bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant
Acinetobacter baumannii
Authors: Russo Thomas A. , Umland Timothy C. , Deng Xiaoyi , El Mazouni Farah , Kokkonda Sreekanth , Olson Ruth , Carlino-MacDonald Ulrike , Beanan Janet , Alvarado Cassandra L. , Tomchick Diana R. , Hutson Alan , Chen Hong , Posner Bruce , Rathod Pradipsinh K. , Charman Susan A. , Phillips Margaret A. 
Published: December 2022

New antimicrobials are needed for the treatment of extensively drug-resistant
Acinetobacter baumannii
. The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that
A. baumannii
DHODH (
Ab
DHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on
Ab
DHODH. The most potent (DSM186, DHODH IC
50
28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse
A. baumannii
strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of
Ab
DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of
Ab
DHODH as a drug target for the development of antimicrobials for the treatment of
A. baumannii
and potentially other high-risk bacterial infections.
Prevalence of Post-Coronavirus Disease Condition 12 Weeks After Omicron Infection Compared With Negative Controls and Association With Vaccination Status
Authors: Nehme Mayssam , Vetter Pauline , Chappuis François , Kaiser Laurent , Guessous Idris ,   for the CoviCare Study Team, Nehme Mayssam , Vetter Pauline , Braillard Olivia , Assal Frederic , Lador Frederic , Guerreiro Ivan , Coen Matteo , Agoritsas Thomas , Reny Jean-Luc , Graf Christophe , Courvoisier Delphine S , Benzakour Lamyae , Genevay Stéphane , Lauper Kim , Salamun Julien , Spechbach Hervé , Jacquerioz Frederique , Grira Marwène , Favale Riccardo , Bondolfi Guido , Tardin Aglaé , Soccal Paola M , Zekry Dina , Stringhini Silvia , Meyer Philippe , Poku Nana Kwabena , Landis Basile N , Sandoval José , Bel Michael , Perisa Damir , Chappuis François 
Published: December 2022

Abstract

Background
Post-coronovirus disease (COVID) symptoms can persist several months after severe acute respiratory syndrome coronavirus 2 infection. Little is known, however, about the prevalence of post-COVID condition following infections from Omicron variants and how this varies according to vaccination status. This study evaluates the prevalence of symptoms and functional impairment 12 weeks after an infection by Omicron variants (BA.1 and BA.2) compared with negative controls tested during the same period.

Methods
Outpatient individuals who tested positive or negative for COVID-19 infection between December 2021 and February 2022 at the Geneva University Hospitals were followed 12 weeks after their test date.

Results
Overall, 11.7% of Omicron cases had symptoms 12 weeks after the infection compared with 10.4% of individuals who tested negative during the same period (P &lt; .001), and symptoms were much less common in vaccinated versus nonvaccinated individuals with Omicron infection (9.7% vs 18.1%; P &lt; .001). There were no significant differences in functional impairment at 12 weeks between Omicron cases and negative controls, even after adjusting for multiple potential confounders.

Conclusions
The differential prevalence of post-COVID symptoms and functional impairment attributed to Omicron BA.1 and BA.2 infection is low when compared with negative controls. Vaccination is associated with lower prevalence of post-COVID symptoms.
Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy
Authors: Schultheis Jennifer M , Durham Mary E , Kram Shawn J , Kuhrt Michelle , Gilstrap Daniel L , Parish Alice , Green Cynthia L , Kram Bridgette L 
Published: December 2022

Abstract

Objectives
To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy.

Methods
This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL.

Results
Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10–8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84–9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09–8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25–7.15) and tobramycin (OR: 5.26; 95% CI: 2.35–11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161).

Conclusions
Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.
Redshift evolution of galaxy group X-ray properties in the Simba simulations
Authors: Robson Dylan , Davé Romeel 
Published: December 2022

ABSTRACT
We examine the evolution of intragroup gas rest-frame X-ray scaling relations for group-sized haloes (M500 = 1012.3–1015  M⊙) in the Simba galaxy formation simulation. X-ray luminosity LX versus M500 shows increasing deviation from self-similarity from z = 3 → 0, with M500 &lt; 1013.5 M⊙ haloes exhibiting a large reduction in LX and slight increase in X-ray luminosity-weighted temperature TX. These shifts are driven by a strong drop in fgas with time for these haloes, and coincides with the onset of Simba’s black hole (BH) jet feedback, occurring when MBH &gt; 107.5 M⊙ and Eddington ratio &lt;0.2, in group haloes at z ∼ 1.5. The connection with BH feedback is corroborated by fBH ≡ MBH/M500 in M500 &lt; 1013.5 M⊙ haloes being strongly anticorrelated with LX and fgas at $z\lesssim 1.5$. This is further reflected in the scatter of LX − TX: haloes with small fBH lie near self-similarity, while those with the highest fBH lie furthest below. Turning off jet feedback results in mostly self-similar behaviour down to z = 0. For the X-ray weighted metallicity ZX, stellar feedback impacts the enrichment of halo gas. Finally, halo profiles show that jet feedback flattens the electron density and entropy profiles, and introduces a core in X-ray surface brightness, particularly at M500 &lt; 1013.5 M⊙. This argues that in Simba, intragroup X-ray evolution is largely driven by jet feedback removing hot gas from the cores of massive groups, and expelling gas altogether in less massive groups.
The velocity distribution of outflows driven by choked jets in stellar envelopes
Authors: Pais Matteo , Piran Tsvi , Nakar Ehud 
Published: December 2022

ABSTRACT
Many stripped envelope supernovae (SNe) present a signature of high-velocity material responsible for broad absorption lines in the observed spectrum. These include SNe that are associated with long gamma-ray bursts (LGRBs) and low-luminosity GRBs (llGRBs), and SNe that are not associated with GRBs. Recently it was suggested that this high-velocity material originates from a cocoon that is driven by a relativistic jet. In LGRBs, this jet breaks out successfully from the stellar envelope, while in llGRBs and SNe that are not associated with GRBs the jet is choked. Here we use numerical simulations to explore the velocity distribution of an outflow that is driven by a choked jet, and its dependence on the jet and progenitor properties. We find that in all cases where the jet is not choked too deep within the star, the outflow carries a roughly constant amount of energy per logarithmic scale of proper velocity over a wide range of velocities, which depends mostly on the cocoon volume at the time of its breakout. This is a universal property of jets driven outflows, which does not exist in outflows of spherically symmetric explosions or when the jets are choked very deep within the star. We therefore conclude that jets that are choked (not too deep) provide a natural explanation to the fast material seen in the early spectra of stripped envelope SNe that are not associated with LGRBs, and that properties of this material could reveal information on the otherwise hidden jets.
The X-ray view of optically selected dual AGN
Authors: De Rosa Alessandra , Vignali Cristian , Severgnini Paola , Bianchi Stefano , Bogdanović Tamara , Charisi Maria , Guainazzi Matteo , Haiman Zoltan , Komossa S , Paragi Zsolt , Perez-Torres Miguel , Piconcelli Enrico , Ducci Lorenzo , Parvatikar Manali , Serafinelli Roberto 
Published: December 2022

ABSTRACT
We present a study of optically selected dual Active Galactic Nuclei (AGN) with projected separations of 3–97 kpc. Using multiwavelength (MWL) information (optical, X-ray, mid-IR), we characterized the intrinsic nuclear properties of this sample and compared them with those of isolated systems. Among the 124 X-ray-detected AGN candidates, 52 appear in pairs and 72 as single X-ray sources. Through MWL analysis, we confirmed the presence of the AGN in &gt;80 per cent of the detected targets in pairs (42 out of 52). X-ray spectral analysis confirms the trend of increasing AGN luminosity with decreasing separation, suggesting that mergers may have contributed to triggering more luminous AGN. Through X-ray/mid-IR ratio versus X-ray colours, we estimated a fraction of Compton-thin AGN (with 1022 cm−2 &lt; NH &lt; 1024 cm−2) of about 80 per cent, while about 16 per cent are Compton-thick sources (with NH &gt; 1024 cm−2). These fractions of obscured sources are larger than those found in samples of isolated AGN, confirming that pairs of AGN show higher obscuration. This trend is further confirmed by comparing the de-reddened [O iii] emission with the observed X-ray luminosity. However, the derived fraction of Compton-thick sources in this sample at the early stages of merging is lower than that reported for late-merging dual-AGN samples. Comparing NH from X-rays with that derived from E(B − V) from narrow-line regions, we found that the absorbing material is likely to be associated with the torus or broad-line regions. We also explored the X-ray detection efficiency of dual-AGN candidates, finding that, when observed properly (at on-axis positions and with long exposures), X-ray data represent a powerful way to confirm and investigate dual-AGN systems.
Gravitational waves from double white dwarfs as probes of the milky way
Authors: Georgousi Maria , Karnesis Nikolaos , Korol Valeriya , Pieroni Mauro , Stergioulas Nikolaos 
Published: December 2022

ABSTRACT
Future gravitational wave detectors, such as the Laser Interferometer Space Antenna (LISA), will be able to resolve a significant number of the ultra compact stellar-mass binaries in our own Galaxy and its neighbourhood. These will be mostly double white dwarf (DWD) binaries, and their underlying population characteristics can be directly correlated to the different properties of the Galaxy. In particular with LISA, we will be able to resolve ${\sim}\mathcal {O}(10^4)$ binaries, while the rest will generate a confusion foreground signal. Analogously to how the total electromagnetic radiation emitted by a galaxy can be related to the underlying total stellar mass, in this work, we propose a framework to infer the same quantity by investigating the spectral shape and amplitude of the confusion foreground signal. For a fixed DWD evolution model and thus a fixed binary fraction, we retrieve percentage-level relative errors on the total stellar mass, which improves for increasing values of the mass. At the same time, we find that variations in the Milky Way shape at a fixed mass and at scale heights smaller than 500 pc are not distinguishable based on the shape of stochastic signal alone. We perform this analysis on simulations of the LISA data, estimating the resolvable sources based on signal-to-noise criteria. Finally, we utilize the catalogue of resolvable sources to probe the characteristics of the underlying population of DWD binaries. We show that the DWD frequency, coalescence time and chirp mass (up to &lt;0.7 M⊙) distributions can be reconstructed from LISA data with no bias.
G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects
Authors: Wang Feng , Calvo-Roitberg Ezequiel , Rembetsy-Brown Julia M , Fang Minggang , Sousa Jacquelyn , Kartje Zachary J , Krishnamurthy Pranathi Meda , Lee Jonathan , Green Michael R , Pai Athma A , Watts Jonathan K 
Published: December 2022

Abstract
Friedreich’s ataxia is an incurable disease caused by frataxin (FXN) protein deficiency, which is mostly induced by GAA repeat expansion in intron 1 of the FXN gene. Here, we identified antisense oligonucleotides (ASOs), complementary to two regions within the first intron of FXN pre-mRNA, which could increase FXN mRNA by ∼2-fold in patient fibroblasts. The increase in FXN mRNA was confirmed by the identification of multiple overlapping FXN-activating ASOs at each region, two independent RNA quantification assays, and normalization by multiple housekeeping genes. Experiments on cells with the ASO-binding sites deleted indicate that the ASO-induced FXN activation was driven by indirect effects. RNA sequencing analyses showed that the two ASOs induced similar transcriptome-wide changes, which did not resemble the transcriptome of wild-type cells. This RNA-seq analysis did not identify directly base-paired off-target genes shared across ASOs. Mismatch studies identified two guanosine-rich motifs (CCGG and G4) within the ASOs that were required for FXN activation. The phosphorodiamidate morpholino oligomer analogs of our ASOs did not activate FXN, pointing to a PS-backbone-mediated effect. Our study demonstrates the importance of multiple, detailed control experiments and target validation in oligonucleotide studies employing novel mechanisms such as gene activation.
Efficacy of Continuous Intrathecal Infusion Trialing with a Mixture of Fentanyl and Bupivacaine in Chronic Low Back Pain Patients
Authors: Hayek Salim M , Jones Bradford A , Veizi Elias , Tran Thang Q , DeLozier Sarah J 
Published: December 2022

Abstract
Intrathecal trialing is used as a screening prognostic measure prior to intrathecal drug delivery system implant. The purpose of this study was to determine the efficacy of a continuous intrathecal infusion of an admixture of bupivacaine and fentanyl in patients with chronic low back pain.
Patients with refractory chronic low back pain in the setting of previous lumbar spine surgery and/or chronic vertebral compression fracture(s) were enrolled in a randomized double blind cross-over study comparing saline infusion to infusion of a solution containing bupivacaine combined with low-dose fentanyl over a 14–18 hour period. The primary outcome measure was the change in pain intensity at the end of the screening trial. Patients who experienced significant pain reduction from either infusion relative to baseline pain were offered a permanent implant.
In total, 36 patients were enrolled, with 31 patients trialed and 25 implanted. At the end of the screening trial, pain scores, at rest or with activity, decreased appreciably in both groups; however, significantly better improvements occurred in the fentanyl/bupivacaine group compared to saline both with activity and at rest (P = .016 and .006, respectively). Treatment order appeared to affect outcome with saline demonstrating a placebo response. At 12 months following implant, primary and secondary outcome measures continued to be significantly reduced from baseline.
Continuous intrathecal delivery of a combination of zlow-dose fentanyl with bupivacaine is superior to saline in screening intrathecal trialing for back pain reduction. With longer term delivery, a sustained reduction of chronic low back pain was also observed.
Early-Stage Phenotyping of Sweet Potato Virus Disease Caused by Sweet Potato Chlorotic Stunt Virus and Sweet Potato Virus C to Support Breeding
Authors: David Maria , Kante Moctar , Fuentes Segundo , Eyzaguirre Raul , Diaz Federico , De Boeck Bert , Mwanga Robert O. M. , Kreuze Jan , Grüneberg Wolfgang J. 
Published: December 2022

Sweet potato virus disease (SPVD) is a global constraint to sweetpotato (Ipomoea batatas) production, especially under intensive cultivation in the humid tropics such as East Africa. The objectives of this study were to develop a precision SPVD phenotyping protocol, to find new SPVD-resistant genotypes, and to standardize the first stages of screening for SPVD resistance. The first part of the protocol was based on enzyme-linked immunosorbent assay results for sweet potato chlorotic stunt virus (SPCSV) and sweet potato virus C (SPVC) with adjustments to a negative control (uninfected clone Tanzania) and was performed on a prebreeding population (VZ08) comprising 455 clones and 27 check clones graft inoculated under screenhouse conditions. The second part included field studies with 52 selected clones for SPCSV resistance from VZ08 and 8 checks. In screenhouse conditions, the resistant and susceptible check clones performed as expected; 63 clones from VZ08 exhibited lower relative absorbance values for SPCSV and SPVC than inoculated check Tanzania. Field experiments confirmed SPVD resistance of several clones selected by relative absorbance values (nine resistant clones in two locations; that is, 17.3% of the screenhouse selection), supporting the reliability of our method for SPVD-resistance selection. Two clones were promising, exhibiting high storage root yields of 28.7 to 34.9 t ha−1 and SPVD resistance, based on the proposed selection procedure. This modified serological analysis for SPVD-resistance phenotyping might lead to more efficient development of resistant varieties by reducing costs and time at early stages, and provide solid data for marker-assisted selection with a quantitative tool for classifying resistance. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
“Time-In”: A Tool for Interrupting Bias in Medical School Admissions Committee Meetings
Authors: Parkas Valerie , Maysonet Jessica , Chudow Jacquelyn , Hess Leona , Swartz Talia H. 
Published: December 2022

Problem
During high-stakes committee meetings, bias is often expressed but goes uninterrupted because there is no formal structure to interrupt it. Bias impacts decision making and can further disadvantage those from backgrounds that have been marginalized.

Approach
The MD and MD–PhD admissions committees at the Icahn School of Medicine at Mount Sinai in NY in the 2020–2021 admissions season introduced a “Time-In” tool to interrupt bias during committee meetings. This study aimed to evaluate the impact of implementing the “Time-In” tool on committee members’ perception of bias as a problem and the likelihood of committee members recognizing, reporting, discussing, and educating others about bias after implementation.

Outcomes
There were 117 responses to the pre- and postseason surveys. In aggregate, respondents reported a statistically significant reduction in the perception of bias in the admissions process from preseason to postseason. There was no change in the likelihood of committee members in aggregate endorsing comfort in recognizing, reporting, discussing, and educating about bias; however, notable gaps existed in the comfort of groups discussing bias publicly, i.e., respondents who are from backgrounds underrepresented in science and medicine, students, and new committee members were less comfortable than their comparators. By the postseason survey, these gaps were closed.

Next Steps
Implementing a “time-in” allows for interruption of bias, with an impact of reducing the perception of bias, empowering individuals, and reducing gaps among groups to discuss bias publicly. A “time-in” can profoundly impact decision-making bodies that are critical gatekeepers to the composition of the physician workforce. Future directions will focus on enhancing committee members’ skills in educating others about bias.
Rejecting Reforms, Yet Calling for Change: A Qualitative Analysis of Proposed Reforms to the Residency Application Process
Authors: Dacre Michael , Branzetti Jeremy , Hopson Laura R. , Regan Linda , Gisondi Michael A. 
Published: December 2022

Purpose
Annual increases in the number of residency applications burden students and challenge programs. Several reforms to the application process have been proposed; however, stakeholder input is often overlooked. The authors examined key stakeholders’ opinions about several proposed reforms to the residency application process and identified important factors to guide future reforms.

Method
Using semistructured interviews, the authors asked educational administrators and trainees to consider 5 commonly proposed reforms to the residency application process: Match to obtain residency interviews, preference signaling, application limits, geographic preference disclosure, and abolishing the Match. The authors conducted a modified content analysis of interview transcripts using qualitative and quantitative analytic techniques. Frequency analysis regarding the acceptability of the 5 proposed reforms and thematic analysis of important factors to guide reform were performed. Fifteen-minute interviews were conducted between July and October 2019, with data analysis completed during a 6-month period in 2020 and 2021.

Results
Participants included 30 stakeholders from 9 medical specialties and 15 institutions. Most participants wanted to keep the Match process intact; however, they noted several important flaws in the system that disadvantage students and warrant change. Participants did not broadly support any of the 5 proposed reforms. Two themes were identified: principles to guide reform (fairness, transparency, equity, reducing costs to students, reducing total applications, reducing work for program directors, and avoiding unintended consequences) and unpopular reform proposals (concern that application limits threaten less competitive students and signaling adds bias to the system).

Conclusions
Key stakeholders in the residency application process believe the system has important flaws that demand reform. Despite this, the most commonly proposed reforms are unacceptable to these stakeholders because they threaten fairness to students and program workload. These findings call for a larger investigation of proposed reforms with a more nationally representative stakeholder cohort.