bluuebunny/crossref_metadata_2025 huggingface dataset:
Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav
Authors: Mellon G , Hammas K , Burdet C , Duval X , Carette C , El-Helali N , Massias L , Mentré F , Czernichow S , Crémieux A -C
Published: July 2020

Background

Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav.

Materials and methods

Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix.

Results

Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral).

Conclusions

Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.
Are subspecies (ofEira barbara) real?
Authors: Schiaffini Mauro Ignacio
Published: July 2020

The subspecies concept is one of the most controversial in Linnean taxonomy. In the past, subspecies were described without a clear conceptual framework, triggering confusion and motivating criticism of the very concept of a subspecies. At present, subspecies are conceived as aggregates of populations that are geographically isolated, are composed of interfertile individuals, and are morphologically diagnosable. The tayra, Eira barbara, was described in 1758 and has had a stable taxonomic history at the species level. However, below the species level, 16 subspecies have been named, with from two to seven subspecies recognized as valid by different authors. None of the subspecies were, however, described within a clear conceptual framework. Using the modern concept of a subspecies, I analyzed subspecies of E. barbara recognized by recent authors. I gathered morphometric data from 155 specimens in mammal collections, georeferenced each specimen, and recorded membership to subspecies assigned by different references and by its location. I gathered climate and geographic data for each location. I analyzed data using Principal Components Analysis (PCA) and analysis of variance (ANOVA). Specimens exhibited sexual dimorphism in size but not in skull shape. I used regression analysis to test for associations between skull shape and size and climate data. Geographic analyses documented that subspecies are not allopatric, violating one of the main properties of the subspecies concept. ANOVA showed significant differences in skull morphology between some pairs of recognized subspecies but not others. However, none of the subspecies segregated in the PCA. Thus, the recognized subspecies could not be diagnosed from morphological data, violating another property of the subspecies concept. Size varied greatly between the sexes using different schemes for recognized subspecies. Climate variables explained between 4% and 6% of size variation for males and females. Skull shape proved not to be geographically variable.
Effect of Aspirin on Cancer Incidence and Mortality in Older Adults
Authors: McNeil John J , Gibbs , *Peter , Orchard Suzanne G , Lockery Jessica E , Bernstein Wendy B , Cao Yin , Ford Leslie , Haydon Andrew , Kirpach Brenda , Macrae Finlay , McLean Catriona , Millar Jeremy , Murray Anne M , Nelson Mark R , Polekhina Galina , Reid Christopher M , Richmond Ellen , Rodríguez Luz Maria , Shah Raj C , Tie Jeanne , Umar Asad , Londen G J van , Ronaldson Kathlyn , Wolfe Rory , Woods Robyn L , Zalcberg John , Chan Andrew T ,   the ASPREE Investigator Group
Published: July 2020

Background

ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.

Methods

19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.

Results

981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).

Conclusions

In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.
Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy
Authors: Franzoi Maria Alice , Eiger Daniel , Ameye Lieveke , Ponde Noam , Caparica Rafael , De Angelis Claudia , Brandão Mariana , Desmedt Christine , Di Cosimo Serena , Kotecki Nuria , Lambertini Matteo , Awada Ahmad , Piccart Martine , Azambuja Evandro de
Published: July 2020

Background

There are limited data regarding the impact of body mass index (BMI) on outcomes in advanced breast cancer, especially in patients treated with endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors.

Methods

A pooled analysis of individual patient-level data from MONARCH 2 and 3 trials was performed. Patients were classified according to baseline BMI into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2) and divided into 2 treatment groups: abemaciclib + ET vs placebo + ET. The primary endpoint was progression-free survival (PFS) according to BMI in each treatment group. Secondary endpoints were response rate, adverse events according to BMI, and loss of weight (≥5% from baseline) during treatment.

Results

This analysis included 1138 patients (757 received abemaciclib + ET and 381 placebo + ET). There was no difference in PFS between BMI categories in either group, although normal-weight patients presented a numerically higher benefit with abemaciclib + ET (Pinteraction = .07). Normal and/or underweight patients presented higher overall response rate in the abemaciclib + ET group compared with overweight and/or obese patients (49.4% vs 41.6%, odds ratio = 0.73, 95% confidence interval = 0.54 to 0.99) as well as higher neutropenia frequency (51.0% vs 40.4%, P = .004). Weight loss was more frequent in the abemaciclib + ET group (odds ratio = 3.23, 95% confidence interval = 2.09 to 5.01).

Conclusions

Adding abemaciclib to ET prolongs PFS regardless of BMI, showing that overweight or obese patients also benefit from this regimen. Our results elicit the possibility of a better effect of abemaciclib in normal and/or underweight patients compared with overweight and/or obese patients. More studies analyzing body composition parameters in patients under treatment with cyclin-dependent kinase 4/6 inhibitors may further clarify this hypothesis.
Dedifferentiated liposarcoma of the scrotum. Case report and literature review
Authors: Salas-Parra Ruben D , Tavares Larissa L , Gupta Ranjan , Silletti Joseph , Shah Ajay
Published: July 2020

Malignant paratesticular and spermatic cord tumors are rare and often misdiagnosed preoperatively due to clinical presentations similar to other benign scrotal mass etiologies. Only a few cases regarding giant, paratesticular liposarcomas (>10 cm) have been reported. We report a unique case of an aggressive giant dedifferentiated liposarcoma of the scrotum with osteosarcoma features in a 70-year-old patient who initially presented with indolent scrotal swelling. A CT scan showed a large, complex, solid and cystic mass (12.0 x 15.5 x 19.0 cm) in the right scrotum. With a concern of a complex hydrocele, the patient was taken to the operating room for a scrotal approach to excise the hydrocele, but the spermatic cord was not traced to any discernible testicle as the entire mass was indurated and multilocular, and was excised. Pathology revealed a dedifferentiated liposarcoma, with MDM2 amplification. The patient’s course was complicated due to metastatic disease.
DNA replication and chromosome positioning throughout the interphase in three-dimensional space of plant nuclei
Authors: Němečková Alžběta , Koláčková Veronika , Vrána Jan , Doležel Jaroslav , Hřibová Eva
Published: July 2020

Despite much recent progress, our understanding of the principles of plant genome organization and its dynamics in three-dimensional space of interphase nuclei remains surprisingly limited. Notably, it is not clear how these processes could be affected by the size of a plant’s nuclear genome. In this study, DNA replication timing and interphase chromosome positioning were analyzed in seven Poaceae species that differ in their genome size. To provide a comprehensive picture, a suite of advanced, complementary methods was used: labeling of newly replicated DNA by ethynyl-2'-deoxyuridine, isolation of nuclei at particular cell cycle phases by flow cytometric sorting, three-dimensional immunofluorescence in situ hybridization, and confocal microscopy. Our results revealed conserved dynamics of DNA replication in all species, and a similar replication timing order for telomeres and centromeres, as well as for euchromatin and heterochromatin regions, irrespective of genome size. Moreover, stable chromosome positioning was observed while transitioning through different stages of interphase. These findings expand upon earlier studies in suggesting that a more complex interplay exists between genome size, organization of repetitive DNA sequences along chromosomes, and higher order chromatin structure and its maintenance in interphase, albeit controlled by currently unknown factors.
Eclipse timing variation of GK Vir: evidence of a possible Jupiter-like planet in a circumbinary orbit
Authors: Almeida L A , Pereira E S , Borges G M , Damineli A , Michtchenko T A , Viswanathan G M
Published: July 2020

Eclipse timing variation analysis has become a powerful method to discover planets around binary systems. We applied this technique to investigate the eclipse times of GK Vir. This system is a post-common envelope binary with an orbital period of 8.26 h. Here, we present 10 new eclipse times obtained between 2013 and 2020. We calculated the O−C diagram using a linear ephemeris and verified a clear orbital period variation (OPV) with a cyclic behaviour. We investigated if this variation could be explained by the Applegate mechanism, the apsidal motion, or the light travel time (LTT) effect. We found that the Applegate mechanism would hardly explain the OPV with its current theoretical description. We obtained using different approaches that the apsidal motion is a less likely explanation than the LTT effect. We showed that the LTT effect with one circumbinary body is the most likely cause for the OPV, which was reinforced by the orbital stability of the third body. The LTT best solution provided an orbital period of ∼24 yr for the outer body. Under the assumption of coplanarity between the external body and the inner binary, we obtained a Jupiter-like planet around the GK Vir. In this scenario, the planet has one of the longest orbital periods, with a full observational baseline, discovered so far. However, as the observational baseline of GK Vir is smaller than twice the period found in the O−C diagram, the LTT solution must be taken as preliminary.
Relativistic AGN jets – III. Synthesis of synchrotron emission from double-double radio galaxies
Authors: Walg S , Achterberg A , Markoff S , Keppens R , Porth O
Published: July 2020

The class of double-double radio galaxies (DDRGs) relates to episodic jet outbursts. How various regions and components add to the total intensity in radio images is less well known. In this paper, we synthesize synchrotron images for DDRGs based on special relativistic hydrodynamic simulations, making advanced approximations for the magnetic fields. We study the synchrotron images for three different radial jet profiles; ordered, entangled, or mixed magnetic fields; spectral ageing from synchrotron cooling; the contribution from different jet components; the viewing angle and Doppler (de-)boosting; and the various epochs of the evolution of the DDRG. To link our results to observational data, we adopt to J1835+6204 as a reference source. In all cases, the synthesized synchrotron images show two clear pairs of hotspots, in the inner and outer lobes. The best resemblance is obtained for the piecewise isochoric jet model, for a viewing angle of approximately ϑ ∼ −71°, i.e. inclined with the lower jet towards the observer, with predominantly entangled (≳70 per cent of the magnetic pressure) in turbulent, rather than ordered fields. The effects of spectral ageing become significant when the ratio of observation frequencies and cut-off frequency νobs/ν∞, 0 ≳ 10−3, corresponding to ∼3 × 102 MHz. For viewing angles ϑ ≲ |−30°|, a DDRG morphology can no longer be recognized. The second jets must be injected within ≲ 4 per cent of the lifetime of the first jets for a DDRG structure to emerge, which is relevant for active galactic nuclei feedback constraints.
High molecular gas content and star formation rates in local galaxies that host quasars, outflows, and jets
Authors: Jarvis M E , Harrison C M , Mainieri V , Calistro Rivera G , Jethwa P , Zhang Z-Y , Alexander D M , Circosta C , Costa T , De Breuck C , Kakkad D , Kharb P , Lansbury G B , Thomson A P
Published: July 2020

We use a sample of powerful $z\, \approx \, 0.1$ type 2 quasars (‘obscured’; log [LAGN/erg s$^{-1}]\, \gtrsim \, 45$), which host kpc-scale ionized outflows and jets, to identify possible signatures of AGN feedback on the total molecular gas reservoirs of their host galaxies. Specifically, we present Atacama Pathfinder EXperiment (APEX) observations of the CO(2–1) transition for nine sources and the CO(6–5) for a subset of three. We find that the majority of our sample reside in starburst galaxies (average specific star formation rates – sSFR – of 1.7 Gyr−1), with the seven CO-detected quasars also having large molecular gas reservoirs (average Mgas = 1.3 × 1010 M⊙), even though we had no pre-selection on the star formation or molecular gas properties. Despite the presence of quasars and outflows, we find that the molecular gas fractions (Mgas/M⋆ = 0.1–1.2) and depletion times (Mgas/SFR = 0.16–0.95 Gyr) are consistent with those expected for the overall galaxy population with matched stellar masses and sSFRs. Furthermore, for at least two of the three targets with the required measurements, the CO(6–5)/CO(2–1) emission-line ratios are consistent with star formation dominating the CO excitation over this range of transitions. The targets in our study represent a gas-rich phase of galaxy evolution with simultaneously high levels of star formation and nuclear activity; furthermore, the jets and outflows do not have an immediate appreciable impact on the global molecular gas reservoirs.
Very high redshift quasars and the rapid emergence of super-massive black holes
Authors: Kroupa Pavel , Subr Ladislav , Jerabkova Tereza , Wang Long
Published: July 2020

The observation of quasars at very high redshift such as Pōniuā’ena is a challenge for models of super-massive black hole (SMBH) formation. This work presents a study of SMBH formation via known physical processes in star-burst clusters formed at the onset of the formation of their hosting galaxy. While at the early stages hyper-massive star-burst clusters reach the luminosities of quasars, once their massive stars die, the ensuing gas accretion from the still forming host galaxy compresses its stellar black hole (BH) component to a compact state overcoming heating from the BH–BH binaries such that the cluster collapses, forming a massive SMBH-seed within about a hundred Myr. Within this scenario the SMBH–spheroid correlation emerges near-to-exactly. The highest-redshift quasars may thus be hyper-massive star-burst clusters or young ultra-compact dwarf galaxies (UCDs), being the precursors of the SMBHs that form therein within about 200 Myr of the first stars. For spheroid masses ≲ 109.6 M⊙ a SMBH cannot form and instead only the accumulated nuclear cluster remains. The number evolution of the quasar phases with redshift is calculated and the possible problem of missing quasars at very high redshift is raised. SMBH-bearing UCDs and the formation of spheroids are discussed critically in view of the high redshift observations. A possible tension is found between the high star-formation rates (SFRs) implied by downsizing and the observed SFRs, which may be alleviated within the IGIMF theory and if the downsizing times are somewhat longer.
Heavy elements nucleosynthesis on accreting white dwarfs: building seeds for the p-process
Authors: Battino U , Pignatari M , Travaglio C , Lederer-Woods C , Denissenkov P , Herwig F , Thielemann F , Rauscher T
Published: July 2020

The origin of the proton-rich trans-iron isotopes in the Solar system is still uncertain. Single-degenerate thermonuclear supernovae (SNIa) with n-capture nucleosynthesis seeds assembled in the external layers of the progenitor’s rapidly accreting white dwarf (RAWD) phase may produce these isotopes. We calculate the stellar structure of the accretion phase of five white dwarf (WD) models with initial masses ≥ 0.85 $\, \mathrm{M}_\odot$ using the stellar code mesa The near-surface layers of the 1, 1.26, 1.32 and 1.38 $\, \mathrm{M}_\odot$ models are most representative of the regions in which the bulk of the p nuclei are produced during SNIa explosions, and for these models we also calculate the neutron-capture nucleosynthesis in the external layers. Contrary to previous RAWD models at lower mass, we find that the H-shell flashes are the main site of n-capture nucleosynthesis. We find high neutron densities up to several 1015 cm−3 in the most massive WDs. Through the recurrence of the H-shell flashes these intermediate neutron densities can be sustained effectively for a long time leading to high-neutron exposures with a strong production up to Pb. Both the neutron density and the neutron exposure increase with increasing the mass of the accreting WD. Finally, the SNIa nucleosynthesis is calculated using the obtained abundances as seeds. We obtain solar to supersolar abundances for p-nuclei with A > 96. Our models show that SNIa are a viable p-process production site.
Binary black holes in young star clusters: the impact of metallicity
Authors: Di Carlo Ugo N , Mapelli Michela , Giacobbo Nicola , Spera Mario , Bouffanais Yann , Rastello Sara , Santoliquido Filippo , Pasquato Mario , Ballone Alessandro , Trani Alessandro A , Torniamenti Stefano , Haardt Francesco
Published: July 2020

Young star clusters are the most common birthplace of massive stars and are dynamically active environments. Here, we study the formation of black holes (BHs) and binary black holes (BBHs) in young star clusters, by means of 6000 N-body simulations coupled with binary population synthesis. We probe three different stellar metallicities (Z = 0.02, 0.002, and 0.0002) and two initial-density regimes (density at the half-mass radius ρh ≥ 3.4 × 104 and ≥1.5 × 102 M⊙ pc−3 in dense and loose star clusters, respectively). Metal-poor clusters tend to form more massive BHs than metal-rich ones. We find ∼6, ∼2, and <1 per cent of BHs with mass mBH > 60 M⊙ at Z = 0.0002, 0.002, and 0.02, respectively. In metal-poor clusters, we form intermediate-mass BHs with mass up to ∼320 M⊙. BBH mergers born via dynamical exchanges (exchanged BBHs) can be more massive than BBH mergers formed from binary evolution: the former (latter) reach total mass up to ∼140 M⊙ (∼80 M⊙). The most massive BBH merger in our simulations has primary mass ∼88 M⊙, inside the pair-instability mass gap, and a mass ratio of ∼0.5. Only BBHs born in young star clusters from metal-poor progenitors can match the masses of GW 170729, the most massive event in first and second observing run (O1 and O2), and those of GW 190412, the first unequal-mass merger. We estimate a local BBH merger rate density ∼110 and ∼55 Gpc−3 yr−1, if we assume that all stars form in loose and dense star clusters, respectively.
A new approach to modelling gamma-ray burst afterglows: using Gaussian processes to account for the systematics
Authors: Aksulu M D , Wijers R A M J , van Eerten H J , van der Horst A J
Published: July 2020

The afterglow emission from gamma-ray bursts (GRBs) is a valuable source of information to understand the physics of these energetic explosions. The fireball model has become the standard to describe the evolution of the afterglow emission over time and frequency. Because of recent developments in the theory of afterglows and numerical simulations of relativistic outflows, we are able to model the afterglow emission with realistic dynamics and radiative processes. Although the models agree with observations remarkably well, the afterglow emission still contains additional physics, instrumental systematics, and propagation effects that make the modelling of these events challenging. In this work, we present a new approach to modelling GRB afterglows, using Gaussian processes (GPs) to take into account systematics in the afterglow data. We show that, using this new approach, it is possible to obtain more reliable estimates of the explosion and microphysical parameters of GRBs. We present fit results for five long GRBs and find a preliminary correlation between the isotropic energetics and opening angles of GRBs, which confirms the idea of a common energy reservoir for the kinetic energy of long GRBs.
RNA-tethering assay and eIF4G:eIF4A obligate dimer design uncovers multiple eIF4F functional complexes
Authors: Robert Francis , Cencic Regina , Cai Renying , Schmeing T Martin , Pelletier Jerry
Published: July 2020

Eukaryotic cellular mRNAs possess a 5′ cap structure (m7GpppN) which plays a critical role in translation initiation mediated by eukaryotic initiation factor (eIF) 4F. The heterotrimeric eIF4F complex possesses several activities imparted by its subunits that include cap recognition (by eIF4E), RNA unwinding (eIF4A), and factor/ribosome recruitment (eIF4G). Mammalian cells have paralogs of all three eIF4F subunits and it remains an open question as to whether these all can participate in the process of ribosome recruitment. To query the activities of the eIF4F subunits in translation initiation, we adopted an RNA-tethering assay in which select subunits are recruited to a specific address on a reporter mRNA template. We find that all eIF4F subunits can participate in the initiation process. Based on eIF4G:eIF4A structural information, we also designed obligate dimer pairs to probe the activity of all combinations of eIF4G and eIF4A paralogs. We demonstrate that both eIF4GI and eIF4GII can associate with either eIF4A1 or eIF4A2 to recruit ribosomes to mRNA templates. In combination with eIF4E and eIF4E3, our results indicate the presence of up to eight eIF4F complexes that can operate in translation initiation.
Analyzing editosome function in high-throughput
Authors: Del Campo Cristian , Leeder Wolf-Matthias , Reißig Paul , Göringer H Ulrich
Published: July 2020

Mitochondrial gene expression in African trypanosomes and other trypanosomatid pathogens requires a U-nucleotide specific insertion/deletion-type RNA-editing reaction. The process is catalyzed by a macromolecular protein complex known as the editosome. Editosomes are restricted to the trypanosomatid clade and since editing is essential for the parasites, the protein complex represents a near perfect target for drug intervention strategies. Here, we report the development of an improved in vitro assay to monitor editosome function. The test system utilizes fluorophore-labeled substrate RNAs to analyze the processing reaction by automated, high-throughput capillary electrophoresis (CE) in combination with a laser-induced fluorescence (LIF) readout. We optimized the assay for high-throughput screening (HTS)-experiments and devised a multiplex fluorophore-labeling regime to scrutinize the U-insertion/U-deletion reaction simultaneously. The assay is robust, it requires only nanogram amounts of materials and it meets all performance criteria for HTS-methods. As such the test system should be helpful in the search for trypanosome-specific pharmaceuticals.
Tumor suppressor p53: from engaging DNA to target gene regulation
Authors: Sammons Morgan A , Nguyen Thuy-Ai T , McDade Simon S , Fischer Martin
Published: July 2020

The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.
SPRINT: a Cas13a-based platform for detection of small molecules
Authors: Iwasaki Roman S , Batey Robert T
Published: July 2020

Recent efforts in biological engineering have made detection of nucleic acids in samples more rapid, inexpensive and sensitive using CRISPR-based approaches. We expand one of these Cas13a-based methods to detect small molecules in a one-batch assay. Using SHERLOCK-based profiling of in vitrotranscription (SPRINT), in vitro transcribed RNA sequence-specifically triggers the RNase activity of Cas13a. This event activates its non-specific RNase activity, which enables cleavage of an RNA oligonucleotide labeled with a quencher/fluorophore pair and thereby de-quenches the fluorophore. This fluorogenic output can be measured to assess transcriptional output. The use of riboswitches or proteins to regulate transcription via specific effector molecules is leveraged as a coupled assay that transforms effector concentration into fluorescence intensity. In this way, we quantified eight different compounds, including cofactors, nucleotides, metabolites of amino acids, tetracycline and monatomic ions in samples. In this manner, hundreds of reactions can be easily quantified in a few hours. This increased throughput also enables detailed characterization of transcriptional regulators, synthetic compounds that inhibit transcription, or other coupled enzymatic reactions. These SPRINT reactions are easily adaptable to portable formats and could therefore be used for the detection of analytes in the field or at point-of-care situations.
Activation of viral transcription by stepwise largescale folding of an RNA virus genome
Authors: Chkuaseli Tamari , White K Andrew
Published: July 2020

The genomes of RNA viruses contain regulatory elements of varying complexity. Many plus-strand RNA viruses employ largescale intra-genomic RNA-RNA interactions as a means to control viral processes. Here, we describe an elaborate RNA structure formed by multiple distant regions in a tombusvirus genome that activates transcription of a viral subgenomic mRNA. The initial step in assembly of this intramolecular RNA complex involves the folding of a large viral RNA domain, which generates a discontinuous binding pocket. Next, a distally-located protracted stem-loop RNA structure docks, via base-pairing, into the binding site and acts as a linchpin that stabilizes the RNA complex and activates transcription. A multi-step RNA folding pathway is proposed in which rate-limiting steps contribute to a delay in transcription of the capsid protein-encoding viral subgenomic mRNA. This study provides an exceptional example of the complexity of genome-scale viral regulation and offers new insights into the assembly schemes utilized by large intra-genomic RNA structures.
Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons
Authors: Mohan Radhe , Liu Amy Y , Brown Paul D , Mahajan Anita , Dinh Jeffrey , Chung Caroline , McAvoy Sarah , McAleer Mary Frances , Lin Steven H , Li Jing , Ghia Amol J , Zhu Cong , Sulman Erik P , de Groot John F , Heimberger Amy B , McGovern Susan L , Grassberger Clemens , Shih Helen , Ellsworth Susannah , Grosshans David R
Published: July 2020

Background

We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM).

Methods

Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis.

Results

Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79–0.94) for the final G3+L prediction model.

Conclusions

Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.
Long-Term Efficacy of Occipital Nerve Stimulation for Medically Intractable Cluster Headache
Authors: Leplus Aurélie , Fontaine Denys , Donnet Anne , Regis Jean , Lucas Christian , Buisset Nadia , Blond Serge , Raoul Sylvie , Guegan-Massardier Evelyne , Derrey Stéphane , Jarraya Bechir , Dang-Vu Bich , Bourdain Frederic , Valade Dominique , Roos Caroline , Creach Christelle , Chabardes Stéphan , Giraud Pierric , Voirin Jimmy , Bloch Jocelyne , Colnat-Coulbois Sophie , Caire François , Rigoard Philippe , Tran Laurie , Cruzel Coralie , Lantéri-Minet Michel ,   French ONS registry group
Published: July 2020

BACKGROUND

Occipital nerve stimulation (ONS) has been proposed to treat refractory chronic cluster headache (rCCH) but its efficacy has only been showed in small short-term series.

OBJECTIVE

To evaluate ONS long-term efficacy in rCCH.

METHODS

We studied 105 patients with rCCH, treated by ONS within a multicenter ONS prospective registry. Efficacy was evaluated by frequency, intensity of pain attacks, quality of life (QoL) EuroQol 5 dimensions (EQ5D), functional (Headache Impact Test-6, Migraine Disability Assessment) and emotional (Hospital Anxiety Depression Scale [HAD]) impacts, and medication consumption.

RESULTS

At last follow-up (mean 43.8 mo), attack frequency was reduced >50% in 69% of the patients. Mean weekly attack frequency decreased from 22.5 at baseline to 9.9 (P < .001) after ONS. Preventive and abortive medications were significantly decreased. Functional impact, anxiety, and QoL significantly improved after ONS. In excellent responders (59% of the patients), attack frequency decreased by 80% and QoL (EQ5D visual analog scale) dramatically improved from 37.8/100 to 73.2/100. When comparing baseline and 1-yr and last follow-up outcomes, efficacy was sustained over time. In multivariable analysis, low preoperative HAD-depression score was correlated to a higher risk of ONS failure. During the follow-up, 67 patients experienced at least one complication, 29 requiring an additional surgery: infection (6%), lead migration (12%) or fracture (4.5%), hardware dysfunction (8.2%), and local pain (20%).

CONCLUSION

Our results showed that long-term efficacy of ONS in CCH was maintained over time. In responders, ONS induced a major reduction of functional and emotional headache-related impacts and a dramatic improvement of QoL. These results obtained in real-life conditions support its use and dissemination in rCCH patients.
Do Respondents Get used to Answering Sensitive Questions?
Authors: Müller Bettina , Schmiedeberg Claudia
Published: July 2020

Issues associated with collecting data on sensitive topics are widely studied in survey research. Respondents’ reactions to sensitive questions have rarely been addressed from a longitudinal perspective, however, despite panel surveys representing a fundamental data source for social research. This article evaluates whether respondents’ acceptance of sensitive questions increases with repeated interviewing in a panel survey. Drawing on data from the German Family Panel (pairfam), we apply fixed-effects regression models to assess within-respondent changes in refusal to items on sexuality and fertility. The analysis reveals that refusal attenuates for some, but not all questions under study and increases for other items over time, with patterns varying across age groups. We conclude that a general beneficial effect of panel experience on the refusal to answer questions regarding sexuality and fertility does not exist. Rather, refusal patterns appear to stem from aging processes and specific life situations.
Rituximab in the treatment of systemic sclerosis–related interstitial lung disease: a systematic review and meta-analysis
Authors: Goswami Rudra P , Ray Animesh , Chatterjee Moumita , Mukherjee Arindam , Sircar Geetabali , Ghosh Parasar
Published: July 2020

Objectives

To assess the effect of rituximab (RTX) on the lung function parameters in SSc interstitial lung disease (SSc-ILD) patients.

Methods

PubMed and Embase were searched to identify studies on SSc-ILD treated with RTX, confined to a predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies on changes in forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) from baseline to 6 and 12 months of follow-up.

Results

A total of 20 studies (2 randomized controlled trials, 6 prospective studies, 5 retrospective studies and 7 conference abstracts) were included (n = 575). RTX improved FVC from baseline by 4.49% (95% CI 0.25, 8.73) at 6 months and by 7.03% (95% CI 4.37, 9.7) at 12 months. Similarly, RTX improved DLCO by 3.47% (95% CI 0.99, 5.96) at 6 months and 4.08% (95% CI 1.51, 6.65) at 12 months. In the two studies comparing RTX with other immunosuppressants, improvement of FVC by 6 months in the RTX group was 1.03% (95% CI 0.11, 1.94) greater than controls. At the 12 month follow-up, RTX treatment was similar to controls in terms of both FVC and DLCO. Patients treated with RTX had a lower chance of developing infections compared with controls [odds ratio 0.256 (95% CI 0.104, 0.626), I2 = 0%, P = 0.47).

Conclusions

Treatment with RTX in SSc-ILD was associated with a significant improvement of both FVC and DLCO during the first year of treatment. RTX use was associated with lower infectious adverse events.
Genomic Characterization and Curation of UCEs Improves Species Tree Reconstruction
Authors: Van Dam Matthew H , Henderson James B , Esposito Lauren , Trautwein Michelle
Published: July 2020

Ultraconserved genomic elements (UCEs) are generally treated as independent loci in phylogenetic analyses. The identification pipeline for UCE probes does not require prior knowledge of genetic identity, only selecting loci that are highly conserved, single copy, without repeats, and of a particular length. Here, we characterized UCEs from 11 phylogenomic studies across the animal tree of life, from birds to marine invertebrates. We found that within vertebrate lineages, UCEs are mostly intronic and intergenic, while in invertebrates, the majority are in exons. We then curated four different sets of UCE markers by genomic category from five different studies including: birds, mammals, fish, Hymenoptera (ants, wasps, and bees), and Coleoptera (beetles). Of genes captured by UCEs, we find that many are represented by two or more UCEs, corresponding to nonoverlapping segments of a single gene. We considered these UCEs to be nonindependent, merged all UCEs that belonged to a particular gene, constructed gene and species trees, and then evaluated the subsequent effect of merging cogenic UCEs on gene and species tree reconstruction. Average bootstrap support for merged UCE gene trees was significantly improved across all data sets apparently driven by the increase in loci length. Additionally, we conducted simulations and found that gene trees generated from merged UCEs were more accurate than those generated by unmerged UCEs. As loci length improves gene tree accuracy, this modest degree of UCE characterization and curation impacts downstream analyses and demonstrates the advantages of incorporating basic genomic characterizations into phylogenomic analyses. [Anchored hybrid enrichment; ants; ASTRAL; bait capture; carangimorph; Coleoptera; conserved nonexonic elements; exon capture; gene tree; Hymenoptera; mammal; phylogenomic markers; songbird; species tree; ultraconserved elements; weevils.]
Addressing the Linnean shortfall in a cryptic species complex
Authors: Walters Ashley D , Cannizzaro Andrew G , Trujillo Daniel A , Berg David J
Published: July 2020

Biodiversity is being lost at an alarming rate, but the rate of this loss is likely to be underestimated as a result of a deficit in taxonomic knowledge (i.e. the Linnean shortfall). This knowledge gap is more extensive for morphologically indistinct taxa. The advancement of molecular techniques and delimitation methods has facilitated the identification of such cryptic species, but a majority of these taxa remain undescribed. To investigate the effects of taxonomic uncertainty on understanding of biodiversity, we applied the general lineage concept of species to an amphipod species complex, the Gammaruslacustris lineage that occupies springs of the northern Chihuahuan Desert, which is emerging in contemporary times. We investigated species boundaries using a validation-based approach and examined genetic structure of the lineage using a suite of microsatellite markers to identify independently evolving metapopulations. Our results show that each spring contains a genetically distinct population that is geographically isolated from other springs, suggesting evolutionary independence and status as separate species. Additionally, we observed subtle interspecific morphological variation among the putative species. We used multiple lines of evidence to formally describe four new species (Gammarus langi sp. nov., G. percalacustris sp. nov., G. colei sp. nov. and G. malpaisensis sp. nov.) endemic to the northern Chihuahuan Desert. Cryptic speciation is likely to be high in other aquatic taxa within these ecosystems, and across arid landscapes throughout North America and elsewhere, suggesting that the magnitude of the Linnean shortfall is currently underestimated in desert springs worldwide.
Loss to Follow-Up After Newborn Hearing Screening: Analysis of Risk Factors at a Massachusetts Urban Safety-Net Hospital
Authors: Razak Alina , Fard Darian , Hubbell Richard , Cohen Michael , Hartman-Joshi Kristin , Levi Jessica R.
Published: July 2020

Objectives:

This study examines the unique factors that influence loss to follow-up after newborn hearing screening for patients at a Massachusetts urban safety-net hospital. We seek to characterize our patient population, investigate correlations between patient factors and rates of follow-up, and understand gaps in care.

Design:

A retrospective chart review was conducted of patients born at an urban safety-net hospital from January 2015 through May 2018 who did not pass the newborn hearing screening in one or both ears. A total of 197 infants were included in our study. Outcomes of interest included rates and latency of follow-up appointments, infant demographics (sex, race, birth weight, risk factors for hearing loss), and maternal factors (age, marital status, smoking status, number of children).

Results:

From January 2015 through May 2018, 17% (n = 34) of infants were lost to follow-up. Of those who attended an initial audiology evaluation, the median time between screening and appointment was 29 days. Newborns were 3.5 times at risk of being lost to follow-up if their mothers smoked during pregnancy compared to those whose mothers did not smoke. Further, newborns with multiple siblings in the home were less likely to utilize any audiological services. High-risk infants, such as those with an extended stay in the neonatal intensive care unit, were found to have higher rates of loss to follow-up.

Conclusions:

Our results indicate that patients at urban safety-net hospitals require increased support to decrease rates of loss to follow-up. In particular, strategies to aid mothers who smoke, have multiple children, or have high-risk infants can address gaps in care for newborns after hearing screening.
Treatment for Severe Coronavirus Disease 2019 With the Seraph-100 Microbind Affinity Blood Filter
Authors: Olson Stephen W. , Oliver James D. , Collen Jacob , Bunin Jessica , Gleeson Todd D. , Foster Brian E. , Simmons Mark P. , Chen Hua W. , Ficke Jennifer B. , Brown Tara E. , Nau Mark T. , Cebula Brennan R. , Kielstein Jan , Chung Kevin K.
Published: July 2020

Objectives:

To determine whether Seraph-100 (Exthera Medical Corporation, Martinez, CA) treatment provides clinical benefit for severe coronavirus disease 2019 cases that require mechanical ventilation and vasopressor support.

Data Sources:

The first two patients in the United States treated with the novel Seraph-100 device. These cases were reviewed by the Food and Drug Administration prior to granting an emergency use authorization for treatment of coronavirus disease 2019.

Study Selection:

Case series.

Data Extraction:

Vasopressor dose, mean arterial pressure, temperature, interleukin-6, C-reactive protein, and other biomarker levels were documented both before and after Seraph-100 treatments.

Data Synthesis:

Vasopressor dose, temperature, interleukin-6, and C-reactive protein levels declined after Seraph-100 treatments. Severe acute respiratory syndrome coronavirus 2 viremia was confirmed in the one patient tested and cleared by the completion of treatments.

Conclusions:

Seraph-100 use may improve hemodynamic stability in coronavirus disease 2019 cases requiring mechanical ventilation and vasopressor support. These findings warrant future study of a larger cohort with the addition of mortality and total hospital day outcomes.
Dressings and Securement Devices of Peripheral Arterial Catheters in Intensive Care Units and Operating Theaters
Authors: Gravante Francesco , Lombardi Andrea , Gagliardi Anna Maria , Pucci Antonello , Latina Roberto
Published: July 2020

Background

Hemodynamic monitoring, implemented by the placement of peripheral arterial catheters (PACs), is a characterizing aspect of the intensive care units. Peripheral arterial catheters can continually detect blood pressure and quickly conduct blood sampling. The use of PACs is generally considered safe, without serious complications. Currently, only 25% of the implanted catheters are actually subject to complications, including accidental removal, dislocation, occlusion, and infection. All of these complications arise from inadequate catheter stabilization at the level of the skin. This study aimed to summarize and describe the effectiveness and characteristics of dressings and securement devices for catheter stabilization.

Methods

A systematic review of literature from the following databases was conducted: MEDLINE, CINAHL, Cochrane, EMBASE, and OvidSP. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to guide article selection and reporting.

Results

Herein 626 articles were referred, with 5 directly related to the topic under discussion. We found 3 studies that describe PAC failure and 4 about dislodgement. We described 6 types of dressings or securement devices and classified them into 3 categories for classifying PAC dressings or securement devices. These were detected and grouped as adhesive tissues, sutureless devices, and transparent polyurethane dressings.

Conclusions

Current research indicates that transparent polyurethane dressings offer the most effective catheter stabilization, but adhesive tissues may constitute a valid alternative. However, there are limited high-quality studies about effective dressings and securement devices for PACs.