bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frailty and incident heart failure in older men: the British Regional Heart Study
Authors: McKechnie Douglas GJ , Papacosta A Olia , Lennon Lucy T , Ramsay Sheena E , Whincup Peter H , Wannamethee S Goya 
Published: June 2021

ObjectiveFrailty and heart failure (HF) are cross-sectionally associated. Published longitudinal data are very limited. We sought to investigate associations between frailty and incident HF.MethodsProspective study of 1722 men, examined at age 72–91 years. Scores based on the Fried phenotype, Gill index and a novel frailty score, based on the Health Ageing and Body Composition Battery, incorporating slow walking speed, low chair-stand time and subjective difficulty with balance, were calculated. Associations between these scores and incident HF were analysed with Cox proportional hazard modelling.Results1445 men with frailty data and without prevalent HF were included. 99 developed HF (mean follow-up 6.1 years). Men scoring 3/3 on our novel frailty score had elevated risk of incident HF (HR 2.77, 95% CI 1.25 to 6.15), which persisted after adjustment for established risk factors and interleukin-6 (HR 3.14, 95% CI 1.35 to 7.31). This risk remained increased, although attenuated, after excluding HF events within 2 years of baseline (HR 2.05, 95% CI 0.61 to 6.92). The frailty phenotype showed a non-significant association with HF (age-adjusted HR 1.92, 95% CI 0.99 to 3.73), which was further attenuated after adjustment for prevalent coronary heart disease and Body mass index (HR 1.60, 95% CI 0.81 to 3.15). Gill-type scores were weakly associated with HF risk after these adjustments (HR 1.31, 95% CI 0.47 to 3.70).ConclusionIn these older men, the combination of slow walk speed, low sit-stand time and balance problems were associated with high risk of incident HF, independent of established risk factors and inflammatory markers. However, undiagnosed HF at baseline may still be a confounder. There is a differential association between aspects of the frailty phenotype and incident HF.
Detection of markers predictive of macrolide and fluoroquinolone resistance in Mycoplasma genitalium from patients attending sexual health services
Authors: Day Michaela Joanne , Cole Michelle Jayne , Fifer Helen , Woodford Neil , Pitt Rachel 
Published: June 2021

ObjectivesThis study sought to provide data on the prevalence of macrolide (23S rRNA) and fluoroquinolone (parC) resistance-associated mutations seen in Mycoplasma genitalium-positive specimens received in the UK national reference laboratory.MethodsIn total, 2580 clinical specimens from patients with suspected or confirmed M. genitalium infection were received at the national reference laboratory between September 2017 and November 2018. M. genitalium-positive clinical specimens were identified using a reverse transcription-PCR targeting two M. genitalium genes: MgPa and gap. Resistance-associated single nucleotide poylmorphisms were sought in all positive specimens by sequence analysis of the 23S rRNA and parC genes.ResultsEighteen per cent (458 of 2580) of clinical specimens were positive for M. genitalium and 389 had sequence data for both macrolide and fluoroquinolone resistance markers. Of these, 71% (275 of 389) had macrolide resistance-associated mutations, 8% (31 of 389) had fluoroquinolone resistance-associated mutations (S83I/R and D87Y/N) and 7% (26 of 389) had mutations associated with resistance to both antimicrobials. Only 28% (108 of 389) had no mutations associated with resistance to either class of antibiotic. Five specimens had mutations of unknown clinical significance in the parC gene (eg, G81C and S83N).ConclusionsMutations associated with resistance to macrolides were very frequent. By contrast, susceptibility to the second-line treatment, moxifloxacin (a fluoroquinolone), was estimated at 92% based on the absence of resistance-associated mutations. The few specimens with mutations of unknown clinical significance in the parC gene were excluded from the analysis and so the actual level of fluoroquinolone susceptibility may be slightly lower than that reported here. Surveillance of antimicrobial resistance in M. genitalium is imperative for this to remain a treatable infection.
Performance of phytoncide (Pinus koraiensis extract) as an alternative to zinc oxide supplementation in weaning pig diet
Authors: Seok Woo Jeong , Hoque Md Raihanul , Serpunja Subin , Kim In Ho 
Published: June 2021

This study was implemented to assess the effect of Pinus koraiensis extract (PKE) compared with zinc oxide on growth performance, nutrient digestibility, blood profile, fecal bacterial count, and fecal gas emission of post-weaned pigs. This 6 wk experiment was divided into phase 1 (days 1–7), phase 2 (days 8–21), and phase 3 (days 22–42). A total of 150 crossbred weaning pigs (body weight; 10.14 ± 0.78 kg) were randomly sorted in five treatment diets (six replications per treatment; five pigs per pen) presented as CON, basal diet; ZnO, CON + 0.30% zinc oxide; PKE1, CON + 0.05% PKE; PKE2, CON + 0.10% PKE; and PKE3, CON + 0.15% PKE. Pinus koraiensis extract supplementation linearly reduced gain to feed ratio in all phases except phase 3. It also linearly increased average daily gain in the overall experiment compared with the CON group. The increasing level of PKE supplementation brought linear improvement in aspartate aminotransferase of blood profile. Escherichia coli bacterial count and NH3 gas emission were decreased linearly by PKE supplementation in comparison to the CON diet. Though PKE supplementation did not show similar influence as ZnO, it showed beneficial results in weaning pigs’ growth, nutrient digestibility, fecal bacterial count, and reduction of fecal gas emission.
Speeding up MadGraph5_aMC@NLO
Authors: Mattelaer O. , Ostrolenk K. 
Published: June 2021

AbstractIn this paper we will describe two new optimisations implemented in MadGraph5_aMC@NLO, both of which are designed to speed-up the computation of leading-order processes (for any model). First we implement a new method to evaluate the squared matrix element, dubbed helicity recycling, which results in factor of two speed-up. Second, we have modified the multi-channel handling of the phase-space integrator providing tremendous speed-up for VBF-like processes (up to thousands times faster).
Observational constraints in metric-affine gravity
Authors: Bahamonde Sebastian , Valcarcel Jorge Gigante 
Published: June 2021

AbstractWe derive the main classical gravitational tests for a recently found vacuum solution with spin and dilation charges in the framework of Metric-Affine gauge theory of gravity. Using the results of the perihelion precession of the star S2 by the GRAVITY collaboration and the gravitational redshift of Sirius B white dwarf we constrain the corrections provided by the torsion and nonmetricity fields for these effects.
Estimating the impact of the QCD dynamics on the determination of the high energy astrophysical neutrino flux
Authors: Gonçalves Victor P. , Gratieri Diego R. , Quadros Alex S. C. 
Published: June 2021

AbstractThe number of ultra-high energy neutrinos arriving at IceCube depends on the energy dependence of the astrophysical neutrino flux and neutrino cross-section. In this paper, we investigate the impact of different assumptions for the description of the QCD dynamics at high energies on the determination of the normalization $$\Phi _{Astro}$$

Φ

Astro

and spectral index $$\gamma $$
γ
of the astrophysical neutrino flux. The distribution of neutrino events at the IceCube is estimated considering the DGLAP, BFKL, CGC and BBMT approaches and the best estimates for $$\Phi _{Astro}$$

Φ

Astro

and $$\gamma $$
γ
are determined using a maximum likelihood fit comparing the predictions with the distribution of observed events at IceCube. Moreover, we also investigate if the increase in the effective exposure time expected in IceCube-Gen2 will to allow us to disentangle the QCD dynamical effects from the description of the astrophysical neutrino flux.
Electromagnetic resonance of nonlinear vacuum in one-dimensional cavity
Authors: Shibata Kazunori 
Published: June 2021

Abstract
Nonlinear corrections on electromagnetic fields in vacuum have been expected. In this study, we have theoretically considered nonlinear Maxwell’s equations in a one-dimensional cavity for a classical light and external static electromagnetic fields. A general solution for the electromagnetic corrective components including that of a longitudinal standing wave was derived after a linearization. The main purpose is to give a detailed feature of the previously reported resonant behavior [Shibata, Euro. Phys. J. D 74:215 (2020)], such as the effect of external static fields and the polarization fluctuation. These results favor the development of new and effective method for experiment.

Graphic abstract
On a Theorem of Lovász that (&sdot,
H
) Determines the Isomorphism Type of
H
Authors: Cai Jin-yi , Govorov Artem 
Published: June 2021

Graph homomorphism has been an important research topic since its introduction [20]. Stated in the language of binary relational structures in that paper [20], Lovász proved a fundamental theorem that, for a graph
H
given by its 0-1 valued adjacency matrix, the graph homomorphism function
G
↦ hom(
G
,
H
) determines the isomorphism type of
H
. In the past 50 years, various extensions have been proved by many researchers [1, 15, 21, 24, 26]. These extend the basic 0-1 case to admit vertex and edge weights; but these extensions all have some restrictions such as all vertex weights must be positive. In this article, we prove a general form of this theorem where
H
can have arbitrary vertex and edge weights. A noteworthy aspect is that we prove this by a surprisingly simple and unified argument. This bypasses various technical obstacles and unifies and extends all previous known versions of this theorem on graphs. The constructive proof of our theorem can be used to make various complexity dichotomy theorems for graph homomorphism
effective
in the following sense: it provides an algorithm that for any
H
either outputs a P-time algorithm solving hom(&sdot,
H
) or a P-time reduction from a canonical #P-hard problem to hom(&sdot,
H
).
Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial
Authors: Subbiah Vivek , Gainor Justin F. , Oxnard Geoffrey R. , Tan Daniel S.W. , Owen Dwight H. , Cho Byoung Chul , Loong Herbert H. , McCoach Caroline E. , Weiss Jared , Kim Yu Jung , Bazhenova Lyudmila , Park Keunchil , Daga Haruko , Besse Benjamin , Gautschi Oliver , Rolfo Christian , Zhu Edward Y. , Kherani Jennifer F. , Huang Xin , Kang Suhyun , Drilon Alexander 
Published: June 2021

Abstract

Purpose:
We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non–small cell lung cancers (NSCLC).

Patients and Methods:
In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.

Results:
Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0–10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60–95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3–NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9–NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.

Conclusions:
Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.
Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in BRAFV600E-Driven Papillary Thyroid Cancer Patients
Authors: Pappa Theodora , Ahmadi Sara , Marqusee Ellen , Johnson Hannah L. , Nehs Matthew A. , Cho Nancy L. , Barletta Justine A. , Lorch Jochen H. , Doherty Gerard M. , Lindeman Neal I. , Alexander Erik K. , Landa Iñigo 
Published: June 2021

Abstract

Purpose:
The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes.

Experimental Design:
We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations.

Results:
Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P &lt; 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043).

Conclusions:
Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.
CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment
Authors: Fujiwara Tomohiro , Yakoub Mohamed A. , Chandler Andrew , Christ Alexander B. , Yang Guangli , Ouerfelli Ouathek , Rajasekhar Vinagolu K. , Yoshida Aki , Kondo Hiroya , Hata Toshiaki , Tazawa Hiroshi , Dogan Yildirim , Moore Malcolm A.S. , Fujiwara Toshiyoshi , Ozaki Toshifumi , Purdue Ed , Healey John H. 
Published: June 2021

Abstract
Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow–derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell–modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.
Oncogenic KrasG12D Activation in the Nonhematopoietic Bone Marrow Microenvironment Causes Myelodysplastic Syndrome in Mice
Authors: Osswald Lena , Hamarsheh Shaima'a , Uhl Franziska Maria , Andrieux Geoffroy , Klein Claudius , Dierks Christine , Duquesne Sandra , Braun Lukas M. , Schmitt-Graeff Annette , Duyster Justus , Boerries Melanie , Brummer Tilman , Zeiser Robert 
Published: June 2021

Abstract

The bone marrow microenvironment (BMME) is key player in regulation and maintenance of hematopoiesis. Oncogenic RAS mutations, causing constitutive activation of multiple tumor-promoting pathways, are frequently found in human cancer. So far in hematologic malignancies, RAS mutations have only been reported to occur in hematopoietic cells. In this study, we investigated the effect of oncogenic Kras expression in the BMME in a chimeric mouse model. We observed that an activating mutation of Kras in the nonhematopoietic system leads to a phenotype resembling myelodysplastic syndrome (MDS) characterized by peripheral cytopenia, marked dysplasia within the myeloid lineage as well as impaired proliferation and differentiation capacity of hematopoietic stem and progenitor cells. The phenotypic changes could be reverted when the BM was re-isolated and transferred into healthy recipients, indicating that the KrasG12D-activation in the nonhematopoietic BMME was essential for the MDS phenotype. Gene expression analysis of sorted nonhematopoietic BM niche cells from KrasG12D mice revealed upregulation of multiple inflammation-related genes including IL1-superfamily members (Il1α, Il1β, Il1f9) and the NLPR3 inflammasome. Thus, pro-inflammatory IL1-signaling in the BMME may contribute to MDS development. Our findings show that a single genetic change in the nonhematopoietic BMME can cause an MDS phenotype. Oncogenic Kras activation leads to pro-inflammatory signaling in the BMME which impairs HSPCs function.

Implications:
These findings may help to identify new therapeutic targets for MDS.
Echinoderms from the Gulf of Venezuela, north-western coast of Venezuela
Authors: Espinoza-Rodríguez Nínive Edilia , Pernía Yumara , Severeyn Héctor , Severeyn Yajaira García de , Barrios-Garrido Héctor 
Published: June 2021

Echinoderms are a major group of marine invertebrates that often play integral roles within the marine ecosystem. Studies about their occurrence, abundance, and distribution in Venezuela are focused in the central-eastern coasts; hence the aim of this study is to describe the echinoderm community in the north-western coast of the Gulf of Venezuela. Samples were collected from three sites in the Venezuelan Guajira Peninsula (Castilletes, Porshoure, and Kazuzain) where patchy coral reefs and seagrass meadows are abundant. According to the substrate, two methods were performed using quantitative (1 m² quadrates), and qualitative free-diving observations. All organisms were counted and identified to the lowest possible taxonomic level; finally, diversity (Shannon diversity index), richness (number of species), and dominance in the different sampled substrates were recorded. The updated list of echinoderms of the Gulf of Venezuela reported in this research, includes 20 genera, 15 families, 10 orders, four classes, and 28 species. The richest class was Ophiuroidea, with 18 species, followed by Asteroidea, Echinoidea and Holothuroidea, with three species each. Castilletes was the sampling site with the higher number of species (18 species), followed by Porshoure (15 species), and lastly Kazuzain (12 species). Our observations indicate that the number of species and abundance were higher when found in coral reefs (21 species, 80.69% of the total collected individuals) in contrast to the species found in seagrass beds (16 species, 19.31% of the total of individuals collected). This updated list of echinoderms represents 11.54% of the total diversity of the phylum in the marine areas from the coast of Venezuela; it is suggested that this percentage is greatly influenced by the differences of habitats and substrates alongside the north-western coast in the Gulf of Venezuela.
MPAs in the Southern Ocean under CCAMLR
Authors: Scott Karen N. 
Published: June 2021

Abstract
In 2016, the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) designated the largest marine protected area (MPA) in the Ross Sea. Hailed as both a precedent and a prototype for MPAs in both Antarctica and in areas beyond national jurisdiction more generally, it is nevertheless proving challenging to implement. Moreover, further MPAs have yet to be designated in the region although a number are under negotiation. This article will evaluate the contribution made by CCAMLR to the implementation of SDG 14.5 (the conservation of at least 20 per cent of marine and coastal areas by 2020), its relationship to area-based protection under the 1991 Environmental Protocol, and highlight the challenges of establishing MPAs beyond the jurisdiction of states.
The Interpretation and Application of the Freedom of Navigation and Flag State Jurisdiction in the M/V “Norstar” and the M/T “San Padre Pio” Cases
Authors: Becker-Weinberg Vasco 
Published: June 2021

Abstract
The M/V “Norstar” and the M/T “San Padre Pio” cases raise important questions regarding the interpretation and application of the freedom of navigation and the principle of exclusive flag State jurisdiction, namely if the latter prohibits the exercise of prescriptive jurisdiction on the high seas by non-flag States. One of the exceptional aspects of the M/V “Norstar” case is the Joint Dissenting Opinion (JDO) by seven judges underlining a distinctive view regarding the interpretation of the freedom of navigation and the principle of exclusive flag State jurisdiction. Subsequent to the M/V “Norstar” case, the M/T “San Padre Pio” case was submitted and bares relevance for the clarification on some of the key matters addressed in the Judgment and the JDO in the M/V “Norstar” case. This article highlights the different views of the Judgment and the JDO and examines the relation with the M/T “San Padre Pio” case.