At any moment, rival bidders can show up and compete for the target. Using a discrete‐time finite‐horizon dynamic programming approach, we derive the equilibrium relations between the negotiation duration, the pressure of potential competition and the learning process. Next, we perform a calibration exercise on a large sample of merger negotiations with hand‐collected data from the Securities and Exchange Commission filings. Our results provide evidence of a very competitive M&A (Mergers and acquisitions) market.
TNF‐α blockade may lead to improvement of vascular function in psoriasis patients
Authors: Wegner Joanna , Karbach Susanne , Drosos Ioannis , Schnorbus Boris , Muxel Selina , Schmidt Frank , Wenzel Philip , Waisman Ari , Münzel Thomas , Gori Tommaso , von Stebut Esther 
Published: August 2021

AbstractPsoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin‐17A (IL‐17A)–mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti‐inflammatory treatment by tumor necrosis factor (TNF)‐α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium‐dependent vascular tone were assessed by ultrasound measurement of flow‐mediated dilation (FMD) and low‐flow–mediated constriction (l‐FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti‐TNF‐α treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti‐TNF‐α treatment significantly improved l‐FMC in psoriasis patients. Noteworthy, both FMD and l‐FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co‐existent classical cardiovascular risk factors on FMD and l‐FMC cannot be ruled out by our small study. The results suggest that anti‐inflammatory treatment with TNF‐α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti‐inflammatory therapy on vascular function in patients with chronic inflammatory diseases.
An investigation on fracture toughness of the heat‐affected zone in the welded joints of 13% Cr‐4% Ni martensitic stainless steels
Authors: Foroozmehr Fayaz , Bocher Philippe 
Published: August 2021

AbstractFracture behavior of the welded joints of 13% Cr‐4% Ni stainless steels deposited using multipass flux‐cored arc welding process was examined in both as‐welded and heat‐treated conditions, and JIc tests were performed. A crack starter notch was placed one millimeter far from the fusion line to evaluate the heat‐affected zone (HAZ). Unstable crack propagations toward the weld metal occurred during stable tearing for both as‐welded and heat‐treated HAZ. Only single‐point fracture toughness Ju values could be determined before fracture instability. The fracture toughness of the as‐welded HAZ was about 60% lower than that of the substrate steel but get significantly improved by heat‐treatment, reaching a value even slightly higher than that of the substrate steel. The fracture mode of the stable tearing was transformed from a mix of cleavage and dimpled rupture occurring by micro‐void coalescence mechanism for the as‐welded condition to a totally dimpled rupture in the case of the heat‐treated material.
Late to bed, late to rise—Warmer autumn temperatures delay spring phenology by delaying dormancy
Authors: Beil Ilka , Kreyling Jürgen , Meyer Claudia , Lemcke Nele , Malyshev Andrey V. 
Published: August 2021

AbstractSpring phenology of temperate forest trees has advanced substantially over the last decades due to climate warming, but this advancement is slowing down despite continuous temperature rise. The decline in spring advancement is often attributed to winter warming, which could reduce chilling and thus delay dormancy release. However, mechanistic evidence of a phenological response to warmer winter temperatures is missing. We aimed to understand the contrasting effects of warming on plants leaf phenology and to disentangle temperature effects during different seasons. With a series of monthly experimental warming by ca. 2.4°C from late summer until spring, we quantified phenological responses of forest tree to warming for each month separately, using seedlings of four common European tree species. To reveal the underlying mechanism, we tracked the development of dormancy depth under ambient conditions as well as directly after each experimental warming. In addition, we quantified the temperature response of leaf senescence. As expected, warmer spring temperatures led to earlier leaf‐out. The advancing effect of warming started already in January and increased towards the time of flushing, reaching 2.5 days/°C. Most interestingly, however, warming in October had the opposite effect and delayed spring phenology by 2.4 days/°C on average; despite six months between the warming and the flushing. The switch between the delaying and advancing effect occurred already in December. We conclude that not warmer winters but rather the shortening of winter, i.e., warming in autumn, is a major reason for the decline in spring phenology.
Enacting a just and sustainable blue economy through transdisciplinary action research
Authors: Heidkamp C. Patrick , Garland Michaela , Krak Louie 
Published: August 2021

AbstractTo enact a just and sustainable blue economy, one must consider all the actors involved in its shaping. This paper argues that a quintuple helix approach to stakeholder engagement – involving government, academia, the business community, and civil society – and an inclusive transdisciplinary action research (TAR) methodology are promising avenues with which to do so. Embracing critical pragmatism as a foundational framework, key ideas from three strands of research are consolidated: (1) the recent work on the geographical dimension of socio‐technical sustainability transitions; (2) the literature on just sustainabilities and just transition; and (3) action research and transdisciplinary approaches to problem solving. This allows for the reimagination of a common future for the blue economy that is developed through a different kind of democratic process driven and informed by co‐learning, and shared experiences. By adopting a transdisciplinary action research approach, actors from different disciplines and spheres of experience can gain a better mutual understanding and find commonality through the open door of collaboration. The theoretical argument presented in this paper is illustrated by a vignette of an ongoing TAR project at Southern Connecticut State University, which outlines the challenges and opportunities inherent to implementing a TAR approach.
Seasonal changes in carbon and nitrogen metabolism of Brachiaria decumbens in a long‐term silvopastoral system
Authors: Lima Marina A. , Lelis Daiana L. , Martins Auxiliadora O. , Paciullo Domingos S. C. , Nunes‐Nesi Adriano , Araújo Wagner L. , Morenz Mirton J. F. , Silva Fabyano F. , Gomide Carlos A. M. , Rodrigues Renato A. R. , Chizzotti Fernanda H. M. 
Published: August 2021

AbstractOur objective was to quantify the metabolites involved in the carbon and nitrogen metabolism of leaf blades of Brachiaria decumbens grown under conditions of intense shade (69%) in the understory of a silvopastoral system (SPS) and compare them to B. decumbens leaf blades grown in an open pasture (OP) under full sunlight. Two treatments corresponding to the specific production system (SPS and OP) were evaluated over four seasons: Spring 2016, Summer 2017, Autumn 2017, and Winter 2017. In the SPS, we observed an increase in the levels of nitrogen‐related metabolites (chlorophyll, nitrate, amino acids and total soluble proteins) and a reduction in carbon‐related metabolites (total soluble carbohydrates, malate, fumarate, starch and sucrose) relative to those in the OP. This pattern of response was also influenced by the seasons, with higher levels of nitrogen‐related metabolites present during seasons with a greater availability of growth resources. In contrast, most carbon‐related metabolites were lower in the spring and summer and higher in the autumn and winter; only sucrose and starch were higher in the spring and winter. Our results demonstrated that intense light restriction in an SPS affects the productivity, longevity and nutritional value of the forage by reducing the levels of metabolites involved in carbon metabolism and increasing the metabolites involved in nitrogen metabolism.
Developing histories of Indian development
Authors: Menon Nikhil 
Published: August 2021

AbstractThis essay offers a tour of historical scholarship produced in the last two decades on economic development in early independent India. It is a sub‐field that for reasons of archival access and renewed interest is growing, like historical works on independent India more generally. Surveying this landscape, it appears that there are some analytical channels that seem to be exhausting themselves after having long pressed forward, and others that are mining rich seams and new terrain. Broadly speaking, these development histories of the early Indian republic cluster around three themes that spill into one another: interactions between the state and industrial capital, the centrality of food and water, and finally, interconnections with global development.
Study of natural product adverse events in adult HIV‐infected patients in Canada
Authors: Sparks Emma , Zorzela Liliane , Necyk Candace , Hughes Christine , Vohra Sunita 
Published: August 2021

AbstractIntroductionMany individuals living with HIV use natural health products (NHPs) in an effort to decrease medication side effects and to enhance overall well‐being.MethodsAn active surveillance study of adult patients (≥ 18 years) with HIV was conducted between 2012 and 2014 to detect prescription drug and NHP use and associated adverse events (AEs) in the last month.ResultsOf the 167 participants, 85 (50.9%) took prescription medications only, three (1.8%) took NHPs only, 75 (44.9%) took NHPs and prescription medications concurrently, and four (2.4%) took neither. Patients who used both prescription drugs and NHPs concurrently were more than three times more likely to experience an AE compared with those who used prescription drugs only (OR, P = 0.003, 95% CI: 1.47–6.91).ConclusionsIncreased AEs are reported in patients with HIV who combine NHPs and prescription medications, and no serious AEs were reported. Active surveillance was found to be feasible in this clinical setting.