bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gargantuan chaotic gravitational three-body systems and their irreversibility to the Planck length
Authors: Boekholt T C N , Portegies Zwart S F , Valtonen M 
Published: February 2020

ABSTRACT
Chaos is present in most stellar dynamical systems and manifests itself through the exponential growth of small perturbations. Exponential divergence drives time irreversibility and increases the entropy in the system. A numerical consequence is that integrations of the N-body problem unavoidably magnify truncation and rounding errors to macroscopic scales. Hitherto, a quantitative relation between chaos in stellar dynamical systems and the level of irreversibility remained undetermined. In this work, we study chaotic three-body systems in free fall initially using the accurate and precise N-body code Brutus, which goes beyond standard double-precision arithmetic. We demonstrate that the fraction of irreversible solutions decreases as a power law with numerical accuracy. This can be derived from the distribution of amplification factors of small initial perturbations. Applying this result to systems consisting of three massive black holes with zero total angular momentum, we conclude that up to 5 per cent of such triples would require an accuracy of smaller than the Planck length in order to produce a time-reversible solution, thus rendering them fundamentally unpredictable.
Dual Eigen-modules ofCis-Element Regulation Profiles and Selection of Cognition-Language Eigen-direction along Evolution in Hominidae
Authors: Li Liang , Zhang Sheng , Li Lei M 
Published: February 2020

AbstractTo understand the genomic basis accounting for the phenotypic differences between human and apes, we compare the matrices consisting of the cis-element frequencies in the proximal regulatory regions of their genomes. One such frequency matrix is represented by a robust singular value decomposition. For each singular value, the negative and positive ends of the sorted motif eigenvector correspond to the dual ends of the sorted gene eigenvector, respectively, comprising a dual eigen-module defined by cis-regulatory element frequencies (CREF). The CREF eigen-modules at levels 1, 2, 3, and 6 are highly conserved across humans, chimpanzees, and orangutans. The key biological processes embedded in the top three CREF eigen-modules are reproduction versus embryogenesis, fetal maturation versus immune system, and stress responses versus mitosis. Although the divergence at the nucleotide level between the chimpanzee and human genome was small, their cis-element frequency matrices crossed a singularity point, at which the fourth and fifth singular values were identical. The CREF eigen-modules corresponding to the fourth and fifth singular values were reorganized along the evolution from apes to human. Interestingly, the fourth sorted gene eigenvector encodes the phenotypes unique to human such as long-term memory, language development, and social behavior. The number of motifs present on Alu elements increases substantially at the fourth level. The motif analysis together with the cases of human-specific Alu insertions suggests that mutations related to Alu elements play a critical role in the evolution of the human-phenotypic gene eigenvector.
Inferring the Demographic History of Inbred Species from Genome-Wide SNP Frequency Data
Authors: Blischak Paul D , Barker Michael S , Gutenkunst Ryan N 
Published: February 2020

AbstractDemographic inference using the site frequency spectrum (SFS) is a common way to understand historical events affecting genetic variation. However, most methods for estimating demography from the SFS assume random mating within populations, precluding these types of analyses in inbred populations. To address this issue, we developed a model for the expected SFS that includes inbreeding by parameterizing individual genotypes using beta-binomial distributions. We then take the convolution of these genotype probabilities to calculate the expected frequency of biallelic variants in the population. Using simulations, we evaluated the model’s ability to coestimate demography and inbreeding using one- and two-population models across a range of inbreeding levels. We also applied our method to two empirical examples, American pumas (Puma concolor) and domesticated cabbage (Brassica oleracea var. capitata), inferring models both with and without inbreeding to compare parameter estimates and model fit. Our simulations showed that we are able to accurately coestimate demographic parameters and inbreeding even for highly inbred populations (F = 0.9). In contrast, failing to include inbreeding generally resulted in inaccurate parameter estimates in simulated data and led to poor model fit in our empirical analyses. These results show that inbreeding can have a strong effect on demographic inference, a pattern that was especially noticeable for parameters involving changes in population size. Given the importance of these estimates for informing practices in conservation, agriculture, and elsewhere, our method provides an important advancement for accurately estimating the demographic histories of these species.
The Impact of Insulin-Like Growth Factor Index and Biologically Effective Dose on Outcomes After Stereotactic Radiosurgery for Acromegaly: Cohort Study
Authors: Graffeo Christopher S , Donegan Diane , Erickson Dana , Brown Paul D , Perry Avital , Link Michael J , Young William F , Pollock Bruce E 
Published: February 2020

Abstract

BACKGROUND
Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly.

OBJECTIVE
To improve understanding of clinical and dosimetric factors predicting biochemical remission.

METHODS
A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission—defined as normalization of insulin-like growth factor-1 index (IGF-1
i
) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1
i
were assessed via systematic literature review and meta-analysis using random-effect modeling.

RESULTS
A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1
i
was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1
i
≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1
i
, only BED remained significant—and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1
i
was 2.25 (95% CI = 1.33-3.16, P < .0001).

CONCLUSION
IGF-1
i
is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.
Oral Cytokine Levels Are More Linked to Levels of Plasma and Oral HIV-1 RNA Than to CD4+ T-Cell Counts in People With HIV
Authors: Rocco Joseph M , York Zachary , Shen Chengli , Shiboski Caroline , Cyriaque-Webster Jennifer , McLaughlin Janet , Borowski Luann , Chen Huichao , Aberg Judith A , Dittmer Dirk P , Ghannoum Mahmoud , Rinaldo Charles R , Macatangay Bernard 
Published: February 2020

Abstract

Background
We determined the levels of 11 soluble immune mediators in oral washings of AIDS Clinical Trials Group A5254 participants with varying degrees of plasma viremia and CD4 T-cell counts to characterize the mucosal immune response at different stages of HIV-1 infection.

Methods
A5254 was a multicenter, cross-sectional study in people with HIV (PWH) recruited into 4 strata based on CD4 count and levels of plasma viremia: stratum (St) A: CD4 ≤200 cells/mm3, HIV-1 RNA (viral load [VL]) &gt;1000 cps/mL; St B: CD4 ≤200, VL ≤1000; St C: CD4 &gt;200, VL &gt;1000; St D: CD4 &gt;200, VL ≤1000. Oral/throat washings were obtained from all participants. Soluble markers were tested in oral/throat washings using a multibead fluorescent platform and were compared across strata. Linear regression was used to determine the associations between cytokines and HIV-1 in plasma and oral fluid.

Results
St A participants had higher levels of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) compared with St B and D (P = .02; P &lt; .0001) but were not different from St C. IL-8, IL-10, and IL-12 were elevated in St A compared with the other 3 strata (P = .046; P &lt; .0001). Linear regression demonstrated that oral HIV-1 levels were associated with IL-1β, IL-6, IL-8, and TNFα production (R &gt; .40; P &lt; .001) when controlling for CD4 count and opportunistic infections.

Conclusions
Our results show that high levels of oral HIV-1, rather than low CD4 counts, were linked to the production of oral immune mediators. Participants with AIDS and uncontrolled viremia demonstrated higher levels of pro- and anti-inflammatory soluble immune mediators compared with participants with lower HIV-1 RNA. The interplay of HIV-1 and these immune mediators could be important in the oral health of PWH.
Point-of-Care Testing to Guide Treatment and Estimate Risk Factors for Sexually Transmitted Infections in Adolescents and Young People With Human Immunodeficiency Virus in Eswatini
Authors: Jasumback Caitlyn L , Perry Sarah H , Ness Tara E , Matsenjwa Martha , Masangane Zandile T , Mavimbela Mpumelelo , Mthethwa Nobuhle , Dlamini Lindokuhle , Mphaya Joyce , Kirchner H Lester , Mandalakas Anna , Kay Alexander W 
Published: February 2020

Abstract

Background
The World Health Organization (WHO) estimates 127 million new cases of Chlamydia trachomatis (CT), 87 million new cases of Neisseria gonorrhea (NG), and 156 million new cases of Trichomonas vaginalis (TV) each year, which corresponds to 355 (219–606), 303 (216–468), and 243 (97.6–425) thousand disability-adjusted life-years. In low-resource settings, however, sexually transmitted infections (STIs) are treated syndromically and many individuals with asymptomatic infection may be missed, especially adolescents and young adults with human immunodeficiency virus (HIV).

Methods
We enrolled patients aged 15–24 with HIV (N = 300) attending a family-centered HIV clinic in Mbabane, Eswatini. Participants completed a sexual history questionnaire and provided urine as well as oropharyngeal and/or vaginal swabs, if sexually active, for testing with Xpert CT/NG and TV tests. Analysis included bivariate and multivariate odds ratios and test sensitivity and specificity.

Results
Sexually transmitted infection rates were highest (25.0%; 95% confidence interval [CI], 15.2–37.3) in females ages 20–24 who were ever sexually active. In patients with confirmed STIs, NG (15 of 32, 47%) was more common than CT (9 of 32, 28%) and TV (8 of 32, 25%). Syndromic screening alone had a sensitivity of 32.0% (95% CI, 14.9–53.3) and specificity of 86.0% (95% CI, 79.0–91.4) but varied by gender. The presence of an STI was associated with reporting new sexual partner(s) (OR = 2.6; 95% CI, 1.1–6.4), sometimes to never using condoms (OR = 4.2; 95% CI, 1.7–10.2), most recent sexual partner &gt;25 years old (OR = 3.2; 95% CI, 1.3–7.9), and HIV diagnosis at age ≥15 years (OR = 3.4; 95% CI, 1.4–8.2).

Conclusions
Syndromic screening alone performed poorly. Routine diagnostic testing significantly increases STI detection and should be considered in high-risk populations, such as adolescents and young adults with HIV.
Insights into the Compositional Evolution of Crustal Magmatic Systems from Coupled Petrological-Geodynamical Models
Authors: Rummel Lisa , Kaus Boris J P , Baumann Tobias S , White Richard W , Riel Nicolas 
Published: February 2020

AbstractThe evolution of crustal magmatic systems is incompletely understood, as most studies are limited either by their temporal or spatial resolution. Exposed plutonic rocks represent the final stage of a long-term evolution punctuated by several magmatic events with different chemistry and generated under different mechanical conditions. Although the final state can be easily described, the nature of each magmatic pulse is more difficult to retrieve. This study presents a new method to investigate the compositional evolution of plutonic systems while considering thermal and mechanical processes. A thermomechanical code (MVEP2) extended by a semi-analytical dike/sill formation algorithm, is combined with a thermodynamic modelling approach (Perple_X) to investigate the feedback between petrology and mechanics. Melt is extracted to form dikes while depleting the source region. The evolving rock compositions are tracked on markers using a different phase diagram for each discrete bulk-rock composition. The rock compositional evolution is thus tracked with a high precision by means of a database with more than 58 000 phase diagrams. This database describes how density, melt fraction, chemical composition of melt and solid fractions and mineralogical assemblages change over crustal to uppermost mantle P–T conditions for a large range of rock compositions. Each bulk rock composition is composed of the 10 major oxides (SiO2–TiO2–Al2O3–Cr2O3–MgO–FeO–CaO–Na2O–K2O–H2O) including an oxygen buffer. The combined modelling approach is applied to study the chemical evolution of the crust during arc magmatism and related melt extraction and magma mixing processes. Basaltic sills are periodically injected into the crust to model heat/magma influx from the mantle. We find that accumulated sills turn into long-lived mush chambers when using a lower rock cohesion or assuming a higher intrusion depth. Associated partial melting of crustal host rocks occurs around densely distributed dikes and sills. High silica rocks (e.g. granites) are generated by partial melting of the host rocks, melt segregation within dikes, and from fractional crystallization of basalts. Although the volume of these rocks is relatively small in our models compared to rocks with a mafic to intermediate composition, they provide important information about the processes of magma differentiation within arc continental crust.
Sex-specific educational attainment is associated with telomere length in an Australian rural population
Authors: Zhou Y , Hambly B D , Simmons D , McLachlan C S 
Published: February 2020

Abstract

Background
There is limited understanding on whether and how socioeconomic status (SES), particularly educational attainment and household income, impacts on telomere length in an Australian rural context. Additionally, it is unknown whether access to health services via the Australian public or private health system influences telomere length.

Aim
This study investigates whether there is a relationship between telomere length and SES indicators (income, education) as well as health insurance status in a rural Australian population.

Methods
Samples were drawn from the Australian Rural Victoria cross-sectional Crossroads Study. Leucocyte telomere length (LTL) was measured using a multiplex quantitative polymerase chain reaction method.

Results
Among 1424 participants, we did not find a significant main effect association with LTL across education, income level and health insurance. An exploratory finding was sex may influence the relationship between educational attainment and LTL (P = 0.021). In males, but not females, higher education was associated with longer LTL by 0.033 [95% confidence interval (CI) 0.002–0.063, P = 0.035]; in those with low education attainment, male participants had shorter LTL by 0.058 (95% CI −0.086 to −0.029) than female participants (P &lt; 0.0001).

Conclusion
Being male and having lower education attainment was associated with shorter telomere length in our rural population. Evidence from our study supports the importance of education on LTL in males in rural Australia. Our studies also support previous findings that LTL in later life may not be closely associated with indicators of SES.
Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response
Authors: Banerjee Nivedita , Wang Hui , Wang Gangduo , Khan M Firoze 
Published: February 2020

AbstractTrichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.
Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs
Authors: Morais Cristiane Luchesi de Mello , Nascimento Jorge Willian Leandro , Ribeiro Aline Corrêa , Cortinez Luis Ignacio , Carmona Maria José Carvalho , Maia Débora Rothstein Ramos , Monsel Antoine , Auler José Otavio Costa , Rouby Jean-Jacques , Otsuki Denise Aya 
Published: February 2020

Abstract

Background
Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets.

Methods
Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling.

Results
One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] μg/g versus 12 [4, 42] μg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) μg/g and 0 (0, 19) μg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l−1
vs. 121 [103, 149] mg · h · l−1, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h).

Conclusions
Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Impact of single-pill combination therapy on adherence, blood pressure control, and clinical outcomes: a rapid evidence assessment of recent literature
Authors: Tsioufis Konstantinos , Kreutz Reinhold , Sykara Georgia , van Vugt Joris , Hassan Tarek 
Published: February 2020

Objective:
The 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the management of arterial hypertension raised the need for evidence to support the use of single-pill combination (SPC) therapy in preference to free-dosed therapy for hypertension. This systematic rapid evidence assessment sought to determine if initiating SPC therapy improves adherence, blood pressure (BP) control and/or cardiovascular outcomes vs. initiation of free-dose combination therapy.

Methods:
Rapid evidence assessment conducted in MEDLINE, EMBASE, and Cochrane Library (1 January 2013–11 January 2019) to identify studies investigating SPC therapy for adults with hypertension. Information on adherence/persistence, BP lowering/goal attainment, and cardiovascular outcomes/events were extracted via two-phase screening process. Studies not focusing on adherence, persistence, or compliance with SPC therapy were excluded. Methodological quality was assessed using appropriate scales.

Results:
Of 863 citations, 752 failed to meet inclusion or were duplicates. Twenty-nine studies remained following full-text screening. Just four studies (14%) were randomized controlled studies; 25 (86%) were observational. A range of SPC therapies were studied, with calcium channel blocker/angiotensin receptor blocker combinations most common (11/29 studies). Adherence and persistence were generally higher with SPC vs. free-dose combination therapy; 15 studies (54%) directly compared adherence and four (14%) compared persistence. Patients achieving BP targets ranged from 25 to 89%. Despite all studies investigating patients with hypertension only 16 (55%) reported change in BP. Few studies reported on cardiovascular outcomes. Methodological reporting was often suboptimal.

Conclusion:
Adherence and/or persistence were generally higher in patients taking antihypertensives as SPC vs. free-dose combination; however, methodological reporting was suboptimal to facilitate comparison. Specifically designed, well reported studies are required to determine if the increased adherence/persistence seen in patients on SPC regimen leads to improved BP control and/or cardiovascular outcomes.