bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with the use and composition of two-drug regimens in a large single-centre HIV cohort
Authors: de Lazzari Elisa , Gonzalez-Cordon Ana , Inciarte Alexy , Ugarte Ainoa , de la Mora Lorena , Martinez-Rebollar Maria , Laguno Montserrat , Ambrosioni Juan , Torres Berta , Mallolas Josep , Blanco Jose L , Miro Jose M , Martinez Esteban
Published: July 2021

Objectives

We aimed to assess the clinical characteristics associated with the use of two-drug regimens (2DRs) and the factors associated with specific antiretrovirals in 2DRs in a large single-centre HIV cohort.

Methods

Retrospective analysis of demographics, HIV characteristics and AIDS events, antiretroviral prescription, virological failure and genotypic resistance testing, and laboratory results from all adult people with HIV (PWH) prospectively followed at the Hospital Clinic of Barcelona who were receiving a 3DR or a 2DR in January 2020. We assessed factors associated with the probability of receiving 2DRs relative to three-drug regimens (3DRs) using a logistic regression model, controlling for age, sex and year of HIV diagnosis. The same methodology was applied to identify factors associated with the prescription of integrase inhibitor-based regimens or PI-based regimens among PWH receiving 2DRs.

Results

There were 3432 (88%) PWH receiving 3DRs and 463 (12%) receiving 2DRs. In the final adjusted model, ≥2 previous virological failures, previous resistance mutations, previous AIDS diagnosis, longer time on current regimen, higher total cholesterol or triglycerides and lower baseline haemoglobin were independent factors associated with 2DRs. The majority of 2DRs included an integrase inhibitor or/and a PI. We identified independent factors associated with the inclusion of integrase inhibitors (lower HDL cholesterol) or PIs (prior AIDS, prior genotypic resistance mutations and lower CD4/CD8 ratio) in the 2DR.

Conclusions

In this large single-centre HIV cohort, a worse cardiometabolic status or more archived resistance were key factors associated with inclusion of integrase inhibitors or PIs, respectively, in 2DRs.
Using a public database of Neisseria gonorrhoeae genomes to detect mutations associated with zoliflodacin resistance
Authors: Adamson Paul C , Lin Eric Y , Ha Sung-Min , Klausner Jeffrey D
Published: July 2021

Background

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent global health threat. Zoliflodacin is a novel antibiotic undergoing clinical trials for the treatment of gonorrhoea. While there are limited data regarding zoliflodacin resistance in N. gonorrhoeae, three amino acid mutations have been associated with increased MICs of zoliflodacin.

Objectives

To determine the prevalence of three amino acid mutations associated with zoliflodacin resistance within a large, public database of nearly 13 000 N. gonorrhoeae genomes.

Methods

PathogenWatch is an online genomic epidemiology platform with a public database of N. gonorrhoeae genomes. That database was used to extract gyrB sequence data and a Basic Local Alignment Search Tool (BLAST) search was performed to identify any of the three amino acid mutations in GyrB that are associated with increased zoliflodacin MICs: D429N, K450N or K450T. As a control for the search methodology, all GyrA sequences were also extracted and S91F mutations were identified and compared with the PathogenWatch database.

Results

In total, 12 493 N. gonorrhoeae genomes from the PathogenWatch database were included. Among those genomes, none was identified that harboured any of the three mutations associated with increased zoliflodacin MICs. One genome was identified to have a mutation at position 429 in GyrB (D429V).

Conclusions

The findings suggest that the prevalence of the three mutations associated with zoliflodacin resistance in N. gonorrhoeae is very low. However, further research into the mechanisms of zoliflodacin resistance in N. gonorrhoeae is needed. Genomic epidemiology platforms like PathogenWatch can be used to enhance the global surveillance of AMR.
Rhabdomyosarcoma in the maxillary gingiva of a child patient
Authors: Komatsu Yuko , Kawai Tadashi , Miura Shoko , Takeda Yasunori , Yamada Hiroyuki
Published: July 2021

Rhabdomyosarcoma (RMS) is a rare, rapidly growing and aggressive malignant neoplasm mainly affecting children. However, mean age at the diagnosis of patients with gingival RMS is 26.9 years. A 12-year-old girl presented to our clinic with a chief complaint of trismus. The examination findings indicated a malignant tumor in the left maxillary gingiva. We performed a biopsy of the tumor, and the histopathological diagnosis was RMS. We report a rare case of primary RMS of the maxillary gingiva in a child patient.
Topological semantics of conservativity and interpretability logics
Authors: Iwata Sohei , Kurahashi Taishi
Published: July 2021

We introduce and develop a topological semantics of conservativity logics and interpretability logics. We prove the topological compactness theorem of consistent normal extensions of the conservativity logic $\textbf {CL}$ by extending Shehtman’s ultrabouquet construction method to our framework. As a consequence, we prove that several extensions of $\textbf {CL}$ such as $\textbf {IL}$, $\textbf {ILM}$, $\textbf {ILP}$ and $\textbf {ILW}$ are strongly complete with respect to our topological semantics.
Feats, Flops, and Free Lessons From NZ’s Response to the COVID-19 Pandemic
Authors: Manning Joanna M
Published: July 2021

Beginning from the first reports of COVID-19 out of China, this article provides a commentary on the actions taken by the Government of New Zealand in terms of nine themes—a national response with an elimination goal, speed, and comprehensiveness of the initial response; an evidence-based, science-led approach, prioritised on protecting lives; effective communication; leadership style which appealed to collective responsibility and attempted to de-politicise the Government’s response to the virus; flexibility of response characterised by ‘learning as you go’; oversight of coercive state powers, including a pragmatic response which attempted to defuse conflict and reserved use of ‘hard power’ to a last resort; deployment of public health interventions, and health system adaptations; the impact on Māori and marginalised communities; and economic protection and stimulus—to identify factors that might help explain why New Zealand’s pandemic response was successful and those which could have been managed better. The partially successful legal challenge brought to the four-and-a half week lockdown, the most stringent in the world, in Borrowdale v Director-General of Health, is also considered.
Indra: a public computationally accessible suite of cosmological N-body simulations
Authors: Falck Bridget , Wang Jie , Jenkins Adrian , Lemson Gerard , Medvedev Dmitry , Neyrinck Mark C , Szalay Alex S
Published: July 2021

Indra is a suite of large-volume cosmological N-body simulations with the goal of providing excellent statistics of the large-scale features of the distribution of dark matter. Each of the 384 simulations is computed with the same cosmological parameters and different initial phases, with 10243 dark matter particles in a box of length 1 h−1 Gpc, 64 snapshots of particle data and halo catalogues, and 505 time-steps of the Fourier modes of the density field, amounting to almost a petabyte of data. All of the Indra data are immediately available for analysis via the SciServer science platform, which provides interactive and batch computing modes, personal data storage, and other hosted data sets such as the Millennium simulations and many astronomical surveys. We present the Indra simulations, describe the data products and how to access them, and measure ensemble averages, variances, and covariances of the matter power spectrum, the matter correlation function, and the halo mass function to demonstrate the types of computations that Indra enables. We hope that Indra will be both a resource for large-scale structure research and a demonstration of how to make very large data sets public and computationally accessible.
Efficient early stellar feedback can suppress galactic outflows by reducing supernova clustering
Authors: Smith Matthew C , Bryan Greg L , Somerville Rachel S , Hu Chia-Yu , Teyssier Romain , Burkhart Blakesley , Hernquist Lars
Published: July 2021

We present a novel set of stellar feedback models, implemented in the moving-mesh code arepo, designed for galaxy formation simulations with near-parsec (or better) resolution. These include explicit sampling of stars from the IMF, allowing feedback to be linked to individual massive stars, an improved method for the modelling of H ii regions, photoelectric (PE) heating from a spatially varying FUV field and supernova feedback. We perform a suite of 32 simulations of isolated $M_\mathrm{vir} = 10^{10}\, \mathrm{M_\odot }$ galaxies with a baryonic mass resolution of $20\, \mathrm{M_\odot }$ in order to study the non-linear coupling of the different feedback channels. We find that photoionization (PI) and supernova feedback are both independently capable of regulating star formation to the same level, while PE heating is inefficient. PI produces a considerably smoother star formation history than supernovae. When all feedback channels are combined, the additional suppression of star formation rates is minor. However, outflow rates are substantially reduced relative to the supernova only simulations. We show that this is directly caused by a suppression of supernova clustering by the PI feedback, disrupting star-forming clouds prior to the first supernovae. We demonstrate that our results are robust to variations of our star formation prescription, feedback models and the baryon fraction of the galaxy. Our results also imply that the burstiness of star formation and the mass loading of outflows may be overestimated if the adopted star particle mass is considerably larger than the mass of individual stars because this imposes a minimum cluster size.
Review of synergic meteor observations: linking the results from cameras, ionosondes, infrasound and seismic detectors
Authors: Kereszturi Á , Barta V , Bondár I , Czanik Cs , Igaz A , Mónus P , Rezes D , Szabados L , Pál B D
Published: July 2021

The joint evaluation of different meteor observation types supports a better understanding of both meteor phenomena and the terrestrial atmosphere. Two types of examples are presented in this work, linking ionospheric effects to specific meteors, with almost one-third of the meteors that emerged at high altitudes simultaneously recorded with an optical camera. Very few such observations have been realized as yet. With daytime fireballs, the recorded infrasound effect and the atmospheric blast produced shock-wave-related small earthquakes which were identified by a network of ground stations. An overview of these observational types highlights specific topics for which substantial improvements and discoveries are expected in the near future.
The loudest stellar heartbeat: characterizing the most extreme amplitude heartbeat star system
Authors: Jayasinghe T , Kochanek C S , Strader J , Stanek K Z , Vallely P J , Thompson Todd A , Hinkle J T , Shappee B J , Dupree A K , Auchettl K , Chomiuk L , Aydi E , Dage K , Hughes A , Shishkovsky L , Sokolovsky K V , Swihart S , Voggel K T , Thompson I B
Published: July 2021

We characterize the extreme heartbeat star system MACHO 80.7443.1718 in the Large Magellanic Cloud using Transiting Exoplanet Survey Satellite (TESS) photometry and spectroscopic observations from the Magellan Inamori Kyocera Echelle (MIKE) and SOAR Goodman spectographs. MACHO 80.7443.1718 was first identified as a heartbeat star system in the All-Sky Automated Survey for SuperNovae (ASAS-SN) with $P_{\rm orb}=32.836\pm 0.008\, {\rm d}$. MACHO 80.7443.1718 is a young (∼6 Myr), massive binary, composed of a B0 Iae supergiant with $M_1 \simeq 35\, {\rm M}_\odot$ and an O9.5V secondary with $M_2 \simeq 16\, {\rm M}_\odot$ on an eccentric (e = 0.51 ± 0.03) orbit. In addition to having the largest variability amplitude amongst all known heartbeats stars, MACHO 80.7443.1718 is also one of the most massive heartbeat stars yet discovered. The B[e] supergiant has Balmer emission lines and permitted/forbidden metallic emission lines associated with a circumstellar disc. The disc rapidly dissipates at periastron that could indicate mass transfer to the secondary, but re-emerges immediately following periastron passage. MACHO 80.7443.1718 also shows tidally excited oscillations at the N = 25 and N = 41 orbital harmonics and has a rotational period of 4.4 d.
Can we distinguish astrophysical from primordial black holes via the stochastic gravitational wave background?
Authors: Mukherjee Suvodip , Silk Joseph
Published: July 2021

One of the crucial windows for distinguishing astrophysical black holes from primordial black holes is through the redshift evolution of their respective merger rates. The low redshift population of black holes of astrophysical origin is expected to follow the star formation rate. The corresponding peak in their merger rate peaks at a redshift smaller than that of the star formation rate peak (zp ≈ 2), depending on the time delay between the formation and mergers of black holes. Black holes of primordial origin are going to be present before the formation of the stars, and the merger rate of these sources at high redshift is going to be large. We propose a joint estimation of a hybrid merger rate from the stochastic gravitational wave background, which can use the cosmic history of merger rates to distinguish between the two populations of black holes. Using the latest bounds on the amplitude of the stochastic gravitational wave background amplitude from the third observation run of LIGO/Virgo, we obtain weak constraints at $68{{\ \rm per\ cent}}$ C.L. on the primordial black hole merger rate index $2.56_{-1.76}^{+1.64}$ and astrophysical black hole time delay $6.7_{-4.74}^{+4.22}$ Gyr. We should be able to distinguish between the different populations of black holes with the forthcoming O5 and A+ detector sensitivities.
Minimum perihelion distances and associated dwell times for near-Earth asteroids
Authors: Toliou Athanasia , Granvik Mikael , Tsirvoulis Georgios
Published: July 2021

The observed near-Earth asteroid (NEA) population contains very few objects with small perihelion distances, say, $q \lesssim 0.2\, \mathrm{au}$. NEAs that currently have orbits with larger q might be hiding a past evolution during which they have approached closer to the Sun. We present a probabilistic assessment of the minimum q that an asteroid has reached during its orbital history. At the same time, we offer an estimate of the dwell time, that is, the time q has been in a specific range. We have re-analysed orbital integrations of test asteroids from the moment they enter the near-Earth region until they either collide with a major body or are thrown out from the inner Solar system. We considered a total disruption of asteroids at certain q as a function of absolute magnitude (H). We calculated the probability that an asteroid with given orbital elements and H has reached a q smaller than a given threshold value and its respective dwell time in that range. We have constructed a look-up table that can be used to study the past orbital and thermal evolution of asteroids as well as meteorite falls and their possible parent bodies. An application to 25 meteorite falls shows that carbonaceous chondrites typically have short dwell times at small q, whereas for ordinary chondrites it ranges from $10\, 000$ to $500\, 000$ yr. A dearth of meteorite falls with long dwell times and small minimum q supports a supercatastrophic disruption of asteroids at small q.
Modelling the linear polarization of GRB afterglows across the electromagnetic spectrum
Authors: Birenbaum Gal , Bromberg Omer
Published: July 2021

Linear polarization measurements in the optical band show polarization degrees of a few per cent at late times. Recently, polarization at sub-per-cent level was also detected in radio by ALMA, opening the window for multiwavelength polarimetry and stressing the importance of properly modelling polarization in GRB afterglows across the EM spectrum. We introduce a numerical tool that can calculate the polarization from relativistically moving surfaces by discretizing them to small patches of uniform magnetic field, calculating the polarized emission from each cell assuming synchrotron radiation and summing it to obtain the total degree of polarization. We apply this tool to afterglow shocks with random magnetic fields confined to the shock plane, considering electron radiative cooling. We analyse the observed polarization curves in several wavelengths above the cooling frequency and below the minimal synchrotron frequency and point to the characteristic differences between them. We present a method to constrain the jet opening angle and the viewing angle within the context of our model. Applying it to GRB 021004, we obtain angles of ∼10○ and ∼8○ respectively and conclude that a non-negligible component of radial magnetic field is required to explain the ${\sim}1{{\ \rm per\ cent}}$ polarization level observed 3.5 days after the burst.
On the effect of pulsar evaporation on the cooling of white dwarfs
Authors: Tang Wenshi , Li Xiang-Dong
Published: July 2021

Evolution of a large part of low-mass X-ray binaries (LMXBs) leads to the formation of rapidly rotating pulsars with a helium white dwarf (He WD) companion. Observations indicate that some He WDs in binary pulsar systems are ultracool (with the effective temperatures Teff ≲ 4000 K). It is hard to cool down a He WD to such low temperatures within the Hubble time because a thick hydrogen envelope was left behind around the He core after the mass transfer process. A possible mechanism that can accelerate the WD cooling is the evaporative wind mass-loss from the He WD driven by the high-energy radiation from the recycled pulsar. In this paper, we evolve a large number of LMXBs and investigate the influence of the pulsar’s high-energy radiation on the WD cooling with different input parameters, including the neutron star’s spin-down luminosity, the evaporation efficiency, and the metallicity of the companion star. By comparing our results with observations we note that, for relatively hot He WDs (with Teff > 7000 K), standard WD cooling without evaporation considered is able to reproduce their temperatures, while evaporation is probably required for the He WDs with relatively low temperatures (Teff < 5000 K).
A systematic reclassification of Type IIn supernovae
Authors: Ransome C L , Habergham-Mawson S M , Darnley M J , James P A , Filippenko A V , Schlegel E M
Published: July 2021

Type IIn supernovae (SNe IIn) are a relatively infrequently observed subclass of SNe whose photometric and spectroscopic properties are varied. A common thread among SNe IIn is the complex multiple-component hydrogen Balmer lines. Owing to the heterogeneity of SNe IIn, online data bases contain some outdated, erroneous, or even contradictory classifications. SN IIn classification is further complicated by SN ‘impostors’ and contamination from underlying H ii regions. We have compiled a catalogue of systematically classified nearby (redshift z < 0.02) SNe IIn using the Open Supernova Catalogue (OSC). We present spectral classifications for 115 objects previously classified as SNe IIn. Our classification is based on results obtained by fitting multiple Gaussians to the H α profiles. We compare classifications reported by the OSC and Transient Name Server (TNS) along with the best matched templates from snid . We find that 28 objects have been misclassified as SNe IIn. TNS and OSC can be unreliable; they disagree on the classifications of 51 of the objects and contain a number of erroneous classifications. Furthermore, OSC and TNS hold misclassifications for 34 and 12 (respectively) of the transients we classify as SNe IIn. In total, we classify 87 SNe IIn. We highlight the importance of ensuring that online data bases remain up to date when new or even contemporaneous data become available. Our work shows the great range of spectral properties and features that SNe IIn exhibit, which may be linked to multiple progenitor channels and environment diversity. We set out a classification scheme for SNe IIn based on the H α profile that is not greatly affected by the inhomogeneity of SNe IIn.
Future radio continuum cosmology clustering surveys
Authors: Asorey Jacobo , Parkinson David
Published: July 2021

The use of continuum emission radio galaxies as cosmological tracers of the large-scale structure will soon move into a new phase. Upcoming surveys from the Australian Square Kilometre Array Pathfinder (ASKAP), MeerKAT, and the Square Kilometre Array project (SKA) will survey the entire available sky down to an $\sim 100\, \mu$Jy flux limit, increasing the number of detected extra-galactic radio sources by several orders of magnitude. External data and machine learning algorithms will also enable some low-resolution radial selection (photometric redshift binning) of the sample, increasing the cosmological utility of the sample observed. In this paper, we discuss the flux limit required to detect enough galaxies to decrease the shot-noise term in the error to be 10 per cent of the total. We show how future surveys of this type will be limited by available technology. The confusion generated by the intrinsic sizes of galaxies may have the consequence that surveys of this type eventually reach a hard flux limit of ∼100 nJy, as is predicted by the current modelling of AGN sizes by simulations such as the Tiered Radio Extragalactic Continuum Simulation (T-RECS). Finally, when considering the multitracer approach, where galaxies are split by type to measure some bias ratio, we find that there are not enough AGN present to achieve a reasonable level of shot noise for this kind of measurement.
Multifrequency study of the peculiar pulsars PSR B0919+06 and PSR B1859+07
Authors: Rajwade K M , Perera B B P , Stappers B W , Roy J , Karastergiou A , Rankin J M
Published: July 2021

Since their discovery more than 50 years ago, broad-band radio studies of pulsars have generated a wealth of information about the underlying physics of radio emission. In order to gain some further insights into this elusive emission mechanism, we performed a multifrequency study of two very well-known pulsars, PSR B0919+06 and PSR B1859+07. These pulsars show peculiar radio emission properties whereby the emission shifts to an earlier rotation phase before returning to the nominal emission phase in a few tens of pulsar rotations (also known as ‘swooshes’). We confirm the previous claim that the emission during the swoosh is not necessarily absent at low frequencies and the single pulses during a swoosh show varied behaviour at 220 MHz. We also confirm that in PSR B0919+06, the pulses during the swoosh show a chromatic dependence of the maximum offset from the normal emission phase with the offset following a consistent relationship with observing frequency. We also observe that the flux density spectrum of the radio profile during the swoosh is inverted compared to the normal emission. For PSR B1859+07, we have discovered a new mode of emission in the pulsar that is potentially quasi-periodic with a different periodicity than is seen in its swooshes. We invoke an emission model previously proposed in the literature and show that this simple model can explain the macroscopic observed characteristics in both pulsars. We also argue that pulsars that exhibit similar variability on short time-scales may have the same underlying emission mechanism.
The effect of continuum elimination in identifying circumstellar dust around Mira
Authors: Shepard Lisa M , Speck Angela K
Published: July 2021

Asymptotic giant branch (AGB) stars are major contributors of cosmic dust to the universe. Typically, dust around AGB stars is investigated via radiative transfer (RT) modelling, or via simple deconstruction of observed spectra. However, methodologies applied vary. Using archival spectroscopic, photometric, and temporal data for the archetypal dusty star, Mira, we identify its circumstellar silicate dust grains. This is achieved by matching the positions and widths of observed spectral features with laboratory data. To do this comparison properly, it is necessary to account for the continuum emission. Here, we investigate various ways in which a continuum is eliminated from observational spectra and how it affects the interpretation of spectral features. We find that while the precise continuum shapes and temperatures do not have a critical impact on the positions and shapes of dust spectral features, it is important to eliminate continua in a specific way. It is important to understand what contributes to the spectrum in order to remove the continuum in a way that allows comparison with laboratory spectra of candidate dust species. Our methodologies are applicable to optically thin systems, like that of Mira. Higher optical depths will require RT modelling, which cannot include many different potential astrominerals because there is a lack of complex refractive indices. Finally, we found that the classic silicate feature exhibited by Mira is not consistent with a real amorphous silicate alone but may be best explained with a small alumina contribution to match the observed full width at half-maximum of the $\sim 10\, \mu$m feature.
Differential efficacies of Cas nucleases on microsatellites involved in human disorders and associated off-target mutations
Authors: Poggi Lucie , Emmenegger Lisa , Descorps-Declère Stéphane , Dumas Bruno , Richard Guy-Franck
Published: July 2021

Microsatellite expansions are the cause of >20 neurological or developmental human disorders. Shortening expanded repeats using specific DNA endonucleases may be envisioned as a gene editing approach. Here, we measured the efficacy of several CRISPR–Cas nucleases to induce recombination within disease-related microsatellites, in Saccharomyces cerevisiae. Broad variations in nuclease performances were detected on all repeat tracts. Wild-type Streptococcus pyogenes Cas9 (SpCas9) was more efficient than Staphylococcus aureus Cas9 on all repeats tested, except (CAG)33. Cas12a (Cpf1) was the most efficient on GAA trinucleotide repeats, whereas GC-rich repeats were more efficiently cut by SpCas9. The main genetic factor underlying Cas efficacy was the propensity of the recognition part of the sgRNA to form a stable secondary structure, independently of its structural part. This suggests that such structures form in vivo and interfere with sgRNA metabolism. The yeast genome contains 221 natural CAG/CTG and GAA/CTT trinucleotide repeats. Deep sequencing after nuclease induction identified three of them as carrying statistically significant low frequency mutations, corresponding to SpCas9 off-target double-strand breaks.
Tertiary lymphoid tissues: a regional hub for kidney inflammation
Authors: Sato Yuki , Tamura Masaru , Yanagita Motoko
Published: July 2021

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that develop at sites of chronic inflammation in nonlymphoid organs. As with lymph nodes, TLTs initiate adaptive immune responses and coordinate local tissue immunity. Although virtually ignored for decades, TLTs have recently received a great deal of attention for their ability to influence disease severity, prognosis and response to therapy in various diseases, including cancer, autoimmune disorders and infections. TLTs are also induced in kidneys of patients with chronic kidney diseases such as immunoglobulin A nephropathy and lupus nephritis. Nevertheless, TLTs in the kidney have not been extensively investigated and their mechanism of development, functions and clinical relevance remain unknown, mainly because of the absence of adequate murine kidney TLT models and limited availability of human kidney samples containing TLTs. We recently found that aged kidneys, but not young kidneys, exhibit multiple TLTs after injury. Interestingly, although they are a minor component of TLTs, resident fibroblasts in the kidneys diversify into several distinct phenotypes that play crucial roles in TLT formation. Furthermore, the potential of TLTs as a novel kidney injury/inflammation marker as well as a novel therapeutic target for kidney diseases is also suggested. In this review article we describe the current understanding of TLTs with a focus on age-dependent TLTs in the kidney and discuss their potential as a novel therapeutic target and kidney inflammation marker.
Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease
Authors: Imenez Silva Pedro H , Unwin Robert , Hoorn Ewout J , Ortiz Alberto , Trepiccione Francesco , Nielsen Rikke , Pesic Vesna , Hafez Gaye , Fouque Denis , Massy Ziad A , De Zeeuw Chris I , Capasso Giovambattista , Wagner Carsten A ,   CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target), Capasso Giovambattista , Andrade Alexandre , Bachmann Maie , Bumblyte Inga , Covic Adrian Constantin , Delgado Pilar , Endlich Nicole , Engvig Andreas , Fouque Denis , Franssen Casper , Frische Sebastian , Garneata Liliana , Gesualdo Loreto , Giannakou Konstantinos , Goumenos Dimitrios , Kartal Ayşe Tuğba , Mani Laila-Yasmin , Marti Hans-Peter , Mayer Christopher , Nielsen Rikke , Pešić Vesna , Rroji Merita , Sakkas Giorgos , Spasovski Goce , Stevens Kate I , Vazelov Evgueniy , Viggiano Davide , Zacharia Lefteris , Ferreira Ana Carina , Malyszko Jolanta , Hoorn Ewout , Figurek Andreja , Unwin Robert , Wagner Carsten , Wanner Christoph , Bruchfeld Annette , Pepin Marion , Wiecek Andrzej , Nitsch Dorothea , Fridolin Ivo , Hafez Gaye , Romeo Maria José Soler , Barbieri Michelangela , Batinić Bojan , Carrasco Laura , Carriazo Sol , Gansevoort Ron , Martino Gianvito , Raso Francesco Mattace , Nistor Ionut , Ortiz Alberto , Paolisso Giuseppe , Rastenytė Daiva , Stefan Gabriel , Tedeschi Gioacchino , Massy Ziad , Bikbov Boris , Endlich Karl Hans , Godefroy Olivier , Chillon Jean-Marc , Kossioni Anastassia , Kurganaite Justina , Perico Norberto , Remuzzi Giuseppe , Grodzicki Tomasz , Trepiccione Francesco , Zoccali Carmine , Arici Mustafa , Blankestijn Peter , Eckardt Kai-Uwe , Fliser Danilo , Jiménez Eugenio Gutiérrez , Konig Maximilian , Rychlik Ivan , Deleidi Michela , Reusz George
Published: July 2021

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10–30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD.
Preclinical modeling in glioblastoma patient-derived xenograft (GBM PDX) xenografts to guide clinical development of lisavanbulin—a novel tumor checkpoint controller targeting microtubules
Authors: Burgenske Danielle M , Talele Surabhi , Pokorny Jenny L , Mladek Ann C , Bakken Katrina K , Carlson Brett L , Schroeder Mark A , He Lihong , Hu Zeng , Gampa Gautham , Kosel Matthew L , Decker Paul A , Kitange Gaspar J , Schmitt-Hoffmann Anne , Bachmann Felix , Vaubel Rachael A , Eckel-Passow Jeanette E , Giannini Caterina , McSheehy Paul , Lane Heidi A , Elmquist William F , Sarkaria Jann N
Published: July 2021

Background

Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.

Methods

Mice bearing intracranial tumors received lisavanbulin +/−RT +/−TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.

Results

Lisavanbulin monotherapy showed significant benefit (P < .01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01).

Conclusions

Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
Exposure to Nicotine Vapor Produced by an Electronic Nicotine Delivery System Causes Short-Term Increases in Impulsive Choice in Adult Male Rats
Authors: Flores Rodolfo J , Alshbool Fatima Z , Giner Priscilla , O’Dell Laura E , Mendez Ian A
Published: July 2021

Introduction

Traditional cigarette use influences cost-benefit decision making by promoting impulsive choice. However, the impact of nicotine exposure via electronic nicotine delivery systems on impulsivity remains unclear. Hence, the present study examined the short- and long-term effects of nicotine vapor on impulsive choice.

Methods

Twenty-four adult male rats were trained in the delay discounting task to choose between small immediate food rewards and large delayed food rewards. After 24 days of training in the task rats were exposed to vapor containing either 0, 12, or 24 mg/mL of nicotine for 10 days. To validate inhalation of nicotine vapor serum cotinine levels were analyzed on exposure days 1, 5, and 10 using enzyme-linked immunosorbent assay. Following vapor exposure, rats were retrained in the discounting task until rats displayed stable responding and the effects of nicotine vapor on choice preference were assessed.

Results

Rats exposed to 12 and 24 mg/mL nicotine vapor displayed higher serum cotinine levels than control rats exposed to 0 mg/mL vapor. There were no differences in impulsive choice between any vapor exposure groups when tested 15 days after exposure, across 6 days of stable responding, suggesting that nicotine vapor does not have long lasting effects on impulsive choice. Interestingly, a subsequent nicotine vapor challenge revealed short-term increases in impulsive choice immediately following a single exposure to 24 mg/mL nicotine vapor, relative to choice preference immediately following exposure to 0 mg/mL vapor.

Conclusions

These results suggest that exposure to nicotine vapor causes immediate, short-term increases in impulsive choice.

Implications

E-cigarette use is increasing at an alarming rate, particularly among adolescents and young adults. This is concerning given the lack of research into the effects of nicotine vapor exposure on the brain and behavior. The present study describes a viable rodent model of human e-cigarette use and suggests that exposure to nicotine vapor produces short-term increases in impulsive choice.
Cigar Use Progression Among New Cigar Initiators: A Two-Part Growth Curve Analysis Among a Youth and Young Adult Cohort
Authors: Cantrell Jennifer , Xu Shu , Kreslake Jennifer , Liu Michael , Hair Elizabeth
Published: July 2021

Introduction

Youth and young adults (YYAs) are at high risk of cigar use. This study’s objective was to examine progression and sociodemographic differences in current cigar use and frequency among new cigar initiators.

Aims and Methods

We conducted a two-part latent growth model among a nationally representative cohort of cigar initiators (aged 15–25) to examine 24-month trajectories of current cigar use and frequency (n = 1483). The cohort was recruited via address-based sampling with online data collection from 2014 to 2019 and surveyed approximately every 6 months.

Results

The unconditional odds of current cigar use (ie, past 30-day use) within 6 months of initiation was 0.72 (95% confidence interval: 0.63, 0.82), corresponding to a probability of 42%. The odds of current use among recent cigar initiates declined 6 months after initiation and was followed by a stabilization in use over time. Among continued users, frequency (# days used in past 30 days) increased linearly over time but remained low (3.47 days/months at 24 months). Younger individuals, non-Hispanic African Americans, those with lower subjective financial status, and current users of cigarettes, other tobacco products and/or marijuana were at highest risk within 6 months of initiation. Males, younger users, and current cigarette smokers had the highest risk for cigar progression over time.

Conclusions

This study is the first to examine longitudinal cigar use patterns among YYA cigar initiators. Findings emphasize the need for research across the cigar use spectrum and the importance of interventions targeted by age, stage of use, cigarette, other tobacco, and marijuana use and key sociodemographics to interrupt use pathways.

Implications

This study is the first to examine progression of cigar use among YYAs who have newly initiated cigars. Results show a high probability of current cigar use within 6 months of initiation followed by a rapid decline and stabilization over time. Frequency increases among those who continue using cigars. Males, younger users, and current cigarette smokers had the highest risk for cigar progression over time. Findings emphasize the need for targeting interventions by age, stage of use, cigarette, other tobacco, and marijuana use and key sociodemographics to interrupt use pathways.
Short-chain fatty acids as anti-inflammatory agents in overweight and obesity: a systematic review and meta-analysis
Authors: Eslick Shaun , Thompson Cherry , Berthon Bronwyn , Wood Lisa
Published: July 2021

Context

Short-chain fatty acids (SCFAs) derived from microbial fermentation of prebiotic soluble fibers are noted for their anti-inflammatory benefits against obese systemic inflammation.

Objective

A systematic review and meta-analysis were undertaken to investigate the effect of SCFAs and prebiotic interventions on systemic inflammation in obesity.

Data Sources

Relevant studies from 1947 to August 2019 were collected from the Cumulative Index to Nursing and Allied Health Literature, Embase, Medline, and Cochrane databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.

Study Selection

Of 61 included studies, 29 were of humans and 32 of animals.

Data Extraction

Methodological quality of studies was assessed using the critical appraisal checklist of the Academy of Nutrition and Dietetics. Data pertaining to population, intervention type and duration, and markers of systemic inflammation were extracted from included studies.

Results

Of 29 included human studies, 3 of 4 SCFA interventions and 11 of 25 prebiotic interventions resulted in a significant decrease in ≥1 biomarker of systemic inflammation. Of 32 included animal studies, 10 of 11 SCFA interventions and 18 of 21 prebiotic interventions resulted in a significant reduction of ≥1 biomarker of systemic inflammation. Meta-analysis revealed that prebiotics in humans reduced levels of plasma high-sensitivity C-reactive protein (standard mean difference [SMD], −0.83; 95%CI: −1.56 to −0.11; I2: 86%; P = 0.02) and plasma lipopolysaccharide (SMD, −1.20; 95%CI: −1.89 to −0.51; I2: 87%; P = 0.0006), and reduced TNF−α levels in animals (SMD, −0.63; 95%CI: −1.19 to −0.07; P = 0.03). Heterogeneity among supplement types, duration, and dose across studies was significant.

Conclusion

Evidence from this review and meta-analysis supports the use of SCFAs and prebiotics as novel aids in treatment of obese systemic inflammation.

Systematic Review Registration

PROSPERO registration no. CRD42020148529.
Advances in Synthetic Fluorescent Probe Labeling for Live-Cell Imaging in Plants
Authors: Yagi Noriyoshi , Yoshinari Akira , Iwatate Ryu J , Isoda Reika , Frommer Wolf B , Nakamura Masayoshi
Published: July 2021

Fluorescent probes are powerful tools for visualizing cellular and subcellular structures, their dynamics and cellular molecules in living cells and enable us to monitor cellular processes in a spatiotemporal manner within complex and crowded systems. In addition to popular fluorescent proteins, a wide variety of small-molecule dyes have been synthesized through close association with the interdisciplinary field of chemistry and biology, ranging from those suitable for labeling cellular compartments such as organelles to those for labeling intracellular biochemical and biophysical processes and signaling. In recent years, self-labeling technologies including the SNAP-tag system have allowed us to attach these dyes to cellular domains or specific proteins and are beginning to be employed in plant studies. In this mini review, we will discuss the current range of synthetic fluorescent probes that have been exploited for live-cell imaging and the recent advances in the application that enable genetical tagging of synthetic probes in plant research.
Health versus Wealth during the Covid-19 Pandemic
Authors: Lesschaeve Christophe , Glaurdić Josip , Mochtak Michal
Published: July 2021

Efforts to combat the COVID-19 crisis were characterized by a difficult trade-off: the stringency of the lockdowns decreased the spread of the virus, but amplified the damage to the economy. In this study, we analyze public attitude toward this trade-off using a survey-embedded experiment conducted with a quota sample of more than 7,000 respondents from Southeast Europe, collected in April and May 2020. The results show that public opinion generally favored saving lives even at a steep economic cost. However, the willingness to trade lives for the economy was greater when the heterogeneous health and economic consequences of lockdown policies for the young and the elderly were emphasized. Free-market views also make people more accepting of higher casualties, as do fears that the instituted measures will lead to a permanent expansion of government control over society.
Roman Transport Network Connectivity and Economic Integration
Authors: Flückiger Matthias , Hornung Erik , Larch Mario , Ludwig Markus , Mees Allard
Published: July 2021

We show that the creation of the first integrated multi-modal pan-European transport network during Roman times influences economic integration over two millennia. Drawing on spatially highly disaggregated data on excavated Roman ceramics, we document that contemporary interregional trade was influenced by connectivity within the network. Today, these connectivity differentials continue to influence integration as approximated by cross-regional firm investment behaviour. Continuity is partly explained by selective infrastructure routing and cultural integration due to bilateral convergence in preferences and values. We show that our results are Roman-connectivity specific and do not reflect pre-existing patterns of exchange using pre-Roman trade data.
Two-year reduction of dual-energy CT urate depositions during a treat-to-target strategy in gout in the NOR-Gout longitudinal study
Authors: Uhlig Till , Eskild Tron , Karoliussen Lars F , Sexton Joe , Kvien Tore K , Haavardsholm Espen A , Dalbeth Nicola , Hammer Hilde Berner
Published: July 2021

Objectives

There is a lack of large longitudinal studies of urate deposition measured by dual-energy CT (DECT) during urate lowering therapy (ULT) in people with gout. We explored longitudinal changes in DECT urate depositions during a treat-to-target strategy with ULT in gout.

Methods

Patients with a recent gout flare and serum-urate (sUA) >360 µmol/l attended tight-control visits during escalating ULT. The treatment target was sUA <360 µmol/l, and <300 µmol/l if presence of tophi. A DECT scanner (General Electric Discovery CT750 HD) acquired data from bilateral forefeet and ankles at baseline and after one and two years. Images were scored in known order, using the semi-quantitative Bayat method, by one experienced radiologist who was blinded to serum urate and clinical data. Four regions were scored: the first metatarsophalangeal (MTP1) joint, the other joints of the toes, the ankles and midfeet, and all tendons in the feet and ankles.

Results

DECT was measured at baseline in 187 of 211 patients. The mean (s.d.) serum urate level (μmol/l) decreased from 501 (80) at baseline to 311 (48) at 12 months, and 322 (67) at 24 months. DECT scores at all locations decreased during both the first and the second year (P <0.001 for all comparisons vs baseline), both for patients achieving and not achieving the sUA treatment target.

Conclusions

In patients with gout, urate depositions in ankles and feet as measured by DECT decreased both in the first and the second year, when patients were treated using a treat-to-target ULT strategy.
Long-term weight changes and risk of rheumatoid arthritis among women in a prospective cohort: a marginal structural model approach
Authors: Marchand Nathalie E , Sparks Jeffrey A , Malspeis Susan , Yoshida Kazuki , Prisco Lauren , Zhang Xuehong , Costenbader Karen , Hu Frank , Karlson Elizabeth W , Lu Bing
Published: July 2021

Objective

To examine the association of long-term weight change with RA risk in a large prospective cohort study.

Methods

The Nurses’ Health Study II started in 1989 (baseline); after exclusions, we studied 108 505 women 25–42 years old without RA. Incident RA was reported by participants and confirmed by medical record review. Body weight was reported biennially through 2015. We investigated two time-varying exposures: weight changes from baseline and from age 18; change was divided into five categories. We used a marginal structural model approach to account for time-varying weight change and covariates.

Results

Over 2 583 266 person-years, with a median follow-up time of 25.3 years, 541 women developed RA. Compared with women with stable weight from baseline, weight change was significantly associated with increased RA risk [weight gain 2–<10 kg: RR = 1.98 (95% CI 1.38, 2.85); 10–<20 kg: RR = 3.28 (95% CI 2.20, 4.89); ≥20 kg: RR = 3.81 (95% CI 2.39, 6.07); and weight loss >2 kg: RR = 2.05 (95% CI 1.28, 3.28)]. Weight gain of 10 kg or more from age 18 compared with stable weight was also associated with increased RA risk [10–< 20 kg: RR = 2.12 (95% CI 1.37, 3.27), ≥20 kg: RR = 2.31 (95% CI 1.50, 3.56)]. Consistent findings were observed for seropositive and seronegative RA.

Conclusion

Long-term weight gain was strongly associated with increased RA risk in women, with weight gain of ≥20 kg associated with more than a three-fold increased RA risk. Maintenance of healthy weight may be a strategy to prevent or delay RA.