bluuebunny/crossref_metadata_2025 huggingface dataset:
Insect—Symbiont Gene Expression in the Midgut Bacteriocytes of a Blood-Sucking Parasite
Authors: Husnik Filip , Hypsa Vaclav , Darby Alistair
Published: February 2020

Animals interact with a diverse array of both beneficial and detrimental microorganisms. In insects, these symbioses in many cases allow feeding on nutritionally unbalanced diets. It is, however, still not clear how are obligate symbioses maintained at the cellular level for up to several hundred million years. Exact mechanisms driving host–symbiont interactions are only understood for a handful of model species and data on blood-feeding hosts with intracellular bacteria are particularly scarce. Here, we analyzed interactions between an obligately blood-sucking parasite of sheep, the louse fly Melophagus ovinus, and its obligate endosymbiont, Arsenophonus melophagi. We assembled a reference transcriptome for the insect host and used dual RNA-Seq with five biological replicates to compare expression in the midgut cells specialized for housing symbiotic bacteria (bacteriocytes) to the rest of the gut (foregut–hindgut). We found strong evidence for the importance of zinc in the system likely caused by symbionts using zinc-dependent proteases when acquiring amino acids, and for different immunity mechanisms controlling the symbionts than in closely related tsetse flies. Our results show that cellular and nutritional interactions between this blood-sucking insect and its symbionts are less intimate than what was previously found in most plant-sap sucking insects. This finding is likely interconnected to several features observed in symbionts in blood-sucking arthropods, particularly their midgut intracellular localization, intracytoplasmic presence, less severe genome reduction, and relatively recent associations caused by frequent evolutionary losses and replacements.
Age-Related Differences in the Gut Microbiome of Rhesus Macaques
Authors: Adriansjach Julie , Baum Scott T , Lefkowitz Elliot J , Van Der Pol William J , Buford Thomas W , Colman Ricki J
Published: February 2020

Aging is a multifactorial process characterized by progressive changes in gut physiology and the intestinal mucosal immune system. These changes, along with alterations in lifestyle, diet, nutrition, inflammation and immune function alter both composition and stability of the gut microbiota. Given the impact of environmental influences on the gut microbiota, animal models are particularly useful in this field. To understand the relationship between the gut microbiota and aging in nonhuman primates, we collected fecal samples from 20 male and 20 female rhesus macaques (Macaca mulatta), across the natural macaque age range, for 16S rRNA gene analyses. Operational taxonomic units were then grouped together to summarize taxon abundance at different hierarchical levels of classification and alpha- and beta-diversity were calculated. There were no age or sex differences in alpha diversity. At the phylum level, relative abundance of Proteobacteria and Firmicutes and Firmicutes to Bacteriodetes ratio were different between age groups though significance disappeared after correction for multiple comparisons. At the class level, relative abundance of Firmicutes_Bacilli decreased and Proteobacteria_Alphaproteobacteria and Proteobacteria_Betaproteobacteria increased with each successively older group. Only differences in Firmicutes_Bacilli remained significant after correction for multiple comparisons. No sex differences were identified in relative abundances after correction for multiple comparisons. Our results are not surprising given the known impact of environmental factors on the gut microbiota.
Seismic inversion of soil damping and stiffness using multichannel analysis of surface wave measurements in the marine environment
Authors: Armstrong M A , Ravasio M , Versteijlen W G , Verschuur D J , Metrikine A V , van Dalen K N
Published: February 2020

Determination of soil material damping is known to be difficult and uncertain, especially in the offshore environment. Using an advanced inversion methodology based on multichannel spectral analysis, Scholte and Love wave measurements are used to characterize subsea soil from a North Sea site. After normalization, a determinant-based objective function is used in a genetic algorithm optimization to estimate the soil shear modulus. The inverted shear-modulus profile is comparable to previously published results for the same data, although a higher degree of certainty is achieved in the near-surface layers. The half-power bandwidth method is used for extracting the attenuation curve from the measurements and efficient reference data points are chosen based on wavelet compression. The material-damping ratio inversion is performed using a modified stochastic optimization algorithm. Accounting for measurement errors, the material-damping ratio profile is retrieved from the fundamental-mode Scholte wave with a high degree of certainty. Furthermore, a method is proposed for identifying the frequency dependence of the material-damping ratio from in situ measurements. No evidence for frequency dependence is found and the small-strain soil material-damping ratio at this site can be said to be frequency independent for the measured conditions.
Transfer functions between teleseismic data components
Authors: Frederiksen A W
Published: February 2020

Different data components of teleseismic waveforms are related by transfer functions that depend only on receiver-side structure. This is the common basis of a number of teleseismic techniques, including receiver functions and shear wave splitting analysis. Common trace misfits used in these analysis techniques are shown to be equivalent to band-limited comparisons of real and synthetic transfer functions. The data deconvolution used in receiver function analysis leads to reduced structural resolution compared to direct trace-based misfits such as cross-convolution, with direct transfer function modelling of a data trace having the particular advantage of a physically meaningful misfit. Having established that the intertrace transfer function contains all available structural information, the sensitivity of transfer functions to structure is examined for a series of teleseismic scenarios. Transfer functions for the teleseismic P coda show a strong sensitivity to shallow low-velocity structures such as sedimentary basins; the Sp precursors used in S receiver functions are less affected. Examination of transfer functions for shear wave splitting shows that response complexities occur at frequencies too high to be observable in teleseismic studies, and that the dominant control on the response is the splitting intensity.
Stent and leaflet stresses across generations of balloon-expandable transcatheter aortic valves
Authors: Xuan Yue , Dvir Danny , Wang Zhongjie , Ye Jian , Guccione Julius M , Ge Liang , Tseng Elaine E
Published: February 2020

OBJECTIVES

Transcatheter aortic valve replacement (TAVR) is established therapy for severe aortic stenosis patients with intermediate-, high- and prohibitive-risk for surgery. A significant challenge when expanding TAVR to low-risk and younger patients is the unknown long-term durability. High leaflet stresses have been associated with surgical bioprosthetic valve degeneration. In this study, we examined the impact of changes in valve design across 3 generations of same-sized TAVR devices on stent and leaflet stresses.

METHODS

The 26-mm Edwards SAPIEN, 23, 26 and 29 mm SAPIEN XT (XT) and 26 mm SAPIEN 3 (S3) (n = 1 each) underwent micro-computed tomography (micro-CT) scanning. Dynamic finite element computational simulations of 23–26 mm SAPIEN, 23–29 mm XT and 23–29 mm S3 were performed with physiological loading and micro-CT or scaled geometries.

RESULTS

Peak stresses were concentrated in the commissure area and along the bottom of the suture, representing areas most likely to develop structural valve degeneration across TAVR generations. Latest-generation S3 showed greatest 99th percentile principal stress on commissural leaflets for 26 and 29 mm, and increased stresses over XT for 23 mm. Percentage of higher stress areas within the leaflets steadily increased across generations, 3.8%, 3.9% and 5.7%, respectively, for 26 mm SAPIEN, XT and S3 with similar trend for 29-mm valves.

CONCLUSIONS

Using computational simulations based on high-fidelity modelling of balloon-expandable TAVRs, our study demonstrated that maximum stress areas existed in similar leaflet locations across SAPIEN generations, while the latest model S3 had the highest magnitude for both 26- and 29-mm valves. S3 also had the largest area of higher stresses than other generations, which would be prone to degeneration. Our study coupled with future long-term clinical outcomes >10 years will provide insight on biomechanics of TAVR degeneration.
Overconstrained gravitational lens models and the Hubble constant
Authors: Kochanek C S
Published: February 2020

It is well known that measurements of H0 from gravitational lens time delays scale as H0 ∝ 1 − κE, where κE is the mean convergence at the Einstein radius RE but that all available lens data other than the delays provide no direct constraints on κE. The properties of the radial mass distribution constrained by lens data are RE and the dimensionless quantity ξ = REα″(RE)/(1 − κE), where α″(RE) is the second derivative of the deflection profile at RE. Lens models with too few degrees of freedom, like power-law models with densities ρ ∝ r−n, have a one-to-one correspondence between ξ and κE (for a power-law model, ξ = 2(n − 2) and κE = (3 − n)/2 = (2 − ξ)/4). This means that highly constrained lens models with few parameters quickly lead to very precise but inaccurate estimates of κE and hence H0. Based on experiments with a broad range of plausible dark matter halo models, it is unlikely that any current estimates of H0 from gravitational lens time delays are more accurate than ${\sim} 10{{\ \rm per\ cent}}$, regardless of the reported precision.
Chromospheric plasma ejection above a pore
Authors: Bharti L , Sobha B , Quintero Noda C , Joshi C , Pandya U
Published: February 2020

We present high spatial resolution observations of short-lived transients, ribbons and jet-like events above a pore in Ca ii H images where fine structure, like umbral dots, light bridges and penumbral microfilaments, is present in the underlying photosphere. We found that current layers are formed at the edges of the convective fine structure, due to the shear between their horizontal field and the ambient vertical field. High vertical electric current density patches are observed in the photosphere around these events, which indicates the formation of a current sheet at the reconnection site. In the framework of past studies, low altitude reconnection could be the mechanism that produces such events. The reconnection is caused by an opposite polarity field produced by the bending of field lines by convective downflows at the edge of pore fine structure.
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

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

To 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

Demographic 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

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

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]) >1000 cps/mL; St B: CD4 ≤200, VL ≤1000; St C: CD4 >200, VL >1000; St D: CD4 >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 < .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 < .0001). Linear regression demonstrated that oral HIV-1 levels were associated with IL-1β, IL-6, IL-8, and TNFα production (R > .40; P < .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

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 >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

The 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

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 < 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

Trichloroethene (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

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
Antihypertensive drugs and the risk of cancer: a critical review of available evidence and perspective
Authors: Battistoni Allegra , Tocci Giuliano , Coluccia Roberta , Burnier Michel , Ruilope Luis M. , Volpe Massimo
Published: February 2020

The issue of a potential danger of antihypertensive drugs related to cancer susceptibility is currently generating a major debate in the scientific community, concerns in the public and emphasized interest from the media. The present article is a thorough review of what is known on the various classes of antihypertensive drugs concerning the risk of developing different neoplasms and about the suggested pathophysiological mechanisms, whenever available. The main limitations of evidence derived from studies currently available in this setting are also discussed, high-lightening the need for newly developed approaches to generate more accurate recommendations and informed advice for physicians.
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.
The influence of SBP amplification on the accuracy of form-factor-derived mean arterial pressure
Authors: Schultz Martin G. , Picone Dean S. , Armstrong Mathew K. , Black J. Andrew , Dwyer Nathan , Roberts-Thomson Philip , Sturgess David , Sharman James E.
Published: February 2020

Objectives:

Accurate assessment of mean arterial pressure (MAP) is crucial in research and clinical settings. Measurement of MAP requires not only pressure waveform integration but can also be estimated via form-factor equations incorporating peripheral SBP. SBP may increase variably from central-to-peripheral arteries (SBP amplification), and could influence accuracy of form-factor-derived MAP, which we aimed to determine.

Methods:

One hundred and eighty-eight patients (69% men, age 60 ± 10 years) undergoing coronary angiography had intra-arterial pressure measured in the ascending aorta, brachial and radial arteries. Reference MAP was measured by waveform integration, and form-factor-derived MAP using 33 and 40% form-factors.

Results:

Reference MAP decreased from the aorta to the brachial (−0.7 ± 4.2 mmHg) and radial artery (−1.7 ± 4.8 mmHg), whereas form-factor-derived MAP increased (33% form-factor 1.1 ± 4.2 and 1.7 ± 4.7 mmHg; 40% form-factor 0.9 ± 4.8 and 1.4 ± 5.4 mmHg, respectively). Form-factor-derived MAP was significantly different to reference aortic MAP (33% form-factor −2.5 ± 4.6 and −1.6 ± 5.8, P < 0.001; 40% form-factor 2.5 ± 5.0 and 3.9 ± 6.4 mmHg, P < 0.001, brachial and radial arteries, respectively), with significant variation in the brachial form-factor required (FFreq) to generate MAP equivalent to reference aortic MAP (FFreq range 20–57% brachial; 17–74% radial). Aortic-to-brachial SBP amplification was strongly related to brachial FFreq (r = −0.695, P < 0.001). The 33% form-factor was most accurate with high aortic-to-brachial SBP amplification (33% form-factor MAP vs. reference aortic MAP difference 0.06 ± 3.93 mmHg, P = 0.89) but overestimated reference aortic MAP with low aortic-to-brachial SBP amplification (+5.8 ± 4.6 mmHg, P < 0.001). The opposite was observed for the 40% form-factor.

Conclusion:

Due to variable SBP amplification, estimating MAP via form-factors produces nonphysiological inaccurate values. These findings have important implications for accurate assessment of MAP in research and clinical settings.
Favorable effect of catheter ablation on nocturnal hypertension in patients with paroxysmal atrial fibrillation
Authors: Wada Tadashi , Sakuragi Satoru , Saito Takaaki , Kawaguchi Tatsuto , Kodera Nobuhisa , Iida Toshihiro , Yamada Takashi , Nakashima Mitsutaka , Koide Yuji , Kawamoto Kenji , Tanakaya Machiko , Katayama Yusuke , Ito Hiroshi
Published: February 2020

Objectives:

The current study was performed to determine whether pulmonary vein isolation (PVI) improves nocturnal hypertension in patients with paroxysmal atrial fibrillation (PAF).

Background:

Abnormal night-time blood pressure (BP) fluctuation is a risk factor for atrial fibrillation. Imbalance of autonomic nervous function is a risk factor common to both of these abnormalities. PVI can reportedly modify the autonomic nervous function balance in patients with atrial fibrillation.

Methods:

The study population comprised 50 consecutive patients (mean age, 69.8 ± 7.5 years; 35.0% male) with PAF scheduled for PVI. Both 24-h ambulatory BP monitoring and heart rate variability analysis were performed before and at 3 months after PVI.

Results:

Patients were classified into two groups according to the presence of nocturnal BP dipping before PVI: the normal dipping group (n = 27) and the nondipping group (n = 23). The low-frequency spectrum power and the ratio of low-frequency spectrum power to high-frequency spectrum power (low-frequency spectrum/high-frequency spectrum) were higher in the nondipping than the normal dipping group (low-frequency spectrum: 219.9 ± 210.2 vs. 92.7 ± 50.5 ms2, respectively,P = 0.03; low-frequency spectrum/high-frequency spectrum: 1.8 ± 1.9 vs. 0.9 ± 0.8, respectively,P = 0.05). In the nondipping group, the elevated night-time BP disappeared in eight (35%) patients at 3 months after PVI, which was associated with an increase in high-frequency spectrum power. These patients did not develop atrial fibrillation recurrence during follow-up (mean, 568 ± 218 days).

Conclusion:

Among patients with PAF, the nondipping group showed greater sympathetic activity (higher low-frequency spectrum power and low-frequency spectrum/high-frequency spectrum) than the dipping group. Restoration of BP dipping after PVI is associated with increased parasympathetic activity (higher high-frequency spectrum power) and reduced recurrence of arrhythmic events.
When Patients Appear in the News: Clinical Considerations for Mental Health Professionals
Authors: Morris Nathaniel P.
Published: February 2020

News media have proliferated across digital platforms, print, radio, television, and other outlets, and mental health professionals may unintentionally learn information about their patients from these sources. Although these kinds of discoveries can pose complex clinical challenges to mental health professionals, there is hardly any literature on this topic, and clinicians may feel alone when facing these situations. Using several case examples, this article examines ways in which mental health professionals might learn about their patients from news media, as well as the potential effects of these discoveries on the practice of psychiatry. This article also offers suggestions for research and for training opportunities that would help prepare mental health professionals for encountering news coverage about their patients.
The Relation Between Posttraumatic Stress Symptom Severity and Startle Potentiation to Predictable and Unpredictable Threat
Authors: Lieberman Lynne , Funkhouser Carter J. , Gorka Stephanie M. , Liu Huiting , Correa Kelly A. , Berenz Erin C. , Phan K. Luan , Shankman Stewart A.
Published: February 2020

Aberrant threat reactivity has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD); however, the literature on this association is mixed. One factor that may contribute to this inconsistent association is differences in severity of posttraumatic stress symptoms (PTSSs) across studies, but no studies have tested this hypothesis. The relation between PTSD and threat reactivity may also differ between unpredictable threats (U-threats) and predictable threats (P-threats), given burgeoning evidence to support a particular role for aberrant responding to U-threat in PTSD. The present study examined how PTSS severity relates to startle potentiation to U-threat and P-threat in a trauma-exposed community sample (N = 258). There was a negative linear, but not quadratic, relation between PTSS severity and startle potentiation to U-threat, but not P-threat. Blunted defensive responding to U-threat may therefore contribute to higher levels of PTSSs and may represent a novel treatment target for higher levels of PTSSs.
The New 2019 Institutional Review Board Common Rule Update: Implications for Plastic Surgery Research
Authors: Crystal Dustin T. , Cuccolo Nicholas G. , Ibrahim Ahmed M. S. , Neligan Peter C. , Janis Jeffrey E. , Lin Samuel J.
Published: February 2020

Clinical research remains at the forefront of academic practice and evidence-based medicine. Unfortunately, history has shown that human subjects are vulnerable to experimentation without regard for their own dignity and informed decision-making. Subsequently, it is vital for research institutes to uphold safeguards and ethical conscientiousness toward human subjects. The establishment of federal regulations and the development of institutional review boards have set guidance on these processes. On January 21, 2019, final revisions to the Federal Policy for the Protection of Human Subjects (the “Common Rule”) went into effect. The purpose of this article is to review changes to the Common Rule and discuss their impact on plastic surgery research.
Potentially highly potent drugs for 2019-nCoV
Authors: Nguyen Duc Duy , Gao Kaifu , Chen Jiahui , Wang Rui , Wei Guo-Wei
Published: February 2020

The World Health Organization (WHO) has declared the 2019 novel coronavirus (2019-nCoV) infection outbreak a global health emergency. Currently, there is no effective anti-2019-nCoV medication. The sequence identity of the 3CL proteases of 2019-nCoV and SARS is 96%, which provides a sound foundation for structural-based drug repositioning (SBDR). Based on a SARS 3CL protease X-ray crystal structure, we construct a 3D homology structure of 2019-nCoV 3CL protease. Based on this structure and existing experimental datasets for SARS 3CL protease inhibitors, we develop an SBDR model based on machine learning and mathematics to screen 1465 drugs in the DrugBank that have been approved by the U.S. Food and Drug Administration (FDA). We found that many FDA approved drugs are potentially highly potent to 2019-nCoV.
Toward point-of-care diagnostics of Candida auris
Authors: Mulberry Geoffrey , Chaturvedi Sudha , Chaturvedi Vishnu , Kim Brian N.
Published: February 2020

Candida auris is a multidrug-resistant yeast that presents global health threat for the hospitalized patients. Early diagnostic of C. auris is crucial in control, prevention, and treatment. Candida auris is difficult to identify with standard laboratory methods and often can be misidentified leading to inappropriate management. A newly-devised real-time PCR assay played an important role in the ongoing investigation of the C. auris outbreak in New York metropolitan area. The assay can rapidly detect C. auris DNA in surveillance and clinical samples with high sensitivity and specificity, and also useful for confirmation of C. auris cultures. Despite its positive impact, the real-time PCR assay is difficult to deploy at frontline laboratories due to high-complexity set-up and operation. Using a low-cost handheld real-time PCR device, we show that the C. auris can potentially be identified in a low-complexity assay without the need for high-cost equipment. An implementation of low-cost real-time PCR device in hospitals and healthcare facilities is likely to accelerate the diagnosis of C. auris and for control of the global epidemic.